Yanoff Ophthalmology 3rd ed

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Third Edition

OPHTHALMOLOGY LEAD EDITORS Myron Yanoff MD

Jay S Duker MD

Professor and Chair Department of Ophthalmology Drexel University College of Medicine Adjunct Professor of Ophthalmology University of Pennsylvania Philadelphia, PA

Director, New England Eye Center Chairman and Professor of Ophthalmology Tufts Medical Center Tufts University School of Medicine Boston, MA

SECTION EDITORS

Jonathan J Dutton MD PhD FACS

Emanuel S Rosen MD FRCS FRCOphth

James J Augsburger MD

Professor of Ophthalmology Department of Ophthalmology University of North Carolina, Chapel Hill Chapel Hill, NC

Visiting Professor Department of Vision Sciences University of Manchester & Honorary Consultant Manchester Royal Eye Hospital Manchester UK

Professor and Chairman of Department Director of Ocular Oncology Department of Ophthalmology University of Cincinnati College of Medicine Cincinnati, OH

Dimitri T Azar MD BA Field Chair of Ophthalmologic Research Professor and Head Department of Ophthalmology and Visual Science Illinois Eye and Ear Infirmary University of Illinois at Chicago Chicago, IL

Gary R Diamond MD Formerly Professor of Ophthalmology and Pediatrics Division of Ophthalmology Drexel University Health Sciences St Christopher’s Hospital for Children Philadelphia, PA

Jay S Duker MD Director New England Eye Center Chairman and Professor of Ophthalmology Tufts New England Medical Center Tufts University School of Medicine Boston, MA

Michael H Goldstein MD MBA Co-Director, Cornea and External Disease Service Assistant Professor of Ophthalmology Tufts New England Medical Center Tufts University School of Medicine Boston, MA

David Miller MD Associate Clinical Professor of Ophthalmology Harvard Medical School Jamaica Plain, MA

Narsing A Rao MD Professor of Ophthalmology and Pathology Department of Ophthalmology USC/Keck School of Medicine Doheny Eye Institute Los Angeles, CA

Alfredo A Sadun MD PhD Flora Thornton Chair of Vision Research and Professor of Ophthalmology and Neurological Surgery Doheny Eye Institute USC/Keck School of Medicine Department of Opthalmology Los Angeles, CA

Joel Schuman MD FACS Eye & Ear Foundation Professor and Chairman Department of Ophthalmology University of Pittsburgh School of Medicine Director UPMC Eye Center Pittsburgh, PA

Janey L Wiggs MD PhD Associate Professor of Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, MA

MOSBY an imprint of Elsevier Inc. © 2009, Elsevier Inc. All rights reserved. First edition 1999 Second edition 2004 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. ISBN here: 978-0-323-04332-8 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress

Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author_assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

Acknowledgements We are grateful to the editors and authors who have contributed to Ophthalmology and to the superb, dedicated Ophthalmology team at Mosby. We especially would like to thank Sharon Nash and Russell Gabbedy for their tireless efforts in keeping us on track and making our job much easier. We would also like to thank Kirsten Lowson, Editorial Assistant; Bryan Potter, Project Manager; Stewart Larking and Jayne Jones, Design; Merlyn Harvey, Illustration Manager; John Canelon and William Vetre, Marketing.

Dedication We would like to dedicate this book to our wives, Karin Yanoff and Julie Duker, and to our children, Steven, David, and Alexis Yanoff and Joanne Grune-Yanoff; and Jake, Bear, Sam and Elly Duker, all of whom play such an important part in our lives and without whose help and understanding we could not have completed this project.

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Acknowledgements We are grateful to the editors and authors who have contributed to Ophthalmology and to the superb, dedicated Ophthalmology team at Mosby. We especially would like to thank Sharon Nash and Russell Gabbedy for their tireless efforts in keeping us on track and making our job much easier. We would also like to thank Kirsten Lowson, Editorial Assistant; Bryan Potter, Project Manager; Stewart Larking and Jayne Jones, Design; Merlyn Harvey, Illustration Manager; John Canelon and William Vetre, Marketing.

Dedication We would like to dedicate this book to our wives, Karin Yanoff and Julie Duker, and to our children, Steven, David, and Alexis Yanoff and Joanne Grune-Yanoff; and Jake, Bear, Sam and Elly Duker, all of whom play such an important part in our lives and without whose help and understanding we could not have completed this project.

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Preface We published the second edition of Ophthalmology in 2004. Now, only 5 years later, we again find that enormous advances have taken place in ophthalmic technology, genetics, and immunology, along with other areas. We continue to recognize the advantage of a complete textbook of ophthalmology in a single volume, rather than a multivolume textbook. Our major effort has been updating and keeping current the third edition. Towards this end we endeavored to delete old out-of-date ­material as we added new material. One of the easiest parts of a revision is adding new material; the most difficult part, but essential, is to delete the old, so as to keep the book at approximately the same size. Throughout our revision we have successfully maintained this balancing act, culminating in a finished product that is essentially the same size as the prior edition. The color coding of the sections in the first and second editions proved highly successful, and we have again used this style in the third edition. We also have carefully integrated the basic visual science with clinical information throughout and have maintained an entire separate section dedicated to genetics and the eye. Once again, we do not intend the third edition of Ophthalmology to be encyclopedic, but strived to make it quite comprehensive.

The book is thoroughly revised. We have discarded out of date material and have added numerous new items. Some examples of new entities include include: Descemet’s stripping endothelial keratoplasty (DSEK), a new corneal surgery that is making a huge impact and is a viable option to penetrating keratoplasty; new techniques in ocular surface reconstruction; new techniques in corneal imaging; new information on herpes zoster, peripheral ulcerative keratitis, blepharitis, contact lens related complications, and acid and alkali burns; elaboration of advances in phacoemulsification, increased awareness of the complications of cataract surgery, and combined techniques in management of multiple pathologies following cataract surgery; anti-VEGF treatment for wet age-related macular edema; bevacizumab treatment for complications of diabetic retinopathy; small gauge vitreous surgery. Tuberculosis is a major disease affecting one-third of the world’s population. We have added new discussions of the diagnosis of this entity along with the various manifestations of this disease including ocular changes. Other additions include new information on hereditary optic neuropathies, new advances in molecular biology and genetics in elucidated the pathology of many entities, and optical coherence tomography (OCT) in optic

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Preface to First Edition Over the past 30 years, enormous technologic advances have occurred in many different areas of medicine—lasers, molecular genetics, and immunology to name a few. This progress has fueled similar advances in almost every aspect of ophthalmic practice. The assimilation and integration of so much new information makes narrower and more focused ophthalmic practices a necessity. As a direct consequence, many subspecialty textbooks with extremely narrow focus are now available, covering every aspect of ophthalmic practice. Concurrently, several excellent multivolume textbooks detailing all aspects of ophthalmic practice have been developed. Yet there remains a need for a complete single-volume textbook of ophthalmology for trainees, non-ophthalmologists, and those general ophthalmologists (and perhaps specialists) who need an update in which they are not expert. Ophthalmology was created to fill this void between the multivolume and narrow subspecialty book. This book is an entirely new, comprehensive, clinically relevant, single-volume textbook of ophthalmology, with a new approach to content and presentation that allows the reader to access key information quickly. Our approach, from the outset, has been to use templates to maintain a uniform chapter structure throughout the book so that the material is presented in a logical, consistent manner, without repetition. The majority of chapters in the book follow one of three templates: the ­disease-oriented template, the surgical procedure template, or the diagnostic testing template. Meticulous planning went into the content, sectioning and chaptering of the book, with the aim of presenting ophthalmology as it is practiced rather than as a collection of artificially divided aspects. Thus, pediatric ophthalmology is not in a separate section but is integrated into relevant sections across the book. The basic visual science and clinical information, including systemic manifestations, is integrated throughout, with only two exceptions. We dedicated an entire section to genetics and the eye, in recognition of the increasing importance of genetics in ophthalmology. Optics and refraction are included in a single section as well, because an understanding of these subjects is fundamental to all of ophthalmology.

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To achieve the same continuity of presentation in the figures as well as in the text, all of the artworks have been redesigned from the author’s originals, maximizing their accessibility for the reader. Each section is color coded for easy cross-referencing and “navigation” through the book. Despite the extensive use of color in artworks and photographs throughout, the cost of this comprehensive book has been kept to a fraction of the multivolume sets. We hope to make this volume more accessible to more practitioners throughout the world. Although comprehensive, Ophthalmology is not intended to be encyclopedic. In particular, in dealing with surgery, we do not stress specific techniques or describe rarer ones in meticulous detail. The rapidly changing nature of surgical aspects of ophthalmic practice is such that the reader will need to refer to one or more of the plethora of excellent books that cover specific current techniques in depth. We concentrate instead on the areas that are less volatile but nevertheless vital: surgical indications, general principles of surgical technique, and complications. The approach to referencing is parallel to this: for every topic, all the key references are listed, but with the aim of avoiding pages of redundant references where a smaller number of recent classic reviews will suffice. The overall emphasis of Ophthalmology is current information that is relevant to clinical practice superimposed on the broad framework that comprises ophthalmology as a subspecialty. Essential to the realization of this ambitious project is the ream of Section Editors, each bringing unique insight and expertise to the book. They have coordinated their efforts in shaping the contents list, finding contributors, and editing chapters to produce a book that we hope will make a great contribution to ophthalmology. We are grateful to the editors and authors who have contributed to Ophthalmology and to the superb, dedicated Ophthalmology team at Mosby. Myron Yanoff Jay S. Duker July 1998

List of Contributors Iqbal ike K Ahmed MD FRCSC Assistant Professor University of Toronto, Toronto, ON, Canada Assistant Professor, University of Utah, Salt Lake City, UT

Desmond B Archer FRCS FRCOphth Emeritus Professor of Ophthalmology at Queen’s University Belfast Ophthalmic Research Center Institute of Clinical Science Belfast UK

Brad J Baker MD Director of Clinical Vitreoretinal services, Assistant Professor of Opthalmology Department of Ophthalmology Boston University (Medical Campus) Boston MA

Irma Ahmed MD Vitreoretinal Fellow; Pacific Vision Foundation San Francisco California Medical Center San Francisco CA

Anthony C Arnold MD Associate Professor of Ophthalmology; Chief NeuroOphthalmology Division; Director Jules Stein Eye Institute Los Angeles CA

Laura Joan Balcer MD MSCE Associate Professor of Neurology at the Hospital of the University of Pennsylvania Chief, Multiple Sclerosis Division, Department of Neurology Senior Scholar, Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics Department of Neurology Philadelphia PA

Everett Ai MD ��� Director, Ophthalmic Diagnostic Centre; Co-Director Vitreoretinal Fellowship, California Pacific Medical Center West Coast Retina Medical Group San Francisco CA Ahmed Al-Ghoul MD FRCSC Clinical Instructor in Ophthalmology Eye and Ear Institute Pittsburgh PA David Allen BSc FRCS FRCOphth Consultant Opthamologist Sunderland Eye Infirmary Sunderland UK Nishat P Alvi MD Associate Director Medical Services West Point PA Rajiv Anand MD FRCS Ophthalmologist Texas Retina Associates Dallas TX Leonard P-K Ang MD FRCS(Ed) MRCOphth MMED (Ophth) Assistant Professor Singapore National Eye Center Singapore Department of Ophthalmology Harvard Medical School Massachusetts Eye and Ear Infirmary Boston MA David J Apple MD Professor of Ophthalmology and Pathology Director of Research Pawek-Vallotton Chair of Biomedical Engineering Former Professor and Chairman, Storm Eye Institute Medical University of South Carolina Charleston South Carolina

Steve A Arshinoff MD FRCS Staff Surgeon Humber River Regional Hospital Toronto Ontario Lecturer University of Toronto Department of Ophthalmology Toronto Ontario York Finch Eye Associates Toronto ON Kerry K Assil MD Medical Director and CEO Assil Eye Institute Beverly Hills CA Neal H. Atebara, MD Assistant Professor University of Hawaii John A. Burns School of Medicine Retina Center of Hawaii Honolulu HI Harvinder K S Atluri MD Chicago Eye Institute Chicago IL James J Augsburger MD Professor and Chairman of Department Director of Ocular Oncology Department of Ophthalmology University of Cincinnati College of Medicine Cincinnati OH G William Aylward MD FRCS FRCOphth Director of Vitreoretinal Service Consultant Ophthalmic Surgeon Moorfields Eye Hospital London UK Dimitri T Azar MD BA Field Chair of Ophthalmologic Research Professor and Head Department of Ophthalmology and Visual Science Illinois Eye and Ear Infirmary University of Illinois at Chicago Chicago IL

C. J. Barnett MD Department of Ophthalmology Rocky Mountain Licns Eye Institute University of Colorado Aurora CO Caroline R Baumal MD FRCSC Assistant Professor, Tufts University School of Medicine Department of Vitreoretinal Surgery New England Eye Center Boston MA Srilaxmi Bearelly MD Assistant Professor of Opthalmology Vitreoretinal Service Duke University Eye Center Durham NC William E Benson MD Professor of Ophthalmology Thomas Jefferson University School of Med. Retinovitreous Associates Ltd. Wyndmoor PA Steven Thomas Berger MD FAAO Baystate Eye Care Group Springfield MA Jyotirmav Biswas MD FAMS Director of Department of Uveitis Vision Research Foundation Sankara Nethralaya Chennai India

Norbert Bornfeld MD Professor of Ophthalmology Zentrum für Augenheilkunde Universitätsklinikum Essen Essen Germany Swaraj Bose MD Associate Professor, Ophthalmology Department of Ophthalmology University of California, Irvine Irvine CA Charles S Bouchard MD Professor and Chairman Department of Ophthalmology Loyola University Medical Center Maywood IL Michael E Boulton PhD The David Weeks Distinguished chair in Ophthalmology Department of Ophthalmology and Visual Sciences University of Texas Medical Branch Galveston TX James D Brandt MD Professor and Director, Glaucoma Service Department of Ophthalmology & Vision Science University of California, Davis Sacramento CA Michael C Brodsky MD �� Professor of Ophthalmology and Pediatrics University of Arkansas for Medical Sciences Arkansas Children’s Hospital Little Rock AR Kimberly Ellen Brown MD PhD Glaucoma Fellow John Hopkins University School of Medicine Baltimore MD Gary C Brown MD MBA Chief and Attending Surgeon, Retina Service, Wills Eye Institute, Philadelphia, PA; Professor of Ophthalmology, Jefferson Medical College; Co-Director, Center for Value-Based Medicine, Flourtown, PA Center for Value-Based Medicine Flourtown PA

James P Bolling MD Associate Professor and Chair Department of Ophthalmology Mayo Clinic Jacksonville FL

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List of Contributors

Melissa M Brown MD MN MBA Director, Center for Value-Based Medicine; Adjunct Senior Fellow, Leonard Davis Institute of Health Economics, Uni of Penn.; Adjunct Assistant Professor, Dep. of Oph., Uni of Penn., Philadelphia Center for Value-Based Medicine Flourtown PA Donald L Budenz MD MPH Professor Department of Ophthalmology, Epidemiology, and Public Health Bascom Palmer Eye Institute Miller School of Medicine University of Miami Miami FL Alex Bui MD Fellow California Pacific Medical Center San Francisco CA Stephen K Burns Senior Lecturer Harvd-MIT Division of Health Sciences & Technology Room 16-387 77 Massachusetts Avenue MA 02139-4307 Brian N Campolattaro MD Clinical Assistant Professor of Ophthalmology New York NY Louis B Cantor MD Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education Director of Glaucoma Service Eugene and Marilyn Glick Eye Institute Department of Ophthalmology Indiana University School of Medicine Indianapolis IN Antonio Capone Jr MD Associate Professor Emory University School of Medicine Atlanta GA Keith D Carter BS MD Professor and Department Head Lillian C. O’Brien and Dr. C. S. O’Brien Chair in Ophthalmology Department of Ophthalmology and Visual Sciences University of Iowa Hospitals and Clinics Iowa City IA Chi-Chao Chan MD Head, Section of Immunopathology Laboratory of Immunology National Eye Institute Bethesda MD

Stanley Chang MD Edward S. Harkness Professor and Chair, Department of Ophthalmology Director, Edward S. Harkness Eye Institute Columbia University College of Physicians & Surgeons New York NY Jennifer R Chao MD PhD Doheny Eye Institute and the Department of Ophthalmology Keck School of Medicine of the University of Southern California, Los Angeles CA George C Charonis MD Athens Vision Eye Institute Athens Greece Paul T K Chew FRCS Group Leader Department of Ophthalmology National University Hospital Singapore Antonio P Ciardella MD Chief Department of Ophthalmology Denver Health Medical Center Denver CO Mortimer M Civan MD Professor of Physiology Department of Physiology University of Pennsylvania Philadelphia PA Abbott F Clark PhD Alcon Research Fort Worth TX Jonathan Clarke MBBS MRCOphth Specialist Registrar and Medical Research Council Research Fellow Glaucoma Unit and Ocular Repair and Regeneration Biology (ORB) Moorfields Eye Hospital and UCL Institute of Ophthalmology London Janice E Contreras MD Department of Ophthalmology, University of Texas Medical Branch at Galveston, Galveston, TX USA J Richard O Collin University of Oxford Oxford UK François Codère MD Associate Professor of Ophthalmology Department of Ophthalmology McGill University Montreal Quebec; Royal Victoria Hospital Montreal Quebec Canada Janice E Contreras MD University of Pittsburgh Pittsburgh PA

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Zélia M Corrêa MD Fellow Oncology Unit Department of Ophthalmology Cincinnati OH Claude L Cowan MD Department of Ophthalmology Georgetown University Medical Center Washington DC E Randy Craven MD Associate Clinical Professor University of Colorado Health Sciences Center Directory Glaucoma Consultants of Colorado, PC Denver CO

Deepinder K Dhaliwal MD Associate Professor, Department of Ophthalmology Director, Cornea and External Disease Service Director, Refractive Surgery Service University of Pittsburgh Pittsburgh PA Gary R Diamond MD Formerly Professor of Ophthalmology and Pediatrics Division of Ophthalmology Drexel University Health Sciences St Christopher’s Hospital for Children Philadelphia PA

Alan F Cruess MD Professor and Head, District Chief, Capital Health Dept. of Ophthalmology and Visual Sciences Dalhousie University Halifax Nova Scotia

Diana V Do MD Fellow in Advanced Specialty Training in Medical and Surgical Diseases of the Retina Assistant Professor of Ophthalmology The Wilmer Eye Institute The Johns Hopkins University School of Medicine Baltimore MD

Phillip L Custer MD Professor of Ophthalmology and Visual Sciences Department of Ophthalmology and Visual Sciences Washington University School of Medicine St. Louis MO

Sean P Donahue MD, PhD Professor of Ophthalmology, Adult Strabismus, Pediatrics & Adult Neuro-ophthalmology Vanderbilt Eye Center Vanderbilt University Medical Center Nashville TN

Elie Dahan MD MMedOphth Senior Consultant in Glaucoma Eintal Eye Institute Tel Aviv Israel

Richard K Dortzbach MD Professor Emeritus Department of Ophthalmology and Visual Sciences University of Wisconsin - Madison Madison WI

Eric Dai MD University Eye Center The University of Texas Medical Branch Galveston TX Bertil E Damato MD PhD FRCOphth Professor of Opthalmology Ocular Oncology Service Royal Liverpool University Hospital Liverpool UK Karim F Damji MD, FRCS(C), MBA Professor of Glaucoma University of Alberta Department of Ophthalmology Edmonton, AB Canada Richard S Davidson MD Assistant Professor Rocky Mountain Lions Eye Institute University of Colorado School of Medicine Aurora CO Elizabeth A Davis MD FACS Adjunct Clinical Assistant Professor, University of Minnesota Partner Minnesota Eye Consultants Bloomington MN

Kimberly A Drenser MD PhD Director of Research and Viteroretinal Surgeon, Associated Retinal Consultants; Assistant Professor, Oakland Unit Associated Retinal Consultants Royal Oak MI Jay S Duker MD Director New England Eye Center Chairman and Professor of Ophthalmology Tufts New England Medical Center Tufts University School of Medicine Boston, MA Jonathan J Dutton MD PhD FACS Professor of Ophthalmology Department of Ophthalmology University of North Carolina, Chapel Hill Chapel Hill NC Bryan Edgington MD Assistant Professor of Ophthalmology George Washington University Medical Faculty Associates Washington DC Howard M Eggers MD Professor of Clinical Ophthalmology Harkness Eye Institute New York NY

David J Forster MD Clinical Associate Professor of Ophthalmology Georgetown University Falls Church VA

Michael Engelbert MD PhD Resident Physician Department of Opthamology Edward S. Harkness Eye Institute Columbia College of Physicians and Surgeons New York NY

Gregory M Fox MD Clinical Instructor of Ophthalmology Allegheny University Wilmington DE

Ladan Espandar MD Resident Department of Ophthalmology Tulane University New Orleans, LA Monica Evans MD Ophthalmologist, specialist in ­uveitis and ocular pathology Miami FL Ayad A Farjo MD President Brighton Vision Center University of Michigan Brighton MI Qais Anastas Farjo MD Clinical Assistant Professor, University of Toledo/Medical University of Ohio Ann Arbor MI Donald C Faucett MD Clinical Instructor Department of Oculoplastics University of MS School of Medicine; Ophthalmic Plastic & Reconstructive Surgeon Jackson MS Vahid Feiz MD Assistant Professor of Ophthalmology Department of Ophthalmology University of California California CA I Howard Fine MD Clinical Professor of Ophthalmology Oregon Health & Science University Drs Fine, Hoffman & Packer LLC Eugene OR Yale L Fisher MD Clinical Professor of Ophthalmology New York Hospital - Cornell Medical Center; Surgeon Director of Ophthalmology Chief of Retinal Surgery Service Manhattan Eye Ear & Throat Hospital Vitreo-Retina-Macula Consultant of New York Riverterrace Medical Building New York NY Gerald A Fishman MD Professor of Ophthalmology; Director Electrophysiology Laboratory University of Illinois at Chicago Chicago IL

Jeffrey Freedman Mb Bch PhD FCS(SA) FRCSE Professor of Clinical Ophthalmology Department of Ophthalmology The State University of New York Brooklyn NY David S Friedman MD Assistant Professor Ophthalmology Department John Hopkins University School of Medicine Wilmer Eye Institute Baltimore MD Neil J Friedman MD Adjunct Clinical Associate Professor Division of Ophthalmology Stanford University School of Medicine Stanford CA Mid-Peninsula Ophthalmology Medical Group Palo Alto CA Deborah I Friedman MD FAAN Professor of Ophthalmology and Neurology University of Rochester Rochester NY Arthur D Fu MD West Coast Retina Medical Group San Francisco CA Nicoletta Fynn-Thompson MD Ophthalmic Consultants of Boston Boston MA Jyotsom Ganatra MD MPH Attending Physician Department of Ophthalmology Kaiser Permanente, San Rafael Downtown Medical Center San Rafael, CA Gregg S Gayre MD Dept. of Ophthalmology Kaiser Permanente Downtown San Rafael Medical Offices San Rafael CA Igal Gery PhD Head Experimental Immunology Section Laboratory of Immunology National Eye Institute Bethesda MD Ramon C Ghanem MD Hospital de Olhos Joinville - SC Brazil

Michael Giblin MBBS FRACO FRACS Clinical Senior Lecturer Clinical Ophthalmology & Eye Health, Central Clinical School Sydney Hospital The University of Sydney NSW Australia James W Gigantelli MD FACS Professor of Ophthalmology Assistant Dean of Government Relations Department of Ophthalmology and Visual Sciences University of Nebraska Medical Center Omaha NE Anna Goldberg Glavooma Service Wills Eye Hospital/Jefferson Medical College Philadelphia PA Robert A Goldberg MD FACS Karen and Frank Dabby Professor of Ophthalmology Chief, Orbital and Ophthalmic Plastic Surgery Division Director, Orbital Disease Center Co-Director, Aesthetic Center Jules Stein Eye Institute UCLA School of Medicine Los Angeles CA William Goldberg Glavooma Service Wills Eye Hospital/Jefferson Medical College Philadelphia PA Ivan Goldberg MBBS (Syd) FRANZCO FRACS Clinical Associate Professor Department of Ophthamology University of Sydney Glaucoma Service Sydney Eye Hospital Sydney NSW Australia Ivan Goldberg MB BS (Syd) FRANZCO FRACS Clinical Associate Professor, Department of Opthamology, University. Director, Eye Assoc Glaucoma Service Sydney Eye Hospital Sydney NSW Australia Debra A Goldstein MD FRCS(C) Associate Professor of Ophthalmology Director, Uveitis Service Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago Michael H Goldstein MD MBA Co-Director, Cornea and External Disease Service Assistant Professor of Ophthalmology Tufts New England Medical Center Tufts University School of Medicine Boston, MA

John R Gonder MD FRCSC Associate Professor of Ophthalmology Ivey Institute of Ophthalmology University of Western Ontario London ON Jeffrey P Green MD New York, NY

List of Contributors

William Ehlers MD Assistant Clinical Professor Health Center University of Connecticut Storrs CT

Donna L Greenhalgh MB ChB FRCA Consultant Anaesthetist Anaesthetic Department Wythenshawe Hospital Manchester UK Craig M Greven MD FACS Professor and Chairman, Dept of Ophthalmology. Director, Wake Forest University Eye Center Wake Forest University Eye Center Winston-Salem NC Nicole E Gross MD The LuEsther T. Mertz Retinal Research Center Manhattan Eye, Ear and Throat Hospital New York NY Ronald L Gross MD Professor of Ophthalmology The Clifton R. McMichael Chair in Ophthalmology Cullen Eye Institute Houston TX Sandeep Grover MD Assistant Professor; Director, Inherited Retinal Diseases & Electrophysiology Department of Ophthalmology University of Florida Shands Hospital Jacksonville FL Jason R Guercio BS University of Pennsylvania School of Medicine Philadelphia PA Vishali Gupta MD Associate Professor of Ophthalmology Advanced Eye Centre Post Graduate Institute of Medical Education and Research Chandigarh India Amod Gupta MBBS MS Professor of Ophthalmology Advanced Eye Centre Post graduate Institute of Medical Education and Research Chandigarh India Sevgi Gurkan MD Assistant Professor of Pediatrics Pediatric Nephrology UMDNJ-Robert Wood Johnson Medical School New Brunswick NJ

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List of Contributors

Rudolf E Guthoff MD Professor and Director University of Rostock Rostock Germany Joelle Hallak BSc Research Assistant Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago IL Julia A Haller MD Robert Bond Welch Professor of Opthamology Wilmer Ophthalmological Institute Johns Hopkins Medical Institutions Baltimore MD Richard S Hamilton MD Retina Specialist and Partner Clinical Practice and Research Department Center for Retina and Macular Disease Winter Haven, FL J William Harbour MD Distinguished Professor of Ophthalmology, Cell Biology, and Medicine (Molecular Oncology) Director, Ocular Oncology Service Department of Ophthalmology Washington University School of Medicine St Louis MO

Allen C Ho MD Professor of Ophthalmology Thomas Jefferson University Retina Service, Philadelphia PA Richard S Hoffman MD Clinical Associate Professor of Ophthalmology Oregon Health & Science University Drs Fine, Hoffman & packer Ophthalmologists Eugene OR Huck A Holz MD Ophthalmologist: Cornea and Refractive Specialist Kaiser Permanente, Santa Clara Santa Clara CA Gene R Howard MD Associate Professor of Ophthalmology Storm Eye Institute Medical University of South Carolina Charleston SC

David R Hardten MD FACS Director of Refractive Surgery Adjunct Associate Professor of Ophthalmology University of Minnesota Minnesota Eye Consultants Minneapolis MN

Frank W Howes MBChB MMed FCS(SA) FRCSE FRCOphth FRANZCO Faculty of Health Sciences and Medicine Bond University Gold Coast Australia

Alon Harris MSc PhD Director, Glaucoma Research and Diagnostic Center Professor of Ophthalmology, Physiology and Biophysics Dept. Of Ophthalmology Indiana University School of Medicine Indianapolis IN

Jason Hsu MD Vitreoretinal Fellow Retina Service Wills Eye Hospital Philadelphia PA

Thomas R Hedges Jr MD Professor of Ophthalmology University of Pennsylvania; Emeritus of Ophthalmology The Pennsylvania Hospital Philadelphia PA Jeffrey S Heier MD Vitreretinal Specialist Ophthalmic Consultants of Boston Boston MA Polly A Henderson MD Chief, Glaucoma Service Department of Ophthalmology Drexel University College of Medicine Philadelphia PA

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Roger A Hitchings FRCOphth Professor of Glaucoma and Allied Studies Consultant Ophthalmologist Glaucoma Unit London UK

Leon W Herndon MD Associate Professor of Ophthalmology Duke University Eye Center Durham NC

Jeffrey J Hurwitz MD FRCS (C) Professor and Chair of Ophthalmology University of Toronto Mount Sinai Hospital Toronto Ontario Canada Hajime Inomata MD PhD Chairman and Professor of Ophthalmology Faculty of Medicine Fuoka Japan Michael Ip MD Associate Professor of Ophthalmology Department of Ophthalmology and Visual Sciences Fundus Photograph Reading Center Madison WI Robert T Isaacs MD Storm Eye Institute Charleston SC

Andrea M Izak MD Instructor of Ophthalmology John A Moran Eye Center University of Utah Salt Lake City UT Henry Jampel MD MHS Associate Professor Department of Opthalmology John Hopkins University School of Medicine Baltimore MD Lee M Jampol MD Louis Feinberg Professor and Chairman Department of Ophthalmology Northwestern University Medical School Chicago IL Julia Jiyamapa MD Harbor-UCLA Medical Center Torrance, CA Chris A Johnson MD Professor Department of Ophthalmology and Visual Sciences University of Iowa Iowa City IO T Mark Johnson National Retina Institute Chevy Chase MD Mark W Johnson MD Vitreoretinal Surgeon; Associate Professor of Ophthalmology W.K. Kellogg Eye Center Ann Arbor MI Nicholas Jones FRCS Consultant Opthalmic Surgeon and Director of Uveitis Service The Royal Eye Hospital Manchester UK Malik Kahook MD Assistant Professor and Director of Clinical Research Rocky Mountain Lions Eye Institute Aurora CO Elliott M Kanner MD PhD Assistant Professor of Ophthalmology Hamilton Eye Institute TN Michael A Kapusta MD Ophthalmologist-in –Chief, Jewish General Hospital Division Head of Vitreo-retinal surgery McGill University Montreal Quebec Randy Kardon MD PhD Associate Professor of Ophthalmology and Director of Neuro-ophthalmology The University of Iowa Hospitals and Clinics Iowa City IA

Carol L Karp MD Associate Professor of Clinical Ophthalmology Department of Ophthalmology Bascom Palmer Eye Insititute Miami FL Michael Kass MD Professor & Head Department of Ophthalmology and Visual Sciences Washington University School of Medicine St. Louis MO L Jay Katz MD FACS Professor, Jefferson Medical College Director of Glaucoma Service & Attending Surgeon Wills Eye Institute Philadelphia PA Paul L Kaufman MD Peter A. Duehr Professor and Chairman Ophthalmology & Visual Science University Wisconsin Madison Madison WI Baseer Khan MD FRCS (C) Fellow University of Toronto Toronto Canada Peng Tee Khaw PhD FRCP FRCS FRCOphth FIBiol Professor of Glaucoma and Ocular Healing and Consultant Opthalmic Surgeon, Director National Institute for Health Research Biomedical Research Centre (Ophthalmology) UCL Institute of Ophthalmology and Moorfields Eye Hospital London UK Gene Kim Medical Student Eye and Ear Institute Pittsburgh PA Alan E Kimura MD Denver CO Anna Kitzmann MD Ophthalmology Resident Department of Ophthalmology Mayo Clinic Rochester MN James M Klancnik Jr MD Assistant Professor of Clinical Ophthalmology New York University School of Medicine Vitreous-Retina-Macular Consultants of New York New York NY Douglas D Koch MD Professor of Ophthalmology Cullen Eye Institute Houston TX

Ridia Lim MBBS MPH FRANZCO Ophthalmic Surgeon Glaucoma Service Sydney Eye Hospital Sydney NSW Australia

Takashi Kojima MD Research Scholar Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago IL

Robert W Lingua MD Associate Professor of Ophthalmology University of California Irvine Irvine CA

Ernest W Kornmehl MD FACS Associate Clinical Instructor Tufts Medical School Clinical Instructor Harvard medical School Medical Director Kornmehl Laser Eye Associates Wellesley MA

William J Lipham MD FACS Clinical Adjunct Associate Professor University of Minnesota Ophthalmic Plastic and Reconstructive Surgery Service Department of Ophthalmology Minneapolis MN

Natalia Kramarevsky MD Attending Surgeon, Instructor of Ophthalmology Hennepin County Medical Center, Hennepin Faculty Associates Hennepin MN

Pedro F Lopez MD Directo Macular and Vitreoretinal Disease and Surgery Unit Center for Excellence in Eye Care Miami FL

Thad Labbe MD Glaucoma Specialist Eye Associates of Central Texas (Private Practice) Taylor TX

Mats Lundstrom MD PhD Professor of Ophthalmology, Lund University EyeNet Sweden Blekinge Hospital Karlskrona Sweden

Stephen S Lane MD Adjunct Clinical Professor Department of Ophthalmology University of Minnesota Associated Eye Care Stillwater MN

Peter Magnante MD Formerly Optical Physicist Ophthalmic Instrument Development Broofield Optical Systems West Brookfield MA

Patrick J M Lavin MD Associate Professor of Neurology and Ophthalmology Vanderbilt University Medical Center Nashville TN

Naresh Mandava MD Associate Professor Department of Ophthalmology Rocky Mountain Lions Eye Institute University of Colorado Aurora CO

Andrew Lawton MD Clinical Associate Professor of Ophthalmology, University of Tennessee, Memphis Medical Director of NeuroOphthalmology Service Little Rock Eye Clinic Little Rock AR

George E Marak Jr MD Clinical Professor of Ophthalmology Georgetown University Medical Center Washington DC

Paul P Lee MD JD James P Gills III, MD and Joy Gills Professor of Ophthalmology Department of Ophthalmology Duke University Durham NC Martha Motuz Leen MD Clinical Assistant Professor of Ophthalmology University of Washington School of Medicine Seattle WA Pacific Eyecare Poulsbo WA Ralph Levinson MD Occular Inflammatory Disease Center Jules Stein Eye Institute David Geffen School of Medicine, UCLA Los Angeles CA

Michael F Marmor MD Professor of Ophthalmology Stanford University Medical Center Stanford CA Lisa Marten MD, MPH Ophthalmologist, South Texas Eye Institute San Antonio TX Jeevan R Mathura Jr MD Department of Ophthalmolgy George Washington University Washington DC Adam Martidis MD Pasadena CA Cynthia Mattox MD Assistant Professor of Opthamology Ophthalmology - New England Eye Center Tufts-New England Medical Center Boston MA

Mark L McDermott MD Associate Professor Department of Ophthalmology Kresge Eye Institute Detroit MI

Lawrence S Morse MD PhD Professor Department of Ophthalmology University of California at Davis Sacramento CA

Stephen D McLeod MD Professor of Ophthalmology Department of Ophthalmology University of California, San Francisco San Francisco CA

Majid Moshirfar MD, FACS Professor of Ophthalmology Director of Cornea & Refractive Surgery Division Department of Ophthalmology and Visual Sciences University of Utah, School of Medicine John A. Moran Eye Center Salt Lake City, UT

Luis J Mejico MD Associate Professor Department of Neurology and Opthamology University Hospital Upstate NY Syracuse NY Sanford M Meyers MD Clinical Professor of Ophthalmology University of Chicago Chicago IL William F Mieler MD Professor and Chairman Department of Ophthalmology and Visual Sciences University of Chicago Chicago IL Clive S Migdal MD FRCS FRCOphth Senior Consultant Ophthalmologist, Glaucoma Service The Western Eye Hospital London UK David Miller MD Associate Clinical Professor of Ophthalmology Harvard Medical School Jamaica Plain, MA Russell Miller Mobil Eyes Apex NC Tatsuya Mimura MD PhD Research Fellow Department of Ophthalmology Eye and Ear Infirmary University of Illinois at Chicago Chicago IL Robert A Mittra, MD VitreoRetinal Surgery, P.A. Minneapolis MN Ramana S Moorthy MD FACS Assistant Clinical Professor of Opthalmology, Director of Uveitis Clinic Wishard Hospital Indiana University School of Medicine Indiana IN Michael G Morley MD Assistant Clinical Professor in Ophthalmology Tufts University School of Medicine Clinical Assistant in Ophthalmology Harvard School of Medicine Boston MA

List of Contributors

Thomas Kohnen MD Professor of Opthamology Deputy Chairman Klinik fur Augenheilkunde Frankfurt Germany

Mark L Moster, MD Director, Neuro-ophthalmology, Albert Einstein Medical Center Professor, Neurology, Thomas Jefferson University School of Medicine Insdtructor, Neuro-ophthalmology, Willis Eye Hospital Department of NeuroOphthalmology Philadelphia PA Sarah M Nehls Rikkers MD Assistant Professor of Ophthalmology Madison WI Ann G Neff MD Assistant Professor of Ophthalmology Ocular Plastics University of Miami School of Medicine Bascom Palmer Eye Institute Miami FL Anna C Newlin MS CGC Genetic Counselor University of Illinois Chicago IL Kenneth G Noble MD Associate Professor of Clinical Ophthalmology Department of Ophthalmology New York University School of Medicine New York NY Robert J Noecker MD MBA Vice Chairman Department of Ophtalmology, Director Glaucoma Service, UPMC Eye Center Associate Professor University of Pittsburgh School of Medicine UPMC Eye Center Pittsburgh PA Annabelle A Okada MD Associate Professor of Ophthalmology Department of Ophthalmology Kyorin University School of Medicine Tokyo Japan

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List of Contributors

Jeffrey L Olson MD Assistant Professor Rocky Mountain Lions Eye Institute Department of Ophthalmology University of Colorado Aurora CO Yvonne AV Opalinski BSc MD Clinical Associate Cardiovascular Surgery St. Michael’s Hospital, Toronto, ON Canada Mark Packer MD FACS Clinical Associate Professor of Ophthalmology Oregon Health & Science University Drs Fine, Hoffman & Packer Ophthalmologists Eugene OR Suresh K Pandey MD Instructor of Ophthalmology John A Moran Eye Center University of Utah Salt Lake City UT Vivek Ravindra Patel MD Clinical Instructor Neuro-ophthalmology Doheny Eye Institute Los Angeles CA Carlos E Pavesio MD FRCOphth Consultant Ophthalmologist Medical Retinal Service Moorfields Eye Hospital London UK Stacy Pineles MD Jules Stein Eye Institute, University of California Los Angeles CA Alfio Piva MD Hospital CIMA San Jose San Jose Costa Rica Jody Piltz-Seymour MD Director Glaucoma Care Center, PC Philadelphia PA John S Pollack MD Assistant Professor of Ophthalmology Rush Medical College Chicago IL F Ryan Prall MD Ophthalmologist Veterans Affairs Medical Center, Cheyenne, Wyoming Fort Collins CO Marianne O Price PhD Director of Research and Education Cornea Research Foundation of America Indianapolis IN Francis W Price MD President Price Vision Group Indianapolis IN

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Jonathan D Primack MD Assistant Professor of Ophthalmology and Visual Sciences Albert Einstein College of Medicine Director of Refractive Surgery Long Island Jewish Hospital Department of Ophthalmology Great Neck NY Ronald C Pruett MD Clinical Senior Scientist The Schepens Eye Research Institute; Associate Clinical Professor in Ophthalmology Harvard Medical School Boston MA Carmen A Puliafito MD MBA Office of the Dean Keck School of Medicine University of California Los Angeles CA

Carl D Regillo MD FACS Professor of Opthamology Wills Eye Hospital Philadelphia PA Elias Reichel MD Associate Professor of Ophthalmology Vitreoretinal Diseases and Surgery Director of Electroretinography Service New England Eye Center Tufts University School of Medicine Boston MA Douglas J Rhee MD Assistant Professor of Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston MA

Emanuel S Rosen MD FRCS FRCOphth Visiting Professor Department of Vision Sciences University of Manchester & Honorary Consultant Manchester Royal Eye Hospital Manchester UK Brett Rosenblatt MD Vitreoretinal Surgeon Long Island Vitreoretinal Consultants Great Neck NY Philip J Rosenfeld MD Bascom Palmer Eye Institute Miami FL

Steven S Rhee DO Kaiser-Permanente Bakersfield CA

Jonathan B Rubenstein MD Vice Chairman and Deutsch Family Professor of Ophthalmology Rush University Medical College Chicago IL

Stephen D Rheinstrom MD Visiting Associate Professor of Clinical Opthalmology University of Illinois at Chicago Eye Center (M/C 648) Chicago IL

Steven E Rubin MD Clinical Assistant Professor NYU School of Medicine New York New York Chief North Shore University Hospital Great Neck NY

Pradeep Ramulu MD PhD Assistant Professor of Ophthalmology Wilmer Eye Institute Johns Hopkins Baltimore MD

Patrick J Riedel, MD Partner, Minnesota Eye Consultants, PA Attending Surgeon, Philips Eye Institute, Minneapolis, MN Adjunct Assistant Professor of Ophthalmology, University of Minnesota

Richard M Rubin LTC USAF MC FS Aerospace Ophthalmology Branch, Clinical Sciences Division United States Air Force School of Aerospace Medicine Brooks City-Base TX

Jerome C Ramos-Esteban Cornea and Refractive Surgery Cole Eye Institute Cleveland Clinic Cleveland OH

Sarah M Rikkers MD Department of Neurosciences and Department of Ophthalmology, University of California, San Diego, La Jolla CA

P Kumar Rao MD Assistant Professor of Ophthalmology and Visual Sciences Department of Ophthalmology and Visual Sciences Washington University in St Louis St Louis MO

Fiona O Robinson MD �� King's College Hospital London UK

Jose S Pulido MD MS MPH MBA Professor Department of Ophthalmology Mayo Clinic Rochester MN Peter A Quiros MD Assistant Professor in Neurological Ophthalmology University of Southern California Los Angeles CA

Narsing A Rao MD Professor of Ophthalmology and Pathology Department of Ophthalmology USC/Keck School of Medicine Doheny Eye Institute Los Angeles CA Russell W Read MD PhD Associate Professor of Ophthalmology and Pathology University of Alabama at Birmingham Birmingham AL Ehud Rechtman MD Department of Ophthalmology, Kaplan Medical Center, Rehovot Israel

Hannah Rodriguez-Coleman MD Staff Clinician Department of Ophthalmology Columbia University Medical Center New York NY Adam Rogers MD Assistant Professor Department of Ophthalmology Tufts University School of Medicine Boston MA Richard Roe MD Department of Ophthalmology California Pacific Medical Center CA Shiyoung Roh MD Assistant Clinical Professor, Tufts University School of Medicine Vice-Chairman, Department of Ophthalmology Lahey Clinic Medical Center Peabody MA

Patrick E Rubsamen MD Associate Professor of Ophthalmology University of Miami Miami FL Hossein G Saadati MD Occuloplastic Specialist Kaiser Permanente Stockton CA Alfredo A Sadun MD PhD Flora Thornton Chair of Vision Research and Professor of Ophthalmology and Neurological surgery Doheny Eye Institute USC/Keck School of Medicine Department of Ophthalmology Los Angeles CA Sarwat Salim MD FACS Assistant Clinical Professor of Opthamology Yale University School of Medicine Yale Eye Center New Haven CT Humberto Salinas MD Thomas W Samuelson MD Attending Surgeon Phillips Eye Institute; Clinical Associate Professor The University of Minnesota Minneapolis MN

Jerome S Sarmiento Cornea Fellow Cornea Consultants Boston MA Tina A Scheufele Cleary MD Vitreoretinal Surgeon Ophthalmic Consultants of Boston Boston MA Paulo Schor Affiliated Professor of Opthamology Federal University of Sao Paulo São Paulo Brazil

Robert P Selkin MD Corneal External Disease and Refractive Surgery Service Massachusetts Eye and Ear Infirmary Boston MA Bruce Shields MD Professor of Ophthalmology and Visual Science Yale Eye Center New Haven CT Bradford Shingleton MD Assistant Clinical Professor of Ophthalmology, Harvard Medical School Ophthalmic Consultants of Boston Boston MA Patricia B Sierra MD Cornea and Refractive Surgery Sacramento, CA

Hermann D Schubert MD Professor of Clinical Ophthalmology and Pathology Harkness Eye Institute New York NY

Paul A. Sieving MD Director National Eye Institute National Institutes for Health Bethesda MD

Joel Schuman MD FACS Eye & Ear Foundation Professor and Chairman Department of Ophthalmology University of Pittsburgh School of Medicine Director UPMC Eye Center Pittsburgh PA

Arunan Sivalingam MD Clinical Asst. Professor of Surgery Medical College of Pennsylvania; Instructor Jefferson Medical College of Thomas Jefferson University. Lankenau Hospital Medical Building East Wynnewood PA

Ivan R Schwab MD FACS Professor of Ophthalmology University of California at Davis Sacramento CA Gary S Schwartz MD Adjunct Associate Professor Department of Ophthalmology University of Minnesota Associated Eye Care Stillwater MN Clifford A Scott OD MPH Professor and Chairman Department of Community Health New England College of Optometry Boston MA Jerry Sebag MD Associate Clinical Scientist Schepens Eye Research Institute Harvard Medical School Boston MA; Associate Clinical Professor of Ophthalmology VMR Institute Huntington Beach CA Jovina LS See MBBChir(Camb), FRCS(Edin), MMed(Ophthalmol), FAMS Consultant & Head of Glaucoma Service Department of Ophthalmology National University Hospital Singapore

Kent W Small MD President: Molecular Insight LLC A Medical Corporation Macula and Retina Center Los Angeles CA William E Smiddy MD Professor of Ophthalmology Bascom Palmer Eye Institute Miami FL Kaz Soong MD Professor of Ophthalmology Division of Cornea, External Disease & Refractive Surgery WK Kellogg Eye Center University of Michigan Medical School Ann Arbor MI Sarkis Soukiasian MD Assistant Clinical Professor, Tufts University School of Medicine Lahey Clinic Peabody MA Richard F Spaide MD Associate Clinical Professor of Opthalmology Vitreous, Retina, Macula Consultants of New York & the LuEsther T. Mertz Retina Research Laboratry Manhattan Eye, Ear, and Throat Hospital New York NY Thomas C Spoor MD Michigan Neuro-Ophthalmology Grosse Point Farms MI

Kalliopi Stasi MD Resident University of Rochester Eye Institute Rochester NY

Matthew TS Tennant MD FRCSC Department of Ophthalmology University of Alberta, Edmonton Canada

David Steel MBBS FRCOPhth Consultant Ophthalmologist Sunderland Eye Infirmary Sunderland UK

Howard H Tessler MD Professor of Ophthalmology Department of Ophthalmology University of Illinois at Chicago Chicago IL

Joshua D Stein MD Assistant Professor, Ophthalmology and Visual Sciences The University of Michigan Kellog Eye Center Ann Arbour MI

Edmond H Thall MD MS Clinical Associate Professor of Pediatrics Texas Tech University Amarillo TX Medical Direc Amarillo TX

Thomas L Steinemann MD Assosciate Professor of Ophthalmology, Case Western Reserve University, Cleveland, Ohi Division of Ophthalmology The MetroHealth Medical Center Cleveland OH Jeanine Suchecki MD University of Connecticutt Health Center Farmington CT Joel Sugar MD Professor and Interim Head Ophthalmology Department of Ophthalmology & Visual Sciences University of Illinois at Chicago Chicago IL Alan Sugar MD Professor of Ophthalmology and Visual Sciences WK Kellogg Eye Center University of Michigan Ann Arbor MI JCH Tan MD Department of Ophthalmology & Visual Sciences University of Wisconsin-Madison Madison WI Myron Tanenbaum MD FACS Private practice Miami FL Michael J Taravella MD Associate Professor of Ophthalmology Rocky Mountain Lions Eye Institute Aurora CO William S Tasman MD Ophthalmologist-in-Chief Professor and chairman Department of Ophthalmology Wills Eye Hospital Philadelphia PA David G Telander MD Department of Ophthalmology and Vision Science, University of California Davis Medical Center, Sacramento CA

List of Contributors

George E Sanborn, MD Private Practice Virginia Eye Institute and Clinical Professor Department of Ophthalmology Medical College of Virginia Richmond VA

David P Tingey MD London Health Sciences Center London ON Canada Faisal M Tobaigy MD Department of Ophthalmology Massachusetts Eye and Ear Infirmary and the Schepens Eye Research Institute Boston MA Steven Truong MD Pennsylvania Retina Specialists, P.C. Camp Hill PA James C Tsai MD Robert R. Young Professor and Chairman Department of Ophthalmology and Visual Science Yale University School of Medicine New Haven CT Julie Tsai MD Assistant Professor Dept of Ophthalmology University of South Carolina School of Medicine Columbia SC William G Tsiaras MD Professor and Chairman Rhode Island Hospital Providence, RI Elmer Y Tu MD Associate Professor of Clinical Ophthalmology, Director of the ­Cornea and External Disease Service Dept. Of Ophthalmology University of Illinois at Chicago Chicago IL Nancy Tucker MD FRCS (C) Private Practice Chicago IL Sonal S Tuli MD Program Director Director Cornea and External Diseases Department of Ophthalmology University of Florida Gainesville FL

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List of Contributors

Shailaja Valluri MD Associate Professor of Ophthalmology Indiana University School of Medicine Indianapolis IN James F Vander MD Clinical Professor of Ophthalmology, Thomas Jefferson University Hospital; Attending Surgeon Retina Service Wills Eye Hospital Philadelphia Retinovitreous Associates Ltd. Philadelphia PA Gregory J Vaughn MD The Vaughn Institute Atlanta GA Vanee Val Virasch MD Cornea Fellow Department of Ophthalmology Washington University in St Louis St. Louis MO Hormuz P Wadia MD Assistant Professor of Ophthalmology Director, Cornea Service University of South Florida Eye Institute Tampa FL Rebecca S Walker MD FACS Private Practive Chalfont PA David Sellers Walton MD Clinical Professor of Ophthalmology Harvard Medical School Boston MA Li Wang MD PhD Department of Ophthalmology Baylor College of Medicine Houston TX

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Frederick M Wang MD Clinical Professor of Ophthalmology and Visual Science Albert Einstein College of Medicine New York NY Ming X Wang MD PhD Assistant Professor of Ophthalmology Director Vanderbilt Laser Vision Center Vanderbilt University School of Medicine Nashville TN Robert C Wang MD Texas Retina Associates Dallas TX Martin Wax MD Vice President, Research and Development Alcon Laboratories, Inc Fort Worth TX David V Weinberg MD Assistant Professor of Ophthalmology; Director Vitreo-Retinal Service Northwestern University Medical School Chicago IL Joel M Weinstein MD Associate Professor of Ophthalmology and Pediatrics Department of Ophthalmology Penn State Milton S. Hershey Medical Center, HU19 Hershey PA John J Weiter MD, PhD Assoc. Clinical Professor of Ophthalmology in Harvard Medical School Retina Specialists of Boston Cambridge MA

Liliana Werner MD John A. Moran Eye Center Salt Lake City UT Mark T Wevill MD FRCSE MBChB FCS(SA) Visiting Lecturer Aston University Birmingham UK Paul F White OD Professor of Optometry New England College of Optometry Boston MA Janey L Wiggs MD PhD Associate Professor of Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston MA Charles P Wilkinson MD Chairman, Department of Ophthalmology, Greater Baltimore Medical Center Professor, Department of Ophthalmology, John Hopkins University Baltimore MD Patrick D Williams MD Texas Retina Associates TX George A Williams MD Chief, Department of Opthamology Director, Beaumont Eye Institute Royal Oak MI William J Wirostko MD Instructor The Eye Institute Milwaukee WI

Gadi Wollstein MD Assistant Professor and Director, Ophthalmic Imaging Research Laboratories UPMC Eye Center, Dept of Ophthalmology The Eye & Ear Institute Pittsburgh PA Robert D Yee MD FACS Professor and Chairman Indiana University School of Medicine Indianapolis IL Joshua A Young Specialist in Refractive Surgery and the Cornea Assistant Professor New York University School of Medicine New York NY Ehud Zamir MD FRANZCO Consultant Ophthalmologist The Ocular Immunology Unit The Royal Victorian Eye and Ear Hospital Melbourne Victoria Australia

PART 1 GENETICS

Fundamentals of Human Genetics Janey L. Wiggs

DNA AND THE CENTRAL DOGMA OF HUMAN GENETICS The regulation of cellular growth and function in all human tissue is dependent on the activities of specific protein molecules. In turn, protein activity is dependent on the expression of the genes that contain the correct DNA sequence for protein synthesis. The DNA molecule is a double-stranded helix. Each strand is composed of a sequence of four nucleotide bases – adenine (A), guanine (G), cytosine (C), and thymine (T) – joined to a sugar and a phosphate. The order of the bases in the DNA sequence forms the genetic code that directs the expression of genes. The double-stranded helix is formed as a result of hydrogen bonding between the nucleotide bases of opposite strands.1 The bonding is specific, such that A always pairs with T, and G always pairs with C. The specificity of the hydrogen bonding is the molecular basis of the accurate copying of the DNA sequence that is required during the processes of DNA replication (necessary for cell division) and transcription of DNA into RNA (necessary for gene expression and protein synthesis; Fig. 1-1-1).2, 3 Gene expression begins with the recognition of a particular DNA sequence, called the promoter sequence, as a start site for RNA synthesis by the enzyme RNA polymerase. The RNA polymerase “reads” the DNA sequence and assembles a strand of RNA that is complementary to the DNA sequence. RNA is a single-stranded nucleic acid composed of the same nucleotide bases as DNA, except that uracil takes the place of thymine. Human genes (and genes found in other eukaryotic organisms) contain DNA sequences that are not translated into polypeptides and proteins. These sequences are called intervening sequences or ­introns. Introns do not have a specific function, and although they are transcribed into RNA by RNA polymerase, they are spliced out of the initial RNA product (termed heteronuclear RNA, or hnRNA) to form the completed messenger RNA (mRNA). The mRNA is the template for protein synthesis. Proteins consist of one or more polypeptide chains, which are sequences of specific amino acids. The sequence of bases in the mRNA directs the order of amino acids that make up the polypeptide chain. Individual amino acids are encoded by units of three mRNA bases, termed codons. Transfer RNA (tRNA) molecules bind specific amino acids and recognize the corresponding three-base codon in the mRNA. Cellular organelles called ribosomes bind the mRNA in such a configuration that the RNA sequence is accessible to tRNA molecules and the amino acids are aligned to form the polypeptide. The polypeptide chain may be processed by a number of other chemical reactions to form the mature protein (Fig. 1-1-2).4

HUMAN GENOME Human DNA is packaged as chromosomes located in the nuclei of cells. Chromosomes are composed of individual strands of DNA wound about proteins called histones. The complex winding and coiling process culminates in the formation of a chromosome. The entire collection of human chromosomes includes 22 paired autosomes and two sex chromosomes. Women have two copies of the X chromosome, and men have one X and one Y chromosome (Fig. 1-1-3).5 The set consisting of one of each autosome as well as both sex chromosomes is called the human genome. The chromosomal molecules of DNA from one human genome, if tandemly arranged end to end, contain a sequence of approximately 3.2 billion base pairs. The ­Human Genome Project was formally begun in 1990 and the defined

1.1

goals were to: identify all the approximately 20 000–25 000 genes in ­human DNA; determine the sequences of the 3 billion chemical base pairs that make up human DNA; store this information in publicly available ­databases; improve tools for data analysis; transfer related technologies to the private sector; and address the ethical, legal, and social issues that may arise from the project. One of the most important goals, the complete sequence of the human genome, was completed in draft form in 2001.6 Catalogues of variation in the human genome sequence have also been completed with the microsatellite repeat map in 19947 and the release of the HapMap from the International HapMap Consortium in 2004.8 The HapMap is a database listing single nucleotide polymorphisms (SNPs) that are single-letter variations in a DNA base sequence. There are over 10 million SNPs present in the human genome with a density of one SNP every 100 bases of DNA. SNPs are bound together to form haplotypes, which are blocks of SNPs that are commonly inherited ­together. This binding occurs through the phenomenon of linkage disequilibrium. Within a haplotype block, which may extend for 10 000 to 100 000 bases of DNA, the analysis of only a subset of all SNPs may “tag” the entire haplotype. The International HapMap project has performed an initial characterization of the linkage disequilibrium patterns between SNPs in multiple different populations. The SNP haplotype blocks identified can be examined for association with human disease, especially common disorders with complex inheritance. Knowledge about the effects of DNA variations among individuals can lead to new ways to diagnose, treat, and prevent human disease. This approach has been successfully used to identify the complement factor H risk allele in age-related macular degeneration.9–11

Mitosis and Meiosis

In order for cells to divide, the entire DNA sequence must be copied so that each daughter cell can receive a complete complement of DNA. The growth phase of the cell cycle terminates with the separation of the two sister chromatids of each chromosome, and the cell divides during mitosis. Prior to cell division, the complete DNA sequence is copied by the enzyme DNA polymerase in a process called DNA replication. DNA polymerase is an enzyme capable of the synthesis of new strands of DNA according to the exact sequence of the original DNA. Once the DNA is copied, the old and new copies of the chromosomes pair, and the cell divides such that one copy of each chromosome pair belongs to each cell (Fig. 1-1-4). Mitotic cell division produces a daughter cell that is an exact replica of the dividing cell. Meiotic cell division is a special type of cell division that results in a reduction of the genetic material in the daughter cells, which become the reproductive cells – eggs (women) and sperm (men). Meiosis begins with DNA replication, followed by a pairing of the maternal and paternal chromosomes (homologous pairing) and an exchange of genetic material between chromosomes by recombination (Fig. 1-1-5). The homo­logous chromosome pairs line up on the microtubule spindle and divide such that the maternal and paternal copies of the doubled chromosomes are distributed to separate daughter cells. A second cell division occurs, and the doubled chromosomes divide, which results in daughter cells that have half the genetic material of somatic (tissue) cells.

BASIC MENDELIAN PRINCIPLES Two important rules central to human genetics emerged from the work of Gregor Mendel, a nineteenth-century Austrian monk.12 The first is the principle of segregation, which states that genes exist in pairs and



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PACKAGING OF DNA INTO CHROMOSOMES

STRUCTURE OF THE DNA DOUBLE HELIX Separation of individual strands allows DNA replication

DNA double helix

sugar– phosphate backbone

one helical turn = 3.4 nm

GENETICS

Sugar–phosphate backbone and nitrogenous bases

Nucleosome histone

nucleosome

DNA 200 bp of DNA bases

Solenoid

5l 3l 5l original new chains chain forming adenine

thymine

3l original chain

guanine

Chromosome

cytosine

chromatin loop contains approximately 100, 000 bp of DNA

Fig. 1-1-1  Structure of the DNA double helix. The sugar-phosphate backbone and nitrogenous bases of each individual strand are arranged as shown. The two strands of DNA pair by hydrogen bonding between the appropriate bases to form the double-helical structure. Separation of individual strands of the DNA molecule allows DNA replication, catalyzed by DNA polymerase. As the new complementary strands of DNA are synthesized, hydrogen bonds are formed between the appropriate nitrogenous bases. chromatin strand

CENTRAL DOGMA OF MOLECULAR GENETICS nucleus cytoplasm

Fig. 1-1-3  The packaging of DNA into chromosomes. Strands of DNA are wound tightly around proteins called histones. The DNA–histone complex becomes further coiled to form a nucleosome, which in turn coils to form a solenoid. Solenoids then form complexes with additional proteins to become the chromatin that ultimately forms the chromosome.

chromosome DNA transcription primary mRNA

processing

mature mRNA

translation nuclear pore plasma membrane

nuclear envelope

protein exon



chromatid

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intron spliced out

Fig. 1-1-2  The central dogma of molecular genetics. Transcription of DNA into RNA occurs in the nucleus of the cell, catalyzed by the enzyme RNA polymerase. Mature mRNA is transported to the cytoplasm, where translation of the code produces amino acids linked to form a polypeptide chain, and ultimately a mature protein is produced.

that only one member of each pair is transmitted to the offspring of a mating couple. The principle of segregation describes the behavior of chromosomes in meiosis. Mendel’s second rule is the law of independent assortment, which states that genes at different loci are transmitted independently. This work also demonstrated the concepts of dominant and recessive traits. Mendel found that certain traits were dominant and could mask the presence of a recessive gene. A practical example of Mendel’s two laws is seen in the inheritance of human eye and hair color. Blue eyes and blond hair are recessive traits, while brown eyes and hair are dominant traits. This means that for an individual to have blond hair and blue eyes, he or she must have two genes for blond hair and two genes for blue eyes (one from the mother and one from the father). An individual with brown eyes and brown hair may have two genes for brown eye color and two genes for brown hair color; however, because the brown genes are dominant, brown eyes may occur when an individual has one gene for brown eye color and one gene for blue eye color. A homozygous individual has two of the same genes (i.e., two blue eye-color genes or two brown eye-color genes), whereas a heterozygous individual has two different genes (i.e., one blue eye-color gene and one brown eye-color gene). Mendel’s rules on segregation and independent assortment are evident when the possible matings and offspring of individuals with blond or brown hair and blue or brown eye color are observed (Fig. 1-1-6).

MEIOTIC CELL CYCLE

MITOTIC CELL CYCLE

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centrioles

plasma membrane cytoplasm nucleolus

nucleus nuclear envelope

Metaphase I

chiasmata Daughter cells

Anaphase I Prophase primary oocyte primary spermatocyte

bipolar spindle fiber Prophase I Telophase

Fundamentals of Human Genetics

Interphase

Telophase I secondary oocyte secondary spermatocyte

Prometaphase microtubule spindle pole centromere chromatid

Anaphase

Metaphase II

Anaphase II

Metaphase

equatorial plane (metaphase plate)

Fig. 1-1-4  The mitotic cell cycle. During mitosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides to form two identical diploid daughter cells.

If two blond-haired, blue-eyed individuals mate, all their offspring will have blond hair and blue eyes, because these individuals must be homozygous, and the only genes available to the offspring are those for blue eyes and blond hair. If a blond-haired, blue-eyed individual mates with a brown-haired, brown-eyed individual who is homozygous for brown hair genes and brown eye genes, all the offspring from this mating will have brown hair and brown eyes because the brown genes are dominant. However, all these offspring will be heterozygous for genes at these loci, because they must have inherited recessive blue eye and blond hair genes. The law of independent assortment becomes evident when the offspring of two individuals who are heterozygous for eye and hair color are examined. Among the offspring of this mating, 25% will have blue eyes, and 75% will have brown eyes (50% will be heterozygous for eye color, and 25% will be homozygous for brown eye color). Similarly, 25% of the offspring will have blond hair, and 75% will have brown hair (again, 50% will be heterozygous for hair color, and 25% will be homozygous for brown hair color). However, the 25% of offspring with blue eyes will not necessarily have blond hair. Some offspring will have blond hair and blue eyes, and some offspring will have brown hair and blue eyes. This is because the eye color and hair color genes are located at distinct loci that segregate independently of each other. Independent segregation, or assortment, occurs because maternal and paternal chromosomes segregate randomly into gametes during meiosis, and because of the random recombination that occurs between homologous chromosomes when they pair during meiosis.

large egg and polar bodies spermatids of equal size

Haploid gametes

Fig. 1-1-5  The meiotic cell cycle. During meiosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides twice to form four haploid cells (gametes). As a consequence of the crossing over and recombination events that occur during the pairing of homologous chromosomes prior to the first division, the four haploid cells may contain different segments of the original parental chromosomes. For brevity, prophase II and telophase II are not shown.

At the same time that Mendel observed that most traits segregate independently, according to the law of independent assortment, he ­ unexpectedly found that some traits frequently segregate together. The physical arrangement of genes in a linear array along a chromosome is the explanation for this surprising observation. On average, a recombination event occurs once or twice between two paired homologous chromosomes during meiosis (Fig. 1-1-7). Most observable traits, by chance, are located far away from one another on a chromosome, such that recombination is likely to occur between them, or they are located on entirely different chromosomes. If two traits are on separate chromosomes, or a recombination event is likely to occur between them on the same chromosome, the resultant gamete formed during meiosis has a 50% chance of inheriting different alleles from each loci, and the two traits respect the law of independent assortment. If, however, the loci for these two traits are close together on a chromosome, with the result that a recombination event occurs between them only rarely, the alleles at each loci are passed to descendent gametes “in phase.” This means that the particular alleles present at each loci in the offspring reflect the orientation in the parent, and the traits appear to be “linked.” For example, in Mendel’s study of pea plants, curly leaves were always found with pink flowers, even though the genes for curly leaves and pink flowers are located at distinct loci. These traits are linked, because the curly-leaf gene and the pink-flower gene are located close to each



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INDEPENDENT ASSORTMENT OF MENDELIAN TRAITS Blond-haired, blue-eyed father and mother

Offspring

GENETICS

blond hair, blue eyes

blond hair, blue eyes

blond hair, blue eyes

blond hair, blue eyes

100% blond hair, blue eyes

Blond-haired, blue-eyed father and brown-haired, brown-eyed mother

Offspring

blond hair, blue eyes

brown hair, brown eyes

blond hair, blue eyes

brown hair, brown eyes

100% brown hair, brown eyes

Couple heterozygous for blond- and brown-hair genes, and for blue and brown eye-color genes Father (sperm)

blond hair, blue eyes

blond hair, brown eyes

Mother brown hair, (eggs) blue eyes

brown hair, brown eyes

blond hair, blue eyes

blond hair, brown eyes

brown hair, blue eyes

brown hair, brown eyes

blond hair/ blond hair

blond hair/ blond hair

brown hair/ blond hair

brown hair/ blond hair

blue eyes/ blue eyes

brown eyes/ blue eyes

blue eyes/ blue eyes

brown eyes/ blue eyes

blond hair/ blond hair

blond hair/ blond hair

brown hair/ blond hair

brown hair/ blond hair

brown eyes/ blue eyes

brown eyes/ brown eyes

brown eyes/ blue eyes

brown eyes/ brown eyes

brown hair/ blond hair

brown hair/ blond hair

brown hair/ brown hair

brown hair/ brown hair

blue eyes/ blue eyes

brown eyes/ blue eyes

blue eyes/ blue eyes

brown eyes/ blue eyes

brown hair/ blond hair

brown hair/ blond hair

brown hair/ brown hair

brown hair/ brown hair

brown eyes/ blue eyes

brown eyes/ brown eyes

brown eyes/ blue eyes

brown eyes/ brown eyes

MUTATIONS

Fig. 1-1-6  Independent assortment of mendelian traits. Shown are the results of a mating between a blond-haired, blue-eyed father and a blond-haired, blueeyed mother; a mating between a blond-haired, blue-eyed father and a brownhaired, brown-eyed mother; and a mating between a couple heterozygous for blond and brown hair and for blue and brown eyes.

GENETIC RECOMBINATION BY CROSSING OVER A

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recombination

Fig. 1-1-7  Genetic recombination by crossing over. Two copies of a chromosome are copied by DNA replication. During meiosis, pairing of homologous chromosomes occurs, which enables a crossover between chromosomes to take place. During cell division, the recombined chromosomes separate into individual daughter cells.



other on a chromosome, and a recombination event only rarely occurs between them. Recombination and linkage are the fundamental concepts behind genetic linkage analysis.13 The search for a gene responsible for a ­phenotypic trait (or disease) depends on the ability to observe linkage between the trait and mapped genetic markers. The identification of a marker that segregates with the trait (i.e., is linked genetically to the trait) defines the location of the gene for that trait, because the lack of recombination between the marker and the trait means that the gene responsible for the trait is located physically near the linked marker. The chromosomal locations of genetic markers are readily available to the public as a result of the successful efforts of the nationally funded Human Genome Project.7, 8 Once an approximate location of a gene responsible for a trait has been determined, analysis of rare recombination events between markers in the region and that trait can help further define the precise physical location of the gene on the chromosome. In this way, “positional cloning” of genes may be accomplished.14, 15

Mutations are changes in the gene DNA sequence that result in a biologically significant change in the function of the encoded protein. If a particular gene is mutated, the protein product might not be made, or it might be produced but work poorly. In some cases, mutations create proteins that have an adverse effect on the cell (dominant negative effect). Point mutations (the substitution of a single base pair) are the most common mutations encountered in human genetics. Missense mutations are point mutations that cause a change in the amino acid sequence of the polypeptide chain. The severity of the missense mutation is dependent on the chemical properties of the switched amino acids and on the importance of a particular amino acid in the function of the mature protein. Point mutations also may decrease the level of polypeptide production because they interrupt the promoter sequence, splice site sequences, or create a premature stop codon. Gene expression can be affected by the insertion or deletion of large blocks of DNA sequence. These types of mutations are less common than point mutations but may result in a more severe change in the activity of the protein product. A specific category of insertion mutations is the expansion of trinucleotide repeats found in patients affected by certain neurodegenerative disorders. An interesting clinical phenomenon, “anticipation,” was understood on a molecular level with the discovery of trinucleotide repeats as the cause of myotonic dystrophy.16 Frequently, offspring with myotonic dystrophy were affected more ­severely and at an earlier age than their affected parents and grandparents. Examination of the disease-causing trinucleotide repeat in affected pedigrees demonstrated that the severity of the disease correlated with the number of repeats found in the myotonic dystrophy gene in affected individuals. This phenomenon has been observed in a number of other diseases, including Huntington’s disease (Fig. 1-1-8). Chromosomal rearrangements may result in breaks in specific genes that cause an interruption in the DNA sequence.17 Usually, the break in DNA sequence results in a truncated, unstable, dysfunctional protein product; occasionally, the broken gene fuses with another gene to cause a “fusion polypeptide product,” which may have a novel activity in the cell. Often, such a novel activity results in an abnormality in the function of the cell. An example of such a fusion protein is the product of the chromosome 9;22 translocation that is associated with many cases of leukemia (Fig. 1-1-9).18 A set consisting of one of each autosome as well as an X or a Y chromosome is called a haploid set of chromosomes. The normal complement of two copies of each gene (or two copies of each chromosome) is called diploidy. Rarely, as a result of abnormal chromosome separation during cell division, a cell or organism may have three copies of each chromosome, which is called triploidy. A triploid human is not viable; however, some patients have an extra chromosome or an extra segment of a chromosome. In such a situation, the abnormality is called trisomy for the chromosome involved. For example, patients with Down’s syndrome have three copies of chromosome 21, also referred to as trisomy 21.19 If one copy of a pair of chromosomes is absent, the defect is called haploidy. Haploidy for an entire human chromosome is probably lethal, but deletions of a segment of a chromosome are common in the human population. Deletions of the X chromosome are frequently the cause of Duchenne’s muscular dystrophy.20 Polymorphisms are changes in DNA sequence that don’t have a significant biological effect. These DNA sequence variants may modify

EXPANDED TRINUCLEOTIDE REPEAT AND ANTICIPATION IN MYOTONIC DYSTROPHY

kilobase 16 (kb)

Affected mild

severe

congenital

+ 1 kb

+ 2.5 kb

+ 4 kb

10 9

Fig. 1-1-8  Expanded trinucleotide repeat and anticipation in myotonic dystrophy. Results of a study to determine the size of the trinucleotide repeat in three individuals affected by myotonic dystrophy.12 The results from a normal individual are shown at the far left. The size of the repeat element increases with the severity of the disease in the affected individuals.

RECIPROCAL TRANSLOCATION

normal 9

normal 22

der (9)

der (22)

Fig. 1-1-9  Reciprocal translocation between two chromosomes. The Philadelphia chromosome (responsible for chronic myelogenous leukemia) is shown as an example of a reciprocal chromosomal translocation that results in an abnormal gene product responsible for a clinical disorder. In this case, an exchange occurs between the long arm of chromosome 9 and the long arm of chromosome 22.

disease processes, but alone are not sufficient to cause disease. Human DNA sequence is highly variable and includes single nucleotide polymorphisms (SNPs), microsatellite repeat polymorphisms (20–50 base pair repeats of CA or GT sequence), variable number of tandem repeat polymorphisms (VNTR, repeats of 50–100 base pairs of DNA), or larger insertion deletions.21

GENES AND PHENOTYPES The relationship between genes and phenotypes is complex: more than one genetic defect can lead to the same clinical phenotype (genetic heterogeneity), and different phenotypes can result from the same genetic defect (variable expressivity). Retinitis pigmentosa is an excellent example of genetic heterogeneity as it may be inherited as an X-linked, autosomal dominant, autosomal recessive, or digenic trait, and at least 20 causative genes have been identified. Other ocular disorders that are genetically heterogeneous include congenital cataract, glaucoma, and age-related macular degeneration. Different genes may contribute to a common phenotype because they affect different steps in a common pathway. Understanding the role of each gene in the disease process can help define the cellular mechanisms that are responsible for the disease. For many genes, a single mutation that alters a critical site in the protein results in an abnormal phenotype. For some diseases, the resulting phenotypes are remarkably similar regardless of the nature of the

1.1 Fundamentals of Human Genetics

Control

mutation. For example, a wide variety of mutations in the Rb gene cause retinoblastoma. Other diseases, however, exhibit variable expressivity, where an individual’s mutation may be responsible for severe disease, mild disease, or disease that is not clinically detectable (incomplete penetrance). There are many examples of ocular disease demonstrating variable expressivity including Kjer’s autosomal dominant optic ­atrophy,22 Axenfeld-Rieger syndrome,23 and aniridia.24 Different mutations in the same gene can also result in different ­phenotypes (allelic heterogeneity). Allelic heterogeneity accounts for the different phenotypes of dominant stromal dystrophies caused by mutations in the TGFB1/BIGH3 gene.25 The phenotypic expression of a mutation may depend upon its molecular site within a particular gene. Such variable expressivity based on the location of the mutation is exemplified by mutations in the rds gene, which may cause typical autosomal dominant retinitis pigmentosa or macular dystrophy depending on the position of the genetic defect.26 As embryonic cells multiply and differentiate in a particular tissue, only a subset of genes becomes active. Consequently, the expression of specific genes becomes limited to precise tissues. Tissue-specific genes explain why certain inherited diseases are restricted to particular parts of the body. However, although the clinical expression of some inherited disorders seems to be localized to special tissues, such as the eye, a number of ocular disorders are caused by genes that are expressed in tissues throughout the body.

PATTERNS OF HUMAN INHERITANCE The most common patterns of human inheritance are autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial. Figure 1-1-10 shows examples of these four inheritance patterns. Other inheritance patterns less commonly encountered in human disease ­include X-linked dominant, digenic inheritance (polygenic), pseudodominance, and imprinting. Figure 1-1-11 defines the notation and symbols used in pedigree construction.

Autosomal Dominant

A disease-causing mutation that is present in only one of the two gene copies at an autosomal locus (heterozygous) is a dominant mutation. For example, a patient with dominant retinitis pigmentosa will have a defect in one copy of one retinitis pigmentosa gene inherited from one parent who, in most cases, is also affected by retinitis pigmentosa. The other copy of that gene, the one inherited from the unaffected parent, is normal (wild type). Affected individuals have a 50% chance of having affected siblings and a 50% chance of passing the abnormal gene to their offspring. Fifty per cent of children of an affected individual will be ­ affected. For a dominant disease, males and females transmit the disease equally and are affected equally. True dominant alleles produce the same phenotype in the heterozygous and homozygous states. In humans, most individuals affected by a disease caused by a dominant allele are heterozygous; however, occasionally homozygous mutations have been described. In cases where the homozygous individual is more severely affected than the heterozygous individual, the disease is more appropriately noted to be inherited as a semidominant trait. For example, alleles in the PAX3 gene, causing Waardenburg’s syndrome, are semidominant, because a homozygote with more severe disease compared with their heterozygote relatives has been described.27 In some pedigrees with an autosomal dominant disease, some individuals who carry the defective gene do not have the affected phenotype. However, these individuals can still transmit the disease gene to offspring and have affected children. This phenomenon is called reduced penetrance and is disease gene specific. The Rb gene responsible for ­retinoblastoma is only 90% penetrant, which means that 10% of the individuals who inherit a mutant copy of the gene do not develop the tumor.28

Autosomal Recessive

Diseases that require both copies of a gene to be abnormal for development are inherited as recessive traits. Heterozygous carriers of mutant genes are usually clinically normal. The same recessive defect might affect both gene copies, in which case the patient is said to be a homozygote. Different recessive defects might affect the two gene copies, in which case the patient is a compound heterozygote. In a family with recessive disease, both parents are unaffected carriers, each having one wild-type gene (allele) and one mutant gene (allele). Each parent has a



1

PATTERNS OF INHERITANCE Pedigrees with an autosomal dominant trait

GENETICS

Generation I

1

2

3

II III Pedigrees with an autosomal recessive trait I

1

2

3

II III IV Pedigrees with an X-chromosomal inheritance I

1

2

3

II III IV V Pedigrees with a mitochondrial trait I II III IV affected male

affected female

unaffected male

unaffected male, gene carrier (heterozygous)

unaffected female

unaffected female, gene carrier (heterozygous)

Fig. 1-1-10  Patterns of inheritance. For pedigrees with an autosomal dominant trait, panel 1 shows inheritance that originates from a previous generation, panel 2 shows segregation that originates in the second generation of this pedigree, and panel 3 shows an apparent “sporadic” case, which is actually a new mutation that arises in the most recent generation. This mutation has a 50% chance of being passed to offspring of the affected individual. For pedigrees with an autosomal recessive trait, panel 1 shows an isolated affected individual in the most recent generation (whose parents are obligatory carriers of the mutant gene responsible for the condition), panel 2 shows a pair of affected siblings whose father is also affected (for the siblings to be affected, the mother must be an obligate carrier of the mutant gene), and panel 3 shows an isolated affected individual in the most recent generation who is a product of a consanguineous marriage between two obligate ­carriers of the mutant gene. For pedigrees with an X-chromosomal trait, panel 1 shows an isolated affected individual whose disease is caused by a new mutation in the gene responsible for this condition, panel 2 shows an isolated individual who inherited a mutant copy of the gene from the mother (who is an obligate carrier), and panel 3 shows segregation of an X-linked trait through a multigeneration pedigree (50% of the male offspring are affected, and their mothers are obligate carriers of the disease). For pedigrees with a mitochondrial trait, the panel shows a large, multigeneration pedigree – men and woman are affected, but only woman have affected offspring.

50% chance of transmitting the defective allele to a child. Since a child must receive a defective allele from both parents to be affected, each child has a 25% chance of being affected (50% × 50% = 25%), while 50% of the offspring will be carriers of the disease. If the parents are related they may be carriers of the same rare mutations and there is a greater chance that a recessive disease can be transmitted to offspring. Males and females have an equal chance of transmitting and inheriting the disease alleles.

X-Linked Recessive



Mutations of the X chromosome produce distinctive inheritance patterns, because males have only one copy of the X chromosome whereas females have two. Most X-linked gene defects are inherited as X-linked recessive traits. Carrier females are typically unaffected because they have both a normal copy and a defective copy of the disease-associated gene. Carrier males are affected because they only have one defective X chromosome and they do not have a normal gene copy to compensate for the defective copy. All of the daughters of an affected male will

be carriers of the disease gene because they will inherit the defective X chromosome. None of the sons of an affected male will be affected or be carriers because they will inherit the Y chromosome. Each child of a carrier female has a 50% chance of inheriting the disease gene. If a son inherits the defective gene he will be affected. If a daughter inherits the defective gene she will be a carrier. An important characteristic of X-linked recessive disorders is that males never transmit the disease to sons directly (male-to-male transmission). Usually female carriers of an X-linked disease gene do not have any clinical evidence of the disease. However, for some X-linked diseases, mild clinical features can be found in female carriers. For example, in X-linked retinoschisis, affected males are severely affected while carrier females have a visually insignificant but clinically detectable retinal abnormality.29 Mild phenotypic expression of the disease gene can be caused by the process of lyonization. In order for males (with one X chromosome) and females (with two X chromosomes) to have equal levels of expression of X-linked genes, female cells express genes from

BASIC PEDIGREE NOTATION normal female

or

normal male single bar indicates mating

I II 1

2

3

normal parents and normal offspring, two girls and a boy, in birth order indicated by the numbers; I and II indicate generations single parent as presented means partner is normal or of no significance to the analysis double bar indicates a consanguineous union (mating between close relatives)

identical twins 2

6

number of children for each sex

or

darkened square or circle means affected individual; arrow (when present) indicates the affected individual is propositus, the beginning of the analysis

and

autosomal heterozygous recessive X-linked carrier

and

dead aborted or stillborn

Fig. 1-1-11  Basic pedigree notation. Typical symbols used in pedigree construction are defined.

only one of their two X chromosomes. The decision as to which X chromosome is expressed is made early in embryogenesis, and the line of descending cells faithfully adheres to the early choice. As a result, females are mosaics with some of the cells in each tissue expressing the maternally derived X chromosome and the remainder expressing the paternally derived X chromosome. When one of the X chromosomes carries an abnormal gene, the proportion of cells that express the mutant versus the normal gene in each tissue can vary. By chance a susceptible tissue might have a preponderance of cells expressing the mutant X chromosome, causing the disease to become manifest. Most females affected with X-linked conditions because of lyonization have milder disease than that found in their male relatives. Females can also be affected by an X-linked recessive disease if the ­father is affected and the mother coincidentally is a carrier of a mutation in the disease gene. In this case, 50% of daughters would be affected, because 50% would inherit the X chromosome from the mother carrying the disease gene and all the daughters would inherit the X chromosome from the father carrying the disease gene. Because most X-linked disorders are rare, the carrier frequency of disease genes in the general population is low, and the chance that a carrier female would mate with a male affected by the same disease is low.

Mitochondrial Inheritance

Mitochondria are small organelles located in the cytoplasm of cells. They function to generate ATP for the cell and are most abundant in cells that have high energy requirements such as muscle and nerve cells. Mitochondria have their own small chromosome – 16 569 base pairs of DNA encoding for 13 mitochondrial proteins, 2 ribosomal RNAs, and 22 tRNAs. Mutations occurring in genes located on the mitochondrial chromosome cause a number of diseases including Leber hereditary optic atrophy30 and Kearns-Sayre syndrome.31 Mutations occurring on the mitochondrial chromosome are inherited only from the mother because virtually all human mitochondria are derived from the maternal egg. Fathers do not transmit mitochondria to their offspring. Cells vary in the number of mitochondria they contain, and when cells divide the mitochondria are divided randomly. As a result, different cells can have varying numbers of mitochondria and if a fraction of the mitochondria contain a mutated gene different cells will have a varying proportion of healthy versus mutant mitochondria. The distribution of mutant mitochondria is called heteroplasmy and the proportion of mutant mitochondria can vary from cell to cell and can

Pseudodominance

This is the term given to an apparent dominant inheritance pattern due to recessive defects in a disease gene. This situation arises when a parent affected by a recessive disease (two abnormal copies of the disease gene) has a spouse who is a carrier of one abnormal copy of the disease gene. Children from this couple will always inherit a defective gene copy from the affected parent and will have a 50% chance of inheriting the defective gene copy from the unaffected carrier parent. On average, half of the children will inherit two defective gene copies and will be affected. The pedigree would mimic a dominant pedigree because of apparent direct transmission of the disease from the ­affected parent to affected children and because approximately 50% of the children will be affected. Pseudodominant transmission is ­uncommon, because few people are asymptomatic carriers for any ­particular recessive gene.

1.1 Fundamentals of Human Genetics

or

fraternal twins (not identical)

also change with age. Differences in the relative proportions of mutant mitochondria can partly explain the observed variable severity of mitochondrial diseases, and also the variable age of onset of mitochondrial diseases.

X-Linked Dominant Inheritance

This inheritance pattern is similar to X-linked recessive inheritance, except that all females who are carriers of an abnormal gene on the X chromosome are affected rather than unaffected. All of the male offspring are also affected. Incontinentia pigmenti is probably inherited as an X-linked dominant trait. Affected females have irregularly ­pigmented atrophic scars on the trunk and the extremities, and congenital avascularity in the peripheral retina with secondary retinal neovascularization.32 This and other X-linked dominant disorders ­occur almost always in females, and it is likely that the X chromosome gene defects causing these diseases are embryonic lethals when present in males.

Digenic Inheritance and Polygenic Inheritance

Digenic inheritance occurs when a patient has heterozygous defects in two different genes, and the combination of the two gene defects causes disease. Individuals who have a mutation in only one of the genes are normal. Digenic inheritance is different from recessive inheritance, because the two mutations involve different disease genes. In some retinitis pigmentosa families, mutation analysis of the peripherin gene and the ROM1 gene showed that the affected individuals had specific mutations in both genes. Individuals who had a mutation in one copy of either gene were unaffected by the disease.33 Triallelic inheritance has been described in some families affected by BardetBiedle syndrome (BBS). In these pedigrees, affected individuals carry three mutations in one or two BBS genes (11 BBS genes have been identified), and unaffected individuals have only two abnormal alleles. In some families, it has been proposed that BBS may not be a singlegene recessive disease but a complex trait requiring at least three mutant ­alleles to manifest the phenotype. This would be an example of ­triallelic inheritance.34 If the expression of a heritable trait or predisposition is influenced by the combination of alleles at three or more loci, it is polygenic. Because of the complex inheritance, conditions caused by multiple alleles do not demonstrate a simple inheritance pattern. These complex traits may also be influenced by environmental conditions. Examples of phenotypes in ophthalmology that exhibit complex inheritance because of contributions of multiple genes and environmental factors are myopia, age-related macular degeneration, and adult-onset openangle glaucoma.35

Imprinting

Some mutations give rise to autosomal dominant traits that are transmitted by parents of either sex, but they are expressed only when ­inherited from a parent of one particular sex. In families affected with these disorders, they would appear to be transmitted in an autosomal dominant pattern from one parent (either the mother or the father) and would not be transmitted from the other parent. Occasionally, the same mutation gives rise to a different disorder depending on the sex of the parent transmitting the trait. These parental sex effects are evidence of a phenomenon called imprinting. Although the molecular mechanisms responsible for imprinting are not completely understood, it appears to be associated with DNA methylation patterns that can mark certain genes with their parental origin.36



1

MOLECULAR MECHANISMS OF DISEASE Autosomal Dominant

GENETICS

Disorders inherited as autosomal dominant traits result from mutations that occur in only one copy of a gene (i.e., in heterozygous individuals). Usually, the parental origin of the mutation doesn’t matter. However, if the gene is subject to imprinting (see below), then mutations in the maternal or paternal copy of the gene may give rise to different phenotypes.

Haploinsufficiency

Under normal circumstances, each copy of a gene produces a protein product. If a mutation occurs such that one copy of a gene no longer produces a protein product then the amount of that protein in the cell has been reduced by half. Mutations that cause a reduction in the amount of protein or lead to inactivation of the protein are called loss-of-function mutations. For many cellular processes, this reduction in protein quantity does not have consequences, i.e., the heterozygous state is normal, and these mutations may be inherited as recessive traits (see below). However, for some cellular processes there is an absolute requirement for the full dosage of protein product, which can only be furnished if both copies of a particular gene are active. Diseases that are caused by inheritance of a single mutation reducing the protein level by half are inherited as dominant traits.

GENE THERAPY USING A RETROVIRUS VECTOR Therapeutic gene engineered into retrovirus DNA retrovirus

therapeutic human gene Recombinant virus replicates in a packaging cell replace retroviral genes with therapeutic human gene packaging cell

virions

unpackagable helper provirus

Gain-of-function dominant negative effect

Autosomal dominant disorders can be caused by mutant proteins that have a detrimental effect on the normal tissue. Mutations in one copy of a gene may produce a mutant protein that can accumulate as a toxic product or in some other way interfere with the normal function of the cell. The mutant protein may also interfere with the function of the normal protein expressed by the remaining normal copy of the gene thus eliminating any normal protein activity.19 It is possible to have gain-of-function mutations that can also be dominant negative because the new function of the protein also interferes with the function of the remaining normal copy of the gene.

Replicated recombinant virus infects the target cell and inserts copies of the therapeutic gene

RNA

DNA

Autosomal and X-Linked Recessive

Recessive disorders result from mutations present on both the maternal and paternal copies of a gene. Mutations responsible for recessive disease typically cause a loss of biologic activity, either because they create a defective protein product that has little or no biologic activity or because they interfere with the normal expression of the gene (regulatory mutations). Most individuals heterozygous for recessive disorders, both autosomal and X-linked, are clinically normal.

GENE THERAPY



Mutations in the DNA sequence of a particular gene can result in a protein product that is not produced, works poorly, or has adopted a novel function that is detrimental to the cell. Gene therapy involves the delivery of a normal gene to the tissue that contains the flawed gene. Theoretically, a normal copy of the gene can physically take the place of the flawed gene and restore the gene function of the cell. In practice, however, actually replacing the flawed gene with a normal gene is a difficult task.37 Currently, the aim of gene therapy is to add a useful gene to the cell or tissue that suffers the consequences of the flawed gene. In some cases, the new gene may code for an entirely different protein whose function compensates for the protein encoded by the flawed gene. A common approach to delivering useful genes to specific tissues is to use modified viruses as vectors.38 Normally, certain types of viruses invade a host cell, are incorporated into the host genome, and express the viral genes required for replication of the virus. The mature virus eventually takes over the cell, with the result that the cell dies and releases new, infectious viral products that can infect adjacent cells. A general approach to gene therapy is to use an altered (recombinant) virus to carry the gene of interest to the desired tissue. Using genetic engineering techniques, the viral DNA is modified so that the viral genes required for virus proliferation are removed and the therapeutic gene is put in their place. Such a virus may invade the diseased tissue, become incorporated into the host DNA, and express the desired gene. Because the modified virus does not have the viral genes required for viral replication, the ­virus cannot proliferate, and the host cell does not die (Fig. 1-1-12). A

reverse transcription human target cell therapeutic gene product

nucleus

Fig. 1-1-12  Gene therapy using a retrovirus vector. A therapeutic gene is engineered genetically into the retrovirus DNA and replaces most of the viral DNA sequences. The “recombinant virus” that carries the therapeutic gene is allowed to replicate in a special “packaging cell,” which also contains normal virus that carries the genes required for viral replication. The replicated ­recombinant virus is allowed to infect the human diseased tissue, or “target cell.” The recombinant virus may invade the diseased tissue but cannot replicate or destroy the cell. The recombinant virus inserts copies of the normal therapeutic gene into the host genome and produces the normal protein product.

successful example of this approach has recently been demonstrated by the restoration of vision in a canine model of Leber congenital amaurosis using a recombinant adeno-associated virus carrying the normal gene (RPE65).39 Human trials are under way. Diseases caused by mutations that create a gene product that is destructive to the cell need to be treated using a different approach. In these cases, genes or oligonucleotides that may inactivate the ­mutated gene are introduced into the cell. This is called “antisense therapy,” and it is proving to be a useful approach for diseases caused by the “gainof-function mutations.”40 A number of different viral vectors likely to be useful for gene therapy are currently under investigation. In ­addition, development of nonviral mechanisms, based on the emerging methodology of nanotechnology, to introduce therapeutic genes into diseased tissue is ongoing.41 In general, most of the current approaches to gene therapy are aimed at repairing the somatic cells of the particular tissue affected by the disease gene.42 Gene delivery may be tailored to the somatic cells affected by the disorder. Gene therapy of ocular disorders benefits from the

cells continue to carry flawed copies of the gene, the disease may still be passed to offspring of the affected patient. Gene therapy targeted to germline cells as well as the diseased somatic cells results in successful treatment of the disease in the affected individual and prevents transfer of the disease to any offspring.

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16. Warren ST. The expanding world of trinucleotide repeats. Science. 1996;271:1374–5. 17. Shaikh TH, Kurahashi H, Emanuel BS. Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review. Genet Med. 2001;3:6–13. 18. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994;372:143–9. 19. Roubertoux PL, Kerdelhue B. Trisomy 21: from chromosomes to mental retardation. Behav Genet. 2006;36: 346–54. 20. Matsuo M. Duchenne/Becker muscular dystrophy: from molecular diagnosis to gene therapy. Brain Dev. 1996;18:167–72. 21. Little PF. Structure and function of the human genome. Genome Res. 2005;15:1759–66. 22. Han J, Thompson-Lowrey AJ, Reiss A, et al. OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy. Genet Med 2006;8:217–25. 23. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld-Rieger syndrome. Expert Rev Mol Med 2005;7:1–7. 24. Vincent MC, Gallai R, Olivier D, et al. Variable phenotype related to a novel PAX 6 mutation (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia. Am J Ophthalmol. 2004;138:1016–21. 25. Stewart HS, Ridgway AE, Dixon MJ, et al. Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis. Hum Mutat. 1999;14: 126–32. 26. Kim RY, Dollfus H, Keen TJ, et al. Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene. Arch Ophthalmol 1995;113:451–5. 27. Wollnik B, Tukel T, Uyguner O, et al. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A. 2003;122:42–5. 28. Harbour JW. Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol 2001;119:1699–704.

29. Kaplan J, Pelet A, Hentati H, et al. Contribution to carrier detection and genetic counselling in X linked retinoschisis. J Med Genet. 1991;28:383–8. 30. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. 2005;140:517–23. 31. Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol. 2003;250:267–77. 32. Emery MM, Siegfried EC, Stone MS, et al. Incontinentia pigmenti: transmission from father to daughter. J Am Acad Dermatol. 1993;29(2 Pt 2):368–72. 33. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science. 1994;264:1604–8. 34. Eichers ER, Lewis RA, Katsanis N, Lupski JR. Triallelic inheritance: a bridge between Mendelian and multi­ factorial traits. Ann Med. 2004;36:262–72. 35. Wiggs JL. Complex disorders in ophthalmology. Semin Ophthalmol. 1995;10:323–30. 36. Lewis A, Reik W. How imprinting centres work. Cytogenet Genome Res. 2006;113:81–9. 37. Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465–8. 38. Mandel RJ, Manfredsson FP, Foust KD, et al. Recombinant adeno-associated viral vectors as therapeutic agents to treat neurological disorders. Mol Ther. 2006;13:463–83. 39. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5. 40. Pelletier R, Caron SO, Puymirat J. RNA based gene therapy for dominantly inherited diseases. Curr Gene Ther. 2006;6:131–46. 41. Vasir JK, Labhasetwar V. Polymeric nanoparticles for gene delivery. Expert Opin Drug Deliv. 2006;3:325–44. 42. Brenner MK. Human somatic gene therapy: progress and problems. J Intern Med. 1995;237:229. 43. Bennett J, Maguire AM. Gene therapy for ocular disease. Mol Ther. 2000;1:501–5.

1.1 Fundamentals of Human Genetics

accessibility of the eye, the ability to visualize the diseased tissue, and the large number of specific gene defects known to be responsible for many inherited eye disorders.43 Specific treatment of the diseased cells does not affect the other cells of the body, which include the germline cells. Because the germline



PART 1 Genetics

Molecular Genetics of Selected Ocular Disorders

1.2

Janey L. Wiggs

INTRODUCTION Tremendous advances in the molecular genetics of human disease have been made in the past 10 years. Many genes responsible for inherited eye disease have been isolated and characterized, and the chromosomal location of a number of additional genes has been determined (Table 1-2-1). Identifying and characterizing genes responsible for human disease has led to DNA-based methods of diagnosis, novel therapeutic approaches including gene therapy, and improved knowledge about the molecular events that underlie the disease processes. These approaches have led to improved methods of diagnosis and treatment and ultimately will improve the prognosis for vision. The disorders discussed in this chapter represent the latest advances in human ocular molecular genetics and illustrate important principles of human genetics. Mutations may result in the formation of a defective gene product. If the normal protein product of a mutated gene is necessary for a critical biological function, an alteration of the normal phenotype may occur. Many changes in phenotype are normal variations of human traits (for example, brown hair instead of blond hair). However, some changes cause severe cellular dysfunction, which may be the cause of a disease. Although all inherited disorders are the result of gene mutations, the molecular consequences of a mutation are quite variable. The type of mutation responsible for a disease usually defines the inheritance pattern. For example, mutations that create an abnormal protein detrimental to the cell are typically autosomal dominant, because only one mutant gene is required to disrupt the normal functions of the cell. Mutations that result in proteins that have reduced biological activity (loss of function) may be inherited as autosomal dominant or autosomal recessive conditions, depending on the number of copies of normal genes (and the amount of normal protein) required. Disorders may be caused by mutations in mitochondrial DNA that result in a characteristic inheritance pattern. Also, mutations in genes carried on the X chromosome result in characteristic inheritance patterns.

DOMINANT CORNEAL DYSTROPHIES

10

The autosomal dominant corneal dystrophies are an excellent example of dominant negative mutations that result in the formation of a toxic protein. Four types of autosomal dominant dystrophies that affect the stroma of the cornea have been described: l Groenouw (granular) type I;1 l lattice type I;2 l Avellino (combined granular-lattice);3, 4 and l Reis-Bücklers.5 Although all four corneal dystrophies affect the anterior stroma, the clinical and pathological features differ. The granular dystrophies typically form discrete, white, localized deposits that may obscure vision progressively. Histopathologically, these deposits stain bright red with Masson trichrome and have been termed “hyalin.” In lattice dystrophy, branching amyloid deposits gradually opacify the visual axis. These deposits exhibit a characteristic birefringence under polarized light after staining with Congo red. Avellino dystrophy includes features of both granular and lattice dystrophies. Reis-Bücklers dystrophy appears to ­involve primarily Bowman’s layer and the superficial stroma. All four dystrophies were mapped genetically to a common interval on chromosome 5q31,6–9 and mutations in a single gene, TGFB1 (also known as BIGH3), located in this region were found in affected individuals.10, 11 The product of this gene, keratoepithelin, is probably an

extracellular matrix protein that modulates cell adhesion. Four different missense mutations, which occur at two arginine codons in the gene, have been found (Fig. 1-2-1). Interestingly, mutations at one of these arginine codons cause lattice dystrophy type I or Avellino dystrophy, the two dystrophies characterized by amyloid deposits. Mutations at the other arginine codon appear to result in either granular dystrophy or Reis-Bücklers dystrophy. The mutation analysis of this gene demonstrates that different mutations within a single gene can result in different phenotypes. The mutation that causes Avellino and lattice dystrophies abolishes a putative phosphorylation site, which probably is required for the normal structure of keratoepithelin. Destruction of this aspect of the protein structure leads to formation of the amyloid deposits that are responsible for opacification of the cornea. Consequently, the mutant protein is destructive to the normal tissue. Mutations at the R555 appear to result in either granular dystrophy or Reis-Bücklers dystrophy. These phenotype–genotype correlations demonstrate the variable expressivity of mutations in this gene and the significance of alteration of the arginine residues 124 and 555. Interestingly, pathologic deposits caused by keratoepithelin accumulation have only been observed in the cornea and not in other tissues or organs.12 Because the TGFB1/BIGH3 gene is expressed in other tissues,13 these results suggest a cornea-specific mechanism causing the accumulation of mutant keratoepithelin. Meesmann’s corneal dystrophy is an autosomal dominant condition that affects the corneal epithelium. The corneal changes consist of fine, punctate opacities in the epithelium and occasionally in Bowman’s membrane.14 The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins K3 and K12. Genetic linkage studies indicate that a gene responsible for this condition is located on the same region of chromosome 12q13 as the location of the K3 and K12 genes. Heterozygous missense mutations in the genes that code for K3 and K12 have been discovered in affected individuals,15, 16 which are likely to be dominant negative or gain-of-function mutations that result in instability of the corneal epithelium.

ANIRIDIA, PETER’S ANOMALY, AUTOSOMAL DOMINANT KERATITIS Some cellular processes require a level of protein production that ­results from the expression of both copies of a particular gene. Such proteins may be involved in a variety of biological processes. Certain disorders are caused by the disruption of one copy of a gene that reduces the protein level by half. Such a reduction is also called “haploinsufficiency.” Mutations in the PAX6 gene are responsible for aniridia, Peter’s anomaly, and autosomal dominant keratitis.17–19 Most of the mutations responsible for these disorders alter the paired-box sequence within the gene (Fig. 1-2-2) and result in inactivation of one copy of the PAX6 gene. The paired-box sequence is an important element that is necessary for the regulatory function of the protein.20 Losing half the normal pairedbox sequence, and probably other regulatory elements within the gene, appears to be the critical event that results in the associated ocular disorders.21 The protein plays an important role in ocular development, presumably by regulating the expression of genes that are involved in embryogenesis of the eye. A reduction in the amount of active gene product alters the expression of these genes, which results in abnormal development. The genes that code for the lens crystallin proteins are one class of genes developmentally regulated by the PAX6 protein.22

   TABLE 1-2-1  SELECTED GENES RESPONSIBLE FOR HEREDITARY OPHTHALMIC DISEASES–cONT’D

   TABLE 1-2-1  SELECTED GENES RESPONSIBLE FOR HEREDITARY OPHTHALMIC DISEASES Disease

Gene

Location

Disease

Gene

Cornea

Dominant corneal dystrophies (lattice, macular, Avellino, ReisBücklers’) Meesmann’s corneal dystrophy Cornea plana (type 2 AR) Fuchs’ endothelial corneal dystrophy

Keratoepithelin (5q31)

Neuroophthalmic

Leber’s optic atrophy Kjer AD optic atrophy Kearns-Sayre syndrome Congenital extraocular fibrosis Duane’s radial ray ­syndrome

Mitochondrial proteins OPA1 (3q28) Mitochondrial DNA ­deletions ARIX (PHOX2A) (12cen) SALL4 (20q13)

Rieger’s syndrome Iridodysgenesis Aniridia Peter’s anomaly Juvenile open-angle glaucoma Adult open-angle glaucoma Congenital glaucoma Glaucoma/nail-patella syndrome Normal-tension glaucoma

PITX2 (4q25) FOXC1 (6p25) PAX6 (11q13)

Zonular pulverulent cataract

Connexin 50 (1q21) γ-C-crystallin (2q35) Connexin 46 (13q11) γ-D-crystallin (2q33) γ-E-crystallin (2q33) BFSP2 (3q21–q22) α-A-crystallin (21q22) α-B-crystallin (11q21)

Anterior segment

Lens

Nuclear cataract Coppock cataract Dominant congenital cataract Congenital posterior Polar cataract Congenital progressive Polymorphic cataract Zonular sutural cataract Presenile cataract Cerulean-blue dot Dominant pulverulent Retina

Retinoblastoma Tritanopia X-linked color blindness Retinitis pigmentosa (AD)

Retinitis pigmentosa (AR)

Retinitis pigmentosa (X-linked) Retinitis pigmentosa (digenic) Usher’s syndrome type I Congenital stationary night blindness Oguchi’s disease Sorsby’s macular dystrophy Stargardt’s disease Norrie’s disease Leber’s congenital amaurosis Gyrate atrophy Abetalipoproteinemia Refsum’s disease Ocular albinism

Keratin K3 (12q12–q13) KERA (keratocan) (12q) Collagen type VIII (1p34)

AD, Autosomal dominant; AR, autosomal recessive.

KERATOEPITHEILIN GENE

MYOC (TIGR) (1q25) CYP1B1 (2p16) LMX1B (9q34) OPTN (10p15)

secretory signal

recognition sequence for integrins

homologous domains D1

D2

D3

Arg124 Cys (lattice type 1) Arg 124 His (Avellino)

D4

1.2 Molecular Genetics of Selected Ocular Disorders

Location

Arg 555 Trp (Groenouw 2) Arg 555 Glu (Reis-Bücklers’ dystrophy)

MIP AQP0 (12q) β-A3-crystallin (17q11) LIM2 (19q) β-B2-crystallin (22q) β-B1-crystallin (22q) RB1 (13q14) Blue opsin (7q22) Red cone opsin (Xq22–q28) Green cone opsin (Xq22–q28) Rhodopsin (3q21) RPI (8p11) RGR (10q23) ROMI (11q13) NRL (14q11) CRX (19q13) PRKCG (19q13) RPE65 (1p31) ABCA4 (1p21) CRBI (1q31) USH2A (1q41) MERTK (2q14) SAG (arrestin) (2q37) Rhodopsin (3q21) PDE6B (4p16) CNGI (4p14) PDE6A (5q31) TULPI (6p21) RGR (10q23) NR2E3 (15q23) RLBPI (15q26) RPGR (Xp11) RP2 (Xp11) RDS (peripherin) (6p21) ROMI (11q13) Myosin VIIa (11q13) Rhodopsin (3q21) Rod transducin (alpha subunit) (3p21) Rod cGMP-phosphodiesterase (4p16) Rod arrestin (2q37) Rhodopsin kinase (13q34) TIMP3 (22q12) ABCR4 (1p21) Norrie’s disease gene (Xp11) RPE65 (1p31) Guanylate cyclase (17p13) Ornithine amino­transferase (10q26) Microsomal triglyceride transfer protein (4q22) Phytanoyl-CoA alpha-­hydroxylase (10pter) OA1 (Xp22)

Fig. 1-2-1  Keratoepithelin gene. Arrows point to the location of the reported mutations.

PAX6 GENE

ATG 5a

1

2

200 bp

3 4 5

TAA

6

7

paired box

8

9

10 11

homeobox

12

13

PST domain

Fig. 1-2-2  The PAX6 gene. (Data with permission from Glaser T, et al. PAX6 gene mutations in aniridia. In: Wiggs JL, ed. Molecular genetics of ocular disease. New York: Wiley-Liss; 1995:51–82.)

The clinical disorders caused by mutations in PAX6 exhibit extensive phenotypic variability. Similar mutations may give rise to aniridia, Peter’s anomaly, or autosomal dominant keratitis.23 Variation in the phenotype associated with a mutation is termed “variable expressivity” and is a common feature of disorders that arise from ­haploinsufficiency. Possibly, the variability of the mutant phenotype results from the ­random activation of downstream genes that occurs when only half the required gene product is available.

RIEGER’S SYNDROME Rieger’s syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye.24 Typical clinical findings may include posterior embryotoxon, iris hypoplasia, iridocorneal adhesions, and corectopia. Approximately 50% of affected individuals develop a high-pressure glaucoma associated

11

1 Genetics

with severe optic nerve disease. The cause of the glaucoma associated with this syndrome is not known, although anomalous development of the anterior chamber angle structures is usually found.25, 26 Genetic heterogeneity of Rieger’s syndrome is indicated by the variety of chromosomal abnormalities that have been associated with the condition including deletions of chromosome 427 and deletions of chromosome 13.28 Genes for Rieger’s syndrome have been located on chromosomes 4q25,29 13q14,28 and 6p25.30 Iris hypoplasia is the dominant clinical feature of pedigrees linked to the 6p25 locus, whereas pedigrees linked to 4q25 and 13q14 demonstrate the full range of ocular and ­systemic abnormalities found in these patients. The genes located on chromosomes 4q25 and 6p25 have been identified. The chromosome 4q25 gene (PITX2) codes for a bicoid homeobox transcription factor.31 Like PAX6, this gene is expressed during eye ­development and is probably involved in the ocular developmental ­processes.32 The chromosome 6p25 gene, FOXC1 (also called FKHL7), is a member of a forkhead family of regulatory proteins.33 FOXC1 is expressed during ocular development, and mutations alter the dosage of the gene product.34 There is some indication that the FOXC1 protein and the PITX2 protein interact during ocular development.35 The identification of other genes responsible for Rieger’s syndrome and anterior segment dysgenesis is necessary to determine whether these genes are part of a common developmental pathway or represent redundant ­functions necessary for eye development.

without ­cytochrome P-4501B1 (mouse knock-out) exhibit ocular developmental abnormalities that may also be modified by tyrosinase.57, 58 Humans with CYP1B1 mutations also exhibit variable expressivity, but tyrosinase has not been shown to contribute to the phenotypic ­variation.59, 60

NONSYNDROMIC CONGENITAL CATARACT At least one third of all congenital cataracts are familial and are not associated with other abnormalities of the eye or with systemic ­abnormalities. Two forms of familial cataract inherited as autosomal dominant traits have been shown to be caused by abnormalities in human lens crystallin proteins. Cerulean cataracts have peripheral bluish and white opacifications in concentric layers. One form of congenital cerulean cataract was mapped to a region of chromosome 22 that contains three β-crystallin genes.61 Affected individuals have been found to have a chain-terminating mutation, as well as missense mutations in one of the β-crystallin genes, CRYBB2.62, 63 Phenotypic heterogeneity is also indicated by CRYBB2 mutations causing ­ Coppock-like cataract.64 The human γ-crystallin genes constitute a multigene family that con­ tains at least seven highly related members. All seven of the γ-crystallin MYOCILIN/TIGR PROTEIN GENE

JUVENILE GLAUCOMA Primary juvenile open-angle glaucoma is a rare disorder that develops during the first two decades of life. Affected patients typically present with a high intraocular pressure, which ultimately requires surgical therapy.36, 37 Juvenile glaucoma may be inherited as an autosomal dominant trait, and large pedigrees have been identified and used for genetic linkage analysis. One gene responsible for this condition, MYOC (also known at TIGR, trabecular meshwork glucocorticoid response protein), codes for the myocilin protein and is located on chromosome 1q23 (GLC1A).38–41 Myocilin has been shown to be expressed in the human retina, ciliary body, and trabecular meshwork.42, 43 The protein has several functional domains, including a region homologous to a family of proteins called olfactomedins. Although the function of the protein and the olfactomedin domain is not known, nearly all the mutations associated with glaucoma have been found in the olfactomedin portion of the protein (Fig. 1-2-3).44, 45 Mutations in myocilin also have been associated with some cases of adult-onset primary open-angle glaucoma. It is unclear why mutations in this gene cause glaucoma and why some mutations cause juvenile-onset disease and others result in adult-onset disease. Patients with only one copy of the myocilin gene (because of chromosomal deletion removing the second copy of the gene) or ­without any functional myocilin (caused by homozygosity of a stop-codon polymorphism in the first part of the gene) do not develop glaucoma.46, 47 These results suggest that mutations in myocilin cause a gain-of-function or dominant negative effect rather than a loss-offunction or haploinsufficiency. Disruption of the myocilin gene in the mouse also supports this conclusion.48 Recent studies have indicated that mutant forms of myocilin form intracellular aggregates that result in cellular dysfunction.49

CONGENITAL GLAUCOMA

12

Congenital glaucoma is a genetically heterogeneous condition, with both autosomal recessive and autosomal dominant forms reported.50 Two genes responsible for autosomal recessive congenital glaucoma have been located in the human genome (GLC3A at 2p21 and GLC3B at 1p36).51 The responsible gene at the chromosome 2p21 location, CYP1B1, is a member of the cytochrome P-450 family of proteins (cytochrome P-4501B1).52 Mutations in CYP1B1 have been identified in patients with autosomal recessive congenital glaucoma from all over the world, but especially in areas where consanguinity is a custom.53 Responsible mutations disrupt the function of the protein, implying that a loss of function of the protein results in the phenotype.54 Recurrent mutations are likely to be the result of founder chromosomes that have been distributed to populations throughout the world.55, 56 Because the defects responsible for congenital glaucoma are predominantly developmental, cytochrome P-4501B1 must play a direct or indirect role in the development of the anterior segment of the eye. Mice

Schematic gene structure 368 364 347

leucine zipper 1 32

117

169

72

179

259

504aa

501

myosin (25%)

signal peptide

437

olfactomedin (40%)

Proposed protein structure 119 126

130

123

133 122

166

158

129

118

134

159

152

169

145

147

138

136

132

leucine

120

131

125

arginine

127

124 121

128

117

Fig. 1-2-3  Myocilin-trabecular meshwork glucocorticoid response (TIGR) protein gene. The myosin-like domain, the olfactomedin-like domain, and the leucine zipper are indicated. Amino acids altered in patients with juvenile- or adult-onset glaucoma are shown. (Data with permission from Orteto J, Escribano J, Coca-Prados M. Cloning and characterization of subtracted cDNAs from a human ciliary body library encoding TIGR, a protein involved in juvenile open angle glaucoma with homology to myosin and olfactomedin. FEBS Lett. 1997;413:349–53.)

RETINITIS PIGMENTOSA The molecular genetics of retinitis pigmentosa (RP) is exceedingly complex. The disease can exhibit sporadic, autosomal dominant, autosomal recessive, X-linked, or digenic inheritance. At least 32 genes are known

   Table 1-2-2  WEB-BASED RESOURCES FOR INHERITED HUMAN OCULAR DISORDERS NCBI

National Center for Biotechnology Information

http://www.ncbi.nlm.nih

OMIM

Online Mendelian Inheritance in Man

http://www.ncbi.nlm.nih

NEIBank

Expression databases

http://www.neibank.nei. nih.gov

RetNet

Retinal disease genes

http://www.sph.uth.tmc. edu/Retnet/

LENSNET

Lens disease genes

http://www.ken.mitton. com/ern/lensbase.html

GENES and DISEASE

Systemic inherited disorders

http://www.ncbi.nlm. nih.gov

Center for Medical Genetics

Gene and genetic marker maps

http://www.research. marshfieldclinic.org/ genetics

UCSC

Human Genome Sequence

http://www.genome. ucsc.edu

to be associated with RP, and a number of genes have been mapped but not yet found.71 Most of these genes are expressed preferentially in the retina, but some are expressed systematically. A useful resource listing genes responsible for various forms of retinal diseases, including retinitis pigmentosa, can be found at the RETNET website (http://www.sph. uth.tmc.edu/Retnet/). Mutations in rhodopsin can cause an autosomal dominant form of retinitis pigmentosa and provides an interesting example of how mutant proteins can interfere with normal cellular processes. Initially, one form of autosomal dominant retinitis pigmentosa was mapped to chromosome 3q24.72 Using a candidate gene approach, the rhodopsin gene was identified as the cause of the disease in affected families.73 Many of the first mutations detected in the rhodopsin protein were missense mutations located in the C-terminus of the gene (Fig. 1-2-4). To explore the pathogenic mechanisms of these mutations, transgenic mice were created that carried mutant copies of the gene.74 Histopathological studies of these mice showed an accumulation of vesicles that contained rhodopsin at the junction between the inner and outer segments of the photoreceptors. The vesicles probably interfere with the normal regeneration of the photoreceptors, thus causing photoreceptor degeneration. Because the C-terminus of the nascent polypeptide is involved in the transport of the maturing protein, the accumulation of rhodopsinfilled vesicles is likely to result from abnormal transport of the mutant rhodopsin to the membranes of the outer segments. Null mutations (mutations that cause a prematurely shortened ­or truncated protein) also have been found in the rhodopsin gene in patients who have autosomal recessive retinitis pigmentosa (see Fig. 1-2-4).75 Mutations responsible for recessive disease typically cause a loss of biological activity, either because they create a defective protein product that has little or no biological activity or because they interfere with the normal expression of the gene (regulatory mutations). Most individuals heterozygous for autosomal recessive disorders are clinically normal. Unlike the missense mutations responsible for the dominant form of the disease, the null mutations in rhodopsin produce an inactive protein that is not destructive to the cell. Null mutations result in retinitis pigmentosa only when they are present in both copies of the gene. Mutations in just one copy of the gene (heterozygous individuals) do not have a clinically detectable phenotype. Retinitis pigmentosa can be inherited as a digenic trait.76 A trait caused by digenic inheritance requires mutations in each of two independent genes simultaneously. Digenic inheritance is an example of the complex interactions that occur between multiple gene products in polygenic ­inheritance (see later). In three families affected by retinitis pigmentosa mutation, analysis of the peripherin gene and the ROM1 gene showed that affected individuals had specific mutations in both genes. Individuals who had a mutation in one copy of either gene were unaffected by the disease (see Fig. 1-2-4). Mutant copies of ROM1 and peripherin also may cause autosomal dominant forms of retinitis ­pigmentosa.77, 78

1.2 Molecular Genetics of Selected Ocular Disorders

genes have been assigned to chromosome 2q34-q35.65, 66 Of the genes mapped to this region, only two of them, γ-C and γ-D, encode abundant proteins. Two of the genes, γ-E and γ-F, are pseudogenes, which means they are not expressed in the normal lens.67 A pedigree affected by the Coppock cataract, a congenital cataract that involves primarily the embryonic lens, was shown to be linked genetically to the region that contains the γ-crystallin genes.68 In individuals affected by the Coppock cataract, additional regulatory sequences have been found in the promoter region of the γ-E pseudogene.69 This result implies that the γ-E pseudogene is expressed in affected individuals and that expression of the pseudogene is the event that leads to cataract formation. A number of other genes have been associated with hereditary cataract (see Table 1-2-1).70 A useful collection of mutations and phenotypes can be found at LENSNET (http://ken.mitton.com/ern/lensbase. html) and OMIM (http://www.ncbi.nlm.nih.gov) (Table 1-2-2).

HUMAN RHODOPSIN MUTATIONS Autosomal dominant

Autosomal recessive C

C

N

N G90D

P23H

K296E K296M

A292E

Fig. 1-2-4  Human rhodopsin mutations. The red circles indicate the amino acids altered by mutations in the gene in patients who have autosomal dominant retinitis pigmentosa. The translational stop site that results from a nonsense mutation is indicated as a red circle in a patient who has autosomal recessive retinitis pigmentosa.

13

1

These results suggest that some mutant forms of peripherin and ROM1 cause retinitis pigmentosa in a digenic pattern, while other mutations ­independently cause autosomal dominant forms of the disease.

Genetics

STARGARDT’S DISEASE Stargardt’s disease is characterized by progressive bilateral atrophy of the macular retinal pigment epithelium (RPE) and neuroepithelium, with the frequent appearance of orange-yellow flecks distributed around the macula. The choroid is characteristically dark on fluorescein angiography. The disease results in a loss of central acuity that may have a juvenile to adult onset and is inherited as an autosomal recessive trait. Inactivation of both copies of the responsible gene is necessary to cause the disease. Mutations in a photoreceptor cell-specific ATP-binding transporter gene (ABCR) have been found in affected patients.79 Most of the mutations reported to date are missense mutations in conserved amino acid positions.80 The retina-specific ABC transporter responsible for Stargardt’s disease is a member of a family of transporter proteins and is expressed in rod photoreceptors, which indicates that this protein mediates the transport of an essential molecule either into or out of photoreceptor cells. Accumulation of a lipofuscin-like substance in Stargardt’s disease may result from inactivation of this transporter protein. Patients who have age-related macular degeneration (ARMD) also may demonstrate an accumulation of lipofuscin-like substance in the RPE and progressive atrophy of the macular RPE.81 Recently, two major genetic factors contributing to ARMD have been identified, Complement Factor H and a novel gene, LOC387715.

X-LINKED JUVENILE RETINOSCHISIS Retinoschisis is a maculopathy caused by intraretinal splitting; the defect most likely involves retinal Müller cells.82 Retinoschisis is inherited as an X-linked recessive trait. X-linked recessive disorders, like autosomal recessive disorders, are caused by inactivating mutations. Because men have only one X chromosome, one mutant copy of a gene responsible for an X-linked trait results in the disease. Usually, women are heterozygous carriers of recessive X-linked traits and do not demonstrate any clinical abnormalities. Mutations in a gene located in the retinoschisis region on the X chromosome,83 and expressed in the retina, have been found in a protein that is implicated in cell–cell interaction and may be active in cell adhesion processes during retinal development. Mutational analysis of the retinoschisis gene (XLRS1) in affected individuals from nine unrelated families showed one nonsense, one frameshift, one splice acceptor, and six missense mutations.84 Presumably, these mutations all result in an inactive protein product.

NORRIE’S DISEASE Norrie’s disease is an X-linked disorder characterized by progressive, bilateral, congenital blindness associated with a dysplastic process of the retina that has been referred to as a “pseudoglioma.” The disease also may be associated with mental retardation and hearing defects.85 Norrie’s disease is inherited as an X-linked recessive trait, and a locus on the X chromosome has been identified using genetic linkage analysis.86 Subsequent cloning and characterization of the Norrie’s disease gene showed that the gene product has a tertiary structure similar to transforming growth factor-β.87–89 Norrie’s disease is a member of the familial exudative vitreoretinopathy (FEVR) syndromes, which are genetically heterogeneous inherited blinding disorders of the retinal vascular system, and to date three other loci have been mapped.90 Mutations in the Norrie’s disease gene have been found in a small subset of patients with severe retinopathy of prematurity (ROP), although defects in this gene do not appear to be a major factor in ROP.91

SORSBY’S MACULAR DYSTROPHY

14

Sorsby’s macular dystrophy is an autosomal dominant disorder characterized by macular edema, hemorrhages, and exudate.92 The disease typically begins at about 40 years of age. Several missense mutations in the gene that codes for tissue inhibitor metalloproteinase-3 (TIMP3) have been found in affected individuals.93 This protein is involved in remodeling of the extracellular matrix. Inactivation of the protein may lead to an increase in activity of the metalloproteinase, which may

contribute to the pathogenesis of the disease. TIMP-3 mutations do not appear to significantly contribute to ARMD.94

GYRATE ATROPHY Hyperornithinemia results from deficiency of the enzyme ornithine ketoacid aminotransferase and has been shown to be the cause of gyrate atrophy, an autosomal recessive condition characterized by circular areas of chorioretinal atrophy.95 Mutations in the gene for ornithine ketoacid aminotransferase mapped to chromosome 10q26 have been associated with the disease in affected individuals.96 Most of the responsible mutations are missense mutations, which presumably result in an inactive enzyme. One mutation has been found in homozygous form in the vast majority of apparently unrelated cases of gyrate atrophy in Finland, an example of a founder effect that produces a common mutation in an isolated population. Identification of the enzyme defect responsible for this disease makes it an interesting candidate for gene therapy. Previous studies indicated that a lower ornithine level, achieved through a strict low-arginine diet, may retard the progression of the disease.97 Replacement of the abnormal gene, or genetic engineering to produce a supply of normal enzyme, may result in a reduction of ornithine levels without dietary restrictions.

COLOR VISION Defective red-green color vision affects 2–6% of men and results from a variety of defects that involve the color vision genes. In humans, the three cone pigments – blue, green, and red – mediate color vision. Each visual pigment consists of an integral membrane apoprotein bound to the chromophore 11-cis retinal. The genes for the red and green pigments are located on the X chromosome, and the gene for the blue pigment is located on chromosome 7. The X chromosome location of the red and green pigment genes accounts for the X-linked inheritance pattern observed in red or green color vision defects. The common variations in red or green color vision are caused by the loss of either the red or the green cone pigment (dichromasy) or by the production of a visual pigment with a shifted absorption spectrum (anomalous trichromasy). A single amino acid change (serine to alanine) in the red pigment gene is the most common color vision variation. Among White men, 62% have serine at position 180 in the red pigment protein, and 38% have alanine in this position. Men who carry the red pigment with serine at position 180 have a greater sensitivity to long-wavelength radiation than do men who carry alanine at this position.98 The red and green pigment genes are organized in a head-to-tail tandem array, and the DNA sequence of the genes is 98% identical. Such an arrangement of repetitive sequences predisposes to unequal recombination that may generate variant arrays in which entire repeat units are gained or lost. Unequal recombination also may generate genes that are red and green hybrids.99 These hybrid genes are the cause of anomalous trichromasy. Most X chromosomes carry more than one green pigment gene, and occasionally, some of the green pigment genes are not expressed. It is possible, therefore, to have an abnormal green pigment gene but have normal color vision (Fig. 1-2-5). Complete absence of the red and green pigment genes results in blue cone monochromasy. Two different types of mutations have been identified as the cause of this condition. First, unequal recombination may reduce the number of red and green pigment genes to one or two genes that are dysfunctional because of point mutations.100 The second type of mutation that results in this condition is a deletion of the X chromosome, which removes the locus control region that allows for normal expression of the red and green pigment genes. In this case, the red and green pigment genes are normal but are not expressed because of the absence or inactivity of the locus control region (see Fig. 1-2-5).101

RETINOBLASTOMA A gene responsible for the childhood eye tumor retinoblastoma was identified in 1986 on chromosome 13q14.102 The gene product is involved in regulation of the cell cycle. Absence of this protein in an embryonic retinal cell results in the uncontrolled cell growth that eventually produces a tumor. Susceptibility to hereditary retinoblastoma is inherited as an autosomal dominant trait. Mutations in the retinoblastoma gene result in underproduction of the protein product or production of an inactive protein product. A retinal cell that has only one mutant copy of

RED AND GREEN PIGMENT GENES

INHERITANCE OF RETINOBLASTOMA

1.2

Normal trichromats retina n

tumor

gametes

n 50% n

50%

retina

Dichromats and anomalous trichromats

gametes

10% no second hit

90% second hit

normal n

affected n

tumor

Fig. 1-2-6  Inheritance of retinoblastoma. Individuals who inherit a mutation in the retinoblastoma gene are heterozygous for the mutation in all cells of the body. The “second hit” to the remaining normal copy of the gene occurs in a developing retinal cell and leads to tumor formation (see text for explanation).

Blue-cone monochromats

n red locus control region

retina

Molecular Genetics of Selected Ocular Disorders

alanine 180 or serine 180

green

Fig. 1-2-5  Red and green pigment genes. Shown for individuals who have normal and variant red and green color vision. (Data with permission from Nathans J. In the eye of the beholder: visual pigments and inherited variation in human vision. Cell. 1994;78:357–60.)

the retinoblastoma gene does not become a tumor. However, inactivation of the remaining normal copy of the retinoblastoma gene is very likely in at least one retinal cell out of the millions present in each retina. Among individuals who inherit a mutant copy of the retinoblastoma gene, 90% sustain a second hit to the remaining normal copy of the gene and develop a tumor (Fig. 1-2-6).103 Fifty per cent of the offspring of individuals affected by hereditary retinoblastoma inherit the mutant copy of the gene and are predisposed to develop the tumor. Approximately 10% of individuals who inherit a mutant copy of the gene do not sustain a second mutation and do not develop a tumor. The offspring of these “carrier” individuals also have a 50% chance of inheriting the mutant copy of the retinoblastoma gene (see Fig. 1-2-6).

ALBINISM Autosomal recessive diseases often result from defects in enzymatic proteins. Albinism is the result of a series of defects in the synthesis of melanin pigment.104 Melanin is synthesized from the amino acid tyrosine, which is first converted into dihydroxyphenylalanine through the action of the copper-containing enzyme tyrosinase. An absence of tyrosinase results in one form of albinism. Mutations in the gene that codes for tyrosinase are responsible for tyrosinase-negative ocular cutaneous albinism. Most of the mutations responsible for this disease cluster in the binding sites for copper and disrupt the metal ion– protein interaction necessary for enzyme function.105 Both copies of the gene for tyrosinase must be mutated before a significant interruption of melanin production occurs. Heterozygous individuals do not have

a clinically apparent phenotype, which suggests that one functional copy of the gene produces sufficient active enzyme for the melanin level to be phenotypically normal (Fig. 1-2-7).

LEBER’S OPTIC NEUROPATHY Mutations in mitochondrial DNA are an important cause of human disease. Disorders that result from mutations in mitochondrial DNA demonstrate a maternal inheritance pattern. Maternal inheritance differs from mendelian inheritance, in that men and women are affected equally, and only affected females transmit the disease to their offspring. The characteristic segregation and assortment of mendelian disorders depend on the meiotic division of maternal and paternal chromosomes found in the nucleus of cells. In contrast, mitochondrial DNA is derived from the maternal egg and replicates and divides with the cell cytoplasm by simple fission. A mutation that occurs in mitochondrial DNA is present in all cells of the organism, which includes the gametes. Female eggs have abnormal mitochondria that may be passed to offspring. Sperm contain mitochondria but do not transmit mitochondria to the fertilized egg. A man who carries a mitochondrial DNA mutation may be affected by the disease, but he cannot transmit the disease to his offspring. Leber’s hereditary optic neuropathy was one of the first diseases to be recognized as a mitochondrial DNA disorder.106 In familial cases of the disease, all affected individuals were related through the maternal lineage, consistent with inheritance of human mitochondrial DNA. Patients affected by Leber’s hereditary optic neuropathy typically present in midlife with acute or subacute, painless, central vision loss that results in a permanent central scotoma and loss of sight. The manifestation of the disease varies tremendously, especially with respect to onset of visual loss and severity of the outcome. The eyes may be affected simultaneously or sequentially; the disease may progress rapidly, over a period of weeks to months, or slowly over several years; within a family, the disease may also vary among affected members. Several factors contribute to the variable phenotype of this condition. Certain mutations are associated with more severe disease. For example, the most severely affected patients who carry the 11 778 bp mutation may have no light perception, whereas the most severely affected patients who carry the 3460 bp mutation may retain light perception.107, 108 Another

15

1

METABOLISM OF TYROSINE TO PRODUCE MELANIN

Genetics

H 2O

O2

NH3�

NH3�

CH2CHCOO�

CO2

CH2CHCOO�

CH2CH2NH3� melanin OH

OH

dihydrobiopterin

OH

OH

dihydroxyphenylalanine

dopamine

tetrahydrobiopterin tyrosine

tyrosine hydroxylase

Fig. 1-2-7  Metabolism of tyrosine to produce melanin. In the final step, dopamine is converted into an indole derivative that condenses to form the highmolecular-weight pigment melanin.

important factor that affects the severity of the disease is the heteroplasmic distribution of mutant and normal mitochondria. Not all mitochondria present in diseased tissue carry DNA mutations. During cell division, mitochondria and other cytoplasmic organelles are distributed arbitrarily to the daughter cells. Consequently, the daughter cells are likely to have unequal numbers of mutant and normal mitochondria (Fig. 1-2-8). Because the diseased mitochondria are distributed to developing tissues, some tissues accumulate more abnormal mitochondria than others. Hence, some individuals have more abnormal mitochondria in the optic nerve and develop a more severe optic neuropathy.

CONGENITAL FIBROSIS SYNDROMES Congenital fibrosis of the extraocular muscles and Duane’s syndrome are inherited forms of congenital fibrosis and strabismus. At least five genes can contribute to these conditions,109 with the ARIX/PHOX2A genes causing congenital fibrosis of extraocular muscles type 2110 and the SALL4 gene causing Duane’s radial ray syndrome.111 Interestingly, the products of both these genes participate in developmental processes, suggesting that these syndromes are developmental defects of the ocular muscles or the nerve nuclei controlling the muscles.

HETEROPLASMY IN MITOCHONDRIA nucleus normal mitochondrion mutant mitochondrion

cell division

replication and cell division

AUTOSOMAL DOMINANT OPTIC ATROPHY Of the inherited optic atrophies, autosomal dominant optic atrophy of the Kjer type is the most common. This disease results in a progressive loss of visual acuity, centrocecal scotoma, and bilateral temporal atrophy of the optic nerve. The onset is typically in the first two decades of life. The condition is inherited as an autosomal dominant trait with variable expressivity, and a locus was mapped to chromosome 3q28-q29.112 Mutations in a gene located in this region, OPA1, have been found in a number of affected families.113 The gene product is a dynamin-related GTPase that is targeted to mitochondria and may function to stabilize mitochondrial membrane integrity. It is interesting that this gene and the gene responsible for another optic atrophy, Leber’s hereditary optic atrophy (see earlier), both function in the mitochondria, emphasizing the role of mitochondria in optic nerve function. A polymorphism in the OPA1 gene may also be associated with low-tension or normal­tension glaucoma.114

COMPLEX TRAITS

16

Human phenotypes inherited as polygenic or “complex” traits do not follow the typical patterns of mendelian inheritance. Complex traits generally are not rare but are commonly found in the human population. Multiple genes are likely to contribute to the expression of the disease phenotype. Some genes render an individual susceptible to the disease phenotype, whereas other genes or environmental conditions may influence the full expression of the disease phenotype. Secondary genes responsible for modulation of the expression of a specific genetic mutation may be referred to as “modifier genes”; these modifier genes may be inherited completely independently from the gene ­directly

Fig. 1-2-8  Heteroplasmy in mitochondria. Daughter cells that result from the division of a cell that contains mitochondria with mutant DNA may contain unequal numbers of mutant mitochondria. Subsequent divisions lead to a population of cells with different numbers of normal and abnormal mitochondria.

r­ esponsible for the disease trait. Not every individual who inherits the mutation responsible for the disease trait also inherits a form of the modifier gene that is required for full expression of the disease. The digenic inheritance of retinitis pigmentosa that occurs via certain mutant alleles of peripherin and ROM1 is an example of the simplest form of polygenic inheritance (see earlier). Some patients with Bardet-Biedle syndrome demonstrate triallelic inheritance indicating that three mutant alleles are required for disease expression.115 Certain conditions may require multiple genes or a combination of different genes and environmental ­conditions to be manifest. For example, recently a single nucleotide polymorphism (SNP) in the complement factor H gene and sequence variants in the LOC37718 gene have been shown to be major genetic risk factors for ARMD,116–119 and combined with smoking the risk is increased.120 Primary open-angle glaucoma is another disease with complex inheritance, and recently one gene that contributes to this disease has been shown to be a modifier gene that can influence the severity of the phenotype.121

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1.2 Molecular Genetics of Selected Ocular Disorders

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17

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92. Sorby A, Mason MEJ, Gardner N. A fundus dystrophy with unusual features (late onset and dominant inheritance of a central retinal lesion showing oedema, haemorrhage and exudates developing into generalized choroidal atrophy with massive pigment proliferation). Br J Ophthalmol. 1949;33:67–97. 93. Weber GHF, Vogt G, Pruett RC, et al. Mutations in the tissue inhibitor metalloproteinase-3 (TIMP-3) in patients with Sorsby’s fundus dystrophy. Nat Genet. 1994;8: 352–6. 94. Li Z, Clarke MP, Barker MD, McKie N. TIMP3 mutation in Sorsby’s fundus dystrophy: molecular insights. Expert Rev Mol Med. 2005;7:1–15. 95. Kennaway NG, Welber RG, Buist NRM. Gyrate atrophy of the choroid and retina with hyperornithinemia; biochemical and histologic studies and response to vitamin B6. Am J Hum Genet. 1980;32:529–41. 96. Mitchell GA, Brody LC, Sipila I, et al. At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. US Natl Acad Sci. 1989;86:197–201. 97. Kaiser-Kupfer MI, deMonasterio FM, Valle D, et al. Gyrate atrophy of the choroid and retina: improved visual function following reduction of plasma ornithine by diet. Science. 1980;210:1128–31. 98. Merbs SL, Nathans J. Absorption spectra of human cone pigments. Nature. 1992;356:433–5. 99. Nathans J, Merbs SL, Sung C-H, et al. Molecular genetics of human visual pigments. Annu Rev Genet. 1992;26:403–24. 100. Nathans J, Maumenee IHG, Zrenner E, et al. Genetics heterogeneity among blue-cone monochromats. Am J Hum Genet. 1993;53:987–1000. 101. Winderickx J, Battisti L, Motulsky AG, et al. Selective expression of human X chromosome-linked green opsin genes. Proc Natl Acad Sci USA. 1992;89:9710–4. 102. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–6. 103. Knudson AG Jr. Genetics of human cancer. Annu Rev Genet. 1986;20:231–51. 104. Spritz RA. Molecular genetics of oculocutaneous ­albinism. Hum Mol Genet. 1994;3:1469–75. 105. Spritz RA, Strunk K, Giebel LB, et al. Detection of mutations in the tyrosinase gene in a patient with type 1A oculocutaneous albinism. N Engl J Med. 1990;322: 1724–8. 106. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic ­neuropathy. Science. 1988;242:1427–30.

107. Johns DR, Smith KH, Savino PJ, et al. Leber’s hereditary optic neuropathy. Clinical manifestations of the 15257 mutation. Arch Ophthalmol. 1993;110:981–6. 108. Johns DR, Smith KH, Miller NR. Leber’s hereditary optic neuropathy����������������������������������������� . Clinical manifestations of the 3460 mutation. Arch Ophthalmol. 1992;110:1577–81. 109. Engle EC. (2006) The genetic basis of complex strabismus. Pediatr Res. 59:343–8. 110. Nakano M, Yamada K, Fain J, et al. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet. 2001;29:315–20. 111. Al-Baradie R, Yamada K, St Hilaire C, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL ­family. Am J Hum Genet . 2002;71:1195–9. 112. Votruba M, Moore AT, Bhattacharya SS. Genetic refinement of dominant optic atrophy (OPA1) locus to within a 2 cM interval of chromosome 3q. J Med Genet. 1997;34:117–21. 113. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26:211–5. 114. Aung T, Ocaka L, Ebenezer ND, et al. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet. 2002;110:52–6. 115. Badano JL, Leitch CC, Ansley SJ, et al. Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature. 2006;439:326–30. 116. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–9. 117. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement ­factor H polymorphism and age-related macular ­degeneration. Science. 2005;308:421–4. 118. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–21. 119. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing ­independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–36. 120. Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet. 2006;78:852–64. 121. Hauser MA, Allingham RR, Linkroum K, et al. Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2006;47:2542–6.

PART 1 GENETICS

Genetic Testing and Genetic Counseling

1.3

Janey L. Wiggs

DNA-BASED GENETIC TESTING The use of molecular tools to demonstrate causative DNA mutations and identify individuals at risk for an inherited condition is called DNAbased diagnosis.1 The goal of genetic diagnosis is early recognition of a disease so that intervention can be undertaken to prevent or reverse the disease process.2 Two general approaches have been used to detect mutations in genes. The indirect approach uses genetic linkage analysis,3 and the direct approach identifies specific changes in DNA sequence. A protocol for clinical genetic testing is outlined in Fig. 1-3-1. A first step is the characterization of a patient with clinical findings suggesting a diagnosis that could be confirmed by genetic testing. Determining if there is a family history of the disease and drawing a pedigree is an important next step. If the family pedigree supports a mendelian inheritance pattern the next step is to use literature information and electronic databases to determine if a gene has been genetically mapped to a chromosomal region (genetic locus), and if the gene has been identified within the locus. Indirect testing can be performed if the gene has been mapped but not identified, and if the gene has been identified and the sequence is known, the gene can be screened using direct testing for disease-causing mutations. The family history may not support an autosomal dominant, autosomal recessive, or X-linked inheritance pattern and in this case, the next step would be to inspect the pedigree for evidence of a maternal inheritance pattern that would support a diagnosis of a mitochondrial DNA disorder. A mitochondrial DNA disorder caused by mutations in mitochondrial DNA would be transmitted only by the mother, but both males and females can be affected. If the pedigree follows this type of inheritance pattern then screening of mitochondrial DNA should be considered. If a “clustering” of the disease is present in the family, but there is no evidence of an identifiable inheritance pattern, then screening of genetic risk factors that contribute to complex traits should be considered. Genetic counseling (see below) will be helpful to avoid risk and to determine the chance that other family members will be affected (recurrence risk). For any other possible outcomes, genetic counseling can help the physician and patient understand the genetic risks associated with the disease.

Indirect Testing Using Linkage Analysis

Linkage analysis can be used to diagnose any genetically mapped disorder. Segregation of genetic markers known to be linked to a gene responsible for a condition is used to determine whether an individual has inherited a chromosome that carries the abnormal gene. This method does not require physical isolation and sequencing of the gene. Linkage analysis is useful when large genes with many possible mutations are responsible for a disease (Fig. 1-3-2). Several important disadvantages of this approach must be recognized. First, analysis of DNA from multiple family members is required to identify the markers that segregate with the abnormal chromosome in each affected pedigree. Second, not all genetic markers provide useful information for this analysis. Some individuals may not be “informative” at a particular marker, and a definitive demonstration of the abnormal chromosome may not be possible. Third, recombination may occur between the genetic markers used for testing and the disease-causing mutation. Although the markers selected for the analysis are physically close to the disease gene, a rare recombination event may occur and result in a misdiagnosis because of an apparent separation between the genetic markers that define the normal and abnormal chromosomes.

Approaches for Direct Mutation Testing

Direct mutation analysis uses a variety of techniques based on the DNA sequence of a gene to identify the specific base-pair change that is responsible for the disease. Because these methods do not rely on the segregation of genetic markers to identify the abnormal chromosome, multiple family members are not usually required. Also, potential errors caused by rare recombination events between the markers and the disease gene do not occur with this method, but there are several drawbacks to direct mutation analysis. The gene responsible for the disease must first be isolated and sequenced. Some genes are very large (e.g., the gene for retinoblastoma spans more than 200 000 kb of DNA sequence) and are difficult and time consuming to sequence. Multiple mutations and novel mutations present in a single gene may require complete sequencing of the DNA for each diagnostic test. Direct testing methods are generally dependent on the polymerase chain reaction (PCR) method (Fig. 1-3-3), which enzymatically makes many copies of the DNA (or RNA) that is needed for the analysis.4 PCR uses short oligonucleotide segments (usually 20–30 bp in length) that are positioned so that they flank the DNA sequence to be studied (usually an exon of a gene). A thermoresistant DNA polymerase is used to make copies of the DNA located between the oligonucleotide primers. After 30–50 reaction cycles, the copied DNA can be purified and used for additional tests to detect mutations. The entire gene can be screened by evaluating each exon, or other designated gene region, or individual regions of a gene can be examined. Failure of the PCR reaction is an important source of DNA-based testing errors. A biological sample from the patient is needed before direct testing can be performed. The inclusion of family members may help the evaluation, but unlike indirect testing, they are not absolutely required. DNA for testing can be obtained from a number of sources including blood samples, mouthwash samples or buccal swabs, archived pathology specimens, or from hair.5–7 Although genetic testing can be performed using DNA, RNA, or protein, DNA is the easiest to work with and most genetic tests use this as the starting material. For some very large disease genes, RNA-based methods may be preferable.8 Ideally, a protein-based assay would be useful for all genetic tests and could measure the reduction in protein function caused by the mutation. However, protein assays are time consuming and difficult to develop, and assaying directly for protein function would be a very inefficient diagnostic approach for most diseases. In some disorders, the majority of stricken individuals are affected by the same mutation. For example, mutations in mitochondrial DNA are a common cause of Leber’s hereditary optic neuropathy, however most patients have one of three mutations.9 Rather than evaluate the entire mitochondrial DNA sequence, it makes more sense to focus first on these three mutations. There are three general causes for mutation redundancy including a hot spot in the gene for mutations, a dependency of the disease on a specific type of abnormality in the protein product caused by only a few mutations, or a founder effect caused by a limited number of original mutations. Founder chromosomes have been iden­tified in patients with congenital glaucoma, and the CYP1B1 gene ­mutations on these chromosomes are found repeatedly in different populations.10 Mutation hot spots in the BIGH3 gene have been proposed to explain the involvement of only two sites in 50% of the diseasecausing mutations.11 If a limited number of mutations are found in affected individuals, then usually those mutations are tested for and if they are not found then the entire gene is evaluated.

19

1

DECISION FLOW DIAGRAM FOR GENETIC TESTING

GENETICS

Phenotype

? Maternal inheritance ? Genetic risk factor No

No

Clinical evaluation Laboratory tests Imaging studies

? Mendelian inheritance No

Yes

Yes

? Genetic loci identified

No

No

Yes

Risk avoidance

Genetic test

? Gene identified

Yes

Screen mitochondrial DNA

Recurrence risks

Indirect testing

Yes Direct testing

Fig. 1-3-1  Decision flow diagram for genetic testing.

DNA DIAGNOSIS USING GENETIC LINKAGE ANALYSIS

Generation I

2, 4

1, 3

affected female

II 2, 4 2, 3 1, 2 1, 4

3, 3

unaffected female unaffected male

III

1, 3

at risk female

Fig. 1-3-2  DNA diagnosis using genetic linkage analysis. This pedigree shows a mother and two daughters affected by a condition inherited as an autosomal dominant trait. Analysis carried out using a marker closely linked to the disease gene shows that allele 1 segregates with the condition. The daughter in the third generation has inherited this allele from her affected mother, which suggests that she has also inherited the disease gene and is therefore at risk for development of the condition.

20

In some patients, screening is directed to only a limited set of mutations, or possibly just one mutation. This situation arises when only a few mutations are responsible for the disease (as described above), or if a mutation has already been identified in a family member. If the mutation is known, different testing methods are used from those used where the mutation is not known. For known mutations, a variety of DNA sequence-specific methods have been devised including: testing for the presence or absence of a restriction enzyme site; allele-specific oligonucleotide hybridization; allele-specific PCR amplification; oligo­ nucleotide ligation assay; and, more recently, quantitative PCR approaches using TaqMan or related fluorescer-quencher methods.12–16 The general principles of the direct methods designed to screen for a single mutation are illustrated by the allele-specific hybridization test. This technique involves the synthesis of an oligonucleotide probe that hybridizes only to the mutated sequence. Such a probe, called an allelespecific oligonucleotide, is very useful when the DNA sequence that causes the genetic disease is known and the number of disease-causing mutations is limited (Fig. 1-3-4). Those patients whose DNA hybridizes with the normal sequence do not have the mutation, and those patients whose DNA hybridizes with the mutant sequence do have the mutation. Most inherited diseases are caused by many different mutations within the causative gene, and the mutation-specific tests described above cannot be used. To identify mutations in these patients, genetic

testing must search for mutations throughout the gene, including coding sequences and regulatory sequences. This type of comprehensive ­genetic screening typically requires PCR amplification of individual gene segments (usually exons) followed by a sequence detection method. The method most commonly used to detect sequence changes is direct sequencing. Screening methods for sequence changes such as singlestrand conformation polymorphism (SSCP)17, 18 or denaturing gradient gel electrophoresis (DGGE)19 can be useful, but generally if an abnormal sequence is detected it needs to be confirmed by direct sequencing. With the improved methods for direct sequencing, in many cases it is most efficient and economical to sequence the entire gene as the initial screen. Newer technology to detect DNA sequence changes includes DNA microarrays or chips.20–21 These chips contain short segments of DNA sequence that match all the normal and possible mutant ­sequences in a given gene. In a similar way to the allele-specific hybridization test described above, the patient DNA is labeled and hybridized to the array. DNA sequencing can also be performed on specially designed chips. Specific oligonucleotide sequencing primers are normal sequence and all possible mutations are used to construct the chip.

Mutation Validation

Novel DNA sequence changes are frequently found as a result of direct sequencing. These changes have not been previously associated with a disease phenotype, and they could be benign polymorphisms or causative mutations. Additional studies must be done before the sequence change can be designated as disease causing. Demonstrating that the mutant protein has an abnormal function would be best, but that is not always possible. Another approach is to create a transgenic animal that expresses the mutant protein, but this is also a difficult and timeconsuming procedure and would not be practical to test all new mutations for biological significance. If the sequence change affects a region of the gene that codes for a critical part of the protein then it is more likely to be a biologically significant change. If the sequence change affects a part of the protein that is evolutionarily conserved then it is also more likely to be disease associated. Screening a control group of individuals without evidence of the disease for the mutations should be done. The analysis should include at least 100 control patients (200 chromosomes) to be reasonably certain that the DNA sequence change is not a rare polymorphism. Segregation of the sequence change can be evaluated in family members (both affected and unaffected) if they are available. If the putative mutation is not present in 100 controls, if it segregates with the disease in a family, and it is located in an evolutionarily conserved portion of the protein that has a critical function it is probably a causative mutation. Studies that advance the knowledge of disease gene (and protein product) functions and development of disease-specific mutation databases will help make this task easier in the future.

POLYMERASE CHAIN REACTION (PCR)

1.3

Double-stranded DNA

Single-stranded DNA

Single-stranded DNA + oligonucleotides

Taq DNA polymerase DNA synthesis

Heat and denature

Genetic Testing and Genetic Counseling

Heat and denature

+ oligonucleotides

Taq DNA polymerase DNA synthesis

Fig. 1-3-3  Polymerase chain reaction (PCR). A DNA sample is heated to produce single-stranded DNA which is then allowed to hybridize with an excess of short oligonucleotide primers. Taq DNA polymerase is added and DNA synthesis proceeds elongating the primers to full-length strands. The newly synthesized doublestranded DNA is heated again, and the cycle repeats. At the end of the second cycle, four double-stranded copies have been formed. Cycles are repeated 30–50 times to generate sufficient DNA for further studies.

DNA DIAGNOSIS USING AN ALLELE-SPECIFIC OLIGONUCLEOTIDE risk for optic nerve disease related to glaucoma. Patients who possess the knowledge that their intraocular pressure is high can initiate treatment to reduce the pressure and lower their risk.22 A genetic test is useful if knowledge of the increased risk makes it possible to pursue treatment or behavior modification that can reduce the risk of developing the disease.23 Ideally, the useful outcome is treatment, but for many diseases this is not currently possible. Other outcomes that may be useful are to avoid environmental exposures that increase the risk and increase disease surveillance. Emerging evidence may suggest that screening macular degeneration patients for the complement factor H risk allele and the LOC387715 risk allele helps identify groups of ­patients that should avoid smoking.24–26

Individual A

B

Specificity and Sensitivity of Genetic Testing

C normal

mutation

Fig. 1-3-4  DNA diagnosis using an allele-specific oligonucleotide. Oligonucleotides specific for mutations are synthesized, as well as oligonucleotides that correspond to the normal sequence. DNA purified from individuals to be tested is placed on a small “dot” on a piece of filter paper and allowed to hybridize (base pair) with the specific oligonucleotides. Individuals A and B are normal, as their DNA hybridizes with the normal sequence only and not with the mutant sequence. Individual C’s DNA hybridizes with both the normal and the mutant sequences; hence, this individual has one normal gene and one mutant gene. Individual C is a carrier of the disease if it is a recessive condition or is affected by the disease if it is a dominant condition.

Population Screening

Individuals who are at high risk for a disease may benefit from screening for a disease-related risk factor. The screening test has merit if this knowledge enables actions that can modify the risk. For example, patients with higher than normal intraocular pressure are at increased

An ideal test should be both specific and sensitive. Sensitivity is the number of affected individuals that are positive for a test compared with the total number of affected individuals (including those that tested negative for the test). Specificity is the number of unaffected individuals that are negative for the test compared with the total number of unaffected individuals tested (including those that tested positive for the test) (Fig. 1-3-5). Serious failures of a diagnostic test are false-­positives (individuals without the disease who test positively) and false-negatives (individuals with the disease who test negatively). The most likely causes of false-positives for genetic tests are laboratory or clerical errors, and these are not common. In DNA testing falsenegative tests are more common and result from: genetic heterogeneity (more than one gene is responsible for the condition); PCR artifacts caused by primer binding site polymorphisms and deletions/insertions of the PCR primer sites; deletion/insertion of an entire exon or the entire gene that interferes with PCR amplification; preferential amplification of the smaller allele in a large insertion; and tissue mosaicism.27 Because a negative result cannot completely eliminate the possibility that a person carries a mutation in a causative gene, genetic counseling and patient and physician education are important components of genetic testing.

21

1

SPECIFICITY AND SENSITIVITY

GENETICS

Affected individuals

Unaffected individuals

Individuals positive for test

A

B

Individuals negative for test

C

D

Sensitivity

A A+C

Specificity

D B+D

Fig. 1-3-5.  Definition of sensitivity and specificity for a laboratory test. Sensitivity is defined as the number of affected individuals positive for the test (A) divided by the total number of affected individuals tested (A + C). Specificity is defined as the number of unaffected individuals negative for the test (D) divided by the total number of unaffected individuals tested (B + D).

CLIA Laboratories

Laboratories offering genetic testing must comply with regulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The Centers for Medicare and Medicaid Services administers CLIA, and requires that laboratories meet certain standards related to personnel qualifications, quality control procedures, and proficiency testing programs in order to receive certification. This regulatory system was put in place to encourage safe, accurate, and accessible genetic tests. In addition to ensuring that consumers have access to genetic tests that are safe, accurate, and informative, these policies encourage the development of genetic tests, genetic technologies, and the industry that ­produces these products. A number of CLIA-certified laboratories performing genetic testing for eye diseases exist in the United States. For a list of CLIA-certified laboratories participating in the National Eye Institute (NEI)-sponsored eyeGENE network, see the NEI website at: http://www.nei.nih.gov.

GENETIC COUNSELING Introduction

Genetic counseling has become an important part of any clinical medicine practice. In 1975, the American Society of Human Genetics adopted the following descriptive definition of genetic counseling:28 Genetic counseling is a communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to: (1) comprehend the medical facts including the diagnosis, probable course of the disorder, and the available management, (2) appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives, (3) understand the alternatives for dealing with the risk of recurrence, (4) choose a course of action that seems to them appropriate in their view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision, and (5) to make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.

Clinical Evaluation and Family History

22

An accurate diagnosis is the first step in productive genetic counseling. The patient−physician discussion of the natural history of the disease and of its prognosis and management is entirely dependent on the correct identification of the disorder that affects the patient. Risk assessment for other family members and options for prenatal diagnosis also depend on an accurate diagnosis. In some cases, appropriate genetic testing may help establish the diagnosis. Examination of other family members may be indicated to determine if a particular finding is hereditary. Sometimes this is incidental to the reason for referral. Findings such as fifth finger clinodactyly, although a part of many syndromes, may also be isolated hereditary traits without other medical implications.

A complete family history of the incidence of the disorder is necessary to determine the pattern of inheritance of the condition. The mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, or maternal) must be known to calculate the recurrence risk to additional family members, and it helps confirm the original diagnosis. For the record of family information, the gender and birth date of each individual and his or her relationship to other family members are indicated using the standard pedigree symbols. It is also helpful to record the age of onset of the disorder in question (as accurately as this can be determined). The pedigree diagram must include as many family members as possible. Miscarriages, stillbirths, and consanguineous parents are indicated. Occasionally, a patient may appear to be affected by a condition that is known to be inherited, but the patient is unable to provide a family history of the disease. Several important explanations for a negative family history must be considered before the conclusion is made that the patient does not have a heritable condition. First, the patient may not be aware that other family members are affected by the disease. Individuals frequently are reluctant to share information about medical problems, even with close family members. Second, many disorders exhibit variable expressivity or reduced penetrance, which means that other family members may carry a defective gene that is not expressed or results in only a mild form of the disease that is not readily observed. Third, false paternity may produce an individual affected by a disease that is not found in anyone else belonging to the acknowledged pedigree. Genetic testing can easily determine the paternity (and maternity) of any individual if blood samples are obtained from relevant family members. Fourth, a new mutation may arise that affects an individual and may be passed to offspring, even though existing family members show no evidence of the disease.

Risk Prediction Based on Inheritance

Once the diagnosis and family history of the disorder are established, risk prediction in other family members (existing and unborn) may be calculated. The chance that an individual known to be affected by an autosomal dominant disorder will transmit the disease to his or her offspring is 50%. This figure may be modified, depending on the penetrance of the condition. For example, retinoblastoma is inherited as an autosomal dominant trait, and 50% of the children of an affected parent should be affected. However, usually only 40–45% of the children at risk are affected, because the penetrance of the retinoblastoma trait is only 80–90%, which means that 5–10% of children who have inherited an abnormal copy of the retinoblastoma gene do not develop ocular tumors. An individual affected by an autosomal recessive trait will have unaffected children unless he or she partners with another individual affected by the disease or with an individual who is a carrier of the disease. Two individuals affected by an autosomal recessive disease produce only affected offspring. (There are some rare exceptions to this rule. If the disease is the result of mutations in two different genes, it is possible for two individuals affected by an autosomal recessive trait to produce normal children. Also, in rare cases, different mutations in the same gene may compensate for each other, and the resultant offspring will be normal.) If an individual affected by an autosomal recessive disease partners with a heterozygous carrier of a gene defect responsible for that disorder, the chance of producing an affected child is 50%. Among the offspring of an individual affected by an autosomal recessive disease, 50% will be carriers of the disorder. If one of these offspring partners with another carrier of the disease, the chance of producing an affected child is 25%. X-linked disorders are always passed from a female carrier who has inherited a copy of an abnormal gene on the X chromosome received from either her mother (who was a carrier) or her father (who was affected by the disease). Man-to-man transmission is not seen in diseases caused by defects in genes located on the X chromosome. Among sons born to female carriers of X-linked disorders, 50% are affected by the disease, and 50% of daughters born to female carriers of X-linked disorders are carriers of the disease. All the daughters of men affected by X-linked disorders are carriers of the disease. Mitochondrial disorders are inherited by sons and daughters from the mother. The frequency of affected offspring and the severity of the disease in affected offspring depend on the number of abnormal mitochondria present in the egg that gives rise to the affected child. Diseased and normal mitochondria are distributed randomly in all cells of the body, including the female gametes. As a result, not all the eggs

Box 1-3-1 Types of Clinical Genetics Services and Programs OUTREACH CLINICS

Ocular and systemic congenital anomalies

INPATIENT CONSULTATIONS SPECIALTY CLINICS l metabolic clinic l spina bifida clinic l hemophilia clinic l craniofacial clinic l other single-disorder clinics (e.g., neurofibromatosis type 1 clinic) PRENATAL DIAGNOSIS PROGRAM: PERINATAL GENETICS l amniocentesis/chorionic villus sampling clinics l ultrasound program l maternal serum α-fetoprotein program GENETIC SCREENING l newborn screening program/follow-up clinic l other population-screening programs (e.g., for Tay-Sachs disease) EDUCATION/TRAINING l health-care professional l general public l school system l teratology information services

Specific Eye Diseases

A genetic evaluation is important for families with inherited eye diseases. Many ophthalmologic diseases have a well-documented inheritance pattern, and describing the inheritance to family members may help identify affected relatives who could be diagnosed and treated early in the course of the disease. This is especially important in families with conditions such as dominantly inherited juvenile glaucoma.

Ocular defects associated with genetic diseases

Many genetic diseases have associated ocular defects. For example, a diagnosis of neurofibromatosis type 1 may be made in a child because Lisch nodules were detected on a clinical exam.30 The child and family should be referred for genetic counseling to help define the recurrence risks for other family members.

present in a woman affected by a mitochondrial disorder have the same number of affected mitochondria (heteroplasmy). Men affected by mitochondrial disorders only rarely have affected children, because very few mitochondria in the developing embryo are derived from the sperm used to fertilize the egg.29 With careful diagnosis and family history assessment, even sporadic cases of heritable disorders are identifiable. In such cases, an estimate of recurrence risk can be calculated using the available pedigree and clinical information and the statistical principle called Bayes’ theorem. These individuals should be referred to clinical genetics services, such as those commonly found in hospital settings (Box 1-3-1).

Indications to Refer for Genetic Counseling Known inherited condition

Individuals with multiple ocular and systemic anomalies may or may not fit into a particular syndrome. In these situations, the experience of a geneticist in recognizing malformation patterns and understanding the variability of genetic conditions can aid diagnosis. If an underlying cause is identified, relatives can then undergo genetic counseling.

1.3 Genetic Testing and Genetic Counseling

CENTER-BASED GENETICS CLINIC

a child has retinoblastoma and a positive family history, the family may be referred for genetic counseling to review recurrence risks. If diagnostic testing has been performed, that can also be discussed and will aid in the presentation of the recurrence risks, especially if other family members have been tested.

Genetic counseling can be useful for a family with a member affected by an established diagnosis. In this case, the goal of the counseling is to describe recurrence risks for other family members. For example, if

Confidentiality

Confidentiality is an important issue in genetic testing and genetic counseling. Insurance companies or employers may discriminate on the basis of genetic information especially if genetic testing has indicated an increased risk of a disease. Insurance companies may use test results to deny coverage, claiming that a genetic disease is a pre-existing condition. Employers may try to use genetic information to make hiring ­decisions, basing their assessment on risk for medical complications or disability. These issues may cause families or individuals to decline genetic testing even if a positive test result could alter medical management. Others choose to pay for testing themselves to prevent the insurance company from having access to this information. Still others request that test results not be put in their medical record. Families may wish to have total control over the information. It is important that genetic professionals support the patients’ right to privacy. Confidentiality issues should be discussed prior to the initiation of testing so there is consensus on how results are reported, who receives results, and where the information is documented.

REFERENCES   1. Korf B. Molecular diagnosis. N Engl J Med 1995;332:1218–20.   2. Caskey CT. Presymptomatic diagnosis: a first step toward genetic health care. Science. 1993;262:48–9.   3. Ott J. Analysis of human genetic linkage. 2nd ed. Baltimore: Johns Hopkins University Press; 1991.   4. MacDonald IM, Sereda C, McTaggart K, Mah D. Choroideremia gene testing. Expert Rev Mol Diagn 2004;4:478–84. Review.   5. Mulot C, Stucker I, Clavel J, et al. Collection of human genomic DNA from buccal cells for genetics studies: comparison between cytobrush, mouthwash, and treated card. J Biomed Biotechnol 2005;3:291–6.   6. Onadim Z, Cowell JK. Application of PCR amplification of DNA from paraffin embedded tissue sections to linkage analysis in familial retinoblastoma. J Med Genet. 1991;28:312–6.   7. Suenaga E, Nakamura H. Evaluation of three methods for effective extraction of DNA from human hair. J Chromatogr B Analyt Technol Biomed Life Sci. 2005; 820:137–41.   8. Tsai T, Fulton L, Smith BJ, et al. Rapid identification of germline mutations in retinoblastoma by protein truncation testing. Arch Ophthalmol. 2004;122:239–48.   9. Spruijt L, Kolbach DN, de Coo RF, et al. Influence of  mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol. 2006.141:676–82.

10. Sena DF, Finzi S, Rodgers K, et al. Founder mutations of CYP1B1 gene in patients with congenital glaucoma from the United States and Brazil. J Med Genet. 2004;41:e6. 11. Munier FL, Frueh BE, Othenin-Girard P, et al. BIGH3 mutation spectrum in corneal dystrophies. Invest Ophthalmol Vis Sci. 2002;43:949–54. 12. Sieving PA, Bingham EL, Kemp J, et al. Juvenile X-linked retinoschisis from XLRS1 Arg213Trp mutation with preservation of the electroretinogram scotopic b-wave. Am J Ophthalmol. 1999;128:179–84. 13. Ali M, Venkatesh C, Ragunath A, et al. Mutation analysis of the KIF21A gene in an Indian family with CFEOM1: implication of CpG methylation for most frequent mutations. Ophthalmic Genet. 2004;25:247–55. 14. Kuo NW, Lympany PA, Menezo V, et al. TNF-857T, a genetic risk marker for acute anterior uveitis. Invest Ophthalmol Vis Sci. 2005;46:1565–71. 15. Li J, Chu X, Liu Y, et al. A colorimetric method for point mutation detection using high-fidelity DNA ligase. Nucleic Acids Res. 2005;33:e168. 16. Hantash FM, Olson SC, Anderson B, et al. Rapid one-step carrier detection assay of mucolipidosis IV mutations in the Ashkenazi Jewish population. J Mol Diagn. 2006;8:282–7. 17. Vincent A, Billingsley G, Priston M, et al. Further support of the role of CYP1B1 in patients with Peters anomaly. Mol Vis. 2006;.12:506–10.

18. Gasser RB, Hu M, Chilton NB, et al. Single-strand conformation polymorphism (SSCP) for the analysis of genetic variation. Nat Protoc. 2006.1: 3121–8. 19. Mashima Y, Shiono T, Inana G. Rapid and efficient molecular analysis of gyrate atrophy using denaturing gradient gel electrophoresis. Invest Ophthalmol Vis Sci. 1994;35:1065–70. 20. Kolchinsky A, Mirzabekov A. Analysis of SNPs and other genomic variations using gel-based chips. Hum Mutat. 2002;19:343–60. 21. Yzer S, Leroy BP, De Baere E, et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006;47:1167–76. 22. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trail determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–13. 23. Henneman L, Timmermans DR, Van Der Wal G. Public attitudes toward genetic testing: perceived benefits and objections. Genet Test. 2006;10:139–45. 24. Schaumberg DA, Hankinson SE, Guo Q, et al. A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors. Arch Ophthalmol. 2007;125:55–62.

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1 GENETICS

24

25. Conley YP, Jakobsdottir J, Mah T, et al. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet. 2006;15:3206–18. 26. Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet. 2006;78:852–64.

27. Pompanon F, Bonin A, Bellemain E, Taberlet P. Genotyping errors: causes, consequences and solutions. Nat Rev Genet. 2005;6:847–59. 28. Epstein CJ, Erickson RP, Hall BD, Golbus MS. The centersatellite system for the wide-scale distribution of genetic counseling services. Am J Hum Genet. 1975;27:322–32.

29. Wallace DC. Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci USA. 1994;91:8739–46. 30. Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol. 2004;88:1429–33.

PART 2 OPTICS AND REFRACTION

2.1

Visible Light

David Miller and Stephen K. Burns

Definition:  Visible light is a small portion of the electromagnetic spectrum with a wavelength range between 400 and 700 nm.

from reaching the Earth. The fast-moving ions of the hot plasma of the solar wind are repulsed by the Earth’s magnetic field.

Effect of Earth’s Atmosphere

Key features T he main source of visible light is the Sun. The Earth’s atmosphere absorbs most of the light below 400 nm. n Visible light sensing by the eye depends upon a. The parameters of the light receptors – Unique size – Unique shape – Spectrum of sensitivity – Orientation as light guides b. The characteristics of the dioptric media n n

Associated features n



 nderstanding the transformation of an optical image composed U of visible light into an electronic image composed of visible light a. Processing of a 2D optical image into an electronic image b. Processing of a 3D optical image into an electronic image 

ORIGIN OF VISIBLE LIGHT Source

In general, clinical optics concerns the focusing or processing of visible light. Of course, visible light comes primarily from suns (stars). Children are taught that this visible light also generates the energy necessary for life. The wavelengths of visible light (4 × 10-6−7 × 10-6 m) represent a minute fraction, about 1%, of the electromagnetic spectrum, which ranges from the shortest ionizing radiation (1 × 10-16 m) to the longest radiowaves (1 × 106 m; Fig. 2-1-1).1 Interestingly, visible light does not start out as such in the core of the Sun. The Sun’s core may be considered a furnace in which thermonuclear fusion takes place. Here, because of the crush of gravity, temperatures close to 16 × 106 K are generated. In such a hot environment the elemental hydrogen protons fuse to produce helium nuclei and energy in the form of gamma rays. (The Sun converts 4 × 106 tons of matter into energy every second.) This resultant short-wavelength energy passes through about half a million miles (8 × 105 km) of dense solar matter before reaching the Sun’s surface. During this long and slow journey, the photons lose energy and hence increase in wavelength. The radiation that leaves the Sun’s surface primarily represents a spectrum of radiation between ultraviolet and infrared, with a small fraction of ionizing radiation in the form of x-rays with wavelengths of 10-10 m and γ-rays with wavelengths of 10-14 m. This ionizing radiation (part of the entire cosmic radiation) can destroy life, however, the Sun also ejects huge amounts of matter (one million tons of hot electrons and protons every second), called the solar wind, which produces a vast shell around the Sun and prevents ionizing radiation

The Earth’s atmosphere is held in position by the gravitational pull of the mass of the Earth. The potentially harmful ultraviolet and infrared radiation released from the Sun’s surface is absorbed by ozone, carbon dioxide, and water vapor in the Earth’s atmosphere (Fig. 2-1-2).1 The Earth’s temperature, which is a result of the temperature of the Sun’s surface (6000 K) and its distance from Earth (almost 100 × 106 miles (160 × 106 km)), is responsible for the volume of atmospheric ­ water ­vaporized from the oceans. Ozone and carbon dioxide result from ­photosynthesis and respiration. Thus, early forms of life had to exist and produce these atmospheric gases before ultraviolet and infrared ­radiation could be absorbed and higher forms of life evolve. The core-produced x-rays are filtered first by the outer layers of the Sun’s matter. The Earth is 1/100th the diameter of the Sun and almost 100 × 106 miles (160 × 106 km) away, and it receives only a tiny fraction of the radiation (about a billionth of the total).2 The radiation that travels toward Earth is further filtered by the particles of the solar wind. In turn, this deadly solar wind is repelled by the Earth’s magnetic field. Finally, the size and temperature of the Earth, as well as life on Earth, combine to produce an atmosphere that allows little more than visible light to pass through.

VISIBLE LIGHT SENSING We have traced the origins of visible light from the Sun to the Earth’s surface. Equally instructive are the mechanisms by which the biological molecule absorbs visible light and then informs the animal of that event. In a sense this represents the equivalent of Einstein’s photoelectric effect. Rhodopsin is the biological molecule typically used for this purpose. Perhaps the earliest form of sensory rhodopsin, ­bacterio­rhodopsin, is found in a primitive purple-colored bacterium, Halobacterium halobium.3 It is not known how long this organism has inhabited the Earth. However, its preference for anaerobic conditions and a very salty environment may mean it developed at a time when little or no oxygen existed in the atmosphere and the sea contained high salt concentrations. Bacteriorhodopsin is a complicated molecule that contains 248 amino acids in the opsin portions, which are linked to one retinal chromophore. Time-resolved spectroscopic measurements have determined that a cis/trans isomerization in the retinal portion of the molecule begins about 10-12 seconds after light stimulation. This is followed by deprotonation in the opsin portion at 10-5 seconds after stimulation.4 This early rhodopsin absorbed light maximally at 495 nm but responded to almost all visible light. Estimates suggest that the ancestor of human color pigment genes diverged from the rhodopsin gene about 800 million years ago and eventually resulted in a series of pigments with maximal absorption peaks in the blue, green, and red areas of the spectrum.5 These specially adapted molecules are needed for accurate color vision. Thus, early animals used something akin to the original rhodopsin and a very simple optical system to see. For example, early worms and shellfish had light-sensing cells that lined a small cup-like structure. Such a system gives a sense of directionality, because each cell is shielded from light that approaches the cup from the nonseeing side. If the cup is made deeper and the sides are turned over, a lensless pinhole

25

2

THE ELECTROMAGNETIC SPECTRUM

OPTICS AND REFRACTION

visible spectrum nm radio

700 1 GHz

600

500

400

100 GHz infrared

AM 540–1650 kHz

�m

FM 88–108 MHz

ultraviolet soft

x-rays

hard �-rays

frequency (Hz) 3 �102

3 �104

106 104 wavelength (m)

mountains

3 �106 102

factory

3 �108 3 �1010 3 �1012 3 �1014 3 �1016 3 �1018 3�1020 3 �1022 3 �1024 1

people

10–2

button

10–4

point

10–6

dust

10–8

bacteria

10–10

virus

10–12

10–14

atom

10–16

atomic nucleus

size

atmospheric transparency

Fig. 2-1-1  The electromagnetic spectrum. The pictures of mountains, people, buttons, viruses, etc., are used to produce a real (i.e., visceral) feeling of the size   of some of the wavelengths. (Adapted from Zeilik M. Astronomy: the evolving universe, 3rd ed. New York: Harper & Row; 1982.)

ABSORPTION OF THE SUN’S RADIATION BY THE EARTH’S ATMOSPHERE relative 22 energy curve for black body at 6000 K intensity 20 solar energy curve outside atmosphere 18 16 solar energy curve at sea level 14 ultraviolet visible infrared 12 10 8 6 4 2 0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 wavelength (�m)

Fig. 2-1-2  Absorption of the Sun’s radiation by the Earth’s atmosphere. The white areas show the actual measured spectrum at sea level. Note the white areas of absorption are produced by ozone, water, and carbon dioxide. (Adapted from Zeilik M. Astronomy: the evolving universe, 3rd ed. New York: Harper & Row; 1982.)

system is produced. Such a system is used by a very primitive swimming mollusk called Nautilus.6 Thus, with visible light falling on the Earth, and rhodopsin already present, the stage was set for the development from simple light-sensing to natural or living optics.

VISIBLE LIGHT RECEPTORS AND THE OCULAR MEDIA

26

Life has existed on Earth for about 4 billion years. Primitive fish that had eyes somewhat like human eyes first appeared about 400 million years ago, so it might be said that ophthalmic optics originated at this time.7–9 The living form of optics operates under the same rules and regulations as mechanical glass optics. Obviously, the various aspects

of natural optics are linked closely to the dimensions of the wavelengths of visible light. Some of the basic elements of optics, using living optics examples, are introduced below.

Receptors

Receptor size and shape

The essential job of an optical system is to convert information about an object into an image. In natural optics, the image is formed on the retina and, therefore, it usually is much smaller than the object. Classically, the object has been considered as made up of a series of luminous points. For example, an object such as a tree does not contain points of light but can be thought of as reflecting points of light. The optical system converts the object points of light into image points. Because the image is smaller, the image points may be considered more densely packed. Thus, an image of high quality − also called an image of high resolution − demonstrates much detail. The finer and more tightly packed the receptors, the more detail is registered. The retinal receptor size and shape is influenced by a number of factors. Because smaller receptors are better for resolution than larger receptors, what factor actually limits the smallness of a photoreceptor such as a retinal cone? The answer is diffraction. The smallest point focus of light is surrounded by a diffraction pattern. Thus, very narrow receptors that receive a large diffraction pattern are wasteful. The size of the diffraction pattern, on the retina or on a screen, is known as an Airy disc. The diameter of this disc determines the distance between two resolvable points. That is to say, the diameter of the Airy disc, Dλ, or the width of the central maxima, also is equal to the just resolvable distance between two intensity peaks when the minima of the interference patterns overlap (equation 2-1-1;10 Fig. 2-1-3).11, 12 Equation 2-1-1

Dλ =

1.22 f λ

kp



 Table 2-1-1  F-Numbers For Several Animal Species

RESOLUTION OF DIFFRACTION PATTERNS OF TWO OBJECT SOURCES OF LIGHT

S2

Light intensity distribution

S1

Appearance of light distribution

central maxima + second minima

central maxima + first minima

�

(angle of separation)

F-Number

Net-casting spider

1.325

0.08

Cat

14

0.89

Flour moth

0.02

1.2

Tawny owl

13.3

1.3

Housefly

0.0025

2.0

Human

7–8

2.1–2.4

Pigeon

0.2

4.0

2.1

(Modified from Lythgoe JN. The ecology of vision. Oxford: Clarendon Press; 1979.)

merge to one image

Mosaic of retinal cones

�

(angle of resolution) intensity

S1

Pupil Width (mm)

Visible Light

Production of diffraction patterns

Animal

S2

Fig. 2-1-3  Two object sources of light (S1 and S2) cannot be resolved if their diffraction patterns (Airy discs) overlap substantially. Two refraction patterns are produced by a circular aperture placed between two lenses, and resultant patterns of the light intensity distribution and appearance are shown: the central maxima of one diffraction pattern falls on the second minima of the diffraction pattern from the second source; the central maxima of one diffraction pattern falls on the first minima of the diffraction pattern from the second source, and the two images can just be resolved (Rayleigh’s criterion); the two images merge as one. Mosaic of retinal cones with the diffraction pattern   superimposed. (Adapted from Jenkins FA, White HE. Fundamentals of optics. New York: McGraw Hill; 1950:290–3; and Emsley HH. Visual optics. London:   Hatton Press; 1950:47.)

increases, because this tends to widen the projection of the diffraction pattern. Thus, a larger f-number suggests a degradation in resolution. The second concept, the angle of resolution, is related closely to the Airy disc. The Airy disc is the physical distance, on the retina or a screen, between two points that are just resolvable. The angle of resolution, AS, is another way to describe just resolvable points in physical space (equation 2-1-3; see Fig. 2-1-3). Equation 2-1-3

AS =

1.22 λ p

where 1.22 = constant for a circular pupil, p = pupil diameter, and λ = 0.000550 mm. The focal length of the system, f, is not used in equation 2-1-3. The angle of resolution, AS, for two distant stars viewed by a healthy, average human eye with a pupil of 8 mm in diameter is given by equation 2-1-4. However, it is known that the human eye can resolve two separate points in 1 minute or even less.11 This discrepancy is explained as follows. The Raleigh criterion for resolution demands that the maxima of one point source must intersect the minima of the second point source (see Fig. 2-1-3),13 which allows a patch of no light (high-contrast image) between the two maxima. However, in the case of the healthy young human eye, contrast determinations can be made for targets of lower contrast. Thus, many human eyes are able to distinguish two point sources or two black bars when the diffraction patterns overlap (see Fig. 2-1-3).

Equation 2-1-4

AS =

(1.22)(0.00055) 8



= 0.000084 radians = 2.5minutes where 1.22 = constant for round pupil, λ = 550 nm (average for ­visible light), f = focal length of system, and p = pupillary diameter. For example, the size of the Airy disc image of a point of light for the human eye under photopic conditions may be determined as ­follows. If f = 17 mm (focal length of eye), p = 4 mm (average ­photopic pupil), l = 0.00055 mm (median wavelength in visible spectrum of 0.0004–0.0007 mm), then the diameter of the Airy disc, Dλ is given by equation 2-1-2. Equation 2-1-2

D = λ

(1.22)(17 )( 0.000555) 4

= 2.8 µm

Note that the size of the Airy disc can vary with the focal length of the eye, the wavelength of light, and the pupil size. Also note that 2.8 μm is close to the size of the average foveal cone (1.5–2.0 μm). In comparison, the eagle has a large photopic pupil (about 6 mm); its foveal cones are thinner than those of the human and the eagle eye’s resolution is finer. Two other important optical concepts are buried in equation 2-1-1. First, note that f/p may be a key factor in determining the size of the Airy disc. The f/p ratio is called the f-number of the system. As p, the pupil diameter, decreases, the diameter of the diffraction pattern increases, and the resolution power lessens. The same occurs if the focal length

For example, if it is assumed that the human separation criterion is one half the width of the Airy disc, then the angle of resolution is close to 1 minute of the arc. If the contrast enhancement known to be built into the neural processing of the human visual system is considered, it becomes apparent how some subjects have a resolution angle of less than 1 minute of arc.10, 14 In conclusion, the resolution limit of natural optics is related to the size of the wavelengths within the spectrum of visible light.

Light sensitivity

When a firefly is seen in the distance, the number of photons collected by the eye from the firefly (per unit time) is distributed over the retinal image. Each image point is an Airy pattern. Thus, the smaller the patterns, the more concentrated the pattern and the brighter is the image. It may be wondered whether animals that have small eyes, with a small focal length, or insects that have even smaller eye facets can collect light as well as the human eye does. From equation 2-1-1, if the light-catching ability of an optical system depends primarily on the f-number (f/p), the small eyes of spiders and each facet of the housefly eye, theoretically, are even more sensitive than the human eye. Table 2-1-1 gives the f-number for some animal species;12 the tiny eye of the net-casting spider sees dim objects better than

27

2 OPTICS AND REFRACTION Fig. 2-1-4  Scanning electron micrograph of photoreceptors that can be considered a light guide. C, Cone; R, rod. (From Prause JU, Jensen OA. Scanning electron micrograph of frozen-crack, dry cracked and enzyme digested retinal   tissue of a monkey and man. Graefes Arch Klin Exp Ophthalmol. 1980;212:261–70.)

eyes of the other animals. In conclusion, we can make the following observations: l Small eyes may have low f-numbers and consequently have very ­sensitive light-catching abilities l The Airy disc or diffraction pattern from any point on the object is important in determining the density of photons that fall on a retinal area Thus, we can appreciate that the level of sensitivity of the receptor is tied ultimately to the wavelength within the spectrum of visible light.

Receptor shape

The shape of the photoreceptor plays an important role in resolution of light and sensitivity. For example, the tighter the packing of receptors, the closer the focused points on the retina may be placed (actually, these are Airy patterns). Theoretical analysis shows that hexagonal cross-sections of close elements allow the tightest packing and, in fact, photoreceptors have such hexagonal cross-sections.13, 14 Of course, the tightness of the packing is related to the angle of resolution.

Receptor as a light guide

A light guide (fiberoptic element) receives light at its entrance. Because the core of the guide has a higher index of refraction than the outer coating, or cladding, light that enters beyond the critical angle is not refracted but forced to reflect continually off the walls of the guide until it reaches the other end. (Critical angle refers to a refracting system, in which the incident ray is reflected instead of refracted.) As might be expected, at angles of entry close to the critical angle, a small amount of light may leak between closely packed light guides. The retinal cone acts as a light guide (Fig. 2-1-4).15 The body of the cone has one index of refraction and the surrounding interstitium, although narrow, has a lower index of refraction. Recall that the index of refraction varies with wavelength. A second point to note is that as the diameter of the guide gets smaller, the wave nature of light plays a more important role in the functioning of the guide. For example, as the diameter of the guide approaches the light’s wavelength, the waves of light that enter interfere more destructively with each other, which reduces the amount of light that reaches the other end. The interference pattern is known as a modal pattern. Because diffraction is ultimately dependent on the wavelength, the limiting diameters of a light-guiding cone are related to the wavelength.16–18 The second limiting factor is light crossover between receptors, which is related to the indices of refraction of the receptor and its surround, as well as to the closeness between receptors.19, 20 Both of these properties may be thought of as related to the wavelength of light. In summary, the dimensions of receptors of about 2 μm in diameter and the separation between receptors of about 0.33 μm are related to the wavelength of visible light.

Dioptric Media

28

It seems obvious that dioptric media, or the optical elements of the eye, must be transparent. A perfectly transparent medium does not absorb or scatter light. Classically, pigments are described as absorbing visible light. The characteristic feature of a pigment molecule is a series of single and double bonds formed by the carbon atoms. The pi electrons of the double bond may be thought of as “free to wander” across the

carbon backbone structure of the molecule, which increases their combined probability distribution over the entire molecule. This condition makes it easier to excite the pi electrons with the less-energetic visible wavelengths; ultraviolet, x-ray, and ionizing radiation have more energy than visible light. Transparent media have few or no pigment molecules. A good example of a medium transparent to visible light is the human ocular media,21 which consists primarily of water. When a beam of visible light passes through pure water, the water appears transparent because it contains no pigments and because the light waves scattered from each of the water molecules interfere destructively with one another in all directions except the forward direction. No light appears to have been scattered, because the scattered waves mutually cancel to give zero net scatter to the side. Water and glass interact with light in this way because their components are all of the same index of refraction and uniformly distributed. The transparent cornea may be thought of as made up of collagen fibers of one index of refraction embedded in a mucopolysaccharide (high water content) of a second index of refraction. However, because the distribution of the elements is in a uniform pattern, and because the collagen fibers are never more than the distance of one half a wavelength of visible light apart, the number of scattered waves is small. In reality the cornea is only 90% transparent (10% of the incident light is scattered). It is functionally transparent,22 although not perfectly transparent. Once again, an important optical property (transparency) may be thought of as dependent on the wavelength of the incident light.

TRANSFORMATION OF A REAL IMAGE TO AN ELECTRONIC IMAGE Light is visible because it can be detected in the retina. It produces changes in receptor cells in our eye. These changes stimulate nervous activity, which is processed by retinal nerve cells and conveyed to our brain. Electrical sensors can “see” light, too. There are two major classes of electrical light sensors, photovoltaic and photoconductive. The photo­ voltaic class generates electrical power, which is related to the power of the light incident to the sensor. Photoconductive devices conduct more electricity with increasing light. A solar cell is a photovoltaic device. The sensor which turns on the streetlights at night is usually a photoconductive device. Either type can produce an electrical signal which can be conveyed to a distant receptor. Light and electricity have long been associated. Lightning is a spectacular example of light and electricity. That electricity can produce light related to the amount of electricity has long been known. The brightness of an electric arc or an incandescent filament of an electric lamp are both related to the current flow producing the light. Television, fax, and electronic cameras all depend on the ability to electrically and proportionally sense and create light. Paul Nipkow invented mechanically scanned television and patented it in 1884 (Fig. 2-1-5). This system “scanned” a real image using a rotating disk pierced with a spiral of holes that presented a small portion of the image to a selenium photoconductive sensor. The sensor was connected to a light source that was observed through a second, synchronized, rotating disk which placed the received light in the right place in the image plane. An electronic image differs from a real image in several ways. (1) The electronic image is sampled. It is made up of a finite number of little light spots, or picture elements called pixels, which are seen together as a continuous image but individually simply represent the light at a point in a real image. (2) The light provided by these (pixels) is made up of three different primary colors (red, blue, and green) which are perceived as nearly any color. (3) Finally, the information is not there all of the time but is presented repeatedly at a rate sufficiently fast that the image is seen as continuous. Electronic images are thus neither spatially nor temporally continuous. Although it is not essential to an electronic image, the information describing the individual pixels is conveyed serially or one at a time. By agreeing on a correspondence between the location of a pixel and the order that it is transmitted, it is unnecessary to transmit the location with the color and brightness information. This orderly sequence of analysis and synthesis describes a pattern known as a raster. Solid state electronic image sensors have replaced mechanically scanned image sensors and electronically scanned sensors like Vidicon tubes with arrays of electrical sensors. Electronic image sensors have a photosensor for each pixel, while mechanically and electronically scanned sensors examine a portion of a photosensitive region large enough to accommodate the entire image. The first solid state image sensor was the

EARLY SCANNING TELEVISION SYSTEM

selenium cells

light

wire image rotating disk with spiral of holes

second disk rotating at the same speed

Fig. 2-1-5  Example of early mechanical version of a scanning television system (patented in 1884 by Paul Nipkow). (Courtesy Cinemedia Corporation)

charge-coupled device (CCD). CCDs represent the amount of light at a pixel by stored electrical charge. The pixels are arranged in rows and columns. The charge is collected by an individual pixel element in each row. This charge is collected and transferred to the CMOS Imager, so called because it incorporates CMOS transistors and includes light sensors with individual transistor amplifiers and electronic switches. The switches can connect the selected sensor to an output amplifier. The switches usually are operated in an orderly sequence. Color filters can be placed in front of individual sensors so that they provide color information as well as a measure of the amount of light. The information associated with an electronic image can produce a visible image in several ways. Probably the most common image presentation uses a cathode ray tube. In this tube, a beam of electrons excites a phosphor that produces light. Modern color cathode ray tubes incorporate a complex image plane with regions of three colored phosphors. The electron beam traces a raster, which corresponds to the raster used to scan the original image. When this original image is stored in an electronic memory, the date is read out in the order needed to display it on a standard raster. This is called a bit-mapped image. Liquid crystal displays (LCDs) are an important current technology. Individual pixels are implemented with tiny “light valves” that control the amount of light coming from that pixel. The light valves work by electrically shifting the polarization of light passing through a liquid crystal material. Polarized light passes through it and encounters a second polarizer which transmits only light aligned with it. The contrast

2.1 Visible Light

screen

ratio (brightest-to-dimmest light) is limited with a light valve. Contrast ratios between 200 and 500 are now available. Transmissive LCD displays can provide around 200 nits of illumination. Color LCDs are implemented by placing color filters in the path of the light valve. LCDs work by controlling transmitted or reflected light. Plasma displays and light-emitting diode (LED) displays, like cathode ray tubes, provide light directly and are consequently quite bright. It is difficult to fabricate small pixels (0.3 mm in a 15-inch cathode ray tube display) with these technologies. Plasma technology creates light from glowing plasma which excites colored phosphors. Pixel dimensions can be made sufficiently small to realize large-format television (50-inch) displays. Conventional semiconductor LEDs are relatively large and are suitable only for very large displays (greater than 10 feet) but can be very bright (5000 nit). Organic LEDs (OLEDs) are evolving rapidly. Very small OLEDs can be fabricated. High-resolution (852 × 3 × 600 pixels) “microdisplays” (0.62-inch diagonal) are currently available.

Processing

An electronic image can be manipulated as data and offers tremendous opportunities to present or receive visual information which is beyond the power of physical optics. Moreover, the current generation of computer technology is fast enough to process an image as we view it. This makes it possible to see subtle differences in light intensity by mapping shades to differences in color. Edges can be enhanced. Reference points can be marked, distances measured, and templates superposed. There is much promise in the computer-enhanced electronic image.

Stereoscopic Vision

We see the world through two eyes. Stereoscopic vision is of immense value to a surgeon. Most surgical microscopes provide a stereoscopic view. Stereoscopy requires acquiring and transmitting images for the left and right eye in the same amount of time required for transmitting a single image. This doubles the required bandwidth. Reducing the bandwidth with slower transmission produces unacceptable flicker and interrupted motion. The current generation of computer technology offers greatly increased bandwidth so we can anticipate economical, highquality stereo imaging will become economically feasible. This suggests the practical possibilities for stereoscopically recording or viewing an image from an operating microscope.

SUMMARY In conclusion, in this chapter a perspective for optics as well as a focus on an important common denominator in optics is given. The common theme is related to the properties of the tiny portion of the electromagnetic spectrum known as visible light. The wavelength of visible light is critical in understanding the structural dimensions of the optical systems of animal and human eyes. Electronic images are increasingly common and have unique characteristics and possibilities, which should be included whenever considering vision and visible light.

References   1. Zeilik M. Astronomy: the evolving universe, 3rd ed. New York: Harper & Row; 1982.   2. Kippenhahn R. Light from the depths of time. New York: Springer-Verlag; 1986.   3. Oesterhelt D, Stoekenius W. Rhodopsin-like protein from the membrane of Halobacterium halobium. Nature New Biol. 1971;233:149–52.   4. Atkinson GH, Blanchard D, Lemaire H, et al. Picosecond time resolved fluorescence spectroscopy of K-590 in   the bacteriorhodopsin photocycle. Biophys J. 1989;55:  263–74.   5. Yokoyama S, Yokoyama R. Molecular evolution of human visual pigment genes. Mol Biol Evol. 1989;6:186–97.   6. Dawkins R. The blind watchmaker. New York: WW   Norton; 1986:85–86.   7. Calder N. The life game. New York: Viking Press; 1974.   8. Burton VL. Life story. Boston: Houghton Mifflin; 1962.

  9. Marshall K. The story of life. New York: Holt, Rinehart, and Winston; 1980. 10. Jenkins FA, White HE. Fundamentals of optics. New York: McGraw Hill; 1950:290–3. 11. Emsley HH. Visual optics. London: Hatton Press; 1950:47. 12. Blatt FJ. Principles of physics. Boston: Allyn and Bacon; 1987. 13. Lythgoe JN. The ecology of vision. Oxford: Clarendon Press; 1979. 14. Snyder AW, Bossomaier JR, Huges A. Optical image quality and the cone mosaic. Science. 1986;231:499–501. 15. Prause JU, Jensen OA. Scanning electron micrograph of frozen-crack, dry cracked and enzyme digested retinal tissue of a monkey and man. Graefes Arch Klin Exp Ophthalmol. 1980;212:261–70. 16. Enoch JM. Retinal receptor orientation and the role of fiber optics in vision. Am J Optom Arch Am Acad Optom. 1972;49:455–70.

17. Snyder AW, Menzal R. Photoreceptor optics. Berlin: Springer-Verlag; 1975. 18. Snyder AW, Miller WH. Photoreceptor diameter and spacing for highest resolving power. J Opt Soc Am. 1977;67:696–8. 19. Snyder AW. Coupled mode theory for optical fibers.   J Opt Soc Am. 1972;62:1267–77. 20. Barlow HB. Critical limiting factors in the design of the eye and visual cortex: The Ferrier Lecture 1980. Proc R Soc Lond B Biol Sci. 1981;212:1–34. 21. Boettner EA, Wolter JR. Transmission of the ocular media. Invest Ophthalmol. 1962;1:776–83. 22. Miller D, Benedek G. Intraocular light scattering.   Springfield: CC Thomas; 1973.

29

PART 2 OPTICS AND REFRACTION

Physical Optics for Clinicians Edmond H. Thall, Russell Miller and Humberto Salinas

Definition:  Whereas geometrical optics considers light to be a series

of rays, physical optics approaches problems in optics by treating light as a waveform.

Key features n n n n n

Interference of light waves. Polarization of light waves. Diffraction effects of light waves. Scattering of light waves (effects on glare and contrast sensitivity). Understanding the quantum model of light waves.

Associated features n n

Lasers and light waves. Interaction of tissue and light waves (i.e., laser light).

INTRODUCTION

30

What is light? The question may seem academic but experience has shown that every advance in understanding the fundamental nature of light has lead to major technological advances. The scientific study of light’s fundamental nature is a vast discipline in its own right. This chapter discusses those aspects of physical optics applicable to clinical practice. According to the oldest surviving documents, the early Greeks (Aristotle, Euclid, Empodocoles, etc.) thought light was a flow of miniscule particles.1 A relatively limited class of materials designated optical media transmitted light. How light particles were able to penetrate solid materials apparently was never addressed, but commonplace observations led to the conclusion that light traversing a single medium followed a straight line (the law of rectilinear propagation). Observations of reflected light suggested the equality of the reflected and incident angles (the law of specular reflection). Sudden directional change occurring when light moves from one medium to another (refraction) was also readily observed, but the underlying relationship between the angles of incidence and refraction was not known. Not surprisingly, there were some erroneous conclusions, for instance, the Greeks believed that light moved instantaneously from one point to another, in other words light moved with infinite speed. Two types of imaging were known. The virtual image formed by the surface of a quiet pool of water and the real image produced by a pinhole. Geometry was the most widely developed branch of mathematics at the time and these forms of imaging clearly followed some geometrical principles. Remarkably, the early philosophers did not associate light with ­vision because nocturnal animals seemed capable of seeing when humans could not detect light and wrongly concluded that light was not essential for sight. Instead, most believed that a visual spirit emanating from the eye interacted with surroundings and produced visual sensations.

2.2

The visual spirit theory was universally accepted until the 1100s when Al Hassen pointed out that to see the distant stars the visual spirit would have to span out over a vast region of space and it was doubtful that there was enough matter in the human body to permit this. In the early 1600s, Kepler put an end to the visual spirit theory by creating a scleral window at the back of a cadaver eye and observing an inverted image on the retina.2 While certain geometrical features of image formation were known for centuries it was not until the early 1600s that Kepler proposed the first tenable theory of imaging based on geometrical principles. Arguably, Kepler’s work initiated the discipline of geometrical optics even though at that time the law of refraction was still unknown. Nevertheless, the astronomical telescope was the first optical instrument based on intentional design instead of empirical discovery. Although there is evidence that others may have been aware of it, in 1620 Snell was the first to publish the law of refraction, but not in the form it is known today. The concept of refractive index did not exist because light was still believed to travel at infinite speed. It was not until the late 1600s that the Danish astronomer Romer noticed a 10-minute variation in the orbit of IO (a Jovian moon discovered by Galileo) and rightly attributed the observation to a finite speed of light. Many authorities did not immediately accept the finite speed of light. Another century passed before the speed of light was measured in the laboratory finally abolishing any doubt that speed of light was finite. Huygens, a contemporary of Newton’s, favored a wave nature of light over the Greek corpuscular theory. However, Huygens believed that light waves were longitudinal, which is to say the waves oscillated and propagated in the same direction like sound waves. Newton rejected the wave theory largely because it was difficult to understand how a wave could obey the law of rectilinear propagation, but based on the laws of motion that Newton had recently developed it was easy to imagine particles doing so. In 1801, Thomas Young, a prominent London physician, performed a critical experiment demonstrating light’s wave nature,3 but the results were not immediately accepted. At roughly the same time, some remarkable developments occurred in seemingly unrelated fields. Electricity and magnetism were also known since ancient times and were thought to be quite distinct and unrelated phenomena. In the early 1800s, it became clear that electricity and magnetism were different manifestations of the same phenomenon4 and in the latter 1800s, Maxwell showed that light was also related to electricity and magnetism, and in fact light was an electromagnetic oscillation.5

ELECTROMAGNETIC AND SCALAR WAVE MODELS OF LIGHT Light can be modeled as an electromagnetic wave consisting of an electric field oscillating perpendicular to an oscillating magnetic field, with both fields perpendicular to the direction of propagation (Fig. 2-2-1).6 Since the magnetic field oscillates in lockstep7 with the electric field, it is often sufficient to consider only the electric field. In the scalar wave model, light is modeled as a single transverse wave (Fig. 2-2-2).

POLARIZATION In both the electromagnetic and the scalar wave models, light is a transverse wave. Unlike the waves envisioned by Huygens, the direction of oscillation is perpendicular to the direction of propagation. Nevertheless, the wave may oscillate in many different directions. A linearly polarized wave oscillates in a single plane (see Fig. 2-2-2).

ΦB = tan −1 n 2/n1 Fresnel took Brewster’s discovery further and calculated the degree of (partial) polarization produced by a reflecting surface at any angle of incidence. Fresnel’s equations are somewhat complicated but can be found in any standard treatment of optics.10 Some materials have different refractive indices, depending on the direction of polarization; they are called birefringent because they have two different refractive indices. Light incident on such birefringent materials travels in different directions, depending on its polarization. Such materials separate a beam of light into two beams, each linearly polarized at right angles to each other.11 Dichroic materials absorb light linearly polarized in one direction and transmit light linearly polarized at right angles to this. These materials are commonly used in polarized sunglasses. Most reflecting Fig. 2-2-1  Electromagnetic wave. An electromagnetic wave consists of an oscillating electric field perpendicular to an oscillating magnetic field. The direction of propagation is perpendicular to both the electric and the magnetic fields.

ELECTROMAGNETIC WAVE

POLARIZATION Horizontally polarized

Vertically polarized

surfaces in human surroundings are horizontally oriented, such as floors, automobile hoods, and so forth. Light reflected from a surface (and consequently at least partially polarized) is absorbed by dichroic materials in the lenses of polarized sunglasses. In sunglasses, the dichroic material is oriented to transmit vertically polarized light and absorb horizontally polarized light. Polarizing sunglasses reduce only reflected glare, and only when the reflecting surface is horizontal. Despite these limitations, polarization is a popular feature in sunglasses. Several ocular structures are birefringent; these include collagen fibers in the cornea and iris and nerve fibers of the inner retina.12 A number of attempts have been made to capitalize on ocular birefringence. The GDx nerve fiber layer analyzer measures birefringence in the retinal nerve fiber layer (NFL) as an indicator of that layer’s thickness.13 However, the correlation between polarization measurements and NFL thickness may be affected by birefringence in other ocular tissues, especially the cornea.14 GDx measurements of nerve fiber layer thickness made just prior to and shortly following laser-assisted in situ keratomileusis (LASIK) differ markedly,15 due to LASIK-induced changes in corneal birefringence16 and not because of any alteration of the NFL. A device to overcome the effects of corneal birefringence has been introduced (the variable corneal compensator), but its efficacy remains uncertain.17 Birefringence in the anterior segment is demonstrated easily using the circular polarizer furnished in some direct ophthalmoscopes to eliminate annoying corneal reflections. In circularly polarized light, the plane of polarization rotates uniformly (Fig. 2-2-3). If the anterior segment is in focus, instead of the retina, a dark Maltese-style cross is seen, with bright, iridescent colors between the arms of the cross. The dark cross is produced by Fresnel reflection at the corneal surface. The colors are probably produced by birefringence of the corneal and iris collagen. Several attempts have been made to measure corneal topography using Fresnel reflection by the anterior corneal surface. When light is reflected from a surface, it is at least partially polarized. The degree of polarization is related to the angle between the light and the reflecting surface. In theory, it is possible to calculate corneal shape from measurements of the degree and direction of polarization of light reflected from the corneal surface, but in practice, this has proved exceedingly difficult. Birefringence has been used to detect defects in intraocular lenses. The birefringence is detected by placing the lens between two linear polarizers at right angles to each other. Any light transmitted appears as a readily recognizable bright spot that indicates a possible defect in the strength of the lens. These defects arise from various causes, such as heat produced when the haptics of a three-piece lens are inserted, or from heat generated during lathe cutting or polishing. Polarization is the basis of the “Fly test” for stereopsis.18 Two images are superimposed and slightly displaced. Each image linearly polarizes light, and the axes of polarization are perpendicular. The patient wears polarizing glasses so that each eye sees only one of the images. Because each image is slightly displaced, the observer perceives the image in front of the page. By wearing the polarizing glasses upside down, each eye sees the opposite image, and the perception is that the image is below the page. Projector charts and polarization are very popular for screening vision in driver licensing agencies. Patients are instructed to keep both eyes open while viewing a chart through a vision testing device that CIRCULARLY POLARIZED LIGHT

2.2 Physical Optics for Clinicians

Polarization may be achieved in several ways.8 If light is reflected specularly from a plane surface, it is polarized partially – the direction of polarization is parallel to the reflecting surface.9 If light is reflected at a specific angle (discovered by Brewster and named in his honor), the reflected light is polarized totally. The Brewster angle can be calculated using the following equation:

Fig. 2-2-3  Circularly polarized light. In circularly polarized light, the electric field has a constant amplitude, and the plane of polarization rotates at a constant speed. The plane of polarization follows a corkscrew path as the wave travels.

direction of propagation

Fig. 2-2-2  Polarization. Both transverse waves propagate in the same direction but oscillate in different planes. Here, only the scalar wave approximation is adopted, and only the electric field is shown.

31

2

CONSTRUCTIVE AND DESTRUCTIVE INTERFERENCE

OPTICS AND REFRACTION

=

Fig. 2-2-4  Constructive and destructive interference. When two or more light waves are superimposed, the amplitudes sum. If two identical waves are in phase, the resulting amplitude doubles   (bottom). If the waves   are perfectly out of phase, the waves cancel out (top).

=

uses polarization so that each eye only sees some of the letters on a given line. A person with a unilateral vision loss will miss half the letters. The same device can be used to detect malingering in patients claiming unilateral vision loss or to rapidly screen vision. If the patient identifies all the letters on the 20/20 line, the unilateral vision loss is factitious.

INTERFERENCE

32

When two different light waves overlap, their amplitudes add. If two waves of equal amplitude are 180° out of phase, the amplitudes cancel out, and the net result is zero (Fig. 2-2-4).19 If the waves are ­perfectly in phase, the amplitudes double, and the intensity (square of the ­amplitude) is four times greater than that of a single wave. Interference refers to the summation of amplitudes that always occurs when two waves overlap. When the waves are in phase, the interference is constructive, and when the waves are out of phase, the interference is destructive. Imagine overlapping the beams from two flashlights so they illuminate the same spot on a wall. You would expect to see twice as much light and in fact you do, but if the waves from each light were perfectly out of phase, you would actually see no light at all. In practice, to observe interference effects, the waves must be coherent and polarized in similar directions. The light from two different sources, such as the two flashlights, always interferes either constructively or destructively, but when the sources are incoherent the interference pattern changes rapidly on the order of 10−14 seconds, which of course is not only too rapid to be observed by the eye but also by any other detector. The eye observes the time average of all the interference patterns, which is uniform. Light from two incoherent sources interferes but the interference is not observable. Interference can be observed when the interference pattern remains stable long enough to be observed and this requires that the interfering light is at least partially coherent. An interference phenomenon widely used in clinical practice, but not widely appreciated, is the basis for antireflection coatings.20 When light travels from one medium to another, a small amount of light is reflected at the interface between the two media. Anyone who has used a direct ophthalmoscope has experienced the annoying reflection from the corneal surface. In indirect ophthalmoscopy, reflection from the hand-held lens may interfere with fundus visualization, particularly when the slit lamp is used. Patients often complain of reflections associated with spectacle lenses. One way to reduce reflected light is to coat lenses with thin films. One type of antireflective coating consists of a thin film (one-half wavelength thick, approximately 250 nm) of material with a refractive index in between those of air and glass. Light is reflected from both the front and back surfaces of the film, but because the film is half a wavelength thick, the two reflections interfere destructively and reduce the amount of back-scattered light. In practice, thin film coatings are much more complicated and usually consist of multiple layers of different materials. A simple one-layer

antireflective coating may eliminate reflection for only one wavelength of light. Multilayer coatings may reduce reflection significantly over a range of wavelengths. Single-layer coatings also are scratched easily and can be removed by routine lens cleaning. Additional layers are used to make the coatings more durable. Thin films also occur clinically. The tear film consists of three layers: an outer oil layer, a middle aqueous layer, and an inner mucin layer. The oil layer constitutes a thin film that produces a colored interference pattern visible on slit-lamp examination.21 The appearance of the interference pattern is similar to the iridescent colors produced by a layer of oil or gasoline on the surface of a puddle of water. Inability to elicit the interference pattern suggests a specific defect in the oil layer. In principle, the aqueous and mucin layers are also thin films, but the mucin aqueous border is neither sharp nor smooth and does not produce thin film interference. Sometimes a nearly transparent layer of inflammatory cells grows on the surface of an intraocular lens implant.22 It may be difficult to see this layer with conventional slit-lamp illumination, but with placement of the slit beam at a slight angle to the visual axis, a rainbow of color caused by thin film interference may be appreciated. Cortical cells growing on the posterior capsule can produce a similar effect. Interference is used to assess retinal function in patients with ­media opacity, especially cataract. A laser light source is split into two narrow beams that presumably pass through small, clear regions of the lens. Because the beams are coherent, they form interference fringes on the retina. The arrangement is essentially a modification of Young’s two-slit experiment. The greater the separation of beams in the pupil, the narrower the interference fringes on the retina. The patient reports when he or she can see the fringes; the narrower the fringes the patient can detect, the better the potential acuity. To avoid a falsely low estimate of potential acuity, the patient must have a sufficiently large pupil to produce narrow fringes on the retina. Unfortunately, a falsely optimistic estimate of acuity can also be obtained in patients with macular edema or degeneration, because the test uses coherent light. The most recent innovative clinical application of interference is optical coherence tomography (OCT).23 The OCT scanner is basically a Michaelson interferometer (Fig. 2-2-5). The light source is a superluminescent diode, which has more coherence than white light but less than a laser diode. The limited coherence allows detection of interference effects over only a small optical path difference. By scanning the reference mirror, the optical path difference between various tissue layers can be measured. When interpreting OCT images, it is important to realize that OCT measures optical path length, not physical length. Optical path length is physical length multiplied by refractive index. OCT has also been used to measure axial length and corneal thickness. Just as the accuracy of ultrasound biometry depends on assumptions about the speed of light in ocular media, the accuracy of OCT measurements depends on assumptions about the refractive index of ocular tissues. Two corneas of identical thickness but with small differences in refractive index will appear to have different lengths when measured by OCT.

FLUORESCENCE Fluorescence is the emission of light of a lower energy light produced by absorption of a higher energy light and persisting only as long as stimulating energy is incident.24 Observation of fluorescence is usually enhanced by using filters to illuminate the fluorescent material only with the higher energy light (exciter filter) and observing only the fluorescent light using another (barrier) filter, although filters are not always necessary. For example, the most common clinical application of fluorescence is applanation tonometry, which uses an exciter filter but no barrier filter. Fluorescein angiography is the other well-known clinical application of fluorescence, and utilizes both exciter and barrier filters. Originally, the filters utilized absorptive dyes and did not perfectly separate the excitation and fluorescent wavelengths that are actually fairly close ­together. The use of thin film interference filters (discussed above) ­overcame this problem. Fluorophotometry is another clinical application of fluorescence that has been used in the past to evaluate the effect of drugs on aqueous dynamics25 and tear film dynamics.26 Vitreous fluorophotometry has also been used to assess vascular competence in patients with diabetes.27

   TABLE 2-2-1  APPROXIMATE AIRY DISK DIAMETERS FOR VARIOUS PUPIL SIZES

MICHAELSON INTERFEROMETER

condensing lens

pinhole (spatial filter)

mirror

objective lens

mirror

Fig. 2-2-5  Michaelson interferometer is the basis of optical coherence tomography. A beam splitter divides one light beam into two, which travel different paths and then are recombined. If the light source has low coherence, interference fringes are observed only when the optical path length of each arm is nearly identical. Placing the eye in one path of the interferometer and varying the length of the other arm can measure the optical path length to various ocular tissues.

DIFFRACTION EFFECTS Diffraction refers to the bending of light as it passes through an aperture; it was first observed independently by Hooke and Grimaldi in the mid-1600s.28, 29 Ultimately, diffraction limits the resolution of optical images. If an imaging system is well corrected, the ­image of a point source is an airy disc, and the radius of the central maximum is:30 r=

1.22λ 2 n′Sin(u′)

For the average eye, the exit pupil diameter is about 3 mm, and it is 18.5 mm from the retina. Thus, for an eye of these dimensions, the airy disc has a radius of about 2 μm or a diameter of 4 μm. This corresponds roughly to the diameter of a photoreceptor. If the airy disc were considerably larger than a photoreceptor, the optics of the eye would limit vision, and the retina would have an unnecessarily large number of photoreceptors. Conversely, if the airy disc were much smaller than the diameter of a photoreceptor, the imaging capabilities of the eye would far exceed the retinal resolution. So it is not surprising that the resolution of the ocular media correlates with the retinal anatomy. The calculation of ocular resolution assumes that the eye is essentially aberration free. Aberrations can be decreased by miosis, but this increases diffraction and the size of the airy disc, decreasing resolution. Conversely, mydriasis decreases diffraction and theoretically would improve resolution. However, the retina cannot make use of the increased resolution, and aberrations increase as the pupil dilates. This may ­explain the physiological purpose of the Stiles-Crawford effect. Rays that traverse the edge of the pupil are not as effective at stimulating the retina as central rays.

Pupil Diameter (mm)

Airy Disk Diameter (μm)

1.0

18.5

1.5

12.3

2.0

9.3

2.5

7.4

3.0

6.2

3.5

5.3

4.0

4.7

4.5

4.1

5.0

3.7

Physical Optics for Clinicians

light source

2.2

An important consequence of diffraction is that aberrations do not always significantly affect image quality, and elimination of aberrations does not always improve vision. Table 2-2-1 gives the diameter of the Airy disc as a function of pupil size for a typical eye. If wavefront measurements indicate a spot size close to the diffraction limit then eliminating higher order aberrations will not improve vision significantly. As an extreme example, in a patient with a 1-mm pupil, the Airy disc is so large that it is unlikely that eliminating high-order aberrations or a spherical aberration correcting lens implant will significantly improve vision. The visual symptoms of glare and haloes may be the result of diffraction.31 In corneal epithelial edema, fluid collects between epithelial cells and has a refractive index different from that of the cells. From an optical standpoint, a cornea that has epithelial edema is effectively a diffraction grating. Diffraction of white light produces a rainbow of colors. When a patient complains of seeing haloes, they are typically seen around streetlights, automobile headlights, or the moon. A distant, discrete light source produces nearly spatially coherent light; haloes from such light are especially prominent. It may be helpful to inquire specifically whether the patient sees a colored halo or a series of black and white rings. It is these authors’ personal experience that the haloes produced by the subepithelial infiltrates of epidemic keratoconjunctivitis are not colored but rather are white-light interference fringes. These occur even in the absence of corneal edema and can be seen even when visual acuity is 20/20 (6/6). The haloes produced by epithelial edema are colored when whitelight objects are viewed. Epithelial edema may be caused by a variety of conditions, some of the most common being glaucoma (with very high intraocular pressure), corneal abrasion, and contact lens overwear. The colored halo also is a useful sign in vitreoretinal surgery. The surgeon’s view may be diminished markedly by corneal epithelial edema or many other causes. Shining the light pipe on the working instrument gives a specular reflection that invariably has a colored halo around it if epithelial edema is present. A diminished view from epithelial edema can be overcome by removing the epithelium, but this can lead to postoperative complications such as corneal ulcer, especially in diabetics, who tend to re-epithelialize slowly. In the absence of a colored halo, the surgeon should consider other possible causes for the decreased view before removing the epithelium, perhaps unnecessarily. Binary optical lenses combine refractive and diffractive effects. Some multifocal intraocular lenses use binary optical designs. In the early 1990s, there was considerable interest in the use of diffractive optics for the correction of presbyopia. The diffractive part of the lens produced two images at different focal lengths. Some patients can tolerate the monocular diplopia and decreased image contrast. However, currently there is greater interest in more physiological approaches.

GLARE AND LIGHT SCATTER In an ideal world, light would travel straight through a material, but in reality, a small amount of light is scattered in all directions.32 Glare occurs when a defect in the ocular media scatters light, which decreases the contrast of the retinal image (Fig. 2-2-6).

33

2

GLARE No light scattering

OPTICS AND REFRACTION Light scatter

Some investigators hoped that objective measurements of light scatter by the crystalline lens would provide a guideline for cataract surgery. However, the appropriateness of cataract surgery depends on the effect of a visual deficit on the patient’s lifestyle, not on the degree of visual loss per se. A better use for light scatter measurements is to evaluate the efficacy of drugs intended to slow or prevent cataract formation. The difficulty in performing useful light scatter measurements cannot be overstated. Generally, to be of value, the amount of light scattered in all directions must be measured for every possible direction of incident beam. The results of such measurements constitute the bidirectional reflection distribution function. No current commercial instrument can measure the bidirectional reflection distribution of crystalline lens light scatter. A device that measures both Mie and Rayleigh scatter has been introduced to quantify both cells and flare in the anterior chamber. To date, the principal value of such measurements is to compare the efficacy of different treatment regimens.

QUANTUM MODEL OF LIGHT Although the wave model is very useful, some phenomena can be explained only on the basis of a quantum or discrete model of light. When electrons change energy levels, they often absorb or emit a photon. An electron in an elevated energy level may drop to a lower energy level spontaneously or as a result of stimulated emission. If a photon of appropriate energy passes by an electron in a high-energy state, the photon induces the electron to drop to a lower energy level and give off a second photon. The two photons are identical in energy and phase.33

BASIC LASER PHYSICS

Fig. 2-2-6  Glare. Without light scatter, light from an off-axis glare source does not overlap with the central retinal image. Light scatter by the ocular media, such as an early cataract, may decrease contrast in the central retinal image.

34

Light scatter generally is caused by particles in the medium. There are two types of scatter: Rayleigh scatter is caused by particles smaller than the wavelength of incident light, and Mie scatter is caused by particles larger than the wavelength of light. In Rayleigh scatter, the amount of scatter is proportional to the fourth power of the wavelength of the incident light. In Mie scatter, the amount of scatter is directly proportional to the wavelength of the incident light. Molecules of air result in Rayleigh scatter of sunlight. In Rayleigh scatter, blue light is scattered about 16-fold more than red. Consequently, the atmosphere acts as a blue-light filter. When the sun is overhead, sunlight traverses relatively little atmosphere, and the sun appears yellow. When the sun is low over the horizon, light must travel through more of the atmosphere, and more blue light is scattered, which gives the sun a red appearance. The same applies to scatter by the ocular media, especially the crystalline lens. As a person ages, light scatter by the lens increases, and fundus features appear more yellow and red. After cataract extraction, fundus details appear whiter. If a patient has had a cataract removed from one eye but has a cataract in the other eye, the optic nerve in the operated eye may appear atrophic by comparison to that in the ­phakic eye. This appearance may result from the difference in light scatter ­bet­ween the two eyes. For several reasons, attempts have been made to measure the amount of light scattered by the crystalline lens. Such measurements may be able to verify whether a cataract is bad enough to explain a patient’s visual loss or whether another cause is present. A fundamental problem is that only back-scattered light can be measured clinically. Back-scattered light is light that hits the lens and is scattered through the pupil and out of the eye. Back-scattered light does not reach the retina and therefore does not affect vision. Forward-scattered light hits the lens and is scattered, but it continues through the crystalline lens to reach the retina (and decrease vision). No definite relationship exists between forwardand back-scattered light.

Stimulated emission is the basis of the laser. The word laser was ­originally an acronym for light amplification by stimulated emission of radiation. In any laser there is a working medium. Normally, in any working material there are more electrons in lower energy levels than in higher levels. By some means, which can vary depending on the type of laser, energy is added to the working material so that a preponderance of electrons are in a high-energy state, a condition referred to as a population inversion. Eventually, one electron spontaneously decays, producing a photon that passes by other electrons and stimulates them to emit more identical photons. Partially reflecting mirrors placed at the ends of the medium cause the photons to pass through the working material multiple times, yielding a chain reaction that produces a beam.34

LIGHT–TISSUE INTERACTIONS Depending on the working material, photons of various wavelengths can be produced. To understand the clinical use of lasers, it is necessary to understand the various ways light interacts with tissue. In photocoagulation, light energy is absorbed by tissue generating heat.35 The heat denatures proteins, producing coagulation, much as the white of an egg coagulates when it is fried. To produce thermal effects, a tissue must absorb light; the more pigmented the tissue, the greater its absorption. The retina is largely transparent and does not absorb much light. However, the retinal pigment epithelium (RPE) and choroid do absorb light and produce heat that coagulates the adjacent retina. It can be difficult to photocoagulate the retina in patients with a blond fundus, because the choroid and RPE absorb less light. For similar reasons, producing a peripheral iridectomy using a thermal laser is more difficult in blue irides. In photodisruption, a shock wave is generated by optical breakdown. Photodisruption is essentially a miniature lightning bolt. In lightning, high electric fields literally tear the electrons away from the molecules of air, generating an expanding plasma. When the lightning stops, the electrons recombine, and the contraction of the air produces an acoustic shock wave commonly called thunder. In photodisruption, a very high power density is produced in a very small region, causing the material in that region to break down into a plasma. A small spark is seen at the site of optical breakdown. Recombination of electrons with ions in the plasma produces an acoustic shock wave that can alter ­ocular tissues.36 Because the posterior capsule is largely transparent, photocoagula­ tion cannot reliably produce a capsulectomy, so photodisruption is

In photoablation, high power densities break chemical bonds and vaporize tissue, but with minimal thermal or acoustic effects. LASIK and photorefractive keratectomy are based on photoablation. It is often stated that each excimer laser pulse removes a precise amount of tissue. This, of course, is nonsense. Many factors affect the amount of tissue removed. The amount of energy delivered in each pulse varies, depending on factors associated with the laser and atmospheric conditions. The amount of tissue removed also varies with corneal hydration and probably other patient-specific factors.

REFERENCES   1. Bragg WL. Universe of light. Smith Peter; 1980.   2. Duke-Elder S. System of ophthalmology. St Louis: CV Mosby; 1970.   3. Young T. Experimental demonstration of the general law of the interference of light. Phil Trans R Soc Lond.1804; 94.   4. Brain RN, Knudson O, Knudson O. Hans Christian Oersted and the romantic quest for unity. New York: Springer-Verlag; 2007.   5. Maxwell JC. A treatise on electricity and magnetism. Oxford: Clarendon Press; 1873.   6. Wood RW. Physical optics, 3rd ed. New York: Optical Society of America; 1988: 1–41.   7. Born M, Wolf E. Principles of optics, 6th ed. New York: Pergamon; 1980: 10–32.   8. Lipson SG, Lipson H, Thannhauser DS. Optical physics, 3rd ed. Cambridge: Cambridge University Press; 1995.   9. Bass M, ed. Handbook of optics, 2nd ed. New York: ­Optical Society of America; 1995:5.1–5.31. 10. Hecht E. Optics. 3rd ed.: Reading: Addison Wesley; 1997: 111–121 . 11. Jenkins FA, White EW. Fundamentals of optics, 3rd ed. New York: McGraw-Hill; 1990. 12. Fariza E, O’Day T, Jalkh AE, Medina A. Use of crosspolarized light in anterior segment photography. Arch Ophthalmol. 1989;107;608–10. 13. Morgan JE, Waldock A, Jefferey G, Cowey A. Retinal nerve fiber layer polarimetry: histological and clinical comparison. Br J Ophthalmol. 1998;82:684–90.

14. Colen TP, Tjon-Fo-sang MJ, Mulder PG, Lemij HG. Reproducibility of measurements with the nerve fiber analyzer (NfA/GDx). J Glaucoma. 2000;9:363–70. 15. Nevyas JY, Nevyas HJ, Nevyas-Wallace A. Change in retinal nerve fiber layer thickness after laser in situ keratomileusis. J Cataract Refract Surg. 2002;28:2123–228. 16. Zhou Q, Weinreb RN. Individualized compensation of anterior segment birefringence during scanning laser polarimetry. Invest Ophthalmol Vis Sci. 2002;43:2221–8. 17. Bagga H, Greenfield DS, Knighton RW. Scanning laser polarimetry with variable corneal compensation: identification and correction for corneal birefringence in eyes with macular disease. Invest Ophthalmol Vis Sci. 2003;44:1969–76. 18. Michaels DD. Visual optics and refraction: a clinical ­approach, 2nd ed. St Louis: CV Mosby; 1980: 702–4 . 19. Malacara D. Optical shop testing, 2nd ed. New York: Wiley; 1992: 1–5 . 20. Macleod A. Thin film optical filters, 2nd ed. New York: McGraw-Hill; 1989: 71–135 . 21. Lamberts DW, MacKeen DL, Holly FJ, eds. The preocular tear film in health, disease, and contact lens wear. Yantis, TX: Dry Eye Institute; 1986. 22. Okada K, Sagawa H. Newton rings on the surface of implanted lenses. Ophthalmic Surg. 1989;20:33–7. 23. Lakowicz JR, Geddes CD. Principles of fluorescence spectroscopy, 3rd ed. New York: Springer-Verlag; 2006.

24. Larsson LI, Pach JM, Brubaker RF. Aqueous humor dynamics in patients with diabetes mellitus. Am J ­Ophthalmol. 1995;120:362–7. 25. Fahim MM, Haji S, Koonapareddy CV, et al. Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease. BNC Ophthalmol. 2006;6:20. 26. Jackson WE, Chase HP, Garg SK, et al. Vitreous fluorophotometry in insulin dependent diabetes mellitus. Correlation with microalbuminuria and diastolic blood pressure. Arch Ophthalmol. 1990;108:1733–5. 27. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254:1178–81. 28. Hooke R. Micrographia. New York: Dover; 1961. 29. Park DA. The fire within the eye. Princeton: Princeton University Press; 1997:190. 30. Smith G, Atchison DA. The eye and visual optical instruments. New York: Cambridge University Press; 1997:656. 31. Ditchburn RW. Light. Mineola: Dover; 1991:1–17. 32. van de Hulst HC. Light scattering by small particles. New York: Wiley; 1957. 33. Eisberg R, Resnick R. Quantum physics of atoms, molecules, solids, nuclei, and particles. New York: Wiley; 1974. 34. Hecht J. Understanding lasers: an entry-level guide, 2nd ed. New York: Wiley-IEEE Press; 1994. 35. Mainster MA, Ho PC, Mainster KJ. Nd:YAG laser photo­ coagulators. Ophthalmology. 1983;90(Suppl):48–54. 36. Mainster MA, Ho PC, Mainster KJ. Nd:YAG laser photo­ disrupters. Ophthalmology. 1983;90(Suppl):45–7.

2.2 Physical Optics for Clinicians

used instead. When performing a capsulectomy, the goal is to produce an optical breakdown behind the lens implant and capsule and let the acoustic shock wave tear the capsule. It is more difficult to perform a capsulectomy in patients with silicone implants, because optical breakdown of silicone occurs at lower power densities than does breakdown of polymethylmethacrylate. Often the optical breakdown occurs in the lens and not posterior to it. Optical breakdown in the lens implant produces a small pit that by itself is usually not visually significant, but severe pitting of the lens can decrease vision.

35

PART 2 OPTICS AND REFRACTION

2.3

Light Damage to the Eye David Miller and Clifford A. Scott

Definition:  Structural or functional damage to the external or internal eye from thermal or photochemical effects of the absorption of light.

Key features n n

 ith age, many of the photoprotective mechanisms of the eye W degrade. Cataract development and the risk of macular degeneration are accelerated by cumulative or excessive exposure to UV radiation.

Associated features n n

 eduction of environmental exposure and the use of absorptive R lenses diminish the risk of light damage to the eye. Intake of antioxidant foods or dietary supplements may slow the development of cataracts and macular degeneration. 

ULTRAVIOLET FILTRATION The oxygen holocaust, a term invented by Margulis and Sagan,1 describes that period in the evolution of life on Earth when the atmospheric oxygen content rose from 0.0001% to 21%. The source of such an atmospheric change was the evolution of photosynthesis by ancient green and purple bacteria, which seems to have started about 2 billion years ago. The change in environment destroyed most of the anaerobic microbes on Earth. Newly evolved resistant bacteria multiplied and ultimately developed the reactions of aerobic metabolism that prevail in life today. A secondary effect of this “newly formed oxygen” was that as it rose into the upper reaches of the Earth’s atmosphere, it reacted with incoming ultraviolet (UV) light from the Sun and formed the ozone layer near the top of the atmosphere, about 30 miles (48.3 km) up. The ozone layer is important in two ways2 (Fig. 2-3-1). First, it helps to stabilize the atmospheric oxygen level at 21% (excess oxygen is used to make more ozone); it has been suggested that many living organisms would not tolerate levels of atmospheric oxygen a few per cent higher than 21%. However, it is the second effect of the ozone layer that is discussed in this chapter. The ozone layer, only about 2−3 mm in thickness, is produced in the stratosphere by a photochemical reaction fueled by UV-C radiation and/ or lightning and spread by the stratospheric winds. This is ironic, because the ozone layer then filters out most of the potentially destructive UV light that arrives from the Sun. Research that started in 1980 noted a 3–6% per decade decay in the ozone layer, notably in the Northern Hemisphere. This depletion of the ozone layer, thought to be caused by chlorine from industrial pollutants, leads to an approximate 1% increase in UV-B radiation that reaches the Earth’s surface for every 1% reduction in ozone.3

Ultraviolet Profile

36

Of all the light energy that rains down on Earth, < 10% may be considered to be UV radiation in the range 280–400 nm.4 The UV spectrum has been subdivided into the following categories: l UV-A, 400–320 nm (90% of UV radiation from the Sun) l UV-B, 320–280 nm l UV-C, 280 nm and below

Although UV radiation with this profile has fallen on Earth from the time the ozone layer was established, forms of life still remain that can be damaged by UV radiation. Of course, the specific wavelength and dosage determine the specific organism’s response. Thus, bacteria may survive under the fluorescent light of the operating room (which has very small amounts of UV) but are destroyed by germicidal lamps (high amounts of short-wavelength UV radiation). Normal human skin maintains health under average light conditions but can experience sunburn in which the skin is damaged under prolonged exposure to high doses of UV radiation.

ULTRAVIOLET VULNERABILITY UV radiation can be potentially damaging if a certain balance is upset. Groups vulnerable to ocular UV radiation damage are discussed below.

Older Individuals

Light damage to tissue ultimately depends on a series of photochemical reactions. The body, in turn, has a series of protective molecules that either filter out the harmful wavelengths or scavenge the harmful photo­ metabolites. With increased age, it has been suggested that the concentration of some of these protective molecules decreases. For example, age-related macular degeneration and cataract formation may be related to a combination of cumulative light exposure and a coincident decrease in protective biochemicals.

Lightly Pigmented Individuals

Studies have shown that patients whose irises are blue (lighterpigmented eyes) have a significantly higher incidence of age-related macular degeneration than a control series of patients who have brown irises.5 Age-related macular degeneration is almost unknown in the genetically pure Black patient. SPECTRAL COMPOSITION OF SUNLIGHT solar flux 0.7 (103W/ m2/�m) 0.6

top of atmosphere

a

0.5 0.4

Earth's surface

b

0.3 0.2 0.1 0 250 260

270

280

deoxyribonucleic acid

290

300

proteins

310

b 320

330 340 350 wavelength (nm)

a spectral composition of sunlight before reaching the ozone layer b spectral composition of sunlight after passing through the ozone layer

Fig. 2-3-1  Spectral composition of sunlight. Before reaching ozone layer and after passing through the ozone layer. (Adapted from MacCracken M, Change J: Preliminary study of the potential chemical and climate effects of atmospheric nuclear explosion. UCRL 51653. San Francisco: Lawrence Livermore Laboratory. 1975;April 25:48.)

2.3

B

C

D

E

F

Light Damage to the Eye

A

Fig. 2-3-2  Increasing yellow to brown coloration in human lenses. (A) 6 months. (B) 8 years. (C) 12 years. (D) 25 years. (E) 47 years. (F) 60 years. (Reproduced with permission from Lerman S. Phototoxicity: clinical considerations. Focal Points. San Francisco: American Academy of Ophthalmology. 1987;1−22.)

MOLECULAR CONFIGURATIONS OF PHOTOSENSITIZING DRUGS Doxycycline CH3

OH

Benoxaprofen

OH N(CH3)2

O

HO

OH

O

OH

COOH

O

S

O

N

CONH2

CI

O Penflutizide

O

N

S

CH3CH

Piroxicam OH

Chloropromazine

N H

N

CH3

H2NSO2

O

S

CI

CH2CH2CH2N(CH3)2 Sulfanilamide

H N

F 3C

N

(CH2)4CH3

NH2

NH O

SO2NH2

Fig. 2-3-3  Molecular configurations of photosensitizing drugs.

Aphakia

Results from the Framingham study suggested that nuclear sclerosis in the elderly protects the retina from age-related degeneration.6 Lerman7, 8 has shown that the aging crystalline lens is an efficient filter against UV radiation and blue light (Fig. 2-3-2). Ham et al.9 may have brought together the above information when they were able to produce retinal injury in aphakic monkeys using short-wavelength visible light.

Use of Photosensitizing Drugs

Chemical compounds with multiple cyclic rings (Fig. 2-3-3) that contain alternating double bonds are often photosensitizing agents. These agents are able to absorb UV radiation and short-wavelength visible light and then generate free radicals, which damage tissue. Compounds that fall into this group include phenothiazines, 8-methoxypsoralen (used in the treatment of psoriasis), allopurinol, tetracyclines, and hematoporphyrins used for phototherapy. When these compounds deposit in the lens or retina, the tissues become more vulnerable to light damage.

Outer Segment Turnover

It appears that nature copes with the anticipated light damage to the discs that contain photopigment through the daily retinal pigment epithelium digestion of a portion of the outer segment. If a malfunction occurs in this digestive system as a result of genetics, malnutrition, or injury, then a buildup

of photoreceptor disc metabolites results. Such a buildup may be related to drusen deposition and clinical age-related macular degeneration. Thus, some form of faulty, radiation-damage defensive system may be partially responsible for age-related macular degeneration.10

BIOCHEMICAL MECHANISM OF UV RADIATION DAMAGE For photodamage to occur, tissue must contain a molecule that absorbs light. Tissue damage may occur in two ways: molecular fragmentation and free radical generation.

Molecular Fragmentation

Proteins, enzymes, and nucleic acids contain alternating double bonds. Such molecular configurations efficiently resonate with radiation of UV wavelength. An analogy is that of opera singers who break wineglasses by striking certain notes; they tap the glass to establish its resonating frequency and sing loudly in that frequency. The resonating frequency may be thought of as fitting snugly into the glass structure. The increased intensity of UV radiation, like a dynamite charge placed snugly in a rock crevice, breaks the molecular bonds. The new molecules may induce inflammation or neoplasm, or affect the immune system.

37

2 OPTICS AND REFRACTION

Pigmented molecules absorb visible light and UV radiation of a specific wavelength. This photon absorption ultimately changes the ­energy level to the unstable triplet state. The molecule then ejects an electron, which usually combines with a neighboring molecule (often oxygen in cases of photodamage). When an oxygen molecule gains an extra electron, it is known as superoxide, one of a family of compounds called free radicals. These are, in truth, super oxidizers. Free radicals may disrupt cell membranes, mitochondrial membranes, and nucleic acids; depolymerize collagen and hyaluronic acid; and destroy tissue. Free radical light damage to tissue requires three components: a light-absorbing molecule (dye, pigment), oxygen, and short-wavelength radiation. Fortunately, specialized molecules occur in the body to disarm any newly arrived free radical. These scavenger molecules (of which many exist) include the ubiquitous superoxide dismutase, vitamin C, vitamin E, glutathione peroxidase, and carotene. A shortage of these scavengers in the very young (premature infants), the old, or the nutritionally impaired can tip the balance toward greater vulnerability to light damage. Can long wavelength UV and short wavelength visible light cause clinical light damage to ocular structures? The answers to this topic will be discussed elsewhere in this book. Suffice to say, the literature is replete with examples of light damage to the lid skin, cornea, lens, and retina.11–39

LIGHT PROTECTION During Surgery

As noted earlier, light from the operating microscope has been shown to produce maculopathy during a prolonged cataract extraction (with or without an implant).29–32 Thus, a number of methods have been suggested to reduce the concentration of light that strikes the retina during surgery. For example, light can be blocked by a small occluder disc placed on the cornea, directly over the pupil. A bubble of air may also be placed in the anterior chamber, which (optically speaking) neutralizes the corneal focusing power. However, the bubble also enhances the refractive power of the anterior surface of the intraocular lens. The combined neutralization and enhancement effects of the bubble substantially defocus the light that strikes the retina. Certain operating microscopes are equipped with an occluder disc that may be placed in the center of the path of the light that strikes the eye. This system produces an annulus of light with a dark center, which is incident upon the cornea. The most effective protective measure against maculopathy induced by operation light is to shorten the time of surgery.

Ultraviolet Filters in Intraocular Lenses

Currently, most intraocular lens manufacturers produce implants with UV filters. In general, these implants filter out all wavelengths of light < 400 nm, which not only protects the plastic of the implant from UV degradation, but appears to prevent decreases in visual function such as color vision and contrast sensitivity.16, 40

Absorptive Lenses

In certain high-illumination situations, sunglasses allow better visual function in a number of ways (Table 2-3-1).

Improvement of Contrast Sensitivity

On a bright sunny day, illuminance from the Sun is in the range 10 000– 30 000 foot lamberts (34 260–103 000 cd/m2). These high light levels tend to saturate the retina and therefore decrease finer levels of contrast sensitivity. The major function of dark sunglasses is to return the retina to a level of maximal contrast sensitivity (i.e., eliminate the “increased noise” of the retina).41 Most dark sunglasses absorb 70–80% of the incident light of all wavelengths. (Light levels are often described in log10 units, i.e., 1, 2, 3 or −1, −2, −3; a log10 value of −1 reduces the light level by 90% and is equivalent to a sunglass that absorbs 90% of the incident light; a lens that absorbs 70% is equivalent to a log10 value of −0.84.)

Improvement of Dark Adaptation

38

   Table 2-3-1  Commonly Prescribed Lens Tints

Free Radical Generation

Experiments have shown that a full sunny day at the beach (without dark sunglasses) may impair dark adaptation for over 2 days. Thus, dark sunglasses (absorption of 70–80% of incident light) are recommended for prolonged periods in bright sun.42

Lens Tint

Visible Light Transmission (%)

Uses

UV absorbing clear

90

Absorbs almost all UV   up to 385 nm

Amber

90

Enhances low light contrast

Light gray

35

Outdoor glare  reduction   Uniform color ­transmission

Standard gray sunglass

15

Uniform color   transmission

Mirrored lenses (reflect rather than absorb light)

15

Uniform color   transmission   No optical advantage

Dark green

2

Shade 5 Welding goggles

PHOTOCHROMIC LENS BEHAVIOR luminous 90 transmittance 80 (%) 70 60 50 40 30 20 10 0

darkening

0

5

10

15

fading

5

PhotoGray Transitions Transitions Plus PhotoGray Extra

10

15

20

25 30 time (min)

Fig. 2-3-4  The darkening and fading of four popular photochromic lenses. Note that most darken maximally by 2−3 minutes and fade in 5 minutes. ­(Modified with permission from Young JM. Photochromics: past and present. Opt World. 1993;Feb.)

Reduction of Glare Sensitivity

A number of sunglass modalities may reduce glare sensitivity. Polaroid sunglasses reduce the intensity of reflected light from road surfaces, glass windows, lake and river surfaces, and metal surfaces. Thus, dazzle and glare sources are reduced in intensity. Since light reflected from a horizontal surface produces light polarized in the horizontal plane, properly oriented Polaroid sunglasses may eliminate this component. For many activities, such as fishing or driving, reduction in surface glare improves overall visual comfort. However, polarized lenses eliminate the clue of reflection to a pilot scanning the skies for other aircraft. Graded density sunglasses are tinted deeply at the top and gradually become light toward the lens center. They effectively remove dazzle from glare sources above the line of sight (e.g., the Sun). Wide temple sunglasses reduce glare from sources at the side.41

Improvement of Color Contrast

Orange sunglasses efficiently absorb wavelengths in the purple through blue−green range. All these colors appear as different forms of dark gray to the wearer. On the other hand, the wearer clearly sees the spectrum from green through yellow to orange to red. Colors appear slightly unreal, but color contrast improves. Patients who have conditions such as cataracts or corneal edema, for whom color contrast sensitivity has decreased, report improvements in color contrast using these sunglasses.43

ABSORPTION SPECTRA FOR LENS MATERIALS

diameter (mm) 9 8 7 6 5 4 3 2

60 40 20 0

300

325

350

exterior (night)

visible

UV-A

375

glass CR-39 polycarbonate CR-39�

400

�6

�5

425 450 wavelength (nm)

Fig. 2-3-5  Absorption spectra for crown glass, CR-39, CR-39+, and polycarbonate lenses.

Use of Photochromic Lenses

Photochromic lenses are either glass or plastic. When short-wavelength light (300–400 nm or longer) interacts with glass photochromic lenses, they darken (Fig. 2-3-4). The chemical reaction (i.e., the conversion of silver ions into elemental silver) is similar to the reaction that ­occurs when photographic film is exposed to light. In contrast to the chemical reaction in film sensitive to radiation of these wavelengths, that in ­photochromic lenses is reversible. With continued exposure to ­radiation of short wavelengths, the lens continually darkens to absorb about 80% of the incident light, and then lightens when the illumination falls to absorb about 20% of the incident light. These lenses take longer to lighten than to darken, but when darkened they are also excellent ultraviolet absorbers.44 Plastic photochromic lenses are coated with an organic molecule from the generic molecular group indolinospironaphthoxazine, which changes shape and consequently light-absorptive properties when illuminated.

�4

interior (night)

�3

�2

exterior (day)

interior (day)

�1 0 �1 �2 �3 �4 logarithm of luminance (foot lamberts)

2.3 Light Damage to the Eye

transmittance 100 (%) 80

UV-B

PUPILLARY DIAMETER AND AMBIENT ILLUMINATION

largest diameter observed average of 6 subjects tested smallest diameter observed

Fig. 2-3-6  Relationship between pupillary diameter and ambient level of illumination. (Modified with permission from Reeves P. Response of the average pupil to various intensities of light. J Opt Soc Am. 1970;4:135−9.)

with a special coating) or polycarbonate. A study of the transmission spectra for nine inexpensive clip-on sunglasses showed that all but the blue-colored clip-ons remove over 90% of the UV.45 Figure 2-3-5 shows the absorption curve for clear glass, CR-39, and clear polycarbonate. It has been suggested that certain sunglasses, ironically, may produce light damage to the eye. The argument contends that the pupil dilates behind dark glasses. Thus, sunglasses that do not absorb significant amounts of UV radiation actually allow more of it to enter the eye than when no sunglasses are worn. Figure 2-3-6 shows that the pupil enlarges most under scotopic conditions. On a bright, sunny day, irradiance is in the range 10 000–30 000 foot lamberts (34 260–103 000 cd/m2) and the pupil constricts maximally. A dark sunglass (one that absorbs 80% of the incident light) reduces the level of light that strikes the eye to the range 2000–6000 foot lamberts (6 850–20 600 cd/m2). Such levels are about ten times higher than those of an averagely lit room. At such light levels, the pupil is still constricted significantly.

Ultraviolet-Absorbing Lenses

Almost all dark sunglasses absorb most of the incident ultraviolet ­radiation, which is also true for certain coated, clear-glass lenses and the clear plastic lenses made of CR-39 (a commonly used clear plastic

References   1. Margulis L, Sagan D. Microcosmos. New York: Summit Books; 1986.   2. MacCracken M, Change J. Preliminary study of the potential chemical and climatic effects of atmospheric nuclear explosion. UCRL 51653. San Francisco: Lawrence Livermore Laboratory, April 25. 1975;48   3. Frederick JE. Yearly Review: Trends in atmospheric ozone and ultraviolet radiation: Mechanisms and observations for the Northern Hemisphere. Photochem Photobiol. 1990;51:757–63.   4. Terrestrial Global Spectral Irradiance Tables for Air Mass 1.5. ASTM Document 138 RI E 44.02, Feb 1981.   5. Hyman LG, Lillienfeld AM, Ferris FL III, Fine SL. Senile macular degeneration. A case controlled study. Am J Epidemiol. 1983;118:350–4.   6. Sperduto TD, Holler R, Seigel D. Lens opacities and senile maculopathy. Am Arch Ophthalmol. 1981;99:1004–9.   7. Lerman S. Phototoxicity: clinical considerations. Focal Points. San Francisco: American Academy of Ophthalmology; 1987:1������������ –22���������.   8. Lerman S. Radiant energy and the eye, New York:   Macmillan; 1980.   9. Ham WT Jr, Mueller HA, Ruffolo JJ Jr, et al. Action spectrum for retinal injury from near ultraviolet radiation in the aphakic monkey. Am J Ophthalmol. 1982;93:299–306.

10. Weiter J. Phototoxic changes in the retina. In: Miller D, ed. Clinical light damage to the eye. New York: Springer-Verlag; 1987:79–125. 11. Bernhard JD. Light induced changes in the skin of the lid. In: Miller D, ed. Clinical light damage to the eye. New York: Springer-Verlag; 1987:127–44. 12. Urbash F. Photocarcinogenesis. In: Regan JD, Parrish JA, eds. The science of photomedicine. New York: Plenum Press; 1982:261–92. 13. Voerhoeff FH, Bell L, Walker CB. The pathological effects of radiant energy on the eye. An experimental investigation with a systemic review of the literature. Proc Am Acad Arts Sci. 1916;51:630–818. 14. Cogan DG, Kinsey VE. Action spectrum of keratitis produced by ultraviolet radiation. Arch Ophthalmol. 1946;35:370–6. 15. Pitts DG, Tredici TJ. The effects of ultraviolet on the eye. Am Ind Hyg Assoc J. 1971;32:235–46. 16. Miller D. Clinical light damage to the eye, New York: Springer-Verlag; 1987. 17. Norn MS. Spheroidal degeneration of cornea and conjunctiva. Prevalence among Eskimos in Greenland and Caucasians in Copenhagen. Acta Ophthalmol. 1978;56:551–62. 18. Cameron EE. Pterygium throughout the world. Springfield: CC Thomas; 1965.

19. Geeraets WJ, Harrel W, Guery D, et al. Aging anomalies and radiation effects on rabbit lens. Acta Ophthalmol. 1965;43:3–10. 20. Giblin FH, Chakrapani B, Reddy VN. High molecular weight aggregates in X-ray induced cataracts. Exp Eye Res. 1978;26:507–15. 21. Hiller R, Sperduto RD, Ederse F. Epidemiologic association with cataract. The 1971−72 natural health and nutrition examination survey. Am J Epidemiol. 1983;118:230–49. 22. Brilliant LB, Grosset NC, Ram PT, et al. Association among cataract prevalence, sunlight hours and altitude. Am J Epidemiol. 1983;118:2350–64. 23. Taylor H. The environment and the lens. Br J Ophthalmol. 1980;64:303–10. 24. Taylor H, West SK, Rosenthal FS, et al. Effect of ultraviolet radiation on cataract formation. N Engl J Med. 1988;319:1429–33. 25. Zigman S. Light damage to the lens. In: Miller D, ed. Clinical light damage to the eye New York: Springer-Verlag;   1987 :65–78. 26. Goosey JD, Zigler JS Jr, Kinoshita JH. Cross linking of lens crystalline in a photodynamic system. Science. 1980;208:1278–80.

39

2 OPTICS AND REFRACTION

40

27. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and visual loss: AREDS report no. 9. Arch Ophthalmol. 2001;119:1439–1452. 28. Jacques PF, Chylak LT Jr, Hankinson SE, et al. Longterm nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119:1009–19. 29. Miranda MN. The environmental factor in the onset of presbyopia. In: Stark L, Obrecht G, eds. Presbyopia. Recent research and reviews from the Third International Symposium. New York: Professional Press; 1987. 30. Calkins JL, Hochheimer BF. Retinal light exposure from operation microscopes. Arch Ophthalmol 1974;97:2363–7. 31. Covard DM. Operating microscope light induced retinal injury. J Am Intraocul Implant Soc. 1984;10:438–43. 32. Irvine AR, Wood I, Morris BW. Retinal damage from the illumination of the operating microscope. Arch Ophthalmol. 1984;102:1358–64.

33. Dawson WW, Herron WL. Retinal illumination during indirect ophthalmoscopy. Invest Ophthalmol. 1970;9:89–95. 34. Davies S, Elliott MH, Floor E, et al. Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med. 2001;31:256–65. 35. Reeves P. Response of the average pupil to various intensities of light. J Opt Soc Am. 1970;4:135–9. 36. Weiter JJ, Delori FC, Wing GL, Fitch KA. Relationship of senile macular degeneration to ocular pigmentation.  Am J Ophthalmol. 1985;99:185–7. 37. Glass P, Avery G. Effect of bright light in the hospital nursery on the incidence of retinopathy of prematurity. N Engl J Med. 1985;313:401–4. 38. Dillon J. The photophysics and photobiology of the eye.  J Photochem Photobiol B. 1991;10:23–40. 39. Taylor H, West S, Munoz B, et al. The long-term effects of visible light on the eye. Arch Ophthalmol. 1992;110:99–104. 40. Waxler M, Hitchins VM. Optical radiation and visual health. Boca Raton: CRC Press; 1986.

41. Miller D, Benedek GB. Intraocular light scattering, Springfield: CC Thomas; 1973. 42. Clark BA. Color in sunglass lenses. Am J Optom. 1969;46:875–80. 43. Tupper B, Miller D, Miller R. The effect of 550 nm cutoff filter on the vision of cataract patients. Ann Ophthalmol. 1985;17:72–4. 44. Young JM. Photochromics: past and present. Opt World. 1993;Feb. 45. Magnante D, Miller D. Ultraviolet absorption of commonly used clip-on sunglasses. Ann Ophthalmol. 1985;17:614–6.

PART 2 OPTICS AND REFRACTION

2.4

Principles of Lasers Neal H. Atebara and Edmond H. Thall

Definition:  “Laser” is an acronym for light amplification by stimulated emission of radiation.

Key features n

n

n

L asers have had a greater impact on ophthalmology than on any other medical specialty, largely because the transparent nature of the ocular tissues allows laser light to reach many parts of the eye noninvasively. In modern ophthalmology, lasers are used to treat a wide range of ocular conditions, and their uses are some of the most commonly performed procedures in medicine. Lasers are also important in a growing number of diagnostic   studies that promise to significantly enhance our understanding and treatment of many disease processes in the eye.

INTRODUCTION The word laser is an acronym for light amplification by stimulated emission of radiation.1Stimulated emission of a photon of electromagnetic radiation is the basic physical principle that makes lasers possible. This process was first predicted theoretically by Albert Einstein in 1917, but for many years it was believed that putting this theory into practice was not possible. The first laser system used in ophthalmology utilized a pulsed ruby laser coupled with a monocular direct ophthalmoscopic delivery system, first reported in 1961.2 It was used to treat retinal breaks and proliferative diabetic retinopathy. In 1968, L’Esperance3 developed the argon laser, which was technically superior to the ruby laser. The argon laser, the diode laser, the yttrium−aluminum−garnet laser, and the ­excimer laser are frequently used in ophthalmology today.

LASER PHYSICS In order to understand how lasers work, we first must review some basic physical principles, including the nature of photons, the nature of atoms, and how photons and atoms interact. Light may be viewed as being comprised of individual “wave packets” called photons. Each photon has a characteristic frequency, and its energy is proportional to its frequency.4 Thus, a photon of blue light carries more energy than a photon of red light. Although an atom may superficially resemble a miniature solar system, with negatively charged electrons that orbit a positively charged nucleus, there are significant differences. In our solar system, each planet stays in one stable orbit, whereas in an atom the electrons are capable of jumping between different orbits. Further, in our solar ­system, a planet may theoretically have any energy, but electron orbits are strictly constrained to discrete energy levels.5 Figure 2-4-1 simplistically depicts a helium atom at one particular instant showing the two electrons that orbit the nucleus and several other empty orbits that electrons could occupy. Each orbit has a unique energy, and to jump from one orbit to another an electron must either gain or lose energy. The amount of energy gained or lost by an electron when it changes orbits equals the energy difference between the two ­ orbits. An atom is extremely dynamic, with electrons constantly ­absorbing and emitting photons and changing orbits.

The three basic ways for photons and atoms to interact include: (1) absorption, (2) spontaneous emission, and (3) stimulated emission. An electron can absorb a passing photon and jump into a higher energy orbit.6 Absorption occurs only if the photon’s energy exactly matches the difference in energy between the two electron orbits. Absorption ­begins with a photon and a low-energy electron and yields a higher ­energy electron with the elimination of the photon. In spontaneous emission, an electron in a high-energy state spontaneously drops into a lower energy state and, in the process, creates a photon.6 The photon created has an energy equal to the difference in ­energies between the two electron orbits. Spontaneous emission begins with a high-energy electron and yields a photon and a low-energy electron. Spontaneous emission is a random process. At any moment, an electron in a high-energy state may drop into a lower state with the emission of a photon. Generally, electrons spend only a few nanoseconds in the high-energy state before this emission occurs. Some high-energy states, however, are metastable. Electrons linger in these states for a lengthy few milliseconds before spontaneous emission occurs.7 In stimulated emission, a photon passes in the vicinity of a high-­energy electron. The photon stimulates the electron to emit a photon and drop into a lower state. The stimulating photon must have an energy equal to the energy difference between the two electron orbits. Stimulated emission begins with a photon and a high-energy electron and yields two photons and a low-energy electron. Stimulated emission is not a random process. The electron drops at the moment a passing photon stimulates the electron to drop and emit a photon. Importantly, the stimulating photon and the emitted photon will be identical in frequency and phase. In other words, the two photons are coherent.8 Many ways exist to produce light, but stimulated emission is the only method known that produces coherent light, a property with many practical applications. Figure 2-4-2 illustrates these three processes − absorption, spontaneous emission, and stimulated emission.

HOW LASERS WORK Gas lasers are commonly used in clinical ophthalmology. Atoms of the working gas, such as argon or krypton, are enclosed in a cylindrical tube, called the laser cavity (Fig. 2-4-3). Under natural conditions there are more electrons in lower energy orbits than higher energy orbits. Eventually one of the high-energy electrons undergoes spontaneous emission, generating a photon. If this photon first encounters a lowenergy electron (which is much more common at this point), it is merely absorbed. However, in the event that it encounters another high-energy electron, stimulated emission occurs. To sustain a large number of stimulated emissions, there must be more electrons in high-energy states than low-energy states, a condition called population inversion. To produce a population inversion in the gas laser, the gas is pumped by a powerful light source or by an electric discharge that forces electrons to go into high-energy states. Merely achieving a population inversion is not sufficient; it must be maintained, because most high-energy states decay in a few nanoseconds by spontaneous emission. However, when electrons are pumped into a metastable state the population inversion may be maintained for a longer period of time. With the majority of electrons in a highenergy metastable state, a photon generated by spontaneous emission is now more likely to produce a stimulated emission instead of merely being absorbed. The two coherent photons generated by a stimulated emission go on to produce more stimulated emissions, and a chain reaction begins.

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2 OPTICS AND REFRACTION

In order to maintain the chain reaction of stimulated emissions, mirrors are placed at each end of the cavity, an arrangement called a resonator.9 One mirror reflects totally and the other partially (see Fig. 2-4-3). Most of the coherent light generated is reflected back into the cavity to produce more stimulated emissions. The relatively small amount of light that is allowed to pass through the partially reflecting mirror produces the actual laser beam.

SIMPLE MODEL OF A HELIUM ATOM AT A SINGLE POINT IN TIME

CONTINUOUS AND PULSED LASERS Lasers emit light either continuously or in pulses. Although a pulsed laser produces only modest amounts of energy, the energy is concentrated into very brief periods, and so each pulse has a relatively high power (power is energy per unit time). Neodymium:yttrium-aluminum-garnet (Nd:YAG) and excited dimer (excimer) lasers are examples of pulsed lasers. A continuous laser modality delivers more overall energy to a target tissue, but it does so over a relatively long time; thus the power is lower. Because clinical applications do not generally require high power (usually less than one watt), most ophthalmic lasers operate continuously with a shutter to control the specific exposure time and thereby allow more control over the energy delivered to the target tissue. Argon lasers, krypton lasers, diode lasers, and dye lasers are all examples of continuous laser modalities.

WHAT COLOR IS YOUR LASER?

neutron

proton

electron

Fig. 2-4-1  Simple model of a helium atom at a single point in time. Electrons orbit a nucleus of protons and neutrons. Each orbit has a unique energy. The two electrons in this case occupy two different orbits. By gaining or losing   energy the electrons can move to other, currently empty, orbits.

The number of optical wavelengths that can be produced by lasers is rather limited, dependent on the particular metastable state of the working material. For instance, in the krypton ion, when an electron drops from its metastable state to a lower energy level, it produces light with a wavelength of 647 nm (which corresponds to red light). Using different nonmetastable states, the krypton ion can produce several other wavelengths, but only at significantly lower powers. For practical reasons, only krypton lasers that operate at the 647-nm wavelength are available commercially. The argon ion has two metastable states, and it therefore produces two prominent wavelengths of light at 488 nm and 514 nm, which correspond to blue−green and green, respectively. Most commercial argon lasers allow the clinician to select either the green 514-nm light or a mixture of blue−green 488-nm and green 514-nm light.

BASIC INTERACTIONS BETWEEN LIGHT (PHOTONS) AND ELECTRONS Absorption electron in orbit

electron in higher orbit

photon Spontaneous emission electron in lower orbit

electron in orbit

photon

Stimulated emission passing photon electron in orbit

42

electron in lower orbit

passing photon emitted photon

Fig. 2-4-2  Three basic interactions between light (photons) and electrons. An electron absorbs a photon, which forces it to move to a higher energy orbit. In   spontaneous emission, a photon is produced by the electron, which then “falls” to a lower energy orbit. In stimulation, a photon passes by an electron and stimulates it to “fall” into a lower energy orbit and produce a second photon, coherent with the first figure.

provide a large number of metastable orbits that differ little in energy, so a variety of different wavelengths are available. Dye lasers may be tuned to the desired wavelength, allowing clinicians to select the optimum wavelength for each procedure. For example, the organic dye laser based on rhodamine 6G can be tuned continuously from 570 nm to 630 nm. The drawbacks of dye lasers are that they are the least efficient producers of laser energy and most expensive to manufacture. In fact, current tunable dye lasers utilize an argon laser to pump energy into the fluorescent dye. This complex system of two lasers increases the manufacturing cost and the likelihood of mechanical failure. Figure 2-4-4 shows the different wavelengths of light produced by the more commonly used ophthalmic lasers and where these wavelengths lie on the electromagnetic spectrum.

2.4 Principles of Lasers

Some laser procedures demand peak wavelengths that do not correspond to the metastable state of any conventional working material. For instance, in the treatment of macular choroidal neovascularization using photocoagulation, xanthophyll pigment in the macula absorbs a significant amount of laser light, thereby increasing the risk of damage to the neurosensory retina and decreasing the amount of energy delivered to the abnormal blood vessels below. Xanthophyll pigment transmits light best at 577 nm, but it is difficult to generate this wavelength with lasers. Two ways exist to increase the number of available wavelengths: harmonic generation and employing organic dyes. In harmonic generation, laser light is passed through an optically nonlinear crystal,10 which doubles its wave frequency. When light traverses any medium, a small amount of the light is absorbed. Typically, the absorption is linear in the sense that doubling the light intensity doubles the amount of energy absorbed. In a nonlinear medium, doubling the intensity does not double absorption; it increases it, by perhaps fourfold or more. Laser light causes such nonlinear crystals to vibrate, not only at the laser’s frequency, but also at exact multiples of the laser’s frequency, called harmonics. For instance, the middle A note on a piano has a frequency of 440 cycles per second; its harmonics include 880, 1320, 1760 cycles per second, and so on. Generally, this method of creating new wave frequencies is quite inefficient, and the harmonics generated have very low power. However, a nonlinear crystal has been found that efficiently doubles the frequency of the 1064-nm output of an Nd:YAG laser, producing a 532-nm wavelength, which is relatively close to the transmission window of xanthophyll (577 nm). This “double-frequency” Nd: YAG laser has, to a large degree, replaced the argon green laser for posterior segment photocoagulation because of its solid-state construction and greater reliability. Another method used to produce more wavelengths employs organic dyes.11 As a result of their complex chemical structure, organic dyes

CLINICAL USE OF LASERS Notwithstanding the planet-destroying capabilities of the lasers depicted in Hollywood movies, real-life lasers are not death rays. Although lasers have been used to target or guide military weapons, no laser has become an effective weapon in its own right despite years of research. In fact, lasers are not particularly powerful (a penlight produces more light than any clinical laser) or efficient (it may require thousands of watts of power to produce a mere 1−2 W of laser light). But despite low power and inefficiency, lasers are very useful, because they produce such a highly concentrated focus of coherent light. Effective clinical use of lasers requires an understanding of the three ­ basic light−tissue interactions as follows: (1) photocoagulation, (2) photodis­ ruption, and (3) photoablation. In photocoagulation, laser light is absorbed by the target tissue or by neighboring tissue, generating heat that denatures proteins (i.e., coagulation). Clinical examples of photocoagulation include panretinal photocoagulation, argon laser trabeculoplasty, peripheral iridectomy, and thermal destruction of choroidal neovascular membranes.

GAS LASER DESIGN Initial state light for optical pumping totally reflecting mirror

partially reflecting mirror

laser cavity

light for optical pumping Optical pumping on

Spontaneous emission

Fig. 2-4-3  Gas laser. A typical design consists of a gas-filled cavity, external optical pumping lights, and a resonator that comprises partially and totally reflecting mirrors. Without optical pumping, most of the gas atoms are in lower energy states and incapable of undergoing either spontaneous or stimulated emission. With optical pumping, photons from the external lights are absorbed by the gas atoms, which raises the energy of the atoms and makes them capable of undergoing spontaneous or stimulated emission. Ultimately, the majority of atoms are in excited states − a population inversion. One of the higher energy atoms spontaneously emits a photon that produces stimulated emissions as it passes by other high-energy atoms. By reflecting the photons back and forth across the cavity multiple times, a chain reaction of stimulated emissions is produced.

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2

WAVELENGTHS OF LIGHT

1064 nm Nd:YAG (infrared)

infrared

OPTICS AND REFRACTION

Types of lasers that produce photocoagulation include the argon green laser (514 nm), the argon blue−green laser (488 nm), the krypton red laser (647 nm), the ruby red laser (694 nm), the diode laser (810 nm near infrared), the rhodamine 6G organic tunable dye laser (570–630 nm yellow to red), and the frequency-doubled Nd:YAG laser (532 nm green). Photodisruption is largely a mechanical effect. Highly focused laser light produces an optical breakdown, which is basically a miniature lightning bolt. Vapor formed by the lightning bolt expands, quickly

collapses, and produces a miniature thunderclap. Acoustic shock waves from the thunderclap cause most of the tissue damage. The principal example of photodisruption is the posterior lens capsulectomy produced by the Nd:YAG laser (1064 nm infrared). Photoablation breaks the chemical bonds that hold tissue together, essentially vaporizing the tissue. Photorefractive keratectomy, using the argon fluoride (ArF) excimer laser (193 nm ultraviolet), is an example. In photoablation, chemical bonds are broken by the absorption of ­photons, without any external physical pressure. Because of this, the laser is able to remove tissue with more precision and with much less damage to surrounding tissue than even the sharpest surgical scalpel. Although exceptions to the rule exist, the wavelength produced by a laser generally determines which of the three types of light−tissue interaction will occur. Visible wavelengths produce photocoagulation, ultraviolet yields photoablation, and infrared is used in photodisruption or photocoagulation.

CLINICAL USE OF LASER PHOTOCOAGULATION 810 nm diode (near-infrared)

694 nm ruby-red visible spectrum

647 nm krypton-red 632 nm He Ne (red-orange) 570–630 nm dye (yellow to red) 532 nm 2x Nd:YAG (green) 514 nm argon-green

ultraviolet

488 nm argon-blue

193 nm ArF excimer (ultraviolet)

Fig. 2-4-4  Wavelengths of light produced by the more commonly used ophthalmic lasers and where these wavelengths lie on the electromagnetic spectrum.

ENERGY DISTRIBUTION IN A TYPICAL CLINICAL LASER

intensity

position

position

One of the most commonly performed laser procedures in ophthalmology is photocoagulation. In the posterior segment, photocoagulation is used to treat numerous conditions such as proliferative diabetic retinopathy, diabetic macular edema, choroidal neovascularization secondary to age-related macular degeneration, retinal breaks, and retinal detachments. In the anterior segment, photocoagulation is used to perform iridoplasty, iridotomy, trabeculoplasty, and cyclophotocoagulation. In photocoagulation the surgeon controls the exposure time, the power, and the spot size. It is important that the surgeon has a clear understanding of how these parameters affect the lesions produced. An increase in exposure time (while all other parameters are maintained constant) modestly increases the lesion’s diameter. A tenfold increase in exposure time roughly doubles lesion diameter. Longer exposure time also extends the damage deeper into the target tissue. Very brief exposure times, of the order 0.01–0.05 seconds, allow little time for heat to dissipate from the burn. A small area of intense damage may be produced, resulting in the perforation of delicate ocular structures such as Bruch’s membrane or the neural retina. An increase in power has a strong influence on lesion diameter. In fact, doubling the laser power almost doubles the size of lesion created. Such increases in laser power create more damage and can be painful to the patient. This can be avoided in some cases by increasing the ­exposure time rather than laser power. Careful control of laser spot size is important in order to achieve the desired therapeutic effect. When working in sensitive areas such as the macula, a small spot size (such as 100 μm) is preferred so as to minimize unnecessary damage to adjacent retinal tissue. In contrast, treatment of broader areas of tissue is facilitated by a larger spot, such as a 200–500-μm spot size for panretinal photocoagulation. Laser contact lenses may also affect the spot size. Whereas the Goldman three-mirror lens will increase spot size only by a factor of 1.08, the Panfundoscope lens has a multiplication factor of 1.41. The Mainster wide-angle lens multiplies spot size by a factor of 1.47, and the QuadrAspheric lens by a factor of 1.92. If the spot size is increased, power needs to be increased, as well. However, because energy is concentrated in the center of the beam, it is best to raise power only modestly (no more than twofold at a time) and to use test burns to refine the power setting. It is important for the laser surgeon to be aware of the laser beam profile, the way light energy is distributed over the beam’s cross-section. In most photocoagulating lasers, the energy is concentrated in the center of the beam, with less energy at the edges (Fig. 2-4-5). Therefore, if excessive power is used during laser treatment of the retina, the center of the laser beam may cause water vaporization, possibly resulting in an inadvertent retinal hole. Also, the lower energy at the periphery of the laser beam may produce permanent tissue damage even though it does not produce a visible reaction. It is therefore important to realize that the area of laser damage may extend beyond the area of immediately visible reaction.

CLINICAL USE OF PHOTODISRUPTION

44

Fig. 2-4-5  Energy distribution in a typical clinical laser. Notice that the energy is concentrated in the center of the beam.

The Nd:YAG laser works on the principle of photodisruption. Light is a type of electromagnetic field, and such fields produce forces on charged particles, including electrons. Typically, light energy causes electrons to oscillate as they travel around their nuclei. Extremely high electromagnetic field strengths, from a laser for example, can actually strip electrons from their nuclei, producing an entirely different physical state of matter called plasma.

CLINICAL USE OF LASER PHOTOABLATION Photoablation is the most recent light−tissue interaction to be exploited clinically. It is used to treat corneal pathology such as ulcers and scars, and its use in keratorefractive surgery has become a

FOCUS OF INFRARED YAG LIGHT

rapidly evolving field. The argon−fluoride (ArF) excimer laser produces electromagnetic energy with a wavelength of 193 nm, in the extreme ultraviolet. With each pulse of the excimer laser, a large area of the cornea is ablated. With such a large area of tissue being treated at a time, it is important to have a uniform beam profile. When the excimer beam initially emerges from the laser cavity it has a Gaussian profile, with energy concentrated more heavily in the center of the beam. Beam-shaping optics are then used to create an even beam profile. However, these beam-shaping optics are, themselves, ablated slowly by the ultraviolet laser beam, and they must be replaced periodically. Although the excimer laser removes approximately 0.1 mm of corneal tissue on average with each pulse, irregularities in the corneal stroma and the presence of keratocytes in the stroma may cause uneven ablation, even when the beam profile is uniform. Further, corneal collagen density varies with a number of factors, including altitude, atmospheric pressure, relative humidity, patient age, and duration of the procedure. Fortunately, the microscopic irregularities that may be produced due to patient-specific corneal factors do not appear to affect final visual acuity to a great extent. In older techniques of corneal ablation, the entire anterior surface of the cornea − including the epithelium and Bowman’s membrane − would be ablated. In laser-assisted in situ keratomileusis (LASIK), a partial lamellar incision through the anterior corneal stroma is performed using a keratome. The anterior corneal surface is then temporarily displaced, exposing the corneal stroma to excimer ­laser treatment. In this manner, the corneal surface contour may be ­reshaped by controlled removal of stromal tissue by the excimer laser, while keeping the corneal epithelium and Bowman’s ­membrane intact.

2.4 Principles of Lasers

Where the plasma forms, the chemical nature of the material is destroyed. The orderly array of molecules is fractured into a random mixture of electrons and protons in a process called optical breakdown. A similar effect occurs when a powerful electric field turns air into a plasma, forming a lightning bolt. After the high-intensity laser light passes, electrons and nuclei reunite, and the plasma collapses. An acoustic shock wave, analogous to a thunderclap, is produced. This acoustic shock wave is responsible for most of the physical damage to the ocular tissue produced by the Nd:YAG laser. Optical breakdown requires electromagnetic fields so powerful they can be produced only by concentrating laser energy into very brief ­periods, thereby giving each pulse an extremely high power level. There are two ways of pulsing an Nd:YAG laser: Q-switching and mode locking. In Q-switching, a shutter in front of one of the mirrors in the laser cavity blocks laser light emission until a large population inversion has been established. The shutter is opened quickly, and the stored energy bursts forward in the form of a brief pulse that lasts about one millionth of a second. Q-switching is comparatively inexpensive and reliable but cannot produce pulses as short or powerful as mode locking. In mode locking, electromagnetic energy in the laser cavity exists in various modes that depend on the length of the laser cavity and the construction of the resonator mirrors. In mode locking, an optical element (Fabry-Perot interferometer) inside the cavity synchronizes the modes so all the light is emitted in extremely brief pulses. Most clinical Nd: YAG lasers today are Q-switched, because mode-locked lasers are more expensive and difficult to maintain. The light produced by the Nd:YAG laser is infrared (1064 nm), invisible to the clinician, so an ancillary aiming system, typically a red helium−neon (HeNe) laser, is necessary. Just as a prism causes blue light to bend more than red light, the optics of the patient’s eye cause the red aiming beam to bend more than the Nd:YAG’s infrared light. Consequently, the focus of the Nd:YAG laser rarely coincides precisely with the focus of the aiming beam (Fig. 2-4-6). Some lasers have an adjustment to compensate for this source of error, called chromatic aberration. Performing an Nd:YAG laser capsulectomy in an eye with a silicone intraocular lens implant poses a particular challenge, because optical breakdown occurs in silicone at relatively low power. Therefore, damage to the intraocular lens may occur even when the laser is focused posterior to the implant. And if the capsule is in intimate contact with the implant, creating the capsulectomy is even more difficult. A corneal contact lens designed for laser capsulectomy causes the Nd:YAG laser beam to converge at a steeper angle, resulting in a more sharply focused beam of light. This makes optical breakdown at sites outside the focal point less likely. Intraocular lenses made of polymethylmethacrylate (PMMA) and acrylic are less susceptible to optical breakdown than ­silicone lenses.

PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) uses a laser for treatment of choroidal neovascularization and various tumors in the eye. In this technique, a special laser-activated dye is used to cause damage selectively to ­abnormal blood vessels, while minimizing damage to the nearby retinal tissue. A photosensitizing dye such as verteporfin is first injected intravenously into the patient. The dye preferentially accumulates in neovascular and neoplastic tissue, possibly because the dye binds with low-density lipoproteins (LDLs). Cells with high mitotic activity, such as neovascular and neoplastic tissue, have high expression of LDL receptors, and the LDL-bound dye may thereby be taken in the cells via receptor-mediated endocytosis. The dye in and of itself causes no significant damage to the neovascular tissue, but upon activation with wavelength-matched diode laser, PDT-mediated tissue destruction occurs by several mechanisms. Direct destruction to cell membranes occurs via lipid peroxidation and protein damage through oxygen and free radical intermediates. Vascular endothelial damage causes platelet aggregation and vessel thrombosis. Direct damage to nuclear components, as well as apoptotic mechanisms, have also been reported. In tumors, PDT may produce increased levels of cytokines, enhancing killing activity of cytotoxic T-lymphocytes. The treatment of age-related macular degeneration with photodynamic therapy (TAP) investigation determined that verteporfin PDT reduces the risk of moderate vision loss, defined as a loss of at least three lines of visual acuity, compared with a placebo sham treatment, with 2 years of follow-up data.12, 13 However, patients often require repeat treatments after 3–4 months due to a recurrence of leakage from the choroidal neovascularization, as determined by fluorescein angiography. Patients must also avoid direct sunlight exposure for up to 5 days after injection with verteporfin, because sunlight can activate the dye, possibly resulting in PDT-mediated damage to the skin and retina. PDT has also been used in the treatment of a number of posterior segment conditions, including myopic and idiopathic ­choroidal neovascularization, choroidal hemangioma, and retinal ­capillary hemangioma.

DIAGNOSTIC USE OF LASERS Fig. 2-4-6  The focus of the infrared YAG light usually does not coincide with the aiming beam’s visible red light.

Lasers also have several important diagnostic applications, including scanning laser ophthalmoscopy, optical coherence tomography, and wavefront analysis.

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Scanning Laser Ophthalmoscopy

OPTICS AND REFRACTION

In the scanning laser ophthalmoscope (SLO), developed by Robert Webb and George Timberlake,14 a narrow laser beam illuminates the retina one spot at a time, and the amount of reflected light at each point is measured. As with natural light, the amount of light reflected back to the observer depends on the physical properties of the tissue, which, in turn, define its reflective, refractive, and absorptive properties. Media opacities, such as retinal hemorrhage, vitreous hemorrhage, and cataract, also affect the amount of light transmitted back to the observer. Because the SLO uses laser light, which has coherent properties, the retinal images produced have a much higher image resolution than conventional fundus photography. Also, because only a single point on the retina is illuminated at any given time, the patient is not affected by a bright illumination source or flash. This allows for high-resolution, real-time motion images of the macula without patient discomfort. Current SLOs use a single wavelength of laser light, so the images produced are monochromatic. SLO angiography can be performed after intravenous injection of fluorescein or indocyanine green in order to study retinal and choroidal blood flow. By varying the brightness of the scanning laser beam, the scanning laser ophthalmoscope also may be used to perform microperimetry, an extremely accurate mapping of the macula’s visual field.

Optical Coherence Tomography

Optical coherence tomography (OCT) uses diode laser light in the nearinfrared spectrum (810 nm) to produce high-resolution cross-sectional images of the retina using coherence interferometry.15 In coherence ­interferometry, a partially reflective mirror is used to split a single laser beam into two, the measuring beam and the reference beam (Fig. 2-4-7). The measuring beam is directed into the patient’s eye and onto the retina. Because many of the retinal layers are transparent to near-infrared light, the laser beam passes through the neurosensory retina to the retinal pigment epithelium (RPE) and the choriocapillaris. At each optical interface, some of the laser light is reflected back to the OCT’s photodetector. The reference beam, on the other hand, is reflected off a reference mirror at a known distance from the beam splitter, back to the photodetector. The position of the reference mirror can be adjusted to make the path traversed by the reference beam equal to the distance traversed by the measuring beam to the retinal surface. When this occurs, the wave patterns of the measuring and reference beams are in precise synchronization, resulting in constructive interference. This appears as a bright area on the resulting cross-sectional image. However, some of the light from the measuring beam will pass through the retinal surface and will

be reflected off deeper layers in the retina. This light will have traversed a longer distance than the reference beam, and when the two beams are brought back together to be measured by the photodetector, some degree of destructive interference will occur, depending on how much further the measuring beam has traveled. The amount of destructive interference at each point measured by the OCT is translated into a measurement of retinal depth and graphically displayed as the retinal cross-section. OCT images are displayed in false color to enhance differentiation of retinal structures. Bright colors (red to white) correspond to ­tissues with high reflectivity, whereas darker colors (blue to black) correspond to areas of minimal or no reflectivity. The OCT can differentiate ­structures with a spatial resolution of only 10 μm (Fig. 2-4-8).

Wavefront Analysis and Photorefractive Keratectomy

Lasers are used in the measurement of complex optical aberrations of the eye using wavefront analysis. Wavefront analysis is the study of the shape of the group of photons that leave an object at any point in time and how they are affected by optical media.16 In an ideal optical system with no aberrations (Fig. 2-4-9), an object located at infinity produces parallel rays of light (see Fig. 2-4-9, red arrows). The photons produced by the object at specific moments in time are called wavefronts (see Fig. 2-4-9, blue lines). These wavefronts are perpendicular to the light rays. As they enter the eye, parallel light from infinity produces planar wavefronts. The wavefront is then affected by the cornea and lens, resulting in a concave spherical surface. In an ideal optical system, this spherical wavefront converges upon the macula, producing a pinpoint retinal image. In an aberrated optical system where there is ectasia of the superior mid-peripheral cornea (Fig. 2-4-10), the wavefronts produced by the cornea and lens are not perfectly spherical. As the light ray passes through areas of higher refractive indices, its velocity is slowed, and this results in an alteration of the shape of the wavefront. The superior aspect of the wavefront is delayed (an ideal sphere is represented by the black dashed line). As this aberrant wavefront converges upon the macula, the light rays are spread out over the superior macula, and a blurry retinal image is produced. In the Hartmann-Shack aberrometer, a low-intensity laser beam is directed to the retinal surface. Light rays from this laser spot are reflected back to the front of the eye. In an optically perfect eye (Fig. 2-4-11), the lens and cornea refract the light rays such that planar wavefronts exit the eye. A lens array then focuses these light rays onto a photodetector

OPTICAL COHERENCE TOMOGRAPHY (OCT) 9 8 mirror

moveable mirror

7

6 position 5 4 3

reference beam

light source

measuring beam constructive interference

light detector

46

A

retina

34 5 6

7

89

Fig. 2-4-7  Optical coherence tomography (OCT). The OCT analyses the interference patterns between a reference beam (directed toward a mirror of known distance) and the object beam (directed toward the retina) to create a precise cross-sectional reflectivity map of the internal retina.

B

Fig. 2-4-8  (A) Cross-sectional image of the macula using optical coherence tomography. There is sufficient resolution on this scan to demonstrate the   various retinal layers, as depicted in the correlative illustration (B).

IDEAL CORNEA WAVEFRONTS

2.4 Principles of Lasers

object (point light source at infinity) pinpoint retinal image (magnified)

ideal corneal shape

Fig. 2-4-9  Wavefronts produced by an ideal cornea.

IRREGULAR CORNEA WAVEFRONTS

object (point light source at infinity) irregular corneal shape

blurry retinal image (magnified)

Fig. 2-4-10  Wavefronts produced by an irregular cornea.

IDEAL CORNEA HARTMANN-SHACK IMAGE

laser spot on retinal surface Hartmann-Shack wavefront sensor (aberrometer)

image formed on CCD

lens array

Fig. 2-4-11  Hartmann-Shack image produced by an ideal cornea.

ideal corneal shape

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IRREGULAR CORNEA HARTMANN-SHACK IMAGE

OPTICS AND REFRACTION

laser spot on retinal surface Hartmann-Shack wavefront sensor (aberrometer)

image formed on CCD

irregular corneal shape

lens array

Fig. 2-4-12  Hartmann-Shack image produced by an irregular cornea.

CORRECTIVE CORNEAL ABLATION WITH HARTMANN-SHACK IMAGE

less ablation more ablation less ablation

data from the sensor determines the amount of tissue ablated at each position on the cornea

Fig. 2-4-13  The Hartmann-Shack image is used to perform corrective corneal ablation.

(charged coupled device, CCD). An ideal optical system would produce Hartmann-Shack images with dots of light that are equally spaced from each other. In an optically aberrated eye (Fig. 2-4-12), the cornea and lens produce wavefronts that are not entirely planar. The images projected onto the photodetector therefore display areas where the spots of light are more closely spaced, representing areas where the aberration of the eye’s optical system is greatest. In wavefront-guided photorefractive keratectomy, the computerized data from the photodetector is analyzed and used to control the amount of ablation performed at each position on the cornea. Areas of more closely spaced spots of light correlate to areas of greater optical aberration, and therefore these areas are treated more heavily with

photoablation. Conversely, areas of widely spaced dots correlate to areas of less optical aberration, and these areas are treated less heavily with photoablation (Fig. 2-4-13).

CONCLUSION In a relatively brief period, lasers have evolved from an obscure research novelty to an invaluable clinical instrument. The continual refinement of existing laser types, as well as the introduction of new laser technology, mark this area of ophthalmology as one of its most energetic and dynamic fields. The role of lasers in clinical ophthalmology has expanded continually, and this trend will doubtless continue.

REFERENCES

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  1. Halliday D, Resnick R, Walker J. Fundamentals of physics, 5th ed. New York: Wiley; 1997:1042.   2. Zaret MM, Mreinin GM, Schmidt H, et al. Ocular ­lesions produced by an optical maser (laser). Science. 1961;134:1525.   3. L’Esperence FA. Ophthalmic lasers. St Louis: CV Mosby; 1989.   4. Reed BC. Quantum mechanics: a first course. Winnipeg: Wuerz; 1990:1–35.   5. Allen L, Eberly JH. Optical resonance and two-level atoms. New York: Wiley; 1975.   6. Halliday D, Resnick R, Walker J. Fundamentals of physics, 5th ed. New York: Wiley; 1997:1043–4.   7. Hecht J. Understanding lasers: an entry level guide. Piscataway: IEEE; 1992:62–3.

  8. Lipson SG, Lipson H, Tannhauser DS. Optical physics,  3rd ed. Cambridge: Cambridge University Press; 1995:423–5.   9. Siegman AE. Lasers, 2nd ed. Mill Valley, CA: University Science Books; 1986:558–891. 10. Hecht J. Understanding lasers: an entry level guide. Piscataway: IEEE; 1992:142–3. 11. Siegman AE. Lasers, 2nd ed. Mill Valley, CA: University Science Books; 1986:295. 12. TAP Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age related macular ­degeneration with verteporfin. One-year results of 2 randomized clinical trials − TAP Report 1. Arch ­Ophthalmol. 1999;117:1329–45.

13. TAP Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age related macular degeneration with verteporfin. Two-year results of 2 randomized clinical trials − TAP Report 2. Arch Ophthalmol. 2001;119:198–207. 14. Timberlake GT, Mainster MA, Webb RH, et al. Retinal localization of scotomata by scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci. 1982;22:91–7. 15. Schuman JS, Puliafito CA, Fujimoto JG. Optical coherence tomography of ocular diseases. 2nd ed. Thorofare, NJ: Slack, Inc.; 2004. 16. Basic and Clinical Science Course, Section 3: Clinical Optics 2006–2007. San Francisco: American Academy of Ophthalmology; 2006.

PART 2 OPTICS AND REFRACTION

2.5

Light Units

David Miller, Jerome S. Sarmiento and Stephen K. Burns

Definition:  Light intensity can be defined either in general energy

units or in operational terms, i.e., units that relate to the amount of light from optical and electronic images, and the amount of light needed to damage the eye. n  Candles, candelas, watts, and joules are units that describe the intensity

of light emitted from a light source. n  Illuminance is the blanket term covering luxes, phots, foot-candles, and lumens, which are light units describing the amount of light falling onto a surface. n  Luminance is the blanket term covering luxes, nits, stilbs, foot lamberts, and candelas/area, which are units describing the amount of light   coming from a surface. n  Joules and watts are the units used to describe the amount of light that causes eye damage (e.g., in laser treatment).

Key Features n���� n����

L ighting levels that damage the eye. Lighting levels used in laser treatment.

Associated features n

L ighting levels needed for patients with cataracts and macular degeneration.

INTRODUCTION A cursory attempt to understand light units may result in a high level of frustration. Candles, candelas, watts, and joules are all used to describe the intensity of light sources; luxes, phots, and foot-candles are used to measure light that falls on a surface (i.e., illumination); and light that comes off a surface is measured in luxes, nits, stilbs, foot lamberts, and candelas/cm2. It was much simpler in 1760, when Lambert wrote his essay on photometry and the only standard source of artificial light was the candle. In the mid-1880s, John Herschel and his sister compared one star with another to measure the brightness of both. Using two telescopes, they kept the control star in focus and placed layers of muslin over the second telescope, until the star in question became as dim as the control; a star’s brightness was thus given by its muslin index. As science developed, more was learned about new light sources, new light sensors, and the wavelength composition of these new light sources. Thus, terms such as candles and the muslin index were used less. With each passing generation of light scientists, new units were developed to replace the older ones. Unfortunately, the new units were not accepted universally, and older books with older units continue to be used.

DEFINING LIGHT OPERATIONALLY As clinicians, we must use the units that manufacturers and ­standards committees use to describe light levels that damage, comfortable ­reading light levels, or projector chart light levels. In other words, the ­definitions are divided into operational categories.

Light Used to Produce Damage

Lasers or conventional light sources damage the eye if the density of energy (i.e., the energy distributed per unit area) exceeds a threshold level. Light is a form of energy that is emitted as photons from a light source. The energy in an individual photon is given by Planck’s equation, E = hc/λ. Light energy depends on the wavelength, λ. Short wavelengths (blue) contain more energy than long wavelengths (red). The basic unit of light energy is the lumen, which measures the total flow of photons or light energy produced by a light source. One lumen represents a power of 1/683 joule per second at a wavelength of 555 nm (yellow−green). Energy is measured in joules or calories. One joule is approximately 0.24 calorie. One joule raises the temperature of 1 g of water 0.24°C. Power is the flow of energy. One joule per second is 1 watt of power, so a lumen is 1/683 watt. A lumen measures the total light (the sum of energy from all the photons) emanating from a source. The luminous intensity of a real light source is measured in candles or candelas. The standard states: “The candela is the luminous intensity, in a given direction, of a source that emits monochromatic radiation of frequency 540 × 1012 hertz and that has a radiant intensity in that direction of 1/683 watt per steradian.”1 The candela measures the luminous intensity/steradian of light originating from a specific direction of a real source as if it were emerging from a point source at that origin. The number of candelas from a real source varies with direction but not with distance. The number of photons per second emitted does not change with distance from the source. The same number strikes a 1-m radius sphere that completely surrounds the source as strikes a 2-m radius sphere. The solid angle is independent of the distance. Light power from a 1 candela source is 1/683 watt/steradian. The total power is 1/683 watt × 4π = 4π lumens = 12.566 lumens. The total amount of light (photons/second) emitted from a point source is constant, but the spatial density (photons/second per unit area) decreases with the square of the distance. Light flux is measured in luxes, where 1 lux = 1 lumen/m2. If you were to enclose a 1-lumen light source in a 1-m radius sphere, the total amount of light striking the surface of the sphere would still be 1 lumen, but the density of the light at the surface would be 1 lumen divided by the area of the sphere (4πR2 = 12.566 m2). So the illumination of the surface would be 1 lumen/12.566 m2 = 1/12.566 lux = 0.0796 lux. A 2-m radius sphere would still receive 1 lumen of light, but this light would now be distributed over 50.265 m2. The surface illumination of the 2-m radius sphere would be 0.0199 lux. The candela specifies light coming from a particular direction, measured as if it were coming from a point source in that direction. The lumen specifies the total amount of light. The lux specifies the amount of light illuminating a surface. To create damage, the power from the light source needs to be concentrated in a small area and develop heat. Thus, it is the power density − power or work per unit area − that gives the best indication of the damage done. Another term for the power density that falls on a surface is irradiance. In terms of damage from laser light, it is the light incident on a surface (irradiance, or illumination) that is important, not the light reflected from the surface (radiance, or luminance). For example, in panretinal photocoagulation for diabetic retinopathy, the irradiance or power density of the argon laser is about 22 mW/ 0.04 mm2, or 22 mW/0.0004 cm2 (spot size of 200 μm), delivered in bursts of 0.1-second duration each. Energy densities from this laser are very high: 22 mW/0.0004 cm2 = 55 000 watts/m2 = 378 565 000 lumens/ m2 = 378 565 000 luxes. The damage is restricted to the area of the spot. A 200-μm cube of tissue is essentially 8 μg of water. The laser delivers

49

2 OPTICS AND REFRACTION

2.2 millijoules = 0.53 millicalorie to 8 μg of tissue. If isolated, this would raise the temperature of 8 μg of the water by 275°C, vaporizing it. The indirect ophthalmoscope can produce retinal damage after a few minutes of steady illumination at its power density of 70 mW/cm2 = 700 w/m2 = 478 100 luxes. This is 70 mW/second = 70 millijoules or 16.8 millicalories delivered to a 1-cm2 area in 1 second. A 1-cm2 area 200 μm deep contains about 20 mg of tissue, and 16.8 millicalories would raise the temperature of 20 mg of isolated water 0.84°C. Of course, the heated volume is not isolated, and some heat would be conducted away to the underlying tissue and circulating blood. A substantial temperature rise would be expected in 10s of seconds from such an exposure. The slit lamp can produce the same damage in less time if the light is focused on the retina, because it emits 200 mW/cm2 (2000 w/m2 = 1 366 000 luxes). The operating microscope emits 1000 mW/cm2 = 10 000 w/m2 =  6 830 000 luxes. Compare this with the argon laser (55 000 w/m2), which is on for 0.1 second. With a moist, smooth corneal surface and clear crystalline lens in place, it may produce retinal damage in a short time. Fortunately, during cataract surgery, the cornea dries and becomes distorted once the eye has been entered via an incision. This, along with the presence of a cataract, diffuses the power density of the light on to the retina. However, once the implant is seated and the incision closed, the eye’s focusing elements can concentrate the enormous light energy of the microscope light on to the retina. At that time, either an opaque disc may be placed on the corneal surface to obstruct the light, or an air bubble may be placed in the anterior chamber to defocus the light. The yttrium-aluminum-garnet (YAG) laser delivers bursts of energy measured in millijoules. The unique effect of the YAG laser is achieved because a burst of one or more pulses is delivered in a billionth or a trillionth of a second and because the energy is concentrated at a point. The power levels of the YAG laser light are immense, since all the energy is delivered in a very short time and concentrated in a very small region. One millijoule delivered in 10-9 seconds corresponds to 1 000 000 watts/beam area. The focused beam further increases the power density. The beam power is so large that any material at the focal point of the laser breaks down, absorbs the energy, and is vaporized. These exceedingly high power levels affect transparent materials and even air.

Light Used to See

Since eyes see certain wavelengths of light better than others, light also can be described in terms relevant to the physiology of the eye. The devices used to describe indoor lighting are calibrated only for visible light and are further calibrated to the most sensitive wavelengths (i.e., green−yellow) to the retina. The lighting engineer divides the analysis of any lighting system into four categories: 1. Light source, described in watts or lumens; dimensions in watts 2. Luminous intensity of a point source, described in candles or candelas; dimensions in watts/steradian 3. Illumination, or light falling on a surface, described in luxes or lumens/m2, foot-candles, or phots; dimensions in watts/unit area 4. Light reflected from the surface, described in candelas/m2, foot ­lamberts, meter lamberts, or nits; dimensions in watts/unit area Table 2-5-1summarizes the categories, and illuminance and luminance are described in Boxes 2-5-1 and 2-5-2, respectively.

250 candelas/m2, or 250 nits. The dynamic range (the ratio of brightest to dimmest perceivable objects) of human vision is very large, around 108:1. Our environment commonly provides wide ranges of illumination. The ratio of light available on a sunny noon to moonlight can be 107:1. Television and computer images, like photography, have much more limited dynamic ranges. The contrast ratio of a modern liquidcrystal display is around 200–400.

ILLUMINANCE Illuminance (E) is the light flux (lumens) incident on a surface and is measured in luxes (1 lux = 1 lumen/m2 = 1 foot-candle/10.764). For example, a visual acuity wall chart is calibrated by measurement of the light that falls on it and should have an illumination in the range 480– 600 luxes, or 44.6–55.74 foot-candles. A well-lit desk is illuminated by 20 foot-candles, or 215 luxes. In the relationship between the point light source and the light incident on a surface, the intensity of the illuminance diminishes as the light is positioned farther away, according to Newton’s inverse square law (the intensity of light is related inversely to the square of the distance from its source). The total amount of light from a source falling on a closed surface is the same no matter what the shape or distance of the surface. For example, consider a source of 1 lumen of light. The total light striking the surface of a 1-m diameter sphere enclosing the 1-lumen source is the same as the total light striking the inside of a 2-m sphere. But the density, measured in luxes, would be four times larger on the surface of the 1-m sphere (1 lumen/π m2 = 0.318 lux) than on the surface of the 2-m sphere (1 lumen/4π m2 = 0.0796 lux). The amount of light (candelas, lumens) is

BOX 2-5-1 ESSENTIAL COMPONENTS OF ILLUMINANCE Illuminance is defined as the luminous flux on a surface per unit area. Illumination decreases as the distance from the source increases. For a point source, illumination decreases as the square of the distance from the source increases. The precise formulation for the decrease in illumination from a finite source is dependent on the nature of the source. The inverse square law applies when: l Illuminance is the luminous flux incident on a surface per unit area at the surface being illuminated without regard to the direction from which the light approaches. l Use of the cosine correction to correct for changes in the illuminated area of a surface as a function of angle incidence guarantees that the measured value of illuminance is independent of the direction from which the light approaches the sensor.1, 4, 8 Units are foot-candles or lumens: l 1 lm/m2 = 1 lx = 1 meter-candle = 0.0929 foot-candle = 0.3183 cd/m2 l 1 lm/ft2 = 1 foot-candle = 10.764 lx l 1 lm/cm2 = 1 phot

Electronic Vision

Television cameras have illumination requirements that are comparable to those of the human eye, typically between 10 and 200 luxes. Television and computer displays typically produce a maximal luminance of

 Table 2-5-1  Simplified Categories Of Light

50

Light Category

Description

Units

Light source

Total light from source

Lumens (lm)

Light source

Light/per unit solid angle   from source

Candles, candelas (cd)  1 candle = 1.02 candelas

Illuminance (see Box   2-5-1)

Light incident on a surface

Luxes (lx; lm/m2)

Luminance (see Box 2-5-2)

Light reflected from a   surface

Luxes (lx; lm/m2);   lamberts; candelas   (cd/m2); nits; stilbs 1 cd/  m2 = 1 nit = 10−4 stilbs

BOX 2-5-2 Essential Components of Luminance Luminance is defined as a luminous flux per unit area per unit solid angle from a surface, whether reflected or emitted. Luminance refers to light that emanates from a source or is reflected from a surface. The inverse square law does not apply because it is the luminous intensity per unit area in a given direction. 1 foot lambert is the luminance of a perfectly diffusing and reflecting surface illuminated by 1 candle at a distance of 1 foot. Unit conversions: l 1 lambert (L) = 1 candle/ft2 l 1 foot lambert = (1/π) lm/steradian/ft2 = (1/π) candle/ft2 = 0.00003426 candle/cm2 l 1 candle/ft2 = 1 lm/steradian/ft2 = 0.001076 candle/cm2 l 1 lm/W/m2 = 1 candle/m2 = 0.3142 millilambert = 0.2919 foot lambert l 1 lm/W/m2 = 1 lambert

given by the density of light (nits or candles/m2; luxes or lumens/m2) multiplied by the total surface area it falls on. Thus, if E is the illuminance, I the point light source intensity, and d the distance, then E = I/d 2, where E is measured in luxes (lumens/m2), I in lumens, and d in meters.

Luminance refers to light that leaves, is reflected, or is back-scattered from a surface. Reflected light requires a few extra considerations, as different surfaces reflect light differently. Thus, white paper may reflect more than 90% of the incident light, and red paper much less. The amount of reflection also depends on the angle of incidence of the light and on the angle of observation. All combine to determine the luminance of the light that reaches the eye. Photographers are particularly interested in reflected light, because they must adjust their camera lenses according to the light that is reflected from the subject and enters the camera. Since lighting engineers must be most rigorous, they use units such as nits, stilbs, and lamberts, which are direction dependent. Photographers use the lux (lumens/m2), which has no directional consideration. Ophthalmologists may want to calibrate the light of a visual acuity chart that is projected onto a screen, for which a light meter that measures reflected light in foot lamberts may be used. The conversion factor for foot lamberts into candelas/m2 is 0.291. For example, the British standard for minimal luminance for an internally illuminated acuity chart (projected chart) is 411.1 foot lamberts,2 which is 411.1 × 0.291 = 120 candelas/m2. People who have normal sight need a luminance of about 70 candelas/m2 (220 luxes), which is produced by varying the wattage of the lamp or adjusting the distance of the light from the printed page.

Cataracts

Opacity that results from cataracts may reduce the amount of light ­incident on the retina by 10–90%. Therefore, such patients require an increased luminance to read or do work. To read efficiently, a patient who has a cataract may (on average) need about double or triple the luminance required by a person of normal sight (about 70 candelas/m2), which may be achieved by using a 75- or 100-watt incandescent bulb held at a distance of 1 ft (0.3 m) or less from the reading material.3 A 100-watt bulb typically produces 1570 lumens, or 125 candelas, when new. A patient who has a cataract may need about double or triple the average illuminance level (750 luxes) for a reading task, which would be 1500–2500 luxes (477–795 candelas/m2).

2.5 Light Units

LUMINANCE

LIGHTING LEVELS FOR PATIENTS WITH EYE DISEASE

Age-Related Macular Degeneration

Patients who have age-related macular degeneration have either a diminished number of photoreceptors within the macular area or photoreceptors that need higher levels of light energy to be stimulated. Logically, the luminance of reading material for these ­patients must be greater than 200 foot-candles (64 candelas/m2, or 2152 luxes). In the literature, the recommended illuminance on the printed page is in the range 400–4000 luxes.4 Understandably, the more serious the level of damage, the greater the illuminance needed. Also, the coefficient of reflectance and the color of the page both influence the amount of light (luminance) that finally reaches the patient.5–8

REFERENCES 1. Ferris FL, Sperduto RD. Standardized illumination for visual acuity testing clinical research. Am J Ophthalmol. 1982;94:97–8. 2. Bergem-Jansen PM. Ergonomic workplace design for a visually impaired person. In: Kooijman AC, Looijestijn PL, Welling JA, van der Wildt GJ, eds. Low vision, Washington DC: IOS Press; 1994. 183–90. 3. Com AL, Koenig AJ. Foundations of low vision: clinical and functional perspectives. New York: American   Foundation of Blind; 1996:137–8 .

4. Faye EE, Hood CM. Low vision. Springfield: CC Thomas; 1975:42–45. 5. Cornelissen FW, Kooijman AC, School AJ, et al. Optimizing illumination for visually impaired persons; comparing subjective and objective criteria. In: Kooijman AC, Looijestijn PL, Welling JA, van der Wildt GJ, eds. Low vision. Washington DC: IOS Press; 1994:68–77. 6. Lagrow SJ. Assessing optimal illumination for visual response accuracy in visually impaired adults. J Vis Impairment Blindness. 1986;8:888–95.

7. Lehon LH. Development of lighting standards for the visually impaired. J Vis Impairment Blindness. 1980;74:249–53. 8. Taylor BN, ed. The international system of units. Special publication 330 (2001). Gaithersburg: National Institute of Standard and Technology; 2001:8.

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PART 2 OPTICS AND REFRACTION

Optics of the Normal Eye David Miller, Paulo Schor and Peter Magnante

Definition:  The classic optics of the eye can best be understood  

in terms of the optical characteristics of its components, the cornea, ­pupil, crystalline lens, and retina, and how they function in combination. New insights are being proposed in terms of neural processing, either by the retina or by the brain.

Key features The quality and characteristics of the different optical components   and the combination are described in the following terms: n Chromatic aberration n Spherical aberration n Coma n High-order aberrations n Light scattering n Retinal factors n Resolution n Focal length n Depth of focus n Neural processing

normal human cornea scatters 10% of the incident light.1 By comparison, the corneal stroma of the eagle is almost as transparent as glass.2 This factor (along with the larger pupil size and finer cone diameter) is why the resolution of the eagle eye is better than 120 cycles per degree, which is equivalent to a Snellen acuity of 20/5 (6/1.5).3 The aspherical shape of the cornea’s anterior surface affects the quality of the retinal image. Normal corneas have a flatter periphery and steeper center, counteracting the effect of paraxial light that tends to bend more at peripheral areas. The “Q” factor, named also asphericity or eccentricity factor, quantifies this central-periphery flattening and averages –0.25 in normal eyes. A more negative number means that this cornea is steeper than normal (i.e., central keratoconus), and less negative “Qs” are seen in postmyopic photo refractive keratotomy (PRK), for instance. Astigmatism is caused by this surface having different radii of curvature along different meridians. A survey of normal eyes shows that almost every human eye has a baseline corneal astigmatism of at least 0.25–0.50 D.4 Spherical aberration is caused by the corneal surface’s radius of curvature changing (generally increasing) with distance from the center of the pupil to the pupillary margin. The amount of spherical aberration contributed by the cornea varies with pupillary aperture and individual corneal shape. For a pupil 4 mm in diameter, spherical aberration varies from +0.21 D to +1.62 D, depending on the specific corneal form.5

Pupillary Factors

INDIVIDUAL OPTICAL ELEMENTS OF THE EYE

The iris expands or contracts to control the amount of light admitted to the eye. The pupil can range in diameter from 8 mm in very dim light down to about 1.5 mm under very bright conditions.6 There is a strong association between visual acuity and pupillary diameter. For example, visual acuity has been shown to improve steadily as background illumination increases up to a value of 3400 cd/m2.7 Also, as the eye focuses on objects close at hand, the pupil gets smaller. Several instruments are proposed to measure pupillary diameter but no correspondence has been demonstrated until now between devices such as pentacam, orbscan, colvard pupilometer, and the classic pupillary ruler. This fact must be taken into account when pupillary size is reflected in refractive treatment choice. Another important feature is its variation throughout the day and among different activities. An infrared spectacle-mounted pupillary monitor might have its value in determining objectively the dynamic real variation in pupillary size throughout the day, and add value to different refractive treatments and challenge diagnosis. Retinal image quality, as determined by optical aberrations such as spherical aberration, tends to improve with decreasing pupil diameter, because optical aberrations decrease with decreasing pupil size. On the other hand, retinal image quality, as determined by diffraction, tends to improve with increasing pupil diameter. For most eyes the best retinal images are obtained when the pupil diameter is about 2.4 mm, which is the diameter at which the effects of aberration and diffraction are balanced optimally. Thus, the optimal pupillary size seems to be determined by several influences. In fact, Campbell and Gregory have shown that pupil size tends to be adjusted automatically to give optimal visual acuity over a wide range of luminance.8

Corneal Factors

Crystalline Lens Factors

Associated features  ptical function is best described by a series of tests: O n Visual acuity n Contrast sensitivity n Modulation transfer function n Wave-front testing n Vernier testing n Detection of fast-moving objects (flicker) n Dark adaptation 

INTRODUCTION Eye clinicians define the abnormal eye by comparison with the normal. Thus, the theoretical limits of the best quality, or threshold, image for the normal, emmetropic eye must be known. In this chapter the optical and neural variables that determine the thresholds of image quality for distant objects for the human eye are discussed.

52

2.6

The cornea’s anterior surface is approximately spherical with a radius of curvature that is typically 8 mm. This surface is responsible for about two thirds of the eye’s refractive power. The corneal stroma must be transparent for high-quality image formation on the retina, yet the

The crystalline lens, which has about one third of the eye’s refractive power, enables the eye to change focus. When the eye views nearby objects, the ciliary muscle changes the shape of the crystalline lens making it more bulbous and, consequently, optically more powerful. The lens

Ocular Aberrations Chromatic aberration

Because the index of refraction of the ocular components of the eye varies with wavelength, colored objects located at the same distance from the eye are imaged at different distances with respect to the retina. This phenomenon is called axial chromatic aberration. In the human eye the magnitude of chromatic aberration is approximately 3 D.13 However, significant colored fringes around objects generally are not seen because of the preferential spectral sensitivity of human photoreceptors. Studies have shown that humans are many times more sensitive to yellow–green light with a central wavelength at 560 nm than to red or blue light.5

Higher order aberrations

The eye’s aberrations of even higher order than the so-called primary aberrations, which include astigmatism, spherical aberration, and coma, are now being measured with wave-front sensors based on entrance rays of light such as Hartmann-Shack and Castro sensors,14 and expressed in microns of elevation from the reference plane. This data

A

B

Fig. 2-6-1  Spherical aberrations produced by lenses of the same shape.   (A) A glass lens. (B) A fish lens. The variation in index of refraction is responsible for the elimination of spherical aberration in the fish lens. (Reproduced from   Fernald RD. Vision and behavior in an African Cichlid fish. Am Sci. 1984;72:58–65.)

is being used to control photorefractive surgical lasers with the hope of achieving aberration-corrected vision.15

Spherical aberration

The variation of refractive power with pupil diameter, which causes light rays to focus at different distances from the retinal plane, is called spherical aberration. The eye’s spherical aberration, in addition to depending on pupil diameter, depends on individual corneal contour, accommodative state, and the age of the lens.16 For a normal photopic eye, spherical aberration may vary from approximately 0.25 D to almost 2 D.5

Coma

A comet-like tail or directional flare appearing in the retinal image, when a point source is viewed, is a manifestation of another aberration called coma. Because the eye is a somewhat nonaxial imaging device, and because the cornea and lens are not perfectly centered with respect to the pupil, coma generally is present in all human eyes.17 A large amount of coma (0.3 μm of coma alone) may point to known corneal diseases, such as keratoconus.

2.6 Optics of the Normal Eye

of a young adult can focus over a range greater than 10 D. Presbyopia, which begins at about 40 years of age, is the inability of the eye to focus (accommodate) due to hardening of the crystalline lens with age. When the eye can no longer accommodate at the reading distance, positive spectacle lenses of about 2–3 D are prescribed to correct the difficulty. The normal 20-year-old crystalline lens scatters about 20% of the incident light. The amount of scatter is more than double this in the normal 60-year-old lens.9 Such scatter significantly diminishes contrast sensitivity.10 Also, the normal 20-year-old lens absorbs about 30% of incident blue light. At age 60, this absorption increases to about 60% of the incident blue light.11 The increase of blue light absorption with age results in subtly decreased color discrimination, as well as decreased chromatic aberration. It is possible that this increased absorption helps to reduce the amount of UV light reaching the older retina, protecting it from oxidative damage, which is seen in age-related macular degeneration. The variation in index of refraction of the crystalline lens (higher index in the nucleus, lower index in the cortex) is responsible for neutralization of a good part of the spherical aberration caused by the human cornea. Figure 2-6-1 shows how this variation of index of refraction in the spherical fish lens almost eliminates its spherical aberration when compared with a spherical glass lens.12

Light scattering

Another significant optical factor that degrades vision is intraocular light scatter. The mechanism of light scatter is different from the aberrations discussed above, each of which deviates the direction of light rays coming from points in object space to predictable and definite directions in image space. With light scattering, incoming light rays are deflected from their initial (i.e., prescattered) direction into random (postscattered) directions, which generally lie somewhere within a cone angle of approximately a degree or so. Therefore a dioptric value cannot be placed on the blur caused by light scatter. A glaring light worsens the effect of light scatter on vision. Thus, a young, healthy tennis player may not see the ball when it is nearly in line with the Sun. Light scattering is the mechanism associated with most cataracts and causes significant degradation of vision due to image blur, loss of contrast sensitivity, and veiling glare.

Retinal Factors

An image may be considered as made up of an array of point-like regions. When a picture on the video screen is viewed with a magnifying glass, these small regions, called pixels, are seen clearly. Similarly, the elements that form a photographic image are the silver halide grains in the film’s emulsion. Likewise, the pixel elements comprising a retinal image are the cone and rod photoreceptors. It is the finite size of these photoreceptors that ultimately determines the eye’s ability to resolve fine details. The finest details in a retinal image can be resolved only within the foveal macular area. This area is an elliptical zone of about 0.1 mm in maximal width (Fig. 2-6-2),18 having an angular size of approximately 0.3 degrees about the eye’s visual axis. It contains over 2000 tightly packed light-sensitive cones. The cones themselves have diameters of 1–2 μm (a dimension comparable to 3–4 wavelengths of green light) and are separated by about 0.5 μm.19 Cone size is an important factor in determining the ultimate resolution of the human eye. In the greater part of the fovea no nerve fiber layer, ganglion cell layer, inner plexiform layer, or inner nuclear layer is present, and in the very center of the fovea no outer nuclear layer is present. Only the outer plexiform and cones exist. Another important aspect of the cone receptors is their orientation. Each cone functions as a “light pipe” or a fiber optic, which is directed to the second nodal point of the eye (Fig. 2-6-3). This orientation optimally receives the light that forms an image and, together with the black pigment epithelium of the retina, partially prevents this light from being scattered to neighboring cones.20 Another retinal factor that helps to improve vision is the configuration of the foveal pit, which is a small concavity in the retina. This recessed shape acts as an antiglare device in which the walls of the depression prevent stray light, within the internal globe of the eye, from striking the cones at the center of the depression. Finally, the yellow macular pigment may be considered to act as a blue filter that limits chromatic aberration and also absorbs scattered light, which is predominantly of shorter wavelength (i.e., the blue end of the spectrum).

Resolution and Focal Length Factors

A derivation of the theoretical diffraction-limited resolution of a normal emmetropic human eye must consider the eye’s optimal pupil diameter, its focal length, which is associated with its axial length,

53

2

ORIENTATION OF PHOTORECEPTORS

OPTICS AND REFRACTION Fig. 2-6-2  Retinal mosaic (rhesus monkey) in an area adjacent to the fovea. The large circles are rods and the clusters of small circles are cones. This   section gives a perspective of the different receptor sizes. (From Wassle H, Reiman HJ. The mosaic of nerve cells in mammalian retina. Proc R Soc Lond B. 1978;200:441–61.)

and the anatomical size of the photoreceptors. A point object imaged by a diffraction-limited optical system has an angular diameter in radians (diameter at one half the peak intensity of the Airy disc) given by equation (2-6-1). Equation 2-6-1

Angular diameter =

1.22 ( wavelength ) pupildiameter

In equation (2-6-1), let pupil diameter be 2.4 mm which, for a normal eye, is the largest pupil diameter for which spherical aberration is insignificant, and let the wavelength be 0.00056 mm (yellow–green light) to find the diffraction-limited angular diameter = 0.00028 radians (or, equivalently, 0.98 minutes of arc). Note that this angular diameter matches the angular resolution of an eye with 20/20 Snellen acuity, because the black-on-white bands of the letter E on the 20/20 line of the Snellen chart are spaced 1 minutes of arc apart. The spatial diameter in millimeters of the diffraction-limited Airy disc on the retina is found by multiplying the angular diameter, given by equation (2-6-1), by the effective focal length of the eye. Equation 2-6-2

Spatialdiameter = (angular diameter )

× (effctivefocallength )

Using the angular diameter found from equation (2-6-1) and a value of 17 mm for the eye’s effective focal length (i.e., second nodal point to retina distance) in equation (2-6-2) results in the diffraction-limited spatial diameter = 0.0048 mm (i.e., 4.8 μm). It is interesting to use our results to make a comparison with Kirschfield’s estimate that about five receptors are needed to scan the Airy disc in order to obtain the maximal visual information available.21 If we assume that the foveal cones are approximately 1.5 μm in diameter and are separated by about 0.5 μm of space, then the distance between neighboring cones is 2.0 m. We estimate the number of receptors covered by the Airy disc by calculating in equation (2-6-3) the ratio of the area of the Airy disc to the area occupied by a single cone. Equation 2-6-3

( spatial diameter of disc ) Number of cones covered by Airy disc = 2 ( distance between cones )

54

2

Using equation (2-6-3) we find that approximately six receptors are covered by the Airy disc in close accord with Kirschfield’s estimate of five. Thus, given an eye with maximal sensitivity to yellow light and an optimal pupil size of 2.4 mm, we find that the human eye’s 17-mm effective focal length and, correspondingly, its 24-mm axial length are properly sized to achieve optimal resolution for the cone sizes present. The higher resolution of the eagle’s eye compared with the human’s eye probably results from a larger pupil size-to-focal-length ratio, cones of smaller diameter, and a clearer cornea and lens.2

Fig. 2-6-3  Orientation of the photoreceptors. They all point toward the second nodal point of the eye.

Depth of Focus

An optical system with a fairly large depth of focus enables a fixed-focus camera to give sharp pictures of both a mountain in the distance and a subject 6 ft (1.8 m) away, an insect or a small animal to see objects clearly from 30 ft (9 m) to 4 inches (10 cm) away with no accommodation mechanism, and a presbyopic patient to read a newspaper through a pinhole with no reading correction. Depth of focus of an imaging system is defined to be the distance range (usually in millimeters) from the best-focused image distance where the resolution does not change or, equivalently, the blur caused by defocusing goes unnoticed. Depth of focus also can be expressed in diopters when the dioptric equivalent is the additional power needed for an optical system to change its focal length by an amount equal to the depth of focus. Depth of field, which is related to but different from depth of focus, is defined as the distance range that an object may move (toward or away from a fixed-focus optical system) and still be considered in focus. In Fig. 2-6-4, the eye is represented in a simplified form with only one refractive element. We define the following symbols: O = The object which can move from infinity to a near point p = Pupillary diameter f = Focal length of the model eye x = Distance from the retina where the object at the near point comes to focus c = Photoreceptor size determining the eye’s ultimate resolution n = Refractive index of the model eye D1 = n/f, which is the dioptric power of the eye when an object is viewed at infinity D2 = n/(f + x), which is the dioptric power of the eye when an object is viewed at the near point The depth of focus may be expressed by equation (2-6-4). n n nx D −D = − = 1 2 f f + x f ( f + x) Equation (2-6-5) is obtained by the method of similar triangles shown in Figure 2-6-4. Equation 2-6-4

Equation 2-6-5

c x = p f +x

Substitution of equation (2-6-5) in equation (2-6-4) results in equation (2-6-6). Equation 2-6-6

D1 − D 2 =

nc fp

BOX 2-6-2 Calculation to Show the Depth of Focus for the Fly’s Eye

MODEL EYE WITH SINGLE REFRACTION SURFACE

near point

far point

O

In the compound eye of the fly the organization is based on ommatidia with separate groups of receptors (about eight) under each lens.25

f receptor plane

p

c

Conditions: p = 26 μm f = 50 μm c = 2 μm n = 1.365 Calculation of depth of focus:

simplified eye n = 1.333

x depth of focus

Fig. 2-6-4  A model eye with a single refraction surface. For definitions and explanation, see text.

Box 2-6-1 Determination of Depth of Focus. The Reduced Human Eye Model with One Refracting Surface EXAMPLE 1 Conditions: p = 3 mm f = 2 2.2 mm (for reduced eye model with one refracting surface) c = three cones (assume each cone is 1.5 μm in diameter and spacing between cones is 0.5 μm); the total cluster of three cones = 4.5 μm + 2 spaces = 5.5 μm n = 1.333 Calculation of depth of focus:

Equation 2-6-7

1.33 × 0.0000055 D1 − D2 = = 0.11D 0.0222 × 0.003

This figure falls within the experimental literature,which shows a range   of depth of foci in human subjects from +0.04 D to +0.47 D.24 EXAMPLE 2 Conditions: Example 1 is calculated for a resolution system of 1 min of arc or the   equivalent of 20/20 (6/6) visual acuity, and a high level of contrast. If the system’s limit is 20/40 (6/12), the angle of resolution may be doubled to   2 minutes, which covers six cones 11  μm. Assume the eye has a 2-mm pupil. Calculation of depth of focus:

Equation 2-6-8

1.33 × 0.000011 D1 − D2 = = 0.33 D 0.0222 × 0.002

EXAMPLE 3 Conditions: The system in Example 2 (i.e., 20/40 (6/12) resolution], but using a 1 mm pinhole.

Equation 2-6-9

1.33 × 0.000011 D1 − D2 = = 0.66 D 0.0222 × 0.001

Equation (2-6-6) shows that the depth of focus (D1 – D2), in diopters, is proportional to the product of the index of refraction (n) and the limiting photoreceptor or grain size (c), and inversely proportional to the product of the focal length of the system (f) and the pupil size (p). Therefore, a small pupillary aperture brings objects at a wide range of distances from the lens into focus. Associated with the smaller pupillary size may be a larger blur spot due to diffraction. However, if the blur spot is no larger than the size of the receptor, the blur will be unnoticed. Examples based on equation (2-6-6) are shown in Box 2-6-1. The examples of Box 2-6-1 use the reduced eye, where f = 22.2 mm and n = 1.33. In the more accurate human schematic eye of Gullstrand, f = 17 mm and n > 1.33, because the different indices of refraction of

Equation 2-6-10

1.365 × 0.000002 0.00005 × 0.000026

= 2100 D

Optics of the Normal Eye

depth of field

2.6

the cornea, aqueous, lens, and vitreous are taken into account. For comparison, a clinically orientated study of humans showed that pupils of diameter 1–2 mm produced a mean depth of focus > 4 D.22–24 The image-enhancing mechanism in the retina and brain may have helped to increase the subjects’ perceived depth of focus in the clinical studies cited when compared with our calculated results found in Box 2-6-1. The example in Box 2-6-2 shows that, even without a mammalian accommodation system, the fly theoretically can see objects from infinity to within 86%

N/A

1.6% by   6 months 1.3% by   1 year 0.8% by   2 years

All eyes with mild to moderate haze   improved   to clear or minimal levels

Autrata and Rehurek 2003 Nidek EC500096

184

24

–1.75 to –7.50 sphere

Lower in LASEK eyes (0.21) than in the PRK eyes (0.43)   (P < 0.05).

67% PRK 73% LASEK

20–25–20/40 22% PRK 18% LASEK >20/40 11% PRK 9% LASEK

57% PRK 62% LASEK

91% PRK 92% LASEK

4.5% PRK 0 LASEK

0

Mean post­ operative pain and discomfort scores were 1.82 ± 1.34 in the PRK eyes and 1.06 ± 0.90 in the LASEK eyes at 1 day

Rajan et al. 2004 Summit Autonomous LADAR  Vision97

68

144   (2 years)

Up to –2   to –7.00

6% grade 0.5 in 3 eyes, grade 1 in 1 eye

94% had BCVA better than or equal to preoperative BCVA. The gain in Snellen lines was retained at 12 years; 11% retained the gain in 1 Snellen line, a 2-line gain was seen in 4%.

4%

1.4 %

Emmetropia was not an aim of the study and therefore 66% were dependent on correction, although the full attempted correction was achieved

Anderson   et al. 2002 VISX STAR S298

343

Up to 6

–1 to –14.00 sphere  0 to 4.75 cylinder

1.6 %

84

N/A

1 eye due to macular cyst

LASEK

N/A

98

85

94

Excimer Laser Photorefractive Keratectomy

Author of Publication/ Year/Laser

Continued

139

3

 TABLE 3-4-1  RESULTS OF PHOTOREFRACTIVE KERATECTOMY (PRK) FOR MYOPIA AND MYOPIC ASTIGMATISM—CONT’D

REFRACTIVE SURGERY

No. of eyes

Follow-Up (Months)

Refractive Error

Corneal Haze

20/20 (%)

20/25 (%)

20/40 (%)

+/–0.50 D (%)

+/–1.0 D (%)

1 Line Loss BSCVA

2 Lines Loss BSCVA

Claringbold 2002VISX STAR S2 excimer99

222

Up to 12

–1.25 to +0.25 to +2.25 cyl

13% trace subepithelial reticular haze, disappeared by 1 year

82

17.9

N/A

96.4

N/A

0%

0%

Shah et al. 2002 Nidek   EC-5000100

6097

12

–0.75 to –13.00 sphere –0.5 to –6.00 cyl

0.23 mean in no cyl, 0.32 in 2.0 to   2.5 D cyl up to 0.44 with 5.0 D cyl

41.7

N/A

91.2

69.8

87.9

N/A

El-Maghraby et al. 1999 Summit OmniMed I excimer101

33

24

Mean: –2.5 to –8.0

At 1 year, 83% no or trace haze; 13% mild haze; 3% severe haze   At 2 years, 93% no or trace haze, 7% moderate haze

37

44

96

65.4

73.1

N/A

0

Three PRKtreated eyes required repeated PRK between 6 and 10 months after the primary surgery 4% gained ≥2 lines BSCVA

McDonald   et al. 1999 Autonomous Technologies Corporation (ATC) LADAR  Vision102

414

12

–1.0 to –6.0

≤ Grade 1 mild at 12 months

72

N/A

98

N/A

94

N/A

1.8 %

Complications 13.7% in the spherical group; 21.8% in the astigmatic

Tole et al. 2001 Nidek   EC-5000103

308

6

–0.5 to –6.0

Less than 0.5

65

N/A

N/A

82

95.5

5.1% for low and 6.3% for moderate myopes

1.8%

0.9% of patients with 2 lines of loss of BSCVA regained 1 line. 3.6% retreatment rate

Fernandez   et al. 2000 Nidek   EC-5000104

75

12

–1.0 to –3.0 –3.25 to –6.0

24% trace 10.6% mild

53

N/A

91.5

N/A

92

N/A

6%

Retrospective comparative study between PRK and LASIK

Stojanoc and Nitter 2001 LaserSight LSX105

54

–1.0 to –15.50 sphere 0 to +4.0 cyl

N/A

77.8

14.9

N/A

7.4 %   reoperation

Author of Publication/ Year/Laser

12

36

82 N/A

98.1

97.7

All data for   12 months   follow-up results LASEK

Gradual increase in vision loss with higher preop cylinder, as well as a concomitant increase in haze

82 77

Remarks

BSCVA, best spectacle-corrected visual acuity; cyl, cylinder; RMS, root mean square; UCVA, uncorrected visual acuity.

140

hyperopic correction requires more time in comparison to the same amount of myopic correction. Therefore, decentration or irregularity of the ablation has been a challenge, which has been addressed by the development of the eye tracking and iris registration devices lately. Hyperopic PRK shows good predictability and safety in those with low and moderate hyperopia; results for high hyperopes have been less impressive (Table 3-4-2). In a study by Pacella et al. including ­hyperopia up to +7.75 D, 100% of patients achieved 20/40 acuity or better and 46.4% achieved 20/20 acuity or better, with no patients losing two or more lines of best spectacle-corrected visual acuity. In contrast, in a study including patients with between +11.00 and +16.00 D of hyper­ opia, only 37% had a spherical equivalent within 1 D of emmetropia.115 All treated eyes had transient haze in an annular fashion, appearing 3–4 weeks after treatment. The haze was greater in patients with deeper

ablations and increased up to 4 months after treatment. Significant loss of acuity under glare conditions was seen, especially in patients with higher degrees of treatment. In another study of patients with between +6.00 and +10.00 D of hyperopia, 15% of eyes lost three lines of bestcorrected visual acuity, and 22% lost two lines.116 Creation of the large epithelial defect in hyperopic PRK leads to prolonged healing to repair the defect, discomfort, and the increased risk of infection.

Photorefractive Keratectomy for Treatment of Residual Myopia after Radial Keratotomy

Residual myopia after previous refractive surgeries can be corrected with PRK.80, 117–119 In one study, 25 eyes underwent PRK for residual myopia after radial keratotomy; 60% of the eyes were within 1 D of emmetropia

 TABLE 3-4-2 Results of prk for hyperopia and ��������������������������� hyperopic astigmatism 20/40 UCVA (%)

Refractive Error

Corneal Haze

24

+0.75 to +5.75 D sphere –1.0 to +1.25 D cyl

N/A

46%

N/A

108 PRK 108 LASEK

24

+2.0 to +5.0 sphere 1.00 D astigmatic change. All these problems were   more frequent in   the +3.00 D and   +4.00 D groups than   in the +2.00 D group

+1.50 to +3.50 (cyl  47.2 D, inferior steepening of > 1.4 D, a difference of > 1.9 between the K values ­between both eyes, or nonorthogonal astigmatism. Rigid contact lens wearers should remove their lenses for 3−4 weeks before examination, and soft contact lens wearers should have 2 weeks without lenses. The possibility of monovision should be discussed with patients near the presbyopic age. A discussion of glare and halos, the possibility of under- and overcorrection, and any special considerations should take place with the patient. Appropriate reading materials are given to the patient for education. This initial examination is the best occasion to counsel and assess the patient’s goals to make certain they are realistic. Informed consent should include a discussion of the most frequent side effects and potential risks involved with the surgery.

Limitations and contraindications

Laser vision correction may have a higher risk in patients with collagen vascular disease,32 although a recent study reported favorable results in this group of patients.33 Patients with autoimmune or immunodeficiency

Microkeratomes

Several different microkeratomes are available for use in LASIK ranging from modern automated steel microkeratomes to waterjet ­ keratomes and laser keratomes.42, 43 The choice depends on the surgeon’s ­preference. The main differences among steel ­microkeratomes are the method of assembly, automated or manual translation across the cornea during the procedure, the location of the corneal flap’s hinge, ­vacuum ­fixation rings of various diameters and depths, and ­ disposability. ­Desirable attributes of any microkeratome system are ­ consistency of flap ­ thickness, minimal rate of flap ­ complications (including epithelial defects, ­ buttonholes, free caps, and flap ­ irregularities), flap size ­ adequate to ­ allow desired ablation diameter, fixed depth plate, adaptability to small and deep-set eyes, loss of suction indicators, and general safety and ­technical ease of use.44

3.5 LASIK

diseases, women who are pregnant or nursing, patients with signs of keratoconus, and those taking isotretinoin (Accutane) or amiodarone­ (Cordarone) may also be at a higher risk of complications with surgery. Other conditions with potentially more common adverse outcomes include ophthalmic herpes simplex or herpes zoster or other systemic diseases likely to affect healing such as diabetes and atopic disease.20 Patients with abnormal corneal topographies or with ocular ­abnormalities as well as systemic conditions that are likely to affect wound healing should be approached with caution. Mean corneal thickness is 515 μm; average central cornea thickness is approximately 550 μm.34 Since the flap thickness is generally between 160 and 180 μm, the average cornea will have 335–355 μm of posterior stromal bed left after the flap creation. The maximal correction that may be performed on a patient depends on the degree of correction, the ablation zone diameter, the corneal thickness, and the ablation characteristics of the laser used. Each keratome may create a different thickness flap with a range of correction for any keratome, so it is ­important to know what the keratome that is being used cuts for depths and ­measure the residual bed thickness if unsure.35 It is thought that leaving at least 250 μm of residual stroma ­untouched posteriorly may reduce the incidence of corneal ectasia. The depth of the ablation (in microns) that is required to achieve a correction of 1D is roughly defined by the Munnerlyn equation to be one third of the square of diameter (in mm).36 According to the Munnerlyn formula, each spherical equivalent ­diopter of myopic correction performed at a 6 mm optical zone will ­ablate 12 μm of tissue. However, each excimer laser ablates a different amount of stromal tissue per diopter of refractive correction. This is due to the differences in the ablation zone diameters and ablation characteristics, with wavefront corrections, in general removing more tissue than ­standard ablations. Patients with a history of strabismus during childhood may be at an increased risk of developing a recurrence of strabismus following LASIK, especially if they notice more strabismus in contact lenses than spectacles.37 Pregnant patients or those who are breastfeeding should be advised to defer surgery until documented refractive ­stability once they have delivered or completed breastfeeding due to higher risks of over- or undercorrections. Other lamellar refractive surgical procedures are available and can be offered to patients in whom LASIK may not be the ideal procedure.­ PRK may be preferred to LASIK in patients with anterior ­ basement membrane dystrophy (ABMD), corneal thinning, small and deep-set orbits, superficial corneal scars, very steep or flat ­keratometry values, anterior scleral buckles, glaucoma after trabeculectomy, optic nerve ­disease, risky occupation or activity, and corneal ectasia. Laser-assisted subepithelial keratectomy (LASEK)38 appears to be a good alternative for patients with thin corneas and large corrections; small palpebral fissures or deep-set eyes; and in those whose job or ­recreational ­activities increase their risk of corneal trauma. In ­patients who experience recurrent corneal erosions and are therefore poor LASIK candidates, LASEK may also reduce the incidence of recurrent ­erosions.39 In this group of patients, another procedure known as epi-LASIK40, 41 can be offered as an advanced alternative surface ­ ablation. The fundamental difference between epi-LASIK and LASEK is that the separation of the epithelial sheet is obtained mechanically without requiring the preparation of the cornea with alcohol or other chemical agents. The ­separated epithelial sheet can be replaced on the operated ­cornea ­after photoablation. Mechanical separation not only avoids the ­probable toxic effect of alcohol on the separated epithelial sheet but also ­provides an automated surgical procedure with a short learning curve for LASIK surgeons.

Fig. 3-5-4  Surgeon verifies the computer data before the ablation. (From Boyd BF, editor in chief. LASIK and beyond LASIK: Wavefront analysis and   customized ablation. In: Highlights of ophthalmology, English ed; 2001.)

The introduction of the epikeratome allowed the development of a new technique for corneal surface ablation known as epi-LASIK. The epikeratome is a microkeratome-like device used to create the mechanical separation of the corneal epithelium before photorefractive treatments. The corneal epithelium can be separated from the underlying stroma without previous preparation of the corneal surface with alcohol. Manufacturers have recently introduced a new microkeratome that can create both epi-LASIK and lamellar flaps (Amadeus II microkeratome, Advanced Medical Optics). Waterjet microkeratomes afford the theoretical advantages of less ­debris and collateral damage than blade keratomes and no requirement for increased intraocular pressure to create the flap. However, these devices may have the undesirable effect of flap and stromal ­hydration. The laser microkeratome (IntraLase, IntraLase Corp.) employs a solid-state laser with a 1053 nm wavelength and 3 μm spot size, and uses brief (femtosecond) laser pulses to cause disruption in a lamellar plane. A minimum of laser energy is thus used to create the flap, and hinge placement and flap thickness can be set to exact specifications by the surgeon. This system may be particularly beneficial in patients with ­ anatomically small eyes, deep-set orbits, and unusually steep or flat corneas. The chance of a flap buttonhole or incomplete, decentered, or free flap should be reduced.45 Differences in the flap creation between the IntraLase laser and mechanical microkeratomes are thought to be responsible for better LASIK astigmatism outcomes with the IntraLase46 (Fig. 3-5-3B).

Operative Technique

Careful candidate selection, as discussed earlier, is critical for optimal outcomes. Surgeon preparation, including a thorough knowledge of the patient, procedure, parameters, and equipment is essential. Patient preparation, including preoperative explanation regarding the steps, sights and sounds of the procedure, serves to maximize comfort and minimize anxiety. Approximately 5–10 minutes before the procedure, 5 mg of diazepam can be given to the patient to alleviate the anxiety of undergoing the procedure and to help them sleep postoperatively. The surgeon should always verify the entered computer data before starting the ablation (Fig. 3-5-4). The microscope should be focused on the corneal surface. The patient should be instructed to fixate on the target light and adequate centration over the pupil should be maintained at all times. This centration is essential in order to achieve the expected visual results (Fig. 3-5-5). Tracking systems and iris registration are now incorporated in most excimer lasers, which aid in the maintenance of centration. If excess fluid is detected during the ablation, the procedure is halted temporarily and the excess fluid removed by using a cellulose sponge to dry the cornea, taking care to ensure even hydration. The patient is then positioned under the microscope, with the head carefully aligned to make sure the iris is perpendicular to the laser beam. Careful centration with the eye aligned in the x, y, and z planes is crucial.

149

3 REFRACTIVE SURGERY Fig. 3-5-5  Centration with laser reticule. Note that the reticule is not perfectly centered on the pupil, but the reticule makes it easy to verify the proper adjustments needed to be well centered.

Fig. 3-5-6  Adequate exposure is necessary with all of the refractive procedures. (From Boyd BF, editor in chief. LASIK and beyond LASIK: Wavefront analysis and customized ablation. In: Highlights of ophthalmology, English ed; 2001.)

150

Topical anesthesia is then applied to the eye. The eyelids are prepared with dilute povidone-iodine solution and a lid speculum is inserted to open the eyelids. Eyelashes should be kept away from the surgical field by the use of adhesive drapes or a closed bladed lid speculum (Figure 3-5-6). The contralateral eye is taped shut to prevent cross-fixation and drying. The microkeratome should be inspected for any defects in the blade or function of the moving parts. It is also vital to confirm that the excimer laser will be able to deliver treatment after the corneal flap is reflected. The cornea can be marked with ink before creating the corneal flap with the microkeratome to more easily realign the corneal flap in the event that a free flap is created. The suction ring is placed using a bimanual technique where the shaft of the suction ring is held in the fingers of one hand and a finger from the other hand provides additional support on the ring itself (Fig. 3-5-7). Once adequate placement has been achieved the suction is engaged by foot control (usually done by the technician). Adequate intraocular pressure (above 65 mmHg) is then verified, with one useful method being an applanation lens (Barraquer tonometer). When adequate suction is achieved, the patient will confirm the temporary loss of ­visualization of the fixation light.

Fig. 3-5-7  Bimanual technique used to place suction ring. Adequate exposure facilitates this process. (From Boyd BF, editor in chief. LASIK and beyond LASIK: Wavefront analysis and customized ablation. In: Highlights of ophthalmology, English ed; 2001.)

Before the pass of the microkeratome, several drops of artificial tears are placed on the cornea. This lubrication reduces the likelihood of a corneal epithelial defect occurring during the microkeratome pass. If using a two-piece microkeratome, the head is slid onto the post of the suction ring and advanced until the gear on the microkeratome head engages the track. It is important to again verify that the suction ring is still firmly attached to the globe at this point by gently lifting the suction ring upwards, making sure that the suction is not lost. The surgeon then activates the microkeratome using forward and reverse foot control, the suction is turned off after the microkeratome pass and the suction ring can then be carefully removed. Prompt attention at this point is extremely important in the case that a free cap or buttonhole has been created. In cases where the stromal bed is too small or irregular for a good result, the laser ablation should not be performed, and the flap is placed carefully back into position. Before lifting the flap, a wet cellulose sponge is used to prevent any cells, debris, or excess fluid from getting onto the stromal bed. Using a flat cannula, iris sweep, or a smooth forceps, the flap can be lifted and directed toward the hinge. Assessment of the thickness of the residual corneal bed may be performed by using ultrasound pachymetry. Microkeratome flap thickness may vary, with differences in thickness even with the same microkeratome, making this measurement more important in eyes that may require a deeper ablation with the excimer laser, thus leaving less tissue in the residual corneal bed. The microscope should be adequately focused on the corneal surface. A dry cellulose sponge is then used to carefully remove any excess fluid from the stromal surface. Hydration of the stromal bed needs to be ­adjusted evenly and consistently in all cases (Fig. 3-5-8). It is important at this point to minimize the procedure time in order to prevent stromal dehydration and subsequent overcorrection. Uneven hydration can lead to central islands and/or irregular astigmatism. Excess pooling of fluid can often be found near the hinge after folding back the flap and should be wicked away. The patient should be instructed to fixate on the target light and adequate centration over the pupil should be reassessed. The laser eye tracker and iris registration are activated. The surgeon should maintain his dominant hand over the laser joystick and maintain adequate centration. If fluid starts accumulating over the stromal surface, the laser ablation can be halted and the fluid should be removed with a cellulose sponge. The hinge should be protected if within the ablation zone. After the ablation, the flap is then repositioned onto the bed using an irrigation cannula or an iris sweep. Saline solution is used to remove debris from the interface (Fig. 3-5-9). A wet cellulose sponge is then used to realign the flap. Sweeping movements should be performed from the hinge toward the periphery of the flap (Fig. 3-5-10). Good adhesion of the flap is verified by stretching the flap toward the gutter. If good adhesion is present, there is minimal space in the gutter and no movement of the flap occurs when stroking the flap with a dry sponge. When the flap is felt to be securely in position, a drop of an antibiotic, a steroid, and a lubricating agent may be applied to the cornea

3.5 LASIK

Fig. 3-5-8  Excess moisture should be removed with a cellulose sponge. Note that the central portion of this cornea has a sheen that reveals excess ­moisture centrally. Close visual monitoring with the ring light of the laser remaining on can facilitate the identification of areas of relative excess hydration or under­ hydration. (Reproduced with permission of WB Saunders from Hardten DR,   Lindstrom RL. Management of LASIK complications. Operative techniques in cataract and refractive surgery. 1998;1:32–9.)

Fig. 3-5-10  Aligning the flap is a critical step in the LASIK procedure.   The gutter should be symmetric and as tight as possible at the completion of the procedure. (Reproduced with permission of WB Saunders from Hardten DR, Lindstrom RL. Management of LASIK complications. Operative techniques in cataract and refractive surgery. 1998;1:32–9.)

activities if the postoperative examination is normal. Instructions not to rub the eyes or swim underwater should be reinforced in order to prevent flap displacement or infectious keratitis.

Complications

Intraoperative complications

Fig. 3-5-9  Irrigation under the flap can remove debris from the interface. Care must be taken not to overirrigate as this can increase the risk of flap striae from overhydration. (Reproduced with permission of WB Saunders from Hardten DR, Lindstrom RL. Management of LASIK complications. Operative techniques in cataract and refractive surgery. 1998;1:32–9.)

before removing the speculum. If bilateral LASIK will be performed, the operated eye is covered and the procedure repeated in the contralateral eye. Both eyes are then protected with transparent plastic shields until the following day.

Postoperative Care

The postoperative care of the typical patient who has undergone LASIK is still quite important. Generally, some tearing and burning occurs ­immediately after surgery for which it is recommended that the patient take a 2-hour nap. Longer naps than this may lead to excess drying of the tear film with the potential for flap slippage. The patient is placed on topical prophylactic antibiotics and topical steroids four times per day for the first week. Preservative-free lubricating drops are helpful in most patients for the first several weeks after surgery and frequent use should be encouraged. On the first postoperative day, careful evaluation of the corneal flap should be performed at the slit lamp. The patient may resume most

An incomplete flap may result from the premature termination of the microkeratome advancement. Reasons for an incomplete pass include inadequate globe exposure due to interference of eyelid, lashes, speculum and/or drape, and loss of suction during the pass. If resistance is met during the forward passage of the keratome or the keratome comes to a stop, the surgeon should stop and examine the field for any obstruction. If this is not successful in allowing the microkeratome to pass forward, then the microkeratome should be reversed and removed from the eye. One should never reverse the microkeratome and then go forward. This can result in the blade penetrating to a deeper level than the initial pass. In case of an incomplete pass, if there is not enough room beneath the flap to perform the ablation, then the surgeon should ­reposition the flap and conclude the surgery. Typically surface laser treatment with mitomycin C can be used at a later time to complete the refractive correction.47, 48 Thin flaps are usually due to poor suction. An extremely thin flap is more difficult to reposition and more likely to wrinkle. If the flap is complete enough to cover the ablated area without a buttonhole, then the ablation portion of the case can proceed. Should a buttonholed flap occur, ablation should not be performed through the remaining epithelium. The flap should be repositioned and smoothed into place. Treatment of the second eye is not advisable at the same setting, as the same complication is likely to happen in the presence of a steep cornea or poor suction. Epithelial ingrowth or haze may occur in the area of the buttonhole, and may require further intervention. Typically, retreatment can be performed with PRK and mitomycin C at a later date.49, 50, 49 Full-thickness resection can occur with entry into the anterior chamber during the creation of the flap. This can occur if the plate is not properly positioned during the assembly process or if it is not tightened into place. Newer microkeratomes, which use a fixed plate, should reduce or eliminate the possibility of entry into the anterior chamber. A free cap can occasionally occur and the surgeon should be prepared to deal with this problem. If the cap is small and/or decentered, it should be replaced without ablation and the procedure aborted. If it is well centered and of adequate size, the cap is typically placed on the conjunctiva with the epithelial side down during the photablation. Care must be taken to reposition the cap into the same orientation after the ablation. Adequate drying time should be allowed for the cap to adhere without sutures. The most frequent cause of a free cap is a flat or small cornea in which there is less tissue to be brought forward into the ­microkeratome. Poor suction can also cause small free flaps. Epithelial defects can be prevented with adequate lubrication of the cornea before the microkeratome pass. Also, toxic anesthetics should be

151

3 REFRACTIVE SURGERY Fig. 3-5-11  Decentered ablation on corneal topography. Note the asymmetry of the elevation and the curvature. The top image is the corneal curvature, and   the bottom image shows the corneal elevation. (Reproduced with permission from Hardten DR. LASIK for myopia. In: Krachmer J, Mannis M, Holland E, eds: Cornea, 2nd ed. Mosby International; 2005.)

kept to a minimum before the procedure. If an epithelial defect occurs, typically the course is minimally changed from normal. A contact lens can be placed over the cornea if the defect is likely to cause significant discomfort to the patient. An epithelial defect may lead to greater cap edema with poorer adherence in the area of the defect, increasing the risk of epithelial ingrowth and diffuse lamellar keratitis.

Ablation complications

152

Central islands are small central elevations in the corneal topography, which may occur for a variety of reasons.50, 51 Beam profile abnormalities, increased hydration of the central corneal stroma, or particulate material falling onto the cornea may block subsequent laser pulses. A flat ablation beam may direct stromal fluid into the central area of ablation, and the hydrated tissue is ablated at a slower rate. This is more common with broad-beamed lasers.52 Laser software can add extra pulses in the central cornea to compensate for this. Typically, these central islands resolve with time as epithelial remodeling fills in the surrounding area. If resolution has not occurred by 3 months, the flap can be lifted, and the island can be retreated to reduce irregular astigmatism. Decentration (Fig. 3-5-11) can result from poor fixation and alignment, eye movement during the laser procedure, significant pupil shift with light, or asymmetric hydration of the cornea. The higher the myopic correction, the greater the risk of a decentered ablation, which can result in glare, irregular astigmatism, and a decrease in best-corrected visual acuity.22,53,54 Low-contrast visual acuity is a more sensitive measurement of visual function than high-contrast Snellan acuity and can be used to assess these patients more accurately.55 Decentration may be decreased with the use of current lasers with incorporated eye-tracking systems and iris registration, yet careful attention must still be paid to patient fixation.56 Typically, if the ablation is more than 1 mm decentered, the irregular astigmatism that occurs is symptomatic. Some topographic changes due to healing postoperatively may mimic decentration, and are treated in the same way. Management of decentration­ by treatment based on wavefront or topographic information may ­decrease symptoms in patients with an unsatisfactory outcome with the first procedure.57 Under- and overcorrection may result from errors of refraction, ­improper surgical ablation, malfunctioning of the excimer laser, abnormal corneal hydration status, or an excessive or inadequate wound healing response. It is crucial to maintain consistent hydration of the cornea,

because excessive fluid on the cornea results in an undercorrection. If desiccation of the corneal stroma is present, then overcorrection and haze may occur. An enhanced wound healing response can cause regression that results in undercorrection and possibly scarring. Often the regression can be asymmetric, leading to an appearance not unlike a decentration. No or minimal tissue healing may sometimes lead to overcorrection.20 The higher the refractive error, the greater the chance of regression.55 Many surgeons find that adjusting the amount of treatment using a nomogram based on their actual surgical results improves their refractive outcomes.

Postoperative complications

Interface debris is common even with aggressive interface irrigation (Fig. 3-5-12). Most frequently, it is meibomian gland material that comes from the lids and is trapped in the interface. Careful cleaning of the interface with balanced salt solution before and after the flap is floated into position can help to reduce the incidence of this problem.58 Pre­ operative treatment of blepharitis with lid hygiene, antibiotic ointments, and oral tetracyclines may reduce the occurrence of this complication. Flap displacement usually occurs in the first 24 hours postoperatively (Fig. 3-5-13). When a flap displacement occurs, it should be lifted and repositioned.59 The epithelium at the flap edge grows remarkably fast to cover the stromal bed. Care must be taken to clean the bed and back of the flap of debris and epithelial cells. Stroking the cap with a cellulose sponge can minimize persistent folds in the flap and properly line up the cap with the bed. Punctate epithelial keratopathy can be seen after LASIK. It is more common in patients with pre-existing dry eye or blepharitis. The corneal nerves are severed during LASIK and this may increase the susceptibility to keratopathy.60, 61 Treatment involves frequent lubrication of the ocular surface with artificial tears. Management of any eyelid disorder may also be of benefit. Punctal plugs may also be employed to assist in the management of this common problem. Diffuse lamellar keratitis (DLK), also known as Sands of Sahara syndrome, is an interface inflammatory process that occurs in the early postoperative period after LASIK (Fig. 3-5-14).60 Patients are usually asymptomatic and often have no visual impairment. A fine granularappearing infiltrate that looks like dust or sand typically presents initially in the interface periphery. The inflammation, if left untreated, can progressively worsen and may lead to corneal scarring with resultant irregular astigmatism. In the typical cases, on the second postoperative

3.5 LASIK

Fig. 3-5-12  Interface debris can occur in LASIK, and is usually not visually significant. (Reproduced with permission of WB Saunders from Hardten DR. Operative techniques in cataract and refractive surgery. 1998;1:32–9.) Fig. 3-5-14  Diffuse lamellar keratitis (DLK). This is stage II DLK, and identification of this should be followed by increased topical steroid administration, and close follow-up. If the cells begin to clump centrally with stage III DLK, then interface irrigation is appropriate. (Reproduced with permission of WB Saunders from Hardten DR. Operative techniques in cataract and refractive surgery. 1998;1:32–9.)

Fig. 3-5-13  Displaced flap can occur and requires repositioning to reduce the striae and decreased vision that results. (Reproduced with permission of WB Saunders from Hardten DR. Operative techniques in cataract and refractive surgery. 1998;1:32–9.)

day, the cells can progress to cover the pupil. On the third day, they may begin to clump and, with the release of inflammatory mediators, can result in a stromal melt by day 4 or 5. The cause of DLK is likely multifactorial. Bacterial toxins or antigens, debris on the instruments, eyelid secretions, or other factors may play a role. 62–65 Treatment involves frequent topical steroids. In cases in which inflammation progresses to where the cells clump centrally on day 3 or 4, the flap should typically be lifted to irrigate the interface.66, 67 Flap striae and microstriae are a common complication after LASIK. Most striae are asymptomatic and can be visualized if the flap is carefully examined with retro illumination (Fig. 3-5-15).60 When microstriae occur over the pupil or when macrostriae exist, irregular astigmatism with visual aberrations and monocular diplopia may result. In such cases, the flap should be relifted, hydrated, and stretched back into position. Epithelial ingrowth into the interface between the cap and the stromal bed occurs in up to 3% of myopic LASIK surgeries, and is more common when an epithelial defect has occurred or after lift flap enhancements (Fig. 3-5-16).68 Rarely, the epithelial ingrowth progresses into the central visual axis causing irregular astigmatism and loss of best-corrected visual acuity. In some cases, the epithelial cells will block nutritional support for the overlying stroma and lead to flap melt.60 If this is the case, the flap should be lifted and careful scraping of the epithelium should be performed at the stromal bed as well as under the

Fig. 3-5-15  Flap striae can be fairly subtle and may not be visually significant as in this eye. (Reproduced with permission of WB Saunders from Hardten DR. Operative techniques in cataract and refractive surgery. 1998;1:32–39.)

flap. In recurrent cases, suturing or flap gluing may help to reduce the incidence of recurrent epithelial ingrowth.69 Infectious keratitis after LASIK is a devastating, vision-threatening complication. Fortunately, the estimated incidence is low and reported to be between 1 in 1000 and 1 in 5000 procedures.70, 71 Reported organisms include Mycobacterium, fungi, Nocardia, Staphylococcus aureus, Streptococcus viridans, coagulase-negative staphylococcus, and Streptococcus pneumoniae.72 The most common organisms cultured in a worldwide survey by the Cornea Clinical Committee of the American Society of Cataract and Refractive Surgery were atypical mycobacteria and staphylococci.73 Symptoms may include pain, photophobia, watering, decreased visual acuity, ghost images, and halos. Slit-lamp examination may reveal ciliary injection, epithelia defect, anterior chamber reaction, and hypo­ pyon. In the case of mycobacteria and fungi, presentation is usually delayed several weeks after the LASIK procedure, with a smoldering course. Clinically, the mycobacteria and fungi are usually seen in the interface, often with a feathery or indistinct margin. The gram-positive

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Results

REFRACTIVE SURGERY Fig. 3-5-16  Epithelial ingrowth under the flap. Progression toward the   center with visual significance is an indication for removal of the epithelium.   (Reproduced with permission of WB Saunders from Hardten DR. Operative   techniques in cataract and refractive surgery. 1998;1:32–39.)

infections are usually seen shortly after the procedure, often at the flap margin, and usually have distinct, sharp margins. It is important to maintain a high suspicion for atypical organisms, and cultures should be inoculated on blood, chocolate, Sabouraud and Lowenstein-Jensen agar; and blood heart infusion. Smears should also be taken for Gram, Giemsa, and Calcofluor white stains, as well as Ziehl-Neelsen for acid-fast bacteria. The flap should be lifted and irrigated. Empiric therapy is not recommended, as most of the organisms are opportunistic and not responsive to conventional therapy.75 The mycobacteria species associated with keratitis following LASIK belong to the nontuberculous mycobacteria group, which are widely found in the environment, including soil, distilled water, body surfaces, body fluid, and in healthy individuals. These species are resistant to chemical disinfectants such as chlorine, which is probably why it may occur after surgical procedures. Clarithromycin and amikacin are the antibiotics of choice, but poor penetration of topical medications leads to persistent infection. Early flap lifting and soaking of the flap and bed with amikacin 0.08% and/or clarithromycin 1% followed by aggressive topical therapy leads to the best results.74 Perhaps the most important factor within our control is prevention. Meibomian gland disease should be treated before LASIK. Proper sterilization of instruments and intraoperative sterile techniques should be used, including sterile gloves and drapes, and disinfection of the skin and eyelids with povidone iodine. During the procedure, instruments should be sterile, and sterile plastic bags can be used for the nonsterile portions of the laser. Efforts should be made to avoid irrigating meibomian secretions into the interface. Suction lid specula may be helpful in removing excessive fluids and debris. Postoperatively, the subject should be instructed to wear shields and not to rub the eye. Prophylactic antibiotics should be used for a few days postoperatively. The subjects should be instructed to avoid sleeping with pets, gardening, swimming, or going into saunas in the perioperative and early postoperative period. Subjects with dry eyes should be instructed to use frequent artificial tears, or, if indicated, punctal plugs may be placed.

Keratectasia

154

There is general agreement on leaving 250 μm of untouched posterior cornea stroma. Ablation below that limit may cause biomechanical weakening and the cornea may bulge forward.74 Another important cause of iatrogenic keratectasia is LASIK performed on unrecognized keratoconus suspects.75 Videokeratographic clues to a keratoconus suspect may include a K value of > 47.2 D, inferior steepening of > 1.4 D, a difference of > 1.9 between the K values between both eyes, or non­ orthogonal astigmatism. Iatrogenic keratectasia has been reported as early as 1 week and as late as 2 years postoperatively, with refractive errors as low as −4.0 D spherical equivalent.76

With traditional LASIK, accuracy is greater for lower degrees of myopia. In one study of 130 eyes with an average preoperative spherical equivalent of −3.61 D followed for 12 months after LASIK, 98% obtained a correction within ±1 D from target and 93% obtained 20/40 or better uncorrected visual acuity.77 Another study showed that in low myopia (−0.75 D to −6.00 D of myopia and 0 to 0.75 D of preoperative astigmatism), 50% were 20/25 or better and 90% were 20/40 or better at 1 month postoperatively and the spherical equivalent was within ±1.00 D of emmetropia in 89% of the patients. In high myopia (−6 to −20 D of myopia and 0 to 4.5 D of preoperative astigmatism), at 1 month, 35% were 20/25 or better and 71% were 20/40 or better and the mean spherical equivalent was within ±1.00 D of emmetropia in 63%.78 Results of this and other studies suggest more predictable results in low myopia without astigmatism than in high myopia correction or in eyes requiring astigmatic correction.79, 80 Data obtained from multicenter trial results on wavefrontguided LASIK ablations for low to moderate myopia and astigmatism revealed 98% of eyes achieved 20/20 uncorrected visual acuity (UCVA) and 71% were at 20/16 or better uncorrected. What is even more impressive is the fact that postoperative uncorrected visual acuity was better than the preoperative best corrected results in 47% of patients.25, 81 Ongoing improvements in the custom wavefront treatments have resulted in more precise treatments and postoperative results even for higher corrections. Results for the VISX Star S4 laser (Advanced Medical Optics, Inc., Santa Ana, CA) treatment of high myopia and astigmatism with Custom Vue customized ablations were remarkable. The mean preoperative refractive spherical error was −8 D (±1.4 D, range −5.5 to −11.3 D). Average cylinder was −1.0 D (±1.0, range 0.0 to −5.3 D). Manifest refraction spherical equivalent (MRSE) was −8.5 D (±1.3, range −6.4 to −11.8 D). At 6 months, 98% of the eyes were seeing 20/40 or better uncorrected, 84% were 20/20 or better, and 65% were 20/16 or better. Three-quarters had the same or better postop UCVA compared to their preop best spectacle-corrected visual acuity (BSCVA). Among the spherical myopes, 99% were 20/20 or better uncorrected, with 84% 20/16 or better at 6 months. Patients’ satisfaction with their quality of vision was also high. This demonstrated that the customized approach offers excellent quantity as well as quality of vision even for higher corrections. Investigators attributed the accurate results obtained to improvements in the VISX platform, which included the Fourier-based wavefront software analysis and the Variable Spot Scanning (VSS) and Variable Repetition Rate (VRR) laser developments.25 Low to moderate levels of spherical hyperopia, simple hyperopic astigmatism, and compound hyperopic astigmatism can be effectively and safely corrected with LASIK. Results of a study evaluating patients with primary and secondary hyperopia who underwent traditional LASIK demonstrated that patients with primary hyperopia and a mean manifest SE of +1.73 ± 0.79 D before surgery, obtained a postoperative SE of −0.13 ± 1.00 D at 6 months after surgery, and −0.18 ± 1.08 D at 1 year after surgery. At 6 months, 84% of patients with secondary hyperopia had UCVA of 20/40 or better; 76% were within ±1 D of emmetropia. At 1 year, 85% had UCVA of 20/40 or better and 85% were within ±1 D of emmetropia. No patients with secondary hyperopia lost 2 or more lines of BCVA at 1 year.82 For higher levels of correction, the predictability within ±1 D of attempted correction decreases to approximately 50– 80% and the loss of BCVA generally ranged from 0 to 7%.83–88 However, LASIK for hyperopia greater than +5.0 D is not recommended as it may result in a loss of best-spectacle-corrected visual acuity in a ­significant number of eyes (13–15%).90 Multicenter clinical trials of wavefront-guided LASIK for the correction of hyperopia and hyperopic astigmatism demonstrated significant improvements compared to traditional LASIK. Mean preoperative spherical error was +1.67 ± 1.0 (up to +4.59 D), average astigmatism of +0.65 ± 0.48 D (up to +2), and MRSE of +1.99 ± 1.0 D (up to 4.84 D). At 6 months, 95% of the eyes had UCVA of 20/40 or better, 62% were 20/20 or better, and 20% were 20/16 or better. UCVA at 9 months was 20/16 or better in 24% of eyes and 20/20 or better in 72%.25 For mixed astigmatism, multicenter trials for custom wavefront LASIK results 6 months after surgery were UCVA of 20/40 or better in 96% of eyes and 20/20 or better in 60% of eyes.25

LASIK ENHANCEMENTS

LASIK IN COMPLEX CASES LASIK after Radial Keratotomy

Between 1980 and 1990, approximately 1.2 million patients underwent incisional radial keratotomy (RK).97 According to the 10-year data reported from the Prospective Evaluation of Radial Keratotomy study, 25–43% of these patients became hyperopic.98 Because of this possible shift, surgeons had a tendency to undercorrect myopia. Patients ­therefore frequently needed subsequent correction for residual myopia or secondary hyperopia. In an order to correct the secondary hyperopia, various surgical procedures have been attempted.84, 99, 100, Various studies have proven LASIK to be safe and effective in treating residual myopia and RK-induced hyperopia.101–105 A stable refraction for at least 6 months before LASIK is mandatory. Patients who wear soft or hard contact lenses should abstain from ­using them for at least 2 and 4 weeks, respectively. A careful evaluation of the RK incisions is mandatory since the presence of epithelial inclusion cysts can predispose to subsequent epithelial ingrowth after LASIK and these patients should be avoided. It is recommended that a 180 μm plate be used to create the flap, although this is limited by the corneal thickness and the amount of ablation to be done. During the LASIK procedure, the flap should be manipulated with extreme care to prevent the RK incisions from splaying.106 Careful observation of the patient during the postoperative period should be granted, as the risk of epithelial ingrowth is higher in this group of patients, particularly following enhancements (Fig. 3-5-17).107

3.5 LASIK

Epithelial hyperplasia is probably the main cause of regression after LASIK89 and, overall, undercorrection is the most common problem following LASIK.90 The initial consideration when deciding to perform a LASIK ­enhancement is to determine the possible reason for failure of the prior procedure. Errors may be related to inadequate preoperative refraction, improper laser ablation, abnormal corneal hydration during the procedure, an excessive or inadequate healing response, or induced corneal ectasia. A careful analysis of anterior and posterior corneal elevation maps should be performed to rule out a decentered ablation or iatrogenic corneal ectasia. Patient selection and appropriate timing are key for a successful LASIK enhancement. It is recommended to wait at least 3 months ­before considering an enhancement.91 Patients with refractive instability should not undergo an enhancement procedure. The stability of the postoperative refraction appears to be related to the magnitude of the ablation, with higher refractive errors requiring longer time periods of stability. A practical estimation is to use the preoperative refraction in diopters to indicate the number of months to wait after the initial LASIK procedure. In other words, waiting at least 6 months in a patient with a preoperative refraction of 6 D. Another important consideration is the measurement of the central corneal thickness, especially in patients who are candidates for further myopic correction. If less than 250 μm of residual untouched stromal bed will be available after the enhancement laser ablation, the risk of inducing corneal ectasia probably outweighs the benefit of the procedure. Central corneal thickness is not as important a consideration in hyperopic enhancements, as the treatment of this condition does not remove tissue from the corneal center. Regarding the decision of recutting the cornea versus lifting the flap, studies have shown the effectiveness and predictability of using different techniques.92, 93 Both procedures have advantages and disadvantages, which should be considered based on the patient’s individual needs. Flap lifting is probably the preferred method in most patients.94 The flap edge can be marked at the slit lamp and lifted before the laser ablation. Unfortunately, this method requires flap manipulation and has been reported to be associated with a higher risk for epithelial ingrowth.95, 94 Flap recutting, however, may be associated with a higher risk of a free, perforated, and thin flap in a cornea following LASIK for myopia, which is flatter than the normal cornea. Furthermore, a second cut can result in loose lamellar wedges of stromal tissue, and some ­surgeons advocate a deeper cut to avoid the previous interface.96 Major flap complications may be more likely to occur with recutting versus lifting the flap95 and, therefore, it is recommended to relift in most patients.

Fig. 3-5-17  Epithelial ingrowth after LASIK following radial keratotomy.   Epithelial ingrowth in this situation is especially difficult to remove.

The epithelial ingrowth can be particularly difficult to manage, and may even require fibrin glue to effectively treat.71 With the availability of mitomycin C to reduce haze in patients having PRK after prior surgery, many surgeons are now using PRK to treat patients with residual refractive errors after RK.108–110

LASIK after Photorefractive Keratectomy

PRK has been proven to be a safe and effective method for treating low to moderate myopia.111–113 Regression as well as the development of corneal haze are the main limiting factors in the correction of higher refractive errors, which are greater in patients treated for more than 6.0 D of myopia. Severe haze interfering with refraction is frequently associated with myopic regression, loss of BCVA, and a greater ­tendency to present in the other eye if treated.115 As with LASIK, under- and overcorrection after PRK may result from errors of refraction, improper surgical ablation, malfunctioning of the excimer laser, abnormal corneal hydration status, or an excessive or inadequate wound healing response. No or minimal tissue healing may sometimes lead to overcorrection.20 PRK re-treatment for undercorrections should be approached with caution as there is a risk of further regression, increased haze, and loss of visual acuity.114, 115 LASIK appears to be a better approach in this group of patients and it has been proven to be a safe, effective, and predictable procedure for treating eyes with no or low haze after PRK.116 Some surgeons suggest that the postoperative care should be the same as after primary PRK, with a prolonged use of topical steroids.117

LASIK after Penetrating Keratoplasty

Residual refractive errors after penetrating keratoplasty (PKP) are usually responsible for decreased visual acuity despite a clear graft. The mean amount of astigmatism that has been reported after penetrating keratoplasty for keratoconus is usually between 2 and 6 D with only 15% > 5.00 D.118 Visual rehabilitation with spectacles or contact lenses should be considered initially, followed by the possibility of ­incisional refractive surgery if the patient is intolerant to either of these alternatives. The primary goal of LASIK after penetrating keratoplasty is to reduce the refractive error to allow spectacle correction. The uncorrected visual acuity should remain a secondary goal. Several studies have shown that LASIK has significant advantages over other surgical procedures in the management of refractive errors after penetrating keratoplasty.119–124 LASIK should be delayed at least 12 months after PKP because of the risk of corneal dehiscence during the creation of the flap. Although the precise safety interval between PKP and LASIK has not been established, some surgeons have performed LASIK as early as 8 months after PRK125 while others advise a minimal period of 2−3 years.121, 122 A comprehensive eye examination should be performed prior to the procedure. Careful attention to the graft as well as the graft-host

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interface is critical in order to prevent further complications. All sutures should be removed prior to performing the lamellar surgery. Any of the previously described complications for LASIK can occur in the setting of previous PKP so the procedure should be performed with extreme care and careful attention to detail. LASIK is more effective in treating myopia than astigmatism after penetrating keratoplasty.127 In a study by Donnenfeld et al., patients with a mean spherical equivalent before surgery of –7.58 ± 4.42 D improved to –1.57 ± 1.20 D 12 months after LASIK. Patients with a mean cylinder of 3.64 ± 1.72 D before surgery improved to 1.29 ± 1.04 D 12 months after. Spherical equivalent anisometropia was reduced from a mean of 6.88 ± 4.4 D to 1.42 ± 1.05 D at the final examination. Bestcorrected visual acuity remained the same or improved in 21 of 23 eyes and decreased by 1 and 3 lines in two patients.127 Our experience in 57 eyes treated for myopia and astigmatism after PKP, was a mean SE decrease from –4.19 ± 3.38 D (range, –0.75 D to –15.25 D) preoperatively, to –0.61 ± 1.81 D postoperatively 2 years after LASIK. The mean preoperative refractive astigmatism decreased from 4.51 ± 2.2 D (range, 0.5−10 D) to 1.94 ± 1.35 D for the 28 eyes with follow-up. UCVA was 20/40 or better in 12 eyes (43%) and BCVA was 20/40 or better in 86%.125 This is very similar to a recent study by Malecha et al. in which the preoperative SE was reduced by 3.93 D and the mean cylinder was reduced by 2.83 D from the preoperative values at the last follow-up visit. Uncorrected visual acuity was 20/40 or better in 73.7% of the eyes after LASIK.126 The long-term results also appear to be quite stable in most eyes.125 In conclusion, the refractive results appear to be less predictable than those obtained in eyes with no history of surgery. Complications such as epithelial ingrowth, poor flap adherence, and graft failure are especially common in patients with mismatch of the donor and host cornea or in those with poor endothelial cell function.125 It is important to remember that the realistic goals of LASIK after PKP are to decrease the degree of anisometropia and ametropia to levels at which spectacle correction or contact lenses can be tolerated.

MINNESOTA EYE CONSULTANTS IOL Calculations after Refractive Surgery Date

Name

History K:

Cylinder

Sphere

156

Postrefractive surgery patients who develop a cataract expect excellent uncorrected visual acuity after cataract surgery, just like after their previous refractive procedure. Experience with eyes after myopic refractive procedures indicates that use of postoperative average standard keratometric readings in standard intraocular lens (IOL) power predictive formulas frequently results in substantial refractive errors, hyperopia being the unexpected surprise in patients who undergo myopic refractive procedures and myopia in those undergoing hyperopic procedures.127–129 Calculations of IOL power in cataract surgery is based on the ­measurements of corneal power/radius of curvature, axial length, and estimation of postoperative anterior chamber depth (effective lens ­position, ELP). The main reason for underestimation of IOL power after refractive corneal surgery lies in the inaccurate determination of keratometric power.130 The keratometer is inaccurate in this setting because it measures only 4 points of the cornea in a paracentral region, ignoring flatter (after myopic refractive surgery) or steeper (after hyperopic refractive surgery) more central regions.131 Computerized videokeratography (CVK) overcomes some of these limitations. However, both keratometry and CVK are inaccurate in eyes that have had myopic PRK or LASIK because the standardized value for the corneal index of refraction (1.3375) used in both devices is not valid for measuring these corneas.129, 132, 133 A second important factor accounting for inaccuracies when using conventional IOL calculations is the ELP, or predicted position of the IOL along the axial length of the eye. Methods of calculating corneal refractive power in patients who have had corneal refractive surgery include the clinical history method, contact lens over-refraction, CVK, the double-K method, and the Gaussian optics formula.131, 134 The clinical history method was first published by Holladay in 1989135 and later by Hoffer136 as the clinical history method for eyes after RK. It requires knowledge of the patient’s preoperative corneal curvature and preoperative and postoperative manifest refractions. This method utilizes difference in the preoperative and postoperative spherical equivalent refractions (at the spectacle or corneal plane) and manual keratometry values to obtain the induced change by the refractive procedure.

Date

SE

Original MR Steep

Flat

Sphere

Cylinder

Ave

Original Manual Ks Original Sim Ks topography Type of Topography Date

Type of Refr Surg Stable MR after refractive surgery, before cataract development Calculated average K – value from refractive data

Date

SE

+ orig ave K

=

orig SE

post refractive surgery SE

Calculated Ave K

Ave K from Rigid CL Trial: Sphere

Cylinder

MRSE

CL Base Curve

Sphere

Cylinder

ORSE

CL Power

MR w/o rigid CL OR with rigid CL Calculated Average

+

K-value from CL Data CL BC

=

-

+ CL Power

ORSE

Date Surgery Scheduled Average MEC Results Suggest with SRK-T:

INTRAOCULAR LENS CALCULATIONS AFTER LASIK

WTW

Lens Thickness (mm)

AC Depth (mm)

Axial Length (mm)

Eye

Tech

Add 0.16 D to ORBSCAN 3 mm K Subtract 0.85 D from Historical K Subtract 2.48 D from Manual K Subtract 1.21 D from Hamid K (Manual K – 0.24*SEChg+0.15) Add 0.19 D to Topo Derived Flattest K

MRSE

CL Derived K

Topo Derived Flattest K 3mm Ave Axial Total Power (from ORBSCAN)

Surgeon’s Desired K

Revised 06/05/2005 – MEC IOL Calc Sheet

Fig. 3-5-18  Corneal power calculations after refractive surgery worksheet.

The hard contact lens method determines the difference between the manifest postoperative refraction with and without a plano hard contact lens of known base curve and subtracts this difference from the base curve.137, 137 The double-K method uses the pre-LASIK keratometry to calculate the ELP and the true post-LASIK K in the rest of the IOL formula, hence the name.137 Other methods take into consideration the posterior corneal curvature, such as the Gaussian optics formula,136 in which to determine accurately the total keratometric diopters of the cornea, the keratometric diopters of the anterior and posterior surface of the cornea must be known. These methods utilize different mathematical formulas to determine the posterior corneal curvature by means of measuring the postoperative anterior corneal keratometric values by scanning slit topography devices that provide individual measurement of the posterior corneal curvature. Development of new devices such as the Pentacam (Oculus Inc., Wetzlar, Germany), which measures the tomography of the cornea by taking 50 meridional Scheimpflug images, may eliminate the need for complex calculations. Pentacam software can accurately calculate the front and back surface powers of the cornea and adjust for any power overestimate and report a term called equivalent keratometric reading (EKR), which can then be used in IOL calculations. Some practical recommendations are as follows: l Use the clinical history method whenever possible, especially if keratometric power and refraction before refractive surgery are known. If keratometric power but not refraction before refractive surgery is known, use the change in anterior surface keratometry readings after LASIK. l In patients undergoing cataract surgery in centers other than those where the refractive procedure was originally performed and thus neither the preoperative keratometry reading nor the exact amount of refractive correction may be available, use a method that utilizes a posterior curvature measurement.

l

BIOPTICS Bioptics, popularized by Roberto Zaldivar, is the planned combination of phakic or aphakic IOL surgery with corneal surgery to correct large refractive errors.138 Typically, the maximum IOL power is used and

the undercorrection is corrected by corneal ablation surgery (PRK or LASIK). The surgeries can be staged with the lens surgery performed first followed later by PRK or LASIK. Alternatively, the LASIK flap can be made at the time of the lens surgery and lifted several weeks later for the laser ablation. Bioptics can be performed with either phakic IOLs or clear lens extraction. Bioptics is especially useful in high myopes, as traditional IOL calculations can be less accurate and is preferable to laser corneal ablation alone because of the reduced risk of visual aberrations, contrast loss, glare, and holes that are associated with extremely large myopic laser ablations. Preliminary results with this technique have been encouraging.140, 139

3.5 LASIK

l

 se more than one modern third-generation formula (Hoffer Q, HolU laday 2, SRK/T, Haigis) or the Holladay 2 fourth-generation formula, but not a regression formula (SRK I or II) to calculate the IOL power and choose the highest value for your implant. For patients with previous myopic corrections, use the flattest corneal power values that are believed to be reliable from the refractive change method, the contact lens over-refraction method, and the topography method. We find a worksheet is helpful in our practice to document these various methods (Fig. 3-5-18). As with all refractive procedures, and because of the possibility of residual refractive errors, it is important that the patient have realistic expectations and that the desired target refraction be discussed beforehand. A well-centered capsulorrhexis that overlaps the optic of the lens for 360 degrees is helpful in case an exchange of the intraocular lens is required.

SUMMARY LASIK is an extremely useful technique, combining safety, rapid visual recovery, and flexibility in its ability to be enhanced or combined with other procedures. As the techniques continue to improve with advances such as wavefront-guided technology, refractive surgery will continue to evolve and will change the way we assess our refractive expectations and outcomes.

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PART 3 REFRACTIVE SURGERY

Laser Subepithelial Keratomileusis (LASEK) and Epi-LASIK

3.6

Leonard Ang and Dimitri T. Azar

Definition n Laser subepithelial keratomileusis (LASEK) and Epi-LASIK  are ­corneal surface ablative refractive procedures.

n LASEK involves creating an epithelial flap with dilute alcohol  and repositioning this flap after laser ablation.

n Epi-LASIK involves the use of a motorized epithelial separator to mechanically separate the corneal epithelium from the stroma.

Key features n

L ASEK and Epi-LASIK are considered in patients with thin, steep,  or flat corneas and in patients that are predisposed to flap trauma.

n

 hen compared to photorefractive keratectomy (PRK), LASEK and W Epi-LASIK may result in greater postoperative comfort, faster visual recovery, and reduced risk of corneal haze.

n

L ASEK-related intraoperative complications: alcohol leakage, incomplete epithelial detachment, laser-related complications.

n

E pi-LASIK-related intraoperative complications include flap-related complications (when these occur the procedure may be converted to PRK), laser-related complications.

n

 ostoperative complications include: epithelial healing, pain,  P infiltrates and infection, dry eye, corneal haze.

INTRODUCTION Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are widely accepted refractive surgical procedures that are generally safe and effective. However, both surgical procedures are associated with problems and complications in certain situations. Although PRK is relatively safe, its major limitations are postoperative pain, subepithelial haze, and prolonged visual rehabilitation.1–4 LASIK offers the advantages of postoperative comfort, faster visual rehabilitation, and minimal postoperative haze.1, 2, 4–7 For these reasons, LASIK has overtaken PRK as the most widely practiced refractive surgical procedure. However, LASIK has its own set of complications related to the use of a microkeratome and the creation of a flap. These include free caps, incomplete pass of the microkeratome, flap wrinkles, epithelial ingrowth, flap melt, interface, debris, and diffuse lamellar keratitis.2, 5 There is also an increased risk of corneal ectasia following excessive tissue removal of the stromal bed.8–11 As such, the extent of refractive correction with LASIK is limited by the preoperative corneal thickness, and may not be able to safely treat high degrees of refractive error with a suitable optical zone. There is a recent trend toward laser surface ablation for correcting refractive errors. Laser-assisted subepithelial keratomileusis (LASEK) and more recently, Epi-LASIK are corneal surface ablative refractive procedures that combine the advantages of both LASIK and PRK, while at the same time overcoming some of their problems.7, 12–15 LASEK involves creating an epithelial flap with dilute alcohol solution and repositioning this flap after laser ablation, thus eliminating any inherent flap

c­ omplications. The first LASEK procedure was performed in 1996 by D. Azar.12 Cimberle and Camellin independently conceived and popularized the procedure and coined the term LASEK.16 This procedure has since then proven to be a safe and effective procedure for the treatment of low to moderate refractive errors. Despite the encouraging clinical results of LASEK, the toxic effect of alcohol on the epithelium and the underlying stroma remain a concern.17 Epi-LASIK represents a recent development in refractive surgery technology, by making use of a motorized epithelial separator to mechanically separate the corneal epithelium en toto from the stroma, without the use of alcohol or chemicals.18, 19 This device makes use of a proprietary oscillating blade that separates the epithelial layer at the layer of Bowman’s membrane, without dissecting the corneal stroma.

INDICATIONS The indications for LASEK and Epi-LASIK are similar with regards to the degree of refractive error to be corrected. LASEK and Epi-LASIK may be performed in patients with low to moderate myopia and myopic astigmatism, who are at a low risk for subepithelial haze. The most ideal candidates for LASEK and Epi-LASIK are those with mild to moderate myopia up to −7.00 D.5, 14 LASEK has also been shown to be effective for hyperopia up to +4.00 D.4 These procedures should be performed in candidates older than 20 years of age, with stable refractions that have not changed by more than 0.25 D within the past year. Surgeons should consider these surface ablative refractive procedures for patients whose corneal characteristics may render them at greater risk for LASIK, such as those with thin corneas where less than 250 μm of residual stromal bed would be left should LASIK be performed, and those with steep or flat corneas. These would also be the preferred surgical procedures in patients with lifestyles or professions that predispose them to flap trauma, such as athletes in contact sports and military personnel. In addition, LASEK may also be a better choice for patients with narrow palpebral fissures where the microkeratome cannot be well applied, or when there is difficulty achieving satisfactory suction for the microkeratome cut. Contraindications for these procedures include exposure keratopathy, neuropathic keratopathy, severe dry eye (Sjögren syndrome), keratoconus, any active ocular infection or inflammation, central or paracentral corneal scars, unstable or progressive myopia, and irregular astigmatism.13, 14

ADVANTAGES The advantages of LASEK and Epi-LASIK over PRK include greater postoperative comfort,15 faster visual recovery,20 and reduced risk of corneal haze. Patients have better immediate postoperative visual acuity compared to PRK, which allows bilateral simultaneous surgery to be performed. Because no corneal flap is created, the risk of flap-related complications,21 such as incomplete flap, irregular flaps, flap displacement, flap slippage, flap striae, epithelial ingrowth, button hole, and diffuse lamellar keratitis,2 is essentially eliminated. In addition, should microkeratome-related problems occur at the time of surgery, the procedure can easily be converted to PRK and completed. The absence of a corneal lamellar flap also reduces the risk of iatrogenic keratectasia.8, 9, 11

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Fig. 3-6-1  Our current LASEK technique. (A) Multiple marks are applied around the corneal periphery, simulating a floral pattern. (B) An alcohol dispenser consisting of a customized 7 or 9 mm semi-sharp marker attached to a hollow metal handle serves as a reservoir for 18% alcohol. Firm pressure is exerted on the cornea, and alcohol is released into the well of the marker. (C) After 25−30 seconds, the ethanol is absorbed using a dry cellulose sponge. (D) One arm of a modified Vannas scissors (note knob at tip of lower arm) is then inserted under the epithelium and traced around the delineated margin of the epithelium, leaving a hinge of 2–3 clock hours of intact margin, preferably at the 12 o’clock position. (E) The loosened epithelium is peeled as a single sheet using a Merocel sponge or the edge of a jeweler’s forceps, leaving it attached at its hinge. (F) After laser ablation is performed, an anterior chamber cannula is used to hydrate the stroma and epithelial flap with balanced salt solution. (G) The epithelial flap is replaced on the stroma using the cannula under intermittent irrigation. (H) Care is taken to realign the epithelial flap using the previous marks and to avoid epithelial defects. The flap is allowed to dry for 2–5 min. Topical steroids and antibiotic medications are applied. (I) A bandage contact lens is placed. (From Azar DT, Taneri S. LASEK. In: Azar DT, Gatinel D, Hoang-Xuan T, eds. Refractive surgery, 2nd ed. Philadelphia: Elsevier; 2007:239–47.)

LASEK is a safer refractive procedure compared to LASIK for patients who have corneal graft-related refractive errors, because these postkeratoplasty corneas tend to be steep, which increases the risk of LASIK flap-­related compl­ i­cations such as buttonhole. Eyes with residual refractive errors follo­wing previous radial keratectomies are also more safely treated with LASEK.

ALCOHOL-ASSISTED EPITHELIAL REMOVAL

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Manual epithelial débridement, which was used in the past to remove the corneal epithelium in PRK and PTK, was shown to produce scratches and nicking in Bowman’s layer, and was found to be inaccurate as variable

amounts of epithelium were left in place.22–24 Abad et al. showed that alcohol-assisted epithelial removal was a simple and safe alternative to mechanical epithelial removal before PRK (Fig. 3-6-1).25 Applying 25% ethanol for 3 minutes, Stein et al. were able to grasp, lift, pull apart, and split the corneal epithelium using two McPherson forceps.26 Shah et al. were able to expose the epithelium with a dry sponge.27 Previous studies have shown that epithelial removal using 18–25% alcohol for 20–25 seconds was fast, easy, and safe compared to mechanical débridement.22–25, 28 These concentrations produced sharp wound edges and clean, smooth Bowman’s layer, and the central epithelium could be translocated in part or completely. Carones et al. found significantly better

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Fig. 3-6-2  Transmission electron micrographs of freed epithelial sheets after 20% alcohol application for 25 seconds (specimen I: A, B; II: C, D; III: E; and IV: F). Varied separation of the basement membrane zone was seen. (A) Specimen I showing basal epithelial cells with intact basement membrane complex (arrows) with intact electron-dense hemidesmosome attachment (arrowheads). (B) Higher magnification exhibited a localized area of irregular basement membrane zone (arrow) and basal cell membrane disruption (arrowheads). (C) The basal epithelial layer in specimen II showed autophagic vacuoles (arrows). (D) Discontinuous basement membrane zone beneath the basal epithelial cells (arrows), evident at higher magnification, was associated with decreased number of electron-dense hemidesmosomes (arrowheads). (E) The basal cell membranes and the basement membrane (arrows) were disrupted in specimen III. Formation of autophagic vacuoles (arrowheads) was extensive in the cytoplasm. (F) Specimen IV: the freed epithelial sheet retained a duplicated basement membrane zone. Pockets of cross-banded anchoring fibrils were arranged in a network between the layers of basal lamina (arrows). Electron-dense hemidesmosomes (arrowheads) were present along the basal cell membrane. Magnifications: (A) ×2500; (B, F) ×17 750; (C) ×6000; (D) ×30 000; (E) ×1650. Bar: 1 μm. (From Chen CC, Chang JH, Lee JB, et al. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci. 2002;43:2593–602.)

results in terms of haze and corneal regularity in epithelial débridement using a 20% alcohol solution compared to mechanical débridement.29 ­The ethanol may be diluted in distilled water12, 15, 25, 28, 30 or balanced salt solution (BSS).26, 29 There is no clear evidence to show that one method is superior over the other, and both methods have been shown to be effective. In vitro studies have demonstrated a dose-dependent and time­dependent effect of alcohol on epithelial cells.30–32 The 25% concentration of dilute alcohol was the inflection point for epithelial survival. Significant increase in cellular death occurred after 35 seconds of 20% alcohol exposure. Forty seconds of exposure resulted in greater cell apoptosis. These findings are consistent with the clinical observations of varied epithelial attachment to the stromal bed after LASEK surgery.

ELECTRON MICROSCOPY Electron microscopy studies on specimens obtained after conventional alcohol-assisted PRK revealed that the epithelial cell layer remained intact with a compact and regular arrangement.12, 33 The basement membrane layer was normal in some areas, and in other areas, showed discontinuities and irregularities. In most situations, the basement

membrane fragments were still attached to the epithelial basal cells. The presence of fragmented hemidesmosomes and basement membrane remnants still attached to the basal epithelial cell layer indicates that the point of separation is likely to be within the basement membrane (Fig. 3-6-2).33, 34 Edematous cells and abnormal vacuoles were also observed in some eyes. Bowman’s layer and corneal stroma were absent, indicating that the epithelial sheets separated from Bowman’s layer with variable amounts of basal lamina attached to the basal ­epithelial cell layer.33 The corneal epithelial anatomic cleavage plane after alcohol-assisted epithelial removal was determined to be at the hemidesmosomal attachments, including the most superficial part of the lamina lucida of the basement membrane.35, 36 The adherence of the basement membrane to the basal layer of the epithelium is significant because it is believed that the basement membrane provides the stability and support that keeps the epithelium intact even after manipulation, thereby preserving the integrity and viability of the entire epithelium.30, 33 The preservation of the hemidesmosomes in the basal epithelial layer ­ provides a structure that may promote the adhesion of a viable epithelium to the ablated stroma.30, 33

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Kim et al.17 evaluated the toxicity of 20% ethanol exposure for 30 seconds, 1 minute, and 3 minutes on rabbit corneal epithelium with scanning and transmission electron microscopy. They found widespread partial or total damage of microvilli, focal breaks of intercellular junction, and cellular edema. The damage increased with exposure time. After 1 minute of ethanol exposure, slough of superficial epithelium was observed, which progressed with time. The histopathology of Epi-LASIK epithelial flaps was evaluated by Pallikaris and associates.37 Transmission electron microscopy of epithelial sheets obtained mechanically with a subepithelial separator (developed by Duckworth & Kent) showed that the basement membrane of the mechanically separated epithelial sheet was mostly intact and showed minimal cellular fragmentation, indicating that in these cells the separation was not within but underneath the basement membrane (Fig. 3-6-3). Lamina densa and lamina lucida were preserved and the hemidesmosomes had normal morphology along almost the entire length of the basement membrane. The basal epithelial cells of the ­separated epithelial disks showed minimal trauma and edema.

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LASEK and EPI-LASIK SURGICAL TECHNIQUES Preoperative Evaluation

For both LASEK and Epi-LASIK, patients should undergo a similar routine preoperative evaluation to other refractive surgical procedures. In the history taking, it is important to obtain a history of contact lens wear, the patient’s occupational and recreational visual requirements, as well as a history of any corneal disorders and use of ocular medication. The ophthalmic evaluation includes the uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), manifest and cycloplegic refraction, ocular dominance, slit-lamp external eye and corneal examination, pupil size, tonometry, keratometry, pachymetry, computerized videokeratography, wavefront analysis, and a dilated fundus examination. Other tests such as corneal aesthesiometry and tear function assessment may be performed as and when required.

LASEK Surgical Technique (see Fig. 3-6-1)

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Just before surgery, topical broad-spectrum antibiotics (e.g., tobramycin or a fluoroquinolone) may be applied prophylactically. Some surgeons also use topical nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief. Dilute ethanol at a concentration of 18% is prepared by drawing 2 mL of dehydrated alcohol (American Reagent Laboratories, Shirley, NY) into a 12 mL syringe and diluting it with sterile water to 11 mL.12, 14 The patient is positioned on the operating table and the fellow eye is covered with a solid eye shield. The head is positioned such that the cornea plane is directed vertically upward, perpendicular to the operating microscope and laser beam. The periocular skin is cleaned with betadine solution and dried with a sterile gauze. A sterile drape is placed around the eye, and a drop of topical anesthetic (e.g., 0.5% proparacaine or tetracaine) is instilled. A lid speculum is placed to provide adequate exposure of the globe so as to allow for temporal or superior surgical approaches. The cornea is marked with 3 mm circles around the corneal periphery to allow the surgeon to have the precise reference points to realign the flap over the corneal bed. An alcohol dispenser consisting of a customized 7 or 9 mm semisharp marker (ASICO, Westmont, IL) attached to a hollow metal handle serves as a reservoir for the 18% alcohol. Firm pressure is exerted on the central cornea and a button is pushed on the side of the handle, releasing the alcohol into the well of the marker. Alternatively, a 7 mm optical marker (Storz, St. Louis, MO) is used to delineate the area centered on the pupil. Gentle pressure is applied on the cornea while the barrel of the marker is filled with two drops of 18% ethanol. After 25–35 seconds, the ethanol is absorbed using an aspiration hole followed by dry sponges (Weck-cel or Merocel; Xomed, Jacksonville, FL), to prevent alcohol spillage onto the epithelium outside the marker barrel. If necessary, the ethanol application may be repeated for an additional 10–15 seconds. One arm of a modified curved Vannas scissors or a jeweler’s forceps is inserted under the epithelium and traced around the delineated margin of the epithelium, leaving 2 to 3 clock hours of intact margin, preferably at the 12 o’clock position. The loosened epithelium is peeled as a single sheet using a jeweler’s forceps, spatula, or a Merocel sponge, leaving a flap of epithelium with the hinge still attached. The laser ablation is then initiated immediately thereafter using an excimer laser. After ablation, a 30-gauge anterior chamber cannula is used to hydrate the stroma and epithelial sheet with balanced salt solution. The

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Fig. 3-6-3  (A) Optical photomicrograph of the cornea of a porcine eye. (From Pallikaris IG, Katsanevaki VJ, Kalyvianaki MI, Naoumidi II. Advances in subepithelial excimer refractive surgery techniques: Epi-LASIK. Curr Opin Ophthalmol. 2003;14:207–12.). (B) Transmission electron micrograph of a mechanically separated epithelial disk. The basal epithelial cells and their intercellular contacts have normal morphology. The basement membrane (thick arrow) looks normal and can be seen along the entire basal border of the layer. The hemidesmosomes (arrowheads) have retained their typical structure (original magnification ×5000). (C) Higher magnification of a fragment of part B shows the basement membrane underlying the epithelial disk consists of lamina lucida (ll), lamina densa (ld), and lamina reticularis (lr). Numerous hemidesmosomes (arrowheads) anchor the epithelial cells to the basement membrane (original magnification ×16 000). (From Pallikaris IG, Naoumidi II, Kalyvianaki MI, Katsanevaki VJ. EpiLASIK: comparative histological evaluation of mechanical and alcohol-assisted epithelial separation. J Cataract Refract Surg. 2003;29:1496–501.)

epithelial sheet is replaced on the stroma using the straight part of the cannula under intermittent irrigation. Care is taken to realign the ­epithelial flap using the previous marks and to avoid epithelial defects. The flap is then allowed to dry for 2–5 minutes. Variations of the basic technique have been described. In the ­Camellin technique,16 a sharp partial-thickness trephination of the ­epithelium is carried our prior to alcohol application. The Vinciguerra butterfly technique involves abrading a thin paracentral epithelial line with a specially designed spatula, applying the alcohol, and then separating the epithelium from the center to the periphery on both sides.38

Epi-LASIK Surgical Technique (Fig. 3-6-4)

The eye is first anesthetized with topical anesthetic (e.g., 0.5% ­proparacaine or tetracaine) eye drops. After cleaning the periocular area, a sterile drape is applied and a lid speculum is inserted to ­ensure adequate exposure. After irrigation with balanced salt solution using an anterior chamber cannula, the corneal epithelium is dried with sponges. The cornea is marked with a standard LASIK marker. The subepithelial separator is applied to the eye and the suction is activated by a foot pedal. The oscillating blade separates the epithelium, leaving a 2 to 3 mm nasal hinge, the suction is released, and the ­device is removed from the eye. The epithelial sheet is reflected nasally ­using

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Fig. 3-6-4  The Epi-LASIK technique. (A) Marks are applied around the corneal periphery. (B,C) The epikeratome is applied to the eye with suction; the oscillating blade separates the epithelium. Once the separator reaches its final position, suction is released and the device is removed from the eye. (D) With the use of either a moistened Merocel sponge or a metallic spatula, the epithelium is reflected to reveal the corneal stroma. (E) Laser ablation is performed. (F,G) The cornea is irrigated with balanced salt solution and the epithelial sheet is carefully repositioned. (H, I) The replaced corneal epithelial sheet is left to dry for 2–3 minutes, and a bandage contact lens is placed. (Reproduced with permission from Refractive Surgery, 2nd Ed. Azar DT, (Ed) Ghanem RC (DVD Editor) Mosby Elsevier 2006.)

a moistened Merocel sponge or a spatula, revealing the underlying corneal stroma. Laser ablation is then initiated immediately thereafter using an excimer laser. The cornea is irrigated with balanced salt solution and the epithelial sheet is carefully repositioned using the straight part of the cannula. The replaced corneal epithelial sheet is then left to dry for 2–3 minutes, to allow adhesion to the ­underlying corneal stroma.

POSTOPERATIVE MANAGEMENT For both LASEK and Epi-LASIK, after repositioning the epithelial flap, a combination of NSAID (e.g., 0.1% diclofenac sodium), antibiotic (e.g., 0.3% tobramycin or ciprofloxacin), and steroid (e.g., 0.1% dexamethasone or 1% prednisolone acetate) eye drops are applied to the eye. A bandage contact lens is placed in the operated eye and kept in place

until complete re-epithelialization of the corneal surface occurs, which is generally on postoperative day 3 to 5. The routine postoperative regimen includes topical fluoroquinolone (ciprofloxacin, ofloxacin, or levofloxacin) and steroid (1% prednisolone acetate) eye drops 4 times per day for 1 week. The topical steroid is continued for another week and tapered over 2 months. Frequent lubrication with preservative-free artificial tears is also advised. Oral analgesics are prescribed for the first few days, and taken as and when required.

COMPLICATIONS LASEK and Epi-LASIK reduce the incidence of significant post­ operative pain and corneal haze observed in PRK and avoids the flap and interface-related problems associated with LASIK. Both LASEK

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and Epi-LASIK procedures have similar postoperative ­ complications, but certain intraoperative complications are specific for each ­procedure.

REFRACTIVE SURGERY

LASEK-Related Intraoperative Complications Alcohol leakage during surgery

Alcohol leakage may occur during LASEK and spill over to the limbal and conjunctival epithelium. When this happens, it should be immediately absorbed with a sponge and the area irrigated thoroughly with balanced salt solution. No significant long-term complications are likely to occur if prompt irrigation is performed.

Incomplete epithelial detachment

Insufficient alcohol exposure and poor surgical technique may lead to incomplete epithelial detachment. This may in turn result in tearing of the flap, fragmentation, or creating a buttonhole. Alcohol exposure may need to be more prolonged in contact lens wearers whose epithelium tends to be more adherent. If epithelial detachment is difficult, additional application of alcohol is usually sufficient to facilitate complete detachment of the epithelial sheet. If this still fails, then the remaining epithelium may be scraped off, and the procedure easily ­converted to PRK.

Epi-LASIK-Related Intraoperative Complications

The major difference between LASEK and Epi-LASIK is that the ­separation of the epithelial sheet is performed mechanically without exposing the cornea to alcohol or other chemical agent that may be toxic to the epithelial cells.17, 30 The use of a motorized epithelial separator, however, creates a different set of flap-related problems, such as a free or incomplete epithelial flap, as well as tearing, fragmentation, or buttonhole of the flap. However, unlike the flap-related complications of LASIK, when these occur in Epi-LASIK, the residual epithelium may be removed mechanically, and the procedure easily converted to a standard PRK, with equally good results. This is where Epi-LASIK offers advantages over LASIK, where the corneal flap-related complications often require that the LASIK procedure be abandoned.

EARLY POSTOPERATIVE COMPLICATIONS OF LASEK AND EPI-LASIK Epithelial Healing

Complete epithelialization in LASEK often occurs in 3–5 days, similar to that of PRK.15, 39–41 Delayed epithelial healing may occasionally occur in patients with dry eye, lagophthalmos, intolerance to contact lenses, and pre-existing basement membrane disease. More prolonged use of a bandage contact lens and topical lubricants are often sufficient to improve healing.

Pain

The postoperative pain of LASEK is less than that of PRK,4 but more than that of Epi-LASIK.19 The reduced pain in LASEK and Epi-LASIK is probably because the epithelial sheet acts as a protective layer over the ablated stroma. Resolution of pain accompanies epithelial closure. Most of the pain may be adequately controlled with oral NSAIDs.

Infiltrates and Infection

Mild sterile infiltrates may be seen after LASEK. These are superficial and may be multiple. Alcohol exposure exceeding 40 seconds is a ­ predisposing factor. The use of NSAID eye drops in the first few ­postoperative days facilitates resolution of these infiltrates. Although infections after LASEK are extremely rare, it should be ­differentiated from sterile infiltrates. An enlarging white infiltrate indicative of infection should be promptly cultured for microbiological identification, and treated with antibiotics.

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Dry eye syndrome may be aggravated following LASEK or Epi-LASIK. Patients with pre-existing dry eye should be warned that their symptoms may worsen after surgery. Frequent lubrication with artificial tears during the day and ointment at night-time is often helpful. Punctal plugs may occasionally be required when the symptoms persist despite topical lubricants.

LONG-TERM POSTOPERATIVE COMPLICATIONS Corneal Haze

LASEK and Epi-LASIK, like PRK, are associated with subepithelial haze with higher diopters of treatment.27 Increased postoperative corneal haze occurs with increased ablation depths. Corneal haze occurs as a corneal healing response following excimer laser treatment that induces activation and migration of keratocytes and synthesis of new collagen.4, 42, 43 Although the epithelial flap covering in LASEK and Epi-LASIK procedures is believed to reduce the release of cytokines and growth factors from the stroma and damaged epithelium, leading to reducing stromal keratocyte apoptosis and less collagen synthesis, moderate to severe haze still occasionally occurs with higher levels of treatment. Corneal haze may be treated by phototherapeutic keratectomy or mechanical scraping with mitomycin treatment.

Laser-Related Complications

Laser-related complications are similar to those of other refractive laser procedures. This includes undercorrection, overcorrection, decentration, glare, haloes, and regression. Patients should be counseled regarding these complications prior to surgery.

CLINICAL OUTCOMES Clinical Results of LASEK

Previous studies have shown that LASEK is a safe and effective procedure for treating low to moderate myopia.5, 6 ,40, 44–47 The majority of patients achieve complete epithelial closure within 5 days, and almost all achieve it within 1 week.15, 39–41 Postoperatively 56−82% of patients achieved an UCVA of 20/20 or better, and more than 95% of patients achieved an UCVA of 20/40 or better.5, 6, 40, 44–46 In terms of the predictability, more than 80% of eyes were within +0.50 D and more than 94% of eyes were within +1.00 D of the desired postoperative refractive ­ error.5, 6, 40, 44–46 The procedure was found to be very stable with very few regressing by more than 1.00 D within the first 2 years.5, 16, 44 Cimberle and Camellin found that intraoperative flap management was easy in 60% of patients, ­average in 28%, and difficult in 12%.16 No pain was experienced by 44% of their cases in the first 24 hours after surgery and 80% of the preoperative BCVA was achieved by 90% of patients within 10 days postoperatively.16

Clinical Results of Epi-LASIK

The preliminary clinical results for Epi-LASIK suggest that it is a safe and efficient method for treating low myopia.19, 48 Pallikaris et al. treated 44 eyes with Epi-LASIK for the correction of low myopia (range −1.75 to −7.00 D), and showed that the mean spherical equivalent at 3 months was −0.010 ± 0.4 D (range −0.75 to 0.75 D). Seventyeight per cent of eyes were within ±0.50 D and 100% were within ±1.00 D of the target refraction. Almost all the eyes (97%) had clear corneas or only trace haze 3 months after treatment.19 The mean epithelial healing time was 4.86 ± 0.56 days (range 3−5 days). Although Epi-LASIK is a fairly new procedure, the preliminary ­results suggest that the duration of epithelial closure and ­postoperative visual results are fairly similar between LASEK and Epi-LASIK. As is the case for LASEK, Epi-LASIK was not totally pain free, with 26% of the patients reporting mild discomfort on the first postoperative day.19

LASEK and Epi-LASIK versus PRK and LASIK

Several studies have shown that LASEK reduced the incidence of significant postoperative pain and corneal haze,4, 15, 27, 46 although others have not shown any benefit.49 Studies that compared the visual results of LASEK and PRK have reported that there were no significant differences in postoperative UCVA, BCVA, and predictability.3, 4, 15, 49 Comparative studies between LASEK and LASIK have demonstrated varying results. Kim et al.50 compared the surgical results of LASIK and LASEK and showed that LASIK eyes had superior results in terms of visual predictability and UCVA, and had less corneal haze, while Scerrati51 showed that the refractive results were slightly better in the LASEK group, in terms of the BSCVA, contrast sensitivity, and corneal topography. Kaya et al. showed that there were no statistically significant differences in the UCVA, BSCVA, spherical, and cylindrical refractive error between both LASEK and LASIK eyes.52

production of extracellular matrix and collagen, thereby reducing pain and haze.27, 53 In conclusion, surface laser ablative procedures in the form of LASEK or Epi-LASIK appear to be safe and effective treatment options for low to high myopia. These may be offered in many situations in which LASIK is not an option because of inadequate corneal thickness, in comparatively high corrections, wide pupils, or forme fruste keratoconus. The refractive outcomes for LASEK and Epi-LASIK are excellent and comparable to the refractive outcomes achieved with LASIK and PRK. The main disadvantages of these procedures remain the unpredictable postoperative pain and epithelial healing. The presence of an intact epithelial flap covering the ablated corneal stroma may hasten epithelial healing and modulate the corneal stromal response leading to reduced haze formation. Additional prospective studies need to be carried out to determine the long-term safety and stability of this procedure.

REFERENCES   1. L ui MM, Silas MA, Fugishima H. Complications of photo­ refractive keratectomy and laser in situ keratomileusis.  J Refract Surg. 2003;19(Suppl 2):S247–9.   2. Melki SA, Azar DT. LASIK complications: etiology, management, and prevention. Surv Ophthalmol. 2001;46:95–116.   3. Hashemi H, Fotouhi A, Foudazi H, et al. Prospective, randomized, paired comparison of laser epithelial keratomileusis and photorefractive keratectomy for myopia less than −6.50 diopters. J Refract Surg. 2004;20:217–22.   4. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy and photorefractive keratectomy for the correction of hyperopia. Results of a 2-year follow-up.  J Cataract Refract Surg. 2003;29:2105–14.   5. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy for myopia: two-year follow-up. J Cataract Refract Surg. 2003;29:661–8.   6. Claringbold TV 2nd. Laser-assisted subepithelial keratectomy for the correction of myopia. J Cataract Refract Surg. 2002;28:18–22.   7. Azar DT, Ang RT. Laser subepithelial keratomileusis: evolution of alcohol assisted flap surface ablation. Int Ophthalmol Clin. 2002;42:89–97.   8. Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg. 2001;27:1796–802.   9. Binder PS. Ectasia after laser in situ keratomileusis.  J Cataract Refract Surg. 2003;29:2419–29. 10. Binder PS, Lindstrom RL, Stulting RD, et al. Kerato­ conus and corneal ectasia after LASIK. J Refract Surg. 2005;21:749–52. 11. Teichmann KD. Bilateral keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2004;30:2257–8. 12. Azar DT, Ang RT, Lee JB, et al. Laser subepithelial keratomileusis: electron microscopy and visual outcomes  of flap photorefractive keratectomy. Curr Opin  Ophthalmol. 2001;12:323–8. 13. Taneri S, Feit R, Azar DT. Safety, efficacy and stability indices of LASEK correction in moderate myopia and astigmatism. J Cataract Refract Surg. 2004;30:2130–7. 14. Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes, and pathophysiology of LASEK: review of the literature. Surv Ophthalmol. 2004;49:576–602. 15. Lee JB, Seong GJ, Lee JH, et al. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg. 2001;27:565–70. 16. Cimberle M, Camellin, M. LASEK technique promising  after 1 year of experience. Ocular Surg News. 2000;18:14–7. 17. Kim SY, Sah WJ, Lim YW, Hahn TW. Twenty percent alcohol toxicity on rabbit corneal epithelial cells: electron microscopic study. Cornea. 2002;21:388–92. 18. Pallikaris IG, Katsanevaki VJ, Kalyvianaki MI, Naoumidi II. Advances in subepithelial excimer refractive surgery techniques: Epi-LASIK. Curr Opin Ophthalmol. 2003;14:207–12. 19. Pallikaris IG, Kalyvianaki MI, Katsanevaki VJ, Ginis HS. Epi-LASIK: preliminary clinical results of an alternative surface ablation procedure. J Cataract Refract Surg. 2005;31:879–85.

20. P  ark CK, Kim JH. Comparison of wound healing after photorefractive keratectomy and laser in situ keratomileusis in rabbits. J Cataract Refract Surg. 1999;25:842–50. 21. Pallikaris IG, Katsanevaki VJ, Panagopoulou SI. Laser in situ keratomileusis intraoperative complications using one type of microkeratome. Ophthalmology. 2002;109:57–63. 22. Griffith M, Jackson WB, Lafontaine MD, et al. Evaluation of current techniques of corneal epithelial removal in hyperopic photorefractive keratectomy. J Cataract Refract Surg. 1998;24:1070–8. 23. Campos M, Raman S, Lee M, McDonnell PJ. Keratocyte loss after different methods of de-epithelialization. Ophthalmology. 1994;101:890–4. 24. Shah S, Doyle SJ, Chatterjee A, et al. Comparison of 18% ethanol and mechanical debridement for epithelial removal before photorefractive keratectomy. J Refract Surg. 1998;14(Suppl 2):S212–4. 25. Abad JC, An B, Power WJ, et al. A prospective evaluation of alcohol-assisted versus mechanical epithelial removal before photorefractive keratectomy. Ophthalmology. 1997;104:1566–74. discussion 1574–5. 26. Stein HA, Stein RM, Price C, Salim GA. Alcohol removal of the epithelium for excimer laser ablation: outcomes analysis. J Cataract Refract Surg. 1997;23:1160–3. 27. Shah S, Sebai Sarhan AR, Doyle SJ, et al. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol. 2001;85:393–6. 28. Abad JC, Talamo JH, Vidaurri-Leal J, et al. Dilute ethanol versus mechanical debridement before photorefractive keratectomy. J Cataract Refract Surg. 1996;22(10):1427–33. 29. Carones F, Fiore T, Brancato R. Mechanical vs. alcohol epithelial removal during photorefractive keratectomy.  J Refract Surg. 1999;15:556–62. 30. Chen CC, Chang JH, Lee JB, et al. Human corneal epithelial cell viability and morphology after dilute alcohol exposure. Invest Ophthalmol Vis Sci. 2002;43:2593–602. 31. Hazarbassanov R, Ben-Haim O, Varssano D, et al. Alcoholvs hypertonic saline-assisted laser-assisted subepithelial keratectomy. Arch Ophthalmol. 2005;123:171–6. 32. Helena MC, Filatov VV, Johnston WT, et al. Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy. Cornea. 1997;16:571–9. 33. Azar DT, Spurr-Michaud SJ, Tisdale AS, Gipson IK. Altered epithelial-basement membrane interactions in diabetic corneas. Arch Ophthalmol. 1992;110:537–40. 34. Espana EM, Grueterich M, Mateo A, et al. Cleavage of corneal basement membrane components by ethanol exposure in laser-assisted subepithelial keratectomy.  J Cataract Refract Surg. 2003;29:1192–7. 35. Browning AC, Shah S, Dua HS, et al. Alcohol debridement of the corneal epithelium in PRK and LASEK: an electron microscopic study. Invest Ophthalmol Vis Sci. 2003;44:510–3. 36. Gabison EE, Oliviera HB, Chang JH, et al. Biochemical basis of epithelial dehiscence and reattachment after LASEK. In: Azar DA, Camellin M, Yee RW, eds. LASEK, PRK, and excimer laser stromal surface ablation, New York: Marcel Dekker; 2005:253–62.

37. P  allikaris IG, Naoumidi II, Kalyvianaki MI, Katsanevaki VJ. Epi-LASIK: comparative histological evaluation of mechanical and alcohol-assisted epithelial separation.  J Cataract Refract Surg. 2003;29:1496–501. 38. Vinciguerra P, Camesasca FI. Butterfly laser epithelial keratomileusis for myopia. J Refract Surg. 2002;18 (Suppl 3):S371–3. 39. Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg. 2001;17(Suppl 2):S222–3. 40. Lee JB, Choe CM, Seong GJ, et al. Laser subepithelial keratomileusis for low to moderate myopia: 6-month  follow-up. Jpn J Ophthalmol. 2002;46:299–304. 41. Camellin M. Laser epithelial keratomileusis for myopia.  J Refract Surg. 2003;19:666–70. 42. Netto MV, Ambrosio R Jr, Chalita MR, et al. Corneal wound healing response following different modalities of refractive surgical procedures. Arq Bras Oftalmol. 2005;68:140–9. 43. Netto MV, Mohan RR, Ambrosio R Jr, et al. Wound healing in the cornea: a review of refractive surgery complications and new prospects for therapy. Cornea. 2005;24:509–22. 44. Rouweyha RM, Chuang AZ, Mitra S, et al. Laser epithelial keratomileusis for myopia with the autonomous laser.  J Refract Surg. 2002;18:217–24. 45. Shahinian L Jr. Laser-assisted subepithelial keratectomy for low to high myopia and astigmatism. J Cataract Refract Surg. 2002;28:1334–42. 46. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK  for the correction of myopia and myopic astigmatism.  J Cataract Refract Surg. 2002;28:1343–7. 47. Chalita MR, Tekwani NH, Krueger RR. Laser epithelial keratomileusis: outcome of initial cases performed by  an experienced surgeon. J Refract Surg. 2003;19:412–5. 48. Zhou XT, Chu RY, Wang XY, et al. The clinical study  of the epithelial flap of painless LASEK and Epi-LASIK. Zhonghua Yan Ke Za Zhi. 2005;41:977–80. 49. Litwak S, Zadok D, Garcia-de Quevedo V, et al. Laser- assisted subepithelial keratectomy versus photorefractive keratectomy for the correction of myopia.  A prospective comparative study. J Cataract Refract Surg. 2002;28:1330–3. 50. Kim JK, Kim SS, Lee HK, et al. Laser in situ keratomileusis versus laser-assisted subepithelial keratectomy for the correction of high myopia. J Cataract Refract Surg. 2004;30:1405–11. 51. Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg. 2001;17(Suppl 2):S219–21. 52. Kaya V, Oncel B, Sivrikaya H, Yilmaz OF. Prospective, paired comparison of laser in situ keratomileusis and laser epithelial keratomileusis for myopia less than −6.00 diopters. J Refract Surg. 2004;20:223–8. 53. Li DQ, Tseng SC. Three patterns of cytokine expression potentially involved in epithelial-fibroblast interactions of human ocular surface. J Cell Physiol. 1995;163:61–79.

3.6 Laser Subepithelial Keratomileusis (LASEK) and Epi-LASIK

There have been no studies comparing Epi-LASIK with either PRK or LASIK. The early results for Epi-LASIK are promising, and suggest that it may be as effective as LASEK in correcting mild to moderate myopia.19 Further studies will need to be conducted to fully evaluate the efficacy and long-term safety of this procedure. The major advantage of LASEK and Epi-LASIK over LASIK is the elimination of the microkeratome, which avoids flap-related complications such as incomplete flap, buttonhole, flap slippage, and diffuse lamellar keratitis. In the case of LASEK or Epi-LASIK, if epithelial flap complications were to occur, the procedure could be safely and effectively completed as a standard PRK procedure. It is postulated that the epithelial flap is responsible for the decrease in incidence of haze and pain seen in LASEK. Covering the ablated ­ stromal surface with an epithelial flap may modify the responses of the stromal keratocytes, the release of cytokines, and the

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PART 3 REFRACTIVE SURGERY

Wavefront-Guided (Customized) ­Excimer Laser Refractive Surgery

3.7

Faisal M. Tobaigy and Dimitri T. Azar

Definition:  Wavefront-guided custom ablation excimer laser

r­ efractive surgery is used to correct higher-order aberrations, in ­addition to spherocylindrical correction.

Key features n n n n n

 ernike polynomials and Fourier transforms are used to analyze   Z the ocular wavefront. Optical properties and image quality. Topography-guided ablation and wavefront-guided ablation. Wavefront-guided customized ablation produced better results   in terms of visual acuity and mesopic contrast sensitivity. Surgeons must consider an offset to avoid overcorrection   in presbyopic patients.

Introduction The eye is an imperfect optical system. As light rays from distant objects pass through the optical components of the eye, they may undergo distortions due to corneal and crystalline lens irregularities. The induced distortions are referred to as “aberrations.” Most of these aberrations create common refractive errors, such as nearsightedness, farsightedness, and astigmatism, known as “lower order aberrations,” which can be corrected with spectacles.1 Other optical aberrations create images that are altered by chromatic aberration, spherical aberration, diffraction, curvature of field, coma, trefoils, and quadrifoils, collectively known as “higher order aberrations.” These higher order aberrations occur in a visually significant manner in 10−15% of the general population. Hard contact lenses correct higher order aberrations resulting from the cornea. Other treatment options for patients with higher order aberrations include the use of a wavefront-guided laser refractive technique to create a completely customized reshaping of the surface of the cornea. A customized corneal shaping requires measuring the higher order optical aberrations using a wavefront analysis system called aberrometry. These alterations can then be analyzed to separate the aberrated wavefront into components, using either Zernike polynomials or Fourier analysis2 and then digitally interfacing it with a laser, using high-speed computerized control to direct the delivery of laser beam across the cornea.

Wavefront optics

166

The wavefront of an eye is a cross section of the light rays traveling through the eye. If all rays are parallel, the wavefront (perpendicular cross section) is perfectly flat. Ideally, all light rays from a single source of light focus onto the retina at a single point. In order for all of the rays to hit a single spot at exactly the same time, they should not encounter any irregularities or aberrations in the optical system along their path. In reality, the focusing properties of the cornea and lens are not completely uniform. Some areas bend light more strongly than others. The wavefront aberration is the deviation of the eye’s wavefront from the ideal wavefront in the plane of exit pupil. This is entirely dependent on the diameter of the pupil; a larger diameter allows more information to be obtained from the optical path and, hence, a larger wavefront error (Fig. 3-7-1).3

Higher order aberrations Higher order aberrations are monochromatic refractive disorders that limit the vision of healthy eyes to less than the retinal limits and cannot be corrected with spherocylinder lens or with standard refractive surgery.4 The two most frequently discussed aberrations are spherical aberration (which causes halos and night vision disturbances) and coma (which is associated with monocular diplopia). The wavefront in spherical aberration is spherical in the center of the pupil but changes its curvature toward the edge of the pupil, giving concentric rings of focus that result in point images with halos. In coma, the wavefront is asymmetric, producing a comet-shaped pattern (Fig. 3-7-2). Trefoil, quadrafoil, and secondary astigmatism can be grouped into “other higher order ­aberrations” (see Fig. 3-7-2).

Measurements of wavefront aberrations Zernike polynomials and Fourier transforms are used to analyze the ocular wavefront. Most aberrometers used for customized laser ­surgery rely on Zernike polynomials to decompose the wavefront aberrations. They can, in principle, measure an infinite number of aberration ­orders. The information obtained from the Zernike data decomposed to the fifth order can adequately capture the majority of aberration variance typically found in normal human eyes.5, 6 The Fourier ­analysis can decompose an image into spatial frequency components (Fig. 3-7-3). The seventh order Zernike and above has little useful clinical information. It is affected by tear film instability and other minor ocular surface changes. The wavefront errors are measured through specialized sensing ­machines and computer analysis that use the root mean square deviations, or root mean square (RMS) units, to measure light deviations. Using the Zernike polynomials, an arbitrary wave aberration can be decomposed into individual Zernike modes in three-dimensional maps. The second-order Zernike modes (astigmatism and defocus) represent the spherocylindrical refraction and are known as low-order aberrations. Higher order aberrations correspond to Zernike modes of third ­order and higher (see Fig. 3-7-2). Each mode has a value that indicates the magnitude of wavefront error, usually expressed in micrometers, ­corresponding to its RMS. Applegate et al.7, 8 evaluated the effect of ­individual Zernike modes on visual quality and noted large differences in their subjective impact. They also found that the impact of the modes in the middle of a given Zernike order on vision is more than those at the periphery. For example, in the second radial order, defocus degrades vision more than astigmatism. Similarly in the third and fourth order, coma and spherical aberration degrade vision more than trefoil and quadrafoil, respectively. Williams9 found similar results using adaptive optics to produce aberrations. They blurred the subjective vision with a single Zernike mode, one at a time, while all other aberrations were corrected. They found that the aberration in the middle of the Zernike pyramid blurred more than those at its periphery.

Quality of vision and measures of optical quality Visual assessment has two parts, acuity and quality. A good visual acuity can be achieved on a high-contrast eye chart by correction of the spherocylinder using the standard refractive ablation. Vision quality refers to all the aspects of images after they have come into the clearest

second describes the effect of those properties on image quality. Optical properties are typically quantified by aberration maps (or wavefront error maps) in the pupillary plane. The second approach describes optical quality in the image plane for fundamental objects such as a point source or a sinusoidal grating.10 Pupil plane metrics measure the undulating wavefront exiting from an aberrated eye and the magnitude of the aberrations is usually quantified by the RMS wavefront error. Although RMS wavefront error is a poor predictor of the subjective impact of aberrations on vision, it can give a rough estimate about overall aberrations of an optical system.7, 8, 11, 12 Image plane metrics quantify the quality of the retinal image for two standard objects: a point of light (the point spread function, PSF) or sinusoidal gratings (optical transfer function, OTF). Optical aberrations will spread out the image of a point object resulting in the point-spread function (PSF). The retinal image of any object can be obtained by a convolution process, which is computed from the retinal image of a point. Any object can be thought of as a collection of points of light, each of which produces its own blurred image. The retinal image of the object is then the sum of these entire blurred images one from each point in the object. An optical system can affect the image of a sinusoidal grating object by reducing the contrast or translating the image sideways, which is called a phase-shift. The ability of an optical system to transfer contrast and phase from the object to the image is called the modulation transfer function (MTF) and phase transfer function (PTF), respectively. The eye’s OTF comprises the MTF and PTF. The aberrated optical system affects the retinal image of an object, which may lower the contrasts (low MTF) and change the relative position (phase shifts in PTF) of each spatial frequency in the object spectrum as it forms a degraded retinal image.

SPHERICAL ABERRATION OF A LENS

narrow pupil

large pupil

Wavefront-measuring devices

Fig. 3-7-1  Spherical aberration of a lens. Rays striking the surface at a greater distance above the axis are focused nearer the vertex. Those rays are stopped when the pupil is narrow. When the pupil is large, the marginal rays are bent too much and focus in front of the paraxial rays. The distance between the axial intersection of a ray and the paraxial focus is known as the longitudinal spherical aberration. Spherical aberration shifts the light out of the central disk to the surrounding rings. If a screen is placed at the focal plane of such a lens, the image of a point source will appear as a bright central spot on the axis surrounded by a symmetrical halo delineated by the cone of the marginal rays. The envelope of the refracted rays is called a caustic. (From Gatinel D. Wavefront analysis. In: Azar DT, Gatinel D, Hoang-Xuan T, eds. Refractive surgery, 2nd ed. Elsevier; 2007:117–45.)

Several methods for assessing the wavefront aberrations in human eyes are currently available. Each method has its own way for measuring the displacement of a ray of light from its ideal position. They can be generally classified as outgoing aberrometers or ingoing aberrometers. Hartmann-Shack style devices are currently the most commonly used. These devices analyze an outgoing light that emerges or is reflected from the retina and passes through the optical system of the eye. A narrow beam of light is projected onto the retina, and the light reflected from the fovea passes through the lens and the cornea

3.7 Wavefront-Guided (Customized) Excimer Laser Refractive Surgery

focus. Vision quality is compromised more at dim light during night and symptomatically represented by double vision, ghosting, glare, ­halos, starbursts, and reduced contrast sensitivity. There are two standard approaches to the quantification of the optical quality of the eye; the first describes the optical properties and the

ZERNIKE PYRAMID f = angular frequency n = radial order

Z(r n,fΘ)=Zfn

4

3

2

1

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(4, 2)

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+3

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(4,0)

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(4, 2)

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trefoil (4, 4)

tetrafoil

Fig. 3-7-2  Zernike pyramid. The defocus, coma, and spherical aberration are located in the middle of the 2nd, 3rd, and 4th order, respectively. The middle aberrations have more impact on vision.

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3

THE BASIS OF FOURIER ANALYSIS

REFRACTIVE SURGERY

0.4 complex signal

0.3 0.2 0.1

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Fig. 3-7-3  Any periodic signal (solid line) can be broken down into fundamental harmonics selectively weighted (dotted lines). Conversely, the addition of the weighted fundamentals allows reconstruction of the original signal. This is the basis of Fourier analysis. (From Gatinel D. Wavefront analysis. In: Azar DT, Gatinel D, Hoang-Xuan T, eds. Refractive surgery, 2nd ed. Elsevier; 2007:117–45.)

168

and exits the eye. The Hartmann-Shack sensor has a lenslet array that consists of a matrix of small lenses.13, 14 The light that emerges from the eye is focused on a charged-coupled device (CCD) camera through each lenslet to form a spot pattern. The spot pattern of an ideal subject with a perfect wavefront will be exactly the same pattern as the reference grid, and the spot pattern of a subject with a distorted wavefront will create an irregular spot pattern. Displacement of lenslet images from their reference position is used to calculate the shape of the wavefront. Examples of these types of devices include VISX (Wavescan, Santa Clara, CA), Alcon (LADARWave, Fort Worth, TX), Bausch & Lomb (Zyoptics, Salt Lake City, UT), and Meditec (WASCA, Carl Zeiaa Meditec) (Fig. 3-7-4). Tscherning aberrometry analyzes the ingoing light, which forms an image on the retina. A grid pattern formed by multiple spots is projected through the optical system of the eye and forms an image on the retina. This image is observed and evaluated by a method similar to indirect ophthalmoscopy and captured on CCD camera. The distortion of the grid pattern enables calculation of the aberrations of the optical system of the eye.15 Tscherning aberrometry is used in WaveLight Laser Technology (Wavelight wavefront analyzer, Erlangen, Germany) and Schwind (Schwind aberrometer). Ray tracing aberrometry measures an ingoing light that passes through the optical system of the eye and forms an image on the retina. It measures one ray at a time in the entrance pupil rather than measuring all the rays at the same time like previously mentioned devices. This decreases the chance of crossing the rays in highly aberrated eyes. The total time of scanning is 10–40 milliseconds. The Tracey aberrometer (Bellaire, TX) is based on the retinal ray tracing technology, and is not currently linked to a customized laser platform.16 Scanning slit refractometer is a double-pass aberrometry (slit skioloscopy) that is based on retinoscopic principles. Both the projecting system, consisting of an infrared light source, and the receiving system rotate at high speed around the optical axis synchronously, and 360° meridians are measured in 0.4 seconds. A group of photodetectors is located above and below the optical axis at 2.0, 3.2, 4.4, and 5.5 mm, which detect the time of its stimulation by reflected light. The time difference depends on the type and amount of refractive error and

is converted into the refractive power.17, 18 This principle is used in the ARK 10000 Optical Path Difference Scanning System (OPD-Scan) distributed by Nidek (Gamagori, Japan).

Types of customization Two main methods of customization are available in refractive surgery: topography-guided ablation and wavefront-guided ablation. Another method of customization is normalized ablation, which is different from customization because it uses a normalized correction based on an individual customized wavefront to determine the treatment. The normalization is used with a radially symmetric higher order aberration such as spherical aberration. The same strategy is used in cataract surgery by incorporating negative spherical aberration in the intraocular lenses (IOLs).19

Wavefront-Guided Customization

The aim of wavefront custom ablation, in addition to spherocylinder correction, is to correct the aberrations that are induced by conventional laser vision correction20, 21 and the pre-existing aberrations. The correction of a higher order aberration requires more accuracy in both wavefront measurement and ablation profiles. Several requirements are important to achieve superior clinical results including efficient eye tracking and registration system, small size laser spot, and sufficient corneal bed thickness. Accurate wavefront measurements are critical for customization. The alignment of the head and eye is important to avoid wavefront artifacts. Common clinical conditions may present challenges to wavefront measurements. Tear film abnormalities can significantly affect the quality of wavefront analysis.13 Eyes with pupils that are significantly miotic may be difficult to measure and provide information beyond the 3 mm optical zone and, therefore, require pharmacological dilatation. However, some variations in the wavefront maps have been demonstrated with the use of pharmaceutical agents. It has been reported that cyclopentolate eye drops wavefront analysis results in significant difference in the preoperative refractive error compared to subjective refraction. The same report also showed that using neosynephrine for pupil

3.7

B

D

Wavefront-Guided (Customized) Excimer Laser Refractive Surgery

A

E

C

Fig. 3-7-4  (A) OPD-Scan. (B) VISX Wavescan. (C) LADARWave system. (D) The Zywave workstation; it consists of the Zywave and ORBSCAN II. (E) The Allegretto   Wave Topolyzer.

dilatation gave comparable refractive results between the aberrometry measurements and subjective refraction.22 An eye with marked aberrations such as scars or keratoconus may be difficult to measure. This is because of complete light scatter and the inability of the source testing light to reach to the retina and reflect back to the CCD camera.13 After obtaining good aberration maps, the next step is conversion of the wavefront measurements data to an ablation profile through a specific algorithm. This algorithm should be optimized to provide the best optical quality over the optical zone and tapering of the ablation in the surrounding zone. The algorithm should also be designed to make the postoperative higher order aberrations as minimal as possible, not only correcting the preoperative higher order aberrations but also preventing the induction of new higher order aberrations. Another important issue for successful custom ablation surgery is registration and eye tracking during corneal laser ablation. The wavefront data must be transferred to the laser machine and applied to the same location of the eye from which it was captured. A small misalignment in the axis can have significant impact on the results of the procedure. It may actually cause new higher order aberrations due to misalignment of the pattern of treatment to the actual wavefront error on the eye. It is common to have 5°–7° of cyclotorsion when changing from sitting position to supine position. Giurao and coworkers found that 50% of the visual benefit correction of higher order aberration is lost with a 250 μm decentration or a 10 degree eye rotation.23 Ideally, the wavefront must be centered and registered with respect to a fixed ocular structure to avoid misalignment between the captured wavefront and the delivered laser. Current laser platforms use the limbus, iris details, or scleral vessels as reference points for accurate registration. Many refractive laser companies have implemented eye-tracking systems in their machines to position the ablation beam accurately onto

the corneal surface and compensate for patient head movements during corneal ablation. The eye tracker should “lock on” in the proper position to get excellent correspondence between the axis and the orientation of the eye measured by the wavefront sensor and the axis and orientation of the eye identified by the eye tracker during ablation.

Customized ablation platforms Nidek NAVEX Platform

The Nidek Advanced Vision Excimer Laser System (NAVEX; Gamagori, Japan) uses the OPD-Scan optical path difference scanning system, the final fit software that takes data from the OPD-Scan and develops a customized ablation profile, and the EC-5000CX II excimer laser that employs both scanning slit and spot ablation capabilities to deliver treatment onto the cornea. The OPD-Scan optical path difference scanning system combines measurement of corneal topography and aberrometry (Fig. 3-7-4A). The OPD has a dynamic range that can measure patients with −20 to +22 D of spherical and up to 12 D of cylindrical refractive error; the Zernike coefficients can be displayed up to eight-order aberrations. The OPD-Scan performs wavefront sensing based on the principle of dynamic SkiaScopy and involves acquisition of 1440 data points to produce a map of the optics of the whole eye. In addition, the OPD Scan simultaneously performs ­corneal topography. Both measures are central to successful customized ablation, because treatments that ignore surface topography can be associated with significant errors. In addition, Zernike polynomials do not adequately ­describe the surface of eyes when significant corneal aberrations are present, and so have limited applicability for guiding ablations, particularly for eyes with irregular corneas secondary to pathology or previous surgery.

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3 REFRACTIVE SURGERY

The Final Fit Software (FFS) is the interface between the OPD-Scan and Excimer laser that has an ablation simulator to display the simulated postoperative maps. It also does component splitting (sphere, cylinder, and irregularity component) and allows a selection of profile types, zone sizes, and nomogram adjustments. The FFS has three treatment options: Optimized Aspheric Treatment Zone (OATZ), Customized Aspheric Treatment Zone (CATZ), and OPD Customized Aspheric Treatment (OPD CAT) OATZ: The OATZ profile was designed to deliver aspheric ablation to reduce the abrupt diopteric power changes and consequently the spherical aberration that is usually induced by many conventional excimer lasers. This profile is ideal for virgin eyes with a smaller amount of irregularities. Patients with larger pupils and higher degrees of myopia will benefit more from OATZ due to a smooth aspheric transition zone. CATZ: Customized aspheric treatment zone profile is a topographybased customized ablation. Indications for CATZ include irregular astigmatism induced by initial corneal injury or treatment of virgin eyes with a naturally irregular cornea. These cases include eyes with decentered ablation, small optical zone, central island, corneal scar, and keratoplasty, in which asymmetrical astigmatism cannot be ­successfully treated by conventional ablation. OPD CAT: This is a customized ablation based on aberrometer data, which is ideal for virgin eyes with less than 10 μm of irregularities. The NAVEX platform uses a high-speed, active-tracking, closed-loop system to follow the patient’s eye, ensuring laser alignment during ablation. It also has a torsion error detector to compensate for the ­cyclotorsion that may occur between sitting and supine positions.

VISX S4 CustomVue Platform

There are three components to the VISX (Santa Clara, CA) CustomVue procedure: wavescan wavefront system, wavescan soft wave, and STAR S4 excimer laser system. The wavescan system employs a HartmannShack wavefront sensor to measure the refractive error and aberrations of the eye. It can measure spherical refractive errors between −8 D and +6 D; cylindrical refractive errors up to 5 D; and higher order aberrations up to sixth-order Zernike terms. The VISX wavescan software obtains the refractive data of the eye from the wavescan sensor and computes the best configuration of pulses to fit the wavefront error of the eye. The VISX algorithm begins

170

Fig. 3-7-5  VISX Wavescan map showing high amount of coma.

the computation with a coarse fit, selecting larger pulses to ensure that the maximum amount of tissue is removed in the minimum amount of time. Next, the algorithm refines the fit by adding smaller pulses (Fig. 3-7-4B, Fig. 3-7-5, and Fig. 3-7-6). The STAR S4 laser system delivers the corneal ablation by scanning a series of variably sized pulses over an area as large as 9.5 mm in diameter. This variable-sized pulse system is flexible enough to create a complex shape of treatment. The STAR laser system has a 3-dimensional active eye-tracking system that tracks X-, Y-, and Z-axis eye movements and repositions the laser accordingly. It uses dual side-mounted infrared cameras that actively follow eye movements during treatment. It pauses the laser if eye movements are large enough to affect treatment, then moves back in position and automatically resumes treatment. It also prevents oblique placement of the beam that may occur when the eye moves during ablation. The VISX platform uses the iris details for registration, which is a noninvasive, automated alignment method. This method captures the images of the eye with cameras on both the measurement and the treatment devices, and the laser adjusts to compensate for cyclotorsional position.

Alcon Customized Cornea Platform

The Alcon (Fort Worth, TX) customized ablation system uses the LADARWave wavefront sensor to detect wavefront errors of the eye, and the LADARVision system to deliver the laser corneal ablation. The LADARWave device is a Hartmann-Shack wavefront ­ sensor. This system requires pupil dilation to capture large amount of data that allows calculation of wavefront aberrations up to the eighth-order Zernike terms. The device can measure wavefronts with a maximum curvature lying between +8 D and −14 D (defined for a 8 mm pupil) and 8D of astigmatism. The LADARVision System uses two ink dots placed on the limbus preoperatively for registration and proper alignment during corneal ablation. The LADAR vision ­ algorithm converts the aberration data into an ablation profile that takes into account the corneal curvature and corneal biomechanics to provide best optical performance over the optical zone and graceful tapering of the ablation in the surrounding blind zone (Fig. 3-7-4C, Figs 3-7-7 to 3-7-9)

Bausch and Lomb Zyoptix System

3.7 Wavefront-Guided (Customized) Excimer Laser Refractive Surgery

The Zyoptix system (Bausch and Lomb Surgical, Rochester, NY) includes diagnostic and treatment components for wavefront customized corneal ablation. The diagnostic part of the Zyoptix system is the Zywave aberrometer and ORBSCAN (Bausch and Lomb Surgical, Rochester, NY).

Both machines are integrated in one workstation. The treatment component consists of Zylink software and the Technolas 217z laser. The Zywave aberrometer is a Hartmann-Shack sensor that measures up to the fifth order Zernike term. It measures sphere from +6 D to −12 D and cylinder from 0 to 5 D with a pupil diameter ranging from 2.5 to 8.6 mm. While the wavefront measurements are taken with a dilated

Fig. 3-7-6 VISX Wavescan map showing high amount of trefoil.

Fig. 3-7-7 LADARWave map showing high amount of coma.

Fig. 3-7-8  LADARWave map showing the lower and higher order aberration in 3D.

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3 REFRACTIVE SURGERY

pupil, the ORBSCAN must be performed with an undilated pupil, so it is usually performed prior to the dilated Zywave map. The ORBSCAN ­provides three-dimensional information about the cornea. The anterior float map measures the anterior elevation of the cornea. The posterior float map measures the posterior elevation of the cornea. It also has a refractive map that is similar to the keratometric map, and pachymetry map that measures the corneal thickness (Fig. 3-7-4D, Fig. 3-7-10).

After obtaining the data from both machines, the Zlink software combines both of them to produce the customs ablation profile in one window that includes the pachymetry map, the anterior keratometric map, the customized ablation map, and the treatment data. The technolas 217z laser system uses what is called a truncated Gaussian beam to achieve the benefits of both beam types. The laser beam has two sizes: 1 mm and 2 mm. The 2 mm beam allows the majority of the refractive error to be corrected in a short time and the 1 mm beam is then used for the more specific ablation pattern on the transition zones. The system has a 120 Hz active eye tracker with a passive automatic shut-off system if the eye moves more than 0.5 mm. It also has an iris recognition feature that compensates and corrects for intraoperative eye movement in every dimension, including cyclotorsion and pupil shift.

The Allegretto Wavefront-Guided Ablation

The allegretto wave analyzer is based on the Tscherning principle of wavefront sensing. It ensures adequate alignment of the measurements to the pupil center with an integrated eye-tracking system that tracks the pupil in the x and y and the eye in a z direction during the measurements. The pupil should be dilated to at least 7 mm during the ­measurements. The allegretto wave analyzer calculates Zernike coefficients up to the sixth ­order (Fig. 3-7-4E, Fig. 3-7-11). The allegretto wave ­system wavefront-­optimized ablation profile compensates for the spherical aberrations that usually result following conventional excimer laser surgery. It compensates for the energy loss in the ­periphery of the ­cornea using a specific short-­pattern algorithm; this is called a ­ wavefront-­optimized ablation profile. The allegretto excimer laser ­system has a high repetition rate spot laser (200 Hz) with a small Gaussian beam size (0.95). An infrared camera is used for eye tracking during laser corneal ablation. It is an active eye-tracking system based on the pupil that ­allows the laser beam to automatically follow the movement of the eye without ­interruption of the treatment.

Results

Fig. 3-7-9  LADARWave screen showing the value of each aberration.

172

Sakimoto et al. reviewed the outcomes for wavefront-guided LASIK in myopia that have been investigated by the Food and Drug Administration (FDA) for three separate laser platforms.24 Grouped data from the FDA-approved wavefront-guided laser platforms (LADAR Vision; ­Technolas 217z; and STAR S4 and Wavescan Wavefront System, VISX,

Fig. 3-7-10  The ORBSCAN map showing the anterior and posterior elevation of the cornea, the keratometry map, and the pachymetry map.

Fig. 3-7-11  The overview screen of the Allegretto Wave Topolyzer.

3.7 Wavefront-Guided (Customized) Excimer Laser Refractive Surgery

Santa Clara, CA, USA, and Bausch & Lomb Technolas 217z) for low to moderate myopia showed manifest refraction spherical equivalent within about 1·00 D in 96% of eyes and within 0·50 D in 81%. ­Uncorrected visual acuities better than 20/40 were measured in 98% of ­patients, and 89% had vision equal to or better than 20/20. A loss of best spectacle-corrected visual acuity of more than two lines was ­recorded in only 0.5% of patients. Wavefront-guided LASIK seems to be most successful in patients who have low myopia, especially for uncorrected ­visual acuities better than 20/20. 95% of the patients up to −2 D achieved 20/20 or better, as did 91% in the range −2 to −4 D.25–27 By comparing the FDA trials data, Sakimoto et al. showed that the additional information obtained with wavefront-guided treatments translated into improved uncorrected acuity compared with conventional myopic LASIK.24 A marked difference in uncorrected visual acuities of 20/20 or better was seen between wavefront-guided and conventional treatments. In wavefront-guided LASIK, 89% of myopic

patients achieved this level of vision, whereas 72% of patients treated with conventional treatment achieved 20/20 or better. These differences were not seen with the 20/40 or better acuity outcome. There were no substantial differences in postoperative manifest refraction spherical equivalent between conventional and custom treatments.24 Similar results were reported by Kim et al., who evaluated the ­effectiveness of wavefront-guided laser-assisted in situ keratomileusis (LASIK) in reducing the increase of higher order aberration.28 They compared aberrational change after LASIK with conventional and ­wavefrontguided customized ablation. The study included 48 eyes of 24 patients, in which conventional LASIK was performed in one eye and wavefrontguided customized ablation in the other eye. They found that wavefrontguided customized ablation reduced the increase of higher order aberrations resulting from LASIK. In terms of visual acuity, ­patient preference, and mesopic contrast sensitivity, wavefront-guided customized ablation produced slightly − but not statistically significant − better results.

REFERENCES   1. Applegate RA. Limits to vision: can we do better than nature? J Refract Surg. 2000;16:S547–51.   2. Maeda N. Evaluation of optical quality of corneas using corneal topographers. Cornea. 2002;21(Suppl 7):S75–8.   3. Huang D. Physics of customized corneal ablation. In: MacRae S, Kreger R, Applegate R, eds. Customized corneal ablation: The quest for supervision, Thorofare, NJ: Slack; 2001; 51–62.   4. Williams D, Yoon GY, Porter J, et al. Visual benefit of correcting higher order aberrations of the eye. J Refract Surg. 2000;16:S554–9.   5. Porter J, Guirao A, Cox IG, Williams DR. Monochromatic aberrations of the human eye in a large population.   J Optical Soc Am. 2001;18:1793–803.   6. Thibos LN, Hong X, Bradley A, Cheng X. Statistical variation of aberration structure and image quality in a normal population of healthy eyes. J Optical Soc Am. 2002;19:2329–48.   7. Applegate RA, Sarver EJ, Khemsara V. Are all aberrations equal? J Refract Surg. 2002;18:S556–62.   8. Applegate RA, Ballentine C, Gross H, et al. Visual acuity as a function of Zernike mode and level of root mean square error. Optom Vis Sci.. 2003;80:97–105.   9. Williams DR. What adaptive optics can do for the eye. Rev Refract Surg. 2002;3:14–20. 10. Cheng X, Thibos LN, Bradley A. Estimating visual quality from wavefront aberration measurements. J Refract Surg. 2003;19:S579–84.

11. Applegate RA, Thibos L, Williams DR. Converting wavefront aberration to metrics predictive of visual performance. Invest Ophthalmol Vis Sci. 2003;44 (Suppl): ARVO E-Abstract 2124. 12. Guirao A, Williams DR. A method to predict refractive errors from wave aberration data. Optom Vis Sci. 2003;80:36–42. 13. Thibos LN, Hong X. Clinical applications of the ShackHartmann aberrometer. Optom Vis Sci. 1999;76:817–25. 14. Thibos LN. Principles of Hartmann-Shack aberrometry.   J Refract Surg. 2000;16:S563–5. 15. Mrochen M, Kaemmerer M, Mierdel P, et al. Principles of Tscherning aberrometry. J Refract Surg. 2000;16:S570–1. 16. Molebny VV, Panagopoulou SI, Molebny SV, et al. Principles of ray tracing aberrometry. J Refract Surg. 2000;16:S572–5. 17. Krueger RR. Technology requirements for Summit − Autonomous CustomCornea. J Refract Surg. 2000;16:S592–601. 18. Mierdel P, Kaemmerer M, Mrochen M, et al. Ocular optical aberrometer for clinical use. J Biomed Optics. 2001;6:200–4. 19. Porter J, MacRae S, Yoon G, et al. Separate effects of the microkeratome incision and laser ablation on the eye’s wave aberration. Am J Ophthalmol. 2003;136:327–37. 20. Seiler T, Kaemmerer M, Mierdel P, Krinke HE. Ocular optical aberrations after photorefractive keratectomy for myopia and myopic astigmatism. Archiv Ophthalmol. 2000;118:17–21.

21. Marcos S. Aberrations and visual performance following standard laser vision correction. J Refract Surg. 2001;17:S596–601. 22. Giessler S, Hammer T, Duncker GI. Aberrometry due to dilated pupils − Which mydriatic should be used? Klinische Monatsblatter fur Augenheilkunde. 2002;219:655–9. 23. Guirao A, Williams DR, Cox IG. Effect of rotation and translation on the expected benefit of an ideal method to correct the eye’s higher-order aberrations. J Optical Soc Am. 2001;18:1003–15. 24. Sakimoto T, Rosenblatt MI, Azar DT. Laser eye surgery for refractive errors. Lancet. 2006;367:1432–47. 25. FDA U. LADARVision® Excimer Laser System. P970043/ S10. 9 May, 2000. http://wwwfdagov/cdrh/pdf/ p970043s010html. 26. FDA U. Bausch & Lomb TECHNOLAS® 217z Zyoptix System for Personalized Vision Correction. P990027S006 10 Oct, 2003. http://wwwfdagov/cdrh/pdf/ p990027s006html. 27. FDA U. STAR S4 Active Trak™ Excimer Laser System and WaveScan Wave Front® System. P930016/S016 5 May, 2003. http://wwwfdagov/cdrh/pdf/p930016s016html. 28. Kim TI, Yang SJ, Tchah H. Bilateral comparison of wavefront-guided versus conventional laser in situ keratomileusis with Bausch and Lomb Zyoptix. J Refract Surg. 2004;20:432–8.

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PART 3 REFRACTIVE SURGERY

Conductive Keratoplasty and Laser Thermal Keratoplasty for Correction of Hyperopia and Presbyopia

3.8

Dimitri T. Azar and Kalliopi Stasi

Definition: Conductive keratoplasty (CK) steepens the cornea using radiofrequency currents. n CK applications in the mid-periphery of the cornea heat the corneal tissue and increase the central corneal curvature.

Key features n n

 K steepens the central cornea by shrinking peripheral collagen. C The corneal time-space heat distributions differ between CK and a previously used procedure known as laser thermal keratoplasty (LTK). This may explain the greater stability of CK as compared to LTK.

Associated features n n

 K may be helpful in the treatment of low hyperopia and/or early C presbyopia. Despite the instability of corrections, LTK and CK have a major advantage of untouched central cornea.

INTRODUCTION Conductive keratoplasty (CK) is a surgical procedure aimed at altering the corneal curvature using radiofrequency to heat the peripheral corneal collagen. This results in shrinking of the peripheral and paracentral stromal collagen, flattening of the peripheral cornea, and steepening of the central cornea. Steepening of the central cornea offers a means of treating hyperopia and hyperopic astigmatism (Fig. 3-8-1). A previously used procedure using laser energy known as laser thermal keratoplasty (LTK) has been plagued by regression of the refractive effect. Improved understanding of the response of corneal collagen to heat and the availability of state-of-the-art heat delivery systems have improved the outcomes of CK and related thermal refractive surgical procedures. Conductive keratoplasty (CK) delivers low-energy, high-frequency (radiofrequency) current to heat the peripheral collagen and shrink it, which results in seemingly more stable central steepening of the cornea (Fig. 3-8-2). The classical approach of conductive keratoplasty required greater indentation of the cornea during the heating process. With the newer light-touch technique, the reduced corneal indentations result in more homogeneous and efficacious corneal heating.

HISTORICAL REVIEW

174

The use of heat to alter the curvature of the cornea can be traced to 1879, when Gayet used cautery to treat keratoconus. That procedure remained popular until penetrating keratoplasty was popularized by Castroviejo

Fig. 3-8-1  Side view of the location of a 16-spot laser thermal keratoplasty application with the resultant corneal steepening.

in 1936.1 In 1898, Lans2 described a method to reduce astigmatism by changing the corneal curvature in rabbit eyes by applying electrocautery to the peripheral cornea. By 1933, three reports of successful correction of severe astigmatism using corneal cautery had been published.3–5 The discovery by Stringer and Parr6 in 1964 of the shrinkage temperature of corneal collagen (55–58°C) led to renewed interest in thermal keratoplasty. Over the past three decades, several nonlaser and laser devices have been tested. In the early 1970s, a thermostatically controlled electric probe was used to flatten the central cornea in keratoconus patients by Gasset et al.,7 who demonstrated excellent 1-year results in five patients. Other investigators reported a high incidence of regression and a case of total regression. Reported complications ranged from mild surface problems to corneal melting and stromal scarring.8–10 Nowadays, this method is used only as a surgical adjunct during keratoplasty to flatten steep cones and improve the quality of the host trephination. In a later attempt to minimize the surface problems of the electric probe, a 1.6 MHz radiofrequency probe (the Los Alamos probe) was designed to deliver thermal energy localized to a zone of 200–400 μm inside the stroma, thus sparing the epithelium and endothelium.11–13 Poor predictability and regression of the effect led to withdrawal of this probe in 1987.14, 15 In 1984, Fyodorov used a retractable wire probe heated to 600°C for 0.3 seconds, preset to penetrate the cornea at 95% depth, to perform deep coagulations in a radial pattern (radial keratoplasty) for the correction of hyperopia.16

LASER THERMAL KERATOPLASTY TREATMENT PATTERNS USED IN SUNRISE CLINICAL TRIALS

90 135

45

180

0

225

315 270

Double ring, staggered pattern

90

Fig. 3-8-2  The ViewPoint CK System from Refractec Inc.

135 A retrospective review of 159 of Fyodorov’s patients revealed unacceptably high unpredictability, regression, and serious complications (stromal ­necrosis, endothelial damage, and corneal decompensation).17, 18 Fyodorov proposed a less invasive approach of laser coagulation of the cornea to overcome some of these problems. This was followed by the development and testing of CO2 lasers for corneal thermal shrinkage. CO2 lasers produced 10.6 μm radiation with very shallow penetration in the corneal tissue (99% was absorbed in the first 50 μm of the stroma).19 A 1.54 μm yttrium–erbium–glass laser was also tested. It created gray coagulation cones that extended to Descemet’s membrane, but its penetration depth of at least 1 mm risked endothelial and iris damage.20 Efforts to find a laser with a penetration depth that approximates the corneal thickness led to the holmium:yttrium–aluminum–garnet (Ho: YAG) solid-state laser. Such a laser would have to emit light in the wavelength range of 1.9–2.3 μm, and to achieve homogeneous coagulation throughout the corneal stroma, the laser beam would have to be focused so that the maximal energy occurs in the central stroma.20 In contrast to the conical footprints of LTK, the CK approach using radiofrequency current results in a cylindrical thermal footprint extending to 80% depth.

CORNEAL RESPONSE TO HEAT Heating can induce collagen shrinkage up to one third of its native length. Thermal energy disrupts the hydrogen bonds of the tertiary ­collagen structure (without altering the primary structure), allowing the collagen triple helix to unwind partially and form new cross-links between amino acids.21 Heating human corneal collagen to temperatures of 55–58°C induces collagen shrinkage by approximately 7%.21 Heating past the shrinkage temperature, into the 65–78°C range, results in relaxation of the contracted collagen secondary to hydrolysis of the heat-labile cross-links. The aging process increases the number of thermally stable cross-links, raising the temperature threshold for collagen relaxation. Further elevation of the temperature (beyond 78°C) eventually leads to collagen fiber necrosis. Appropriate elevation of corneal collagen fiber temperature results in contraction and subsequent flattening of the area of heating. Central heating of the cornea (to the 4 mm-diameter zone) results in central corneal flattening, decrease of the refractive power of the cornea, and a hyperopic shift. Peripheral heating of the cornea produces a belt-like effect of peripheral flattening with evident collagen stress lines emanating from each stromal burn, resulting in central steepening and increase of the refractive power of the eye (Fig. 3-8-3). In general, the greater the number of peripheral burns or radials, and the smaller the optical zone beyond the 4.5 mm diameter, the greater the central steepening and the concomitant myopic shift. For astigmatic corrections, peripheral heating along a single meridian (the flatter meridian) causes central steepening along the meridian of treatment (similar to a wedge resection). A compound treatment for hyperopia with astigmatism can be designed by treating more of the cornea or closer to the visual axis along the ­flattest meridian of the cornea.21 The effect of corneal collagen contraction tends to decrease with time in both human and animal studies (Fig. 3-8-4), which might be explained by the production of new collagen by corneal fibroblasts.21, 22 At least

45

180

0

225

315 270

Double ring, radial pattern

90 135

45

180

0

225

315 270 0

5mm

Fig. 3-8-3  Laser thermal keratoplasty treatment patterns used in some of the Sunrise clinical trials.

Conductive Keratoplasty and Laser Thermal Keratoplasty for Correction of Hyperopia and Presbyopia

Single ring

3.8

three key factors are believed to play a role in achieving adequate refractive results: the collagen shrinkage temperature, the collagen stability, and the keratocyte response.23 Because of the narrow temperature range for collagen shrinkage, thermal keratoplasty requires excellent control of corneal temperature. Normal corneal collagen appears to be very stable, with a probable half-life greater than 10 years, but the stability of thermally contracted collagen is not known.24 Minimal wound healing with a minimal inflammatory and keratocyte wound healing response would probably require minimization of temperature levels.21 As the heating temperature increases, the likelihood of tissue destruction and an inflammatory response, with subsequent wound healing and remodeling, also increases. Normal energy levels from the noncontact Ho:YAG laser tested in rabbits produced the expected stromal scarring, but the endothelium appeared to be only minimally affected.25 With a maximal energy of 32 spots treated with at least 20 J/cm2, the total endothelial loss was less than 1.2%.

HOLMIUM:YAG LASER THERMAL KERATOPLASTY AND CONDUCTIVE KERATOPLASTY Ho:YAG laser devices provide adequate control to avoid overheating of the cornea past the shrinkage temperature, which could result in collagen relaxation and a wound healing response. The corneal

175

3 REFRACTIVE SURGERY Fig. 3-8-4  Photographs of a cornea treated with laser thermal keratoplasty at different intervals after the procedure.

Fig. 3-8-6  Noncontact holmium:yttrium–aluminum–garnet laser (Sunrise Technologies). Left, the slit-lamp delivery system; right, the laser unit, which has a fiber-optic cable to transmit the energy to the delivery system. (Reproduced with permission from Sunrise Technologies, Fremont, CA.)

Fig. 3-8-5  Probe applied to the corneal surface.

176

penetration depth of this laser light, 480–530 μm, is ideal for stromal heating with minimal damage to adjacent tissue. The beam produces a cone-shaped temperature profile, which leads to more pronounced shrinkage of the collagen fibrils in the anterior than the posterior stroma, resulting in better refractive correction and long-term ­stability.26–29 Two principal Ho:YAG laser delivery systems have been investigated: 1. The contact probe types previously manufactured by Summit Technology and Technomed (Fig. 3-8-5); and 2. The noncontact device manufactured by Sunrise Technologies (Fig. 3-8-6). The CK approach is a contact method employing a disposable stainless steel tip that penetrates about 450 μm into the corneal stroma. The eyelid speculum is attached to the probe to allow for the electrical return path (see Figs 3-8-2 and 3-8-7). These systems produce different corneal temperature–time–space distributions. The laser contact mode procedure almost certainly heats stromal collagen to a higher average temperature, because of the delivery of approximately twice as much energy per spot (19 mJ  × 25 pulses, versus 24–30 mJ × 10 pulses), at three times the pulse repetition frequency (15 Hz vs 5 Hz), and in a higher irradiance (strongly versus weakly focused) geometry. The CK approach may seem more invasive, but the temperature distribution is such that the treated zone is cylindrical (which seems to be more favorable than the conical distribution of the laser approaches).

Fig. 3-8-7  An eye immediately after undergoing conductive keratoplasty.

CK: INDICATIONS, TECHNIQUES, AND OUTCOMES Conductive keratoplasty has been shown to be effective for reducing hyperopia. Given the relatively small permanent effect, hyperopic patients older than 40 years of age will have a greater benefit from CK as compared to younger patients. The indications for CK also include BCVA > 20/40, pachymetry readings > 500 μm in the 6 mm optical zone, stable preoperative refraction, and a history of successful monovision trial (for presbyopic emmetropes). Preoperative topography is important to rule out keratoconus or other irregularities such as pellucid marginal degeneration. Examination of the ocular surface, anterior segments, and fundoscopic examination are also important prior to surgical planning. For presbyopic patients seeking monovision correction, it is also important to evaluate the manifest and cycloplegic refractive errors and to estimate the accommodative amplitude. A trial of spectacle correction in which the dominant eye is optimized (for distance) and the nondominant

TABLE 3-8-1  Uncorrected Visual Acuity After Conductive Keratoplasty (Eyes Treated With Current Nomogram)* 3 Months (n = 358)

6 Months (n = 352)

9 Months (n = 35)

12 Months (n = 354)

24 Months (n = 70)

UCVA 20/20 or better

29%

40%

45%

49%

54%

54%

UCVA 20/25 or better

51%

63%

64%

73%

74%

77%

UCVA 20/32 or better

68%

77%

81%

85%

88%

85%

UCVA 20/40 or better

79%

86%

90%

93%

92%

91%

UCVA, uncorrected visual acuity. *No retreatment was performed during the study.

eye is overcorrected (for near) is also helpful to counsel the patient. One cannot overestimate the importance of patient education of monovision correction. Not only should patient needs and expectations be evaluated and addressed appropriately, but also an explanation of the compromises that would accompany monovision should be provided. Often patients may need to return for another preoperative visit to get answers for additional questions regarding the expected postoperative limitations of being able to see very small print and/or of being able to see sharply at distance. The surgical technique that was employed in the Food and Drug Administration (FDA) trials involved application of pressure to ensure proper corneal indentation during corneal heating. More recently, the light-touch technique has allowed greater refractive correction with ­reduced CK applications. Notwithstanding this advance in the surgical technique, the concept of increased number of spots leading to higher correction remains valid. The centration of the CK spots during surgery is extremely important. After insertion of a specialized eyelid speculum, the surgeon applies a marker on the cornea while the patient is fixating at the microscope light. The surgeon inserts the CK tips into the stroma at the delineated spots (based on a previously determined surgical plan). The spots are applied in a ring pattern with the CK tip perpendicular to the cornea. If excessive pressure on the tip results in corneal indentation, the surgeon reduces the pressure allowing the corneal rebounding prior to application of the CK current. An insulator cuff around the CK tip ensures that the 450 μm tip does not perforate the cornea. The procedure takes a few minutes to complete according to the manufacturer’s guidelines/nomograms.

A

CLINICAL OUTCOME Several reports on the clinical outcome of using contact LTK devices for the treatment of hyperopia revealed important regression, poor predictability, and significant induced astigmatism.30–51 Treatment of astigmatism, with two coagulation spots placed on each side of the flat meridian in the 8.5 mm zone, resulted in high regression.33 Thereafter, astigmatism treatment was tried in rabbits34 or human eye-banked eyes.35 The efficacy of LTK on corneas that have already undergone photorefractive keratectomy (PRK) might be different from the treatment of primary hyperopia or astigmatism, because Bowman’s layer is removed by PRK. Two reports showed that in eyes with hyperopia induced by PRK, LTK appeared to be more successful than in eyes with primary hyperopia, even if the predictability of the method is low and astigmatism can be induced with the attempted spherical correction.36, 37

Conductive Keratoplasty

Conductive keratoplasty uses a probe that heats the cornea through high-radiofrequency currents in eight peripheral locations (similar to LTK). Its major advantage is the greater stability of the refractive effect. In CK, topical anesthetics are applied, followed by insertion of the eyelid speculum (which acts as a return pathway for the electrical current) without an eyelid drape. The CK tip is inserted in premarked peripheral corneal spots, and the treatment is applied according to published nomograms. For lower hyperopic corrections, eight spots are applied at the 6 mm optical zone and eight spots are applied at the 7 mm optical zone. For greater hyperopic corrections (+2 to +2.50 D), 24 spots are applied (eight additional spots at the 8 mm optical zone). For even greater hyperopic corrections, 32 spots are applied (Table 3-8-1). Newer nomograms have been established for the light-touch technique in which the number of spots is reduced as compared to the FDA-approved approach. The efficacy, stability, and safety of CK have been established. It is not clear why there are major differences in the stability of CK

3.8 Conductive Keratoplasty and Laser Thermal Keratoplasty for Correction of Hyperopia and Presbyopia

1 Month (n = 354)

B

Fig. 3-8-8  (A) Human cornea 6 weeks after laser thermal keratoplasty. Note the wedge-shaped area (apex toward the endothelium) of relatively homogeneous corneal stroma and acellularity. (B) Histology of a pig cornea 1 week after conductive keratoplasty (CK). The footprint is cylindrical and approximately 80% of corneal depth. Such deep treatment penetration is likely to contribute to permanence of the effect.

and LTK. Further studies are needed to determine the basis for these differences.

Myopic Overcorrection

Reports of CK and noncontact LTK for treating overcorrection after myopic PRK,48, 49 LASIK,50 and corneal lamellar cutting51 found that these procedures were more effective and stable than for primary hyperopia.52 This phenomenon may be attributed to the absence of Bowman’s layer or to low central corneal pachymetry. The wedge-shaped area of heating after LTK is evident histologically (Fig. 3-8-8A). A more cylindrical effect is noted after CK (see Fig. 3-8-8B)

177

3

BINOCULAR UCVA – NEAR INTENDED CORRECTION

REFRACTIVE SURGERY

100

96 98

90 89 81

80

77

56

60

47 37

40 20 0

1

1 J1 or better

preop n =133 month 1 n =129 month 6 n =130 month 12 n = 64

15

J2 or better

J3 or better

J5 or better

Fig. 3-8-9  Binocular uncorrected visual acuity (UCVA): near intended correction (+1.00 to +2.25 D). Efficacy data for 16 and 24 spot treatment range only.

BINOCULAR UCVA – DISTANCE INTENDED CORRECTION 100 100

100

100

99 98

98

98

97

96

95

94 92

92 preop n =147 month 1 n =142 month 6 n =144 month 12 n =76

90 88 20/20 or better

20/20 or better

20/20 or better

Fig. 3-8-10  Binocular uncorrected visual acuity (UCVA): distance intended correction (+1.00 to +2.25 D). Efficacy data for 16 and 24 spot treatment range only.

CK and LTK Undercorrections

CK and LTK overcorrections have been treated with hyperopic LASIK.53–56 Hyperopic LASIK after LTK is safe and effective, without vision-threatening complications, and is a good alternative for hyperopic regression. Predictability and efficacy are less than with primary LASIK for hyperopia, but the procedure is equally safe.

Near Vision CK

178

The use of CK for presbyopic correction may be more rewarding than for distance corrections in hyperopia. As mentioned above, the ideal patient for near vision CK is one who has an understanding of the compromises associated with monovision surgery. These include appreciation of the potential limited predictability of the procedure, acceptance of the distance blur in the near eye under monocular viewing conditions, appreciation of the fact that the procedure would reduce (rather than completely eliminate) the need for glasses, and understanding of the progressive nature of presbyopia and the regression of the refractive effect of CK over time. Although near vision CK can be used to help presbyopic hyperopes, it is often used to treat presbyopic emmetropes, many of whom have

not used glasses for distance correction. This is an especially important consideration because the improvement of near vision with CK is often accompanied by a deterioration of distance vision in the operated eye. The emmetropic patient who is considering near vision CK should be aware of the potential reduction of vision (under monocular conditions). To proceed with surgery, the patient should be convinced that the increased range of vision (under binocular conditions) outweighs the monocular distance blur. The FDA clinical outcomes for the treatment of presbyopia are shown in Figs 3-8-9 to 3-8-11. These results demonstrate that under binocular viewing conditions CK dramatically increases the percentage of patients seeing J3 or better at near correction (see Fig. 3-8-9) without compromising binocular distance vision (see Figs 3-8-10 and 3-8-11). Caution needs to be exercised when determining the intended “add” using CK for emmetropic patients. The risks of overcorrection, induced astigmatism, and inability to achieve the desired affect should be emphasized. The use of the loose lens test prior to surgery is useful to avoid operating on patients who would not tolerate monovision after CK. Another pitfall that can be avoided by the proper administration of the loose lens is undercorrection. A reduced power add used during the loose lens test

BINOCULAR UCVA 20/20 – DISTANCE & NEAR INTENDED CORRECTION

85 87 77 75

80 60

95

97

40 20 0

92 20/20 & J1 or better

6 20/20 & J2 or better

14

preop n =133 month 1 n =128 month 6 n =130 month 12 n =64

20/20 & J3 or better

Fig. 3-8-11  Binocular uncorrected visual acuity (UCVA): 20/20 distance and near intended correction (+1.00 to +2.25 D). Efficacy data for 16 and 24 spot treatment range only. J1: this is the drop off you have to prepare your patients for; goal is J3; how many achieve J1 initially?

A

A

Conductive Keratoplasty and Laser Thermal Keratoplasty for Correction of Hyperopia and Presbyopia

100

3.8

B

Fig. 3-8-12  Slit-lamp photographs 2 years after two-ring noncontact Ho:YAG laser thermal keratoplasty. (A) The spots are almost imperceptible with direct slit-beam illumination. (B) The spots are readily visible with sclerotic scatter.

at an extended reading distance may falsely reassure the patient regarding the distance blur; the resultant undercorrection is often perceived by the patient as a failure to achieve the desired effect. Additional CK spots may be needed to remedy the near vision problem, which may be associated with increased blur at distance in the operated eye.

FUTURE DIRECTIONS All studies of pulsed LTK in congenital hyperopia with a minimum of 1-year follow-up have shown that the amount of correction is limited to a maximum of 2.50 D with contact and 2.0 D with noncontact devices.

B

Fig. 3-8-13  Computerized videokeratographs following noncontact Ho: YAG laser thermal keratoplasty with two-ring application. (A) Intervals for the topographical maps from upper left to lower right are preoperative and 1 week, 1 month, and 3 months postoperatively. (B) Intervals for the topographical maps from upper left to lower right are 6, 12, 18, and 24 months postoperatively. This patient showed an increase in corneal steepening of 2.12 D and a change in subjective manifest refraction (spherical equivalent) of –1.75 D. The postoperative topographical maps demonstrate surgically induced peripheral corneal flattening and central corneal steepening with excellent stability between 12 and 24 months. Note the large (approximately 5 mm) central steepened zone.

179

3 REFRACTIVE SURGERY

A change of more than 4.0 D was achieved only if the central cornea was thinned by previous ablative surgeries.57 The fact that the effect of LTK with a pulsed laser depends strongly on the pulse repetition rate led to the idea of using a continuously emitting laser source, such as a diode, to achieve a more steady temperature rise and to avoid temperature peaks. Diode LTK can induce a more lasting refractive change than pulsed holmium LTK.58, 59 Trials in porcine eyes60, 61 have shown that diode LTK can provide defined and uniform coagulation resulting in sufficient refractive changes. Although the potential exists for endothelial cell damage, diode LTK appears to be superior to pulsed holmium LTK (Figs 3-8-12 and 3-8-13). The first trial of the diode LTK technique in blind human eyes for treating hyperopia revealed that at a wavelength of 1.870 μm, corneal endothelial damage was limited, and the procedure appeared to be safe and effective.62 Regression occurred mainly in the first 3 ­ postoperative months.

Another direction of CK and LTK is that of wavefront-guided treatment. This has been shown to be possible via an adaptation to the currently available system, but the FDA has not approved it as yet. The major advantage of this modification is that it is, theoretically, the only keratorefractive procedure for hyperopia wherein wavefrontguided treatment effects can be monitored and adjusted continuously during treatment. Energy adjustments during surgery may allow greater predictability, reduced astigmatism, and the ability to achieve a predetermined amount of overcorrection to ensure acceptable visual results for the longest possible duration. This approach may also be used as an adjunct to other refractive procedures for hyperopia, including LASIK and CK. Real-time wavefront-guided LTK will overcome several of the known limitations of LTK and may become an important adjunct procedure for the correction of hyperopia in the next decade.

REFERENCES

180

  1. Gasset A. Changes in corneal curvature associated with thermokeratoplasty. In: Schachar RA, Levy NS, Schachar L, eds. Keratorefraction. Benison, TX: LAL Publishing; 1980.   2. Lans LJ. Experimentalle Untersuchungen uber Entstehung von Astigmatismus durch nicht-perforirende Corneawunden. Albrecht v Graefes Arch Ophthalmol. 1898;45:117–52.   3. Terrien F. Dystrophia marginale symetrique des deux cornees avec astigmatisme regular consequitif et guerison par la cauterisation ignee. Arch Ophthalmol. 1900;20:12.   4. Wray C. Case of 3 D of hypermetropic astigmatism cured by the cautery. Trans Ophthalmol Soc UK. 1914;34:109.   5. O’Connor R. Corneal cautery for high myopic astigmatism. Am J Ophthalmol. 1933;16:337.   6. Stringer H, Parr J. Shrinkage temperature of eye collagen. Nature. 1964;204:1307.   7. Gasset AR, Shaw EL, Kaufman HE, et al. Thermokeratoplasty. Trans Am Acad Ophthalmol Otolaryngol. 1973;77:441.   8. Keates RH, Dingle J. Thermokeratoplasty for keratoconus. Ophthalmic Surg. 1975;6:89.   9. Aquavella JV, Smith RS, Shaw EL. Alterations in corneal morphology following thermokeratoplasty. Arch Ophthalmol. 1976;94:2082. 10. Kenyon KR. Histological changes in Bowman’s ­membrane associated with thermokeratoplasty. In: Schachar RA, Levy NS, Schachar L ed. Keratorefraction, Benison, TX: LAL Publishing; 1980. 11. Rowsey JJ. Radio frequency probe keratoplasty. In: Schachar RA, Levy NS, Schachar L, eds. Keratorefraction, Benison, TX: LAL Publishing; 1980. 12. Rowsey JJ, Gaylor JR, Dahlstrom R, et al. Los Alamos keratoplasty techniques. Contact Intraocul Lens Med J 1980; 6:1. 13. Rowsey JJ, Doss JD. Preliminary report of Los Alamos keratoplasty techniques. Ophthalmology. 1981;88:755. 14. McDonnell PJ, Garbus J, Romero JL, et al. Electrosurgical keratoplasty: clinicopathological correlation. Arch Ophthalmol. 1988;106:235. 15. Rowsey JJ. Electrosurgical keratoplasty: update and retraction. Invest Ophthalmol Vis Sci. 1987;28:224. 16. Caster AI. The Fyodorov technique of hyperopia correction by thermal coagulation: a preliminary report. J Refract Surg. 1988;4:105. 17. Neumann A, Sanders D, Salz J. Radial thermokeratoplasty for hyperopia. II. Encouraging results from early laboratory and human trials. Refract Corneal Surg 1989;5:52. 18. Neumann A, Sanders D, Raanan M, et al. Hyperopic ­thermokeratoplasty: clinical evaluation. J Cataract Refract Surg. 1991;17:830. 19. McCally R, Bargeron C, Green W, et al. Stromal damage in rabbit corneas exposed to CO2 laser radiation. Exp Eye Res. 1983;37:543. 20. Seiler T. Ho:YAG laser thermokeratoplasty for hyperopia. Ophthalmol Clin North Am 1992;5:773–780. 21. Ogawa GSH, Azar DT, Koch DD. Laser thermokeratoplasty for hyperopia, astigmatism and myopia. In: Azar DT, ed. Refractive surgery, Stamford, CT: Appleton & Lange; 1997. 22. Feldman ST, William E, Frucht-Pery J, et al. Regression of effect following radial thermokeratoplasty in humans. Refract Corneal Surg. 1989;5:288. 23. Koch DD. Histological changes and wound healing response following noncontact holmium:YAG laser thermal keratoplasty. Trans Am Ophthalmol Soc. 1996;94:745.

24. Smelser CK, Polack FM, Ozanies V. Persistence of donor collagen in corneal transplants. Exp Eye Res. 1965;4:349. 25. Moreira H, Campos M, Sawasch MR, et al. Holmium laser thermokeratoplasty. Ophthalmology. 1993;100:752. 26. Seiler T, Matallana M, Bende T. Laser thermokeratoplasty by means of a pulsed holmium:YAG laser for hyperopic correction. J Refract Corneal Surg. 1990;6:335. 27. Thompson VM, Seiler T, Durrie DS, et al. Holmium:YAG laser thermokeratoplasty for hyperopia and astigmatism: an overview. Refract Corneal Surg. 1993;9:S134. 28. Durrie DS, Schumer J, Cavanaugh TB. Holmium:YAG laser thermokeratoplasty for hyperopia. J Refract Corneal Surg. 1994;10:S277. 29. Yanoff M. Holmium laser hyperopia thermokeratoplasty update. Eur J Implant Refract Surg. 1995;7:89–91. 30. Tutton MK, Cherry PM. Holmium:YAG laser thermokeratoplasty to correct hyperopia: two years follow-up. Ophthalmic Surg Lasers. 1996;27(Suppl 5):S521–4. 31. Tassignon MJ, Trau R, Mathys B. Le traitement de l’hypermetropie a l’aide du laser holmium laser thermokeratoplastie (LTK). Bull Soc Belge Ophthalmol. 1997;266:75. 32. Eggink CA, Bardak Y, Cuypers MHM, Deutman AF. Treatment of hyperopia with contact Ho:YAG laser thermal keratoplasty. J Refract Surg. 1999;15:16. 33. Thompson VM. Holmium:YAG laser thermokeratoplasty for correction of astigmatism. J Refract Corneal Surg. 1994;10:S293. 34. Lim KH, Kim WJ, Wee WR, et al. Holmium:YAG laser thermokeratoplasty for astigmatism in rabbits. J Refract Surg. 1996;12:190. 35. Bende T, Jean B, Derse M, et al. Holmium:YAG thermokeratoplasty: treatment parameters for astigmatism induction based upon spherical enucleated human eyes. Graefes Arch Clin Exp Ophthalmol. 1998;236:405. 36. Goggin M, Lavery F. Holmium laser thermokeratoplasty for the reversal of hyperopia after myopic photorefractive keratectomy. Br J Ophthalmol. 1997;81:541. 37. Eggink C, Meurs P, Bardak Y, et al. Holmium laser thermal keratoplasty for hyperopia and astigmatism after photo­ refractive keratectomy. J Refract Surg. 2000;16:317. 38. Koch DD, Kohnen T, Anderson J, et al. Histologic changes and wound healing response following 10-pulse noncontact holmium:YAG laser thermal keratoplasty. J Refract Surg. 1996;12:623. 39. Kohnen T, Husain SE, Koch DD. Corneal topographic changes after noncontact holmium:YAG laser thermal keratoplasty to correct hyperopia. J Cataract Refract Surg. 1996;22:427. 40. Koch DD, Abarca A, Villareal R, et al. Hyperopia correction by noncontact holmium:YAG laser thermal keratoplasty. Clinical study with two-year follow-up. Ophthalmology. 1996;103:731. 41. Kohnen T, Villareal R, Menefee R, et al. Hyperopia correction by noncontact holmium:YAG laser thermal keratoplasty: five-pulse treatments with 1-year follow up. Graefes Arch Clin Exp Ophthalmol. 1997;235:702. 42. Gezer A. The role of patient’s age in regression of holmium:YAG thermokeratoplasty-induced correction of hyperopia. Eur J Ophthalmol. 1997;7:139. 43. Koch DD, Kohnen T, McDonnell PJ, et al. Hyperopia correction by noncontact holmium:YAG laser thermal keratoplasty. United States phase IIA clinical study with 1-year follow-up. Ophthalmology. 1996;103:1525. 44. Kohnen T, Koch DD, McDonnell PJ, et al. Noncontact holmium:YAG laser thermal keratoplasty to correct hyperopia: 18-month follow-up. Ophthalmologica. 1997;211:274.

45. Koch DD, Kohnen T, McDonnell PJ, et al. Hyperopia correction by non-contact holmium:YAG laser thermal keratoplasty. U.S. phase IIA clinical study with 2-year follow-up. Ophthalmology. 1997;104:1938. 46. Alio JL, Ismail MM, Sanchez Pego JL. Correction of hyperopia with noncontact Ho:YAG laser thermal keratoplasty. J Refract Surg. 1997;13:17. 47. Nano HD, Muzzin S. Noncontact holmium:YAG laser thermal keratoplasty for hyperopia. J Cataract Refract Surg. 1998;24:751. 48. Vinciguerra P, Kohnen T, Azzolini M, et al. Radial and staggered treatment patterns to correct hyperopia using noncontact holmium:YAG laser thermal keratoplasty. J Cataract Refract Surg. 1998;24:21. 49. Alio JL, Ismail MM, Artola A, et al. Correction of hyper­ opia by photorefractive keratectomy using noncontact Ho:YAG laser thermal keratoplasty. J Refract Surg. 1997;13:13. 50. Pop M. Laser thermal keratoplasty for the treatment of photorefractive keratectomy overcorrections. A 1-year follow-up. Ophthalmology. 1998;105:926. 51. Ismail MM, Alio HL, Perez-Santonja JJ. Noncontact ­thermokeratoplasty to correct hyperopia induced by laser in situ keratomileusis. J Cataract Refract Surg. 1998;24:1191. 52. Hersh PS, Fry KL, Chandrashekhar R, Fikaris DS. Conductive keratoplasty to treat complications of LASIK and photorefractive keratectomy. Ophthalmology. 2005;112:1941–7. 53. Ismail MM, Perez-Santonja JJ, Alio HL. Laser thermokeratoplasty after lamellar corneal cutting. J Cataract Refract Surg. 1999;25:212. 54. Portellinha W, Nakano K, Oliveira M, et al. Laser in situ keratomileusis for hyperopia after thermal keratoplasty. J Refract Surg. 1999;15(Suppl):S218. 55. Kymionis GD, Aslanides IM, Khoury AN, et al. Laser in situ keratomileusis for residual hyperopic astigmatism after conductive keratoplasty. J Refract Surg. 2004;20:276–8. 56. Klein S, Fry K, Hersh PS. Laser in situ keratomileusis after conductive keratoplasty. J Cataract Refract Surg. 2004;30:702–5. 57. Attia W, Perez-Santonja JJ, Alio JL. Laser in situ keratomileusis for recurrent hyperopia following laser thermal keratoplasty. J Refract Surg. 2000;16:163. 58. Geerlng G, Koop N, Brinkmann R, et al. Continuous-wave diode laser thermokeratoplasty: first clinical experience in blind human eyes. J Cataract Refract Surg. 1999;25:32. 59. Geerling G, Brinkmann R, Koop N, et al. Laser thermo­ keratoplasty – experimental study in minipigs with a CW-IR laser diode. Invest Ophthalmol Vis Sci. 1996;37:S65. 60. Brinkmann R, Koop N, Geerling G, et al. Diode laser thermokeratoplasty: application strategy and dosimetry. J Cataract Refract Surg. 1998;24:1195. 61. Wirbelauer C, Koop N, Tuengler A, et al. Corneal endothelial cell damage after experimental diode laser thermal keratoplasty. J Refract Surg. 2000;16:323. 62. Brinkmann R, Radt B, Flamm C, et al. Influence of ­temperature and time on thermally induced forces in corneal collagen and the effect on laser thermo­ keratoplasty. J Cataract Refract Surg. 2000;26:744.

PART 3 REFRACTIVE SURGERY

Intrastromal Corneal Ring Segments for Low and High Myopia

3.9

Takashi Kojima, Jonathan D. Primack and Dimitri T. Azar

Definition:  Polymethyl methacrylate (PMMA) arcuate segments   that are placed within the peripheral cornea to correct myopia.

key features n n n n

I nner diameter of 6.8 mm. Refractive effect is related to the thickness of the segments. Initial enthusiasm regarding beneficial effect in low myopia. Emerging role as adjunct for keratoconus and corneal ectasia.

Associated features n n n

S urgical steps include intrastromal corneal ring segment channel formation, insertion of segments, and suturing of entry site. Surgical techniques are slightly modified for keratoconus. Reversibility, hyperacuity, and maintenance of corneal asphericity are potential advantages.

INTRODUCTION In 1949, Barraquer first proposed the use of alloplastic materials as a method to correct refractive errors. Several intracorneal implants, or inlays, made of various materials (hydrogels, polysulfones) have been evaluated in animal and human eyes for the correction of myopia, aphakia, or presbyopia. However, none of them are currently used routinely. Among the materials that have been tested for use as intra­ corneal implants are polysulfone lenses, small diameter corneal inlays, and hydrogel lenses (Figs 3-9-1 to 3-9-4). Intrastromal corneal ring segments (ICRSs), or Intacs, are placed in the peripheral stroma at approximately two thirds depth, outside the central optical zone, to reshape the anterior corneal surface while main­ taining the positive asphericity of the cornea.1–8 The first-­generation design of Intacs was referred to as the 360° intrastromal corneal ring (ICR). The current design consists of two polymethyl methacrylate (PMMA) segments, each with an arc length of 150° (Fig. 3-9-5). Each Intacs segment has a hexagonal cross section that lies along a conic section. With a fixed outer diameter of 8.1 mm and an inner diameter of 6.8 mm, Intacs leave a relatively large, clear central optic zone. Each segment has a small positioning hole at the superior end to aid with surgical manipulation once the segments have been inserted. The two segments are designated as clockwise and counterclockwise to correspond to their orientation during insertion in the intrastromal tunnel.1 Intacs change the arc length of the anterior corneal curvature. The ­refractive effect achieved is directly related to the thickness of the ­product. Placing the product in the periphery of the cornea causes local separation of the corneal lamellae, which results in shortening of the corneal arc length. This has a net effect of flattening the cornea, thereby correcting for myopia by lowering the optical power of the eye. Increas­ ing the thickness of intacs causes greater degrees of local separation and increased corneal flattening. Thus, the degree of corneal flattening – or correction – achieved by Intacs is directly related to thickness.1

Fig. 3-9-1  Slit-lamp photograph of corneal opacity after implantation of a polysulfone intracorneal lens. (Courtesy of Stephen S. Lane, MD.)

The same effect can be observed by placing a pencil underneath a sheet of paper. With the added bulk of the pencil, the paper is no ­longer flat and is shorter. In much the same way, when Intacs are placed within the stromal layers of the cornea, they shorten the arc length across the optical zone.1 Intacs are available in the United States in three different thick­ nesses, 0.25, 0.30, and 0.35 mm, and are intended for the reduction or elimination of low myopia (Table 3-9-1). The initial enthusiasm regarding ICRSs for the correction of myopia has faded for multiple reasons, including a limited range of correction, induced astigmatism, and slow visual recovery. Although the future role of ICRSs in refrac­ tive surgery is unclear, they may evolve into an important therapeutic intervention in corneal ecstatic diseases such as keratoconus9, pellucid marginal degeneration10, 11 and post-laser surgery corneal ectasia.12, 13 Another potential application of ICRSs may be to minimize the risk of corneal ectasia following laser-assisted in situ keratomileusis (LASIK) in patients with high myopia. Intacs are also available in a thickness of 0.4 mm to correct myopia up to −4.5 D.

SURGICAL TECHNIQUE Topical anesthetic and antibiotic drops are administered preopera­ tively. The operative eye is prepped with an antiseptic solution, and sterile drapes are placed appropriately. Peri- or retrobulbar anesthesia is unnecessary.

ICRS Channel Formation

The center of the cornea is located and an incision and placement marker (KeraVision, Fremont, CA) is applied to indicate where the PMMA seg­ ments and the superior, radial incision will ultimately lie.8, 14 Ultrasonic pachymetry is performed at the 12 o’clock incision site, and an approxi­ mately 1 mm incision of 68% corneal thickness is created with a cali­ brated diamond knife. A modified Suarez spreader is used to perform a small lamellar dissection at the base of the incision, to create an entry pocket on either side. Next, a vacuum centering guide (KeraVision) is positioned on the globe and stabilized under suction. Specially designed 0.9 mm dissectors are then introduced through the incision (clockwise

181

3

SMALL DIAMETER INTRACORNEAL INLAY LENS PLACEMENT IN CORNEA

REFRACTIVE SURGERY

inlay

inlay

incision

incision

Fig. 3-9-2  Schematic of small diameter intracorneal inlay lens placement in cornea. (Adapted with permission of Judy Gordon, MD, and Richard L. Lindstrom, MD.)

Fig. 3-9-3  Slit-lamp photograph of a hydrogel intracorneal lens in position in the patient’s cornea. (Courtesy of Roger F. Steinert, MD.)

INTRASTROMAL CORNEAL RING IN THE CORNEAL STROMA

Fig. 3-9-5  A 150° intrastromal corneal ring segment. (Courtesy of Thomas Loarie.) TABLE 3-9-1  INTACS FOR THE REDUCTION OR ELIMINATION OF LOW MYOPIA Intacs Thickness (mm)

Predicted Nominal Correction (D)

Recommended Prescribing Range (D)

0.25

−1.03

−1.00 to −1.63

0.30

−2.00

−1.75 to −2.25

0.35

−2.70

−2.38 to −3.00

The femtosecond laser is applied within the stroma at approximately two thirds corneal depth. After release of suction, the Suarez spreader is used to facilitate subsequent segment insertion.

Segment Insertion

Fig. 3-9-4  Intrastromal corneal ring in the corneal stroma. (Original drawing courtesy of Thomas Loarie.)

and counterclockwise) to create stromal tunnels by blunt dissection (Fig. 3-9-6). Ideally, the channels are located at two thirds corneal depth. Suction is then released and the centering guide is removed.

ICRS Channeling with Femtosecond Laser

182

After application of the specialized suction ring, the femtosecond ap­ planator is positioned over the cornea and proper centration is verified. If needed, the treatment area can be moved to ensure proper centration.

Using forceps, the PMMA segments are introduced into the channels. In their final position, the segments are located 3 mm apart superiorly. If necessary, the flap is refloated to eliminate any iatrogenically induced wrinkles. The incision site is hydrated and closed with 10-0 nylon sutures.8 Fig. 3-9-7 illustrates the appearance of the cornea following these procedures.

Injection Adjustable Keratoplasty

A modification of ICRS surgery is gel injection adjustable keratoplasty. In this procedure, a delaminator is used to separate the stromal lamel­ lae (Fig. 3-9-8). This is followed by gel injection into the stromal chan­ nel. After polymerization, the gel induces central flattening without

3.9

Fig. 3-9-6  Vacuum centering guide and stromal separator used to create the channel for the intrastromal corneal ring. (Reproduced with permission from Assil KK, Barrett AM, Fouraker BD, et al. One-year results of the intrastromal corneal ring in nonfunctional human eyes. Arch Ophthalmol. 1995;113:159–67.)

­significant postoperative inflammation (Fig. 3-9-9). This procedure may have potential advantages over ICRSs, but the United States Food and Drug Administration (FDA) has not approved it.

CLINICAL OUTCOME The initial reports of ICRSs and ICRs were very encouraging. Studies of ICRs in blind eyes followed for 1 year showed the ring to be safe and effec­ tive for the modification of corneal curvature.15 Schazlin et al.8 reported the 1-year results from the Phase II clinical trial of 360° ICR in 81 eyes: 88% of cases had uncorrected visual acuity (UCVA) of 20/40 or better, with 73% of patients within 1 D of intended correction, 2-month stabil­ ity, and positive asphericity. According to Phases II and III of the FDA trials,16, 17 12 months after surgery, 74% of the patients had UCVA with 20/20 or better, 97% of the patients with 20/40 or better. As for predict­ ability, 69 patients had a manifest refractive spherical error within 0.5 D, and 92% within 1 D. Increased cylinder (> 1 D to 2 D) occurred in 4.3% of patients; 0.2% of patients had a cylinder increase exceeding 2 D. Compared by thickness of Intacs, patients who had 0.25 and 0.30 mm rings had higher predictability as compared to the 0.35 mm ring. Post­ operative mean refractive spherical error within 0.5 D was 69.6% and 78.3% in patients with the 0.25 and 0.3 mm ring, respectively, as com­ pared to 59.9% in patients with the 0.35 mm ring. The adverse event rate was 1.1% including infectious keratitis (0.2%), shallow placement (0.2%), loss of 2 lines of best-corrected visual acuity (BSCVA) (0.2%), and anterior chamber perforation during initial and exchange procedures (0.4%).16, 17 Nine per cent of patients had a reduced central ­corneal sen­ sation  =  20 mm 6 months after surgery, and 5.5% showed a reduction in corneal sensitivity at 12 months after surgery. At 12 months, 4.4% of patients reported difficulty with night vision, 2.9% reported blurry vision, 1.6% diplopia, 1.3 % glare, and 1.3% halos. The explantation rate of Intacs was 8.7%, with 19 out of 39 (49%) due to dissatisfaction with visual symptoms such as glare, halos, and night vision problems; 15 out of 39 (38%) were due to dissatisfaction with the correction achieved. There were no clinically significant complica­ tions related to explantation. After explantation, all patients returned to BSCVA of 20/20 or better, a clear central cornea with remaining stromal haze, and deposits within the peripheral tunnels. Burris et al.3 analyzed corneal topography in 74 phase II participants and found that corneal flattening increased with ring thickness. Most other laser refractive surgeries convert corneal asphericity from a prolate shape with negative asphericity, which is steeper centrally than peripherally, to an oblate shape with positive asphericity, which is flatter centrally than peripherally. Holmes-Higgin et al.18 reported topographic corneal flattening with Intacs prolately aspheric in the patients of a FDA Phase III clinical trial, with relatively greater flatten­ ing induced pericentrally than centrally. This property is thought to be more beneficial to maintain the corneal optical quality compared to laser refractive surgery such as photorefractive keratectomy (PRK) and LASIK, which usually lose corneal prolate asphericity.

The more centrally placed incisions tended to cause more induced astigmatism, whereas more peripherally placed incisions tended to be vascularized.15 Transient loss of corneal sensation was noted 2 months postoperatively but returned to normal by 6 months. Asbell et al.19 reported the potential reversibility of the ICR refractive effect. They showed that ICR explantation resulted in return of corneal curvature and refractive error to preimplant values. Similar results were reported by Davis et al.20 and Twa et al.21 ICRSs, as opposed to LASIK, do not remove corneal tissue, but induce corneal curvature change. In addition, intraocular pressure may be reduced after Intacs implants as shown by Ruckhofer et al.22 (significant decrease at 6 months). Another advantage of Intacs compared to laser refractive surgery is that the duration of dry eye symptoms after surgery is quite short, r­esolving within 1 week.23 Undisturbed corneal nerve plexus is thought to be attributed to this feature.

Intrastromal Corneal Ring Segments for Low and High Myopia

Fig. 3-9-7  Slit-lamp photograph of the intrastromal corneal ring segments in position in the patient’s cornea. (Courtesy of Thomas Loarie.)

Wound Healing

A histopathological study using a rabbit model showed that the tissue adjacent to the ring had activated keratocyte, intracellular lipid accu­ mulation, and new formation of collagen.24 The evaluation of wound healing after Intacs implantation was done by Ruckhofer et al. using confocal microscopy.25 In the central cornea, all layers of corneas had normal morphologic features. At the peripheral area, epithelial cells had high-density nuclei especially in the basal cell layer (35% of eyes). The nerve plexus and corneal endothelium underneath the ring was intact, and the tissue adjunct to the ring segment showed moderate fibrosis.

POSTOPERATIVE CARE AND MANAGEMENT Immediately following surgery, an antibiotic–steroid combination oint­ ment or solution (0.1% dexamethasone – 9.3% tobramycin or equiva­ lent) is applied to the operative eye. Small epithelial defects are treated with lubricating drops, and bandage contact lenses are used for large defects. The segment placement and incision closure should be ob­ served using slit-lamp examination. The operative eye is protected with a clear shield, and the patient should be given appropriate postoperative instructions.14, 26 Foreign body sensation or “scratchiness” is common during the im­ mediate postoperative recovery period. Symptoms of infection include dull, aching pain or discomfort, with or without photophobia, any time in the postoperative period. During recovery, eyes may feel dry for the first 2–3 months. Vision is expected to fluctuate during the first month.14, 26

ICRS FOR KERATOCONUS AND AFTER LASIK Intacs have been used to treat patients with keratoconus. The results are encouraging, especially in terms of decreasing astigmatism, increas­ ing topographical abnormalities, and minimizing the risk of further progression of corneal ectasia. Similarly, ICRSs have been used as an adjunct to LASIK surgery. LASIK and Intacs differ in several respects. LASIK is a more versatile technique that corrects low to moderately high levels of myopia (< 10 D) and myopic astigmatism (up to 5 D).27–29 In contrast, ICRSs are designed to treat only low levels of near sight­ edness (up to 3 D) without clinically significant astigmatism.8, 21 The

183

3

SURGICAL CONCEPT OF GEL INJECTION ADJUSTABLE KERATOPLASTY

REFRACTIVE SURGERY

Peripheral corneal incision

Separate stromal lamellae

80% depth

Placing lamellar guide plane

Inserting helicoid spatula

Annular dissection

Injecting gel

Fig. 3-9-8  Surgical concept of gel injection adjustable keratoplasty. A 0.8 mm peripheral corneal incision is made at a selected depth (50–80% of corneal ­thickness) with a diamond knife. The stromal lamellae are then separated with a blunt spatula, and the lamellar plane guide is placed. The helicoid spatula   is inserted below the guide, and the annular dissection is performed. Last, the gel is injected. (Reproduced with permission from Simon G, Parel J-M, Lee W,   Kervick GN. Gel injection adjustable keratoplasty. Graefes Arch Clin Exp Ophthalmol. 1991;229:418–24.)

184

dissimilarity between the underlying mechanism responsible for the ­induced central corneal flattening suggests that the procedures could be additive. Using ICRSs as an adjunct to LASIK surgery carries several of the advantages of using ICRSs to treat keratoconus,9 without further compromising corneal thickness and stability. Colin et al.9 reported clinical application of Intacs for the optical cor­ rection of keratoconus patients who were contact lens intolerant. After implantation, UCVA and corneal regularity improved, and the amount of astigmatism and spherical error were reduced. This procedure seems to be promising in terms of avoiding penetrating keratoplasty and in­ creasing the patient’s quality of vision. In more severe cases, caution should be exercised; this surgery may not be effective in patients with severe keratoconus who have thin corneas. The treatment of iatrogenic ectasia after LASIK has emerged as an im­ portant issue. Few case series reported that Intacs for corneal ­ectasia after LASIK improved the posterior and anterior corneal steepening, UCVA, and topographical regularity at about 9 months postoperatively.12, 13 Questions remain as to whether the insertion of Intacs prevents the

­ rogression of the ectasia and how the PMMA segments affect the bio­ p mechanical properties of the cornea. There have been reports of eyes receiving both LASIK and In­ tacs as sequential surgeries. We have implanted Intacs in patients as a means of treating residual myopia 2 years after LASIK. Further ­excimer laser surgery might have been unsafe in these patients and may have increased the risk of keratoectasia.30 Our first patient was a 38-year-old woman with a corneal thickness of 539 μm who un­ derwent LASIK on the right eye (OD) for a refractive error of −8.00 −0.5 × 75 (­ablation depth 96 μm). Three months postoperatively, the UCVA was 20/20. Over the following year, however, regression oc­ curred, with a resultant UCVA of 20/40 and a refractive error of −1.99 −0.75 × 18. Given the patient’s low pachymetry value of 439 μm and a theoretical flap thickness of 180 μm, an ICRS procedure was of­ fered as a means of treating the residual myopia. Three weeks after receiving 0.25 mm ICRS OD, the patient’s UCVA was 20/30 and her BSCVA was 20/20 with 11.75 −1.00 × 118. The second patient was a 50-year-old woman who had undergone LASIK on the left eye (OS)

for a refractive error of −6.75 −1.5 × 180. Eleven months after sur­ gery, the patient regressed to −1.00 −1.5 × 180, with a BSCVA of 20/25+ and a UCVA of 20/150. The patient ­underwent relifting of the flap and a second laser ablation, which resulted in a UCVA of 20/60 and BSCVA of 20/20 with −0.75 −0.75 × 175. ORBSCAN revealed

CONCLUSION Intacs surgical techniques have advanced with the advent of femto­ second laser. The indications for surgery, initially encompassing low to moderate myopia, have recently become limited to the treatment of early to moderate keratoconus. The preservation of corneal prolateness and the reversibility of the procedure are major advantages of Intacs. Additional studies are needed to determine the best approach for using Intacs to correct residual myopia after LASIK.

REFERENCES   1. Assil KK, Barrett AM, Fouraker BD, Schanzlin DJ. One-year results of the intrastromal corneal ring in nonfunctional human eyes. Intrastromal Corneal Ring Study Group. Arch Ophthalmol. 1995;113:159–67.   2. Colin J CB. Intraocular lenses in cataract and refractive surgery. Philadelphia: WB Saunders; 2001:273–278.   3. Burris TE, Ayer CT, Evensen DA, Davenport JM. Effects of intrastromal corneal ring size and thickness on corneal flattening in human eyes. Refract Corneal Surg. 1991;7:46–50.   4. Cochener B, Le Floch G, Colin J. Les anneaux intracorneens pour la correction des faibles myopies. J Fr Ophthalmol. 1998;21:191–208.   5. Fleming JF, Reynolds AE, Kilmer L. The intrastromal corneal ring: two cases in rabbits. J Refract Surg. 1987;3:227–32.   6. Fleming JF, Wan WL, Schanzlin DJ. The theory of corneal curvature change with the intrastromal corneal ring. CLAO J. 1989;15:146–50.   7. Nose W, Neves RA, Burris TE, et al. Intrastromal corneal ring: 12-month sighted myopic eyes. J Refract Sur. 1996;12:20–8.   8. Schanzlin DJ, Asbell PA, Burris TE, Durrie Ds. The intrastromal corneal ring segments. Phase II results for the correction of myopia. Ophthalmology. 1997;104:1067–78.   9. Colin J, Cochener B, Savary G, Malet F. Correcting keratoconus with intracorneal rings. J Cataract Refract Surg. 2000;26:1117–22. 10. Akaishi L, Tzelikis PF, Raber IM. Ferrara intracorneal ring implantation and cataract surgery for the correction of pellucid marginal corneal degeneration. J Cataract Refract Surg. 2004;30:2427–30. 11. Mularoni A, Torreggiani A, di Biase A, et al. Conservative treatment of early and moderate pellucid marginal degeneration: a new refractive approach with intracorneal rings. Ophthalmology. 2005;112:660–6.

12. Alio J, Salem T, Artola A, Osman A. Intracorneal rings to correct corneal ectasia after laser in situ keratomileusis.   J Cataract Refract Surg. 2002;28:1568–74. 13. Siganos CS, Kymionis GD, Astyrakakis N, Pallikaris IG. Management of corneal ectasia after laser in situ keratomileusis with INTACS. J Refract Surg. 2002;18:43–6. 14. Colin J, Cochener B. Intraocular lenses in cataract and refractive surgery. Philadelphia: WB Saunders; 2001. 273–278. 15. Friedman NJ, Husain SE, Kohnen T, Koch DD. Investigational refractive procedures, 1st ed. London: Mosby; 1999: 4–6. 16. Rapuano CJ, Sugar A, Koch DD, et al. Intrastromal corneal ring segments for low myopia: a report by the American Academy of Ophthalmology. Ophthalmology. 2001;108:1922–8. 17. FDA. Summary of safety and effectiveness data, 1999. 18. Holmes-Higgin DK, Burris TE. Corneal surface topography and associated visual performance with INTACS for myopia: phase III clinical trial results. The INTACS Study Group. Ophthalmology. 2000;107:2061–71. 19. Asbell PA, Ucakhan OO, Abbott RL, et al. Intrastomal corneal ring segments: reversibility of refractive effect.   J Refract Surg. 2001;17:25–31. 20. Davis EA, Hardten DR, Lindstrom RL. Laser in situ keratomileusis after intracorneal rings. Report of 5 cases.   J Cataract Refract Surg. 2000;26:1733–41. 21. Twa MD, Karpecki PM, King BJ, et al. One-year results from the phase III investigation of the KeraVision Intacs. J Am Optom Assoc. 1999;70:515–24. 22. Ruckhofer J, Linebarger EJ, Schanzlin DJ. Goldmann applanation tonometry after intacs corneal ring segments(1). J Cataract Refract Surg. 2000;26:1332–8. 23. Kessler D, El-Shiaty AF, Wachler BS. Evaluation of tear film following Intacs for myopia. J Refract Surg. 2002;18:127–9.

3.9 Intrastromal Corneal Ring Segments for Low and High Myopia

Fig. 3-9-9  Histological section of a cat cornea 23 months after being subjected to gel injection adjustable keratoplasty. Note the absence of a cellular reaction or scarring in the tissue that lines the gel injection adjustable keratoplasty site. (Courtesy of Jean-Marie Parel, MD, and Gabriel Simon, MD.)

a ­ central pachymetry of 467 μm without signs of ectasia or irregu­ larity. To prevent further corneal thinning, an ICRS procedure was ­offered as a means of treating the myopia. Six weeks after receiving 0.25 mm ICRS OS, the patient’s UCVA was 20/30 and her BSCVA was 20/20 with 11.50 −1.25 × 090. Similar reports of sequential treatment have been published. Fleming and Lovisolo31 reported a patient who received ICRS 10 months follow­ ing LASIK that left a residual spherical equivalent (SE) OD −3.375 D. Four months after ICRS placement, the UCVS was 20/20. No flap com­ plications occurred. Eyes that received LASIK after ICRS have been reported only fol­ lowing explantation of the PMMA segments. Asbell et al.32 described 10 patients who received LASIK following ICRS explantation. No complications were reported. Davis et al.20 reported five patients who received LASIK following ICRS explantation for induced astig­ matism and intraoperative complications. All patients experienced uneventful LASIK.

24. Twa MD, Ruckhofer J, Kash RL, et al. Histologic evaluation of corneal stroma in rabbits after intrastromal corneal ring implantation. Cornea. 2003;22:146–52. 25. Ruckhofer J, Bohnke M, Alzner E, Grabner G. Confocal microscopy after implantation of intrastromal corneal ring segments. Ophthalmology. 2000;107:2144–51. 26. Linebarger EJ, Song D, Ruckhofer J, Schanzlin DJ. Intacs: the intrastromal corneal ring. Int Ophthalmol Clin. 2000;40:199–208. 27. Lindstrom RL, Hardten DR, Chu YR. Laser in situ   keratomileusis (LASIK) for the treatment of low, ­moderate, and high myopia. Trans Am Ophthalmol   Soc. 1997;95:285–96. discussion 296–306. 28. Salah T, Waring GO 3rd, el Maghraby A, et al. Excimer   laser in situ keratomileusis under a corneal flap for myopia of 2 to 20 diopters. Am J Ophthalmol. 1996;121:143–55. 29. Farah SG, Azar DT, Gurdal C, Wong J. Laser in situ keratomileusis: literature review of a developing technique. J Cataract Refract Surg. 1998;24:989–1006. 30. Primack JD, Azar DT. Laser in situ keratomileusis and   intrastromal corneal ring segments for high myopia. Three-step procedure. J Cataract Refract Surg. 2003;29:869–74. 31. Fleming JF, Lovisolo CF. Intrastromal corneal ring segments in a patient with previous laser in situ keratomileusis.   J Refract Surg. 2000;16:365–7. 32. Asbell PA, Ucakhan OO, Durrie DS, Lindstrom RL.   Adjustability of refractive effect for corneal ring   segments. J Refract Surg. 1999;15:627–31.

185

PART 3 REFRACTIVE SURGERY

Phakic Intraocular Lenses Ramon C. Ghanem and Dimitri T. Azar

3.10

Definition:  Phakic intraocular lenses (IOLs) are artificial lenses

i­mplanted in the anterior or posterior chamber of the eye in the ­presence of the natural crystalline lens to correct refractive errors.

Key features n

n

T hree kinds of phakic IOLs are available: anterior chamber   angle-supported, anterior chamber iris-fixated, and posterior chamber IOLs. New improved designs are providing increasing safety and efficacy for the correction of severe ametropias.

Associated features n

n

n

E arly models of angle and iris-supported phakic IOLs were made   of polymethyl methacrylate (PMMA). Newer lenses are foldable,   as are posterior chamber phakic IOLs. Complications include glare and haloes, pupil ovalization, iris ­atrophy, endothelial cell loss, glaucoma, pigment dispersion, ­uveitis, and cataract formation. Surgical iridectomy or preoperative neodymium: yttrium­aluminum-garnet (Nd:YAG) laser iridotomies are necessary to   avoid postoperative pupillary block glaucoma.

Fig. 3-10-1  Angle-supported Baikoff ZB5M (left) and the NuVita MA20 (right).

INTRODUCTION For patients with high ametropia, the laser options for surgical correction (excimer laser photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK)) are limited by a decreased safety, predictability, and efficacy of postoperative results. For these reasons, there has been a growing interest in the use of phakic intraocular lenses (PIOLs) to correct these refractive errors. For high ametropia, PIOL implantation has the advantage of preserving the architecture of the cornea; additionally, it may provide more predictable refractive results and better visual quality than surgical techniques that manipulate the corneal curvature.

Fig. 3-10-2  Iris-fixated Verisyse lens in situ.

HISTORY OF PHAKIC LENSES

186

Clear lens extraction for the correction of myopia was a concept introduced in the early 1800s, and the technique became increasingly popular from 1850 to 1900.1 After the discovery of sterilization in 1889, a rush for myopia correction by clear lens extraction was started by Fukala in Austria/Germany (“Fukala Surgery”) and Vacher in France.1 It was not until the end of the nineteenth century, however, that complications of this operation (e.g., retinal detachment and choroidal hemorrhages) began to be reported, and the technique largely fell out of favor. The 1950s saw the emergence of the idea of correcting myopia by inserting a concave lens into the phakic eye. At this time, Strampelli, Barraquer,2 and Choyce experimented with anterior chamber angle-fixed lenses, which were eventually abandoned owing to complications of corneal edema and chronic iritis (Fig. 3-10-1). In 1988, Baikoff3 presented his version of an anterior chamber angle-fixed IOL. The Baikoff IOL was a single-piece, biconcave anterior chamber lens based on a multiflex Kelman anterior chamber IOL. This IOL had 4.5  mm PMMA optics and was initially angulated posteriorly at 25˚. This angle was modified later to 20˚ to increase the distance of the IOL to the endothelium and the optic was increased

to 5.0 mm (4.0 mm effective) − the model ZB5M (see Fig. 3-10-1; left). In 1997,4 thinner optics were implemented, the effective optic diameter was increased to 4.5 mm (total 5.0 mm), the anterior face was flattened, and the profile of the loop was modified to give its extremity an arched shape to reduce angle trauma; the name was changed to Baikoff NuVita MA20 (Bausch & Lomb Inc., Claremont, CA) (see Fig. 3-10-1; right). The iris-claw or lobster-claw lens was first designed by Worst in 1977 for aphakic eyes. Later, in 1986, Worst and Fechner5, 6 modified this IOL to a biconcave anterior chamber lens for the correction of myopia. To increase the safety of this IOL and minimize the possibility of IOL−cornea contact, in 1991 the biconcave design was changed to a convex−concave model with a lower shoulder, a thinner periphery, and a larger optic diameter (5.0 mm) to reduce photic phenomena (Fig. 3-10-2). This lens, called the Worst myopia claw lens, has been implanted successfully since then. In 1998, the name of the lens was changed to the Artisan-Worst lens (Ophtec Inc., Groningen, Netherlands), without a change in lens design. In 2002, AMO (Santa Ana, CA) acquired the global distribution rights of the Artisan, now known as the Verisyse lens.

BOX 3-10-1  General Criteria for Implanting Phakic IOLs

Phakic Intraocular Lenses

Stable refraction (less than 0.5 D change for 6 months) Clear crystalline lens Ametropia not suitable/appropriate for excimer laser surgery Unsatisfactory vision with/intolerance of contact lenses or spectacles Anterior chamber depth greater than or equal to 3.2 mm for the Verisyse (“iris-claw” lens)* and angle-supported PIOLs †2.5 mm for posterior chamber PIOLs* A minimum endothelial cell density of:* ≥ 3500 cells/mm2 at 21 years of age ≥ 2800 cells/mm2 at 31 years of age ≥ 2200 cells/mm2 at 41 years of age ≥ 2000 cells/mm2 at 45 years of age or more No ocular pathology (corneal disorders, glaucoma, uveitis,   maculopathy, etc.)

3.10

PIOLS, phakic intraocular lenses. *According to the FDA (http://www.fda.gov/cdrh/mda/docs/p030028.html) †3.0  mm according to the FDA (http://www.fda.gov/cdrh/mda/docs/p030016.html).

Fig. 3-10-3  Posterior chamber phakic refractive lens for myopia (top) and hyperopia (bottom).

Fig. 3-10-4  Posterior chamber sulcus supported implantable contact lens.

In the mid-1980s, the implantation of posterior chamber IOLs in phakic eyes was reported by Fyodorov. In 1987, the Moscow Research Institute of Eye Microsurgery reported favorably on posterior chamber IOL implantation in phakic eyes to correct high myopia.7 The original lens design was a collar-button type, with the optic located in the anterior chamber and the haptics behind the iris plane. Later, ChironAdatomed modified this design to produce a silicone elastomer posterior chamber lens. This lens was reported to have a high incidence of cataract formation.8 Modifications on the IOL vault has decreased the incidence of this complication.9 This IOL is currently called a phakic refractive lens (PRL; Ioltech/CIBA Vision) (Fig. 3-10-3). In 1993, Zaldivar, Davidorf, and Oscherow began implanting a plate posterior chamber phakic IOL (Staar surgical implantable contact lens, ICL).10 This lens design was modified from the one originated by Fyodorov in 1986. Incorporation of a porcine collagen-HEMA (2-hydroxyethyl methacrylate) copolymer into the lens material has improved the lens’ biocompatibility. The current model (Staar ICL V4) has shown excellent results and low incidence of complications (Fig. 3-10-4).

INDICATIONS OF PHAKIC LENSES Regardless of the type of phakic IOL, general criteria should be followed (Box 3-10-1).

High Myopia

Patients who are poor candidates for laser correction may be candidates for phakic IOL. Excimer lasers approved by the Food and Drug Administration (FDA) can usually treat myopia of up to −12 to −14 D. However, the higher the intended correction, the thinner and flatter the cornea will be postoperatively. For LASIK surgery, one has to preserve a safe residual corneal stromal bed of at least 250 μm (we prefer a more conservative value of 300 μm).11 There is also a limit in the amount of central flattening that one can induce in the cornea, which is usually around 34−36 D (final keratometry). Beyond these limits, there is an increased risk of developing corneal ectasia due to thin residual stromal bed, and loss of visual quality and night vision problems due to excessive corneal flattening. It was also shown that LASIK induces significant spherical aberration and coma compared to phakic IOLs for high myopia.12 Because of these risks there is a current trend toward reducing the upper limits of LASIK and PRK to around −8 to −10 D. Above these limits and in cases where the cornea is too thin or too flat for laser surgery, phakic IOLs become the major alternative. Most phakic IOLs for myopia can correct up to around −20 to −30 D (Table 3-10-1). In September 2004, the FDA approved the first phakic IOL designed to correct high myopia. The Verisyse (AMO/Ophtec, USA Inc.), also known as Artisan/Worst “iris-claw” lens, was approved for: l Myopia ranging from −5 to −20 D. l Astigmatism less than or equal to 2.5 D. l Adults 21 years of age or older with an anterior chamber depth (ACD) of 3.2 mm or greater and Shaffer grade II as determined by gonioscopy. In December 2005, a second phakic IOL was approved by the FDA for the correction of high myopia. The Visian ICL (implantable collamer lens) is a posterior chamber phakic IOL approved for the correction of: l Myopia ranging from −3 to −20 D. l Astigmatism less than or equal to 2.5 D. l Adults 21–45 years of age with an ACD of 3.0 mm or greater and Shaffer grade II as determined by gonioscopy

High Hyperopia

The upper limits for hyperopic laser surgery are around +4 to +6  D. Higher attempted corrections can cause excessive steepening of the cornea (above 50  D), usually with a small optical treatment zone, leading to induced aberrations and degradation of optical quality. Phakic IOLs are available for the correction of hyperopia up to +3.0  D (see Table 3-10-1).

High Astigmatism

LASIK is the treatment of choice for astigmatism of up to 4–5 D. One may consider implanting toric phakic IOLs in cases of high degrees of astigmatism whether associated with myopia or hyperopia (see Table 3-10-1). Both spherical and cylindrical corrections can be combined in these lenses, which aims to correct the total refractive error, but to date, only spherical ­corrections are FDA-approved. High primary astigmatism can also be treated with relaxing procedures such as arcuate and transverse keratotomies, and with toric pseudophakic IOLs in cases where the crystalline lens is opaque.

187

3

TABLE 3-10-1  MAIN CURRENT PHAKIC IOLS

REFRACTIVE SURGERY

Type of Lens

Name/Model

Power range (D)

Optic Size (mm)

Length (mm)

Incision size (mm)

Material

Manufacturer

AC Angle-  supported

NuVita MA 20

−7 to −20

5.0 (4.5 effective)

12.0 to 13.5 (0.5 steps)

5.5

PMMA

Bausch & Lomb

Vivarte*

−7 to −22

5.5

12.0, 12.5, 13.0

3.2 (foldable)

Hydrophilic Acrylic (1.47) PMMA Haptics

Ioltech/CIBA Vision

ZSAL-4 Plus

−6 to −23

5.8 (5.3 effective)

12.0, 12.5, 13.0

6.0

PMMA

Morcher

Phakic 6

−25 to +10

5.5 or 6 mm

12.0 to 14.0   (0.5 steps)

6.0

PMMA

O.I.I.

Kelman Duet* (two parts)

−6 to −20

6.3 (5.5 effective)

12 to 13.5 (0.5 steps)

2.0 (foldable)

Silicone (1.43) PMMA Haptics

TEKIA

I-CARE

−23 to +10

5.75

12 to 13.5 (0.5 steps)

3.2 (foldable)

Hydrophilic Acrylic (1.47)

CORNEAL

Acrysof AC

?

6.0

?

3.0 (foldable)

Hydrophilic Acrylic

ALCON

Artisan 202 Ped

−3 to −23.5

5.0

7.5

5.3

PMMA

Ophtec/AMO

Artisan 203 (H)

+1 to +12

5.0

8.5

5.3

PMMA

Ophtec/AMO

Artisan 204 (M)

−1 to −15.5

6.0

8.5

6.3

PMMA

Ophtec/AMO

Artisan 206 (M)

−1 to −23

5.0

8.5

5.3

PMMA

Ophtec/AMO

Artiflex/Veriflex

−2 to −14.5

6.0

8.5

3.2 (foldable)

Polysiloxane PMMA Haptics

Ophtec/AMO

ICL†

−23 to +20

4.65 to 5.5

11.0 to 13.0 (0.5 steps)

2.5 (foldable)

Collamer

STAAR

PRL 100 (M) 101 (M) 200 (H)

−20 to +15

4.5 to 5.0

10.6 (H); 10.8 and 11.3 (M)

1.8 (foldable)

Silicone (1.46)

Ioltech/CIBA Vision

Sticklens

−25 to +7

6.5

11.5

3.0 (foldable)

Hydrophilic Acrylic

Ioltech

AC Iris-fixated†

PC sulcus-  supported

AC, anterior chamber; H, hyperopic; ICL, implantable collamer lens; M, myopic O.I.I. Ophthalmic Innovations International; PC, posterior chamber; Ped, pediatric; PRL, phakic refractive lens. *Multifocal models available. †Toric models available.

ADVANTAGES AND DISADVANTAGES OF PHAKIC IOLS For the advantages and disadvantages of phakic IOLs see Box 3-10-2.

INTRAOCULAR LENS POWER CALCULATION Van der Heijde13 proposed the theoretical basis for IOL power calculations based on studies of patients implanted with a Worst and Fechner lens, which are directly applicable to angle-supported IOLs. The power calculation for a phakic anterior chamber (AC) lens is independent of the axial length of the eye. Rather it depends on: (1) central corneal curvature (power) − keratometry (K); (2) anterior chamber depth; and (3) patient refraction (preoperative spherical equivalent). When calculating posterior chamber phakic IOL power, corneal thickness and axial length are also taken into consideration and applied to the manufacturers’ nomograms.7 With current IOL formulas and nomograms there is great accuracy on IOL power calculations, provided that the measurements they require are precise. Inaccuracies still arise, mainly due to errors in measuring corneal curvature (especially in eyes after keratorefractive surgery).

ANCILLARY TESTS

188

The eye’s anterior segment anatomy differs significantly among individuals and from myopes to hyperopes, affecting the indications of phakic IOLs in different refractive errors.14 Most of the complications of these lenses, such as pupil ovalization with angle-supported IOLs, endothelial-IOL touch, cataract, and uveitis are due to inappropriate

sizing and inaccurate measurements of the AC dimensions. The whiteto-white (w-w) measurement (external measurement from limbus to limbus) provides an approximate estimation of the AC diameter (angleto-angle distance). This is usually measured with calipers between the 3 and 9 o’clock meridians or with other methods, such as the ORBSCAN IIz (Bausch & Lomb) or other videokeratoscopes. In general, the overall diameter of the lens is chosen by adding 0.5−1.0 mm to the w-w distance for both sulcus and angle-supported IOLs.15 High-frequency (50 MHz) ultrasound biomicroscopy (UBM 840, Zeiss-Humphrey Inc. Dublin, CA) has been used to evaluate the anatomic condition of the anterior segment. However, it was not until recently that more adequate devices for imaging and measuring the anterior segment became available. The highfrequency (50 MHz) 3 D-digital ultrasound biometry (Artemis, Ultralink LLC, St. Petersburg, FL) (Fig. 3-10-5) and the anterior segment optical coherence tomography (Visante OCT, Carl Zeiss Meditec, Jena, Germany) offer an adequate alternative for the purpose of sizing phakic IOLs.

Sizing the Anterior Chamber Angle-Supported Phakic IOLs

Overall lengths for angle-supported phakic IOLs range from 11.5 mm to 14.0 mm with 0.5 mm intervals. The main challenge, however, is to precisely measure the distance between the angles (angle-to-angle distance). The w-w measurement, a commonly used index for predicting anterior chamber and ciliary sulcus diameters, is now well known to suffer from significant inaccuracies.16, 17 In a study comparing vertical and horizontal w-w measurements with direct anatomic measurements (post-fixation) in post-mortem eyes, positive correlation was found only between the vertical white-to-white distance and the anterior chamber angle diameter.

BOX 3-10-2  Advantages and Disadvantages of Phakic IOLs DISADVANTAGES Potential risks of an intraocular procedure (e.g. endophthalmitis) Nonfoldable models require large incision that may result in high postoperative astigmatism Highly ametropic patients may require additional photorefractive surgery (“Bioptics”) for fine-  tuning the refractive outcome May cause irreversible damage   (i.e., endothelial cell loss, cataract formation, glaucomatous optic neuropathy) Implantation in hyperopic patients can be followed by loss of BSCVA due to loss of magnification ­effect of glasses Other complications are common: pupil ovalization, induced astigmatism, chronic uveitis, pupillary block, pigment dispersion

BSCVA , best spectacle-corrected visual acuity.

Since these IOLs are fixated to the mid-peripheral iris, not the angle or sulcus, they have the advantage of being one-size-fits-all length (8.5 mm).

Sizing the Posterior Chamber Phakic IOLs

Ultrasonic anterior segment imaging devices, such as the Artemis and the UBM, are currently the best tools to measure the sulcus-to-sulcus distance. The Visante OCT, which uses a 1310 nm infrared light, is usually unable to provide adequate measurements of sulcus-to-sulcus diameter. The iris-pigmented-epithelium blocks the penetration of the OCT infrared light.19–21 When adequate devices are unavailable, the w-w measurement can help estimate the sulcus-to-sulcus distance, despite its inaccuracies. Most studies have used the w-w measurement plus 0.5 mm, rounded to the nearest 0.5 mm increment.7, 10

3.10 Phakic Intraocular Lenses

ADVANTAGES Potential to treat a large range of myopic, hyperopic, and   astigmatic refractive error Allows the crystalline lens to   retain its function preserving accommodation Excellent visual and refractive results (induces less coma and spherical aberration than LASIK) Removable and exchangeable Frequently improve BSCVA in myopic eyes by eliminating minification effect of glasses Results are predictable and stable Flat learning curve

Sizing the Anterior Chamber Iris-Fixated Phakic IOLs

VISUAL OUTCOMES3, 9, 10, 22–38 (TABLE 3-10-2) Phakic IOLs are the most predictable and stable of the refractive methods for preserving the crystalline lens in high myopia. New improved designs and current methods for power determination are providing increasing safety and efficacy for the correction of severe ametropias. In high myopia correction, significant postoperative gain of best-­corrected visual acuity over the preoperative levels likely occur as a result of a ­reduction in the image minification that is present with spectacle correction of high myopia. A loss of best-corrected visual acuity is uncommon. The loss of contrast sensitivity observed after LASIK for high myopia does not occur after phakic IOL.39, 40 In fact, with phakic IOLs there is an increase in contrast sensitivity in all spatial frequencies when compared with preoperative levels with best spectacle correction.41

ANTERIOR CHAMBER ANGLE-SUPPORTED PHAKIC INTRAOCULAR LENSES

Fig. 3-10-5  Artemis high-frequency (50  MHz) 3D-digital ultrasound imaging of the anterior segment. Red arrows indicate angle-to-angle distance; yellow arrows indicate sulcus-to-sulcus distance.

There was no correlation between the horizontal white-to-white distance and the anterior chamber angle diameter; nor was there correlation between either technique of external measurement and the ciliary sulcus diameter.17 In the same study, a manual plastic anterior chamber sizer showed good reproducibility of anterior ­chamber angle diameter, but it is obviously limited to intraoperative use.17, 18 It was also observed that the white-to-white measurement in the 12 o’clock meridian is significantly less than the same measurement between 3 and 9 o’clock. Consequently, an angle-supported phakic IOL length based on the horizontal measurement may be too large for the anterior chamber if the IOL is oriented vertically. Proper sizing is crucial to reduce the risk of complications such as pupil ovalization, IOL decentration, endothelial touch, chronic inflammation, and secondary glaucoma. Despite these limitations, the white-to-white measurements (with the addition of 0.5−1.0  mm) and the intraoperative AC sizer are still the most commonly used tools to size angle-supported IOLs. The recently introduced devices, however, like the Artemis and the Visante OCT offer a more adequate measurement of the angle-to-angle distance, and should be used when available.

Baikoff et al.3, 4 described a Z-shaped, angle-supported anterior chamber IOL derived from the Kelman aphakic implant. The footplates had a 25° vaulting and were large to avoid iris wrapping. The total optic diameter was 4.5 mm, and the real one was 4 mm. This size was supposed to provide sufficient distance to the endothelium, but endothelial damage did occur. In an attempt to minimize the complications, Baikoff modified his original design and lowered the vaulting to 20° and thinned the optic edge to increase the distance from the endothelium by 0.6 mm (see Fig. 3-10-1, ZB5M lens, left). The optical results were as good as with the earlier lenses, and the endothelial loss decreased. Despite good anatomical and optical results, haloes, glare, and pupil distortion prompted Baikoff to design a new rigid PMMA lens called NuVita MA20. The real optic diameter was increased to 4.5 mm and the total diameter to 5 mm (see Fig. 3-10-1, NuVita MA20, right). The thickness of the edge was decreased by 20% to increase the distance from the endothelium. The edge of the optic was modified to decrease the incidence of haloes. Other models of angle-supported phakic IOLs include: l Two rigid PMMA devices: 1. ZSAL-4 (Morcher, Stuttgart, Germany) (Fig. 3-10-6). 2. Phakic 6 (O.I.I./Ophthalmic Innovations International, Ontario, Canada) (Fig. 3-10-7). l Three foldable hydrophilic acrylic IOLs: 1. Vivarte/GBR (Ciba Vision, Salt Lake City, UT, USA, and IOLTECH, La Rochelle, France) (Fig. 3-10-8). 2. I-CARE (Corneal Inc., Paris, France) (Fig. 3-10-9). 3. Acrisof AC14 (Alcon, Fort Worth, USA). l One foldable “two parts” silicone/PMMA IOL: Kelman-Duet42 (Tekia Tekia, Irvine, CA,) (Fig. 3-10-10) (see Table 3-10-1).

Surgical Procedure

Anterior chamber phakic IOL implantation can be performed under topical or peribulbar anesthesia. Retrobulbar anesthesia should be avoided in high myopes because of the increased risk of perforation. Pilocarpine is instilled in the eye 30 minutes before surgery to protect the crystalline lens at the time of IOL implantation.3, 4, 15 The surgeon begins by creating a superior scleral tunnel or a temporal clear corneal incision. The wound size varies according to the IOL model, varying from 2 to 6.5 mm (Table 3-10-1).

189

3 REFRACTIVE SURGERY

The anterior chamber is filled with a cohesive viscoelastic and the lens is introduced toward the angle from the incision. The first footplate is inserted in the iridocorneal angle, avoiding having the iris folding over the haptic. The second haptic is then placed. The lens is then rotated with a lens dialer to the meridian in which the pupil is best centered in relation to the IOL optic. A peripheral iridectomy is always performed to reduce the risk of pupillary block and angle closure. The iridectomy should not interfere with the stability of the lens, and the lens should not touch the ciliary body. Preoperative laser iridotomy is less preferable because of the risk of closure by the inflammatory process after surgery, but can be performed as an alternative in cases where a small-incision IOL implantation is planned. In these cases two laser iridotomies should be performed.

The incision is closed with a running or interrupted 10-0 nylon suture. The anterior chamber must be irrigated to remove the viscoelastic and avoid postoperative elevation of intraocular pressure (IOP). The iridocorneal angle is then examined for a possible improper position of the footplates. Topical corticosteroids and antibiotics are applied three times daily for 4–6 weeks.

Complications3, 22, 27, 28, 32, 43 (Table 3-10-3) Haloes and glare

The incidence of haloes and glare has a clear relationship to the diameter of the IOL optic and the size of the pupil. In darkness, with a mid-dilated pupil, the optical zone can be smaller than the pupil, and this may be responsible for night haloes. They occur in about 20% of

TABLE 3-10-2  VISUAL AND REFRACTIVE RESULTS FOR PHAKIC IOLS

Study

IOL Model

Number of Eyes

Mean Preop SE (Range) (D)

Postop SE within ±0.5  D of ­Emmetropia

Postop SE within ±1.0  D of ­Emmetropia

UCVA ≥  20/40

BSCVA Gain ≥  2 Lines

BSCVA Loss ≥  2 Lines

50.7%

8.3%

AC angle-supported Baikoff (1998)

ZB5M

134

−12.5 (−7 to −18.8)

32%

58.8%

57%

Perez-Santoja (2000)

ZSAL-4

23

−19.6 (−16.7 to −23)

56.5%

82.6%

60.8%

Allemann (2000)

NuVita

21

−18.95

Leccisotti (2005)

ZSAL-4

190

−14.37

19%

40%

Leccisotti (2005)

Morcher type 54

42

+6.61 (+4 to +10.5)

57%

Menezo (1998)

Artisan

111

−14.8 (−8 to −20)

Budo (2000)

Artisan

518

−12.9 (−5 to −20)

Saxena (2003)

Artisan(Hiperopia)

26

Tehrani (2005)

Artiflex(Foldable)

Asano-Kato (2005) FDA Trial (2005)

Mean SE −1.93

0% 65%

0%

Mean 0.55

≈  45%

0%

81%

≈  55%

≈  15%

0%

82.9%

36.3%

77%

57.1

78.8%

76.8%

42.6%

1.2%

+ 6.8 (+3 to +11)

59.1%

81.8%

90.9%

1%

0%

41

−8.2 (−12 to −3.75)

91%

97%

100%

78%

0%

Artisan

44

−12.8

36.1%

55.6%

18.2%

4.5%

Verisyse/Artisan

662

−12.6 (−5 to −20)

71.7%

94.7%

84%

AC iris-fixated

0.3%

PC Sulcus-supported Zaldivar (1998)

ICL

124

−13.4 (−8.5 to −18.6)

44%

69%

68%

36%

0.8%

Arne (2000)

ICL

58

−13.8 (−8 to −19.2)

Mean SE −1.22

56.9%

Mean 0.4

Hoyos (2002)

PRL

31

−18.5/+7.77 (−26 to +11)

≈  50%

≈  80%

Mean 0.52

10%

0%

FDA Trial Sanders (2004)

ICL

526

−10.0 (−3 to −20)

67.5%

88.2%

81.3%

10.8%

0.8%

3.4%

Bioptics (Phakic IOL followed by LASIK)

190

Zaldivar (1999)

ICL

67

−23 (−18.7 to −35)

67%

85%

69%

76%

0%

Guell (2001)

Artisan

26

−18.4 (−16 to −23)

80.7%

100%

77%

42%

0%

Sanchez-Galeana (2001)

ICL

37

−17.7 (−9.75 to −28)

83.7%

97.2%

89.1%

64.8%

3%

Munoz (2005)

ZSAL-4

24

(−9 to −26)

75%

91.7%

83.3%

37.5%

0%

Munoz (2005)

Artisan (hyperopia)

39

+7.39 (5.25 to 9.75)

79.5%

94.9%

89.7%

2.6%

0%

BSCVA, best spectacle-corrected visual acuity; Postop, postoperative; Preop, preoperative; SE ,spherical equivalent; UCVA, uncorrected visual acuity.

patients at 1  year, but tend to decrease at longer follow-ups.43 IOLs with larger optic sizes (usually = 6.0 mm) are associated with a decreased incidence of these symptoms. Pupil ovalization is one of the most prevalent complications of anglesupported phakic IOLs, with a reported incidence of between 7% and 22%.22, 27, 28, 32, 42–44 This wide range can be due to the subjective method used to quantify whether the deformation is significant and

Fig. 3-10-6  Rigid PMMA anglesupported ZSAL-4 lens.

Endothelial damage

3.10 Phakic Intraocular Lenses

Pupillary ovalization

different follow-up durations. Pupillary abnormalities are usually progressive and are more frequent with longer follow-up visits.22, 43 The cause of pupillary distortion is not completely understood. The most accepted mechanism is related to haptic compression of the angle structure, due to an oversized lens, causing inflammation of the angle, peripheral synechia formation, and pupillary ovalization. This mechanism was believed to be associated with iris ischemia.15, 32 Iris hypoperfusion was recently confirmed using indocyanine green (ICG) angiography.44 The axis of the deviation usually coincides with the ­major axis of the lens. Another complication usually associated with pupil ovalization is iris retraction and atrophy;43 the atrophy usually occurs in the iris sector affected by ovalization. Total sector iris atrophy can occur after progressive pupil ovalization in long-standing cases (Fig. 3-10-11). With the continuous improvement in IOL design and surgical techniques, endothelial cell damage has decreased. Still, most recent studies of angle-supported IOLs show moderate endothelial losses, mainly related to surgical trauma.3, 27, 28, 32, 43, 45 This loss was estimated at 300 cells/mm2 by Perez-Santonja et al.32 with the ZB5M phakic IOL. However, a permanent implant in the anterior chamber is a continuous risk for progressive endothelial loss with cell abnormalities and marked pleomorphism. The rate of endothelial cell loss at 1 year is about 5–7%, which is no greater than that after modern cataract surgery,46 and continues after the first and second years after surgery, but at a slower rate. Alio et al.43 reported that after 7 years the cell loss was 9.6% with the Fig. 3-10-8  Foldable hydrophilic acrylic angle-supported Vivarte lens.

Fig. 3-10-7  Rigid PMMA angle-supported Phakic 6 lens.

A

B

C

Fig. 3-10-9  Foldable hydrophilic acrylic angle-supported I-CARE lens (A and B). Ultrasound biomicroscopy (UBM) showing the position of the haptic in the anterior chamber angle (C). (Courtesy of Simonetta Morselli, MD; Verona, Italy.)

191

3 REFRACTIVE SURGERY B

A

C

D

Fig. 3-10-10  Foldable “two parts” (Silicone optic/PMMA haptics) Kelman-Duet lens (A). The haptics are implanted initially through a small incision (B), then the optic is injected (C). The complex optic-haptics is assembled inside the anterior chamber (D).

ZB5M lens. In the same study, the authors43 expressed concern about implanting patients at a young age and the long-term relative risks they might face. According to the data, it might take 20–30 years before reaching the lower limit of endothelial cell count (1500 cells/mm2), at which point the eye may have a decreased ability to sustain other types of surgery, including cataract extraction.

Elevation of intraocular pressure

192

Elevation of IOP usually occurs transiently during the early postoperative period, but may become chronic.3, 27, 28, 32, 43 The most frequent cause is inadequately removed viscoelastic and postoperative use of topical steroids; however, a more important cause is acute glaucoma secondary to pupillary block. Pupillary block happens when, in the

r­ etro­pupillary space, resistance prevents the physiological flow of aqueous through the pupil opening, pushing forward the iris and closing the iridocorneal angle.27, 28 Because the space between the anterior crystalline lens surface and the posterior pigment epithelium of the iris is very narrow indeed, pupillary block is more likely to occur after a posterior chamber IOL than anterior chamber IOL implantation. Preoperative peripheral laser iridectomies (usually two) or intraoperative iridectomy, when patent, can prevent the occurrence of this complication.

Uveitis

Transient acute uveitis is usually secondary to iris trauma during surgery. Usually there is only a mild increase in the level of cell and flare counts; however, in some cases, the inflammation can be so severe as

TABLE 3-10-3  ANGLE-SUPPORTED PHAKIC IOLS: INCIDENCE OF COMPLICATIONS

3.10

IOL Model

Number of Eyes

Glare/Haloes

Pupil Ovalization

Baikoff (1998)

ZB5M

134

27.8%

22.6%

4.6% at 3  y

Alio (1999)

ZB5M/MF/ ZSAL-4

263

20.2% at 1  y 9.6% at 7  y

10.3%

1.8% at 1  y 8.4% at 7  y

7.2% (C)

4.6%   acute PO

0%

4.2%/3.4%

Perez-Santoja (2000)

ZSAL-4

23

26.1% at 2  y

17.4% at 2  y

4.2% at 2  y

13% (A)

8.7%

0%

0%/0%

Allemann (2000)

NuVita

21

20%

40% at 2  y

12% at 2  y

4.7%

4.7%

0%

4.7%/0%

Leccisotti (2005)

ZSAL-4

190

18% at 1  y

11% at 1  y

6.2% at 1  y

8% (A) 18% (C)

1%

3%

2.1%/0.05%

Leccisotti (2005)

Morcher   type 54

42 (H)

10% at 1  y

7% at 1  y

6% at 1  y

12% (A) 2% (C)

5%

7%

0%/5%

IOP Elevation

Chronic Uveitis

Pupillary Block

1.5%

Explant./ Cataract 2.3%

Phakic Intraocular Lenses

Study

Endothelial Cell Loss (Mean)

A, acute (due to residual OVD); C, chronic (include IOP rise due to topical steroids); H, hyperopia; Explant., explantation.

barrier (BAB) permeability. The chronic inflammation may continue for several years inducing pupil ovalization, iris atrophy, and other complications, such as glaucoma, cataract, or anterior synechiae.

Cataract

A

Care must be taken to avoid lens trauma during surgery. The miotics and ophthalmic microsurgical device (OVD) help maintain the distance from the lens. Cataract development after an anterior chamber phakic lens, although much less common than with posterior chamber IOLs, can still occur, mainly due to chronic uveitis and other complications. In a 7-year follow-up study of three kinds of ACPIOLs, Alio et al.43 reported an incidence of 3.4% of cataract formation (mostly nuclear) requiring cataract surgery and IOL explantation. The authors found that it is unlikely that the lens implantation triggered the development of cataracts, as this complication was observed in a significantly older age group than the mean age of the study. Age at implantation of older than 40 years and an axial length greater than 30 mm were two factors significantly related to nuclear cataract development.43 Phakic IOL ­ explantation followed by phacoemulsification and posterior chamber IOL implantation was shown to be successful.47

Retinal detachment

B

Fig. 3-10-11  Pupil ovalization 2 years after implantation of an angle-supported phakic IOL (A). At 5 years, progressive ovalization was observed and the lens was explanted (B).

to cause sterile hypopyon. In mild to moderate cases there is usually a quick response to topical steroids, with no delayed sequelae. Chronic uveitis is sometimes observed after angle-supported IOLs with rates from 1% to 5%.3, 27, 28, 32, 43 An oversized lens can be a potential cause, compressing the angle structures and altering the blood−aqueous

Retinal detachment (RD) is a potential hazard of phakic IOL implantation. The reported incidence is very low, but Ruiz-Moreno et al.48 reported a rate of 4.8% in a large study with ZB5M lenses. The incidence was significantly higher, 14.28%, in patients who had been treated before surgery with laser for predisposing lesions in the retina, versus only 3.94% in the nontreated group. However, the lesions that caused the RD were unrelated to the treated area. The incidence of RD in patients with predisposing lesions previously treated with laser confirmed the doubtful efficacy of such prophylactic treatment in these patients. Nonetheless, it is very difficult to say whether RD was ­induced by the phakic IOL or the myopia, because the incidence of RD in highly myopic patients is much higher than that in the emmetropic population.48 The mean time to develop RD was 17.4 months (range, 1−44 months). In a more recent report by the same group on 522 patients, the incidence was 2.87% with a mean time after surgery of 24 months (1 to 92 months). The risk was greater in eyes with an axial length > 30.24 mm.49 The authors concluded that the correlation of phakic IOL implantation and the eventual occurrence of RD could not be demonstrated. These RDs were treated with classic procedures. The surgery was more difficult owing to poor visualization through the phakic IOL. In seven of the eight cases of Ruiz-Moreno et al.48 the surgery was successful, and it was not necessary to remove the lens to do the procedure.

Other complications

A small number of eyes have been reported with other complications of phakic IOLs, such as corneal decompensation and cataract progression,50 Urrets-Zavalia syndrome,51 malignant glaucoma,52 endophthalmitis,53 and others.

193

3 REFRACTIVE SURGERY A

Fig. 3-10-12  Artisan/Verysise lens. Detail of the mid-peripheral iris stroma enclavated by the haptic claw.

B

Fig. 3-10-14  (A,B) Foldable iris-fixated Artiflex lens.

A

B

Fig. 3-10-13  Artisan/Verysise lens. FDA-approved models (A) 204 (6.0 mm optic) and (B) 206 (5.0 mm optic) for the correction of myopia.

IRIS-FIXATED PHAKIC INTRAOCULAR LENSES

194

The first iris-fixated lenses were sutured to the iris stroma with a Perlon stitch or a stainless-steel suture.54 The claw fixation method rendered iris stitching unnecessary. Various lens designs with midperipheral ­fixation by a claw mechanism were tested before 1978, when Worst ­introduced

his final conceptual model of the iris-claw lens for secondary lens ­implantation or as a standby lens in cases of posterior capsule rupture. Because of the good tolerance and refractive results, the iris-claw lens was used as a primary implant after intracapsular and extracapsular cataract extraction (about 12 000 implantations in the Netherlands up to 1990). In 1986, the concept of the claw lens was applied to correct myopia in phakic patients. Initially, the iris-claw phakic IOL for myopia was biconcave (Worst-Fechner biconcave lens).5, 6 The iris-claw lens is fixated to the anterior iris surface by enclavation of a fold of iris tissue into the two diametrically opposed “claws” of the lens (Fig. 3-10-12). The fixation sites are located in the midperiphery of the iris, which is virtually ­immobile during pupillary movements. In 1991, this lens was modified into a convex-concave design to increase the distance between the IOL and the corneal endothelium. ­Suppression of the prominent optical rim has also allowed a reduction in the prismatic effect, which could be responsible for haloes or glare. Initially called Artisan/Worst Claw Lens, this iris-claw phakic IOL is currently manufactured by Ophtec (Groningen, Netherlands) and distributed globally by AMO (Santa Ana, CA) with the name of Verisyse Lens. The vaulted design (0.5 mm) of the posterior face of the IOL ensures optimal space in front of the natural lens (about 0.8 mm) and prevents aqueous flow blockage. It also accounts for the forward displacement of the human lens during accommodation, which is about 0.6 mm maximum. The Verisyse lens has a total length of 8.5 mm and two different optic diameters: 5.0 and 6.0 mm (see Table 3-10-1). The thickness of the myopic IOL in the optical axis is 0.2 mm, the total height is about 0.9 mm, and the weight is 10 mg in air (15.0 D lens). Currently, this lens is mainly used to treat high primary myopia (FDA approved – Models 204 and 206; Fig. 3-10-13), hyperopia,35 and astigmatism 5–57 in adults (see Table 3-10-2). Other indications include: l Treatment of refractive errors after penetrating keratoplasty.36, 58–60 l Treatment of anisometropic amblyopia in children.61, 62 l Secondary implantation for aphakia correction.63–65

3.10 Phakic Intraocular Lenses

Fig. 3-10-15  Enclavation spots are marked on the cornea to guide fixation.

Fig. 3-10-16  The incision is enlarged to the appropriate size.

 reatment of refractive errors in patients with keratoconus.66 T Correction of progressive high myopia in pseudophakic children,67 and postoperative anisometropia in unilateral cataract patients with bilateral high myopia.68 The foldable model (Artiflex, Ophtec, Groningen, The Netherlands (Conformitié Européenne approved)) is now under clinical investigation in selected clinical sites in Europe. This lens is a convex-concave three-piece PIOL with a silicone 6 mm optic and PMMA haptics (Fig. 3-10-14A,B). The total diameter is 8.5 mm. The PIOL currently is available from −2.0 D to −14.5 D power. l l

Surgical Procedure

Preoperative application of topical pilocarpine results in miosis. Miosis is mandatory, as it forms a protective shield for the natural lens during the insertion and fixation of the iris-claw lens. A constricted pupil also facilitates proper centration of the lens. Although there is theoretically a very low risk of pupil block glaucoma (because the vaulted configuration of the Verisyse lens ensures a normal aqueous outflow), a peripheral iridectomy during surgery is mandatory. Various incision techniques (e.g., corneal, limbal, or scleral tunnel incision) can be used. Usually, a superior limbal incision is used. Depending on the diameter of the lens used − 5.0 mm or 6.0 mm − the incision should be at least 5.3 mm or 6.3 mm, respectively, to avoid difficulties with IOL insertion. The enclavation spots can be marked on the cornea at the beginning of the procedure (Fig. 3-10-15).

Fig. 3-10-17  Blunt iris entrapment needles are used to create a fold of ­midperipheral iris tissue through vertical movement of the needle.

The incision is performed and enlarged to the appropriate size (Fig. 3-10-16). The “claw” haptics are fixated to the iris by a process called enclavation, and specially designed bended needles are used. Two 1.0 mm side-port incisions at 10 and 2 o’clock positions are required for enclavation. The lens is implanted vertically through the incision, then rotated and centered in front of the pupil with the haptics at 3 and 9 o’clock positions. The anterior chamber is filled to capacity with cohesive OVD ­material. It is recommended to use high-viscosity sodium ­hyaluronate to maintain working space in the anterior chamber. The OVD is injected through one of the puncture incisions to create a deep ­anterior chamber. If additional OVD material needs to be injected during ­surgery, care should be taken not to let it slip under the IOL. It should be used as a stabilizing agent that presses the implant onto the iris surface. Centration and fixation of the IOL are probably the most critical steps of the procedure, and their accuracy influences the postoperative results. The pupil is used as a reference for centration. Fixation is performed by gently creating an iris fold under the claw and then entrapping the iris fold into the claw (Fig. 3-10-17). If adjustment of the lens is needed after fixation, the iris must first be released before the lens is moved. The number of stitches depends on the type of incision. Watertight wound closure is of paramount importance to prevent a shallow anterior chamber from leading to IOL–endothelial contact in the immediate postoperative period. A small incision will help minimize surgically induced astigmatism and inflammation. When the foldable Artiflex is used, a small 3.2 mm clear cornea incision may be preferred. In this case, a special Artiflex implantation spatula and a lens holder are necessary (Fig. 3-10-18A,B). The OVD material should be completely removed after the wound has been almost completely closed to prevent a shallow anterior chamber and contact between the IOL and the cornea. Incomplete removal of the OVD material may induce an early postoperative rise in IOP. Steroidal anti-inflammatory drugs are usually prescribed for 2–4 weeks after surgery. Regular follow-ups, in particular long-term evaluations of the corneal endothelium, are recommended.

Complications24, 25, 29, 35, 37 (Table 3-10-4) Glare and haloes

The incidence of glare and haloes has been greater with the 5.0 mm than with the 6.0  mm optic diameter.25, 29 The general incidence has varied from 0 to 8.8%. In the FDA prospective study as much as 13.5−18.2% of the patients had glare and haloes postoperatively; however, approximately 10−13% had these symptoms preoperatively with an improvement after surgery. Patients with pupils larger than 5.5 mm were at a significantly increased risk for glare and haloes (http://www. fda.gov/cdrh/PDF3/p030028d.pdf; accessed May 2006).

195

3

Anterior chamber inflammation/pigment dispersion

REFRACTIVE SURGERY

Cases of severe iritis are rarely observed after surgery, but can occur after repeated traumatic attempts at iris enclavation or occasionally without any predisposing factors.69, 70 Pigment dispersion syndrome has occasionally been observed. A known mechanism is poor ­fixation/ enclavation of the IOL to the iris with subsequent pseudophakodonesis (IOL movement), which may cause chronic inflammation with the need for reintervation for re-fixation (Fig. 3-10-19A,B). Poor fixation has been observed in as much as 3% of cases.29 In the FDA trial, iritis was observed in 0.5% of cases and poor fixation in 2.1%. In a recent study with anterior chamber OCT, Baikoff et al. observed that crystalline lens raise can be a cause of pigment dispersion in eyes

with an Artisan IOL. They observed that the higher the crystalline lens rises, the greater the risk for developing pigment dispersion in the area of the pupil. The risk was higher in hyperopic eyes.71 With the Artiflex, foldable model of Artisan lens, Tehrani et al.37 observed an increased incidence of pigment dispersion (12.2%). This was believed to be due to a slight step within the implant in the area of the connection of the foldable silicone optic to the rigid haptic (claw), which may have caused iris pigment abrasion during pupillary movement.

A

A

B

B

Fig. 3-10-18  (A,B) The foldable Artiflex (Veryflex) lens is introduced vertically with a special spatula through a clear corneal incision.

Fig. 3-10-19  Poorly fixated Artisan lens with pseudophakodonesis causing chronic uveitis (A). Note the prominent ciliary injection (B).

Table 3-10-4  Iris-Fixated Phakic IOLs: Incidence of Complications

196

Study

IOL Model (OZ/Diameter)

Number of Eyes

Glare/Haloes

Pigment Dispersion/Uveitis

Endothelial cell loss (Mean)

IOP elevation

Poor fixation / decentration

Menezo (1998)

Artisan

111

1.8%

12.8%

9.22% at 2  y 13.42% at 4  y

5.3%

3.6%

0.9% (corneal touch)

Budo (2000)

Artisan 5/8.5

518

6%/8.8%

0%

9.6% at 3  y

0%

0%‡

2.8%

Saxena (2003)

Artisan 5/8.5 (H)

26

0%

1%

8.5% at 2  y 11.7% at 3  y

0%

0%

1% (iris convex)

FDA Trial (2005)

Artisan 5 & 6/8.5

662

13.5%/18.2%†

0.5%

2.9% to 6.3% at 3  y*

0%

2.1%/0.8%

1.5%

Asano-Kato (2005)

Artisan 5 & 6/8.5

44

0%

4.5%

2.8% at 2 y (NS)

9% (A)

0%

0%

Tehrani (2005)

Artiflex (Foldable)

41

0%

12.2%

2.3% at 6  mo

0%

0%

0%

NS, not significant; OZ, optical zone. *Excluding patients with AC depth less than 3.2  mm (data obtained from 353 eyes). †Approximately 13% of the patients had glare and 10% had haloes preoperatively with an improvement postoperatively (after IOL implantation). ‡IOL repositioning because of poor initial placement was performed in 2% of the cases.

Explantatation

Endothelial cell loss

Glaucoma

Postoperative glaucoma after Artisan lens implantation can occur due to: residual OVD in the AC; dispersion of iris pigment during surgery with partial occlusion of the trabecular meshwork; use of topical corticosteroids; and postoperative inflammation.24, 29, 70 Temporary ocular hypertension was demonstrated in a prospective study of 100 eyes with ­Artisan IOL. IOP showed a mean increase of 2.1 mmHg at 3 months after surgery, but returned to preoperative levels by 6 months.72 In the same study, one lens was explanted due to chronic high IOP at 11 months. In the FDA study, no case of raised IOP requiring treatment was observed.

The PRL (see Fig. 3-10-3A,B), manufactured by Ioltech/CIBA Vision, has been in development since 1987 and is based on previous work by ­Fyodorov et al. in Moscow.8–10 The PRL is a hydrophobic silicone singlepiece plate design IOL with a refractive index of 1.46. Earlier designs of this IOL caused cataract formation because of mechanical touch, impermeability of nutrients, and stagnation of aqueous flow without the elimination of waste products.8, 9, 80 Further developments in this lens changed its vaulting to avoid contact between the crystalline lens and the IOL and to allow aqueous to flow over the crystalline lens. The new models (PRL-100 and 101 (myopia), and PRL-200 (hyperopia)), which are claimed to float in the posterior chamber with its haptics resting on the zonules, decreased the incidence of cataract formation to almost zero. However, recent reports observed other unexpected complications, such as lens decentration and zonular dehiscence with dislocation of the lens into the vitreous cavity.81–83 In 1993, a posterior chamber phakic IOL made of collamer, which is a copolymer of HEMA (99%) and porcine collagen (1%), was developed.84–86 The implantable contact lens (ICL) (STARR, Nidau, Switzerland; Fig. 3-10-4) is a refractive phakic lens designed to be implanted in the posterior chamber with support on the ciliary sulcus. Collamer is a hydrophilic flexible material with a high biocompatibility and permeability to gas (oxygen) and metabolites.84 These features and the free space left between the IOL and the crystalline lens, which will be filled by the aqueous humor, should allow the crystalline lens to have a normal metabolism, and therefore avoid the development of cataracts. Despite these characteristics, cataract formation and glaucoma are still the main complications of this lens.23, 33, 87 The new design of the Starr lens (ICL-V4) with greater vaulting than the V2 and V3 models, and the increased surgical experience with this lens, has been associated with a decrease in the frequency of lens opacification.34, 88

3.10 Phakic Intraocular Lenses

Intraoperative trauma is considered the main cause of early cell loss. Investigators have found an acceptable mean endothelial loss of 2.8– 9.2% 2 years following iris-claw phakic lens implantation, 24, 25, 29, 35, 37 which is similar to results of posterior chamber IOL implantation.46 Menezo et al.29 noted endothelial cell loss of 13.4% at 4 years, without morphometric changes. The largest cell loss was observed in the first 6 months after surgery. In the FDA trial, the endothelial cell numbers were collected from 353 eyes. Artisan phakic IOLs implanted in eyes with anterior ­chamber depths less than 3.2 mm exhibited the greatest cumulative endothelial cell loss (9%) at 3 years. For this reason, the FDA panel contraindicated the use of this lens for patients with an AC depth of less than 3.2 mm. The highest rate of cell loss (2.37%) was experienced between the second and third years and not from baseline to 6 months (0.4%), as would be expected from surgical trauma (http://www.fda.gov/cdrh/ PDF3/p030028d.pdf; accessed May 2006). With adequate technique and experience, the implantation of this IOL can be done with extremely low levels of cell loss. It is important to point out, however, that this study observed a continual steady loss of endothelial cells of −1.8% per year, and this rate was not established as safe on a long-term basis. Periodic monitoring of endothelial cell density was advised.

Iris atrophy or dislocation

Despite successful implantation of an Artisan lens, there is a risk of subsequent IOL dislocation. In the FDA trial, IOL dislocation occurred in 5 cases (0.8%) at 3 years. IOL dislocation can occur due to iris atrophy at the site of enclavation, usually when a small amount of tissue is entrapped, or due to blunt ocular trauma, as reported previously in two cases.73, 74 Repositioning of the lens may be done with an excellent visual outcome in most cases (Fig. 3-10-20A,B).

Cataract

Nuclear cataract developed in 7 of 231 eyes (3%) with an Artisan lens after 8 years follow-up in one study.75 Patients older than 40 years of age at implantation of the IOL and axial length greater than 30 mm were factors significantly related to nuclear cataract formation.75 In the FDA trial, the cumulative incidence of lens opacity was 4.5% (49/1088 eyes). The majority of these opacities were not visually significant. During the study, four opacities were determined to be visually significant and three required cataract extraction. The authors pointed out that the rate of cataract surgery in the general population for greater than 40 years of age is 1.7−10.8% (http://www.fda.gov/cdrh/PDF3/p030028d.pdf; accessed May 2006).

A

Other complications

Other complications include hyphema,25 intermittent myopic shift (of 4.0 D),76 retinal detachment and giant retinal tears,25, 77, 78 and ­others.

POSTERIOR CHAMBER PHAKIC INTRAOCULAR LENSES Since 1986 when Fyodorov first implanted a phakic IOL in the prelenticular space to correct high myopia, several posterior chamber phakic IOLs of his derivation have been developed.7, 79 Results with phakic IOL materials and designs used to date suggest that both biocompatibility with and adequate spacing from sensitive intraocular structures are required for improved safety in all patients. For implantation of a phakic IOL in the prelenticular space, we would ideally desire materials that would allow permeability of nutrients and circulation of aqueous humor, and would not cause crystalline lens or zonular trauma. There are currently three models of posterior chamber phakic IOLs, all made with flexible materials: the PRL (phakic refrative lens) made of silicone; the ICL (implantable contact lens) made of collamer; and the Sticklens made of hydrophilic acrylic.

B

Fig. 3-10-20  (A) Artisan lens dislocation after blunt trauma. (B) After repositioning. (Courtesy of Emir A. Ghanem, MD; Joinville, Brazil.)

197

3 REFRACTIVE SURGERY

A

A

B

B

Fig. 3-10-21  A posterior chamber lens is folded (A) and inserted through a small incision (B) with a forceps. (Courtesy of Jean L. Arne, MD; Toulouse, France.)

Fig. 3-10-22  After the lens unfolds (A), the footplates are placed underneath   the iris (B).

TABLE 3-10-5  POSTERIOR CHAMBER PHAKIC IOLS: INCIDENCE OF COMPLICATIONS Study

IOL Model

Number of Eyes

Glare/Haloes

Cataract

Pigment Dispersion/Uveitis

Zaldivar (1998)

ICL

124

2.4%

2.4%

0.8%

Brauweiler (1999)

Adatomed Silicone

18

Arne*(2000)

ICL

58

54.3%

3.4% ASC at 1  y

Hoyos (2002)

PRL

31

12.9%

FDA Trial Sanders† (2004)

ICL

526

≈  8.5%‡

52.9% 81.9% at 2  y

IOP Elevation

Decentration

Explantatation

11.3% 4.8% PB

2.4% 1.6% >  1  mm

4%

22% PB

81.9%

15.5%

3.4%

1.7%

3.2%

3.2%

3.2% 6.4% PB

2.7% ASC at 3  y 0.9% NC at 3  y

0%

0.2%

9.7% 0.6%

ASC, anterior subcapsular cataract; NC, nuclear cataract; PB, pupillary block. *Mean endothelial cell loss  1.2 D, and skewing of the radial axis of astigmatism by greater than 21°. These findings have a sensitivity of 98% and a specificity of 99.5% for the diagnosis of keratoconus. Such analyses have been used to demonstrate that keratoconus is almost always a bilateral disease, even when not evident at the slit lamp in the fellow eye. The inheritance pattern of keratoconus is incompletely defined. In the past it was believed that more than 90% of cases were sporadic. With the advent of videokeratography to assess family members, however, pedigrees have been analyzed. These studies show corneal changes consistent with keratoconus in some family members, which suggests an autosomal dominant pattern of inheritance.13

DIFFERENTIAL DIAGNOSIS The differential diagnosis of keratoconus includes the other corneal ectasia disorders listed here. Post-traumatic corneal ectasia or protrusion of the cornea subsequent to corneal thinning from ulceration is also included in the differential diagnosis. The symptoms of keratoconus, which include decreased acuity, polyopia, and decreased contrast sensitivity, may be seen in other disorders, especially early nuclear sclerotic cataract.

SYSTEMIC ASSOCIATIONS

300

A number of systemic and ocular disorders have been described in association with keratoconus. Atopy commonly is associated and is seen in as many as 35% of patients,14 vernal keratoconjunctivitis, and the eye rubbing seen in systemic atopy may play a role in this development.8 Down’s syndrome patients have been reported to show keratoconus in 5.5% of cases.15 Among these patients, the frequency of acute hydrops is higher, perhaps because of eye rubbing and/or because these patients are treated infrequently with keratoplasty and their disease is allowed to progress further. Other systemic associations include Ehlers-Danlos, Marfan’s, Cruzon’s, Apert’s, and other syndromes. Ocular-associated disorders include Leber’s congenital amaurosis, retinitis pigmentosa, and retinopathy of prematurity. Fuchs’ dystrophy and posterior polymorphous dystrophy have been

PATHOLOGY Examination of pathologic specimens from keratoconus shows irregular epithelium, breaks in Bowman’s layer, and fibrosis filling in the breaks that extend beneath the epithelium (Fig. 4-18-4). With hydrops, breaks at the layer of Descemet’s membrane are seen, with inward curling of Descemet’s membrane, which is otherwise normal. Electron microscopy shows decreased thickness of the cornea with fewer lamellae. The collagen fibrils in the lamellae are thickened mildly and the space ­between fibrils is increased.16

TREATMENT Treatment consists of spectacles for myopic astigmatism and then rigid contact lenses once spectacle-corrected acuity becomes inadequate. When contact lenses fail, surgical treatment is indicated. In one series, the most frequent reason for contact lens failure that resulted in the need for keratoplasty was inadequate acuity (43%), followed by inadequate lens tolerance (32%), frequent lens displacement (13%), and peripheral thinning (12%).17 Standard surgical treatment consists of keratoplasty; lamellar keratoplasty is effective, but most surgeons prefer not to use this because of the technical difficulties involved and the slightly reduced visual outcome.18 Epikeratoplasty has success as well, but has been abandoned because of the suboptimal visual outcome. By far the most frequent procedure is penetrating keratoplasty, which accounted for over 14.5% of all penetrating keratoplasties carried out in the United States in 2000.19 At the time of keratoplasty, decreasing the donor/recipient size disparity reduces postkeratoplasty myopia.20 Recent advances in surgical technique have propelled interest in deep anterior lamellar keratoplasty (DALK). Primary advantages include increased structural integrity and reduced risk of graft rejection. While challenging to perform, innovative techniques such as the big-bubble technique have reduced surgical operating time and improved the safety of the procedure.21 Intracorneal ring segments have achieved some success in patients without corneal scarring in reducing the myopia and astigmatism and improving spectacle-corrected visual acuity.22 In a study of 57 eyes with clear corneas with a diagnosis of keratoconus, placement of INTACS (Addition Technology, Des Plaines, IL) reduced mean keratometry values by −4.3 +/−2.8 D, and improved UCVA by 2 lines or more in 78% of patients.23 Another study has shown significant postoperative problems in 30% of INTACS with thinning and ring exposure.24 A less invasive technique that shows promise is combined riboflavinultraviolet type A rays (UVA) collagen cross-linking. This procedure consists of photopolymerization of corneal stroma by combining ­vitamin B2 (photosensitizing substance) with UVA. This process increases rigidity of corneal collagen and thus reduces the likelihood of further ectasia. In a recent study of 60 eyes treated with collagen cross-linking, 31 eyes had a reversal and flattening of the keratoconus

KERATOGLOBUS At least two forms of keratoglobus appear to exist: a congenital or juvenile form and an acquired adult form. The acquired form may be an end-stage form of keratoconus – patients have been described with ­initial keratoconus followed by later keratoglobus – or acquired keratoglobus may be seen with no known prior keratoconus. This form of keratoglobus has been seen in association with vernal keratoconjunctivitis, blepharitis, and orbital diseases that cause proptosis.29 The congenital form appears to be part of at least two different autosomal recessive syndromes. One is Ehlers-Danlos syndrome Type VI. Another clinically similar syndrome, but with normal lysyl hydroxylase activity, is brittle corneal syndrome with associated blue sclera and red hair, which mimics Ehlers-Danlos syndrome Type VI.30 Fig. 4-18-5  Typical inferior thinning of pellucid marginal corneal ­degeneration. Note the subepithelial fibrosis from keratoconus   (which is also present more centrally).

up to 2.87 D. With follow-up at 3 and 5 years, all 60 eyes did not show any progression of the keratoconus.25

COURSE AND OUTCOME Outcomes in terms of graft clarity and improved vision are excellent, ­although residual astigmatism and myopia remain problematic. Despite the proven outcome with keratoplasty, it is still the authors’ belief that contact lens use should be the treatment of choice for most patients who have keratoconus. A recent publication suggested that keratoplasty should be carried out once keratoconus patients do not see well with spectacles, although this approach is controversial.26 The complication of a fixed and dilated pupil after keratoplasty for keratoconus has been described (Urrets-Zavalia syndrome), but it is rare and appears to be related to iris ischemia.27 Recurrence of keratoconus after keratoplasty is rare. Authors have postulated that recurrence could be related to incomplete excision of the cone at the time of surgery, unrecognized keratoconus in the corneal donor, or host cellular activity that causes changes in the donor corneal material.28

PELLUCID CORNEAL DEGENERATION Pellucid marginal corneal degeneration appears to be a variant of ­keratoconus, with some different clinical features. Corneal thinning and protrusion are seen in the inferior peripheral cornea; the thinning begins 1–2 mm inside the inferior limbus in a horizontal oval band approximately 2 mm in radial extent and 6–8 mm in horizontal extent (Fig. 4-18-5). The involved area is clear, and usually no iron line occurs central to it. Hydrops may occur. The central cornea is regular, but usually with marked against-the-rule astigmatism. Some patients who have pellucid may have more typical central corneal changes of keratoconus, as may family members, although the inheritance of pellucid is not clear. Pathology appears to be the same as in keratoconus. Treatment, as for keratoconus, consists of spectacles or contact lenses. When these are insufficient, results are best found with large, eccentric penetrating keratoplasty. Lamellar keratoplasty, thermokeratoplasty, and corneal imbrication have all been reported as treatments that have limited success.

OCULAR MANIFESTATIONS

Keratoconus and Other Ectasias

EPIDEMIOLOGY AND PATHOGENESIS

4.18

Keratoglobus is a disorder characterized by the presence of limbus-tolimbus corneal thinning with globular corneal protrusion. Usually the thinning is greatest in the corneal periphery or midperiphery. Hydrops occurs not infrequently, and perforations may occur with relatively minor trauma. In Ehlers-Danlos syndrome Type VI, patients have diffuse corneal thinning with corneal rupture spontaneously or after minor trauma, and corneal hydrops also is common. Blue sclera is present and is most apparent over the ciliary body; it creates a “blue halo” around the limbus. These patients may have systemic connective tissue abnormalities as well, with hyperextensible joints, bone anomalies, and hearing loss.31 A defect in lysyl hydroxylase activity is present.

PATHOLOGY Pathology of acquired keratoglobus is similar to that of keratoconus, whereas congenital keratoglobus shows an absence of Bowman’s membrane, stromal disorganization, and thickening of Descemet’s membrane with breaks.32

TREATMENT Treatment includes protection from trauma. Lamellar epikeratoplasty has been used successfully to reinforce thin corneas and, in some cases, to improve vision.33 For acquired keratoglobus, large penetrating keratoplasty may be successful.

POSTERIOR KERATOCONUS Posterior keratoconus refers to a congenital corneal anomaly in which the posterior corneal surface protrudes into the stroma, which usually occurs in a localized area, but may be more diffuse. This disorder usually is sporadic, unilateral, and is nonprogressive. Bilateral and familial cases do occur but are less frequent. Often, the anterior corneal contour is affected minimally, although anterior protrusion and even a surrounding iron line have been described. Frequently, scarring occurs in the stroma anterior to the Descemet’s bulge. On pathologic examination, scarring at the level of Bowman’s membrane is seen and thinning of Descemet’s membrane with excrescences has been reported variably.34 The Descemet’s membrane changes and congenital nature of this disorder suggest that it is a variant of corneal mesenchymal dysgenesis. Treatment usually is not necessary, although occasionally keratoplasty is indicated.

REFERENCES   1. Kenney MC, Chwa M, Atilano SR, et al. Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Invest Ophthalmol Vis Sci. 2005;46:823–32.   2. Nielsen K, Heegaard S, Vorum H, et al. Altered expression of CLC, DSG3, EMP3, S100A2, and SLPI in corneal epithelium from keratoconus patients. Cornea. 2005;24:661–8.   3. Nielsen K, Vorum H, Fagerholm P, et al. Proteome profiling of corneal epithelium and identification of marker proteins for keratoconus, a pilot study. Exp Eye Res. 2006;82:201–9.

  4. Rabinowitz YS, Dong L, Wistow G. Gene ­expression ­profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin Five. Invest ­Ophthalmol Vis Sci. 2005;46:1239–46.   5. Maruyama Y, Wang X, Li Y, et al. Involvement of sp1 elements in the promoter activity of genes ­affected in keratoconus. Invest Ophthalmol Vis Sci. 2001;42:1980–5.   6. Bron AJ. Keratoconus. Cornea. 1988;7:163–9.

  7. Karseras AG, Ruben M. Aetiology of keratoconus.   Br J Ophthalmol. 1976;60:522–5.   8. Macsai MS, Varley GA, Krachmer JH. Development of ­keratoconus after contact lens wear: patient ­characteristics. Arch Ophthalmol. 1990;108:534–8.   9. Wilson SE, Yu Guang HE, Weng J, et al. Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing. Exp Eye Res. 1996;62:325–37.

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302

10. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol. 1986;101:267–73. 11. Nesburn AB, Bahri S, Salz J, et al. Keratoconus detected by videokeratography in candidates for photorefractive keratectomy. J Refractive Surg. 1995;11:194–201. 12. Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refractive Surg. 1995;11:371–9. 13. Gonzalez V, McDonnell PJ. Computer-assisted corneal topography in parents of patients with keratoconus. Arch Ophthalmol. 1992;110:1412–4. 14. Rahi A, Davies P, Ruben M, et al. Keratoconus and coexisting atopic disease. Br J Ophthalmol. 1977;61:761–4. 15. Cullen JF, Butler HG. Mongolism (Down’s syndrome) and keratoconus. Br J Ophthalmol. 1963;47:321–30. 16. Pouliquen Y. Doyne lecture: keratoconus. Eye. 1987;1:1–4. 17. Dana MR, Putz JS, Viana MAG, et al. Contact lens failure in keratoconus management. Ophthalmology. 1992;99:1187–92. 18. Waller SG, Steinert RF, Wagoner MD. Long-term results of epikeratoplasty for keratoconus. Cornea. 1995;14:84–8.

19. Eye Bank Association of America. 2000 statistical report. Washington: Eye Bank Association of America; 2001. 20. Wilson SE, Bourne WM. Effect of recipient-donor trephine size disparity on refractive error in keratoconus. Ophthalmology. 1989;96:299–305. 21. Shimmura S, Tsubota K. Deep anterior lamellar keratoplasty. Curr Opin Ophthalmol. 2006;17:349–55. 22. Colin J, Cochenee B, Savary G, et al. Intacs inserts for treating keratoconus: one-year results. Ophthalmology. 2001;108:1409–14. 23. Colin, J. European clinical evaluation: Use of Intacs for the treatment of keratoconus. J Cataract Refract Surg. 2006;32:747–55. 24. Kanellopoulos AJ, Pe LH, Perry HD, et al. Modified intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: efficacy and complications. Cornea. 2006;25:29–33. 25. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356–60. 26. Buzard KA, Fundisland BR. Corneal transplant for keratoconus: results in early and late disease. J Cataract Refractive Surg. 1997;23:398–406.

27. Tuft SJ, Buckley RJ. Iris ischaemia following penetrating keratoplasty for keratoconus (Urrets-Zavalia syndrome). Cornea. 1995;14:618–22. 28. Bechrakis N, Blom ML, Stark WJ, Green WR. Recurrent keratoconus. Cornea. 1994;13:73–7. 29. Cameron JA. Keratoglobus. Cornea. 1993;12:124–30. 30. Royce PM, Steinmann B, Vogel A, et al. Brittle cornea syndrome: an heritable connective tissue disorder distinct from Ehlers-Danlos syndrome type VI and fragilitas oculi, with spontaneous perforations of the eye, blue sclerae, red hair, and normal collagen lysyl hydroxylation. Eur   J Pediatr. 1990;149:465–9. 31. Cameron JA. Corneal abnormalities in Ehlers-Danlos syndrome type VI. Cornea. 1993;12:54–9. 32. Pouliquen Y, Dhermy P, Espinasse MA, et al. Keratoglobus. J Fr Ophthalmol. 1985;8:43–54. 33. Cameron JA, Cotter JB, Risco JM, Alvarez H. Epikeratoplasty for keratoglobus associated with blue sclera. Ophthalmology. 1991;98:446–52. 34. Al-Hazzaa SAF, Specht CS, McLean IW, Harris DJ. ­Posterior keratoconus: case report with scanning   electron microscopy. Cornea. 1995;14:316–20.

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 6 Corneal Diseases

Anterior Corneal Dystrophies Bryan Edgington and Michael H. Goldstein

Recurrent Erosion Syndrome – Anterior Basement Membrane Dystrophy ­(Cogan’s microcystic, Map-Dot-Fingerprint, ­Epithelial Basement Membrane) Definition:  Recurrent breakdown of the corneal epithelium.

Key features n n n

Usually bilateral. Involves corneal epithelium. Discomfort typically occurs first thing in the morning.

Associated features n n

May be asymptomatic. Important to screen for as part of the preoperative refractive surgery evaluation.

Post-traumatic Key features n n

History of trauma or epithelial injury (fingernail injury is common). Typically unilateral.

Associated features n n

Inciting trauma may be minor and not remembered by the patient. Common in patients with diabetes mellitus.

Meesman’s Epithelial Dystrophy Definition:  Epithelial corneal dystrophy with microcysts and “peculiar substance” on electron microscopy.

Key features n n n n

Rare. Autosomal dominant, bilateral. Microvesicles seen on indirect slit or retroillumination. Symptoms mild or nonexistent, corneal erosions are uncommon

4.19

Associated features n n

Surgical intervention rarely needed. Recurrences in the corneal graft following keratoplasty have been described.

INTRODUCTION Most corneal dystrophies are autosomal dominant, bilateral disorders that primarily affect one layer of an otherwise normal cornea, progress slowly after their appearance in the first or second decade, and are not associated with any systemic disease. Epithelial dystrophies are characterized by intraepithelial cysts and abnormal basement membrane.1 The distinctive clinical appearance of most corneal dystrophies allows accurate diagnosis based on clinical grounds. Transmission electron microscopy is the most accurate method for histopathologic diagnosis.1 Genetic studies on the corneal dystrophies provide insight at a basic molecular level and are assisting in refining the classification systems. Several corneal dystrophies have been found to be closely related at the molecular level with different phenotypes resulting from mutations within the same gene. For example, the BIGH3 gene on chromosome 5q31 is associated with granular corneal dystrophy (Type I, II, and III), lattice corneal dystrophy (Type I, IIIA, IIIA-like, and IV), and corneal dystrophy of Bowman’s (Type I and II).2

RECURRENT EROSION SYNDROME – ANTERIOR BASEMENT MEMBRANE DYSTROPHY Anterior basement membrane dystrophy (ABMD) is the most common anterior corneal dystrophy. It is seen frequently in the clinic.1 A familial pattern has been described for ABMD,3 but many patients with the disorder will not have a known family history. Most patients describe mild pain on awakening, but larger erosions can cause severe pain. Patients also note blurred vision or occasionally monocular diplopia or image ghosting. The clinical symptoms overlap considerably with recurrent erosions secondary to trauma. Recurrent erosions are equally divided between ABMD and trauma.4 In some cases, both entities are present and the diagnosis of ABMD is made by carefully examining the unaffected eye after trauma. In both conditions, recurrent erosions are felt to be secondary to friability of the superficial epithelium due to poor adhesion of epithelial cells to each other as well as to the underlying basement membrane.5, 6 ABMD is characterized by several changes apparent in the anterior cornea on slit-lamp examination. They are often best seen with a dilated pupil and retroillumination. Subtle cases can be detected by looking for negative staining using cobalt blue filter after the application of fluorescein (Fig. 4-19-1). Changes found with ABMD include intraepithelial microcysts (dots) (Fig. 4-19-2), map-like grayish patches, and fingerprint parallel lines (Fig. 4-19-3).7–9 Given the appearance, ABMD is often called map-dot-fingerprint corneal dystrophy. It is also referred to as Cogan’s microcystic dystrophy when only microcysts are present. Confocal microscopy has been investigated as a supplemental examination tool, particularly for corneas with a history of erosions that appear to be normal on clinical examination. Corneas with recurrent erosions or epithelial basement membrane dystrophy showed deposits in basal epithelial cells, sub-basal microfolds and streaks, damaged sub-basal nerves, or altered morphology of the anterior stroma.10, 11

303

4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-19-1  Area of epithelial thickening, demonstrating negative staining, in a patient with anterior basement membrane dystrophy. (Courtesy of Anthony J. Aldave, MD.)

Fig. 4-19-3 Prominent epithelial map lines in a patient with epithelial basement membrane dystrophy. (Courtesy of Anthony J. Aldave, MD.)

30 gauge needles.15 Micropuncture should be used with great care for erosions in the visual axis. PTK is a safe and effective procedure for recurrent corneal erosions (trauma and ABMD) refractory to conventional treatment. The rate of recurrence of erosions in ABMD treated with PTK is low (14%) during a 12-month follow-up period.16 On average, recurrences occurred after 6–9 months.17 In many patients, visual fluctuation and monocular diplopia or “ghost images” resolved. A hyperopic shift can be an adverse side effect in some individual cases.18 It is possible to combine PTK with PRK in select patients.19–21 ABMD has been reported as a risk for increasing complication rates after laser-assisted in situ keratomileusis (LASIK) (including epithelial defect and epithelial ingrowth), so these patients are better photorefractive keratectomy (PRK) candidates.22 Diamond burr superficial keratectomy (DB) appears to be an effective and safe method of treating recurrent erosions (both post-traumatic and ABMD). There is no refractive shift with this method.23 As an alternative to diamond burr, an Amoils epithelial scrubber may be used to débride the epithelium and buff Bowman’s layer.24 Diamond burr is simple, office-based, and inexpensive, so it may be the preferred technique in some settings.25 Fig. 4-19-2 Opaque epithelial cysts in a patient with epithelial basement membrane dystrophy. (Courtesy of Anthony J. Aldave, MD.)

The clinical appearance of ABMD corresponds well with the pathology. Specimens from affected patients show protrusions of basement membrane, microcysts of degenerated cellular material, and refractile striae. There is often a bilaminate subepithelial layer of fibrogranular material.1, 5, 6 The majority of patients with recurrent corneal erosions will respond to conventional forms of therapy such as topical lubricants, patching, débridement, or bandage soft contact lenses.12 Topical hyperosmotic solutions are well tolerated and appear effective in treating ­ recurrent corneal erosion in some cases.13 Therapy with a combination of ­medications that inhibit metalloproteinase-9 (topical steroid and oral doxycycline) may produce rapid resolution and help prevent further recurrence in cases unresponsive to conventional therapies.14 In some cases, surgical intervention will be required. Anterior micropuncture, superficial keratectomy, and excimer laser ablation (phototherapeutic keratectomy, PTK) have all been used extensively.4 Anterior stromal puncture was the first to be described, and presumably stimulates more secure epithelial adhesion to the underlying stroma.12 Some authors recommend the use of 23 or 25 gauge needles instead of

304

MEESMAN’S EPITHELIAL DYSTROPHY Meesman’s epithelial dystrophy is a rare, bilateral condition confined to the corneal epithelium. It is an autosomal dominant disorder that leads to fragility of the anterior corneal epithelium. It has been linked to ­ mutations in corneal keratin (K3 and K12) that are specifically ­expressed in the epithelium and not in other layers.26–29 Symmetric intraepithelial microcysts appear in the first few years of life and are visible only at the slit lamp. They are concentrated within the visual axis and mid-periphery. They are best seen with indirect illumination or retroillumination. Symptoms are usually mild or nonexistent, but patients may report recurrent erosions or minimal loss of visual acuity. These can usually be treated with topical lubricants. Surgical intervention is rarely needed. Histological examination shows two characteristic findings in the corneal epithelium – intracellular “peculiar substance” and intraepithelial microcysts. The epithelial cells are rich in glycogen and many contain the fibrogranular “peculiar substance,” possibly derived from tonofilaments.30, 31 There are tiny cysts containing cellular debris.30–32 There is also a nonspecific thickening of the epithelial basement membrane.­30, 32 There is no apparent modification of Bowman’s layer or superficial stroma.30 A case report of a recurrence after penetrating keratoplasty confirmed that the pathology is limited to the corneal epithelium.31

REFERENCES 13. Foulks GN. Treatment of recurrent corneal erosion and corneal edema with topical osmotic colloidal solution. Ophthalmology. 1981;88:801–3. 14. Dursun D, Kim MC, Solomon A, Pflugfelder SC. Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids. Am J Ophthalmol. 2001;132: 8–13. 15. Katsev DA, Kincaid MC, Fouraker BD, et al. Recurrent corneal erosion: pathology of corneal puncture. Cornea. 1991;10:418–23. 16. Cavanaugh TB, Lind DM, Cutarelli PE, et al. Phototherapeutic keratectomy for recurrent erosion syndrome in anterior basement membrane dystrophy. Ophthalmology. 1999;106:971–6. 17. Dinh R, Rapuano CJ, Cohen EJ, Laibson PR. Recurrence of corneal dystrophy after excimer laser phototherapeutic keratectomy. Ophthalmology. 1999;106:1490–7. 18. Orndahl MJ, Fagerholm PP. Phototherapeutic keratectomy for map-dot-fingerprint corneal dystrophy. Cornea. 1998;17:595–9. 19. Ho CL, Tan DT, Chan WK. Excimer laser phototherapeutic keratectomy for recurrent corneal erosions. Ann Acad Med Singapore. 1999;28:787–90. 20. Jain S, Austin DJ. Phototherapeutic keratectomy for treatment of recurrent corneal erosion. J Cataract Refract Surg. 1999;25:1610–4. 21. Zaidman GW, Hong A. Visual and refractive results of combined PTK/PRK in patients with corneal surface disease and refractive errors. J Cataract Refract Surg. 2006;32:958–61. 22. Dastgheib KA, Clinch TE, Manche EE, et al. Sloughing of corneal epithelium and wound healing complications associated with laser in situ keratomileusis in patients with epithelial basement membrane dystrophy. Am J Ophthalmol. 2000;130:297–303.

23. Soong HK, Farjo Q, Meyer RF, Sugar A. Diamond burr superficial keratectomy for recurrent corneal erosions. Br J Ophthalmol. 2002;86:296–8. 24. Hodkin MJ, Jackson MN. Amoils epithelial scrubber to treat recurrent corneal erosions. J Cataract Refract Surg. 2004;30:1896–901. 25. Sridhar MS, Rapuano CJ, Cosar CB, et al. Phototherapeutic keratectomy versus diamond burr polishing of Bowman’s membrane in the treatment of recurrent corneal erosions associated with anterior basement membrane dystrophy. Ophthalmology. 2002;109: 674–9. 26. Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann’s corneal dystrophy. Nat Genet. 1997;16:184–7. 27. Nichini O, Manzi V, Munier FL, Schorderet DF. Meesmann corneal dystrophy (MECD): report of 2 families and a novel mutation in the cornea specific keratin 12 (KRT12) gene. Ophthalmic Genet. 2005;26:169–73. 28. Corden LD, Swensson O, Swensson B, et al. A novel keratin 12 mutation in a German kindred with Meesmann’s corneal dystrophy. Br J Ophthalmol. 2000;84: 527–30. 29. Coleman CM, Hannush S, Covello SP, et al. A novel mutation in the helix termination motif of keratin K12 in a US family with Meesmann corneal dystrophy. Am J Ophthalmol. 1999;128:687–91. 30. Tremblay M, Dube I. Meesmann’s corneal dystrophy: ultrastructural features. Can J Ophthalmol. 1982;17: 24–8. 31. Chiou AG, Florakis GJ, Copeland RL, et al. Recurrent Meesmann’s corneal epithelial dystrophy after penetrating keratoplasty. Cornea. 1998;17:566–70. 32. Fine BS, Yanoff M, Pitts E, Slaughter FD. Meesmann’s epithelial dystrophy of the cornea. Am J Ophthalmol. 1977;83:633–42.

4.19 Anterior Corneal Dystrophies

  1. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman’s layer and stroma. Surv Ophthalmol. 1978;23:71–122.   2. Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol. 1999;128:747–54.   3. Laibson PR, Krachmer JH. Familial occurrence of dot (microcystic), map, fingerprint dystrophy of the cornea. Invest Ophthalmol. 1975;14:397–9.   4. Reidy JJ, Paulus MP, Gona S. Recurrent erosions of the cornea: epidemiology and treatment. Cornea. 2000;19:767–71.   5. Ghosh M, McCulloch C. Recurrent corneal erosion, microcystic epithelial dystrophy, map configurations and fingerprint lines in the cornea. Can J Ophthalmol. 1986;21:246–52.   6. Dark AJ. Cogan’s microcystic dystrophy of the cornea: ultrastructure and photomicroscopy. Br J Ophthalmol. 1978;62:821–30.   7. Cogan DG, Donaldson DD, Kuwabara T, Marshall D. Microcystic dystrophy of the corneal epithelium. Trans Am Ophthalmol Soc. 1964;62:213–25.   8. Guerry D. Observations on Cogan’s microcystic dystrophy of the corneal epithelium. Am J Ophthalmol. 1966;62:65–73.   9. Levitt JM. Microcystic dystrophy of the corneal epithelium. Am J Ophthalmol. 1971;72:381–2. 10. Rosenberg ME, Tervo TMT, Petroll WM, Vesaluoma MH. In vivo confocal microscopy of patients with corneal recurrent erosion syndrome or epithelial basement membrane dystrophy. Ophthalmology. 2000;107:565–73. 11. Hernandez-Quintela E, Mayer F, Dighiero P, et al. Confocal microscopy of cystic disorders of the corneal epithelium. Ophthalmology. 1998;105:631–6. 12. McLean EN, MacRae SM, Rich LF. Recurrent erosion. Treatment by anterior stromal puncture. Ophtha lmology. 1986;93:784–8.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 6 Corneal Diseases

4.20

Stromal Corneal Dystrophies Joel Sugar and Hormuz P. Wadia

Definition:  A corneal dystrophy is an inherited, usually bilateral  

disorder in which typically an abnormal substance accumulates in   the cornea.

Key features n n n

 haracteristically bilateral. C Progressive. Isolated to the cornea.

Associated findings n n

 sually autosomal dominant. U Not associated with systemic disease, with rare exceptions.

INTRODUCTION A corneal dystrophy is classically bilateral, progressive, and isolated to the cornea. The disorder is inherited, characteristically in a dominant fashion, and often appears clinically to involve only one layer of the cornea. With the progressive identification of genes involved in these entities, much hope exists that a better pathophysiological understanding and ultimately better treatment will be developed for these diseases. The epithelial and endothelial dystrophies are discussed in their respective chapters.

ANTERIOR MEMBRANE DYSTROPHIES The anterior membrane dystrophies involve Bowman’s layer and involve the epithelium as well. The category anterior membrane is arbitrary, since many of the stromal dystrophies also involve Bowman’s layer and epithelium. The genetic understanding of these disorders makes this classification even less appropriate and many of these conditions will ultimately be better classified and named by their specific biochemical defects (Table 4-20-1).

Dystrophy

Defect

Reis-Bücklers’

Arg555Gly, Arg124Leu, Arg555Gln

Thiel-Behnke

Arg124Leu (other families chromosome 10)

Lattice I

Arg124Lys

Lattice IIIA

Arg124Thr, Pro501Thr

Lattice IV

Leu527Arg

Granular I

Arg555Trp, Arg124Ser

Granular II (Avellino)

Arg124His

Ocular Manifestations

Reis-Bücklers’ dystrophy is characterized by recurrent painful corneal epithelial erosions that often begin in the first 1–2 years of life. Minimal corneal changes are seen at first, but then ring and map-like opacities appear at the level of Bowman’s membrane; these become denser and more irregular over time (Fig. 4-20-1). By the second or third decade of life the painful erosions diminish as corneal sensitivity decreases, but the increasing fibrosis results in visual difficulty.

Pathology

Pathology shows eosinophilic and fibrotic material beneath the corneal epithelium and within the anterior stroma, with destruction of Bowman’s membrane. The material is somewhat granular in appearance. Electron microscopy shows rod-shaped bodies that replace Bowman’s layer and lie between epithelial cells. These pathological findings are the same as those seen in superficial granular dystrophy.

Treatment

REIS-BÜCKLERS’ DYSTROPHY

Treatment of Reis-Bücklers’ dystrophy is symptomatic for the recurrent erosions. Superficial keratectomy, either by mechanical stripping or by excimer laser ablation, is the appropriate treatment for the visual disturbance. Recurrence may be relatively rapid and keratoplasty may become necessary after multiple treatments.

Introduction

HONEYCOMB DYSTROPHY

“True” Reis-Bücklers’ dystrophy, also known as corneal dystrophy of Bowman’s I (CDB I) or granular dystrophy type III, is discussed here. Grayson-Willbrandt and Stocker-Holt dystrophies appear to be variants of Reis-Bücklers’ dystrophy.

Epidemiology and Pathogenesis

306

   TABLE 4-20-1  CORNEAL DYSTROPHIES DUE TO KERATOEPITHELIN GENE DEFECTS

The cause of Reis-Bücklers’ dystrophy is unknown (see the “Avellino Dystrophy” section). It is autosomal dominant in inheritance and has been linked to a specific defect in the keratoepithelin gene on chromosome 5q. An arginine replaced by a glycine at codon 555 has been found in most families with this disorder, although other defects have been found in other families.1,2 No systemic associations are known. The diagnosis is made on the basis of clinical appearance, although differentiation from honeycomb dystrophy is often difficult.

Also known as Thiel-Behnke dystrophy, Waardenburg and Jonkers dystrophy, or corneal dystrophy of Bowman’s membrane II (CDB II), honeycomb dystrophy is often confused in the literature with Reis-Bücklers’ dystrophy. Patients have recurrent erosions, although less severe than those associated with Reis-Bücklers’ dystrophy, and develop a ­reticular array of anterior stromal opacities that elevate the corneal epithelium in a “saw-tooth” pattern. The disorder is inherited as an autosomal dominant. A defect has been found in the keratoepithelin gene.3 In other families, a defect has been found on chromosome 10. No known associated systemic abnormality exists. Histopathology shows wavy, subepithelial fibrosis with disruption of Bowman’s layer and epithelial basement membrane. Electron microscopy reveals that curly collagen filaments replace Bowman’s layer.4 Treatment is the same as for

4.20

Fig. 4-20-2  Lattice dystrophy Type I. This patient has very fine, rod-like   opacities in the anterior stroma.

Stromal Corneal Dystrophies

Fig. 4-20-1  Reis-Bücklers’ corneal dystrophy. Note the irregular opacities at the level of Bowman’s layer.

Reis-Bücklers’ dystrophy, namely superficial keratectomy or excimer ablation. Keratoplasty may become necessary after multiple ­recurrences.

SUPERFICIAL GRANULAR DYSTROPHY Superficial granular dystrophy is likely a variant of Reis-Bücklers’ dystrophy and has been referred to as granular dystrophy type III. It occurs less frequently with recurrent erosions but may occur early in life with photophobia and decreased vision. Histopathology and electron microscopy findings are the same as those for Reis-Bücklers’ dystrophy. Some family members of patients who have this entity have a more typical stromal granular dystrophy. Treatment consists of excimer ablation or lamellar keratoplasty.

STROMAL DYSTROPHIES introduction

Fig. 4-20-3  Lattice dystrophy Type I. Denser, ropier opacities than those shown in Fig. 4-20-2.

The stromal dystrophies are classified as such because they appear to accumulate material predominantly in the stroma. Nonetheless, like anterior membrane dystrophies, strong evidence exists that in at least some of these disorders, the epithelium plays a significant role. Lattice dystrophy is a term given to a subgroup of stromal dystrophies. All the lattice dystrophies have amyloid accumulation in the stroma, often arranged in a branching pattern.

LATTICE DYSTROPHY TYPE I Ocular Manifestations

The most frequently found lattice dystrophy is Type I, which has been referred to as Biber-Haab-Dimmer corneal dystrophy. Rod-like glassy opacities appear in the anterior stroma in the first or second decade of life and become denser over time; linear, often branching, opacities are seen (Figs 4-20-2 and 4-20-3). Recurrent erosions often occur and over time central anterior stromal haze may develop. The opacities usually are most dense anteriorly and centrally with a clear zone in the corneal periphery. The lines are relatively fine, as opposed to the more ropy opacities seen in lattice dystrophy Type III. While the disorder is bilateral, asymmetry is found and occasional unilateral involvement may occur.

Diagnosis

Diagnosis of lattice dystrophy Type I is based on clinical appearance. Inheritance is autosomal dominant and the disorder has been demonstrated to be due to defects at various codons on the BIGH3 (keratoepithelin) gene. The most frequent defect is at codon 124 where the amino acid arginine is replaced by cysteine.5

Pathology

Histopathologically, dense deposits are seen in the stroma, which stain with Congo red, periodic acid-Schiff, and Masson’s trichrome (Fig. 4-20-4). Dichroism and birefringence are seen with polarized light and fluorescence is seen with thioflavin-T. All of these findings are characteristic for amyloid, a β-pleated protein structure. The amyloid appears to be distinct from that seen in Type II lattice dystrophy.6 Some granular deposits, typical of those seen in granular dystrophy, have been described

Fig. 4-20-4  Lattice dystrophy Type 1. Histopathology using Congo red stain shows the amyloid accumulations throughout the stroma (arrows).

in histopathologic evaluations of specimens of patients who have lattice dystrophy Type I.7

Treatment

Treatment consists of soft contact lenses for corneal epithelial erosion. When acuity decreases significantly, penetrating keratoplasty is the treatment of choice. Recurrence is common and may respond to phototherapeutic keratectomy using the excimer laser. This same modality is of benefit in some early cases as an alternative to keratoplasty. Recent interest in a keratoplasty technique known as deep anterior lamellar keratoplasty (DALK) has gained popularity. There have been favorable

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4 CORNEA AND OCULAR SURFACE DISEASES

outcomes with this procedure in diseases that do not affect the endothelium such as keratoconus.8 A comparative study looking at PKP versus DALK in 84 eyes with lattice corneal dystrophy or macular corneal dystrophy (mean follow-up of 29 months) showed that final BCVA was similar for both procedures. However, while PKP and DALK had similar endothelial cell loss rates in lattice corneal dystrophy, the macular corneal dystrophy group that underwent DALK had progressive loss of endothelial density.9 A theoretical advantage is achieved with keeping the host endothelium intact to decrease the risk of immunologic graft rejection. In addition, with less dependency on steroid use, secondary glaucoma can also be reduced.

LATTICE DYSTROPHY TYPE II Ocular Manifestations

Lattice dystrophy Type II is part of the systemic disorder familial amyloid polyneuropathy Type IV (Finnish type), also known as Meretoja’s syndrome. In this disorder, fine lattice lines extend to the limbus. The lattice lines are not related to corneal nerves, although the sub-basal nerve density is reduced.10 Recurrent erosions are less frequent and visual disturbance is less.

Fig. 4-20-5  Gelatinous drop-like dystrophy. Note the dense mulberry-like subepithelial accumulation. (Courtesy Deepak Edward, MD.)

Systemic Associations

The frequency of glaucoma is increased with lattice dystrophy Type II. In addition, these patients have cranial neuropathy with facial weakness and systemic amyloid deposition. Lattice dystrophy Type II results from a single amino acid substitution in the plasma protein gelsolin, the consequence of a single nucleotide guanine to adenine change on chromosome 9q 32-34, leading to replacement of aspartic acid by asparagine or tyrosine at amino acid 187.6

Pathology

The pathology is similar to lattice dystrophy Type I.

Treatment

Treatment, if necessary, is the same as for lattice dystrophy Type I, although additional consideration must be given to the risk of corneal exposure from the facial neuropathy present in these patients.

LATTICE DYSTROPHY TYPE III Lattice dystrophy Type III is a disorder characterized by the presence of thick, ropy lattice lines in the cornea without corneal erosions. This appears to be autosomal recessive and occurs later than lattice dystrophy Type I, often after 40  years of age. Histopathology shows amyloid deposition in the mid stroma, as well as in the superficial stroma beneath Bowman’s membrane.11 A lattice dystrophy Type IIIA has been described with identical corneal changes, but also the presence of recurrent erosions and a dominant inheritance pattern.12 This disorder is due to a defect in the keratoepithelin gene, demonstrated at various codons (see Table 4-20-1).13 A late onset lattice dystrophy, Type IV, with deep stromal opacities has also been reported.14

GELATINOUS DROP-LIKE DYSTROPHY

308

Gelatinous drop-like dystrophy, also known as familial subepithelial amyloidosis of the cornea, appears to be an autosomal recessive disorder. The majority of reported cases have been from Japan, although some families have been reported in the United States as well as in Europe, Africa, and India. The disorder presents with severe photophobia, tearing, and decreased vision. Gray to white-to-yellow subepithelial nodules appear in the central cornea in the first or second decade of life. Over time these become confluent and give a nubbly, mulberry surface to the cornea (Fig. 4-20-5). Late in the progress of the disorder, superficial vascularization and deeper corneal deposition of amyloid occur. Histopathology shows subepithelial and anterior stromal ­accumulation of amyloid (Fig. 4-20-6).15 The gene responsible appears to be the M1S1 gene on chromosome 1p with a Q118X mutation.16 Treatment consists of superficial keratectomy, which is often repeated every 2  years. Keratoplasty is followed by early recurrences. Other forms of corneal amyloid deposition are seen, including secondary amyloidosis. Degenerative amyloid also occurs and can anatomically resemble lattice dystrophy in polymorphic amyloid corneal ­degeneration.

Fig. 4-20-6  Gelatinous drop-like dystrophy. Histopathology using Congo red stain shows the subepithelial accumulation of amyloid. (Courtesy Deepak Edward, MD.)

GRANULAR CORNEAL DYSTROPHY (GROENOUW TYPE I) Ocular Manifestation

Granular corneal dystrophy is characterized by the presence of discrete opacities in the corneal stroma, with the intervening stroma being clear. The opacities have irregular crumb-like or flake-like shapes and are whitish or slightly glassy in appearance (Fig. 4-20-7). The pattern within a given family appears to be consistent.

Diagnosis

In many patients no symptoms occur, whereas some patients develop recurrent erosions. In the fifth decade or later, some patients develop sufficient visual difficulties to require keratoplasty. The disorder is autosomal dominant and maps to chromosome 5q as does lattice Type I, Reis-Bücklers’, and Avellino dystrophies. The most common defect is Arg555Trp on the BIGH3 (keratoepithelin) gene, although other defects, including those at codon 124, have been found.17 No systemic associations are known.

Pathology

Histopathologic findings show red staining (Fig. 4-20-8) with Masson trichrome18 without Congo red staining, although Congo red staining has been noted around the hyaline granules in some patients.19 Electron microscopy shows electron-dense, rod-like deposits and microfibrils, which are present in keratocytes as well as epithelial cells.20 The material is thought to be phospholipid.

Treatment

Patients who require keratoplasty do well, although the granules recur superficially in the graft, at times in a swirling pattern that suggests the epithelium is the source of the deposits.21 Superficial recurrences may respond to keratectomy or excimer ablation.

4.20 Stromal Corneal Dystrophies

Fig. 4-20-7  Granular dystrophy. Note the more crumb-like opacities in this patient who has sufficient clear cornea to have normal acuity.

Fig. 4-20-9  Macular corneal dystrophy. Note the stromal haze between the denser macular opacities in this 40-year-old woman.

Diagnosis

Decreased vision and photophobia become evident in the second and third decades; keratoplasty is often necessary by the fourth decade. This disorder appears to be the result of a metabolic abnormality in keratan sulfate. Two types have been defined in macular corneal dystrophy. In Type I, typical keratan sulfate is not present in the cornea or in the serum. The material accumulated in the cornea is an abnormal keratan sulfate that alters corneal transparency and hydration. In macular corneal dystrophy Type II, antigenic keratan sulfate is present in both the cornea and the serum. In a Type I patient, characteristic antigenic keratan sulfate is absent in the cartilage as well.23 Clinically and histopathologically, Types I and II are indistinguishable.24 Heterozygote carriers of macular corneal dystrophy Type I have normal serum antigenic keratan sulfate levels.25 Mutations in the carbohydrate sulfotransferase 6 gene (CHST6) on chromosome 16q have been found to cause both types of macular corneal dystrophy.26

Systemic Associations Fig. 4-20-8  Granular corneal dystrophy. Masson trichrome stain shows   accumulation of hyaline material in the corneal stroma and beneath the   epithelium.

AVELLINO DYSTROPHY A dystrophy that combines features of both granular and lattice dystrophies has been described, with the majority of patients from the Avellino region of Italy. This is also referred to as granular dystrophy Type II. These patients have granular deposits in the anterior stroma as well as the presence of lattice-like lines deeper within the stroma. Gray subepithelial haze may develop centrally along with corneal erosions and can reduce visual acuity. The disorder is autosomal dominant with gene ­defects in keratoepithelin (BIGH3) with arginine replaced by histidine at residue 124.17 Histopathology shows superficial, discrete, red granular deposits with Masson trichrome stain, as well as mid-to-deep stromal fusiform deposits with the typical Congo red and other stains (which are characteristic of lattice dystrophy Type I).22 Treatment is the same as for granular and lattice dystrophies.

MACULAR CORNEAL DYSTROPHY Ocular Manifestations

Macular corneal dystrophy is autosomal recessive. Faint anterior stromal white opacities are seen early in life, often in the first decade. The opacities progress over time and a grainy, ground-glass haze becomes evident between the opacities and then throughout the stroma from limbus to limbus (Fig. 4-20-9).

Although abnormalities in keratan sulfate in the blood and in cartilage have been reported, no systemic clinical abnormalities have been found in patients who have macular corneal dystrophy.

Pathology

Pathology shows glycosaminoglycan accumulation within and ­outside stromal keratocytes, beneath the corneal epithelium, and within corneal endothelial cells. This is evident with alcian blue, colloidal iron (Fig. 4-20-10), and periodic acid-Schiff stains. ­Electron microscopy shows intracytoplasmic vacuoles that contain ­glycosaminoglycans.

Treatment

Treatment consists of penetrating keratoplasty and has good outcomes. Recurrence in grafts has been reported, although infrequently.

SCHNYDER CRYSTALLINE DYSTROPHY Ocular Manifestations

Schnyder crystalline dystrophy is an autosomal dominant disorder with variable phenotypic expression. It begins with central subepithelial corneal crystals, often described in a ring pattern (Fig. 4-20-11). The crystals usually are evident in the first decade of life. With advancing age, arcus lipoides and more diffuse stromal haze may emerge. In other patients, however, even in those from the same family, such crystals may not be evident. With advancing age, there is a central corneal haze that becomes more diffuse and dense. This has been called Schnyder crystalline dystrophy sine crystals by Weiss.27 Corneal sensitivity diminishes and acuity decreases from the fourth decade of life. The gene has been localized to chromosome 1p.28

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4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-20-12  Findings typical of central cloudy dystrophy (posterior crocodile shagreen) are shown. Such patients are almost always asymptomatic.

Fig. 4-20-10  Macular corneal dystrophy. Colloidal iron shows accumulation of glycosaminoglycan at all levels of the cornea.

CENTRAL CLOUDY DYSTROPHY Central cloudy dystrophy, also known as central cloudy dystrophy of Francois, has the same clinical appearance as Vogt’s posterior crocodile shagreen, with the exception being that central cloudy dystrophy appears to be dominantly inherited whereas posterior crocodile shagreen appears to be sporadic. These disorders have central corneal haze in a mosaic pattern like crocodile skin that involves the posterior stroma (Fig. 4-20-12). Patients typically are asymptomatic and histopathology shows a “saw-tooth” disarray of the corneal stromal lamellae.32

FLECK DYSTROPHY Fleck dystrophy, also referred to as speckle or Francois-Neeten’s dystrophy or cornea en mouchetee, is autosomal dominant. Patients have discrete, small, white-to-gray opacities, which may be solid in appearance or have clear centers, scattered throughout the stroma. The corneal epithelium and endothelium are uninvolved. Most patients are asymptomatic, although the occasional patient may be photophobic. Pathology shows distention of some keratocytes with membrane-bound vacuoles filled with electron-dense material. Electron microscopy shows staining with oil-red O consistent with the presence of lipid and acid mucopolysaccharide.33 The epithelium and endothelium are normal. No treatment is necessary.

POSTERIOR AMORPHOUS CORNEAL DYSTROPHY Fig. 4-20-11  Schnyder crystalline dystrophy. This patient has a paracentral ring of crystals. (Courtesy Frederick Brightbill, MD.)

Systemic Associations

Systemic hypercholesterolemia is frequent both in affected and unaffected family members. Genu valgum (knock knees) is rarely associated.

Pathology

Histopathology shows oil-red-O positive material throughout the stroma, which is more prominent peripherally, in Bowman’s membrane, and just anterior to Descemet’s membrane. Electron microscopy shows membrane-bound intracellular and extracellular vacuoles that contain electron-dense material throughout the stroma29 and cholesterol clefts that may be seen in the anterior stroma. The accumulated material appears to be phospholipid with esterified and unesterified cholesterol.

Treatment

310

Treatment consists of corneal transplantation when the acuity declines sufficiently, although phototherapeutic keratectomy may be beneficial in some patients.30 Crystals have been reported to diminish after corneal erosions.31

Posterior amorphous corneal dystrophy is a rare disorder, dominantly inherited, and defined by the presence of central and peripheral, deep corneal, gray, broad sheets of opacification.34 Some patients have only peripheral changes (which extend to the limbus); corneal flattening and thinning are associated, and iridocorneal adhesions have been reported. The disorder appears to be nonprogressive, which prompts the ­suggestion that this entity be considered a dysgenesis rather than a dystrophy.35 Pathologic evaluation has shown irregular disorganization of the corneal lamellae anterior to Descemet’s membrane, with lipid deposition in the cytoplasm of some keratocytes.36 A case has also been reported in which subepithelial deposits and a thick collagenous layer posterior to Descemet’s membrane were found.37 Usually, vision is affected only minimally, so treatment is unnecessary. The pathology reports come from two cases that had sufficient visual decrease to warrant keratoplasty.

CONGENITAL HEREDITARY STROMAL ­DYSTROPHY Epidemiology and Pathogenesis

Congenital hereditary stromal dystrophy is present at birth and nonprogressive, so it better fits the category of congenital anomalies. ­Nonetheless, since it is named a dystrophy and resembles many of the dystrophies, it is discussed here.

Ocular Manifestations

Differential Diagnosis

The differential diagnosis includes congenital corneal edema (from congenital hereditary endothelial dystrophy), congenital glaucoma, and posterior polymorphous dystrophy. The absence of epithelial edema and the presence of normal corneal thickness and intraocular pressure, however, exclude these. Corneal haze from metabolic disorders usually is

Pathology

Pathologic evaluation reveals normal epithelium and Bowman’s layer, whereas the stroma shows separation of lamellae with layers of normal fibrillar arrangement separated by loosely packed layers of irregularly arrayed collagen. The collagen fibrils are about half the normal diameter. The normally banded anterior portion of Descemet’s membrane lacks bandings, but the posterior portion of Descemet’s membrane and the endothelium are normal.38

Treatment

Treatment consists of penetrating keratoplasty, usually with good ­outcomes.

4.20 Stromal Corneal Dystrophies

Congenital hereditary stromal dystrophy is a very rare autosomal dominant disorder that is characterized by the presence of bilateral feathery or flaky, white, diffuse stromal clouding, most prominent in the central cornea. The corneal epithelium is normal and no corneal edema occurs. The opacification is present at birth and is nonprogressive. Without treatment visual acuity is reduced significantly and nystagmus may ensue.

less evident at birth, increases over time, and is associated with systemic findings. In congenital hereditary stromal dystrophy, no known systemic abnormalities have been found.

REFERENCES   1. Mullahy JE, Afshari MA, Steinert RF, et al. Survey of patients with granular, lattice, Avellino, and Reis-Bückler’s corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Arch Ophthalmol. 2001;119:16–22.   2. Takahashi K, Murakami A, Okisaka S. Keratoepithelin mutation (R555Q) in a case of Reis-Bückler’s corneal dystrophy. Jpn J Ophthalmol. 2001;44:191.   3. Yee RW, Sullivan LS, Lai HT, et al. Linkage mapping of Thiel-Behnke corneal dystrophy (CDB2) to chromosome 10q 23-q24. Genomics. 1997;46:152–4.   4. Kuchle M, Green WR, Volcker AG, Barraquer J. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis-Bücklers’ and Thiel-Behnke types): a light and electron microscopy study of eight corneas and a review of the literature. Cornea. 1995;14:333–54.   5. Korvatska E, Munier FL, Djemai A, et al. Mutation hot spots in 5q31- linked corneal dystrophies. Am J Hum Genet. 1998;62:320–4.   6. deLaChapelle A, Tolvanen R, Boysen G, et al. Gelsolinderived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187.   Nat Genet. 1992;2:157–60.   7. Folberg R, Stone EM, Sheffield VC, Mathers WD. The relationship between granular, lattice type I and Avellino corneal dystrophies. A histopathologic study. Arch Ophthalmol. 1994;112:1080–5.   8. Watson SL, Ramsay A, Dart JK, et al. Comparison of deep lamellar keratoplasty and penetrating keratoplasty in patients with keratoconus. Ophthalmology. 2004;111:1676–82.   9. Kawashima M, Kawakita T, Den S, et al. Comparison of deep lamellar keratoplasty and penetrating keratoplasty for lattice and macular corneal dystrophies. Am J Ophthalmol. 2006;142:304–9. 10. Rosenberg ME, Tervo TMT, Gullen J, et al. Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type). Invest Ophthalmol Vis Sci. 2001;42:634–41. 11. Hida T, Proia AD, Kigasawa K, et al. Histopathologic and immunological features of lattice corneal dystrophy Type III. Am J Ophthalmol. 1987;104:249–54. 12. Stock EL, Feder RS, O’Grady RB, et al. Lattice corneal dystrophy type III A: Clinical and histopathologic correlations. Arch Ophthalmol. 1991;109:354–8.

13. Kawasaki S, Nishida K, Quantock AJ, et al. Amyloid and Pro 501 Thr-mutated Big-h3 gene product colocalize in lattice corneal dystrophy type IIIA. Am J Ophthalmol. 1999;127:456–8. 14. Fujiki K, Hotta Y, Nakayasu K, et al. A new L527 mutation of the BIGH3 gene in patients with lattice corneal dystrophy with deep stromal opacities. Hum Genet. 1998;103:286–9. 15. Li S, Edward DP, Ratnakar KS, et al. Clinicohistopathological findings of gelatinous droplike corneal dystrophy among Asians. Cornea. 1996;15:355–62. 16. Tsujikawa M, Kurahashi H, Tanaka T, et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat Genet. 1999;21:420–3. 17. Kanishi M, Yamada M, Nakamura Y, Mashima Y.   Immunohistology of keratoepithelin in corneal   stromal dystrophies associated with R124 mutations   of the BIGH3 gene. Curr Eye Res. 2000;21:891–6. 18. Dighiero P, Niel F, Ellies P, et al. Histologic phenotypegenotype correlation of corneal dystrophies associated with eight distinct mutations in the TGFB1 gene. Ophthalmology. 2001;108:818–23. 19. Jones ST, Zimmerman LE. Histopathologic differentiation of granular, macular and lattice dystrophies of the cornea. Am J Ophthalmol. 1961;51:394–410. 20. Rodrigues MM, Streeten BW, Krachmer JA, et al. Microfibrillar protein and phospholipid in granular corneal dystrophy. Arch Ophthalmol. 1983;101:802–10. 21. Lyons CJ, McCartney AC, Kirkness CM, et al. Granular corneal dystrophy: visual results and pattern of recurrence after lamellar or penetrating keratoplasty. Ophthalmology. 1994;101:1812–7. 22. Holland EJ, Daya SM, Stone EM, et al. Avellino corneal dystrophy, clinical manifestations and natural history. Ophthalmology. 1992;99:1564–8. 23. Edward DP, Thonar EJ-MA, Srinivasan M, et al. Macular dystrophy of the cornea, a systemic disorder of keratan sulfate metabolism. Ophthalmology. 1990;97:1194–200. 24. Edward DP, Yue BYJT, Sugar J, et al. Heterogeneity in macular cornea dystrophy. Arch Ophthalmol. 1988;106:1579–83. 25. Jonasson F, Oshima E, Thonar EJ-MA, et al. Macular corneal dystrophy in Iceland: a clinical, genealogic, and immunohistochemical study of 28 patients. Ophthalmology. 1996;103:1111–7.

26. Akama TO, Nishida K, Nakayama J, et al. Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulfotransferase gene. Nat Genet. 2000;26:237–41. 27. Weiss JS. Schnyder crystalline dystrophy sine crystals; recommendation for a revision of nomenclature. Ophthalmology. 1996;103:465–73. 28. Shearman AM, Hudson TJ, Andresen JM, et al. The gene for Schnyder’s crystalline corneal dystrophy maps to human chromosome 1p 34.1-p36. Hum Mol Genet. 1996;5:1667–72. 29. McCarthy M, Innis S, Dubord P, White V. Panstromal Schnyder corneal dystrophy: a clinical pathologic report with quantitative analysis of corneal lipid composition. Ophthalmology. 1994;101:895–901. 30. Paparo LG, Rapuano CJ, Raber IM, et al. Phototherapeutic keratectomy for Schnyder’s crystalline corneal dystrophy. Cornea. 2000;19:343–7. 31. Chern KC, Meisler DM. Disappearance of crystals in Schnyder’s crystalline corneal dystrophy after epithelial erosion. Am J Ophthalmol. 1995;120:802–3. 32. Meyer JC, Quantock AJ, Thonar EJ-MA, et al. Characterization of a central corneal cloudiness showing features of posterior crocodile shagreen and central cloudy dystrophy of Francois. Cornea. 1996;15:347–54. 33. Nicholson DH, Green WR, Cross HT, et al. A clinical and histopathologic study of Francois-Neetens speckled corneal dystrophy. Am J Ophthalmol. 1977;83:544–60. 34. Carpel EF, Sigelman RJ, Doughman DJ. Posterior amorphous corneal dystrophy. Am J Ophthalmol. 1977;83:629–32. 35. Grimm BB, Waring GO, Grimm SB. Posterior amorphous corneal dysgenesis. Am J Ophthalmol. 1995;120:448–55. 36. Johnson AT, Folberg R, Vrabec MP, et al. The pathology of posterior amorphous corneal dystrophy. Ophthalmology. 1990;97:104–9. 37. Roth SI, Mittelman D, Stock EL. Posterior amorphous corneal dystrophy: an ultrastructural study of a variant with histopathologic features of an endothelial dystrophy. Cornea. 1992;11:165–72. 38. Witschel H, Fine BS, Grutzner P, McTigue JW. Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol. 1978;96:1043–51.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 6 Corneal Diseases

Corneal Endothelium

Steven T. Berger, Mark L. McDermott and Harvinder K.S. Atluri

4.21

Definition:  Hexagonal nonreplicating monolayer of neural crest-  derived tissue that regulates the hydration state of corneal stroma.

Key feature n

 tissue containing large quantities of membrane-bound Na+,K+A ATPase with specialized intercellular junctions that establish   a pump–leak process in the maintenance of corneal deturgescence.

Associated feature n

 delicate tissue subject to alteration from age, trauma, systemic A or ocular disease, contact lens wear, surgery, intraocular solutions, and unique dystrophic conditions.

INTRODUCTION The effects of external trauma and of ophthalmic and systemic disease on human corneal endothelium are best understood by reviewing the anatomy and physiology of the adult human endothelium. A comprehensive review of this material can be found in Chapter 4-1.

FUCHS’ DYSTROPHY INTRODUCTION Fuchs’ dystrophy (combined dystrophy) consists of bilateral, noninflammatory, progressive loss of endothelium that results in reduction of vision. The key features are guttae, folds in Descemet’s membrane, stromal edema, and microcystic epithelial edema. Corneal endothelial degeneration is the primary defect; corneal edema is secondary. Associated features are prominent corneal nerves, stromal opacification, recurrent corneal erosions, open-angle glaucoma, female gender, and familial predisposition.

EPIDEMIOLOGY AND PATHOGENESIS

312

Fuchs’ dystrophy is perhaps the most common corneal dystrophy to require keratoplasty, accounting for approximately 15% of all penetrating keratoplasties in the United States in 2000.1 Pedigree analysis suggests that Fuchs’ dystrophy is an inherited dystrophy with an autosomal dominant inheritance pattern.2 A significant variation occurs in expressivity between males and females, with a 4:1 female–male ratio at the time of keratoplasty.3 It is equally common among Whites and Blacks who undergo keratoplasty, but is relatively rare in Asians.4 Development of guttae and the onset of symptoms are more common in middle age.2 Fuchs’ dystrophy patients are believed to have an increased incidence of open-angle glaucoma.5 Short axial length, shallow anterior chamber, and angle-closure glaucoma also have been seen in conjunction with Fuchs’ dystrophy,6 but only rarely has it been associated with keratoconus.7, 8 The progressive loss of endothelial function is primary in nature rather than secondary to any alteration in aqueous humor flow rate9 or constituency.10 Endothelial dysfunction

Fig. 4-21-1  Slit-lamp view of Fuchs’ dystrophy. Note the guttae on the   specularly reflected image of the endothelium.

is ­primarily a result of a reduction in Na+,K+-ATPase pump activity,11 which leads to a reduction in ion flux across the endothelium but the relative maintenance of barrier function throughout the course of the disease.9 Mutations in the gene that codes for the α2 chain of type VIII collagen have been reported in patients with Fuchs’ endothelial dystrophy and in families with posterior polymorphous corneal dystrophy. A ­defect in type VIII collagen may play a role in these disorders.12

OCULAR MANIFESTATIONS The earliest slit-lamp finding in Fuchs’ dystrophy is the presence of excrescences of Descemet’s membrane, called guttae (cornea guttata), in the central corneal endothelium (Fig. 4-21-1). Guttae are not specific for Fuchs’ dystrophy and may be seen in asymptomatic patients and in the setting of uveitis and nonspecific superficial keratopathies. Up to 11% of eyes in patients older than 50  years have guttae.13 Pathologically identical lesions in peripheral Descemet’s membrane are known as Hassall-Henle warts and are part of the normal aging process (see Chapter 4-22). The guttae initially appear on specular reflection as scattered, discrete, isolated dark structures, smaller than an individual endothelial cell.14 An associated fine pigment dusting occurs within the central ­endothelium. At this stage, referred to as stage 1, the patient’s vision is normal, and the stroma and epithelium are uninvolved.13 Over time, these individual excrescences increase in number, enlarge, and may fuse with adjacent guttae to disrupt the normal endothelial monolayer’s specular reflection.14 This produces a roughened surface with a specular reflection similar to beaten metal in appearance. Eventually, this process expands from the center of the cornea to involve the corneal periphery as well. As the disorder progresses, the endothelial monolayer becomes attenuated in thickness, with an increase in average cell size, a decrease in the percentage of hexagons, and an increase in the ­coefficient of variation in cell size. In the last stages of the dystrophy, effacement of the endothelium results in overlying stromal edema. The endothelium becomes unobservable using conventional specular microscopy but still may be seen using confocal microscopy techniques.14

4.21 Corneal Endothelium

A

Fig. 4-21-2  Specular photomicrograph of Fuchs’ dystrophy. Note dark areas that represent guttae adjacent to areas of enlarged endothelial cells. (Spacing   of grid 0.1 mm.)

As endothelial function progressively declines, the fluid ­accumulated in the stroma during night-time lid closure is removed at a ­ reduced rate, which results in significant stromal edema upon awakening.15 This heralds the onset of stage 2.13 Patients note blurred vision, glare, and colored haloes around lights. Initially, the stromal edema is ­localized in front of Descemet’s and behind Bowman’s membranes.16 Eventually the entire stroma swells, taking on a ground-glass appearance. With the increase in corneal thickness, the posterior stroma and Descemet’s membrane are thrown into folds. Vision at this time is variable. With progressive endothelial dysfunction, bulk fluid flow across the cornea results in microcystic and bullous epithelial edema. With involvement of the epithelial layer, the optical quality of the tear–air interface is severely degraded, which produces a profound reduction in vision. With the onset of epithelial edema, basal adhesion complexes become disrupted to produce recurrent corneal erosions. As a slit-lamp marker of recurrent epithelial slough, duplication of basement layers occurs, which creates fingerprint and map changes. If erosions are prominent, a vascular pannus between epithelium and Bowman’s membrane may be induced and results in an anterior stromal haze, with further reduction in vision. This development represents stage 3 of the disease.13 However, the associated secondary fibrotic layer produced within the pannus often reduces or eliminates the painful recurrent epithelial erosions experienced by the patient. With the progressive increase in stromal water content, glycosaminoglycans elute from the stroma,17 causing disorganization of the collagen fibrils, which contributes to additional stromal opacification.

DIAGNOSIS AND ANCILLARY TESTING The earliest observable change suggestive of Fuchs’ dystrophy is the presence of guttae on slit-lamp examination (see Fig. 4-21-1). Specular microscopy gives a photographic record that can be a useful educational aid for the patient (Fig. 4-21-2). Cell counts are readily determined from the micrograph. Subtle stromal edema can be observed using sclerotic scatter techniques. As the disease progresses, corneal pachymetry can be used to document increased corneal thickness over the normal thickness of 0.5  mm centrally. Later, more obvious signs include folds in Descemet’s membrane, stromal haze, microcystic and bullous epithelial edema, subepithelial fibrosis, and pannus formation. When corneal opacification precludes specular microscopy, confocal microscopy can be used to image the endothelium. Pathological changes in Fuchs’ dystrophy can be demonstrated in all corneal layers. Reliable endothelial cell counts can be obtained by confocal microscopy.14, 15

DIFFERENTIAL DIAGNOSIS Differential diagnosis includes posterior polymorphous dystrophy, ­congenital hereditary endothelial dystrophy, aphakic or pseudophakic bullous keratopathy, and Hassall-Henle bodies. No associated systemic diseases exist.13

B

Fig. 4-21-3  Characteristic wart-like bumps present within Descemet’s membrane. (A) Periodic acid-Schiff stain. (B) Scanning electron microscopy shows this better. (Courtesy of Dr. R. C. Eagle, Jr.)

PATHOLOGY Light microscopy shows a thickened Descemet’s membrane, which may be laminated in appearance with buried guttae, guttae on the surface, or devoid of guttae but thickened (Fig. 4-21-3).3 The endothelial layer is attenuated. Transmission electron micrographs of Descemet’s membrane demonstrate an abnormal posterior banded layer and a fibrillar layer, both of which result in gross thickening of Descemet’s membrane. The production of this morphologically abnormal Descemet’s membrane serves as a marker for a dysfunctional endothelium.18 Molecular biological studies of corneal buttons from patients with Fuchs’ dystrophy, using nucleus labeling and electron microscopy techniques, suggest that apoptosis may play an important role in endothelial cell degeneration.19 If further study confirms the role of apoptosis in endothelial cell loss, pharmacological inhibition of apoptosis may be possible.19

TREATMENT Treatment is usually supportive and temporizing until keratoplasty. Medical management includes the use of hypertonic solutions or ointments, decreasing ambient humidity, and use of a hair dryer to ­increase tear evaporation. If intraocular pressure (IOP) is above 20  mmHg (2.67 kPa), attempts to lower it may reduce the force that drives fluid into the stroma. Treatment measures for painful erosions include ­hypertonics, bandage contact lenses, anterior stromal puncture, and conjunctival flaps.

COURSE AND OUTCOME With progressive corneal edema, unrefractory to supportive measures, keratoplasty is usually offered. Long-term results show that graft clarity is close to 90%, and approximately 60% of patients have 20/40 (6/12) or better visual acuity following keratoplasty.20 If the patient is older than 60 years and shows early lens changes, keratoplasty should be combined

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4 CORNEA AND OCULAR SURFACE DISEASES

with cataract extraction.21 Recently, posterior lamellar keratoplasty (also known as endokeratoplasty, deep lamellar keratoplasty, or Descemet’s stripping automated endothelial keratoplasty) has been presented as an alternative to conventional full-thickness corneal transplantation for the treatment of endothelial disorders.22–24 This procedure involves replacing the diseased endothelium and deep stroma with a posterior lamellar disc of tissue and has shown encouraging results in early clinical experience. If interface clarity can be maintained, posterior lamellar keratoplasty ­offers the potential advantages of reduced postoperative astigmatism and visual recovery time and a possible reduction in risk of immune rejection.

CONGENITAL HEREDITARY ENDOTHELIAL DYSTROPHY INTRODUCTION First described by Maumenee25 in 1960, congenital hereditary endothelial dystrophy (CHED) is but one of the many causes of bilateral corneal clouding in full-term infants and usually requires keratoplasty. Key features of this autosomal dominant or recessive condition are a corneal thickness two to three times normal, normal IOP, and normal corneal diameter. Associated features are corneal pannus, nystagmus, and esotropia.

EPIDEMIOLOGY AND PATHOGENESIS Prevalence, incidence, and sex distribution for this disorder are unknown. The onset is usually at birth in a term infant; corneal clouding may be maximal at birth or progress over a period of years. Family pedigree studies support autosomal dominant and recessive forms, as well as sporadic occurrence. Autosomal recessive inheritance is associated with the presence at birth of bilateral corneal edema without photophobia but with nystagmus.26 Autosomal dominant inheritance is associated with the progressive onset of corneal edema 1–2  years postpartum with associated photophobia but without nystagmus.26 Autosomal dominant CHED has been linked to the pericentric region of chromosome 20 within the genetic interval containing the posterior polymorphous dystrophy locus.27 Genetic studies in autosomal recessive pedigrees indicate that the locus for autosomal recessive CHED is distinct from this region of chromosome 20, but it has not yet been identified.27 A related X-linked endothelial dystrophy has been described in males that clinically ­resembles CHED very closely.28 CHED is believed to result from abnormal neural crest cell terminal induction during the late term to perinatal period. At this time, failure to complete final differentiation of the endothelial monolayer occurs, which results in a dysfunctional endothelium.29 This dysfunctional endothelium is believed to have faulty growth regulation mechanisms that lead to accumulation of a functionally abnormal and structurally exaggerated form of posterior nonbanded Descemet’s membrane.30

OCULAR MANIFESTATIONS The usual presentation is bilateral symmetrically edematous, cloudy corneas.26 Examination under anesthesia reveals the corneas to have a diffuse gray-blue ground-glass coloring.26 Corneal thickness is two to three times normal and often greater than 1 mm centrally. Both IOP and horizontal corneal diameter are normal. Rarely, CHED is associated with glaucoma and should be considered if corneal opacification fails to resolve after normalization of IOP.31 Closer examination reveals the texture of the epithelial surface to be irregular, with a diffuse pigskin-like roughness.26 Occasionally, discrete white dots also may be seen in the stroma. In areas where stromal opacification is less dense, Descemet’s membrane appears gray and on specular reflection may have a peau d’orange texture.26 The endothelial layer may or may not be visualized. A fine corneal pannus may be seen, as well as low-grade inflammation.

DIAGNOSIS

314

A tentative diagnosis is usually possible when examination under anesthesia demonstrates the typical bilateral stromal opacification, gross corneal thickening, normal horizontal diameter, normal IOP, and absence of breaks in Descemet’s membrane.

DIFFERENTIAL DIAGNOSIS Differential diagnosis is glaucoma without buphthalmos, posterior polymorphous dystrophy, macular stromal dystrophy, mucopolysaccharidosis, intrauterine infection, and birth trauma from forceps. One family has an association with sensory neural deafness.32

PATHOLOGY Light microscopy shows epithelial atrophy with basal cell hydrops, subepithelial calcification or fibrosis, patchy loss of Bowman’s membrane, and variable vascularization or spheroidal degeneration of the stroma.30 Descemet’s membrane is thickened, often with discrete laminations, and the endothelial layer is attenuated.30

TREATMENT If the edema is stationary and mild, use of hypertonics and desiccating measures may be employed. Usually, however, these patients require keratoplasty due to the bilateral nature of the corneal edema. Keratoplasty in infants and children is a high-risk procedure and is technically difficult, and the long-term prognosis for graft clarity is worse than for adults. No definitive clinical guidelines have emerged regarding the timing of surgical intervention due to significant heterogeneity in disease severity, follow-up periods, and ages at diagnosis and surgery among the few published studies.33 The decision regarding surgery may be difficult, because despite significant corneal haze and absence of a red reflex, patients often seem to see much better than expected.34 If patients maintain good fixation with normal alignment, surgery may be delayed; loss of fixation or development of nystagmus should lead to prompt intervention.34

COURSE AND OUTCOME In one large study, 38% of patients younger than 12 years of age who underwent keratoplasty had haze or opaque grafts at the most recent office visit. In the same study, the 5-year graft survival rate was about 50%.35 First graft survival rates range from 25% at 3  months in earlier studies to 62–90% at 2–3  years in more recent series.33, 34 Visual acuity is always limited by degrees of amblyopia.

POSTERIOR POLYMORPHOUS DYSTROPHY INTRODUCTION First described in 1916 by Koeppe, this rare dystrophy has a clinical spectrum that ranges from congenital corneal edema to late-onset ­corneal edema in middle age. Many cases are subclinical – the majority of ­patients have good vision and only subtle slit-lamp and specular micrographic abnormalities. Posterior polymorphous dystrophy (PPMD) is a bilateral autosomal dominant disorder characterized by polymorphic posterior corneal surface irregularities with variable degrees of corneal decompensation. Key features are: l Vesicular, curvilinear, and placoid irregularities found on slit-lamp examination. l Rounded dark areas with central cell detail that produce a doughnutlike pattern on specular microscopy. l Epithelial-like transformation of endothelium on histological ­examination. l Reduced vision from the corneal edema. Associated features are iridocorneal adhesions, peripheral anterior synechiae, glaucoma, and a tendency to recur in graft patients. Some of these features overlap with iridocorneal endothelial (ICE) syndrome, Peters’ anomaly, and Axenfeld-Rieger syndrome, suggesting that PPMD may be part of a broader spectrum of disorders united by abnormalities of terminal neural crest cell differentiation.36, 37 PPMD associated with posterior amyloid degeneration of the cornea, keratoconus, and Alport’s syndrome has been reported.36, 38, 39

EPIDEMIOLOGY AND PATHOGENESIS The prevalence of this rare disorder in the general population is ­unknown. It is believed to be mainly autosomal dominant with variable penetrance, but cases of autosomal recessive inheritance are seen.40 The

4.21 Corneal Endothelium

Fig. 4-21-5  Slit-lamp appearance of the band form of posterior ­polymorphous dystrophy. Note the vertical serpentine band. (Courtesy of Dr. Richard Yee.) Fig. 4-21-4  Slit-lamp appearance of vesicles in posterior polymorphous dystrophy. Note the small vesicular lesions on retroillumination. (Courtesy of   Dr. Richard Yee.)

autosomal dominant form has been linked to the long arm of chromosome 20.27 The pathogenesis is thought to be due to focal metaplasia of endothelial cells into a population of aberrant keratinized epithelial-like cells.36, 39 Immunohistochemical analyses of these transformed cells show that they contain antigens and cytokeratins that are usually associated with epithelial cells.41 The transformation of a single-cell layer of endothelium into a multilayered epithelium-like tissue is believed to be responsible for the loss of stromal deturgescence, the observed specular microscopic patterns, and the tendency toward synechiae formation. As in Fuchs’ dystrophy, a different defect in the gene that codes for the α2 chain of type VIII collagen has been found.12

OCULAR MANIFESTATIONS The most common finding is isolated vesicles bilaterally, which appear as circular or oval transparent cysts with a gray halo at the level of Descemet’s membrane, best viewed by retroillumination with a widely dilated pupil (Fig. 4-21-4).42 The vesicular or doughnut-like lesions have diameters in the range of 0.2–1 mm.43 They may be few or many, widely separated or clustered close together to create confluent geographic patches. Less common are band-shaped or “snail track” areas, which typically have scalloped edges and are about 1 mm across (Fig. 4-21-5).42 Their length can range from 2 to 10 mm.43 In both vesicular and band presentations, the overlying stroma and epithelium are uninvolved, and vision is normal. The least common slit-lamp finding is placoid or diffuse involvement of the endothelium.42 Patients who have placoid-type PPMD often present with reduced vision. Specular microscopy of the presenting lesions shows them to be sharply demarcated from uninvolved endothelium. In this presentation, Descemet’s membrane and the posterior stroma are hazy, and usually areas of corneal edema and iridocorneal adhesions occur.43 On specular microscopy the vesicles appear as circular dark rings around a lighter, though mottled, center in which some cellular detail is evident.42–46 These vesicles represent steep-sided, shallow depressions in the endothelium42; the steep sides correspond to the peripheral dark ring seen on specular reflection, and the depressed center corresponds to the lighter, mottled central portion (Fig. 4-21-6). Specular microscopy of the band-shaped areas shows them to be composed of a chain of overlapping vesicles, which create a shallow trench with scalloped borders that represent the edges of individual vesicles that have fused.42 Rarely, patients with the typical corneal endothelial changes of PPMD exhibit broad-based iridocorneal adhesions and peripheral anterior synechiae. These are most often seen in corneas with placoid areas of involvement.43 Elevation of IOP refractory to medical measures is common in this group of patients. All patients who have PPMD have reduced endothelial cell counts compared with age-matched controls.42, 44

Fig. 4-21-6  Specular photomicrograph of vesicles in posterior polymorphous dystrophy. Note the doughnut-like appearance of the vesicles. (Courtesy of   Dr. Richard Yee.)

DIAGNOSIS The majority of patients are diagnosed using the slit lamp by observing vesicular, band-like, or placoid areas on the posterior corneal surface. The diagnosis of PPMD in patients with corneal edema of unknown cause is based on light and electron microscopy of the excised buttons obtained during keratoplasty.

DIFFERENTIAL DIAGNOSIS Differential diagnosis includes tears in Descemet’s membrane, interstitial keratitis, Fuchs’ dystrophy, and ICE syndrome (ICE syndrome is discussed in detail in Chapter 10-20). As in PPMD, endothelial cells in ICE syndrome may show epithelial characteristics, leading to speculation that they represent a spectrum of the same disease.37 However, unlike PPMD, ICE syndrome is unilateral, occurs sporadically, is more common in females, and is typically progressive and symptomatic. Glaucoma and iris changes can be found in PPMD but are much more prominent features of ICE syndrome. No systemic associations exist except for rare reports of PPMD associated with Alport’s syndrome.

PATHOLOGY Light microscopy shows pits in the posterior corneal surface, which correspond to the vesicles seen on slit-lamp examination. Descemet’s membrane in these areas is attenuated, and the endothelium may be

315

EPIDEMIOLOGY AND PATHOGENESIS

4 CORNEA AND OCULAR SURFACE DISEASES

Although superficial trauma is common, endothelial trauma is ­fortunately less so. Direct puncture injuries to the anterior cornea, such as those that occur when the cornea is struck by high-velocity small projectiles, may cause annular buckling stress on the ­ endothelium. Buckling of the cornea also can arise as a result of surgical trauma in large incision surgeries, and lens fragments striking the ­ endothelium can cause trauma at cataract surgery. All these injuries represent ­focal destruction of endothelial cells. Sliding in of surrounding healthy ­endothelial cells leads to rapid replacement of the damaged cells, and clinically the changes are no longer evident 1–3  days after injury. In addition to focal endothelial trauma, more severe trauma may rupture Descemet’s membrane. This can occur as a result of severe indentation injuries to the cornea, forceps delivery, or corneal stretching (as with buphthalmos or keratoconus). Descemet’s membrane curls in toward the stroma. Surrounding endothelial cells slide in to cover the defect and produce new Descemet’s membrane. The corneal edema resolves as the endothelial cells fill the defect, which leads to deturgescence of the cornea. Fig. 4-21-7  Light micrograph of keratoplasty button from posterior polymorphous dystrophy (hematoxylin & eosin). Note the multilayered   epithelial-like endothelium and variably attenuated Descemet’s membrane. (Courtesy of Dr. Richard Yee.)

multilayered (Fig. 4-21-7).45, 46 In other areas, Descemet’s membrane appears multilayered, of variable thickness, and with attenuation or loss of endothelium. Discontinuities in Descemet’s membrane with anterior migration of cells to form slit-like structures or clefts in pre-Descemet’s stroma have been described.38 Scanning electron microscopy of keratoplasty buttons may show a striking juxtaposition of ­normal-appearing endothelial cells adjacent to epithelial cell-like areas that show myriad surface microvilli.45, 46 Transmission electron microscopy shows multilayered cells that contain numerous desmosomes and intracytoplasmic filaments.45, 46 Cell culture studies demonstrate features similar to cultured epithelial cell lines.46

TREATMENT The majority of patients require no treatment; those with corneal opacification are offered keratoplasty.

COURSE AND OUTCOME In the majority of patients, PPMD is believed to be a nonprogressive type of dystrophy, usually without vision impairment. Those patients who require keratoplasty appear to be at risk for recurrence of this dystrophy in the grafted cornea,47, 48 as well as for the development of a difficult-to-manage glaucoma.46 It is thought that the genesis of this behavior is due to the epithelial-like transformation and subsequent migration of host endothelium to encroach on donor corneal tissue and host angle structures.46

ENDOTHELIAL TRAUMA

OCULAR MANIFESTATIONS Buckling stress on the endothelium leads to the clinical appearance of a grayish ring on the posterior cornea. Buckling of the cornea may lead to “snail tracks” due to grayish swelling of endothelial cells. Endothelial swelling as a result of trauma appears as dark spots at the level of the endothelium. This also may be seen in eyes with inflammation in the presence of keratic precipitates and in eye bank corneas stored in refrigerated media. The appearance may resemble the guttae in Fuchs’ dystrophy, but it is reversible, more regular in size, and not associated with the presence of pigment. More severe trauma may lead to acute, massive corneal swelling or hydrops.

DIAGNOSIS Diagnosis is based on history and clinical appearance.

DIFFERENTIAL DIAGNOSIS Differential diagnosis includes guttae from Fuchs’ dystrophy and the presence of endothelial keratic precipitates.

PATHOLOGY Specular microscopy shows the endothelial disruption as dark spots. Histopathology is not usually obtained, but with massive trauma leading to keratoplasty, the acute absence of endothelial cells in the area of trauma is seen.

TREATMENT Usually no treatment is necessary, as the surrounding endothelial cells enlarge and slide in to fill the defect. When inflammation is the source of the trauma, anti-inflammatory treatment is appropriate. In acute hydrops, hypertonic saline may be of benefit, and in the presence of persistent edema, keratoplasty may be indicated.

COURSE AND OUTCOME

INTRODUCTION As mentioned in the section on endothelial responses to stress, endothelial trauma can be a significant cause of corneal edema, because endothelial cells that are destroyed cannot be replaced by the production of new cells.

Recovery is usually rapid. However, if a sufficient number of endothelial cells is lost, persistent edema may result. Also, if recovery of corneal compensation occurs, the combination of the acute loss of endothelial cells from trauma and the normal attrition over time may lead to late corneal decompensation.

REFERENCES

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  1. 2000Eye banking statistical report. Washington, DC: Eye Bank Association of America; 2000.   2. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea. 1988;7:2–18.   3. Lang GK, Naumann GOH. The frequency of corneal ­dystrophies requiring keratoplasty in Europe and the USA. Cornea. 1987;6:209–11.

  4. Santo RM, Yamaguchi T, Kanai A, et al.   Clinical and histopathologic features of corneal   dystrophies in Japan. Ophthalmology. 1995;  102:557–67.   5. Kolker AE, Hetherington J Jr.. Becker-Shaffer’s diagnosis and therapy of the glaucomas. 5th ed. St Louis: CV Mosby; 1983:275.

  6. Pitts JF, Jay JL. The association of Fuchs’ corneal endothelial dystrophy with axial hypermetropia, shallow anterior chamber, and angle closure glaucoma. Br J Ophthalmol. 1990;74:601–4.   7. Lipman RM, Rubenstein JB, Torczynski E. Keratoconus and Fuchs’ corneal endothelial dystrophy in a patient and her family. Arch Ophthalmol. 1990;108:993–4.

23. Busin M, Arffa RC, Sebastiani A. Endokeratoplasty as an alternative to penetrating keratoplasty for the surgical treatment of diseased endothelium: initial results.   Ophthalmology. 2000;107:2077–82. 24. Melles GR, Lander F, van Dooren BT, et al. Preliminary clinical results of posterior lamellar keratoplasty through a sclerocorneal pocket incision. Ophthalmology. 2000;107:1850–6. 25. Maumenee AE. Congenital hereditary corneal dystrophy. Am J Ophthalmol. 1960;50:1114–24. 26. Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies. II. Endothelial dystrophies. Surv Ophthalmol. 1978;23:147–67. 27. Kanis AB, Al-Rajhi AA, Taylor CM, et al. Exclusion of AR-CHED from the chromosome 20 region containing the PPMD and AD-CHED loci. Ophthalmic Genet. 1999;20:243–9. 28. Schmid E, Lisch W, Philipp W, et al. A new X-linked endothelial corneal dystrophy. Am J Ophthalmol. 2006;141:478–87. 29. Bahn CF, Falls HF, Varley GA, et al. Classification of   corneal endothelial disorders based on neural crest origin. Ophthalmology. 1984;91:558–63. 30. Kirkness CM, McCartney A, Rice SC, et al. Congenital hereditary corneal oedema of Maumenee: its clinical features, management, and pathology. Br J Ophthalmol. 1987;71:140–4. 31. Mullaney PB, Risco JM, Teichmann K, Millar L. Congenital hereditary endothelial dystrophy associated with glaucoma. Ophthalmology. 1995;102:186–92. 32. Harboyan G, Mamo J, Der Kaloustian V, Karam F. Congenital corneal dystrophy: progressive sensorineural deafness in a family. Arch Ophthalmol. 1981;85:27–32. 33. Schaumberg DA, Moyes AL, Gomes JA, et al. Congenital hereditary endothelial dystrophy. Multicenter Pediatric Keratoplasty Study. Am J Ophthalmol. 1999;127:373–8. 34. Sajjadi H, Javadi MA, Hemmati R, et al. Results of penetrating keratoplasty in CHED: congenital hereditary endothelial dystrophy. Cornea. 1995;14:18–25. 35. Dana M-R, Moyes AL, Gomes JAP, et al. The indications for and outcome in pediatric keratoplasty. Ophthalmology. 1995;102:1129–38. 36. Molia LM, Lanier JD, Font RL. Posterior polymorphous dystrophy associated with posterior amyloid degeneration of the cornea. Am J Ophthalmol. 1999;127:86–8.

37. Anderson NJ, Badawi DY, Grossniklaus HE, et al. Posterior polymorphous membranous dystrophy with overlapping features of iridocorneal endothelial syndrome. Arch Ophthalmol. 2001;119:624–5. 38. Feil SH, Barraquer J, Howell DN, et al. Extrusion of abnormal endothelium into the posterior corneal stroma in a patient with posterior polymorphous dystrophy. Cornea. 1997;16:439–46. 39. Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the pathogenesis of posterior polymorphous dystrophy. Arch Ophthalmol. 1995;113:340–5. 40. Cibis GW, Krachmer JA, Phelps CD, Weingeist TA. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol. 1977;95:1529–37. 41. Ross JR, Foulks GN, Sanfilippo FP, Howell DN. Immunohistochemical analysis of the pathogenesis of posterior polymorphous dystrophy. Arch Ophthalmol. 1995;113:340–5. 42. Laganowski HC, Sherrard ES, Kerr Muir MG. The posterior corneal surface in posterior polymorphous dystrophy: a specular microscopical study. Cornea. 1991;10:224–32. 43. Hirst LW, Waring GO III. Clinical specular microscopy of posterior polymorphous endothelial dystrophy.   Am J Ophthalmol. 1983;95:143–55. 44. Brooks AMV, Gillies WE. Differentiation of posterior polymorphous dystrophy from other posterior corneal opacities by specular microscopy. Ophthalmology. 1989;96:1639–45. 45. Henriquez AS, Kenyon KR, Dohlman KH, et al.   Morphologic characteristics of posterior polymorphous dystrophy: a study of nine corneas and review of the literature. Surv Ophthalmol. 1984;29:139–47. 46. Krachmer JH. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans Am Ophthalmol Soc. 1985;83:413–75. 47. Boruchoff SA, Weiner MJ, Albert DM. Recurrence of posterior polymorphous corneal dystrophy after penetrating keratoplasty. Am J Ophthalmol. 1990;109:323–8. 48. Sekundo W, Lee WR, Aitken DA, Kirkness CM. Multirecurrence of corneal posterior polymorphous dystrophy. Cornea. 1994;13:509–15.

4.21 Corneal Endothelium

  8. Orlin SE, Raber IM, Eagle RC Jr, Scheie HG. Keratoconus associated with corneal endothelial dystrophy. Cornea. 1990;9:299–304.   9. Wilson SE, Bourne WM, O’Brien PC, Brubaker FR. ­Endothelial function and aqueous humor flow rate in patients with Fuchs’ dystrophy. Am J Ophthalmol. 1988;106:270–8. 10. Wilson SE, Bourne WM, Maguire LJ, et al. Aqueous humor composition in Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. 1989;30:449–53. 11. McCartney MD, Wood TO, McLaughlin BJ. Moderate Fuchs’ endothelial dystrophy ATPase pump site density. Invest Ophthalmol Vis Sci. 1989;30:1560–4. 12. Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001;21:2415–23. 13. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea. 1988;7:2–18. 14. Laing RA, Leibowitz HM, Oak SS, et al. Endothelial mosaic in Fuchs’ dystrophy. Arch Ophthalmol. 1981;99:80–3. 15. Mandell RB, Polse KA, Brand RJ, et al. Corneal hydration control in Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. 1989;30:845–52. 16. Adamis AP, Filatov V, Tripathi BJ, Tripathi RC. Fuchs’ endothelial dystrophy of the cornea. Surv Ophthalmol. 1993;38:149–68. 17. Kangas TA, Edelhauser HF, Twining SS, O’Brien WJ. Loss of stromal glycosaminoglycans during corneal edema. Invest Ophthalmol Vis Sci. 1990;31:1994–2002. 18. Levy SG, Moss J, Sawada H, et al. The composition of wide-spaced collagen in normal and diseased Descemet’s membrane. Curr Eye Res. 1996;15:45–52. 19. Borderie VM, Baudrimont M, Vallee A, et al. Corneal   endothelial cell apoptosis in patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. 2000;41:2501–5. 20. Pineros O, Cohen EJ, Rapuano CJ, Laibson PR. Long-term results after penetrating keratoplasty for Fuchs’ endothelial dystrophy. Arch Ophthalmol. 1996;114:15–18. 21. Payant JA, Gordon LW, VanderZwaag R, Wood TO. Cataract formation following corneal transplantation in eyes with Fuchs’ endothelial dystrophy. Cornea. 1990;9:286–9. 22. Terry MA, Ousley PJ. Deep lamellar endothelial keratoplasty in the first United States patients: early clinical results. Cornea. 2001;20:239–43.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 6 Corneal Diseases

4.22

Corneal Degenerations Qais A. Farjo and Alan Sugar

Definition:  Secondary deterioration or deposition in the cornea, distinct from the dystrophies.

Key features n���� n���� n����

 ommon. C Bilateral usually. Typically does not affect vision.

Associated features n���� n���� n���� n

I ncreased prevalence with age. Often associated with chronic light exposure. May follow past inflammation. Not inherited.

A

INTRODUCTION Degenerations of the cornea are common conditions that in most cases have relatively little effect on ocular function and vision. These conditions occur with increasing age, as a result of past inflammation, and with long-term toxic effects of environmental exposure. Unlike corneal dystrophies, corneal degenerations are not inherited, may be unilateral or bilateral, and are often associated with corneal vascularization. ­Degenerations tend to involve the peripheral cornea and may overlap the limbus and conjunctiva. The conditions that occur in the corneal periphery are discussed first, followed by the conditions that occur more centrally. This is an arbitrary division as many conditions, such as spheroidal degeneration or band keratopathy, can be found in either or both locations.

CORNEAL ARCUS (ARCUS SENILIS)

318

Corneal arcus is the deposition in the corneal periphery of a grayto-white or occasionally yellow band of opacity. It comprises fine dots and has a clear zone between it and the limbus, about 0.3 mm wide, known as the clear interval of Vogt. Arcus usually has a diffuse central border and a sharper peripheral border (Fig. 4-22-1). It begins superiorly and inferiorly, gradually spreading to involve the entire corneal periphery but becoming densest and widest superiorly. The deposits occur in the deep stroma initially and later in super­ ficial stroma, with less density in the midstroma. The central extent may show crossing lines of darkness or lessened deposition, similar to the patches seen in the central cornea in crocodile shagreen, discussed later. The arcus is almost always bilateral. It may be asymmetric when carotid vascular disease on one side is associated with decreased arcus or when arcus is increased in eyes with chronic ­hypotony.1 The frequent designation of corneal arcus as arcus senilis recognizes its association with aging. Arcus is the most common of the corneal degenerations. In men, it occurs with increasing frequency from the ages of 40 to 80  years, in 90% of normal men between 70

B

Fig. 4-22-1  Arcus senilis. (A) Corneal arcus in an elderly man. (B) Histologic ­section shows that the lipid is concentrated in the anterior and posterior stroma as two red triangles, apex to apex, with the bases being Bowman’s and ­Descemet’s membranes, both of which are infiltrated heavily by fat (red ­staining), as is the sclera.

and 80 years of age, and in essentially all those older than 80 years. In women a similar pattern is seen, but with a delay of about 10 years.1 The deposits of arcus are made up of extracellular steroid esters of lipoproteins, most of a low density. Lipid material leaks from limbal capillaries, but its central flow is limited by a functional barrier to the flow of large molecules in the cornea, which keeps the deposits in their peripheral location.2, 3 The most important systemic association of corneal arcus is with aging. Also, good evidence exists for an association with increased plasma cholesterol and low-density lipoprotein cholesterol, particularly in men younger than 50  years (arcus juvenilis). Young patients who have ­arcus also have an increased risk for type IIa dyslipoproteinemia but a decreased risk for type IV.4 Men with arcus juvenilis have a fourfold increased relative risk of mortality from coronary heart disease and cardiovascular disease. Arcus in young men therefore is a useful clinical indication for the need for lipid and cardiovascular evaluation.5 In older patients, including those with diabetes, arcus does not correlate with mortality.6

4.22 Corneal Degenerations

Fig. 4-22-2  Dense lipid keratopathy. Note the central and peripheral lipid deposits that followed zoster keratitis with vascularization.

Fig. 4-22-3  Vogt’s limbal girdle. The fimbriated peripheral corneal opacity is visible in the 9 o’clock position (arrow).

LIPID KERATOPATHY

TERRIEN’S MARGINAL CORNEAL DEGENERATION

Lipid keratopathy may be peripheral, central, or diffuse but is discussed here because of its similarity to arcus. It occurs rarely in a primary form and more often in a secondary form. Primary lipid keratopathy has ­ features of a corneal dystrophy. It is usually bilateral and occurs in a previously normal cornea. Central lipid, often with cholesterol crystals, may severely decrease vision and warrant penetrating keratoplasty.7 Secondary lipid keratopathy appears as a white or yellow stromal deposit separated by a narrow, clear zone from corneal stromal neovascularization8 (Fig. 4-22-2). It is often denser than arcus and may appear rather suddenly as a circular deposit at the end of long-standing stromal vessels. Such lipid deposits have been known to follow corneal edema, as in hydrops.9 Histopathologically, the ­material consists of intra- and extracellular lipids, similar to those of arcus.10 Lipid deposition may also occur secondary to systemic disorders in lipid processing. Defects in esterification of cholesterol and in lipo­ protein scavenging of corneal lipid have been implicated in progressive opacification of the cornea in lecithin cholesterol acyltransferase (LCAT) deficiency, Fish-eye disease, and Tangier disease. Disorders of HDL lipoprotein function appear to be important in allowing accumulation of cholesterol centrally within the cornea1.

This condition is described in Chapter 4-17.

VOGT’S WHITE LIMBAL GIRDLE Vogt11 was the first to describe two types of limbal girdle – white, arclike opacities in the cornea central to the limbus in the 3 and 9 o’clock positions. What Vogt described as type I is probably a mild, early form of calcific band keratopathy with a peripheral clear zone and scattered clear holes. The much more common type II lacks a peripheral clear zone between the arc and the limbus and consists of fine, white radial lines, located nasally more often than temporally (Fig. 4-22-3). This condition increases in prevalence with age. It is present in normal eyes in 50% of those who are 40–60  years of age and increases to essentially 100% in those older than 80  years.12 Histologically, Vogt’s limbal girdle type II is made up of hyperelastotic and hyaline deposits peripheral to Bowman’s membrane. These findings are similar to those seen in pinguecula and pterygium.

SENILE CORNEAL FURROW DEGENERATION A peripheral corneal furrow that occurs between corneal arcus and the limbus in the elderly is found, but rarely.11 The lucid interval peripheral to arcus may appear to be furrowed because of the clarity of the ­superficial cornea, but it was considered to be falsely thinned by Vogt.11 Rarely, true thinning with no inflammation, vascularization, or induced corneal astigmatism can occur in this region, usually in the very elderly. It requires no therapy, but it should be considered when cataract ­incisions are made in these patients.

PERIPHERAL CORNEAL GUTTAE The corneal endothelium undergoes degeneration with age, as manifested by a decreasing endothelial cell density13 and thickening of the posterior, nonbanded layer of Descemet’s membrane.14 Degenerating endothelial cells produce localized nodular thickenings of Descemet’s membrane, known as guttae. The incidence of central guttae increases with age.14 The relationship of central guttae to Fuchs’ corneal endothelial dystrophy is discussed elsewhere with the corneal dystrophies. Peripheral guttae, known as Hassall-Henle warts, are visible in normal adult corneas and are thought to be truly degenerative and unrelated to Fuchs’ dystrophy (see Chapter 4-21). They are not associated with functional corneal changes.

CALCIFIC BAND KERATOPATHY Band keratopathy is a common corneal degeneration that can occur at any age and can occur peripherally or centrally. Whereas primary ­idiopathic forms rarely occur, it most commonly occurs in eyes with chronic ­disease, particularly uveitis, glaucoma, keratitis, or trauma. It also occurs with elevated serum calcium or phosphate. A toxic form ­resulting from mercurial preservatives in pilocarpine has been described. Associated ­systemic diseases include sarcoidosis, hyperparathyroidism, vitamin D toxicity, and extensive metastatic neoplasm to bone, all of which are associated with elevated serum calcium. In children, band keratopathy may be the presenting sign of chronic uveitis as a result of juvenile rheumatoid arthritis. It may also occur in patients with chronic renal failure from secondary hyperparathyroidism. Local corneal damage has occurred as a result of intraocular silicone oil, viscoelastics ­manufactured in the past with high phosphate levels, and phosphate forms of ­corticosteroids.15–17 The mechanism of calcium deposition in the cornea is unknown, but it is associated with corneal exposure, as deposition occurs primarily in the exposed area. It may result from precipitation left as tears evaporate or because of a lower pH in this region.18 Calcium is deposited in the cornea as a horizontal band that begins near the corneal periphery and appears as a hazy deposit in the peripheral stroma separated from the limbus by a clear zone (Fig. 4-22-6). The more central areas have clear circles where Bowman’s membrane is traversed by nerve endings. Gradually, the deposits move centrally, although the central areas may occasionally occur first. The most severely affected area is centered on the junction of the middle and inferior thirds of the cornea, the area of greatest exposure to the atmosphere. The deposits begin as a gray haze but can become densely white with a rough, pebbly surface that elevates the epithelium and results in pain, foreign body sensation, recurrent corneal erosions, and decreased vision. The rate of development is variable; it may take many years, although it may occur rapidly in very dry eyes.19

319

4 CORNEA AND OCULAR SURFACE DISEASES

A

A

E

P

CB

S B

Fig. 4-22-4  Terrien’s marginal corneal degeneration. (A) Note the lipid deposit along the central edge. (B) Histologic section shows limbus on the left (iris not present) and central cornea to the right. Note marked stromal thinning.

B

Fig. 4-22-6  Band keratopathy. (A) Calcium deposits in the cornea of a   13-year-old with juvenile rheumatoid arthritis. (B) A fibrous pannus (P) is   present between the epithelium (E) and a calcified Bowman’s membrane (CB). Some deposit is also present in the anterior corneal stroma (S).

discomfort or decreased vision occurs, the central deposits may be ­removed. Traditionally, this is done by removal of the epithelium over the deposits and the application of 0.05  mol/L disodium ethylenediaminetetraacetic acid as a chelator of calcium.20 After several minutes the surface is rubbed with a sponge or blade. This process is repeated until the central cornea becomes clear. Coverage of the resulting corneal defect by transplanted amniotic membrane may help to restore the surface.21 A diamond burr may be used to help remove dense deposits. Excimer laser phototherapeutic keratectomy may also be used to remove band keratopathy, although visual improvement is often limited by the ­underlying disease.22

SPHEROIDAL DEGENERATION

Fig 4-22-5  Fuchs’ superficial marginal keratitis. There is severe thinning ­following years of recurrent inflammation, with descemetocele formation ­superiorly. Lipid deposition is noted within and anterior to the area of thinning and a pseudopterygium is present at both sides of the thinning.

320

Histopathologically, calcium is deposited as the hydroxyapatite salt in the epithelial basement membrane, basal epithelium, and Bowman’s membrane.18 The deposits are usually extracellular, although hypercalcemia may cause intracellular epithelial accumulation. Band keratopathy usually does not decrease vision and requires no treatment or only treatment of the underlying condition. If persistent

Spheroidal degeneration may have a distribution in the cornea similar to that of band keratopathy, and it also occurs in the conjunctiva. It has been given a variety of names, of which the most commonly used are climatic droplet keratopathy, hyaline degeneration, and local designations such as Labrador keratopathy.23 Spheroidal degeneration occurs as a primary corneal form, a secondary corneal form in eyes with prior keratitis or trauma, and a conjunctival form. Its frequency varies with geographic location and increases with age. It occurs most often in ­areas that have high sunlight exposure and sunlight reflection off snow or sand, in combination with wind-driven corneal damage by snow and sand. It is twice as prevalent in men as in women. Prevalence varies from 6% in England to over 60% in males in Labrador. It is thought to be a result of ultraviolet light exposure and may also be associated with blue-light exposure.24, 25 Drying of the cornea and repeated corneal trauma are thought to be risk factors. The secondary forms occur with corneal scars after keratitis or trauma, lattice corneal dystrophy, and glaucoma.

4.22 Corneal Degenerations

Fig. 4-22-7  Spheroidal degeneration. Central spheroidal droplets in the cornea of an eye that is blind from glaucoma.

Typically, spheroidal degeneration is characterized by the presence of fine droplets, yellow or golden in color, beneath the conjunctival or corneal epithelium (Fig. 4-22-7). The droplets appear oily, although they are not of lipid origin. They may be clear but often become cloudy or opaque over time. In the cornea they may occur along the edge of scars. In the primary form, they begin peripherally and advance toward the center in the palpebral fissure area. As the condition advances, the droplets become larger and more nodular and lift the central corneal epithelium. Three stages of the primary form have been described: l Grade I – fine shiny droplets are present only peripherally without symptoms. l Grade II – the central cornea is involved and vision may be as low as 20/100 (6/30). l Grade III – there are large corneal nodules and vision is no better than 20/200 (6/60). These forms are always bilateral. Stage III disease may be rapidly progressive followed by ulceration of involved areas of cornea, with ­secondary bacterial infection.26 Histologically, deposits of spheroidal degeneration appear as extracellular amorphous globules, which may coalesce to form larger masses in Bowman’s membrane. These globules are made up of a protein material with elastotic features, as in pinguecula. The source of the protein is unknown, but it has been postulated to result from the action of ultraviolet light on proteins that diffuse into the stroma from limbal vessels.23, 27 The majority of cases of spheroidal degeneration are asymptomatic. In those who have visual loss from central corneal lesions, as occurs frequently in the developing tropical areas, superficial keratectomy and lamellar or penetrating keratoplasty have been used. Reports of excimer laser phototherapeutic keratectomy in the climatic form have shown encouraging results.28

IRON DEPOSITION Iron deposition occurs in the corneal epithelium in several clinical situations in which the smooth spreading of the tear film is disturbed. The prototype is the Hudson-Stähli line, which is located at the junction of the middle and lower thirds of the cornea (Fig. 4-22-8). It is yellowbrown in color and curves downward at its center. It is usually about 0.5  mm wide and 1–2  mm long. It is seen most clearly in blue light as a black line. Hudson-Stähli lines occur in most patients over the age of 50  years and decrease in density and frequency after the age of 70  years.29 Similar iron deposition occurs at the base of the cone in keratoconus (Fleischer ring), around filtering blebs (Ferry line), central to pterygium (Stocker line), and around Salzmann’s nodules. Iron lines occur within the margin of corneal grafts, between radial keratotomy scars, and following laser in situ keratomileusis (LASIK).30 Reversible arcuate deposition of iron has also been noted following intrastromal corneal ring placement.31 The source of the iron is unknown, but it most likely comes from the tear film. It is postulated that altered tear flow secondary to distorted corneal shape is a factor in the formation of these lines and that epithelial migration patterns affect the shape of the Hudson-Stähli line. Histologically, the iron associated with these conditions is deposited intracellularly in the corneal epithelial cells as a ferritin-like material,

Fig. 4-22-8  Hudson-Stähli line. Thin horizontal brown line in inferior cornea   of a healthy 57-year-old male. (Courtesy of the photography department, WK Kellogg Eye Center, University of Michigan.)

possibly hemosiderin.32 These iron lines do not affect vision or cause any symptoms and thus require no treatment. Coats’ white ring is an iron deposition that occurs just deep to the corneal epithelium in the anterior portion of Bowman’s membrane. It appears as a tiny ring of white dots, most often inferiorly. It is thought to result from previous iron deposition by a corneal foreign body and occurs long after resolution of the corneal iron ring. It has no symptoms.33

CROCODILE SHAGREEN Anterior or posterior polygonal opacities in the corneal stroma occur as a consequence of aging. Crocodile shagreen was first described by Vogt11 in an elderly woman who had a gray opacity of the central cornea, with opacities separated by darker clear zones. The pattern resembles that of crocodile skin and is thought to be related to the oblique insertion of the collagen lamellae that constitute the corneal stroma.34 The same pattern is transmitted to the normal corneal epithelium and may be seen after fluorescein is applied to the cornea and pressure applied through the closed lid, in hypotony of the globe, and in contact lens wearers with keratoconus. No information is available on the incidence of this degeneration, but it is a very common, although frequently subtle, finding in older patients. The anterior form is thought to be more common than the posterior, but posterior crocodile shagreen is similar, although it occurs in the deep central stroma (Fig. 4-22-9). The opacities in posterior crocodile shagreen may occur peripherally, in which case they may be indistinguishable from the central extension of corneal arcus. Postmortem histology shows a serrated configuration of collagen ­lamellae in the stroma with widely spaced collagen fibers rather than any abnormal deposition of material.35 Familial forms of posterior crocodile shagreen have been described in a dominant juvenile form and in a form associated with X-linked megalocornea. Central cloudy dystrophy of François appears to be similar, but it is a true dystrophy that is inherited dominantly. This dystrophic form rarely interferes with vision (see Chapter 4-18).

CORNEA FARINATA Like many of the other degenerations, this common but subtle finding was described by Vogt.11 It occurs in the corneas of older patients and is always an incidental finding as it causes no symptoms. The corneal opacities in this condition are very fine, dust-like dots of white or gray color in the deep central stroma, just anterior to Descemet’s membrane.36 The name farinata, meaning “like wheat flour,” refers to the appearance of the dots. The bilateral deposits are very difficult to visualize at the slit lamp, except by retroillumination. The cause of the condition is unknown. The histology of similar conditions suggests that the deposits may be composed of lipofuscin in stromal keratocytes.37, 38

SALZMANN’S CORNEAL DEGENERATION This degenerative condition was described originally as a dystrophy. It may occur at any age but is primarily a condition of the elderly. It develops in corneas with previous keratitis but often several decades

321

4 CORNEA AND OCULAR SURFACE DISEASES

322

Fig. 4-22-9  Posterior croc\odile shagreen. A mottled, gray pattern is visible in the central cornea.

Fig. 4-22-11  Corneal keloid recurrence. A central, elevated, fibrous opacity is present centrally. The photo was taken 6  months after superficial keratectomy for the original lesion.

Fig. 4-22-10  Salzmann’s nodular degeneration. Severe corneal involvement in an elderly woman.

Fig. 4-22-12  Polymorphic amyloid degeneration. Glassy, fine deep corneal deposits in the central cornea of an elderly woman.

later. It has been associated particularly with past phlyctenular keratitis but may also follow interstitial keratitis, vernal keratitis, trachoma, or Thygeson’s superficial punctate keratitis, or it may occur with no history of prior corneal disease. It may be unilateral or bilateral and occurs more often in women than in men. Salzmann’s degeneration is characterized by the presence of whiteto-gray or light blue nodules that elevate the epithelium in the superficial corneal stroma (Fig. 4-22-10). They may be single or occur as clusters in a circular array, often at the edge of old corneal scars. Each nodule is about 0.5–2  mm in diameter, not vascularized, and separated from other nodules by clear cornea. An epithelial iron line may outline the base of the lesion. The onset of the lesions is gradual, over many years, during which time they increase in both size and number. They may decrease vision as they encroach upon the central cornea or, more often, as they alter the corneal shape and may be associated with recurrent corneal erosions.39 Histologic examination shows thinned epithelium that overlies hyalinized avascular collagen. Bowman’s membrane is damaged or focally absent and replaced by material that is similar to basement membrane.40 Usually, evidence is seen of old keratitis in the surrounding stroma. Many elderly patients who have peripheral Salzmann’s nodules are asymptomatic and require no treatment. If vision is altered or if recurrent erosions are frequent, the nodules may be removed. Often, they may be peeled from the underlying stroma. Excimer laser phototherapeutic keratectomy has been used to remove these lesions, with

success in improving vision.22 In the past, lamellar or penetrating keratoplasty has been used. Recurrences have been found after all forms of ­treatment.41

CORNEAL KELOIDS Corneal keloids are a rare condition resulting from progressive growth of fibrous tissue on the cornea. Unlike hypertrophic scars, they outgrow their original boundaries. They will typically appear following trauma, surgery, or inflammatory processes and may appear months or years following the inciting event. The appearance is of an elevated gray-white mass involving the entire stroma or as isolated nodules (Fig. 4-22-11). Microscopic findings vary based on age of the lesions with poorly arranged collagen fibers, myofibroblasts, and blood vessels noted in early stages. In later stages, there is compaction of collagen and reduction in vascularity and cellularity. Significant keloids may be treated by superficial keratectomy, lamellar keratoplasty, or penetrating keratoplasty.42

CORNEAL AMYLOID DEGENERATION Amyloid is a group of hyaline proteins deposited in tissues in a variety of systemic and localized conditions. These conditions may be primary or secondary, localized or systemic, and familial or nonfamilial. The deposits of proteins may be derived from ­immunoglobulin

A more specific form of corneal amyloid degeneration has been described as polymorphic amyloid degeneration.44 Usually, this condition is an incidental finding in the elderly. It is characterized by the presence of glass-like deposits in the deep central corneal stroma, which often indent Descemet’s membrane. The deposits are punctate or rod-like and may appear identical to the deposits of lattice dystrophy, although they are usually much less dense (Fig. 4-22-12). They are bilateral, generally occur after the age of 50  years, and do not affect vision. Histologically, they appear similar to lattice dystrophy deposits and are composed of amyloid. The cause is unknown and the condition requires no ­treatment. Another stromal deposition with features of both spheroidal degeneration and amyloid deposition has been called climatic proteoglycan stromal keratopathy.45 This has been described in Saudi Arabian patients, and the risk factors are similar to those of spheroidal degeneration. The patients have bilateral, horizontal, oval, central anterior stromal, ground glass haze. Some have refractile stromal lines. Both proteoglycan and amyloid have been found histopathologically. This condition does not usually affect vision.45

4.22 Corneal Degenerations

light chains as in primary systemic amyloidosis, from amyloid A protein in secondary amyloid, from some forms of albumin in familial amyloidosis, and as a protein known as AP. Primary systemic amyloidosis causes heart failure, neuropathies, and other disorders. Secondary systemic amyloid follows long-standing inflammatory diseases such as tuberculosis or syphilis. Nonfamilial localized amyloidosis of a primary form can present with conjunctival or lid nodules. Familial localized amyloidosis is seen in the cornea as lattice, Avellino, and gelatinous drop-like corneal dystrophies discussed in Chapter 4.20. The degenerative forms of amyloid seen in the cornea and conjunctiva are secondary, localized, and nonfamilial. These occur as nonspecific corneal deposits that follow corneal trauma or keratitis. They may also follow chronic intraocular inflammation. Usually, they are not diagnosed clinically as amyloid deposits but are seen histopathologically, often in nonspecific corneal opacities.43 Histologic diagnosis can be made with Congo red staining of extracellular hyaline deposits or with immunofluorescence staining for specific amyloid proteins.

REFERENCES   1. Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism. Surv Ophthalmol. 1991;36:1–22.   2. Cogan DG, Kuwabara T. Arcus senilis, its pathology and histochemistry. Arch Ophthalmol. 1959;61:553–60.   3. Crispin S. Ocular lipid deposition and hyperlipoproteinaemia. Prog Retinal Eye Res. 2002;21:169–224.   4. Segal P, Insull W, Chambless LE, et al. The association of dyslipoproteinemia with corneal arcus and xanthelasma. The Lipid Research Clinics Program Prevalence Study. Circulation. 1986;73:108–18.   5. Fernandez A, Sorokin A, Thompson PD. Corneal arcus as coronary artery disease risk factor. Atherosclerosis. 2006;Oct 16 (Epub ahead of print).   6. Moss SE, Klein R, Klein BE. Arcus senilis and mortality in a population with diabetes. Am J Ophthalmol. 2000;129:676–8.   7. Duran JA, Rodriguez-Ares MT. Idiopathic lipid corneal degeneration. Cornea. 1991;10:166–9.   8. Cogan DG, Kuwabara T. Lipid keratopathy and   atheromas. Circulation. 1958;18:519–25.   9. Shapiro LA, Farkas TG. Lipid keratopathy following corneal hydrops. Arch Ophthalmol. 1977;95:456–8. 10. Croxatto JO, Dodds CM, Dodds R. Bilateral and massive lipoidal infiltrates of the cornea (secondary lipoidal degeneration). Ophthalmology. 1985;92:1686–90. 11. Vogt A. Textbook and atlas of slit lamp microscopy of the living eye. Bonn: Wayenborgh Editions; 1981. 12. Sugar HS, Kobernick S. The white limbus girdle of Vogt. Am J Ophthalmol. 1960;50:101–17. 13. Carlson KH, Bourne WM, McLaren JV, Brubaker R. Variations in human corneal endothelial cell morphology and permeability to fluorescein with age. Exp Eye Res. 1988;47:27–41. 14. Lorenzetti DW, Uotila MH, Parikh N, et al. Central   cornea guttata, incidence in the general population.   Am J Ophthalmol. 1967;64:1155–8. 15. Azen SP, Scott IU, Flynn HW, et al. Silicone oil in the repair of complex retinal detachments. A prospective observational multicenter study. Ophthalmology. 1998;105:1587–97. 16. Nevyas AS, Raber IM, Eagle RC, et al. Acute band keratopathy from intracameral Viscoat. Arch Ophthalmol. 1987;105:958–64.

17. Taravella MJ, Stulting RD, Mader TH, et al. Calcific band keratopathy associated with the use of topical steroid-phosphate preparations. Arch Ophthalmol. 1994;112:608–13. 18. O’Connor GR. Calcific band keratopathy. Trans Am   Ophthalmol Soc. 1972;70:58–85. 19. Lemp MA, Ralph RA. Rapid development of band keratopathy in dry eye. Am J Ophthalmol. 1977;83:657–9. 20. Najjar DM, Cohen EJ, Rapuano CJ, Laibson PR. EDTA chelation for calcific band keratopathy: results and longterm follow-up. Am J Ophthalmol. 2004;147:1056–64. 21. Anderson DF, Prabhasawat P, Alfonso E, Tseng SC. Amniotic membrane transplantation after primary surgical management of band keratopathy. Cornea. 2001;20:354–61. 22. Maloney RK, Thompson V, Ghiselli G, et al. A prospective multicenter trial of excimer laser phototherapeutic keratectomy for corneal vision loss. Am J Ophthalmol. 1996;122:144–60. 23. Gray RH, Johnson GJ, Freedman A. Climatic droplet keratopathy. Surv Ophthalmol. 1992;36:241–53. 24. Norn M, Franck C. Long-term changes in the outer part of the eye in welders. Acta Ophthalmol. 1991;69:382–6. 25. Taylor HR, West S, Munoz B, et al. The long-term effects of visible light on the eye. Arch Ophthalmol. 1992;110:99–104. 26. Ormerod LD, Dahan E, Hagele JE, et al. Serious occurrences in the natural history of advanced climatic keratopathy. Ophthalmology. 1994;101:448–53. 27. Johnson GJ, Overall M. Histology of spheroidal degeneration of the cornea in Labrador. Br J Ophthalmol. 1978;62:53–61. 28. Badr IA, Al-Rajhi A, Wagoner MD, et al. Phototherapeutic keratectomy for climatic droplet keratopathy. J Refract Surg. 1996;12:112–22. 29. Norn MS. Hudson-Stähli’s line of cornea I. Incidence and morphology. Acta Ophthalmol (Copenh). 1968;46:106–18. 30. Probst LE, Almasswary MA, Bell J. Pseudo-Fleischer ring after hyperopic laser in situ keratomileusis. J Cataract Refract Surg. 1999;25:868–70. 31. Assil KK, Quantock AJ, Barrett AM, Schanzlin DJ. Corneal iron lines associated with the intrastromal corneal ring. Am J Ophthalmol. 1993;116:350–6.

32. Gass JDM. The iron lines of the superficial cornea. Arch Ophthalmol. 1964;71:348–58. 33. Nevins RC, Davis WH, Elliott JH. Coats’ white ring of the cornea – unsettled metal fettle. Arch Ophthalmol. 1968;80:145–6. 34. Tripathi RL, Bron AJ. Secondary anterior crocodile shagreen of Vogt. Br J Ophthalmol. 1975;59:59–63. 35. Krachmer JH, Dubord PJ, Rodriguez MM, et al. Corneal posterior crocodile shagreen and polymorphic amyloid degeneration. Arch Ophthalmol. 1983;101:54–9. 36. Kobayashi A, Ohkubo S, Tagawa S, et al. In vivo confocal microscopy in the patients with cornea farinata. Cornea. 2003;22:578–81. 37. Curran RE, Kenyon KR, Green WR. Pre-Descemet’s membrane corneal dystrophy. Am J Ophthalmol. 1974;77:711–6. 38. Durand L, Bouvier R, Burillon C, et al. Cornea farinata à propos d’un cas: Etude clinique, histologique et ultrastructurale. J Fr Ophtalmol. 1990;13:449–55. 39. Wood TO. Salzmann’s nodular degeneration. Cornea. 1990;9:17–22. 40. Vannas A, Hogan MJ, Wood I. Salzmann’s nodular degeneration of the cornea. Am J Ophthalmol. 1975;79:211–19. 41. Severin M, Kirchof B. Recurrent Salzmann’s corneal degeneration. Graefes Arch Clin Exp Ophthalmol. 1990;222:101–4. 42. Bourcier T, Baudrimont M, Boutboul S, et al. Corneal keloid: clinical, ultrasonographic, and ultrastructural characteristics. J Cataract Refract Surg. 2004;30:921–4. 43. Dutt S, Elner VM, Soong HK, et al. Secondary localized amyloidosis in interstitial keratitis (IK): clinicopathologic findings. Ophthalmology. 1992;99:817–23. 44. Mannis MJ, Krachmer JH, Rodriguez MM, et al. Polymorphic amyloid degeneration of the cornea. Arch Ophthalmol. 1981;99:1217–23. 45. Waring GO, Malaty A, Grossniklaus H, et al. . Climatic proteoglycan stromal keratopathy, a new corneal degeneration. Am J Ophthalmol. 1995;120:330–41.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 6 Corneal Diseases

4.23

Dry Eye

Elmer Y. Tu and Stephen Rheinstrom

Definition:  Clinical condition characterized by deficient tear ­production or excessive tear evaporation.

Key features n n

 cular and conjunctival irritation. O Ocular surface disruption.

to periodically distribute tears evenly over the ocular surface and encourages both secretion and mechanical drainage of tears through the lacrimal drainage system. Regulation likely involves both neuronal and hormonal pathways. Direct innervation of the lacrimal gland, meibomian glands, and goblet cells has been demonstrated, with M3 class cholinergic receptors predominating in the lacrimal gland.11 While estrogen has little effect on tear secretion, it may have a supportive role on the ocular surface.12 Androgens appear to have a positive effect on the secretion of both aqueous and lipid tears.13, 14

Classification of Dry Eye Associated features  ossible autoimmune disease. P Possible conjunctival or lid abnormalities. n Systemic and topical medications. n Blurred or unstable vision. n n

INTRODUCTION Dry eye syndrome (DES) is characterized by ocular irritation resulting from an alteration of the tear film. The effects of DES can vary from minor inconvenience for most sufferers to rare sight-threatening complications in severe cases. Although the diagnosis of DES has traditionally focused on inadequate secretion, or aqueous tear deficiency, the tear film is a complex and delicately balanced unit dependent on the normal function of several distinct components.1–3 Current treatment is heavily weighted toward supplementation, stimulation, or preservation of aqueous tears, which is satisfactory for most patients. DES, however, often involves multiple deficiency states that, when disregarded, can result in treatment failure and frustration for both the patient and the physician.

EPIDEMIOLOGY AND PATHOGENESIS Normal Physiology

324

The stratified tear film is composed of mucin, aqueous, and lipid components. The mucin layer consists of high-molecular-weight glycoproteins closely adherent to an inherently hydrophobic surface epithelium and its glycocalyx. Mucin provides a smooth, hydrophilic surface4 permitting even distribution of the overlying aqueous layer. Its primary source is conjunctival goblet cells with a small contribution from surface epithelial cells.5 Comprising the largest volume of the tear film, the aqueous is secreted by the main lacrimal gland, the accessory glands of Krause and Wolfring, and, minimally, a transudate of the conjunctival vessels and cornea. Consisting primarily of water, it also contains electrolytes (Na, K, Cl) and myriad proteins, including epidermal growth factor, immunoglobulins (IgA, IgG, IgM), lactoferrin, lysozyme, and other cytokines.6, 7 These components likely play both a protective and a homeostatic role for the ocular surface. Lastly, meibomian glands secrete a lipid layer, containing chiefly sterol esters and wax monoesters.8, 9 Although only 0.1 μm thick, the lipid layer serves to stabilize the tear film by increasing surface tension and retarding evaporation. The tear layer maintains a smooth surface for optical clarity, lubricates to facilitate eyelid blink, and offers protection against ocular infection.1 Average tear flow is about 1.2 μm/minute.10 Blinking serves

The National Eye Institute/Industry Workshop adopted the following definition of dry eye: Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation that causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.15 This definition encompasses all the clinical entities associated with systemic disease, as well as idiopathic dry eye disease. As a result of these workshops, a classification system algorithm for dry eye was produced (Fig. 4-23-1).

Tear-deficient dry eye

The description of keratoconjunctivitis sicca (KCS) that Sjögren16 gave in his 1933 article has become associated with his name and has been incorporated into the nomenclature of dry eye. Consequently, defective lacrimal function is subdivided into: non-Sjögren’s tear deficiency (NSTD) and Sjögren’s syndrome tear deficiency (SSTD). NSTD has no association with systemic autoimmune disease, which is a cardinal feature of SSTD.

Non-Sjögren’s tear deficiency

NSTD can occur from impaired glandular production, impaired afferent or efferent stimulation, or local ocular surface disease. Primary lacrimal deficiency may rarely result from congenital alacrima, primarily absent or hypoplastic lacrimal glands. The large majority of patients with DES, however, are categorized as having acquired lacrimal gland deficiency, primary lacrimal deficiency, or idiopathic KCS syndrome. This acquired form may result from either age-related changes in the lacrimal gland17 or an immune round cell infiltration of the lacrimal gland and ductal tissue.18 Secondary lacrimal deficiency from infiltration and damage to the lacrimal gland in lymphoma, sarcoidosis, hemochromatosis, amyloidosis, human immunodeficiency virus infection, and graft-versus-host disease can all result in dry eye.19, 20 Surgical or radiation-induced destruction of lacrimal tissue can also result in secondary lacrimal deficiency. Systemic medications are a common source for the inhibition of ­efferent lacrimal gland stimulation through anticholinergic activity or decreased secretion through systemic dehydration (Table 4-23-1).21 Mechanical trauma to efferent secretomotor fibers or Riley-Day syndrome, a disorder of aberrant systemic parasympathetic innervation with preserved reflex tearing, may similarly result in efferent stimulationdeficient dry eye.20 As shown by studies utilizing topical anesthetic, interruption of the afferent stimulus of tear production, or sensory loss (denervation), results in decreased tear secretion and reduced blink rate.22, 23 Damage to afferent sensory fibers occurs after incisional corneal surgery (penetrating keratoplasty, radial keratotomy, and limbal cataract incision) and after damage to the first division of the trigeminal ganglion from trauma, tumor, herpes simplex, or zoster resulting in reduced tear production. LASIK and photorefractive keratectomy resulting in decreased corneal sensation and blink rate are recognized as precipitating causes of dry eye.24–27 LASIK incisions involve 270o of the paracentral corneal

DRY EYE CLASSIFICATION

Sjögren's syndrome

Evaporative

Dry eye – keratoconjunctivitis sicca

Non-Sjögren tear deficiency

Lacrimal disease

Congenital alacrima acquired primary lacrimal gland disease

Lacrimal obstruction

Reflex

Oil deficient

Trachoma, cicatricial pemphigoid Neuro-paralytic keratitis Erythema multiforme Contact lens Burns VIIth nerve palsy

Rheumatoid arthritis Systemic lupus erythematosus Wegener's granulomatosis Systemic sclerosis Primary biliary cirrhosis Other autoimmune diseases primary

Dry Eye

Tear deficient

4.23

Sarcoid HIV Graft vs. host Xerophthalmia ablation Other diseases

Absent glands Distichiasis

Posterior blepharitis Obstructive meibomian gland disease

Lid related

Blink abnormalities

Contact lens

Aperture abnormalities

Surface change

Lid surface incongruity

Xerophthalmia

Anterior blepharitis

secondary

Fig. 4-23-1  Dry eye classification. (With permission from Lemp MA. The 1998 Castroviejo lecture. New strategies in the treatment of dry-eye states. Cornea. 1999;18:625–32.)

   TABLE 4-23-1  MEDICATIONS ASSOCIATED WITH DRY EYE SYNDROME Mechanism of Action

Class

Medications

Anticholinergic

Antimuscarinics

Tolterodine tartrate (Detrol) Scopolamine

circumference, severing penetrating corneal nerves and leaving a hypesthetic corneal cap. Avoidance of surgery, especially LASIK, in patients at risk for corneal neuropathy28 (i.e., those with advanced diabetes or pre-existing severe dry eye) is strongly recommended. While DES has been reported in association with menopause, estrogen supplementation has not been shown to have a beneficial effect.29, 30 Alterations in other hormones, especially androgens, which are also reduced during menopause, have been implicated.

Sjögren’s syndrome tear deficiency

Antihistamines (sedating compounds are associated with greater dryness)

Chlorpheniramine   (Chlor-Trimeton) Diphenhydramine   (Benadryl) Promethazine (Phenergan)

Anti-parkinsonian

Benzotropine (Cogentin) Trihexyphenidyl (Artane)

Antidepressants MAO inhibitors

Amitriptyline (Elavil) Nortriptyline (Pamelor) Imipramines (Tofranil) Doxepin (Sinequan) Phenelzine

Antipsychotics

Chlorpromazine   (Thorazine) Thioridazine (Mellaril) Fluphenazine (Prolixin)

Antimanics

Lithium

Antiarrhythmics

Disopyramide (Norpace) Mexiletine (Mexitil)

Sjögren’s syndrome is a clinical condition of aqueous tear deficiency combined with dry mouth. The syndrome is classified as primary – patients without a defined connective tissue disease – and secondary – patients who have a confirmed connective tissue disease. Secondary SSTD is associated with rheumatoid arthritis, systemic lupus erythematosus, polyarteritis, Wegener’s granulomatosis, scleroderma, polymyositis, dermatomyositis, and primary biliary cirrhosis. All feature progressive lymphocytic infiltration of the lacrimal and salivary glands and can be associated with severe and painful ocular and oral discomfort. The pathogenesis of the tear deficit in SSTD is infiltration of the lacrimal gland by B and CD4 lymphocytes (with some CD8 lymphocytes) and by plasma cells, with subsequent fibrosis. Fox19 laid out criteria to establish the diagnosis of Sjögren’s syndrome: l Abnormally low Schirmer’s test result. l Objectively decreased salivary gland flow. l Biopsy-proved infiltration of the labial salivary glands. l Serum autoantibodies (antinuclear antibody, rheumatoid factor, or the specific antibodies anti-Ro [SS-A] and anti-La [SS-B]). When all four factors are present, a definite diagnosis of Sjögren’s syndrome is made; if three of the four are met, a provisional diagnosis can be made.

Alpha agonists

Clonidine (Catapres) Methyldopa (Aldomet)

Evaporative dry eye

Beta blockers

Propranolol (Inderal) Metoprolol (Lopressor)

Diuretic

Thiazides

Hydrochlorothiazide

Other

NSAIDs

Ibuprofen (Advil) Naproxen (Naprosyn, Aleve)

Antiadrenergic

Cannabinoids

Marijuana

Excessive evaporation that occurs in specific periocular disorders can cause dry eye disease with or without concurrent aqueous tear deficiency. Evaporation leads to both loss of tear volume and a disproportionate loss of water, resulting in hyperosmolarity. Environmental conditions such as high altitude, dryness, or extreme heat accelerate tear loss even in normal eyes.

Meibomian gland disease and blepharitis

Meibomian gland dysfunction (MGD) leads to both decreased secretion and abnormal composition of the tear film lipid layer. The abnormal composition leads to meibomian gland blockage and reduced

325

4 CORNEA AND OCULAR SURFACE DISEASES

e­ ffectiveness in the tear film. The resulting ocular surface and eyelid inflammation perpetuates a cycle of inflammation, scarring, hyperkeratosis, stenosis, and further MGD. Often associated, abnormal bacterial colonization acts directly by altering secreted lipids and indirectly by causing inflammation. An association is also seen with dermatologic conditions such as seborrheic dermatitis and acne rosacea, a disorder resulting in vascular dilatation, telangiectasias, and plugging of sebaceous glands of both facial and eyelid skin.

Exposure

Excessive exposure of the ocular surface leads to increased evaporative loss of tears; thus, any disorder that results in increased ocular exposure can cause evaporative dry eye. Psychological, psychiatric, mechanical, neurological, or traumatic impairment of eyelid function may result in impaired or reduced blinking, lagophthalmos, or an increased palpebral fissure width resulting in an evaporative dry eye. Evaporative dry eye can be seen in thyroid eye disease secondary to proptosis or lid retraction.

Mucin deficiency

Local conjunctival damage from cicatrizing disease or surgical trauma results not only in aqueous tear deficiency, but also in depopulation of mucin-producing goblet cells and creation of anatomical abnormalities of the conjunctiva leading to improper tear distribution. Although uncommon in incidence, trachoma, mucous membrane pemphigoid, Stevens-Johnson syndrome, and chemical and thermal burns can result in severe DES characteristically resistant to aqueous tear replacement therapy. Vitamin A deficiency can similarly result in extensive goblet cell loss and squamous metaplasia.31

OCULAR MANIFESTATIONS

326

Regardless of the cause, most forms of dry eye share similar symptoms, interpalpebral surface damage, tear instability, and tear hyperosmolarity. Typical complaints include burning, itching, foreign body sensation, stinging, dryness, photophobia, ocular fatigue, and redness. Although symptoms are usually nonspecific, careful attention to details will help refine the diagnosis. Patients commonly describe a diurnal pattern with aqueous tear deficiency with progression of symptoms over the day and decompensation in particular environmental conditions such as low humidity in airline cabins, climate control, and the use of video display terminals.32, 33 ­Conversely, night-time exposure, floppy eyelid syndrome, and inflammatory conditions often present with worst discomfort upon awakening. Meibomian gland disease creates an unstable tear film resulting in intermittent visual blurring and a gritty or sandy sensation. DES in diabetes and other corneal neuropathies may exhibit little or no discomfort and create high risk for keratolysis. Common signs of DES include conjunctival injection, decreased tear meniscus, photophobia, increased tear debris, and loss of corneal sheen found more commonly in the exposed interpalpebral fissure. Paradoxical epiphora in DES is usually a result of reflex tearing. Greater risk for external infections exists secondary to decreased tear turnover and desiccation of the surface epithelium. Instability of the surface epithelium and disordered mucin production may lead to painful and ­ recurrent filamentary keratitis. Although keratinization may occur uncommonly in chronic DES, vitamin A deficiency should also be suspected. Meibomian gland inspissation, telangiectasias, glandular dropout (seen on transillumination of the tarsus), chalazions, and eyelash debris are signs of meibomian gland disease and blepharitis. Patients who have SSTD tend to have more severe symptoms and more serious findings than do NSTD patients. Sterile ulceration of the cornea in SSTD can be peripheral or paracentral; both thinning and perforation of these ulcers can occur (Fig. 4-23-2). Acute lacrimal enlargement may be seen in SSTD but should be differentiated from Mikulicz’s disease, which results from infiltration of the gland without surface findings.34 The common result of DES is hyperosmolar toxicity and damage of the ocular surface. Chronicity leads to a loss of conjunctival goblet cells, epithelial cell dysfunction, and, in advanced cases, metaplasia and keratinization. Disruption of the normal epithelial barrier promotes release of the proinflammatory cytokines interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor, among others, leading to a self-perpetuating cycle of conjunctival damage. The cornea exhibits similar changes, with disruption of tight junctions and abnormal epithelial–mucin interaction.

DIAGNOSIS AND ANCILLARY TESTING Diagnostic Dye Evaluation

Fluorescein is a large molecule unable to traverse normal corneal epithelial tight junctions. In advanced DES, these junctions are disrupted, allowing characteristic diffuse subepithelial or punctate staining. Rose bengal, a derivative of fluorescein, in a 1% solution or impregnated strips stains devitalized epithelial cells (Fig. 4-23-3). Feenstra and Tseng35 showed that rose bengal stains healthy epithelial cells if a normal amount of mucin does not overlie the cell surface. Typically, the conjunctiva stains to a greater extent than the cornea, and the nasal conjunctiva shows more stain than the ­temporal.17 Van Bijsterveld created a grading scale for rose bengal dye that divides the ocular surface into three zones: nasal bulbar conjunctiva, cornea, and temporal bulbar conjunctiva, each graded 0–3 (0, none; 3, ­confluent staining).36 Lemp and the National Eye Institute/Industry Workshop group15 suggest that the conjunctiva be divided into six areas and graded in a similar manner (Fig. 4-23-4). Alternatively, lissamine green stains for cell death or degeneration, as well as cell-to-cell junction disruption, but does not irritate the eye.37

Tear Film Stability

Tear film instability may be a result of either tear deficiency or evaporative DES. In tear breakup time (TBUT), described by Norn and revised by Lemp and Holly,38 fluorescein dye is instilled and the time interval is measured between a complete blink to the first appearance of a dry spot in the precorneal tear film. Theoretically, TBUTs shorter than the blink interval of 5 seconds could result in surface damage, and very short TBUTs (less than 2 seconds) indicate KCS.

Fig. 4-23-2  Seventy-three-year old patient with rheumatoid arthritis and secondary Sjögren’s syndrome.

Fig. 4-23-3  Dry eye syndrome with rose bengal staining.

Measurement of Tear Production

DRY EYE CLASSIFICATION

4.23 Dry Eye

For years, the most common means of measuring tear production has been Schirmer’s test, the details of which were first published in 1903.39 Jones40 later advocated the use of topical anesthesia combined with a Schirmer’s test strip for 5 minutes to reduce the stimulating effect of the filter paper strip; the “basal” test. Inconsistencies in its application limit repeatability in DES,41 but it still enjoys widespread use. With these caveats in mind, the following general guidelines are recommended: l A 5-minute test that results in less than 5 mm of wetting confirms the clinical diagnosis of DES. l A result of 6–10 mm of wetting suggests a dry eye problem. Hamano et al.42 developed the phenol red thread test to obviate the disadvantages of Schirmer’s test by eliminating the need for anesthesia. Three millimeters of a fine dye-impregnated 75 mm cotton thread is placed under the lateral one fifth of the inferior palpebral lid margin for 15 seconds; alkalinity changes its color to bright orange from tear

contact. Asian populations show a lessened wet-length response with diminishing racial differences with advancing age.43 Direct stimulation of the nasociliary nerve through irritation of the nasopharynx confirms the presence or absence of reflex tearing. Hyperosmolarity is a common endpoint for all DES and its measurement is a sensitive, but not specific, test since it does not distinguish between tear-deficient and tear-sufficient dry eye. Other rarely performed tests for reduced tear function include fluorophotometry for decreased protein content, lysozyme levels, ocular ferning, impression cytology, and lactoferrin assays.

Other Tests

Corneal sensation may be qualitatively assessed with a cotton wisp, but quantification requires an instrument such as the Cochet-Bonnet aesthesiometer, a subjective test using a thin standardized wisp of variable length. More predictive than Schirmer’s test, the tear clearance test measures tear turnover with serial tear collection after instillation of a ­standardized volume of dye.41, 44 Serological tests, including antinuclear, anti-Ro, and anti-La antibodies, should be performed in patients suspected of having autoimmune DES. A definitive diagnosis of Sjögren’s syndrome requires, however, minor salivary or, rarely, lacrimal gland biopsy.

Diagnosis

1

2

4

3

5

6

right eye

6

Grade 0

4

2

5

3

Neither clinical presentation nor individual ancillary tests alone are sufficient for an accurate diagnosis of DES. Because of the therapeutic importance of appropriate categorization of patients, Pflugfelder et al.45 combined standard subjective examination with ancillary tests in the evaluation of SSTD, NSTD, inflammatory MGD, and atrophic MGD patients. Clinically important results were identified and compiled into an algorithm that helps differentiate DES patients with available tests (Fig. 4-23-5).

1

left eye

Grade 1

TREATMENT

Grade 2 Grade 3

Fig. 4-23-4  Modified van Bijsterveld conjunctival rose bengal grading map. The density of rose bengal staining is recorded on a scale of 0–3 for each of six areas of the conjunctiva, and then summed for each eye. (With permission from Lemp MA. The 1998 Castroviejo lecture. New strategies in the treatment of   dry-eye states. Cornea. 1999;18:625–32.)

Significant advances have been made in treating the many facets of dry eye, but it remains a disorder of long-term maintenance rather than permanent cure. Current therapy focuses on restoring a normal ocular surface through tear supplementation as well as inhibition of aberrant inflammation seen in chronic DES. Since the tear film is a highly integrated unit, addressing each component is central to the successful treatment of DES.

ALGORITHM FOR OCULAR IRRITATION

Symptoms of ocular irritation Consider non-tear film related problems

No

Fluorescein tear break-up time

10 sec

Yes Tear film instability

Yes

1. Schirmer 1 5 mm in one or both eyes 2. Aqueous tear deficiency pattern on fluorescein clearance test 3. Grid distortion by xeroscope

No

Aqueous tear deficiency 1. Absence of nasal-lacrimal reflex 2. Presence of serum autoantibodies 3. van Bijsterveld rose bengal staining score 3 4. Exposure zone fluorescein staining score 3

Yes Sjögren syndrome

No Non-Sjögren syndrome

Meibomian gland pathologic signs 1. Orifice metaplasia 2. Acinar atrophy 3. Reduced expressible meibum

Yes Meibomian gland disease

Fig. 4-23-5  Diagnostic algorithm for ocular irritation. (With permission from Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17:38–56.)

327

4

Aqueous Tear Deficiency

CORNEA AND OCULAR SURFACE DISEASES

As the first line of treatment, artificial tears increase available tears and, through dilution, reduce tear hyperosmolarity. Commercial artificial tears differ in electrolyte composition, thickening agents (methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol), physiologic buffering, tonicity, and preservative system. Individual patient preferences involve such disparate concerns as cost, comfort, visual blurring, and ease of use, but clearly, toxically preserved tears (i.e. benzalkonium) in moderate or severe dry eye are poorly tolerated and harmful. For patients with significant dry eye, single-dose, nonpreserved tear preparations are the mainstay of therapy with bottled tear products a reasonable alternative when preserved with relatively nontoxic compounds. Artificial tear ointments are effective for longer-lasting control of symptoms especially during sleep, but visual blurring limits their daytime usefulness. Punctal occlusion retards tear drainage, thereby increasing tear volume on the ocular surface and lowering tear osmolarity. Occlusion may be achieved irreversibly by cauterization or semi-permanently with the use of nonabsorbable plugs. Occlusion with collagen or 5-0 chromic gut provides temporary relief and may identify those at risk for epiphora prior to permanent occlusion. Epiphora in the setting of one functional punctum is uncommon. Secretagogues, agents that stimulate lacrimal gland secretion, require functional glandular tissue. Oral pilocarpine (Salagen) and cevimeline (Evoxac) are M3 cholinergic agonists approved for use in dry mouth that also stimulate tear secretion.11, 46, 47 Their effect tends to be greater in oral rather than ocular dryness, and systemic cholinergic side effects reduce patients’ acceptance. Various nutritional supplements are also touted for DES but without clear confirmation of their safety or ­efficacy.

Evaporative Dry Eye

Primary treatment of MGD involves improving the quality and quantity of native meibomian gland secretions. Lid hygiene, in the form of warm compresses and lid massage, is effective in improving meibomian

gland secretion. Lid scrubs with dilute detergents decrease the seborrheic or bacterial load, thereby breaking the proinflammatory cycle of MGD. Systemic tetracyclines have been shown to decrease ­local inflammation and improve meibomian gland function after several weeks. ­Erythromycin is an alternative in intolerant patients. A number of lipid-like tear substitutes have become commercially available, which have been used with some success.48 Correction of eyelid abnormalities that increase exposure of the ocular surface, such as lower lid ptosis and lagophthalmos, can stabilize a decompensated ocular surface. In severe cases, a partial or complete ­ tarsorrhaphy or a conjunctival flap may be necessary to prevent complete decompensation of the cornea. The use of humidifiers, moisture chambers, glasses, or goggles decreases surface evaporative pressure. New high-Dk, high-water-content contact lenses and new polymer lenses, accompanied by proper tear supplementation and hygiene, are effective in treating DES patients with poor corneal wetting.

Ocular Surface Inflammation

Ocular surface inflammation and its consequential cellular changes are not only a common endpoint of all DES, but also prevent ­restoration of the ocular surface by tear supplementation alone. DESinduced ocular surface inflammation disrupts the epithelial and mucin layers, further exacerbating tear film breakdown. Suppression of inflammation creates a supportive environment for reversal of DESinduced cellular changes.49, 50 Topical ciclosporin A has been shown to increase tear production in a subset of patients through inhibition of lacrimal gland inflammation and suppression of DES-induced ­ocular surface inflammation.51–53 Judicious use of topical steroids has also been shown to reduce inflammation and allow normal reparative mechanisms to restore the natural equilibrium of the ocular ­surface.54, 55 Control of these reactive epithelial changes has been shown to restore normal cell morphology, cell-to-cell interactions, and critical mucin production and clearly has a role in the global treatment in all forms of DES.

REFERENCES

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  1. Rolando M, Zierhut M. The ocular surface and tear film and their dysfunction in dry eye disease. Surv Ophthalmol. 2001;45(Suppl 2):S203–10.   2. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders. Am J Ophthalmol. 1997;124:825–35.   3. Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78:409–16.   4. Argueso P, Gipson IK. Epithelial mucins of the ocular surface: structure, biosynthesis and function. Exp Eye Res. 2001;73:281–9.   5. Watanabe H, Fabricant M, Tisdale AS, et al. Human corneal and conjunctival epithelia produce a mucin-like glycoprotein for the apical surface. Invest Ophthalmol Vis Sci. 1995;36:337–44.   6. Barton K, Nava A, Monroy DC, Pflugfelder SC. Cytokines and tear function in ocular surface disease. Adv Exp Med Biol. 1998;438:461–9.   7. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-  inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42:2283–92.   8. Bron AJ, Tiffany JM. The meibomian glands and tear film lipids. Structure, function, and control. Adv Exp Med Biol. 1998;438:281–95.   9. Driver PJ, Lemp MA. Meibomian gland dysfunction. Surv Ophthalmol. 1996;40:343–67. 10. Mishima S, Gasset A, Klyce SD Jr, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966;5:264–76. 11. Fox RI, Michelson P. Approaches to the treatment of Sjogren’s syndrome. J Rheumatol Suppl. 2000;61:15–21. 12. Smith JA, Vitale S, Reed GF, et al. Dry eye signs and symptoms in women with premature ovarian failure. Arch Ophthalmol. 2004;122:151–6. 13. Krenzer KL, Dana MR, Ullman MD, et al. Effect of androgen deficiency on the human meibomian gland and ­ocular surface. J Clin Endocrinol Metab. 2000;85:4874–82. 14. Lemp MA. The 1998 Castroviejo Lecture. New strategies in the treatment of dry-eye states. Cornea. 1999;18:625–32. 15. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221–32.

16. Sjogren H. Zur kenntnis der keratoconjunctivitis sicca (Keratitis filiformis bei hypofunktion der tranendrusen). Acta Ophthalmol (Copenh). 1933;2:1–151. 17. Obata H, Yamamoto S, Horiuchi H, Machinami R. Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging. Ophthalmology. 1995;102:678–86. 18. Nasu M, Matsubara O, Yamamoto H. Post-mortem prevalence of lymphocytic infiltration of the lacrymal gland:   a comparative study in autoimmune and non-  autoimmune diseases. J Pathol. 1984;143:11–5. 19. Fox RI. Systemic diseases associated with dry eye. Int Ophthalmol Clin. 1994;34:71–87. 20. Gilbard J. Dry eye disorders. In: Albert J, ed. Principles and practice of ophthalmology. Philadelphia:   WB Saunders; 1994 :257–76. 21. Fraunfelder FFF. Drug-induced ocular side effects. 5th ed. Boston: Butterworth-Heinemann; 2001. 22. Collins M, Seeto R, Campbell L, Ross M. Blinking and corneal sensitivity. Acta Ophthalmol (Copenh). 1989;67:525–31. 23. Jordan A, Baum J. Basic tear flow. Does it exist? Ophthalmology. 1980;87:920–30. 24. Ang RT, Dartt DA, Tsubota K. Dry eye after refractive surgery. Curr Opin Ophthalmol. 2001;12:318–22. 25. Battat L, Macri A, Dursun D, Pflugfelder SC. Effects of laser in situ keratomileusis on tear production, clearance, and the ocular surface. Ophthalmology. 2001;108:1230–5. 26. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and corneal sensitivity after laser in situ keratomileusis. Cornea. 2001;20:30–2. 27. De Paiva CS, Chen Z, Koch DD, et al. The incidence and risk factors for developing dry eye after myopic LASIK. Am J Ophthalmol. 2006;141:438–45. 28. Wilson SE. Laser in situ keratomileusis-induced ­(presumed) neurotrophic epitheliopathy. Ophthalmology. 2001;108:1082–7. 29. Mathers WD, Stovall D, Lane JA, et al. Menopause and tear function: the influence of prolactin and sex ­hormones on human tear production. Cornea. 1998;17:  353–8. 30. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA. 2001;286:2114–9.

31. Smith J, Steinemann TL. Vitamin A deficiency and the eye. Int Ophthalmol Clin. 2000;40:83–91. 32. Sommer HJ, Johnen J, Schongen P, Stolze HH. Adaptation of the tear film to work in air-conditioned rooms (office-eye syndrome). Ger J Ophthalmol. 1994;3:406–8. 33. Tsubota K, Nakamori K. Dry eyes and video display terminals. N Engl J Med. 1993;328:584. 34. Tsubota K, Fujita H, Tsuzaka K, Takeuchi T. Mikulicz’s disease and Sjogren’s syndrome. Invest Ophthalmol Vis Sci. 2000;41:1666–73. 35. Feenstra RP, Tseng SC. Comparison of fluorescein and rose bengal staining. Ophthalmology. 1992;99:605–17. 36. van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol. 1969;82:10–4. 37. Norn MS. Lissamine green. Vital staining of cornea and conjunctiva. Acta Ophthalmol (Copenh). 1973;51:483–91. 38. Lemp MA, Holly FJ. Recent advances in ocular surface chemistry. Am J Optom Arch Am Acad Optom. 1970;47:669–72. 39. Schirmer O. Studien zur Physiologie and Pathologie der Tranenabsonderung and Tranenabfuhr. Albrecht von Graefes Arch Ophthalmol. 1903;56:197–291. 40. Jones LT. The lacrimal secretory system and its treatment. Am J Ophthalmol. 1966;62:47–60. 41. Afonso AA, Monroy D, Stern ME, et al. Correlation of tear fluorescein clearance and Schirmer test scores with ocular irritation symptoms. Ophthalmology. 1999;106:803–10. 42. Hamano T, Mitsunaga S, Kotani S, et al. Tear volume in relation to contact lens wear and age. CLAO J. 1990;16:57–61. 43. Sakamoto R, Bennett ES, Henry VA, et al. The phenol red thread tear test: a cross-cultural study. Invest Ophthalmol Vis Sci. 1993;34:3510–4. 44. Macri A, Pflugfelder S. Correlation of the Schirmer 1 and fluorescein clearance tests with the severity of corneal epithelial and eyelid disease. Arch Ophthalmol. 2000;118:1632–8. 45. Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17:38–56. 46. Ono M, Takamura E, Shinozaki K, et al. Therapeutic   effect of cevimeline on dry eye in patients with Sjogren’s syndrome: a randomized, double-blind clinical study.   Am J Ophthalmol. 2004;138:6–17.

51. Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology. 2005;112:1790–4. 52. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000;118:1489–96. 53. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000;107:631–9.

54. Marsh P, Pflugfelder SC. Topical nonpreserved   methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology. 1999;106:811–6. 55. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of   keratoconjunctivitis sicca in patients with delayed   tear clearance. Am J Ophthalmol. 2004;138:444–57.

4.23 Dry Eye

47. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren syndrome: a randomized, placebocontrolled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med. 1999;159:174–81. 48. Di Pascuale MA, Goto E, Tseng SC. Sequential changes of lipid tear film after the instillation of a single drop   of a new emulsion eye drop in dry eye patients. Ophthalmology. 2004;111:783–91. 49. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004;137:337–42. 50. Pflugfelder SC, Wilhelmus KR, Osato MS, et al. The autoimmune nature of aqueous tear deficiency. Ophthalmology. 1986;93:1513–7.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 7 Miscellaneous

4.24

Contact Lens-Related Complications Thomas L. Steinemann, William Ehlers and Jeanine Suchecki

   TABLE 4-24-1  FDA LENS GROUPS

Definition:  Contact lens complications include inflammatory,

­ echanical, metabolic, or infectious events that interfere with a m patient’s wearing of their contact lenses.

Key features n n n

n

Overall safety record of contact lens use is excellent. Many factors play a part in safely wearing contact lenses. Low Dk lenses, overnight wear, and poor lens care practices are modifiable risk factors for the development of contact lens-related problems. Proper education of patients and appropriate follow-up are ­necessary for safe contact lens wear.

Associated features n

 ecent changes in the contact lens marketplace have an effect on R the overall safety record of contact lens wear.

INTRODUCTION In the United States, contact lenses are Class II medical devices, regulated by the Food and Drug Administration (FDA). As such, they must be evaluated for both safety and efficacy. They are among the safest medical devices ever made, but complications do occur. About 6% of the 36 million contact lens wearers in the United States experience some type of contact lens-related problem each year.1–3 Most problems are minor and simply an annoyance to the wearer. Rarely, serious and sightthreatening complications do occur. Eye care professionals want lenses that satisfy the needs of their patients without significant risk of complications. For this reason, overnight contact lens wear remains problematic, as this wearing schedule has been associated with increased risks of complications.4, 5 Modern advances in lens materials have reduced some of the risks associated with overnight wear, but many, including microbial keratitis, remain.6, 7

CONTACT LENS AND CORNEAL PHYSIOLOGY

330

Contact lenses are synthetic polymer foreign bodies worn on the surface of the eye. Although they are generally very well tolerated, they cause numerous changes in corneal physiology and the tear film. Most ­attention has been given to corneal hypoxia: decreased oxygen tension that occurs with contact lens use, and especially when contact lenses are worn overnight. If the lids are closed for more than 5 minutes, the oxygen tension drops from 155 mmHg to 57 mmHg.8 Corneal carbon dioxide also increases due to retention and a shift in glucose metabolism that increases the production of CO2, causing a shift to acidic pH in the corneal stroma.9 Stromal edema following hypoxia reflects an osmotic solute load produced by lactate accumulation.9, 10 Corneal swelling occurs in response to the decreased oxygen tension and averages 1–2% overnight in eyes without contact lenses and approximately 9–15% with a conventional low Dk hydrogel lens and eye closure.11, 12 In addition, there is also a slight increase in the temperature of the ocular surface.8

Low Water Content ( 50%)

Surface characteristics: non-ionic

Group I

Group II

Surface characteristics: ionic

Group III

Group IV

Wearers of all types of lenses have a decrease in corneal sensitivity that is, in part, adaptive. This change is more pronounced in the wearers of rigid gas permeable (RGP) lenses than for soft lens wearers.13 Tear film changes due to contact lens wear include decreased volume, owed in part to increased evaporation, which leads to a hyperosmolar shift in the tear film.14 There is also an increase in total tear protein, as well as secretory IgA and albumin, and there is activation of complement and plasminogen with resultant production of chemokines and recruitment of polymorphonuclear lymphocytes.15 The net effect of these changes is a state of subclinical inflammation that plays a part in the development of contact lens-related problems.

RISK FACTORS FOR CONTACT LENS ­COMPLICATIONS We divide risk factors into lens factors and patient factors.

Lens Factors Lens material

Rigid gas permeable (RGP) lenses have been reported to have fewer severe complications than soft daily wear or extended wear lenses.16 Despite the safety of RGP lenses, they have declined in popularity in the United States, representing only 3% of new contact lens fittings.1 Hydrogel (soft) lenses are the most popular, and they are categorized into four groupings for purposes of evaluating effects of accessory products on the lens material. Lenses with less than 50% water content are considered to be “low water” and the others are “high water.” Lenses with less reactive surfaces are termed “nonionic” and more reactive materials are labeled “ionic” (Table 4-24-1). Although frequent replace­ ment low Dk hydrogel lenses are the most commonly used lenses, sili­ cone hydrogel lenses, with their higher oxygen permeability, have been growing in popularity and now represent 25% of new lens fits.1 Silicone lenses have been associated with lower and less severe complication rates than other types.7, 17 Published reports indicate that overnight wearers of silicone hydrogel lenses have corneal swelling of about 3.6% (range 2.7–4.7%) compared to 1.8% for non-lens wearers.18–21 Although this difference is statistically significant, it is not considered clinically significant (overnight wear of conventional hydrogels is associated with a 9–15% swelling).22, 23 In addition, the stromal pH remains normal and there is no increase in endothelial polymegathism.24, 25 It has also been found that silicone lenses have less risk of limbal injection or corneal neovascularization.26, 27 The health of the epithelium is also improved with maintenance of the barrier function.24 The findings that generated the most enthusiasm amongst clinicians with regard to these lenses were those of ­Cavanaugh and others, which demonstrated that bacterial binding to corneal epithelial cells was inversely proportional to the oxygen ­permeability of the lens material.28, 29

4.24

Fig. 4-24-2  When mucus and lipid deposits form around a calcium nidus, the deposits have a characteristic appearance termed “jelly bumps.”

Contact Lens-Related Complications

Fig. 4-24-1  This soft lens shows protein coating that is thin and hazy, but also demonstrates focal protein coating.

Contact lens deposits and lens spoilage

The water content of hydrogel lens material, as well as the chemical and ionic characteristics of the material, affects the degree of lens coating that develops in the course of routine wear, and coating is a factor in the development of some complications. In general, high-water-content lenses (Groups II and IV) accumulate greater amounts of deposits compared to low-water-content lenses (Groups I and III) and ionic lenses (Groups III and IV) tend to accumulate higher levels of protein deposits, such as lysozyme, compared to nonionic lenses.30 Coating begins within minutes of lens insertion, and generally increases with the duration of lens wear. Most of the deposits found on a contact lens are proteins and lipids from the tear film. Proteins (Fig. 4-24-1) appear as a thin hazy coating on the lens surface, and the most common protein found is denatured lysozyme, but albumin and gamma globulin are also deposited.31 Lipid deposits, on the other hand, are predominately from the meibomian glands, and give a greasy or oily appearance to the lens surface.32 Calcium deposits are also found, and these focal deposits typically have a translucent or white appearance. Lipid and mucus can accumulate around these deposits forming a raised mass often referred to as “jelly bumps” (Fig. 4-24-2) because of their characteristic appearance. Studies have suggested that lens deposits may cause both immunologic and mechanical stimulation of the conjunctiva.33, 34 A variety of contaminants in the environment can form lens deposits. These include oils, dirt, lotions, makeup, hairspray powders, perfumes, and other substances transferred from the hands. Hairspray coating is commonly seen and resembles protein coating in appearance. Dust, smoke, and other aerosolized particles can also contribute to lens spoilage. Bacteria, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, as well as fungi and protozoa, can also adhere to lens surfaces. Bacteria can form a biofilm on the surface of a lens or lens case, while the deposits associated with fungi are filamentous in appearance and can even invade the lens polymer, especially high-water-content polymers.35–37 The ability of microorganisms to adhere to the surface of a lens and the increase of epithelial bacterial binding sites, coupled with the fact that contact lens wearers often have compromised epithelium, underscore the multifactorial nature of the risk factors associated with the development of microbial keratitis, one of the most serious contact lens complications.

Lens warpage and damage

Contact lens warpage refers to a change in the base curve of a rigid lens (RGP or polymethyl methacrylate (PMMA)) from the original parameters. These changes can be related to the application of too much pressure or heat during the cleaning process, or storage in an excessively hot environment. Contact lens warpage can lead to a poor fit with excessive or decreased lens movement. This can cause trauma to the epithelium, increasing the likelihood of other lens-related complications. Lens warpage should be suspected if there is a change in the patient’s acuity, and it can be confirmed if changes in the fluorescein pattern are observed. It can be verified in the contact lens lab with a spherometer. Contact lens warpage can lead to corneal warpage, in which the corneal shape changes in an irregular and unpredictable fashion and this can

Fig. 4-24-3  Irregular astigmatism is demonstrated by this topography of a patient with contact lens-induced corneal warpage.

be demonstrated with changes in corneal topography38 (Fig. 4-24-3). Patients may notice reduced vision with their contact lenses, but are more likely to notice blurred vision when the lenses are removed and eyeglasses are worn (spectacle blur). Contact lens-induced topographical changes may resemble keratoconus.

Lens care systems

Proper cleaning of contact lenses is particularly important in lenses that are replaced at intervals longer than 1 month. The current trend in contact lens care is toward the use of multipurpose solutions and “norub” solutions.1 A multipurpose solution may contain surfactant cleaners, disinfecting agents, preservatives, and polymers or conditioners to make the contact lens more comfortable. The disinfecting component contains a concentration of antimicrobial agents sufficient to destroy microorganisms. It requires no separate rubbing or rinsing steps to meet FDA minimum standards for “stand alone” reduction of microorganisms.39 The solution must demonstrate sufficient antimicrobial activity in the “soak only” phase to reduce an inoculum of several bacterial species (Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens) by 3 log units (1000-fold reduction) and fungal (Fusarium solani) and yeast organisms (Candida albicans) by 1 log unit (10-fold reduction) within the manufacturer’s recommended soaking time. The popularity of frequent replacement lenses has contributed to this trend, along with the desire of manufacturers to provide contact lens wearers with convenience. All care products approved for use in the United States must meet or exceed these FDA requirements for ­biocidal ­activity. Many practitioners believe manual rubbing of the contact lenses in the palm of the hand is necessary for complete cleansing.

331

4 CORNEA AND OCULAR SURFACE DISEASES

The impact of lens care products on the risk of developing microbial keratitis is clearly related to their efficacy, but the relationship is more complex. In 2003, researchers found that four common lens care systems actually increased the binding of Pseudomonas to epithelial cells and decreased the rate of epithelial cell exfoliation.40 Another recent study found that contact lens wearers with solution-associated corneal staining were significantly more likely to develop corneal infiltrates.41

Patient Factors

The importance of the role played by the patient in maintaining safe contact lens wear cannot be overstated. The patient has the ultimate control over lens care, wearing, and replacement schedules. Deviation from the practices recommended by the eye care professional is common.42

Pre-existing conditions

Many pre-existing conditions that lead to ocular surface irritation or inflammation can limit a patient’s ability to wear contact lenses. These conditions include allergic eye diseases such as seasonal and perennial allergic conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis. Another particularly common cause of ocular surface irritation is dry eyes or keratoconjunctivitis sicca. Many systemic diseases, such as autoimmune diseases and thyroid disease, can be associated with dry eyes. Rosacea and other dermatologic conditions may be associated with meibomian gland dysfunction and can also affect the quality of the tear film. Patients with these conditions can often be successful contact lens wearers, but attention must be given to the quality and quantity of the tear film to help minimize complications. The use of punctal occlusion, tear supplements, and topical ciclosporin 0.05% (Restasis) can help many patients with dry eyes continue contact lens wear.43, 44 Nonpreserved tear supplements are preferred as preservatives may be absorbed into the matrix of hydrogel lenses and sometimes cause eye irritation. The use of high-water-content lenses is generally avoided in dry-eye patients as the lens may dehydrate and tighten, causing a tight lens syndrome, discussed later in this chapter.

Incomplete blinking

Abnormal blinking is seen frequently in all types of contact lens wear and can lead to ocular surface and contact lens-associated problems. A reduced blink rate or incomplete blink can cause contact lens drying and deposit formation. Reduced tear exchange beneath the contact lens can lead to corneal hypoxia and retention of debris beneath the lens. Collins and coworkers found 22% of blinks were incomplete in both controls and soft contact lens wearers.

Use of medications

The use of many common medications such as diuretics, antihistamines, anticholinergics, and psychotropic medications can cause decreased tear production, increasing surface dryness. Another area of concern is the use of steroids or other immune-modulating drugs that may alter the body’s natural defenses, increasing the risk of infection in contact lens wearers.

Smoking

Several studies have identified smoking as a risk factor for the development of contact lens-related problems, e.g., Schein and coworkers found that smokers had a 1.6-fold increase in risk for ulcerative keratitis with overnight lens wear.4 When smoking was analyzed along with age, the risk of complications was 2.7 times greater in smokers under the age of 30 than nonsmokers of the same age, and this was significant.45

Wearing schedule

332

Some of the physiologic changes that occur with contact lens wear are increased with extended or continuous wear. Epithelial changes also occur, which include thinning of the epithelium and a slowing of the rate of cell exfoliation.46 In addition, there is an increase in the size of the superficial epithelial cells, and a slowing of differentiation of the basal epithelial cell size.47, 48 These same changes are seen when high Dk silicone lenses are worn on an extended wear basis, but the work of Ren and coworkers demonstrates that these changes are significantly reduced with high Dk lenses.49 It is well known that overnight wear is a risk factor for a variety of lens-related problems. Infectious keratitis is potentially blinding and the most feared contact lens complication. The landmark studies by Schein and coworkers, and by Poggio and associates in 1989 identified an incidence of ulcerative keratitis in overnight lens wearers of about 1 in 500, compared to a risk of 1 in 2500 for daily wear.4, 5 Subsequent

work confirmed higher complication rates for overnight wear, whether the lenses used are conventional hydrogels or disposable hydrogels, although the infiltrative events associated with the use of disposable lenses tended to be peripheral and less severe than the central ulcers associated with conventional hydrogels.50–54 It was hoped that silicone hydrogel lenses with their improved oxygen permeability would provide overnight wear with fewer complications, but the rate of infiltrative events appears similar to that found with low Dk lenses.55 Orthokeratology, sometimes called corneal refractive therapy, uses specially designed RGP lenses worn only at night to alter the shape of the cornea. This technique improves uncorrected vision, and is an alternative to conventional lens wear or refractive surgery for some patients. This approach has been around for years but has generated increased interest in recent years with refinement of the technique and the availability of high Dk RGP materials. However, serious complications including bacterial and Acanthamoeba infections have been reported.56–59 Proponents sometimes recommend orthokeratology for children who are too young for refractive surgery, so serious complications are of great concern.

Replacement schedule

It is known that contact lens polymers age, and over time there is an accumulation of deposits on lenses that is only partially removed by lens cleaning and disinfection. As our understanding of the problems associated with coating of lenses and aging of the contact lens polymers has increased, there has been a strong trend for shorter replacement schedules. Single use or daily disposable lenses are the ultimate extension of this concept. Several studies have documented the improved safety profile associated with shorter replacement intervals.

Noncompliance

Patients will often make changes for reasons of economy or convenience, or simply in error. It has long been felt that noncompliance was responsible for a large number of contact lens complications. A 1986 study by Collins and Carney found 74% of patients were noncompliant in at least one aspect of lens use.60 Another study published in 1998 found that 24% of patients never cleaned their lenses prior to disinfection. An additional 5% used only saline for disinfection, and 43% of soft lens wearers and 71% of RGP lens wearers used enzymatic cleaners less than once a month or not at all.53 The situation has not changed much: in a 2003 study, 79.1% of college students and health-care workers admitted not performing lens care properly.61 Studies like these were one force driving the simplification of contact lens wear and care, in the belief that if lens care were made simpler, compliance would be improved.

Unsupervised Lens Wear

Unsupervised lens wear occurs when individuals without contact lens experience obtain lenses from unlicensed sellers without a contact lens prescription. These lenses are typically plano lenses worn to change the color of the eye or for some dramatic effect. The sale of these “black market” lenses occurs at unlikely locations such as convenience stores, nail salons, beauty parlors, internet suppliers, etc. The typical customer is a young person, and the risks may be multiplied by the overnight wearing of these lenses and sharing and swapping of lenses amongst friends. As this practice gained popularity, eye care professionals began to see problems, including infectious keratitis sometimes resulting in loss of vision, hospitalization, and penetrating keratoplasty62–65 (Fig. 4-24-4). The FDA shared the concern of eye care professionals with regard to the danger of these lenses and issued a consumer warning regarding the unsupervised wearing of these lenses in the fall of 2003.66 Finally, legislation was passed classifying these decorative lenses as prescription medical devices and was signed into law (Public law 109-96) in late 2005.67

CONTACT LENS COMPLICATIONS – AN ­ANATOMICAL ANALYSIS Contact lens complications can be analyzed in terms of etiology – infectious, inflammatory, toxic, or allergic. They may also be analyzed by the ocular structure involved.

Conjunctival Complications Giant papillary conjunctivitis

Giant papillary conjunctivitis (GPC), first reported in the 1970s, is thought to be a result of both mechanical irritation and immunologic stimulation.38, 39, 68–70 Patients complain of itching, burning, blurred

4.24

Fig. 4-24-6  As giant papillary conjunctivitis progresses, the papillae can grow to over 1 mm in size, and advanced lid changes may not resolve completely with treatment.

Fig. 4-24-5  Early to moderate giant papillary conjunctivitis, highlighted with fluorescein dye.

Fig. 4-24-7  The use of fluorescein dye highlights the large papillae in this patient with advanced giant papillary conjunctivitis.

vision, increased mucus production, and contact lens intolerance. Examination reveals conjunctival injection, increased mucus in the tear film, contact lens coating, and the characteristic papillae 0.3 mm in size or larger on the tarsal conjunctiva40 (Fig. 4-24-5). As the severity of the problem progresses, the papillae become larger and can reach 1 mm in size (Figs. 4-24-6 and 4-24-7). There is also general thickening of the tarsal conjunctiva and hyperemia. The normal vascular pattern is obscured and in severe cases the apices of the papillae may become white in appearance as fibrosis develops. GPC is associated with lenses worn on an extended wear basis, lenses that are not properly cleaned, and lenses that are not replaced at regular intervals.82 Also, environmental allergies or allergic reactions to systemic medications has been associated.71, 72 It has been hypothesized that a cell-mediated reaction occurs to antigens associated with deposits on the contact lens surface.38 This coating causes trauma to the tarsal conjunctiva and the antigens are then exposed to the ocular immune system initiating the reaction.38, 39, 73–75 GPC has also been reported in non-contact lens wearers who have other causes of mechanical irritation such as exposed sutures, extruded scleral buckles, cyanoacrylate glue, ocular prostheses, and filtering blebs. Treatment of giant papillary conjunctivitis consists of discontinuation of the contact lenses in patients with moderate to severe disease. Symptoms typically improve quickly when the contact lenses are discontinued, but severe cases may require several weeks for symptoms to subside.

Superior limbic keratoconjunctivitis

Hydrogel contact lens wear has been associated with injection and fluorescein staining of the superior bulbar conjunctiva, termed superior limbic keratoconjunctivitis (SLK). Patients experience tearing, burning, a foreign body sensation, and contact lens intolerance. The appearance

Contact Lens-Related Complications

Fig. 4-24-4  This corneal ulcer caused by Pseudomonas aeruginosa occurred in a young man who wore decorative contact lenses without professional supervision.

is similar to idiopathic SLK described by Theodore in 1963 (see Chapter 4-17).76 In contact lens-associated SLK, a papillary reaction is often present on the superior tarsal conjunctiva, but the papillae tend to be smaller then those seen in GPC. The superior corneal epithelium is irregular with a micropannus and punctate staining (Fig. 4-24-8). Superior limbic keratoconjunctivitis in contact lens wearers has been associated with preservatives in contact lens solutions. Poor-fitting contact lenses with resultant mechanical irritation may also be a factor. Discontinuation of lens wear, along with topical lubrication, is generally effective treatment, although resolution may take several weeks or months. A severe form of contact lens-induced keratopathy (CLIK) has been described in which the keratoconjunctivitis progresses to diffuse corneal scarring and vascularization, sometimes requiring penetrating keratoplasty.77 There is destruction of Bowman’s membrane and replacement by fibrous scar tissue with deep stromal vascularization. It is felt by some that this entity represents a contact lens-induced limbal stem cell deficiency.78 Limbal stem cell transplantation or amniotic membrane grafting, or combined grafts, have been used for surface rehabilitation in patients with severe disease as an alternative to penetrating keratoplasty.79–81

Toxic and allergic reactions

Both toxic and allergic conjunctivitis are most likely to occur in response to some component of the lens care system. Allergic reactions are hypersensitivity reactions that occur after repeated exposure to the sensitizing antigen. Thimerosal had been a common offender, but is not used very often today.82 Sorbate and benzalkonium chloride are common offenders now, but any component of a lens care system may cause an allergic or toxic reaction.40 Typically, patients use the care system for 3 months or longer before symptoms of conjunctival ­injection

333

4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-24-8  Conjunctival injection, corneal pannus, and punctate keratitis is seen in contact lens-induced superior limbic keratoconjunctivitis .

and ­irritation develop. Corneal involvement occurs with a superficial punctuate keratopathy or scattered infiltrates. Discontinuation of the solution results in resolution of symptoms, but if the symptoms are severe, a short course of topical steroids may be needed. Toxic conjunctivitis can also occur in response to lens care solutions, but can occur the first time the solution is used, or may result from a buildup of the toxic component in the hydrogel material (Fig. 4-24-9). Patients with a toxic reaction experience immediate ocular discomfort and conjunctival injection when their lenses are inserted. Corneal involvement with superficial punctate keratitis can also be seen. On examination, conjunctival hyperemia, follicles, corneal epithelial erosions, fine infiltrates, and superior limbic keratoconjunctivitis may be seen. Incorrect use of solutions and cleaners can also cause toxic reactions. Incomplete rinsing of surfactant cleaner or failure to neutralize peroxide-based solutions are common causes of toxic conjunctivitis.40 When toxic reactions occur, the contact lenses should be discontinued and nonpreserved tears should be started. A short course of topical steroids can be used if the inflammation is severe. Patients can be switched to care systems with different preservatives, such as Polyquad or Dymed (which may also cause toxic reactions), or to a nonpreserved system or a peroxide-based system, and should also use a nonpreserved, aerosolized saline. The use of daily disposable lenses to avoid contact with lens care solutions is another effective approach.

Fig. 4-24-9  Generalized conjunctival injection is seen in this patient with a toxic reaction to a contact lens cleaning solution.

Corneal Complications

Corneal staining and superficial punctate keratitis

Contact lens-associated superficial punctate keratitis (SPK), the most common corneal complication, may have many causes including toxic and allergic reactions.83, 84 The most common cause of contact lens SPK is likely dry eyes, but other causes include mechanical irritation, hypoxia, tight lens syndrome, and contact lens over wear. Careful observation of the pattern of staining, along with associated symptoms, may aid in determining the specific cause.85 Staining at the 3 and 9 o’clock positions on the peripheral cornea is one of the most common patterns seen with contact lens wear. It occurs most frequently with RGP lenses, but a similar pattern can sometimes be seen with hydrogel lenses. The staining should improve with a properly fit lens, supplemental lubrication, or improved blinking by the patient. Mild-to-moderate SPK on the inferior one third to one half of the cornea suggests dry eyes associated with contact lens wear. Patients experience symptoms of burning, irritation, and dryness. Environmental factors such as low humidity, wind, smoke, and dust may exacerbate the condition. A variety of mechanical causes can also result in SPK, including lens defects, such as tears or cracks, lens dehydration, or debris trapped under the lens (Fig. 4-24-10). Trauma to the epithelium may occur with lens insertion or removal. If lens damage is seen, replacement is needed and any causes of debris in the tear film should be addressed.

Epithelial microcysts

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Microcysts are small (10–50 μm), irregular epithelial vesicles most often seen with extended wear hydrogel lenses and often caused by hypoxia (Fig. 4-24-11).86, 87 Although generally associated with extended wear, microcysts are seen in daily wear lens wearers and even non-lens

Fig. 4-24-10  The localized superficial punctate staining seen in this contact lens wearer was caused by debris beneath his contact lens.

­ earers. The incidence varies between 30% and 49%, but typically w only a few microcysts are seen.88, 89 Epithelial microcysts are generally thought to be benign and are an incidental finding.

Mucin balls/retrolental debris

Debris trapped behind contact lenses may be associated with adverse reactions in extended wear. With low Dk hydrogel materials, streaks and clumps of cellular material have been reported after overnight wear, but high Dk silicone lens wearers sometimes develop distinctive back surface debris known as mucin balls. They form spherical, translucent deposits that cause indentations of the ocular surface observed immediately after lens removal90 (Fig. 4-24-12). Although mucin balls are seen in the wearers of conventional hydrogel lenses, they are more commonly seem in the wearers of high Dk lenses.91 Mucin balls are generally felt to be a benign finding, but must be differentiated from corneal staining.

Superior epithelial arcuate lesions (SEALs)

A superior epithelial arcuate lesion, or epithelial splitting, is a particular type of epithelial defect that has been associated with silicone hydrogel lenses; it is seen less frequently with conventional hydrogel lenses.92, 93

4.24 Contact Lens-Related Complications

Fig. 4-24-11  Epithelial microcysts in a contact lens wearer are often a sign of corneal hypoxia. Fig. 4-24-13  Stromal thickening and faint endothelial striae are seen in a patient with chronic stromal edema.

Fig. 4-24-12  Mucin balls are most often seen beneath the contact lens in patients wearing silicone hydrogel lenses and are thought to be a benign finding.

This is believed to be a mechanical event, and the silicone polymer’s stiffer modulus of elasticity is the reason it is seen more frequently with that lens.94 Patients may have burning, irritation, redness, and lens awareness, but more often they are asymptomatic while wearing their lenses, and experience a foreign body sensation after the lenses are removed. On examination, an area of arcuate linear staining is seen at the superior limbus. The cause is unknown.95, 110 Discontinuation of the lens and treatment with lubricating drops and topical antibiotics should result in resolution of the defect.

Corneal edema/hypoxia

The corneal findings with hypoxia will vary depending on the chronicity of the condition. Diffuse microcystic epithelial changes in the central cornea are associated with acute edema (“Sattler’s Veil”), but with continuing hypoxia epithelial cell death occurs leading to epithelial erosion or necrosis and desquamation.96 This causes decreased vision, pain, tearing, and photophobia. Chronic edema is more common with extended wear, and the symptoms and findings may be subtler. Chronic low-grade hypoxia causes gradual alterations in corneal physiology and structure, with epithelial microcysts, stromal thickening and striae, and endothelial blebs11 (Fig. 4-24-13). If hypoxia persists, corneal neovascular ingrowth may occur (Fig. 4-24-14). Patients may be asymptomatic or experience only subtle blurring of their vision when they awake. If the patient is examined late in the day, the

Fig. 4-24-14  Chronic hypoxia associated with contact lens wear can lead to corneal neovascularization.

examination may be normal, but an early morning examination may reveal evidence of edema. The solution to hypoxia is discontinuation of lens wear with refitting to a high Dk material when the edema resolves.

Tight lens syndrome

Hydrogel lenses, especially those with high water content, are prone to dehydration on the eye. This can lead to steepening of the base curve and tightening of the lens fit. Patients note irritation, pain, photophobia, and blurred vision after a period of lens wear. The conjunctiva becomes injected and the lens shows very poor movement on the eye. After the lens is removed, there is sometimes an “imprint” of the lens on the conjunctiva and there will be corneal edema and superficial punctate staining of the corneal epithelium114 (Fig. 4-24-15). Epithelial defects and infiltrates may be seen; and in severe cases, anterior chamber flare and cells. Treatment options depend on the severity of the inflammation. Early recognition is important. In all cases, the tight lens must be discontinued. If the inflammation is severe, topical steroids and cycloplegia may be needed. If the epithelium is compromised, a short course of prophylactic topical antibiotics may be wise. In less severe cases, lubrication and lens discontinuation may suffice. Refitting with a lower water content lens or a high Dk lens when the inflammation has resolved is necessary for continued lens wear.

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4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-24-15  When a contact lens is removed in tight lens syndrome, the lens may leave an imprint on the conjunctiva, and this lens impingement is best seen with fluorescein dye.

Fig. 4-24-17  Contact lens-induced acute red eye (CLARE) is seen most often in patients after overnight lens wear.

Contact lens-induced acute red eye

Contact lens-induced acute red eye (CLARE), first reported in 1978, is an inflammatory condition associated with extended wear contact lenses and is characterized by the acute onset of a red eye with associated corneal infiltrates.101 The infiltrates are in the anterior stroma, typically near the limbus, and there may be an associated cellular ­reaction (Fig. 4-24-17). The epithelium is intact or may show mild overlying SPK.33 Symptoms are usually unilateral and consist of ocular discomfort, foreign body sensation, and redness noted upon awakening. These signs and symptoms may occur in as many as 12% of extended wear patients.102 When cultures are obtained, bacteria are sometimes isolated from the contact lenses of these patients, leading to the hypothesis of toxins from these bacteria causing an inflammatory response in conjunction with the closed eye conditions.103 Discontinuation of lens wear is typically the only treatment required and CLARE will typically resolve within 2 weeks, although recurrences have been reported with a return to extended wear.

Infiltrative keratitis

Fig. 4-24-16  Rarely, corneal neovascularization can lead to an intrastromal hemorrhage, seen at the 2 o’clock position in this patient.

Neovascularization

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Corneal neovascularization probably is related to chronic low-grade hypoxia that results in the accumulation of lactic acid and carbon dioxide, with resulting stimulation of vascular ingrowth.11, 118 It is also related to hypoxic dilation of limbal vessels.97 Typically it is associated with low Dk hydrogel lenses, but it may also be seen with RGP lenses due to poor lens fit and chronic irritation. Although the use of PMMA lenses is rare, a poor fitting PMMA lens with poor tear exchange can result in chronic hypoxia as the lens itself is impermeable to oxygen. Superficial neovascular changes are common in patients wearing conventional hydrogel lenses on a regular basis, and a small amount of superficial neovascular change is acceptable if it extends less than 1.5 mm onto the cornea. Vascular ingrowth in the corneal stroma is more worrisome as these vessels can lead to lipid exudation, scarring, and intracorneal hemorrhages (Fig. 4-24-16). If neovascular changes are mild, the patient can simply be monitored, but refitting with a flatter lens with better oxygen permeability, such as a high Dk silicone contact lens or an RGP lens, may be advantageous. On the other hand, stromal neovascular changes or superficial neovascularization that extends more than 2 mm onto the cornea should be considered abnormal and unacceptable. When the ­patient is refitted with high Dk silicone hydrogel lenses, regression of the abnormal vessels can occur, and limbal erythema is reduced.98–100

An agreed upon unified classification of corneal infiltrates has not been established.125, 104–106 To make matters more complicated, the same clinical entity may be discussed under several different names in the literature; for example, small peripheral corneal infiltrates have ­variously been called sterile infiltrates, peripheral infiltrates, and ­contact lens-induced peripheral ulcers (CLPU). In addition, laboratory studies ­including cultures of suspected lesions are not as helpful as one would hope. Cultures of “obvious” microbial keratitis are positive about 43–86% of the time.107–109 Yet one study of “sterile” peripheral infiltrates found positive cultures in 50% of the subset of patients who were cultured.110 Peripheral corneal infiltrates and central infiltrates typically have markedly different implications regarding etiology, treatment, and prognosis. This was confirmed in a recent study by Efron and associates that found a significant correlation between severity of an infiltrate and distance from the corneal limbus.111

Peripheral corneal infiltrates

Peripheral infiltrates of the cornea are thought to be inflammatory events caused by an immunologic reaction to the lens material, a component of the lens care system, or microbes. Multiple other causes have been proposed and investigated, including hypoxia, retrolental debris, staphylococcal immune complexes, and infectious agents.112–115 Infiltrates are grayish-white, small (usually less than 1.5 mm), round or oval, subepithelial, and located in the peripheral cornea (Fig. 4-24-18). These infiltrates may be single or multiple, and the epithelium is usually intact or may show overlying SPK, and the anterior chamber shows no more than minimal reaction.116–118 Symptoms typically include irritation, pain, and a foreign body sensation. If the

4.24

inflammation is severe, patients may complain of photophobia and tearing. Corneal infiltrates are composed of polymorphonuclear leukocytes and mononuclear cells that migrate from the tear film and limbal arcades in response to chemotactic factors.119, 124 Many clinicians believe that small peripheral infiltrates do not require cultures, but organisms have been isolated from cultures of peripheral infiltrates, particularly in the presence of an epithelial defect.142, 143 When organisms are cultured from patients with peripheral infiltrates, the organisms recovered are generally less virulent than those associated with central ulcers. The most common isolate is Staphylococcus species, but even in the face of positive cultures, many researchers believe the cause of peripheral infiltrates is inflammatory.120, 121 Nevertheless, along with discontinuation of contact lenses, many clinicians prefer to give patients a short course of topical, broad-spectrum antibiotics, such as one of the fluoroquinolones. Because the clinical appearance can change rapidly, most patients are seen back in 24 hours and therapy is modified based on the changes in the infiltrate. Because of the serious consequences of bacterial keratitis, patients wearing extended wear lenses, particularly with an associated epithelial defect or significant inflammation, should be cultured before beginning therapy. Any patient who presents with corneal infiltration and pain out of proportion to the slit-lamp findings should be considered to have possible Acanthamoeba infection, particularly if appropriate risk factors are present.

Microbial keratitis

Contact lens wear is now considered a major risk factor for the development of microbial keratitis, and about 65% of all new ulcers are contact lens related.122, 123 In contrast to ulcerative keratitis that occurs in non-contact lens wearers where gram-positive organisms predominate, the most common isolates from contact lens wearers are gram-negative organisms, particularly Pseudomonas aeruginosa, followed by gram-positive organisms (Staphylococcus species predominate), fungi, and Acanthamoeba.124–127 Overnight lens wear is the major risk factor for the ­development of microbial keratitis. Schein and associates and Abelson and coworkers found the risk of ulcerative keratitis in extended wear ­patients to be 0.2%, 5 times the risk found in daily wear patients.4, 5 Subsequent work by other investigators has confirmed the risk of overnight lens wear.64–66, 128 Ten years after the Poggio and Abelson studies, a study in the Netherlands found similar rates of microbial keratitis with lens use.2 Dk silicone lenses have a low incidence of vision loss due to microbial keratitis; the overall rate of presumed microbial keratitis with up to 30 nights of continuous wear was similar to that previously reported for conventional extended wear soft lenses worn for fewer consecutive nights.129 Infiltrates in microbial keratitis are usually larger than 1.5 mm, stromal, and are often white with an overlying epithelial defect (Fig. 4-24-19). The conjunctiva shows significant injection, and anterior chamber activity is frequently seen associated with microbial infection of the ­cornea. Patients typically are symptomatic and complain of significant pain, irritation, photophobia, and tearing. Suspected microbial ulcers must be scraped, cultured, and a Gram stain should be performed. If possible, contact lens care solutions and the contact lens case should be cultured along with the ulcer. Aggressive therapy using broad-spectrum topical

Fig. 4-24-19  This Fusarium ulcer occurred in a contact lens wearer using ReNu with MoistureLoc, which was subsequently withdrawn from the market.

Contact Lens-Related Complications

Fig. 4-24-18  This patient has several peripheral corneal infiltrates, often called sterile or immune infiltrates, and they are often thought to be an immunologic reaction to toxins produced by staph species.

fortified antibiotics should be initiated as soon as possible. A combination of either fortified cefazolin or vancomycin and tobramycin or gentamicin is recommended. Careful follow-up and adjustment of therapy based on identification of the organism, sensitivity testing, and clinical response is essential. Duration of therapy is determined by clinical response. Unfortunately, patients with microbial keratitis are often left with corneal scarring and decreased acuity, as these lesions are often central in location. It has been reported that 25% of patients are left with irregular astigmatism and visual acuity less than 20/200.130 Patients may need to undergo corneal transplantation to improve visual acuity after the eye has healed completely. Although microbial keratitis is relatively rare, the risk is real and occurs in about 1 in 2500 daily wear lens users. Extended wear increases the risk approximately fivefold with a rate of about 1 in 500.

Fungal keratitis

Fungal infections are a relatively rare cause of corneal infection; trauma and immune suppression are thought to be important predisposing factors.131 All types of contact lenses have been associated with fungal keratitis, and it has even been reported in association with daily disposable lenses.132 When fungal infections do occur with contact lens wear, Candida species have been the most common nonfilamentous isolate, and Aspergillus and Fusarium have been the most common filamentous offenders.133 The wide variation in the reported incidence (1–35%) is largely dependent on the geography of the reporting site, with fungal infections, including Fusarium, commonly found in tropical locations, but rare in temperate zones. Patients with fungal infections present with decreased vision, injection, and pain, which may be severe. Early filamentous fungal infections have a feathery appearance at the edges and may be less dense than those seen with bacterial keratitis. Fungal infections in general are slowly progressive, and there is often a delay in the correct diagnosis. Cultures and Gram stains from corneal scrapings should be taken, and cultures of the lenses and lens cases are also advised. In late 2005, eye care professionals in Singapore and Hong Kong began to notice an unusual increase in Fusarium corneal infections in contact lens wearers, and there seemed to be an association with a specific lens care product.134 In the spring of 2006, eye care professionals in the United States began to see Fusarium infections of the cornea in contact lens wearers, also apparently associated with the same product135 (see Fig. 4-24-19). These infections were ultimately seen in 33 states, including northern states where Fusarium infection is typically rare. Subsequently, ReNu with MoistureLoc (Bausch & Lomb, Rochester, New York) was withdrawn from the market worldwide. Researchers found that although this lens care product had easily passed existing FDA standards for biocidal efficacy against Fusarium in the laboratory, when tested under simulated conditions of patient noncompliance, there was a marked reduction of efficacy against Fusarium species.136 Although the total number of cases in the United States and worldwide are small, this incident gained national attention and calls into sharp focus the importance of proper lens care and the role of patient compliance in safe contact lens wear.

337

is resistant to treatment, resulting in recurrences and a protracted clinical course. Penetrating keratoplasty is often required, but infection may reoccur in the graft. Acanthamoeba keratitis typically presents as a unilateral central or paracentral corneal infiltrate, often with a ring-shaped peripheral infiltrate or a radial keratoneuritis with infiltrates along the corneal nerves (Fig. 4-24-20). The lesion is often confused with fungal, bacterial, or herpetic keratitis. The rate of Acanthamoeba infection has been reported to be 0.2–1 infections per 10 000 contact lens wearers per year.138, 139 Recent work by Mathers, using confocal microscopy, found evidence of Acanthamoeba infection at a rate 10 times higher than the previously reported rates.140 This work suggests that many infections are mild and respond to treatment, or simply fail to develop the full spectrum of corneal disease.

4 CORNEA AND OCULAR SURFACE DISEASES

CONCLUSIONS Fig. 4-24-20  Patients with Acanthamoeba keratitis often show radial keratoneuritis (arrow) with infiltration along the corneal nerves.

Acanthamoeba keratitis

Acanthamoeba infections have been associated with wearing contact lenses while swimming or using tap water as part of the lens care ­regimen.137 Acanthamoeba have the ability to bind to contact lenses and cases.162 Pain is usually severe, and the encysted form of the ­organism

Overall, contact lenses have a very good safety profile, and many complex factors affect the safety of contact lens wear. Despite new lens materials and our increased understanding of contact lenses, ­complications continue to occur. The twin driving forces of ­convenience and safety sometimes work oppositely. In addition, the involvement of the eye care professional has been threatened by alternative lens suppliers, including internet lens sellers and other discounters who compete for a share of the 1.9 billion dollar United States ­market. It is the responsibility of eye care professionals to inform their patients regarding the risks of contact lens wear, and ways to ­minimize those risks.

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84. Cunha M, Thomassen TS, Cohen EJ, et al. ­Complications associated with soft contact lens use. CLAO J. 1987;13:107–11. 85. Watanabe K, Hamano H. The typical pattern of superficial punctate keratopathy in wearers of extended wear disposable contact lenses. CLAO J. 1997;23:134–6. 86. Rivera RK, Polse KA. Corneal response to different   oxygen levels during extended wear. CLAO J. 1991;17:  96–101. 87. Holden BA, Grant T, Kotow M, et al. Epithelial microcysts with daily and extended wear of hydrogel and rigid gas permeable contact lenses. Invest Ophthalmol Vis Sci. 1987;28(Suppl):372. 88. Zantos S. Cystic formations in the corneal epithelium during extended wear of contact lenses. Int Contact Lens Clin. 1983;10:128–46. 89. Hickson S, Papas E. Prevalence of idiopathic corneal anomalies in a non contact lens-wearing population. Optom Vis Sci. 1997;74:293–7. 90. Pritchard N, Jones L, Dumbleton K, Fonn D. Epithelial inclusions in association with mucin ball development in high-oxygen permeability hydrogel lenses. Optom Vis Sci. 2000;77:68–72. 91. Tan J, Keay L, Jalbert I, et al. Mucin balls with wear of conventional and silicone hydrogel contact lenses. Optom Vis Sci. 2003;80:291–7. 92. Horowitz GS, Lin J, Chew HC. An unusual corneal complication of soft contact lenses. Am J Ophthalmol. 1985;100:794–7. 93. Jalbert I, Sweeney DF, Holden BA. Epithelial split associated with wear of a silicone hydrogel contact lens. CLAO J. 2001;27:231–3. 94. Morgan PB, Efron ND, Maldonado-Cosina C, et al. Adverse events and discontinuations with rigid and soft hyper Dk contact lenses used for continuous wear. Optom Vis Sci. 2005;82:528–35. 95. Davis LJ, Lebow KA. Noninfectious corneal staining. In: Silbert J, ed. Anterior segment complications of contact lens wear. Boston: Butterworth-Heineman; 2000 :67–93. 96. Stapleton F, Dart J, Minassian D. Non-ulcerative complications of contact lens wear. Arch Opthalmol. 1992;110:1601–6. 97. Holden BA, Sweeney DF, Swarbick HA, et al. The vascular response to long-term extended contact lens wear. Clin Exp Optom. 1986;69:112–9. 98. Covey M, Sweeney DF, Terry RL, et al. Hypoxic effects on the anterior eye of high Dk soft contact lens wearers are negligible. Optom Vis Sci. 2001;78:95–9. 99. Stefansson E, Foulks GN, Hamilton RC. The effect of corneal contact lenses on the oxygen tension in the anterior chamber of the rabbit eye. Invest Ophthalmol Vis Sci. 1987;28:1716–9. 100. Stretton S, Jalbert I, Sweeney DF. Cornea hypoxia secondary to contact lenses: the effect of high-Dk lenses. Ophthalmol Clin North Am. 2003;16:327–40. 101. Zantos SG, Holden BA. Ocular changes associated with continuous wear of contact lenses. Aust J Optom. 1978;62A:418–26. 102. Holden BA, Sankaridurg PR, Jalbert I. Adverse events and infection: which ones and how many?. In: Sweeney DF, ed. Silicone hydrogels: the rebirth of continuous wear contact lenses. Oxford and Boston: Butterworth-Heineman, Linacre House Jordan Hill; 2000 :150–213. 103. Sankaridurg PR, Sharma S, Wilcox M, et al. Colonization of hydrogel lenses with Streptococcus pneumoniae: risk of development of corneal infiltrates. Cornea. 1999;19:289–95. 104. Sweeny DF, Jalbert I, Covey M, et al. Clinical characterization of corneal infiltrative events observed with soft contact lens wear. Cornea. 2003;22:435–42. 105. Efron N, Morgan PB. Can subtypes of contact lens­associated corneal infiltrative events be clinically ­differentiated? Cornea. 2006;25:540–4. 106. Baum J, Donshik PC. Corneal infiltrates associated with soft contact lens wear. Cornea. 2004;23:421–2. 107. Srinivasan M, Gonzales CA, George C, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, South India. Br J Ophthalmol. 1997;81:965–71. 108. Levey HB, Katz HR, Abraham DA, et al. The role of cultures in the management of ulcerative keratitis. Cornea. 1997;16:383–6. 109. Schaefer F, Bruttin O, Zografos L, Guex-Crosier Y. Bacterial keratitis: a prospective clinical and microbiological study. Br J Ophthalmol. 2001;85:842–7. 110. Donshik PC, Suchecki JK, Ehlers WH. Peripheral corneal infiltrates associated with contact lens wear. Trans Am Ophthalmol Soc. 1995;93:49–64.

111. Efron N, Morgan PB, Hill E, et al. The size, location, and clinical severity of infiltrative events associated with contact lens wear. Optom Vis Sci. 2005;82:519–27. 112. Aquavella JV, Depaolis MD. Sterile infiltrates associated with contact lens wear. Int Ophthalmol Clin. 1991;31:127–31. 113. Smolin G, Okumoto M, Nozik RA. The microbial flora in extended wear soft contact lens wearers. Am J ­Ophthalmol. 1979;88:543–7. 114. Mondino BJ, Groden LR. Conjunctival hyperemia and corneal infiltrates with chemically disinfected soft ­contact lenses. Arch Ophthalmol. 1980;98:1767–70. 115. Vikoren Mertz PH, Bouchard CS, Mathers WD, et al. Corneal infiltrates associated with disposable extended wear soft contact lenses: a report of nine cases. CLAO J. 1990;16:269–72. 116. Stein RM, Clinch TE, Cohen EJ, et al. Infected vs. sterile corneal infiltrates in contact lens wearers. Am J Ophthalmol. 1988;105:632–6. 117. Suchecki JK, Ehlers WH, Donshik PC. Peripheral corneal infiltrates associated with contact lens wear. CLAO J. 1996;22:41–6. 118. Bates AK, Morris RJ, Stapleton F, et al. ‘Sterile’ corneal infiltrates in contact lens wearers. Eye. 1989;3:803–10. 119. Mondino BJ, Kowalski R, Ratajczak HV, et al. Rabbit model phlyctenulosis and catarrhal infiltrates. Arch Ophthalmol. 1981;99:891–5. 120. Holden BA, Reddy MK, Sankaridurg PR. Contact lens induced peripheral ulcers with extended wear of disposable hydrogel lenses: histopathologic observations on nature and type of corneal infiltrate. Cornea. 1999;28:538–43. 121. Baum J, Dabezies OH. Pathogenesis and treatment   of “sterile” midperipheral corneal infiltrates associated with soft contact lens use. Cornea. 2000;19:771–81. 122. Erie JC, Nevitt MP, Hodge DO, Ballard DJ. Incidence of ulcerative keratitis in a defined population from 1950 through 1988. Arch Ophthalmol. 1993;111:1665–71. 123. Stern GA. Contact lens associated bacterial keratitis: past, present, future. CLAO J. 1998;24:52–6. 124. Cohen EJ, Gonzalez C, Leavitt KG, et al. Corneal ulcers   associated with contact lenses including experience with disposable lenses. CLAO J. 1991;17:173–6. 125. Laibson PR, Cohen EJ, Rajesh RK. Corneal ulcers related to contact lenses. CLAO J. 1993;19:73–8. 126. Liesegang TJ. Contact lens-related microbial keratitis. Part I. Epidemiology. Cornea. 1997;16:125–31. 127. Varaprasathan G, Miller K, Lietman T, et al. Trends in the etiology of infectious corneal ulcers at the F.I. Proctor Foundation. Cornea. 2004;23:360–4. 128. Dart JKG, Stapleton F, Minassian D. Contact lenses and other risk factors in microbial keratitis. Lancet. 1991;338:650–3. 129. Schein OD, McNally JJ, Katz J. The incidence of   micro­bial keratitis among wearers of a 30-day silicone hydrogel extended-wear contact lens. Ophthalmol. 2005;112:2172–9. 130. Wilhelmus KR. Review of clinical experience with microbial keratitis associated with contact lens wear. CLAO J. 1987;12:211–4. 131. Dignani MC, Anaissie E. Human fusariosis. Clin Microbiol Infect. 2004;10(Suppl 1):67–75. 132. Le Liboux MJ, Ibara SA, Quinio D, et al. Fungal keratitis in a daily disposable soft contact lens wearer. J Fr Ophtalmol. 2004;27:401–3. 133. Thomas PA. Fungal infections of the cornea. Eye. 2003;17:852–62. 134. Khor W-B, Aung T, Saw S-M, et al. An outbreak of   Fusarium keratitis associated with contact lens wear   in Singapore. JAMA. 2006;295:2867–73. 135. Chang DC, Grant GB, O’Donnell K, et al. Multi-state outbreak of Fusarium keratitis associated with the use   of a contact lens solution. JAMA. 2006;296:953–63. 136. Levy B, Heiler D, Norton S. Report on testing from an investigation of Fusarium keratitis in contact lens wearers. Eye Contact Lens. 2006;32:256–61. 137. Stehr-Green JK, Bailey TM, Visvesvara GS. The epidemiology of acanthamoeba keratitis in the United States.   Am J Opthalmol. 1989;107:331–6. 138. Radford CF, Minassian DE, Dart JK. Acanthamoeba keratitis in England and Wales; incidence, outcome, and risk factors. Br J Ophthalmol. 2002;86:536–42. 139. Mathers WD, Nelson SE, Lane JL, et al. Confirmation of confocal microscopic diagnosis of acanthamoeba keratitis using polymerase chain reaction analysis. Arch Opthalmol. 2000;118:178–83. 140. Mathers WD. Acanthamoeba: A difficult pathogen to evaluate and treat. Cornea. 2004;23:325.

4.24 Contact Lens-Related Complications

53. Nilsson SEG, Montan PG. The hospitalized cases of contact lens induced keratitis in Sweden and their relation to lens type and wear schedule: results of a three-year retrospective study. CLAO J. 1994;20:97–101. 54. Nilsson SEG, Montan PG. The annualized incidence of contact lens induced keratitis in Sweden and its relation to lens type and wear schedule: results of a three-month prospective study. CLAO J. 1994;20:225–30. 55. Nilsson SEG. Seven-day extended wear and 30-day continuous wear of high oxygen transmissibility soft silicone hydrogel contact lenses: a randomized 1-year study of 504 patients. CLAO J. 2001;27:125–36. 56. Young A. Orthokeratology lens-related corneal ulcers in children. A case series. Ophthalmology. 2004;111:590–5. 57. Wang JC, Med M, Lim L. Unusual morphology in orthokeratology contact lens-related corneal ulcer. Eye Contact Lens. 2003;29:190–2. 58. Wilhelmus K. Acanthamoeba keratitis during orthokeratology. Cornea. 2005;24:864–6. 59. Macsai M. Corneal ulcers in two children wearing Paragon corneal refractive therapy lenses. Eye Contact Lens. 2005;31:9–11. 60. Collins MJ, Carney LG. Compliance with care and ­maintenance procedures amongst contact lens wearers. Clin Exp Optom. 1986;69:174–7. 61. de Oliveira PR, Temporini-Nastari ER, Ruiz Alves M, Kara-Jose N. Self-evaluation of contact lens wearing and care by college students and health care workers. Eye Contact Lens. 2003;29:164–7. 62. Steinemann TL, Pinninti U, Szczotka L, et al. Ocular ­complications associated with the use of cosmetic contact lenses from unlicensed vendors. Eye Contact Lens. 2003;29:196–200. 63. Cavanagh HD. Over the counter cosmetic colored ­contact lenses. Eye Contact Lens. 2003;29:195. 64. Saviola J. Soft plano contact lenses: Medical devices or not? Rev Contact Lens. ������������������������ 2003:16–9. 65. Steinemann TL, Fletcher M, Bonny AE, et al. Over-  the-­counter decorative contact lenses: cosmetic or medical devices? A Case Series. Eye Contact Lens. 2005;31:194–200. 66. Meadows M. FDA issues warning on decorative contact lenses. FDA Consumer. 2003;37:18–9. 67. Amending Federal Food Drug and Cosmetic Act to provide for regulation of all contact lenses as medical devices. Congressional Record,��������������������������������� 16 oct,2005:H9196–8. 68. Spring TF. Reaction to hydrophilic lenses. Med J Aust. 1974;1:449–50. 69. Donshik PC. Giant papillary conjunctivitis. Trans Am Ophthalmol Soc. 1994;92:687–744. 70. Skotnitksy C, Sankaridurg P, Sweeney DF, Holden BA. Generalized and local contact lens induced papillary conjunctivas (CLPC). Clin Exp Optom. 2002;85:193–7. 71. Freidlander MH, Rigglea A, Tuel JA. Some unusual non-allergic causes of GPC. Trans Am Ophthalmol Soc. 1990;88:343–8. 72. Begley CG. Association of GPC with seasonal allergies. Optom Vis Sci. 1990;67:192–5. 73. Pritchard N, Fonn D, Weed K. Ocular and subjective responses to frequent replacement of daily wear contact lenses. CLAO J. 1996;22:53–9. 74. Ehlers WH, Donshik PC, Gillies C. Induction of an inflammatory reaction (similar to GPC) by CF derived from conjunctival cells. Invest Ophthalmol Vis Sci. 1990;31:241. 75. Palmisano PC, Ehlers WH, Donshik PC. Causative factors in unilateral GPC. CLAO J. 1993;19:103–7. 76. Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Monthly. 1963;42:25. 77. Bloomfield SE, Jacobiec FA, Theodore FH. Contact lens induced keratopathy: a severe complication extending the spectrum of keratoconjunctivitis in contact lens wearers. Ophthalmology. 1984;91:290–4. 78. Puangsricharern V, Tseng SC. Cytologic evidence of corneal diseases with limbal stem cell deficiency. ­Ophthalmology. 1995;102:1476–85. 79. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in patients with unilateral corneal stem cell deficiency. Br J Ophthalmol. 2000;84:273–8. 80. Anderson DF, Ellies P, Pires RTF, Tseng SCG. Amniotic membrane transplantation for partial limbal stem cell deficiency. Br J Ophthalmol. 2001;85:567–75. 81. Tseng SC, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol. 1998;116:431–41. 82. Tosti A, Tosti G. Thimerosal: a hidden allergen in ophthalmology. Contact Dermatitis. 1988;18:268–73. 83. Keech PM, Ichikawa L, Barlow W. A prospective study of contact lens complications in a managed care setting. Optom Vis Sci. 1996;73:653–8.

339

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 7 Miscellaneous

Corneal and External Eye Manifestations of Systemic Disease

4.25

Anna C. Newlin, Hormuz Wadia and Joel Sugar

CHROMOSOMAL DISORDERS

Definition:  Disorders with cornea and external eye manifestations as part of systemic syndromes.

The chromosomal disorders are defined by the location of the abnormality in the genetic material (Table 4-25-2). In the future, a more thorough understanding of the regulatory or other gene mechanisms involved will allow better interpretation of the widespread, multisystemic findings in these disorders (see Part I: Genetics). It is often striking how different chromosomal defects may lead to similar phenotypic abnormalities.

Key feature n

Anterior segment anomalies as well as systemic abnormalities.

Associated feature n

INHERITED CONNECTIVE TISSUE DISORDERS

Usually genetic defect with multisystem clinical findings.

Some of the inherited connective tissue disorders are given in Table 4-25-3. More detailed discussions of these disorders are found elsewhere in this text (see Chapters 4-3, 4-19, and 4-21).

INTRODUCTION As seen in many sections throughout this book, the eye commonly exhibits manifestations of more widespread systemic disorders. Although these disorders are too numerous to discuss at length, this chapter presents in tabular form some of the conditions that involve the cornea and external eye. The grouping of these presentations is in some cases obvious and in others more arbitrary. In many, if not most cases, the listings are incomplete, because the intention is to present only disorders that have corneal and external ocular findings. Many other disorders are discussed elsewhere in this book. Where it is appropriate and information is available, genetic localizations are provided.

CONGENITAL Disorders Congenital disorders are nonmetabolic disorders present at birth that have generalized systemic findings as well as ocular abnormalities of the anterior portion of the eye. These groupings are arbitrary and may change as genetic information allows more specific categorizations. Some of the craniofacial malformation syndromes with associated corneal and external disease findings are given in Table 4-25-1. These disorders usually are readily recognizable. Their management requires a multidisciplinary approach with involvement of ophthalmologists, facial plastic surgeons, neurosurgeons, and others.

Fig. 4-25-1  Goldenhar’s syndrome. Pedunculated temporal limbal dermoid present in a patient who had Goldenhar’s syndrome. (With permission from Ziavras E, Farber MG, Diamond G. A pedunculated lipodermoid in oculoauri­ culovertebral dysplasia. Arch Ophthalmol. 1990;108:1032–3.)

 TABLE 4-25-1  CRANIOFACIAL MALFORMATION SYNDROMES WITH CORNEAL INVOLVEMENT

340

Syndrome

Ocular Manifestations

Systemic Manifestations

Gene Locus

Crouzon and Apert

Shallow orbits, decreased motility,   secondary corneal exposure

Craniofacial malformation and syndactyly (Apert)

10q261

Meyer-Schwickerath (oculodentodigital dysplasia)

Microphthalmos and microcornea

Syndactyly, dysplastic tooth enamel

6q22–q242

Goldenhar (oculoauriculovertebral dysplasia)

Limbal dermoids, microphthalmos, anophthalmos, lid notching, blepharophimosis (Fig. 4-25-13)

Facial asymmetry, vertebral anomalies,   ear deformities

Hallermann-Streiff

Microphthalmos, spontaneously   resorbing cataracts, macular   pigment changes, Coats’ disease

Facial malformation, hypoplastic mandible, short stature, skin atrophy

 TABLE 4-25-2  CHROMOSOMAL DISORDERS WITH CORNEAL MANIFESTATIONS

4.25

Ocular Manifestations

Systemic Manifestations

13q deletion

Hypertelorism, ptosis, ­epicanthal folds, microphthalmos, retinoblastoma

Microcephaly, facial ­malformation, absent thumbs

18p deletion

Ptosis, epicanthal folds, hypertelorism, ­corneal opacity, ­keratoconus, ­microphthalmos

Brachycephaly, growth retardation, mental retardation

18q deletion

Hypertelorism, epicanthal folds, nystagmus, corneal opacity, microphthalmos, corneal staphyloma, microcornea

Growth retardation, ­mental retardation, facial malformation, ­microcephaly

18r

Same as 18p deletion, 18q deletion

Growth retardation, ­mental retardation, facial malformation, ­microcephaly

4p deletion (Wolf-Hirschhorn syndrome)

Hypertelorism, ptosis, microphthalmos, strabismus, cataract

Growth retardation, ­microcephaly, micrognathia, hypotonia seizures

Ring D chromosome

Ptosis, epicanthal folds, microphthalmos, strabismus,   nystagmus

Mental retardation, ­microcephaly, facial ­malformation

Turner’s syndrome (45 × 0)4

Ptosis, epicanthal folds, strabismus, rarely microcornea, blue sclera, corneal opacity

Female, short stature, webbed neck

Trisomy 13 (Patau’s syndrome)

Microphthalmos, corneal opacity, Peters’ anomaly, cataract, retinal dysplasia (Fig. 4-25-2)

Microcephaly, cleft lip and palate, low set ears

Trisomy 18 (Edwards’ syndrome)

Corneal opacity, ptosis, epicanthal folds, ­microphthalmos, ­colobomas, cataract, retinal dysplasia

Low birth weight; failure to thrive; brain hypoplasia; cardiac, gastrointestinal, renal, and musculoskeletal anomalies

Trisomy 21 (Down’s syndrome)

Shortened, slanted palpebral fissure, neonatal ectropion, later trichiasis and entropion, keratoconus, cataract

Cardiac defects, mental retardation, short stature,   characteristic facies

Partial trisomy 22 (cat’s eye syndrome)

Microphthalmos, ­hypertelorism, colobomas

Mental retardation, microcephaly, cardiac anomalies, ear anomalies, anal atresia

Corneal and External Eye Manifestations of Systemic Disease

Genetic Findings

 TABLE 4-25-3  INHERITED CONNECTIVE TISSUE DISORDERS WITH CORNEAL MANIFESTATIONS Disease

Biochemical Defect

Gene Locus

Ocular Manifestations

Systemic Manifestations

Marfan syndrome5

Fibrillin-I gene mutations

15q21.1

Megalocornea, lens subluxation, high myopia, retinal detachment

Long extremities, lax joints, aortic/ mitral dilatation, aortic dissection

Osteogenesis imperfecta6

Type I procollagen COLIA1 COLIA2

17q21.31−q22 7q22.1

Blue sclera, keratoconus, megalocornea, optic nerve compression

Bone deformities, otosclerosis, dental anomalies

Ehlers-Danlos syndrome   type VIA7

Lysyl hydroxylase

lp36.3–p36.2

Blue sclera, keratoconus, keratoglobus, lens subluxation, myopia, ocular fragility to trauma

Skin stretching, scarring joint hypermobility, scoliosis

Ehlers-Danlos syndrome   type VIB7

Normal lysyl hydroxylase

Unknown

Same as VIA

Same as VIA

R

A

B

C

C

Fig. 4-25-2  Trisomy 13. (A) An inferior nasal iris coloboma and leukokoria are present. (B) A coloboma of the ciliary body is filled with mesenchymal tissue that contains cartilage (C); note the retinal dysplasia (R). Generally, in trisomy 13, cartilage is present in eyes less than 10 mm in size. (C) A karyotype shows an extra chromosome in group 13 (arrow). (A, Courtesy of Shaffer DB. In: Yanoff M, Fine BS, eds. Ocular pathology, 4th ed. London: Mosby; 1996. C, Courtesy of Drs. B.S. Emanuel and W.J. Mellman.)

341

4

 TABLE 4-25-4  DISORDERS OF PROTEIN AND AMINO ACID METABOLISM

CORNEA AND OCULAR SURFACE DISEASES

Disorder

Enzyme Deficiency

Gene Locus

Metabolite ­Accumulated

Mode of Inheritance

Ocular Manifestations

Systemic Manifestations

Cystinosis8

Probable defect of lysosomal cysteine transport protein

17p13

Cystine

Autosomal recessive

All forms − conjunctival and corneal cystine crystal deposition (needleshaped, refrac­tile, polychromatic crystals in full thickness of peripheral corneal and anterior central stroma), band keratopathy, photophobia Infantile and adolescent forms−patchy retinal abnormalities, occasional macular changes   (Fig. 4-25-3)

Infantile form,   renal failure, death Adolescent form,   renal failure Adult form,   no renal failure

Tyrosinemia9 type II (tyrosinosis, RichnerHanhart syndrome)

Tyrosine transaminase deficiency

16q22.1-22.3

Tyrosine

Autosomal recessive

Dendritiform corneal epithelial changes (branches or snowflake opacities), red eye, photophobia

Palmar–plantar   hyper-keratosis,   mental retardation, growth retardation

Alkaptonuria10

Homogentisate-1, 2-dioxygenase

3q21−q23

Homogentisic acid

Autosomal recessive

Triangular patches of in-trascleral pigmentation near insertion of horizontal rectus muscles, “oil-droplet” opacities in limbal corneal epithelium and Bowman’s layer, pigmented pingue­ culae, irregular pigmented granules   in episclera, no functional changes

Joint pain and stiffness

Wilson’s disease11

Defective excretion of copper from hepatic lysosomes

13q14.3– q21.1

Copper

Autosomal recessive

Kayser-Fleischer ring, “sunflower” cataract (Fig. 4-25-4)12

Liver dysfunction, spasticity, behavior disturbance, nephrotic syndrome

Lattice dystrophy type II (Meretoja’s syndrome)13

Gelsolin gene defect

9q34

Amyloid

Autosomal dominant

Lattice dystrophy, ptosis, glaucoma

Progressive ­cranial ­neuropathy, cardiac ­disease

METABOLIC DISORDERS A number of systemic metabolic disorders of genetic origin affect the anterior portion of the eye. These disorders usually are autosomal ­recessive, and a single enzyme deficiency accounts for the clinical manifestations. In many of these disorders, the specific gene locus has been determined, as has the biochemical defect. Unlike the corneal changes in many of the corneal dystrophies, the corneal changes in metabolic disorders may involve more than one layer of the cornea, affect the peripheral as well as the central cornea, and progress over time. The disorders are subdivided according to the biochemical group in which the abnormality is found.

A

 

Protein and Amino Acid Metabolic Defects

Protein and amino acid metabolic defects are listed in Table 4-25-4. These disorders are quite diverse, both clinically and biochemically.

E

Mucopolysaccharidoses

The mucopolysaccharidoses (Table 4-25-5) are a group of related disorders in which mucopolysaccharides or glycosaminoglycans are ­ progressively accumulated in lysosomes. Glycosaminoglycans are carbohydrates made up of chains of uronic acids and amino and neutral sugars. These chains are joined to protein and form proteoglycans, the ground substance between the collagen fibrils in the corneal stroma. Keratan sulfate (lumican) and chondroitin sulfate or dermatan sulfate (decorin) are found in the normal cornea. Dermatan sulfate is also found in corneal scars. In the mucopolysaccharidoses, deficiency in a catabolic enzyme results in accumulation of glycosaminoglycan. The excess of dermatan sulfate and keratan sulfate in the cornea produces corneal clouding, while excess heparan sulfate results in retinal and central nervous system dysfunction.

Sphingolipidoses

342

C

B

Fig. 4-25-3  Cystinosis. (A) Myriad tiny opacities give the cornea a cloudy ­appearance. (B) Polarization of an unstained histological section of the cornea shows birefringent cystine crystals (C). E, Epithelium. (A, Courtesy of Shaffer DB. In: Yanoff M, Fine BS, eds. Ocular pathology, 4th ed. London: Mosby; 1996.)

The sphingolipidoses also arise from dysfunction of catabolic enzymes that results in accumulation of sphingolipids (Table 4-25-6). A number of sphingolipidoses in which corneal abnormalities do not occur have been described but are not included in this discussion.

in retinal blood vessels, or in the eyelid skin. Greater understanding of these disorders has led to the subdivision of some categories and more specific nomenclature based on the pathophysiological processes involved.

Dyslipoproteinemias

Mucolipidoses

The dyslipoproteinemias (Table 4-25-7) are an often vague group of disorders because of the large number of lipid metabolic processes that exist. They are characterized by accumulation of lipid in the cornea,

The mucolipidoses are characterized by the presence of abnormalities in the carbohydrate moiety of both glycoprotein and glycolipid. Oligosaccharides accumulate, which results in changes similar to

4.25

Fig. 4-25-4  Wilson’s disease, Kayser-Fleischer ring. (A) The deposition of copper in the periphery of Descemet’s membrane, seen as a brown color, partially   obstructs the view of the underlying iris, especially superiorly. A “sunflower” (disciform) cataract is present in the lens of this patient who has Wilson’s disease.   (B) An unstained section shows copper deposition (arrow) in the inner portion of peripheral Descemet’s membrane. (Modified from Tso MOM, Fine BS,   Thorpe HE. Kayser-Fleischer ring and associated cataract in Wilson’s disease. Am J Ophthalmol. 1975;79:479–88.)

 TABLE 4-25-5  THE MUCOPOLYSACCHARIDOSES Mode of Inheritance

Gene Locus

Ocular Manifestations

Systemic Manifestations

Heparan sulfate ­Dermatan sulfate

Autosomal recessive

4p16.3

Corneal clouding, pigmentary retinopathy, optic atrophy, trabecular involvement

Gargoyle facies,   mental retardation, dwarfism, skeletal dysplasia

α-L-Iduronidase

Heparan sulfate ­Dermatan sulfate

Autosomal recessive

4p16.3

Corneal clouding, ­pigmentary retinopathy, opticatrophy, glaucoma

Coarse facies, claw-like hands, aortic valve disease

Mucopolysaccharidosis I-H/S (HurlerScheie syndrome; Fig. 4-25-5)

α-L-Iduronidase

Heparan sulfate ­Dermatan sulfate

Autosomal recessive

4pl6.3

Corneal clouding, ­pigmentary retinopathy, opticatrophy (Fig. 4-25-5)

More severe than I-S, less severe than I-H

Mucopolysaccharidosis II (Hunter’s syndrome)15

Iduronate sulfate sulfatase (iduronate sulfatase)

Heparan sulfate ­Dermatan sulfate

X-Linked recessive

Xq28

Rare corneal clouding, pigmentary retinopathy optic atrophy

Similar to I-H with less bony deformity

Mucopolysaccharidosis III (Sanfilippo’s syndrome)16,17

A: heparin-S-sulfaminidase (heparin sulfate N-sulfatase) B: α-N-acteyl-  glucosaminidase   (N-acetyl   d-glucosaminidase) C: acetyl-CoA-  glucosaminidase-N, N-acetyltransferase D: N-acetylglucosamine6-sulfate sulfatase

Heparan sulfate

Autosomal recessive

17q25.3 17q21.1

All forms: clinically clear cornea, occasional slitlamp corneal opacities (mu-copolysaccharide accumulation in intracytoplasmic vacuoles in keratocytes, endothelium and ­epithelium), ­pigmentary ­retinopathy, optic atrophy

All forms: mild dysmorphism, progressive dementia

Mucopolysaccharidosis IV (Morquio’s syndrome)18, 19

A: galactose-  6-sulfatase B: β-galactosidase

Keratan sulfate

Autosomal recessive Autosomal recessive

16q24.3 3p21.33

Corneal clouding,   optic atrophy

Severe bony deformity, aortic valve disease, normal intelligence

Mucopolysaccharidosis VI (Maroteaux– Lamy syndrome)

N-acetylgalactosamine-4-sulfatase

Dermatan sulfate

Autosomal recessive

5q11–q13

Corneal clouding,   opticatrophy

Similar to I-H, but normal intellect

Mucopolysaccharidosis VII (Sly’s syndrome)

β-glucuronidase

Dermatan sulfate Heparan sulfate

Autosomal recessive

7q21.1

Corneal clouding

Similar to I-H

Disorder

Enzyme Deficiency

Mucopolysaccharidosis I-H (Hurler’s syndrome)14

α-L-Iduronidase

Mucopolysaccharidosis I-S (Schieie’s syndrome)

Metabolite Accumulated

12q14 Chr #14

Corneal and External Eye Manifestations of Systemic Disease

B

A

Mucopolysaccharidosis V (reclassified as mucopolysaccharidosis I-S)

those seen in the mucopolysaccharidoses and the sphingolipidoses (Table 4-25-8).

OCULAR ANATOMICAL DISORDERS Although such a classification of disorders is not biochemically rational, it does provide a framework within which potential associations between disorders that involve both nonocular organs and the eye may

be considered. The corneorenal syndromes are a disparate group of disorders in which corneal abnormalities combine with renal disease (Table 4-25-9). The hepatocorneal syndromes are less common (Table 4-25-10). The cutaneous disorders with anterior segment ocular findings are numerous, and only a few are listed here (Table 4-25-11). This tabular review serves to emphasize the frequent associations ­between systemic disorders and the cornea and external eye. Numerous other disorders exist but are not included in this summary.

343

Fig. 4-25-5  The mucopolysaccharidoses. The cornea is clouded diffusely in this case of HurlerScheie syndrome. (Courtesy of Shaffer DB. In: Yanoff M, Fine BS, eds. Ocular pathology, 4th ed. London: Mosby; 1996.)

4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-25-6  Fabry’s disease. Verticillate changes in the cornea of a   carrier.

TABLE 4-25-6  THE SPHINGOLIPIDOSES Disorder

Enzyme Deficiency

Gene Locus

Metabolite Accumulated

Mode of Inheritance

Ocular Manifestations

Systemic Manifestations

GM2 gangliosidosis II (Sandhoff’s disease)

Hexosaminidase B, HEX B chain

5q13

Ganglioside GM2

Autosomal recessive

Membrane-bound vacuoles within corneal keratocytes, cherry-red macula

Psychomotor   retardation,   hepatosplenomegaly

Metachromatic leuko­ dystrophy (Austin’s juvenile form)20, 21

Arylsulfatase A   isozymes

22q13.31-qter

Sulfatide

Autosomal recessive

Corneal clouding

Mental retardation, seizures

Fabry’s disease22

α-Galactosidase

Xq22

Ceramide trihexoside

X-Linked recessive

Conjunctival and retinal vascular tortuosity, white granular anterior subcapsular lens opacities, oculomotor abnormalities,   whorl-like corneal   epithelial changes (cornea verticillata;  Fig. 4-25-6)

Renal failure,   peripheral   neuropathy

Ocular ­ anifestations M

Systemic ­Manifestations

TABLE 4-25-7  THE DYSLIPOPROTEINEMIAS23

344

Disorder

Deficiency

Gene Locus

Metabolite ­ ccumulated A

Mode of Inheritance

Lecithin–cholesterol   acyltransferase   deficiency24

Lecithin–cholesterol acyltransferase

16q22.1

Free cholesterol

Autosomal recessive

Dense peripheral arcus, diffuse grayish dots in central stroma, no visual changes

Atherosclerosis, renal insufficiency

Fish eye disease (high-  density lipoprotein   lecithin–cholesterol   acyltransferase)25

α-Lecithin–cholesterol acyltransferase

16q22.1

Triglycerides,   very low density   lipoproteins;   low-density   lipoproteins

Autosomal dominant

Progressive graywhite–yellow dot corneal clouding, increased corneal thickness

None

Tangier disease   (analphalipoproteinemia)

High-density ­lipoprotein

9q22–q31

Triglycerides (low high-density lipoproteins, cholesterol and phospholipids)

Autosomal recessive

Fine dot corneal clouding, severe visual loss, incomplete eyelid closure, ectropion, no arcus

Lymphadenopathy ­hepatosplenomegaly, coronary artery ­disease

Hyperlipoproteinemia I   (hyperchylomicronemia)26

Lipoprotein lipase

8p22

Triglycerides,   chylomicrons

Autosomal recessive

Lipemia retinalis, palpebral eruptive xanthomata

Xanthomas

Hyperlipoproteinemia II hyper-β-lipoproteinemia IIa hyper-β-lipoproteinemia IIb

Thought to be ­defective or ­absent low-density ­lipoprotein receptors

Low-density lipo­ proteins, cholesterol Low-density lipo­ proteins, very low density lipoproteins, cholesterol,   triglycerides,   hypertriglyceridemia

Autosomal dominant

Both forms; ­corneal ­arcus, ­conjunctival xanthomata, ­xanthelasma

Coronary artery disease

Hyperlipoproteinemia III (dys-β-lipoproteinemia; broad β-disease)

Defective remnant metabolism in   the liver caused by an abnormality in apolipoprotein E

Very-low-denisty lipoprotein remnants, cholesterol,   triglycerides

Autosomal   recessive with   pseudodominance

Arcus, xanthelasma, lipemia retinalis

Peripheral vascular ­disease, diabetes mellitus

19q13.2

TABLE 4-25-7  THE DYSLIPOPROTEINEMIAS23–cONT’D Mode of Inheritance

Ocular ­Manifestations

Systemic ­Manifestations

Disorder

Deficiency

Hyperlipoproteinemia   IV (hyperpre-β-lipo­ proteinemia)

Unknown

Triglycerides, very low density lipoproteins, cholesterol usually normal

Autosomal dominant

Arcus, xanthelasma, lipemia, retinalis

Vascular disease, diabetes mellitus

Hyperlipoproteinemia   V (hyperprelipoproteinemia and hyperchylomicronemia)

Unknown

Very-low-­density ­lipoproteins, ­chylomicrons

Unknown

Lipemia retinalis,   no arcus

Xanthomas,   hepatosplenomegaly

 TABLE 4-25-8  THE MUCOLIPIDOSES Disorder

Enzyme Deficiency

Gene Locus

Metabolite ­ ccumulated A

Mode of Inheritance

Ocular Manifestations

Systemic Manifestations

Mucolipidosis I (dysmorphic sialidosis, Spranger syndrome)27

Glycoprotein sialidase (neuraminidase I)

6p.21.3

Unknown

Autosomal recessive

Macular cherry-red spot, tortuous retinal and conjunctival vessels, spoke-like lens opacities, progressive corneal clouding

Coarse facies, hearing loss, normal IQ

Mucolipidosis II   (I-cell disease)28

GluNac-I­phosphotransferase

4q21–q23

Increased plasma   lysosomal hydrolases

Autosomal recessive

Small orbits, hypoplastic supraorbital ridges and prominent eyes, glaucoma, megalo-cornea, corneal clouding

Hurler-like facies, mental retardation

Mucolipidosis III (pseudo-Hurler   polydystrophy)29

GluNac-I­phosphotransferase

4q21–q23

Increased plasma   lysosomal hydrolases

Autosomal recessive

Corneal clouding

Milder growth and mental retardation

Mucolipidosis IV (Berman’s syndrome)

Possible ganglioside sialidase

19p13.3–p13.2

Sialogangliosides

Autosomal recessive

Corneal clouding   retinal degeneration

Slowed psychomotor development

Goldberg’s syndrome (galactosialidosis)

β-Galactosidase   Neuraminidase

20q13.1

Unknown

Autosomal recessive

Macular cherry-red spot, diffuse mild corneal clouding, conjunctival telangiectases

Seizures, mental   retardation, hearing loss, hemangiomas

Mannosidosis30

α-d-Mannosidase

19cen–21q

Unknown

Autosomal recessive

No corneal abnormalities or mild corneal clouding lens opacities

Coarse facies,   mental retardation, hearing loss

Fucosidosis

α-l-Fucosidase

lp34

Unknown

Autosomal recessive

4.25 Corneal and External Eye Manifestations of Systemic Disease

Gene Locus

Metabolite ­Accumulated

Coarse facies,   mental retardation, angiokeratoma

 TABLE 4-25-9  CORNEORENAL SYNDROMES Syndrome

Gene Locus

Ocular Manifestations

Systemic Manifestations

Alport mainly X-linked dominant Also X-linked recessive and autosomal recessive

Xq22.3 COL4A5 2q36–q37 COL4A3-COL4A4

Posterior polymorphous corneal dystrophy, juvenile arcus, pigment dispersion, lenticonus, retinal pigmentary changes

Renal failure, hearing loss

Cystinosis

17p13

See Fig. 4-25-3

Infantile form: renal failure, death Intermediate form: renal failure Adult form: no renal failure

Fabry’s disease

Xq22

See Fig. 4-25-6

Renal failure, peripheral neuropathy

Lowe’s syndrome (oculocerebrorenal)

Xq26.1

Corneal keloids, glaucoma, cataracts

Mental retardation, amino acid urea, tubular acidosis, angiokeratomas

Wegener granulomatosis

Nongenetic

Marginal keratitis, scleritis, episcleritis

Granulomatous vasculitis of lungs, kidneys, nasopharynx

WAGR

11p13

Superficial corneal opacity and vascularization, aniridia, glaucoma, foveal hypoplasia, optic nerve hypoplasia

Wilms’ tumor, mental retardation, craniofacial anomalies, growth retardation

Zellweger

2p15(PEX 13) lq22 12p 13.3 (PEX 5) 7q21–q22(PEX1) 6q23–q24

Axenfeld’s anomaly, corneal clouding, glaucoma, retinal degeneration

Craniofacial anomalies, hypotonia seizures, retardation, hepatic degeneration, cystic kidneys, cardiac defects, early death

WAGR, Wilms’ tumor, aniridia, genital anomalies, and mental retardation.

345

4

 TABLE 4-25-10  HEPATOCORNEAL SYNDROMES

CORNEA AND OCULAR SURFACE DISEASES

Syndrome

Gene Locus

Ocular Manifestations

Systemic Manifestations

Gaucher’s disease

lq21

Prominent pingueculae, white deposits   in corneal epithelium, vitreous opacities, paramacular gray ring

Hepatosplenomegaly, bone pain,   accumulation of glucocerebroside

Wilson’s disease

13q14.3–21.1

Kayser-Fleisher ring (see Fig.4-25-4)

Liver dysfunction; neurological   dysfunction with dysarthria, spasticity, behavior disturbances

Zellweger syndrome

7q21–q22

See Table 4-25-9

See Table 4-25-9

Alagille’s syndrome31

20p11.2–p12

Posterior embryotoxon, anterior chamber anomalies, eccentric or ectopic pupils, chorioretinal atrophy, retinal pigment clumping

Cholestatic liver disease, structural heart defects

 TABLE 4-25-11  CUTANEOUS DISORDERS Syndrome

Gene Locus

Ocular Manifestations

Cutaneous/Systemic Manifestations

Basal cell nevus syndrome

9q22.3, 9q31, lp32

Multiple basal cell carcinomas of the eyelid, hypertelorism

Multiple basal cell carcinomas, jaw cysts, bony anomalies

Xeroderma pigmentosum

3p25

Lid neoplasms, conjunctival and corneal neoplasia, corneal exposure, drying

Basal cell carcinoma, squamous cell carcinomas, and malignant melanomas develop in   sun-exposed areas

Ichthyosis (multiple types)

lq21,12q11−q13, 14q11.2, X922.32, 19p 12−q12

Eyelid and lash scaling (all types), ­ectropion with corneal exposure   (lamellar ichthyosis)

Scaly skin

Keratoconjunctivitis with corneal pannus formation

Ichthyosis, deafness

Keratitis-ichthyosis-deafness syndrome Epidermolysis bullosa (numerous types)

lq32, lq25–q31, 10q24.3

Corneal epithelial cysts, blebs, corneal erosions, corneal scarring, conjunctival bullae, eyelid deformities

Skin blistering, contractures in severe   dystrophic type

Ectrodactyly–ectodermal   dysplasia–clefting

7p11.2–q21.3

Dysplasia of meibomian glands, blepharitis, corneal pannus formation, corneal scarring

Lobster-claw deformity of hands and feet,   ectodermal dysplasia, cleft lip and palate

Corneal conjunctival and eyelid scarring, scleral necrosis

Photosensitivity of skin

See Table 4-25-4

See Table 4-25-4

Porphyria (numerous types) Richner-Hanhart syndrome (tyrosinemia type II)

16q.22.1–q22.3

CONCLUSION This brief overview of systemic diseases with corneal involvement, even though incomplete, emphasizes the importance of taking into account the whole patient, not just the cornea or the eye. As our understanding of the basic mechanisms involved in the disorders discussed increases, these conditions will be important areas for new

therapeutic ­ interventions. One such modality of treatment includes enzyme replacement therapy that has recently been used to treat Fabry disease. Enzyme supplementation with alpha-galactosidase A has shown promise compared to placebo in both reduction of symptoms and improvement in organ function. However, more prospective studies are needed to illustrate the long-term beneficial gains of this new therapy.

REFERENCES

346

  1. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165–72.   2. Gladwin A, Donnai D, Metcalfe K, et al. Localization of a gene for oculodentodigital syndrome to human chromosome 6q22–q24. Hum Mol Genet. 1997;6:123–7.   3. Ziavras E, Farber MG, Diamond G. A pedunculated lipodermoid in oculoauriculovertebral dysplasia. Arch Ophthalmol. 1990;108:1032–3.   4. Chrousos GA, Ross JL, Chrousos G, et al. Ocular findings in Turner syndrome. Ophthalmology. 1984;91:926–8.   5. Ramirez F. Fibrillin mutations in Marfan syndrome and ­related phenotypes. Curr Opin Genet Dev. 1996;6:  309–15.   6. Willing MC, Pruchno CJ, Byers PH. Molecular heterogeneity in osteogenesis imperfecta type I. Am J Med Genet. 1993;45:223–7.   7. Hautala T, Byers MG, Eddy RL, et al. Cloning of human lysyl hydroxylase: complete cDNA-derived amino acid sequence and assignment of the gene (PLOD) to chromosome 1p36.3-p36.2. Genomics. 1992;13:62–9.

  8. Jean G, Fuchshuber A, Town MM, et al. High-resolution mapping of the gene for cystinosis, using combined biochemical and linkage analysis. Am J Hum Genet. 1996;58:535–43.   9. Natt E, Kida K, Odievre M, et al. Point mutations in the tyrosine aminotransferase gene in tyrosinemia   type II. Proc Natl Acad Sci USA. 1992;89:  9297–301. 10. Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, et al. The molecular basis of alkaptonuria. Nat Genet. 1996;14:19–24. 11. Thomas GR, Roberts EA, Walshe JM, Cox DW. Haplotypes and mutations in Wilson disease. Am J Hum Genet. 1995;56:1315–9. 12. Tso MOM, Fine BS, Thorpe HE. Kayser-Fleischer ring and associated cataract in Wilson’s disease. Am J Ophthalmol. 1975;79:479–88. 13. Haltia M, Levy E, Meretoja J, et al. Gelsolin gene mutation − at codon 187 − in familial amyloidosis, Finnish:   DNA-diagnostic assay. Am J Med Genet.   1992;42:357–9.

14. Scott HS, Ashton LJ, Eyre HY, et al. Chromosomal   localization of the human alpha-L-iduronidase   gene (IDUA) to 4p16.3. Am J Hum Genet. 1990;  47:802–7. 15. Wilson JP, Meaney CA, Hopwood JJ, Morris CP. S­equence of the human iduronate 2-sulfatase (IDS) gene. Genomics. 1993;17:773–5. 16. Zhao HG, Li HH, Bach G, et al. The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA. 1996;93:6101–5. 17. Zaremba J, Kleijer WJ, Huijmans JG, et al. Chromosomes 14 and 21 as possible candidates for mapping the gene for Sanfilippo disease type IIIC. J Med Genet. 1992;29:514. 18. Tomatsu S, Fukuda S, Yamagishi A, et al. Mucopolysaccharidosis IV A: four new exotic mutations in patients with N-acetylgalactosamine-6-sulfate deficiency.   Am J Hum Genet. 1996;58:950–62. 19. Takano T, Yamanouchi Y. Assignment of human betagalactosidase-A gene to 3p21.33 by fluorescence in situ hybridization. Hum Genet. 1993;92:403–4.

25. Funke H, von Eckardstein A, Pritchard PH, et al. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc Natl Acad Sci U S A. 1991;88:4855–9. 26. Ma Y, Henderson HE, Venmurthy MR, et al. A mutation in the human lipoprotein lipase gene as the most common cause of familial chylomicronemia in French Canadians. N Engl J Med. 1991;324:1761–6. 27. Bonton E, van der Spoel A, Fornerod M, et al. Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev. 1996;10:3156–69. 28. Mueller OT, Honey NK, Little LE, et al. Mucolipidosis II and III: the genetic relationships between two disorders of lysosomal enzyme biosynthesis. J Clin Invest. 1983;72:1016–23.

29. Mueller OT, Wasmuth JJ, Murray JC, et al. Chromosomal assignment of N-acetylglucosaminylophosphotransferase, the lysosomal hydrolase targeting enzyme deficient in mucolipidosis II and III. Cell Genet. 1987;46:664. 30. Nebes VL, Schmidt MC. Human lysosomal alpha-  mannosidase: isolation and nucleotide sequence of the full-length cDNA. Biochem Biophys Res Commun. 1994;200:239–45. 31. Hol FA, Hamel BCJ, Geurds MPA, et al. Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family. Hum Genet. 1995;95:687–90.

4.25 Corneal and External Eye Manifestations of Systemic Disease

20. Stein C, Gieselmann V, Kreysing J, et al. Cloning and expression of human arylsulfatase A. J Biol Chem. 1989;264:1252–9. 21. Gieselmann V, Zlotogora J, Harris A, et al. Molecular genetics of metachromatic leukodystrophy. Hum Mutat. 1994;4:233–42. 22. Bishop DF, Calhoun DH, Bernstein HS, et al. Human alpha galactosidase A; nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci U S A. 1986;83:4859–63. 23. Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism. Surv Ophthalmol. 1991;  36:1–22. 24. McLain J, Fielding C, Drayna D, et al. Cloning and expression of human lecithin-cholesterol acyltransferase cDNA. Proc Natl Acad Sci U S A. 1986;83:2335–9.

347

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 8 Trauma

4.26

Acid and Alkali Burns Steven Rhee and Michael H. Goldstein

Definition:  Chemical exposure to the external eye can result in

trauma ranging from mild irritation to severe damage of the ocular surface and anterior segment with permanent vision loss.

Key features n n n

 lkali burns are typically more severe compared with acid burns. A Acute management should be directed at eliminating the   causative agent. Initial evaluation includes assessment of degree of corneal   epithelial injury, corneal opacity, and limbal ischemia.

Associated features n

L imbal stem cell deficiency, glaucoma, symblepharon, cicitricial entropion, trichiasis, fibrovascular pannus.

INTRODUCTION Chemical exposure to the external eye can result in trauma ranging from mild irritation to severe damage of the ocular surface and anterior segment with permanent vision loss. Chemical burns constitute between 7.7% and 18% of all ocular trauma.1–4 The majority of victims are young. Injuries are usually work related with the remainder occurring at home or during an assault.5, 6 In industry, many caustic chemicals and solvents are used often under high temperature and pressure; ocular injury may occur despite the use of protective equipment. In the household setting, chemicals abound in the form of solutions in automobile batteries, pool cleaners, detergents, ammonia, bleach, and drain cleaners. Although most injuries are mild with minimal sequelae, severe cases present a management challenge (Fig. 4-26-1).

ALKALI INJURIES Alkali injuries occur more frequently than acid injuries and are more severe.1, 5 Common causes of alkali injury include ammonia (NH3), lye (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH)2), and lime (Ca(OH)2).7 Alkalis penetrate more readily into the eye than acids, damaging stroma and endothelium as well as intraocular structures such as the iris, lens, and ciliary body. Ammonia, which is found in household cleaning agents and lye, is associated with the most severe alkali injuries. Ammonia can be detected in the anterior chamber with a rise in pH within seconds of exposure.8 Irreversible intraocular damage has been noted to occur at aqueous pH levels of 11.5 or greater.9 Lime, found in cement and plaster, is the most common cause of alkali injury. Damage from lime injury is limited, however, due to precipitation of calcium soaps that limit further penetration.

ACID INJURIES

348

Sulfuric (H2SO4), sulfurous (H2SO3), hydrofluoric (HF), acetic (CH3COOH), and hydrochloric (HCL) acids are the most common causes of acid burns.7 Hydrofluoric acid causes the most serious acid

Fig. 4-26-1  Complete corneal vascularization and opacification in patient with previous alkali injury. (Courtesy of Anthony J. Aldave, MD.)

i­njuries due to its low molecular weight, which allows easier penetration through the stroma.10 The most common cause of acid burns is sulfuric acid, which is commonly found in industrial cleaners and automobile batteries. The injury may be compounded by thermal burns from heat generated by the acid’s reaction with water on the corneal tear film.11 Acids generally cause less severe ocular injury than alkalis as the immediate precipitation of epithelial proteins offers some protection by acting as a barrier to intraocular penetration causing more superficial damage.12 Very strong or concentrated acids, however, can penetrate the eye just as readily as alkaline solutions.

PATHOPHYSIOLOGY The severity of ocular injury from alkali or acid is related to the type of chemical, the concentration of the solution, the surface area of contact, the duration of exposure, and the degree of penetration. The hydroxyl ion (OH) of alkaline solutions saponifies fatty acids in cell membranes leading to cell disruption and cell death, while the cation component reacts with the carboxyl groups of stromal glycosaminoglycans and collagen.11, 13 The hydrogen ion (H) of acidic solutions alters the pH, while the anion causes protein binding and precipitation in the corneal epithelium and superficial stroma.14 This protein precipitation produces the typical ground glass appearance of the epithelium and acts as a barrier to further penetration. If penetration of either alkali or acid occurs, the hydration of glycosaminoglycans leads to the loss of stromal clarity. The hydration of collagen results in thickening and shortening of the fibrils, which can lead to an immediate rise in intraocular pressure due to shrinkage of the collagenous envelope of the eye as well as distortion of the trabecular meshwork.15 The release of prostaglandins also contributes to the rise in intraocular pressure following alkali and acid injuries.16, 17 In addition to corneal and intraocular injury, chemical burns result in complications due to damage to the conjunctiva and anterior orbital tissues.18 Ischemic necrosis of the conjunctiva induces the loss of vascularization at the limbus as well as the infiltration of leukocytes.14 Late sequelae of severe burns include cicatrization of the conjunctiva with symblepharon formation and entropion.14

CLINICAL COURSE McCulley has divided the clinical course of chemical injury into four distinct phases: immediate, acute (0–7 days), early reparative (7–21 days), and late reparative (after 21 days).11 The clinical findings immediately following chemical exposure can be used to assess the severity and prognosis of the injury. The Hughes classification as modified by Ballen and Roper-Hall provides a prognostic guideline based on corneal appearance and extent of limbal ischemia.26, 27 In Grade I injury, there is corneal epithelial damage, no corneal opacity, no limbal ischemia, and the prognosis is good. In Grade II injury, the cornea is hazy with visible iris details. There is also ischemia involving less than one third of the limbus and the prognosis is good. In Grade III injury, there is total epithelial loss, stromal haze with obscuring of iris details, ischemia of one third to one half of the limbus, and the prognosis is guarded. In Grade IV injury, the cornea is opaque with no view of the iris or pupil, the ischemia is greater than one half of the limbus, and the prognosis is poor. In the acute phase during the first week, Grade I injuries heal while Grade II injuries slowly recover corneal clarity. Grade III and IV ­injuries have little or no re-epithelialization, with no collagenolysis or vascularization. Intraocular pressure may be elevated due to inflammation or decreased due to ciliary body damage.28 During the early reparative phase, re-epithelialization is completed with clearing of opacification in Grade II injury. In more severe cases, there may not be a change in clinical appearance with delayed or arrested re-­epithelialization. Keratocyte proliferation has occurred with production of collagen and collagenase resulting in progressive thinning and potential for perforation.28 In the late reparative phase, re-epithelialization patterns divide injured eyes into two groups. In the first group, epithelialization is complete or is nearly complete with sparing of limbal stem cells. Corneal anesthesia, goblet cell and mucin abnormalities, and irregular epithelial basement membrane regeneration may persist. In the second group, limbal stem cell damage results in corneal re-epithelialization from conjunctival epithelium. This group has the worst prognosis with severe ocular surface damage characterized by vascularization and scarring, goblet cell and mucin deficiency, and recurrent or persistent erosions.28 Ocular surface abnormalities may be exacerbated by symblepharon formation, cicatricial entropion, and trichiasis.14 A fibrovascular pannus results if ulceration does not occur, compromising visual rehabilitation.

THERAPY Immediate Phase

Since the area and duration of contact determines the extent of subsequent injury and prognosis, immediate copious irrigation upon exposure is of paramount importance. Irrigation with the lids held open with a speculum should be initiated and maintained for at least 30 minutes, which would require 1–2 L of solution. If a pH check of tears does not show neutrality, further irrigation must be continued. A retained reservoir of chemical should be suspected if neutrality cannot be achieved, especially with exposure to lime, which can be embedded in the fornices and the upper tarsal conjunctiva.28 After thorough inspection with eversion or double eversion of the lids, lime particles should be removed with forceps; a cotton tipped applicator soaked in EDTA 1% may help with the removal of stubborn particles.29 If an acid burn is suspected, a base should not be used for irrigation in an effort to neutralize the acid. Currently available solutions suitable for irrigation include normal saline, normal saline with bicarbonate, lactated Ringer’s, balanced salt solution, and BSS-plus. No therapeutic differences have been noted among these solutions.30 After copious irrigation, necrotic corneal epithelium should be débrided to promote re-epithelialization. Necrotic conjunctival and subconjunctival tissue in severe injuries provides a stimulus for continued inflammation with recruitment of neutrophils and MMP production and should, therefore, be débrided.29

4.26 Acid and Alkali Burns

Damage to the epithelium with injury to solely the basal lamina and anterior stroma may lead to recurrent corneal erosion. Damage to the limbal stem cells with loss of the phenotypic source of the ­corneal ­epithelium, however, results in more serious injury.19 The cornea ­becomes resurfaced by conjunctival epithelium resulting in delayed re-epithelialization, the persistence of goblet cells within the corneal epithelium, and superficial and deep neovascularization.14 Chemical penetration into the eye may damage stromal keratocytes, stromal nerve endings, endothelium, lens epithelium, and the vascular endothelium of the conjunctiva, episclera, iris, and ciliary body.14 A compromise in the blood–aqueous barrier results leading to a severe fibrinous inflammatory reaction. A compromise in keratocyte collagen synthesis and stromal repair results from decreased secretion from ciliary epithelium of ascorbate, which is a cofactor in the rate-limiting step in collagen synthesis.20 Within 12–24 hours of injury, necrotic tissue of the conjunctiva as well as the hydrolysis of cellular and extracellular proteins produces chemotactic inflammatory mediators that stimulate the infiltration of the peripheral cornea with neutrophils.1, 21 The neutrophils potentiate surface inflammation and release a variety of degradative enzymes such as N-acetylglucosaminidase and cathepsin-D.19 Damage to the corneal stroma and subsequent ulceration is mediated by the interaction among keratocytes, epithelial cells, and neutrophils. Stromal repair is marked by a balance between collagen synthesis and degradation.22 Keratocytes are multipotential cells capable of producing new type I collagen as well as the matrix metalloproteinase (MMP), type I collagenase.23 MMPs are a group of enzymes that can degrade matrix macromolecules such as collagen. The three major groups of MMPs include collagenases, gelatinases, and stromelysins and all require Zn2+ and Ca2+ to function.22 Keratocyte activity may be regulated by cytokines from epithelial cells, inflammatory cells, and other keratocytes. A close interaction exists between keratocytes and the overlying epithelial cells; type I collagenase production by keratocytes is both stimulated and inhibited by epithelial cytokines.24, 25

Acute and Reparative Phases

After irrigation, all efforts are made to promote epithelial wound healing, reduce inflammation, minimize ulceration, and control intraocular pressure. Better outcomes can be expected with prompt re-epithelialization, while delayed or absent re-epithelialization in Grade III or IV injury may require surgical intervention. Intensive corticosteroid therapy (dexamethasone 1% or equivalent q 1 hour) in the first 2 weeks decreases the inflammatory response that can delay epithelial migration, and thus will enhance re-epithelialization in the early phases of injury.31 Corticosteroid use in the first 10 days of injury has no adverse effect on outcome with little risk of sterile ulceration.32 Prolonged use of corticosteroids, however, can be deleterious since steroids can blunt stromal wound repair by decreasing keratocyte migration and collagen synthesis.33 Beyond 2 weeks at the peak of the early reparative phase, suppression of keratocyte collagen production by continued use of steroids may offset the benefits of inflammatory suppression and lead to stromal ulceration.33, 34 Corticosteroid use should, therefore, be stressed in the first 2 weeks with subsequent taper as dictated by clinical exam. Medroxyprogesterone (Provera 1%) is a progestational steroid that has weaker anti-inflammatory activity than corticosteroids. Medroxyprogesterone inhibits collagenase but, unlike corticosteroids, minimally suppresses stromal wound repair.33 As such, medroxyprogesterone can be substituted for corticosteroid after 10–14 days if worsening ulceration is of concern. Topical sodium ascorbate (10%, q 1 hour) and systemic ascorbate (2 g p.o. q.i.d.) replenish levels depleted from the aqueous following alkali injury. Ascorbate is a cofactor in the rate-limiting step of collagen synthesis and has been shown to decrease the incidence of stromal ulceration.35 Citrate is a calcium chelator that decreases intracellular calcium levels of neutrophils and thus impairs chemotaxis, phagocytosis, and release of lysosomal enzymes.36 Applied topically, citrate has been shown to reduce corneal ulceration and perforation.37 Tetracyclines have been shown to offer protection against collagenolytic degradation. Proposed mechanisms for MMP inhibition include suppression of neutrophil collagenase and epithelial gelatinase gene expression, inhibition of α1-antitrypsin degradation, and scavenging of reactive oxygen species.22

Surgical Therapy

Surgical interventions that may help stabilize the ocular surface in severe chemical injury include tenonplasty, limbal stem cell transplantation, and amniotic membrane transplantation. Tenonplasty attempts to re-establish limbal vascularity in Grade IV injury and to promote reepithelialization.38 In this procedure, all necrotic conjunctival and episcleral tissues are excised, Tenon’s capsule is bluntly dissected, and the resultant flap with its preserved blood supply is advanced to the limbus. Limbal stem cell transplantation attempts to restore the normal corneal epithelial phenotype. In the technique described by Kenyon and Tseng, two crescents of peripheral corneal limbal epithelium with a section of conjunctiva from either the patient’s uninjured eye (conjunctival limbal

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350

autograft, CLAU) or that of a close relative (living related conjunctival limbal allograft, LR-CLAL) are harvested and secured to the host bed.39 In Grade IV injury, extending the vascular supply with tenonplasty may be necessary to ensure graft survival. Amniotic membrane is the innermost layer of the placenta and ­consists of a stromal matrix, a thick basement membrane, and a single epithelial layer. Amniotic membrane has been shown to promote epithelialization and reduce ocular surface inflammation, vascularization, and scarring. Amniotic membrane transplantation (AMT) has been found to reduce proteolytic activity, increase goblet cell density, and downregulate conjunctival and corneal fibroblasts.40–42 These actions are beneficial in restoring the ocular surface, especially in Grade II and III chemical burns, and may be considered in the acute stage.43 AMT for Grade IV injury may be limited due to stem cell loss and ischemia;

however, when used in conjunction with limbal stem cell transplantation, AMT may provide a substrate for stem cell proliferation and re-epithelialization.44 Penetrating keratoplasty for visual rehabilitation after chemical ­injury can be fraught with complications. Prognosis is poor in the setting of glaucoma, hypotony, limbal stem cell dysfunction, conjunctival cicatrization, entropion, and trichiasis.14 If intraocular complications are minimized in the setting of an optimized ocular surface and limited deep stromal vessels, penetrating keratoplasty may be performed with favorable results. A large-diameter penetrating keratoplasty may be considered in the acute and chronic setting. Transplant of the cornea provides tectonic support in the event of an impending perforation, while the limbal stem cells of the donor address any ocular surface issues.45, 46

REFERENCES   1. Pfister RR. Chemical injuries of the eye. Ophthalmology. 1983;90:1246–53.   2. Liggett PE, Pince KJ, Barlow W, et al. Ocular trauma in an urban population. Review of 1132 cases. Ophthalmology. 1990;97:581–4.   3. Macewen CJ. Eye injuries: a prospective survey of 5671 cases. Br J Ophthalmol. 1989;73:888–94.   4. Zagelbaum BM, Tostanoski JR, Kerner DJ, et al. Urban eye trauma. A one-year prospective study. Ophthalmology. 1993;100:851–6.   5. Morgan SJ. Chemical burns of the eye: causes and management. Br J Ophthalmol. 1987;71:854–7.   6. Kuckelkorn R, Luft I, Kottek AA, et al. Chemical and thermal eye burns in the residential area of RWTH Aachen. Analysis of accidents in 1 year using a new automated documentation of findings. Klin Monatsbl Augenheilkd. 1993;203:34–42.   7. Pfister RR, Pfister DR. Alkali injuries of the eye. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. Philadelphia: Elsevier Mosby; 2005:1285–93.   8. Paterson CA, Pfister RR, Levinson RA. Aqueous humor   pH changes after experimental alkali burns. Am J   Ophthalmol. 1975;79:414–9.   9. Pfister RR, Friend J, Dohlman CH. The anterior segments of rabbits after alkali burns. Metabolic and histologic alterations. Arch Ophthalmol. 1971;86:189–93. 10. McCulley JP. Ocular hydrofluoric acid burns: animal model, mechanism of injury and therapy. Trans Am Ophthalmol Soc. 1990;88:649–84. 11. McCulley JP. Chemical injuries. In: Smolin G, Thoft RA, eds. The cornea, Boston: Little, Brown and Co; 1987 :527–42. 12. Friedenwald JS, Hughes WF, Herrmann H. Acid injuries of the eye. Arch Ophtalmol Rev Gen Ophtalmol. 1946;35:98–108. 13. Grant WM, Kern HL. Action of alkalies on the corneal stroma. Arch Ophthalmol. 1955;54:931–4. 14. Wagoner MD. Chemical injuries of the eye: current concepts in pathophysiology and therapy. Surv Ophthalmol. 1997;41:275–313. 15. Chiang TS, Moorman LR, Thomas RP. Ocular hypertensive response following acid and alkali burns in rabbits. Invest Ophthalmol. 1971;10:270–3. 16. Paterson CA, Pfister RR. Intraocular pressure changes after alkali burns. Arch Ophthalmol. 1974;91:211–8. 17. Paterson CA, Pfister RR. The ocular hypertensive   response following experimental acid burns in the   rabbit eye. Invest Ophthalmol Vis Sci. 1979;18:67–74. 18. Schirner G, Schrage NF, Salla S, et al. Conjunctival tissue examination in severe eye burns: a study with scanning electron microscopy and energy-dispersive X-ray analysis. Graefes Arch Clin Exp Ophthalmol. 1995;233:251–6.

19. Pfister RR, Pfister DR. Alkali injuries of the eye. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea, Philadelphia: Elsevier Mosby; 2005:1285–94. 20. Levinson RA, Paterson CA, Pfister RR. Ascorbic acid prevents corneal ulceration and perforation following experimental alkali burns. Invest Ophthalmol. 1976;15:986–93. 21. Pfister RR, Haddox JL, Sommers CI, et al. Identification and synthesis of chemotactic tripeptides from alkalidegraded whole cornea. A study of N-acetyl-prolineglycine-proline and N-methyl-proline-glycine-proline. Invest Ophthalmol Vis Sci. 1995;36:1306–16. 22. Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea. 2000;19:274–7. 23. Fini ME, Girard MT. Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci. 1990;31:1779–88. 24. Johnson-Muller B, Gross J. Regulation of corneal collagenase production: epithelial-stromal cell interactions. Proc Natl Acad Sci U S A. 1978;75:4417–21. 25. Johnson-Wint B, Bauer EA. Stimulation of collagenase synthesis by a 20  000-dalton epithelial cytokine. Evidence for pretranslational regulation. J Biol Chem. 1985;260:2080–5. 26. Ballen PH. Treatment of chemical burns of the eye. Eye Ear Nose Throat Mon. 1964;43:57–61. 27. Roper-Hall MJ. Thermal and chemical burns. Trans Ophthalmol Soc U K. 1965;85:631–53. 28. Wagoner MD, Kenyon KR. Chemical injuries of the eye. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Philadelphia: Saunders;   2000:943–59. 29. Kuckelkorn R, Schrage N, Keller G, et al. Emergency treatment of chemical and thermal eye burns. Acta Ophthalmol Scand. 2002;80:4–10. 30. Herr RD, White GL, Bernhisel K, et al. Clinical comparison of ocular irrigation fluids following chemical injury.   Am J Emerg Med. 1991;9:228–31. 31. Ho PC, Elliott JH. Kinetics of corneal epithelial regeneration. II. Epidermal growth factor and topical corticosteroids. Invest Ophthalmol. 1975;14:630–3. 32. Donshik PC, Berman MB. Dohlman, et al. Effect of topical corticosteroids on ulceration in alkali-burned corneas. Arch Ophthalmol. 1978;96:2117–20. 33. Phillips K, Arffa R, Cintron C, et al. Effects of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Arch Ophthalmol. 1983;101:640–3. 34. Brown SI, Weller CA, Vidrich AM. Effect of corticosteroids on corneal collagenase of rabbits. Am J Ophthalmol. 1970;70:744–7.

35. Pfister RR, Paterson CA. Ascorbic acid in the treatment   of alkali burns of the eye. Ophthalmology. 1980;87:1050–7. 36. Pfister RR, Haddox JL, Dodson RW, et al. Polymorphonuclear leukocytic inhibition by citrate, other metal chelators, and trifluoperazine. Evidence to support calcium binding protein involvement. Invest Ophthalmol Vis Sci. 1984;25:955–70. 37. Pfister RR, Nicolaro ML, Paterson CA. Sodium citrate reduces the incidence of corneal ulcerations and perforations in extreme alkali-burned eyes – acetylcysteine and ascorbate have no favorable effect. Invest Ophthalmol Vis Sci. 1981;21:486–90. 38. Teping C, Reim M. Tenonplasty as a new surgical principle in the early treatment of the most severe chemical eye burns. Klin Monatsbl Augenheilkd. 1989;194:1–5. 39. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders; Ophthalmology. 1989;96:709–22; discussion 722–3. 40. Kim JS, Kim JC, Na BK, et al. Amniotic membrane patching promotes healing and inhibits proteinase activity   on wound healing following acute corneal alkali burn. Exp Eye Res. 2000;70:329–37. 41. Prabhasawat P, Tseng SC. Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved human amniotic membrane. Arch Ophthalmol. 1997;115:1360–7. 42. Lee SB, Li DQ, Tan DTH, et al. Suppression of TGF-beta signaling in both normal conjunctival fibroblasts and pterygial body fibroblasts by amniotic membrane. Curr Eye Res. 2000;20:325–34. 43. Meller D, Pires RTF, Mach RJS, et al. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology. 2000;107:980–9; discussion 990. 44. Holland EJ, Schwartz GS, Nordlund ML. Surgical techniques for ocular surface reconstruction. In: Krachmer JH,   Mannis MJ, Holland EJ, eds. Cornea. Philadelphia:   Elsevier Mosby; 2005:1799–812. 45. Kuckelkorn R, Redbrake C, Schrage NF, et al. Kerato­ plasty with 11–12  mm diameter for management of   severely chemical-burned eyes. Ophthalmologe. 1993;90:683–7. 46. Kuckelkorn R, Keller G, Redbrake C. Long-term results of large diameter keratoplasties in the treatment of severe chemical and thermal eye burns. Klin Monatsbl   Augenheilkd. 2001;218:542–52.

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 9 Surgery

Corneal Surgery

Lisa Martén, Ming X. Wang, Carol L. Karp, Robert P. Selkin and Dimitri T. Azar

Definition:  Corneal procedures generally performed either to restore vision or restore globe integrity.

Key features n n

 areful preoperative preparation and planning critical for success. C Understand intraoperative and postoperative complications and management.

Associated features n

Be alert to the signs and symptoms of graft rejection.

KERATOPLASTY INTRODUCTION The successful outcomes enjoyed by patients who undergo modern penetrating keratoplasty and lamellar keratoplasty are the result of advances in operating microscope design, suture technology, surgical techniques, and corneal topography. The availability of carefully preserved corneal tissue along with a better understanding of corneal and ocular surface physiology also is important.

4.27

In an anterior lamellar keratoplasty procedure, the transplanted tissue does not include corneal endothelium. This procedure avoids endothelial rejection and thus donor tissue may be obtained from older eyes. Indications for anterior lamellar keratoplasty mainly include anterior corneal pathology in which the posterior cornea is unaffected. In recent years, deep lamellar keratoplasty and posterior lamellar keratoplasty techniques have been developed in which the main objective is to replace diseased corneal endothelium while keeping the anterior corneal surface intact.

Preoperative evaluation and diagnostic approach

Two major indications exist for anterior lamellar keratoplasty5, 6 – tectonic graft for structural support and/or cosmesis and optical grafts. For posterior lamellar keratoplasty, the aim is to replace the diseased endothelium. A tectonic graft is the most common type of anterior lamellar keratoplasty performed. It is used to reinforce areas of thinned cornea to prevent melting and perforation or to restore ocular surface integrity, such as after pterygium surgery. Optical grafts are used to replace diseased anterior cornea to improve visual function and require that the posterior stroma of the recipient is healthy. Lamellar optical grafts are seldom used today because of the increased use of phototherapeutic keratectomy and the excellent outcomes with penetrating keratoplasty. The main advantage of posterior lamellar keratoplasty is the preservation of the anterior corneal tissue and thus maintenance of the refractive character of the cornea. The rationale for a lamellar keratoplasty must be examined carefully and the various surgical options thoroughly discussed with patients.

HISTORICAL REVIEW

Surgical techniques

Corneal grafting techniques date back to the latter part of the 19th century and earlier part of the 20th century,1 as exemplified by pioneer ophthalmologists such as Reisinger,2 von Hippel,3 and Elschnig.4 Today, penetrating keratoplasty is the most common and successful human transplantation procedure. Over 30 000 corneal transplantations are performed in the United States each year. Optical results have improved greatly as a result of advances in tissue selection and preservation, trephines, and management of postoperative astigmatism. Lamellar corneal grafts date back to 1886, when von Hippel3 successfully performed the first lamellar graft in a human. In the past few decades, however, lamellar keratoplasty has become less popular because of the remarkable success of the penetrating corneal graft technique.

If necessary, the globe is stabilized with bridle sutures passed beneath both superior and inferior rectus muscles. A trephine is used ­gently to mark the extent of graft needed. A partial-thickness trephination then is performed until the desired depth of dissection is reached (Fig. 4-27-1). A blade or a microkeratome is used to extend the dissection plane along the entire host corneal tissue until the dissection of the host tissue is completed. The goal is to create a smooth, uniplanar recipient bed (Fig. 4-27-2). If globe perforation occurs, the procedure is converted into a penetrating keratoplasty. In recent years, another technique has been developed for deep anterior lamellar dissection.7, 8 In this new technique, aqueous fluid is first exchanged with air, creating an air–­endothelium interface for visualization. A deep stromal pocket is then created using viscoelastic material followed by trephination of the anterior lamellar disc. In posterior lamellar keratoplasty, there are two main techniques: microkeratome-assisted posterior lamellar keratoplasty9–13 and posterior lamellar keratoplasty using a deep stromal pocket approach.14–17 In the first technique, a corneal flap is created using a microkeratome similar to that used in a LASIK procedure. Posterior stromal tissue is then excised by trephination and replaced by a donor disc. The anterior lamellar flap is then repositioned to its original place and sutured. In the second approach to posterior lamellar keratoplasty, a deep stromal pocket is created across the cornea through a superior scleral incision. A posterior lamellar disc is then excised using a custom-made flat trephine placed into the deep stromal pocket.

ANESTHESIA Depending on the age and patients’ cooperation, corneal transplant ­surgeries may be performed using local or general anesthetic. Typically, local anesthetic consists of peribulbar or retrobulbar injection of lidocaine 2%, bupivacaine 0.75%, and hyaluronidase. To prevent squeezing during surgery, a lid block is commonly employed.

SPECIFIC TECHNIQUES Lamellar Keratoplasty Lamellar keratoplasty is a procedure in which a partial-thickness graft of donor tissue is used to provide tectonic stability and/or optical improvement. A partial-thickness section of donor stroma or sclera is used. Two types of lamellar keratoplasty exist: anterior lamellar keratoplasty and posterior lamellar keratoplasty.

Anterior lamellar dissection of the host tissue 

Donor preparation 

Because the donor endothelium is not used, the criteria for donor tissue for anterior lamellar keratoplasty are less stringent than those used in penetrating keratoplasty; the tissue does not need to be as fresh as

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PARTIAL-THICKNESS TREPHINATION

CORNEA AND OCULAR SURFACE DISEASES

scar or diseased tissue

SEPARATION OF CADAVERIC CORNEA

trephine

lateral dissection

partial thickness incision to desired depth

scar or diseased tissue

trephine dissector

Fig. 4-27-1  Partial-thickness trephination. This is performed on the host in the desired location and to the desired depth. Care must be taken not to perforate the cornea.

Fig. 4-27-3  Separation of cadaveric cornea. A dissector, such as the Martinez dissector or a cyclodialysis spatula, is used to separate gently the cornea along the lamellar cleavage plane through the entire cornea.

SEPARATION OF CADAVERIC DONOR TISSUE

DISSECTION OF DISEASED AREA bed of cornea clear

area of trephination

previously dissected cornea

trephine

forceps holding tissue 64 Beaver blade

352

area of trephination

dissected cornea

gauze

donor lamellar tissue

Fig. 4-27-2  Dissection of diseased area. The diseased area in the host cornea is dissected gently to create a uniplanar, disease-free bed.

Fig. 4-27-4  Donor tissue is harvested. A trephine is placed on the cadaveric globe in the size and the shape desired. A circular lamellar graft is being   harvested here.

that used in penetrating keratoplasty. The corneal stroma may be used up to 7 days postmortem.18 In contrast, posterior lamellar keratoplasty requires the same stringency of donor tissue as in penetrating keratoplasty because the endothelium is to be transplanted. A fresh or frozen whole donor eye should be used to fashion the anterior lamellar donor tissue.19 In anterior lamellar keratoplasty, using a scalpel, an incision is made just inside the limbus of the donor cornea to reach the depth of the desired dissection. A Martinez dissector or a cyclodialysis spatula is used to extend the dissection plane within the corneal stroma and harvest the donor tissue (Fig. 4-27-3). The tissue harvested may be circular, annular, or any other shape, depending on the needs of the patient (Figs 4-27-4 and 4-27-5). Both cornea and sclera may be used. Usually, donor tissue is slightly oversized (0.25–0.5  mm) compared with the recipient bed. As

described previously, donor tissue suitable for penetrating keratoplasty is made available in case perforation occurs in the lamellar dissection of the host tissue. Newer microkeratomes may allow future anterior donor dissection. In posterior lamellar keratoplasty, either an inflated whole globe should be used or an artificial chamber can be used to anchor the scleral rim when only anterior corneal-sclera donor tissue is available. Donor tissue is fashioned in a manner similar to that of the recipient counterpart.

Suture of the donor lamellae to host bed 

In anterior lamellar keratoplasty, the edge of the host bed should be undermined to create a horizontal groove using a Paufique knife.19 The donor lamella is placed on the recipient bed and secured with interrupted 10-0 nylon sutures (Fig. 4-27-6). The depth of the suture is about 90%

HORSESHOE OR ANNULAR LAMELLAR GRAFT

Corneal Surgery

previously dissected cornea

4.27 trephine

crescentic donor material

A

cut limbus

crescentic donor material

trephine

B

Fig. 4-27-5  Horseshoe or annular lamellar graft. A combination of corneal and scleral tissue may be harvested to give a different tissue shape.

Fig. 4-27-7  Lamellar keratoplasty for granular dystrophy. (A) Preoperative appearance of a patient who had granular dystrophy limited to the anterior cornea. (B) Postoperative appearance following lamellar keratoplasty. (Courtesy of Dr W. W. Culbertson.)

LAMELLAR TISSUE SUTURE TO HOST BED

suture lamellar graft

A

suture

donor lamellar tissue undermined edge

Fig. 4-27-6  The lamellar tissue is sutured to the host bed. Suture placement is facilitated if the edge of the host bed is undermined. Traditionally, the graft is sutured with 10-0 nylon.

of the corneal stroma’s depth. The donor tissue margins should not ride anterior to the rim of the recipient bed. At times, an anterior chamber paracentesis may become necessary before lamellar sutures are placed. In microkeratome-assisted posterior lamellar keratoplasty, the ­posterior lamellar disc is sutured onto the recipient posterior stromal rim using 10-0 or 11-0 nylon. The knots are rotated and buried. The anterior stromal flap is then reflected back and repositioned in its original position and sutured. With the deep stromal pocket approach to posterior lamellar keratoplasty, the donor posterior lamellar disc is placed within the recipient rim via the anterior chamber but not sutured.

B

Fig. 4-27-8  Lamellar keratoplasty for peripheral corneal melt and perforation. (A) Preoperative appearance of a patient who had a peripheral corneal melt and perforation (see arrows). (B) Postoperative appearance after the placement of a horseshoe corneal scleral lamellar graft. (Courtesy of Dr W. W. Culbertson.)

Complications and postoperative management

In general, an anterior lamellar graft can be extremely successful (Figs 4-27-7 and 4-27-8). Complications are less frequent or serious in nature than those of penetrating keratoplasty. Complications of lamellar graft include perforation of the recipient cornea, interface scarring and vascularization, persistent epithelial defect, inflammatory necrosis of the graft and graft melting, infection, astigmatism, and allograft rejection. Careful irrigation and cleaning of the host bed may reduce the incidence of complications. With regard to allograft rejection, lamellar keratoplasty has a significantly reduced incidence as there is no transplantation of foreign endothelium. Posterior lamellar keratoplasty carries the same

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risk of graft rejection as in penetrating keratoplasty. In addition, wound leak due to poor tissue apposition may result because both the posterior and anterior lamellar tissues need to be sealed adequately.

CORNEA AND OCULAR SURFACE DISEASES

Penetrating Keratoplasty

Penetrating keratoplasty refers to the full-thickness replacement of ­diseased corneal tissue with a healthy donor.

Preoperative evaluation and diagnostic approach

Penetrating keratoplasty may be used to provide tectonic support (such as in corneal thinning and perforation), and to improve visual outcome (such as in the replacement of a scarred cornea). Indications for penetrating keratoplasty include: keratoconus, pseudophakic or aphakic bullous keratopathy, graft failure, Fuchs’ endothelial dystrophy, graft rejection, corneal scars, chemical burns, corneal ulcers (bacterial, fungal, parasitic, or viral), corneal dystrophies and degenerations, herpetic keratitis, trauma, or any other causes of corneal decompensation. The rate of success of penetrating keratoplasty for the first four indications listed is excellent, but the chance of graft rejection increases significantly in instances of active or recurrent infection, inflammation, corneal vascularization, or previous graft rejection. Because penetrating keratoplasty involves a significant amount of postoperative care, it is important to perform a careful preoperative evaluation and thoroughly discuss with patients the surgery, visual expectation, possible complications, and, in particular, the long process of postoperative care. The recipient must be prepared for lifelong management of the eye. In general, important considerations for preoperative evaluation for penetrating keratoplasty are as follows: l Evaluation of visual potential. l Ocular surface abnormality – a variety of ocular surface diseases must be recognized and treated prior to penetrating keratoplasty. These include rosacea, dry eyes, blepharitis, trichiasis, exposure keratopathy, ectropion, and entropion. l Intraocular pressure (IOP) must be controlled adequately prior to surgery. l Ocular inflammation – must be recognized and treated. l Prior corneal diseases and vascularization – a history of herpetic keratitis significantly reduces the chance of graft success as a result of several factors, which include recurrent disease in the graft, vascularization, trabeculitis with increased IOP, and persistent inflammation that causes rejection. l Peripheral corneal melting – corneal thinning and melting, such as that associated with rheumatoid arthritis, may significantly affect the surgical outcome of penetrating keratoplasty and thus must be treated adequately prior to the surgery. Corneal surgery in these eyes can be technically difficult. Surgical complications include irregular astigmatism because of peripheral ectasia and recurrent corneal thinning.

Donor selection 

The Eye Bank Association of America has developed a set of criteria for donor corneas.20 Contraindications for the use of donor tissue for penetrating keratoplasty include: l Death of unknown cause. l Central nervous system diseases, such as Creutzfeldt-Jakob disease, subacute sclerosing panencephalitis, rubella, Reye’s syndrome, ­rabies, and infectious encephalitis.

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Fig. 4-27-9  The corneal button is cut. A Katena blade mounted on a gravity punch may be used to cut the button from the endothelial side. (Courtesy   of Dr W. W. Culbertson.)

I nfections such as human immunodeficiency virus, hepatitis, septicemia, syphilis, and endocarditis. l Eye diseases such as retinoblastoma, malignant tumor of anterior segment, and active ocular inflammation (e.g., uveitis, scleritis, retinitis, and choroiditis). l Prior ocular surgery (although pseudophakic eyes may be used with good cell densities). l Congenital or acquired anterior segment abnormalities such as keratoconus and Fuchs’ endothelial dystrophy. Prior to penetrating keratoplasty, donor blood must be evaluated for communicable disease and donor tissues inspected by the surgeon ­under the slit lamp. A new factor will be donors with previous corneal refractive surgery. l

Surgical techniques

Because penetrating keratoplasty involves an “open sky” exposure of the intraocular contents, adequate decompression of the globe prior to penetrating keratoplasty is an important step as excessive preoperative IOP may increase the risk of expulsive choroidal hemorrhage. Intravenous mannitol or mechanical ocular decompression, such as with the Honan balloon, may be considered. Patients who undergo a simple ­penetrating keratoplasty have miotics placed preoperatively to protect the lens during surgery. Scleral supporting rings are used when the surgeon is concerned about ocular collapse during the procedure – principally in aphakic eyes or with very young patients. These rings are sutured to the sclera with 6-0 silk or Vicryl suture, with care taken to balance the suture positions and tensions. Inadvertent misalignment of the rings may result in an irregular trephination. Using a caliper, the horizontal and vertical diameters of the recipient cornea are measured and the size of the graft is determined based on pathology and clinical judgment. Traditionally, a size disparity in which the donor tissue is 0.25 mm larger in diameter than that of the recipient is used. In certain circumstances, a larger (0.5 mm) donor, such as in a hyperopic eye, or a same size or smaller (0.25 mm) donor button, such as in a recipient with keratoconus, may be chosen judiciously. The center of the recipient cornea is marked with a marking pen. A radial keratotomy marker stained with ink may be used to mark the peripheral cornea. If a sclerally sutured intraocular lens (IOL) is planned, the scleral flaps are made prior to trephination, and the IOL is prepared. Attention is directed to the donor tissue, and a donor corneal button is punched. Several systems are available for donor trephination, which include a hand-held trephine, the universal punch, and the Katena ­trephine blade attached to a gravity corneal punch (Fig. 4-27-9). These devices all cut the donor from endothelium to epithelium. In some of these systems, the epithelium may be marked prior to trephination to help with tissue distribution. The donor may also be cut from epithelium to endothelium with a system such as the Hanna artificial anterior chamber. This has the theoretical advantage that both the donor and recipient are cut in the same fashion with the same blade, which reduces donor-recipient disparity and potentially reduces astigmatism. The recipient cornea may be cut using a variety of trephines, such as the Hessburg-Barron suction trephine, Hanna trephine (Fig. 4-27-10), Castroviejo trephine, and a number of other designs. The ­ HessburgBarron suction trephine consists of a circular blade assembly that has a vacuum chamber attached to a spring-loaded syringe. The Hanna

Fig. 4-27-10  Hanna suction trephine. The anterior chamber of the patient may be filled with viscoelastic material and trephination then performed. (Courtesy of Dr W. W. Culbertson.)

Complications and postoperative management

Intraoperative complications include poor graft centration, excessive bleeding, damage to ocular structures (such as donor endothelium, iris, lens, or posterior capsule), or expulsive hemorrhage. During the process of excision of the recipient button, it is imperative to monitor continuously the depth of the anterior chamber and the red reflex. A sudden shallowing of the anterior chamber or disappearance of the red reflex may signify an impending expulsive choroidal hemorrhage. The authors typically have a Cobo prosthesis available, which can be placed quickly on the recipient bed to seal the globe in the event of ­expulsive choroidal hemorrhage. The success of penetrating keratoplasty depends significantly on ­adequate postoperative care and management. The surgeon must be able to recognize and manage a variety of possible complications, such as wound leak and infection, glaucoma, and graft rejection or failure. The common postoperative complications and their management are discussed in the following subsections.

4.27 Corneal Surgery

trephine has a unique, funnel-shaped design with a vacuum chamber created around a circular disposable blade. The Castroviejo trephine is made of a circular blade in a handle. Ideally, to achieve optimal graft– host tissue apposition, the trephination cut lies perpendicular to the corneal surface. The hand-held Castroviejo trephine may be used for decentered grafts in which flexibility of orientation of the trephine is desired. A partial-thickness trephination followed by a controlled entry into the anterior chamber using a No. 75 Beaver blade or a continued trephination that is stopped as soon as aqueous egress shows the anterior chamber has been entered may be performed. Suction is released the moment entry is noted. Viscoelastic is then injected. The recipient ­button is then excised using forceps and corneal scissors (Fig. 4-27-11). The edge of the recipient bed is made perpendicular for optimal graft– host apposition. Depending on the case, the patient may need cataract extraction, IOL explantation, anterior vitrectomy, or the placement of a new IOL (Figs 4-27-12 and 13). The donor button is placed over the recipient bed and sutured in place with four cardinal sutures (Fig. 4-27-14). The depth of suture is typically 90% of the corneal thickness. Proper tissue distribution is paramount. After placement of the 12 o’clock suture, particular attention is paid to the 6 o’clock suture such that these two sutures follow a vertical line and bisect the entire donor button. The 3 and 9 o’clock sutures are similarly placed. The rest of the sutures are a combination of interrupted and running sutures (Fig. 4-27-15) or solely interrupted sutures. Interrupted sutures are suited for vascularized or thinned cornea as subsequent selective removal may be necessary to prevent the advancement of vessels or to control astigmatism. Running sutures, on the other hand, have the advantage of speedy placement intraoperatively and better tension distribution and healing. Prior to the completion of all sutures, the ­viscoelastic material in the anterior chamber is removed. The running sutures may be adjusted intraoperatively by using a keratoscope to project a circular image onto the donor cornea. When the graft sutures are completed, the security of the wound is tested.

Wound leak 

A shallow anterior chamber in a soft globe the day after penetrating keratoplasty may indicate a wound leak. Measures that can be taken to manage wound leak include patching, aqueous suppressant, lubrication, or bandage contact lenses. Significant wound leak that arises from either a broken suture or poor wound apposition may require the wound to be resutured.

Flat anterior chamber with increased intraocular pressure 

Flat anterior chamber with increased IOP may result from pupillary block, anterior rotation of the lens–iris diaphragm (such as is found in choroidal hemorrhage), choroidal effusion, or malignant glaucoma. The cause must be identified and treated.

Endophthalmitis 

Postoperative endophthalmitis may result from a variety of factors, such as contamination of donor or host tissue or postoperative infection. It is a devastating complication that requires aggressive management, which includes aqueous and vitreous cultures, intraocular antibiotics, and possibly vitrectomy (Fig. 4-27-16).

Persistent epithelial defect 

An epithelial defect after penetrating keratoplasty usually heals within 1  week. Persistent epithelial defects occur in eyes that have ocular surface disorders, such as dry eye, blepharitis, exposure keratopathy, and rosacea, or in patients who have systemic diseases, such as diabetes or rheumatoid arthritis. Frequent lubrication with preservative-free drops and lubricating ointment is applied, and all possible causes of topical toxicity must be eliminated. If the problem does not resolve, a tarsorrhaphy and/or punctal occlusion may be necessary.

Primary graft failure  Fig. 4-27-11  Excision of corneal button. The corneal button is removed ­completely using corneal scissors. (Courtesy of Dr W.W. Culbertson.)

A

B

Primary graft failure (which is different from graft rejection – see the following) is recognized when significant edema of the donor tissue in a noninflamed eye is present on the first postoperative day and does

C

Fig. 4-27-12  Removal of anterior chamber intraocular lens. (A) Care is taken when the anterior chamber haptics are removed, as they may become encysted in the peripheral iris and bleeding may occur on removal. (B) An anterior vitrectomy is performed – an iris hook may be used to improve visualization. (C) A 10-0 Prolene suture is passed beneath the iris and through the scleral sulcus and out through the previously prepared scleral flap. This is performed on both sides. (Courtesy of Dr W. W. Culbertson.)

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4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-27-13  Prolene suture passed through the sclera and tied under the flap. This is carried out after the suture-supported lens has been placed in the sulcus. The Prolene suture is tied to itself beneath the scleral flap. Alternatively, the knot may be rotated beneath the sclera. (Courtesy of Dr W. W. Culbertson.)

Fig. 4-27-14  The corneal button is placed. Care is taken in the placement of cardinal sutures to ensure adequate tissue distribution. (Courtesy of Dr W. W. Culbertson.)

Fig. 4-27-15  Placement of a 10-0 running suture. (Courtesy of Dr W. W. ­Culbertson.)

not clear. Primary graft failure may be attributed to either poor donor endothelial function or iatrogenic damage to the donor tissue during penetrating keratoplasty. The graft is observed for several weeks and a regraft considered if the corneal edema fails to resolve.

Problems related to sutures 

A variety of suture-related complications may occur after penetrating keratoplasty. If found, a loose or broken suture must be removed because it may result in vascularization or abscesses.

Graft rejection 

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Graft rejection remains the most common cause of graft failure. Alldredge and Krachmer21 reported an overall incidence of endothelial graft rejection of 21%. Symptoms of endothelial graft rejection include pain,

Fig. 4-27-16  Endophthalmitis. This was caused by Proteus infection 5  weeks following penetrating keratoplasty. (Courtesy of Dr R. K. Forster.)

Fig. 4-27-17  Subepithelial infiltrates secondary to subepithelial graft ­rejection. (Courtesy of Dr W. W. Culbertson.)

Fig. 4-27-18  Graft rejection. Note the inflammatory precipitates and ­Khodadoust line secondary to endothelial rejection. (Courtesy of Dr E. C. Alfonso.)

photophobia, redness, and decreased vision. Patients must be educated carefully with regard to these symptoms, and must seek medical attention immediately should they occur. Graft rejection may be divided anatomically into three categories: l Epithelial rejection – may be recognized by observation of an epithelial line, which represents the replacement of the donor epithelium by that of the recipient. l Subepithelial rejection – multiple subepithelial infiltrates limited to the corneal graft may be observed (Fig. 4-27-17). l Endothelial rejection (the most severe type characterized by ­keratic precipitates, iritis, and corneal edema) – a Khodadoust line may be seen, which represents the advancing front of the host immuno­ logical and inflammatory cells against a receding front of donor ­endothelium (Fig. 4-27-18).

The treatment of graft rejection consists primarily of topical c­ orticosteroids. For epithelial graft rejection, the frequency of the corticosteroid drops is increased to hourly; endothelial graft rejection warrants frequent (hourly or more often) topical corticosteroids until the process is reversed. Subconjunctival injection of corticosteroids may also be used. Systemic corticosteroids (oral or intravenous) may be ­utilized in severe cases but are usually not necessary.

4.27 Corneal Surgery

Treatment for astigmatism 

Adequate control of postoperative astigmatism is vital to achieve the best visual acuity possible. Typically starting at 6–8  weeks after ­penetrating keratoplasty, the patient is followed using serial corneal ­ topography and interrupted sutures are removed selectively or a running suture ­adjusted as necessary to reduce astigmatism. The continuous 10-0 ­nylon sutures may be adjusted at the slit lamp postoperatively to reduce astigmatism.22 Early removal of sutures may have a more significant effect on astigmatism, although care is required with regard to wound stability if sutures are removed too early.

Corneal ulcers 

Patients who have undergone penetrating keratoplasty are more susceptible to infectious keratitis. Factors such as suture abscess and ­persistent epithelial defect may contribute to the development of corneal ulcers.

Recurrence of diseases 

Various corneal dystrophies and infections (Fig. 4-27-19) may recur in grafts. Among the three stromal corneal dystrophies (macular, granular, and lattice), lattice corneal dystrophy has the highest recurrence rate. In the setting of keratic precipitates on a graft in a patient who has a history of herpes simplex virus, it is sometimes difficult to distinguish recurrence of a disease from graft rejection. It is important, however, to make such a distinction as the treatment for recurrence of herpes simplex virus (antiviral agent) is different from treatment for rejection (corticosteroid). The observation of keratic precipitates and corneal edema confined only to the donor button may suggest a graft rejection.

Artificial Cornea (Keratoprosthesis)

Keratoprosthesis implantation is a procedure designed to help patients whose conditions are the most difficult to treat, such as multiple graft failures or deep neovascularization of the cornea.

Boston K-Pro

The Boston Keratoprosthesis has been under development since the 1960s and received Food and Drug Administration (FDA) approval in 1992. It is the most commonly used keratoprosthesis in the United States. The keratoprosthesis is made of clear plastic and has two pieces that take the shape of a collar button. The device is inserted into a ­corneal graft, which is then sutured into the patient’s cloudy cornea.

AlphaCor

The Alphacor implant is made of a flexible hydrogel material similar to a soft contact lens. It was FDA approved in 2003. It contains a central clear zone that provides refractive power and a peripheral skirt or rim made of a special material that encourages the eye to heal over the device. The device is available in two powers: one for aphakes and one for phakic patients. The surgery occurs in two stages. The first is the implantation of the AlphaCor device into the cornea of the recipient, and the creation of a protective conjunctival flap. The second is the removal of the flap to allow light to pass through the central clear zone to restore vision. A retroprosthetic membrane can occur following implantation of any artificial cornea and can be removed using a YAG laser, unless blood vessels have grown into it. Migration of the Alphacor under the lamellar flap can occur. Human tissue transplants can be done following ­artificial corneas.

Triple Procedure (Combined Procedure)

Preoperative evaluation and diagnostic approach

A combined procedure or triple procedure refers to penetrating keratoplasty, cataract extraction, and IOL implantation. The procedure is indicated for patients who have visually significant cataract and who require penetrating keratoplasty for visual rehabilitation. The leading indication for a triple procedure is Fuchs’ endothelial dystrophy, which accounts for up to 77% of eyes that require a triple procedure.23–26 Other

Fig. 4-27-19  Herpetic keratitis recurrence in graft. Note positive staining with rose bengal. (Courtesy of Dr E. C. Alfonso.)

indications for triple procedures include: corneal leukoma, keratoconus, herpes simplex infection, and interstitial keratitis. Compared with penetrating keratoplasty, a combined procedure ­requires the additional calculation of the power of the IOL. The ­authors use the Sanders-Retzlaff-Kraff formula (equation 4-27-1),27 in which A is the constant for an IOL, AL is the axial length, and K is the ­keratometric measurement. The determination of K varies from surgeon to surgeon. The authors normally advocate one of two alternative ­ approaches. ­Either the average of the past postoperative keratometric readings associated with the surgical technique or the K reading from the contralateral eye is used for IOL calculation. In the instances in which an over- or ­undersized graft is required, 1–2  D is subtracted from the IOL power for a 0.5  mm oversized graft or 1–2  D is added to the IOL power for 0.5  mm undersizing.19 Equation 4-27-1 IOL power = A − 2.5 AL − 0.9 K

Surgical techniques

The detailed surgical technique for penetrating keratoplasty is as described previously. The additional components of the surgery related to cataract extraction and IOL implantation are described here. After the recipient button has been excised, a can-opener type of anterior capsulectomy, a continuous curvilinear capsulorrhexis, or a square capsulectomy using Vannas scissors may be performed. The capsulectomy must be sufficiently large to allow subsequent expression of the lens nucleus. Care is taken during the capsulorrhexis because the lens–iris diaphragm is rotated anteriorly with an open-sky eye. No counterpressure is used on the anterior chamber to keep the anterior capsule flat, and thus the capsulectomy tends to extend peripherally if excessive IOP or insufficient use of preoperative mannitol occurs. After hydrodissection using balanced salt solution and mobilization of the lens nucleus, the lens is expressed gently using pressure at the 6 o’clock position to tilt the superior or inferior edge of the lens anteriorly above the plane of the anterior capsular opening. The lens is rotated out using a No. 25 gauge needle or a lens loop. The remaining cortical material is removed using a manual irrigation and aspiration device, which must be carried out carefully because the anterior and posterior capsules tend to collapse together. The posterior chamber is then inflated with viscoelastic material and the appropriate posterior IOL is inserted using a lens forceps. In the event that a posterior capsular tear and anterior extension of vitreous occur, a limited anterior vitrectomy is performed and the IOL either inserted in the bag or sulcus or ­sutured to the sclera, depending on the available capsular support (see Figs 4-27-12 and 4-27-13). An open-loop anterior chamber IOL may also be used. The remainder of the procedure for penetrating keratoplasty is the same as that described in the appropriate ­sections earlier. Phacoemulsification is often difficult to perform because it ­requires a clear view through the cornea, which is rarely the case in patients ­undergoing a triple procedure.

OUTCOME Corneal grafting techniques, such as penetrating keratoplasty, lamellar keratoplasty, and triple procedures, have become reliable and popular surgical techniques. Careful attention to preoperative evaluation,

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4

s­ urgical techniques, and postoperative management will improve surgical outcome and patients’ satisfaction.

CORNEA AND OCULAR SURFACE DISEASES

SUPERFICIAL CORNEAL PROCEDURES HISTORICAL REVIEW Superficial corneal procedures include corneal glue application (see Chapter 4-32), superficial keratectomy for anterior corneal degenerations and dystrophies, treatment of band keratopathy using ethylenediaminetetraacetic acid (EDTA), and corneal biopsy. With regard to superficial keratectomy for corneal dystrophies and other anterior ­pathologies, the advent of excimer laser phototherapeutic keratectomy has offered an effective alternative.

ANESTHESIA

Fig. 4-27-20  Nonresolving culture-negative corneal ulcer. (With permission from Karp CL, Forster RK. The corneal ulcer. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St Louis: Mosby; 1997:403–8.)

Superficial corneal procedures are performed mostly using topical ­anesthetic. Proparacaine hydrochloride eye drops are used frequently.

SPECIFIC TECHNIQUES Superficial Keratectomy

Preoperative evaluation and diagnostic approach

Superficial keratectomy may be carried out either mechanically or by using excimer lasers. Mechanical keratectomy consists of removal of pathological epithelial or subepithelial tissues. The procedure is indicated in patients who have:19 l Anterior corneal dystrophies. l Band keratopathy. l Superficial pannus or scar. l Corneal dermoid, pterygium, or Salzmann’s nodules. l Excision of retained foreign bodies. In addition, superficial keratectomy is used to obtain corneal tissue for microbiological or histological examination in the setting of infection.

Surgical techniques

Fig. 4-27-21  Partial trephination of the cornea. A 3  mm dermatological trephine is used to trephinate the cornea partially – both infected and noninfected cornea are straddled. (With permission from Karp CL, Forster RK. The corneal ulcer. In:   Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St Louis: Mosby; 1997:403–8.)

After the epithelium has been removed, the plane between abnormal tissue and the underlying normal tissue is identified. The lesion is dissected in a lamellar fashion using a sharp or blunt blade. The corneal bed is left as smooth as possible to facilitate epithelialization. If possible, injuries to the limbal epithelium are avoided, as limbal stem cells are important for the subsequent re-epithelialization. Bandage contact lenses or antibiotic ointment with a patch can be administered after keratectomy.

Complications and postoperative management

Bandage soft lenses, an eye patch, antibiotic drops, or aggressive lubrication is continued until the corneal epithelium has healed. Complications after superficial keratectomy include persistent epithelial defect, infection, and corneal scarring. Occasionally, a limbal stem cell transplant is necessary to provide a source for re-epithelialization.

Treatment of Band Keratopathy Using EDTA Please see Chapter 4-22.

Corneal Biopsy

Preoperative evaluation and diagnostic approach

Corneal biopsy is indicated in a patient who has an unresponsive and culture-negative corneal ulcer.28 Infections that arise from atypical mycobacteria, fungus, and Acanthamoeba and crystalline keratopathy as a result of Streptococcus viridans are examples of infectious disorders that may require corneal biopsy for definitive identification of the causative organisms. A corneal biopsy provides tissue for both microbiological and histopathological evaluation.

Surgical techniques

358

After topical anesthetic, a sterile, hand-held trephine (2–3  mm diam­ eter dermatological punch) under a slit lamp is used to achieve a partial-thickness trephination that contains the pathological specimen. The size of the trephine depends on that of the lesion, and the trephine is positioned to straddle some normal corneal tissue. After the partial-thickness trephination, the edge of the lesion is lifted using a 0.12 forceps and dissected off the cornea using a blade (Figs 4-27-20 to

Fig. 4-27-22  A blade is used gently to dissect the corneal tissue. (With ­permission from Karp CL, Forster RK. The corneal ulcer. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St Louis: Mosby; 1997:403–8.)

4-27-22). It is usually easiest to begin the dissection in the area of normal corneal tissue. Tissue is divided and sent for microbiological and histopathological evaluation.

Complications and postoperative management

Intraoperatively, it is important to gauge the depth of the trephination appropriately to avoid perforation. This is especially important in the setting of microbial infection with corneal thinning. Continual broadspectrum antibiotic therapy is maintained until positive identification of the causative organism is achieved.

OUTCOME Eyes that undergo superficial corneal procedures, such as superficial keratectomy, EDTA scrub, corneal biopsy and adhesive application, in general heal well. The success of these techniques depends on the rate of re-epithelialization and the underlying ocular surface pathology.

REFERENCES 11. Jain S, Azar DT. New lamellar keratoplasty techniques: posterior keratoplasty and deep lamellar keratoplasty. Curr Opin Ophthalmol. 2001;12:262–8. 12. Azar DT, Jain S, Sambursky R, Strauss L. Microkeratomeassisted posterior keratoplasty. J Cataract Refract Surg. 2001;27:353–6. 13. Ehlers N, Ehlers H, Hjortdal J, Moller-Pedersen T. Grating of the posterior cornea. Description of a new technique with 12-month clinical results. Acta Ophthalmol Scand. 2000;78:543–6. 14. Melles GR, Lander F, Nieuwendaal C. Sutureless, ­posterior lamellar keratoplasty: a case report of a ­modified technique. Cornea. 2002;21:325–7. 15. Terry MA, Ousley PJ. Endothelial replacement without ­surface corneal incisions or sutures. Cornea. 2001;  20:14–18. 16. Melles GR, Lander F, van Dooren BT, et al. Preliminary clinical results of posterior lamellar keratoplasty through a sclerocorneal pocket incision. Ophthalmology. 2000;107:1850–6. 17. Melles GR, Lander F, Beekhuis WH, et al. Posterior ­lamellar keratoplasty for a case of pseudophakic bullous keratopathy. Am J Ophthalmol. 1999;127:340–1. 18. Steele ADM, Kirkness CM. Manual of systematic   corneal surgery. New York: Churchill Livingstone; 1992:57. 19. Hersh PS. Ophthalmic surgical procedures. Boston: Little, Brown; 1988:213.

20. O’Day DM. Donor selection. In: Brightbill FS, ed. Corneal surgery, theory, technique and tissue. St Louis: Mosby–Year Book; 1993:549–62. 21. Alldredge OC, Krachmer JH. Clinical types of corneal transplant rejection. Arch Ophthalmol. 1981;99:599–604. 22. McNeill JL, Wessels IF. Adjustment of single continuous suture to control astigmatism after penetrating   keratoplasty. Refract Corneal Surg. 1989;5:216–23. 23. Pamel GJ, Taylor DM. Combined procedures. In: ­Brightbill FS, ed. Corneal surgery, theory, technique and tissue. St Louis: Mosby–Year Book; 1993:177–92. 24. Binder PS. Refractive errors encountered with the triple procedure. In: Cornea, refractive surgery, and contact lens. Transactions of the New Orleans Academy of ­Ophthalmology. New York: Raven Press; 1987:111–20. 25. Meyer RF, Musch DC. Assessment of success and complications of triple procedure surgery. Trans Am Ophthalmol Soc. 1987;85:350–67. 26. Taylor DM, Stern AL, McDonald P. The triple ­procedure: 2–10 year follow-up. Trans Am Ophthalmol Soc. 1986;84:221–49. 27. Retzlaff J. Posterior chamber implant power ­calculation: regressive formula. J Am Intraocular Implant Soc. 1980;6:268–73. 28. Karp CL, Forster RK. The corneal ulcer. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St Louis: Mosby; 1997:403–8.

4.27 Corneal Surgery

  1. Boruchoff SA, Thoft RA. Keratoplasty: lamellar and ­penetrating. In: Smolin G, Thoft RA, eds. The cornea, Boston: Little, Brown; 1994:645–65.   2. Reisinger F. De Keratoplastic, ein Versuch zur ­Erweiterring dev Augenhelkunde. Baiersche Ann ­Abhandl. 1824;1:207.   3. von Hippel A. On transplantation of the cornea. Berichte Ophthalmol Gesellschaft Herdelberg. 1886;18:54.   4. Elschnig A. On keratoplasty. Prag Med Wochenschr. 1914;39:30.   5. Paton D. Lamellar keratoplasty. In: Symposium on ­medical and surgical disease of the cornea. Transactions   of the New Orleans Academy of Ophthalmology. St Louis: Mosby–Year Book; 1980;406–27.   6. Arentsen JJ. Lamellar keratoplasty. In: Brightbill FS, ed. Corneal surgery, theory, technique and tissue. St Louis: Mosby–Year Book; 1993:360–8.   7. Melles GR, Remeijer L, Geerardes AJ, Beekhuis WH. A quick surgical technique for deep, anterior lamellar keratoplasty using visco-dissection. Cornea. 2000;19:427–32.   8. Melles GR, Lander F, Rietveld FJ, et al. A new surgical   technique for deep stromal, anterior lamellar ­keratoplasty. Br J Ophthalmol. 1999;83:327–33.   9. Azar DT, Jain S. Microkeratome-assisted posterior ­keratoplasty. J Cataract Refract Surg. 2002;28:732–3. 10. Yeung EF, Chi CC, Li J, et al. Microkeratome-assisted posterior lamellar keratoplasty. J Cataract Refract Surg. 2001;27:1903–4.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 9 Surgery

Excimer Laser Treatment of Corneal Pathology

4.28

Lisa Martén, Ming X. Wang, Carol L. Karp, Robert P. Selkin and Dimitri T. Azar

Definition:  Use of excimer laser in the treatment of anterior corneal pathology.

Key features n n n

Adjunct to more conservative measures. Smooths corneal surface irregularities. Most patients experience hyperopic shift.

Associated features n

 ecurrences are seen with varying frequency depending on R ­underlying corneal pathology.

INTRODUCTION The use of high-energy ultraviolet radiation of wavelength 193 nm is used to treat corneal pathology and smooth corneal surface irregularities. Laser energy emitted by the argon-fluoride (ArF) excimer laser for these purposes is termed phototherapeutic keratectomy (PTK). The concept was first suggested by Trokel in 1983, and investigational protocols using PTK in clinical trials have been under way since 1988. These studies culminated in United States Food and Drug Administration approval of PTK in 1995. Advantages of excimer laser technology in the treatment of corneal pathology include: l Corneal tissue can be ablated with precision and minimal thermal damage to nonablated tissue. l The depth and diameter of treatment can be controlled carefully (which enables precise removal of epithelium, Bowman’s membrane, and anterior stromal tissue). l A smooth template is provided for re-epithelialization. Enormous potential lies in the ability of the ArF excimer laser to treat anterior corneal pathology and thereby postpone or eliminate the need for lamellar or penetrating keratoplasty.1 Despite the precision of the excimer laser in the treatment of anterior corneal pathology, PTK should be viewed as an adjunct to more conservative measures, and its limitations must be understood. Optimal results occur with pathology in the superficial 100 μm of the cornea, and treatment must always allow the cornea to have at least 350 μm thickness after the procedure.2

PREOPERATIVE EVALUATION AND DIAGNOSTIC APPROACH

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Preoperative evaluation includes uncorrected visual acuity, best-corrected visual acuity by manifest refraction, hard contact lens fitting, pupil size measurements in room light and in near-dark lighting, slit-lamp biomicroscopy, dilated fundus examination, keratometry, corneal topography, and wavefront analysis. The type of pathology and the depth estimated by optical pachymetry are documented, as well as the proximity of the pathology to the pupillary center. To plan the most effective procedure, determination of the pathology’s ablation characteristics is important.

Indications for PTK include: anterior basement membrane dystrophy, Bowman’s membrane dystrophies (Reis-Bückler), and stromal dystrophies, such as lattice, Schnyder’s, and granular. Additional indications include superficial corneal scars (traumatic, surgical, or infectious), Salzmann’s nodules, and fibroblastic nodules in keratoconus patients. Band keratopathy may be treated using the excimer laser, but a highly irregular base is often left because of the nonuniformity of the calcium density in the band across the cornea.3–5. Irregular corneal surfaces that result from pterygium removal and climatic droplet keratopathy are further possibilities for treatment.6, 7 Contraindications to PTK include severe keratoconjunctivitis sicca, ­uncontrolled uveitis, severe blepharitis, lagophthalmos, and systemic ­immunosuppression. Also, PTK should be avoided in patients who have neurotrophic corneas (including previous herpes simplex or zoster or trigeminal nerve injury), exposure keratitis, collagen vascular disease, and diabetes because of potential problems with wound healing. Because it is possible that ­microorganisms may be spread during treatment, PTK should not be used for deep corneal scars and microbial keratitis, including infectious crystalline keratopathy.8, 9 Significant corneal thinning is a further contraindication.

SURGICAL TECHNIQUES Corneal Dystrophies, Scars, and Elevated Opacities

The goals of treatment of anterior stromal dystrophies are to ablate the confluent opacities in the visual axis and to remove tnhe least amount of tissue possible to achieve the optimal visual outcome. Typically, anterior stromal dystrophies have the bulk of lesions anteriorly (Fig. 4-28-1).10 The middle and deep stroma often have fewer lesions with intervening clear stroma. In the course of treatment, deeper ­lesions are not ablated.3, 11 Masking fluids are used to help fill in depressions and expose elevations of an irregular corneal surface. They also absorb laser energy and thus shield depressions and expose tissue peaks. Numerous masking fluids are available. The most important principle is to use just enough masking fluid to cover the “valleys.” Carboxymethylcellulose 0.5% is of medium viscosity and efficiently covers the valleys and exposes the elevated ­areas. Methyl­ cellulose 1–2% is a high-viscosity fluid that may cover peaks, whereas hydroxypropylmethylcellulose 0.1% with dextran is of low viscosity and may leave valleys as well as peaks partly exposed. It is often best to use more than one agent depending on the particular corneal surface. Corneal dystrophies may recur after PTK in much the same way that dystrophies recur after penetrating keratoplasty. Recurrences are usually more superficial and may be retreated with PTK or, in a corneal graft, treated with PTK for the first time. The success rate for recurrent granular or lattice dystrophy is extremely high and comparable to the high success rate for primary Reis-Bückler dystrophy, in which the deposits occur at Bowman’s layer.1 Macular and Aellino dystrophies have deeper lesions, and macular has intervening confluence; both are usually not amenable to PTK. Elevated corneal opacities represent a major challenge to the PTK ­surgeon. This type of pathology is often amenable to manual ­keratectomy using a blade, which is efficacious when a suitable plane is found to leave a smooth surface on the cornea. When a plane ­cannot be found, it is possible to “debulk” the elevation and smooth the ­remaining area using the excimer laser. Alternatively, the epithelium may be removed from the area over the elevated lesion and then photoablation ­performed to the underlying pathology.3 The surrounding epithelium is left in place to serve as a masking agent and to avoid the ablation of normal tissue around the lesion. After removal of the nodule, the entire area is

Pain

Delayed Epithelialization

A

Epithelial healing is usually complete within the first week. It is ­desirable to avoid prolonged epithelial healing because without an ­intact epithelium, a port of entry into the subepithelial tissue exists for microorganisms, visual acuity is reduced, and pain may be severe. Persistent epithelial defects or recurrent erosions are possible complications that may result and seem to be more common in patients who have preoperative epitheliopathy. Active inflammation is treated aggressively. Bandage contact lenses and lubrication are typically very helpful in the promotion of epithelial healing.1 Punctal plugs are often helpful in patients who have dry eye signs or symptoms, and tarsorrhaphy may be considered in recalcitrant cases. Preoperative epitheliopathy must be treated and medications carefully reviewed.

Bacterial Keratitis

B

Fig. 4-28-1  Granular dystrophy. (A) Preoperative anterior appearance of the opacities in a patient who has granular dystrophy. (B) The same eye 3 months ­after phototherapeutic keratectomy. (With permission from Salz JJ, McDonnell PJ,  McDonald MB, eds. Corneal laser surgery. St Louis: Mosby; 1995.)

smoothed with additional use of masking agents, such as hydroxypropylmethylcellulose 0.1% with dextran. In this way, Salzmann’s nodular degeneration and keratoconus nodules have been treated successfully.

Postoperative care

Immediately postoperatively, a bandage soft contact lens is applied and the patient is instructed to use topical antibiotics, often a broad-­spectrum antibiotic such as a fluoroquinolone. Alternatively, bacitracin or erythromycin ophthalmic antibiotic ointment is applied along with a cycloplegic drop (homatropine), and a pressure patch is placed. Topical corticosteroid such as prednisolone acetate 1%, dexamethasone phosphate 0.1%, or fluorometholone 0.1%, four times a day, is used. The corticosteroid is tapered to once daily within 1 month. In many compromised corneas that undergo PTK, the benefits of continued corticosteroid drops may be outweighed by the potential side effects of a rise in IOP, cataract, risk of microbial infection, or recurrent herpetic disease. Topical nonsteroidal anti-inflammatory drops given for 1 day may help control pain, which may be severe.1, 12–14 Patients are examined every 24–72 hours until epithelialization is complete, which generally occurs within 1 week. Eye examinations are performed at 1 month, 3 months, 12 months, and annually thereafter.15

Bacterial keratitis is a feared postoperative complication because of the ­existence of an epithelial defect and the placement of a contact lens on what may be an already compromised cornea. Al-Rajhi et al.17 reported three cases of bacterial keratitis, all of which had a preoperative diagnosis of climatic droplet keratopathy, out of 258 eyes that underwent PTK. All three had gram-positive keratitis. However, the authors maintain that the risk of infection after PTK is lower than the risk associated with the natural history of the disease. Most PTK surgeons believe the ability of bandage contact lenses to decrease pain and help epithelial wound healing outweighs the risk of bacterial keratitis. Prophylactic antibiotic drops are used postoperatively. In addition, stromal infiltrates are managed similarly to those in patients who have not had PTK. Nonsteroidal anti-inflammatory agents, contact lenses, and infectious keratitis may also produce infiltrates.

Viral Keratitis

Herpes simplex virus may be reactivated after PTK. Pepose et al.18 demonstrated reactivation in latently infected mice, possibly related to ­irritation of the corneal nerve plexus by excimer keratectomy. In a study of 166 eyes, Fagerholm et al.19 reported one patient who had three recurrences of herpes simplex. Vrabec et al.20 described two cases of recurrence of herpetic dendritic keratitis in which PTK was performed to ablate stromal scars secondary to recurrent herpes simplex. McDonnell et al.21 reported recurrence of herpes epithelial keratitis after excimer astigmatic photokeratectomy in a corneal graft. Whenever possible, treatment of ­patients who have a history of herpes is avoided. In cases that are treated, regimens of preoperative and postoperative acyclovir are given.

Recurrence and Haze

COMPLICATIONS

Corneal dystrophies treated with PTK may recur, as they do in corneal grafts. Retreatment may be undertaken, although the possibility of the inducement of further hyperopia and possibly anisometropia must be considered. Furthermore, haze often results after PTK and may be confluent and visually significant. Haze often decreases over time, and a period of 12  months is allowed to elapse before the haze is treated.

Hyperopia

Graft Rejection

The most common side effect of PTK is induced hyperopia, which ­results from flattening of the central cornea. To avoid this problem, the authors’ preferred method is to include 1 D of hyperopic correction for every 25 μm of PTK tissue ablation.

Corneal graft rejection in PTK-treated patients has been reported, as in patients treated by Hersh et al.22 for recurrent lattice dystrophy and Epstein and Robin23 for postoperative astigmatism. Medical treatment of the rejection episodes was successful in both instances.

Myopia/Myopic Astigmatism

OUTCOME

Myopia and myopic astigmatism may be induced when the periphery or paracentral cornea undergoes a deeper ablation than the central cornea, which may occur in the treatment of paracentral opacities. Sher et al.16 observed myopic shift in 3% of PTK-treated patients, and Campos et al. found a rate of 16.6%.4

Irregular Astigmatism and Decentration

Irregular astigmatism is an undesirable potential outcome that may be minimized by using masking agents to help achieve a smooth corneal contour postoperatively. Decentration may also lead to irregular astigmatism.

4.28 Excimer Laser Treatment of Corneal Pathology

Pain may be severe after excimer laser photoablation. Judicious use of topical nonsteroidal anti-inflammatory agents, which include diclofenac sodium, ketorolac tromethamine (ketorolac trometamol), and flurbiprofen sodium, has helped in pain control after excimer laser treatment.

Corneal Light Scattering and Wound Healing after Phototherapeutic Keratectomy

The transparency and minimal degree of light scatter of the cornea largely result from the tight packing and small diameter of stromal collagen fibrils. Fibrils within lamellae scatter light inefficiently, and each lamella scatters light. The light scattered by the different lamellae undergoes mutually destructive interference.23 Further, the cornea is a thin structure, which also helps to decrease light scatter. A functional

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endothelium is necessary for corneal transparency because corneal edema increases the packing distance between fibrils.24 After ablation of the anterior cornea using the ArF excimer laser, reepithelialization occurs within the first week.1, 12–14 One hypothesis is that photoablation leads to the formation of a “pseudomembrane,” which serves as a template for migrating hyperplastic epithelial cells, as well as a water barrier, and thus helps prevent corneal edema after photoablation.25, 26 The use of mitomycin C (during PTK) to treat corneal scarring after PRK has reduced the likelihood of recurrences of haze and scarring and improved visual outcomes.27–29 Anchorage of the epithelium to the stroma occurs approximately 1–3 months after photoablation through the reformation of three different structural groups that participate in the bonds between the epithelium and stroma – hemidesmosomes, anchoring fibrils containing type VII collagen, and basal laminae. These groups are restored over a period of many months, but abnormalities may still persist after a year and perhaps become a permanent feature.30 Although such abnormalities are noted after PTK, the technique has been used successfully to treat disorders of the cornea that involve faulty epithelial adhesion, such as recalcitrant recurrent erosion syndrome.6 Stromal wound healing occurs simultaneously with reformation of the anchoring complexes. Activated keratocytes repopulate the area

and actually increase in number by the third week after photoablation. Histologically, the activity of the cells is evident by a large increase in rough endoplasmic reticulum. New collagen, predominantly type III, and proteoglycan matrix, believed to be primarily keratan sulfate, are produced.31, 32 The activated keratocytes and their products (newly formed ­collagen and proteoglycans in an irregular network) result in the haze that contributes to light scatter.2, 33, 34 Morphological studies of animal and ­human endothelium have failed to show evidence of endothelial cell loss in ablations at least 40 mm anterior to Descemet’s membrane.2, 34, 35

SUMMARY In conclusion, the 193 nm ArF excimer laser has great potential for the treatment of anterior corneal pathology and surface irregularities. The expenses and risks of penetrating keratoplasty, including the risks of intraocular surgery and anesthesia, may be avoided. Treatment must be individualized depending on the type of pathology and its ablation characteristics and depth. Clinical studies have demonstrated the success of PTK for anterior corneal pathology.36, 37 Its use is an exciting addition to the treatment options available to corneal surgeons.

REFERENCES   1. Stark WJ, Chamon W, Kamp MT, et al. Clinical follow-up of 193  nm ArF excimer laser photokeratectomy. Ophthalmology. 1992;99:805–11.   2. Marshall J, Trokel S, Rothery S, Krueger RR. Photoablative reprofiling of the cornea using an excimer laser: photorefractive keratectomy. Lasers Ophthalmol. 1986;1:23–44.   3. Rapuano CJ. Excimer laser phototherapeutic keratectomy. Int Ophthalmol Clin. 1996;36:127–36.   4. Campos M, Nielson S, Szerenyi K, et al. Clinical follow-up of phototherapeutic keratectomy for treatment of corneal opacities. Am J Ophthalmol. 1993;115:433–40.   5. Chamon W, Azar DT, Stark WJ, et al. Phototherapeutic keratectomy. Ophthalmol Clin North Am. 1993;6:399–413.   6. Ohman L, Fagerholm P, Tengroth B. Treatment of recurrent corneal erosions with the excimer laser. Acta Ophthalmol. 1994;72:461–3.   7. Hersh PS, Spinak A, Garrana R, Mayers M. Phototherapeutic keratectomy: strategies and results in 12 eyes. Refract Corneal Surg. 1993;9(2 Suppl):90–5.   8. Gottsch JD, Gilbert ML, Goodman DF, et al. Excimer laser ablative treatment of microbial keratitis. Ophthalmology. 1991;98:146–9.   9. Eiferman RA, Forgey DR, Cook YD. Excimer laser ablation of infectious crystalline keratopathy. Arch Ophthalmol. 1992;110:18. 10. Salz JJ, McDonnell PJ, McDonald MB, eds. Corneal laser surgery. St Louis: Mosby; 1995. . 11. Thompson V, Durrie DS, Cavanaugh TB. Philosophy and technique for excimer laser phototherapeutic keratectomy. Review. Refract Corneal Surg. 1993;9(2 Suppl):81–5. 12. Salz JJ, Maguen E, Macy JI, et al. One-year results of excimer laser photorefractive keratectomy for myopia. Refract Corneal Surg. 1992;8:270–3. 13. Gaster RN, Binder PS, Coalwell K, et al. Corneal surface ablation by 193  nm excimer laser and wound healing in rabbits. Invest Ophthalmol Vis Sci. 1989;30:90–7. 14. Sanders D. Clinical evaluation of phototherapeutic keratectomy – VISX Twenty/Twenty excimer laser. Submitted to the FDA. Written Communication 2/7/94.

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15. Azar DT, Jain S, Woods R, et al. Phototherapeutic keratectomy: the VISX experience. In: Salz JJ, McDonnell PJ, McDonald MB, eds. Corneal laser surgery. St Louis: Mosby; 1995:213–26. 16. Sher NA, Bowers RA, Zabel RW, et al. Clinical use of   193-nm excimer laser in the treatment of corneal scars. Arch Ophthalmol. 1991;109:491–8. 17. Al-Rajhi AA, Wagoner MD, Badr IA, et al. Bacterial ­keratitis following phototherapeutic keratectomy. J Refract Surg. 1996;12:123–7. 18. Pepose JS, Laycock KA, Miller JK, et al. Reactivation of latent Herpes simplex virus by excimer laser photokeratectomy. Am J Ophthalmol. 1992;114:45–50. 19. Fagerholm P, Fitzsimmons TD, Orndahl M, et al. ­Phototherapeutic keratectomy: long-term results in 166 eyes. Refract Corneal Surg. 1993;9(2 Suppl):76–81. 20. Vrabec MP, Anderson JA, Rock ME, et al. Electron ­microscopic findings in a cornea with recurrence of herpes simplex keratitis after excimer laser ­phototherapeutic keratectomy. CLAO J. 1994;20:41–4. 21. McDonnell PJ, Moreira H, Clapham TN, et al. Photorefractive keratectomy for astigmatism. Arch Ophthalmol. 1991;109:1370–3. 22. Hersh PS, Jordan AJ, Mayers M. Corneal graft rejection episode after excimer laser phototherapeutic keratectomy. Arch Ophthalmol. 1993;111:735–6. 23. Farrell RA. Corneal transparency. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology: basic sciences. Philadelphia: WB Saunders; 1994:64–81. 24. Olsen BR, McCarthy MT. Molecular structure of the sclera, cornea, and vitreous body. In: Albert DM, ­Jakobiec FA, eds. Principles and practice of ophthalmology: basic sciences. Philadelphia: WB Saunders; 1994:47–8. 25. Gordon M, Brint SF, Durrie DS, et al. Photorefractive keratectomy at 193  nm using an erodible mask. In: Parel JM, ed. Ophthalmic technologies II. Bellingham, WA: SPIE; 1992. 26. Campos M, Wang X, Hertzog LL, et al. Ablation rates and surface ultrastructure of 193  nm excimer laser keratectomies. Invest Ophthalmol Vis Sci. 1993;34:2493–500.

27. Majmudar PA, Forstot SL, Dennis RF, et al. Topical ­mitomycin C for subepithelial fibrosis after refractive corneal surgery. Ophthalmology. 2000;107:89–94. 28. Azar DT, Jain S. Topical MMC for subepithelial fibrosis after refractive corneal surgery. Ophthalmology. 2001;108:239–40. 29. Jain S, McCally RL, Connolly PJ, Azar DT. Mitomycin C reduces corneal light scattering after excimer keratectomy. Cornea. 2001;20:45–9. 30. Fountain TR, De la Cruz Z, Green WR, et al. Reassembly of corneal epithelial adhesion structures after excimer laser keratectomy in humans. Arch Ophthalmol. 1994;112:967–72. 31. Fantes FE, Hanna KD, Waring GO, et al. Wound healing after excimer laser keratomileusis (photorefractive   keratectomy) in monkeys. Arch Ophthalmol. 1990;  108:665–75. 32. Tuft SJ, Zabel RW, Marshall J. Corneal repair following keratectomy. Invest Ophthalmol Vis Sci. 1989;30:1769–77. 33. Courant D, Fritsch P, Azema A, et al. Corneal wound healing after photo-kerato-mileusis treatment on the primate eye. Lasers Light Ophthalmol. 1990;3:189–95. 34. Bende T, Seiler T, Wollensak J. Side effects in excimer corneal surgery: corneal thermal gradients. Graefes Arch Clin Exp Ophthalmol. 1988;226:277–80. 35. Ozler SA, Liaw LL, Neev J, et al. Acute ultrastructural changes of cornea after excimer laser ablation. Invest Ophthalmol Vis Sci. 1992;33:540–6. 36. Ashraf F, Azar D, Odrich M. Clinical results of PTK using the VISX excimer laser. In: Azar DT, Steinert RF, Stark WJ, eds. Excimer laser phototherapeutic keratectomy. Baltimore: William & Wilkins; 1997:169–72. 37. Steinert RF. Clinical results with the Summit Technology excimer laser. In: Azar DT, Steinert RF, Stark WJ, eds. Excimer laser phototherapeutic keratectomy. Baltimore: William & Wilkins; 1997:155–66.

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 9 Surgery

Conjunctival Surgery

Lisa Martén, Ming X. Wang, Carol L. Karp, Robert P. Selkin and Dimitri T. Azar

4.29

Definition:  Conjunctival procedures may be used to cover an ­unstable or painful corneal surface or to remove pterygium.

Key features n n

 areful preoperative preparation and planning critical for success. C Understand intraoperative and postoperative complications and management.

Associated features n

 ecurrences of pterygium may be more aggressive than initial R pterygium.

HISTORICAL REVIEW Conjunctival procedures include conjunctival flap preparation, pterygium surgery, and limbal cell transplantation. In a conjunctival flap procedure, a hinged flap of conjunctiva is created to cover an unstable or painful corneal surface. Originally described by Gundersen,1 conjunctival flaps have remained an effective procedure for the treatment of unresponsive corneal ulcers in which visual expectation is poor. The conjunctival flap provides a source of blood vessels and cellular nutrients, and the goal is to reduce ocular surface inflammation. Corneal procedures for visual rehabilitation may be performed at a later date. Pterygium surgery dates back to 1855, when Desmarres2 first performed a transposition of the pterygium head. Arlt in 1872 recognized the importance of covering the epibulbar defect after pterygium excision and described the first conjunctival graft.3 With respect to limbal transplantation (see Chapter 4-31 for more detail), Kenyon and Tseng4 described the technique of limbal autograft transplantation for ocular surface disorders.

ANESTHESIA Conjunctival surgeries may be performed using topical, local, or general anesthetic. Local or topical anesthetic is indicated for adult and cooperative patients. To prevent squeezing during surgery, a lid block is sometimes employed. General anesthetic is reserved for pediatric ­patients and uncooperative adults.

SPECIFIC TECHNIQUES Conjunctival Flap

Preoperative evaluation and diagnostic approach

Common indications for conjunctival flap include: l Nonhealing sterile corneal ulcerations secondary to chemical or thermal injuries, herpetic infections, exposure keratopathies, and neurotrophic diseases. l Painful bullous keratopathy in eyes that have low visual potential in which penetrating keratoplasty is not indicated and in which simpler management techniques, such as soft contact lenses or anterior ­stromal puncture, have failed. l Blind eyes in need of surface preparation for prosthetic shells or ­contact lenses.

Fig. 4-29-1  360° peritomy. Westcott scissors is used. The dissection is carried out toward the corneal limbus with care not to buttonhole the conjunctiva. (Courtesy of Dr R. K. Forster.)

Contraindications for conjunctival flap include: active bacterial or fungal keratitis and corneal perforation. As a result of advances in antimicrobial therapy, bandage lenses, tarsorrhaphy, and penetrating keratoplasty, conjunctival flaps are used less frequently today.

Surgical techniques

The availability of mobile conjunctiva is evaluated. If superior conjunctival scarring precludes mobilization, a conjunctival flap may be fashioned from the inferior bulbar conjunctiva, although often less tissue is available. When superior conjunctiva is available, the globe is ­ rotated inferiorly using a traction suture placed at the 12 o’clock ­limbus. A semicircular incision, parallel to the superior corneal limbus, is made as posterior as possible using Westcott scissors. Using a smooth ­forceps, the dissection of a thin conjunctival flap is carried inferiorly until the superior corneal limbus is reached. Adequate dissection and undermining of this flap laterally is important for the subsequent downward mobilization of the flap over the cornea and to prevent traction. It is imperative in the dissection process that particular care is taken not to create buttonholes in the conjunctival flap. The conjunctival flap is freed completely of its underlying Tenon’s capsule to enable adequate mobilization of the flap. With the use of a No. 64 Beaver blade, the corneal epithelium is removed completely. Application of lidocaine 4% or absolute alcohol may help loosen the corneal epithelium. A 360° limbal peritomy is performed using Westcott scissors or a blade (Fig. 4-29-1). The well-mobilized conjunctival flap is stretched to cover the desired area (Fig. 4-29-2). The superior and inferior aspects of the flap are secured on the sclera using interrupted or running 10–0 nylon sutures. The inferior edges of the conjunctiva may also be reapposed with 8-0 Vicryl suture in a running fashion (Fig. 4-29-3). A partial Gundersen flap is used in certain circumstances, such as for focal nonhealing corneal ulcers. The procedure also includes scraping of the corneal epithelium, mobilization of the conjunctiva in the appropriate quadrant, and suturing of the conjunctival flap over a localized corneal defect.

Complications and postoperative management

The most common perioperative complication of a conjunctival flap procedure is the creation of a buttonhole of the conjunctiva during dissection. If this occurs, the holes are closed using purse-string sutures on the flap. Alternatively, when the flap has covered the cornea, the holes

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Fig. 4-29-2  Mobilization of the conjunctival flap to the desired area of the cornea. (Courtesy of Dr R. K. Forster.)

Fig. 4-29-4  Dissection of the head of the pterygium from the cornea. A blade is used.

Fig. 4-29-5  Removal of the body of the pterygium. Westcott scissors are used with care to avoid damage to the underlying rectus muscle. Fig. 4-29-3  Here, the conjunctival flap covers the area of sterile ulceration. The flap is sutured into position with 10-0 nylon sutures superiorly and 7-0 Vicryl sutures through the inferior limbal episclera. (Courtesy of Dr R. K. Forster.)

are repaired by suturing the conjunctiva to the underlying corneal ­tissue. Postoperative complications include retraction of the ­conjunctival flap, hemorrhage and epithelial mucous cysts, and recurrence of infection, such as that caused by herpes simplex virus.5 Adequate undermining during the flap dissection minimizes the likelihood of subsequent flap retraction. After healing, a cosmetic contact lens is fitted if the patient desires. In certain circumstances, penetrating keratoplasty is indicated for visual rehabilitation. Because a conjunctival flap may have destroyed corneal limbal stem cells, a limbal allograft may be considered prior to removal of the conjunctival flap and the penetrating keratoplasty.

Pterygium Surgery

Pterygium refers to conjunctival or fibrovascular growth over the sclera and onto the cornea; it occurs most commonly in the nasal aspect of the interpalpebral exposure zone. Pathologically, pterygium is characterized by elastoid degeneration of subepithelial tissue and destruction of Bowman’s membrane. The cause of pterygium is believed to be related to ultraviolet and dust exposure. Clinically, a characteristic iron line (Stocker’s line) may be seen at the advancing front of a ­pterygium.

Preoperative evaluation and diagnostic approach

Surgical indications for a pterygium excision include: l Growth of pterygium such that it has impinged on the visual axis. l Reduced vision as a result of astigmatism induced by the pterygium. l Severe irritation not relieved by medical therapy. l Surgery for cosmesis. l Reduced motility secondary to pterygium. l Recurrence, which may grow more aggressively than the primary ­lesions.

Surgical techniques

364

Several techniques are available for the excision of pterygium, which include the bare sclera technique, autograft, antimetabolites, radiation, and the recently developed techniques using amniotic ­membranes.

Fig. 4-29-6  A diamond burr is used to smooth the corneal tissue.

Bare sclera technique/simple closure

The bare sclera technique is technically simple, although it is associated with a recurrence rate as high as 40%.6 Surgically, the lesion may be outlined using spot cautery. To facilitate the dissection, the eye is rotated laterally using traction sutures (6-0 Vicryl or silk) placed at the corneal limbus at the 6 and 12 o’clock positions. The dissection may be initiated at the corneal side of the pterygium. Using forceps, the head of pterygium is lifted and dissected off the cornea in a lamellar fashion using a No. 64 or No. 69 Beaver blade (Fig. 4-29-4). The scleral portion of the pterygium is excised using Westcott scissors (Fig. 4-29-5). Care is taken to identify the rectus muscle, especially in surgery for recurrent pterygium in which fibrous tissue may be adherent to the underlying muscle. The dissected area near the limbus is polished using a diamond burr (Fig. 4-29-6). Alternative techniques include removal of the scleral portion first, followed by blunt dissection or avulsion of the corneal portion. Antimitotic agents, such as mitomycin C, have also been used to prevent recurrence in conjunction with this technique.

Autograft

A conjunctival autograft after pterygium excision has been shown to decrease significantly the chance of recurrence to 5%.6 After excision of the pterygium, as already described, the size of the bare sclera defect is measured. Commonly, the superotemporal conjunctiva is used as donor if the pterygium is located nasally. The tractional sutures may be used to rotate the eye downward. The donor conjunctiva is outlined using spot cautery and a conjunctival flap is dissected with smooth ­ forceps and

4.29 Conjunctival Surgery

Fig. 4-29-7  Dissection of the conjunctiva. The limbus is marked and the healthy conjunctiva is harvested. The conjunctiva is dissected gently with care not to buttonhole the donor tissue.

Fig. 4-29-8  Conjunctival autograft in position over the previously excised pterygium. Two 10-0 nylon sutures are placed at the limbus and 8-0 Vicryl sutures are used along the conjunctiva in an interrupted fashion. Care is taken to maintain the limbus-to-limbus position of the graft.

Westcott scissors (Fig. 4-29-7). It is important to handle the ­conjunctiva carefully to avoid the creation of buttonholes. The ­ orientation of the conjunctival flap is maintained when it is transferred to the recipient bed to ensure the proper positioning of limbal stem cells, although the presence of limbal cells may not be necessary. Alternatively, the conjunctival flap may be rotated on a pedicle. The authors use a 10-0 nylon suture at the limbus to secure the graft and several interrupted 8-0 Vicryl sutures elsewhere (Fig. 4-29-8). The nylon sutures are ­removed 2  weeks postoperatively and the Vicryl sutures are left to be reabsorbed. In general, the donor conjunctival defect is left unsutured.

Fibrin glue

Antimetabolites and radiation

Mitomycin has been used both intraoperatively and postoperatively and appears to reduce significantly the recurrence rate. Antimetabolites, however, have been associated with serious complications including corneal or scleral melting. In addition, beta radiation using strontium-90 has been employed and has decreased recurrence successfully. Radiation treatment, however, may cause significant complications such as scleral necrosis, cataract, and persistent epithelial defect. As a result, beta radiation and mitomycin treatment after pterygium surgery have been supplanted largely by conjunctival transplantation.

Fibrin glue is a two-component tissue adhesive that is used in many surgical procedures, including cardiac surgery and plastic surgery. It has also been used as a sealant for corneal perforations and in eye muscle surgery. One component consists of a protein solution fibrinogen sealant; the other is a thrombin solution. Equal amounts of the two components are mixed together, producing a fibrin clot. There has been a transition in recent years to using fibrin glue for attaching conjunctival autografts, other grafts, and amniotic membranes to the sclera during pterygium surgery. It has been shown in several studies to decrease postoperative pain and foreign body sensation as well as reduce operative time and blood loss during surgery.7, 8 In addition, fibrin glue replaces Vicryl sutures or reduces the number required. Patients must understand that this is not a Food and Drug Administration (FDA)approved use for fibrin glue. Patients also need to give their consent for blood product use because the fibrin glue is derived from pooled human and bovine blood. However, it has been used for many years in millions of surgeries with no documented cases of transmission of hepatitis B or C, HIV, bovine spongiform encephalopathy, or prion-mediated disease. Furthermore, donated plasma undergoes viral polymerase chain reaction (PCR) screening before use.

REFERENCES 1.  Gundersen T. Conjunctival flaps in the treatment of corneal disease with reference to a new technique of application. Arch Ophthalmol. 1958;60:880. 2.  Desmarres LA. Traité théorique et practique des ­maladies des yeux, Vol. 2. Paris: G Bailliere; 1855. 3.  Rosenthal JW. Chronology of pterygium therapy. Am J Ophthalmol. 1953;36:1601.

4.  Kenyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989;96:709–22. 5.  Rosenfeld SI, Alfonso EC, Gollamudi S. Recurrent Herpes simplex infection in a conjunctival flap. Am J Ophthalmol. 1993;116:242–4. 6.  Jaros PA, deLuise VP. Pingueculum and pterygium. Surv Ophthalmol. 1988;33:41–9.

7.  Marticorena J, Rodriguez-Ares MT, Tourino R, et al. Pterygium surgery: conjunctival autograft using a fibrin adhesive. Cornea. 2006;25:34–6. 8.  Kaufman H. Human fibrin tissue adhesive for sutureless lamellar keratoplasty and scleral patch adhesion: a pilot study. Ophthalmology. 0000;110:2168–72.

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PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 9 Surgery

Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

4.30

Marianne O. Price and Francis W. Price Jr

Definition:  Endothelial keratoplasty is a technique that provides an

alternative to penetrating keratoplasty as a method to more specifically replace endothelial cells in the treatment of endothelial dysfunction.

Key features n

Targeted replacement of endothelial cells.

Associated features n n n n n

 uicker visual recovery. Q No significant increase in astigmatism. Significantly smaller wound size. Minimal disruption of corneal innervation. Minimal loss of tectonic strength of the cornea.

INTRODUCTION Penetrating keratoplasty (PK) has long been the gold standard for treatment of endothelial dysfunction. However, recent advances in endothelial keratoplasty (EK) techniques facilitate targeted endothelial replacement, instead of a full-thickness graft, so EK is rapidly gaining popularity. The limitations of PK include the following: it generally takes 6 months to several years for the refraction to stabilize;1-3 10–15% of the patients typically require a hard contact lens for best vision;4, 5 and a final mean refractive cylinder of 4–5 D is common.3, 5 Furthermore, a PK incision severs all corneal nerves, so the inclination to blink and produce tears is reduced postoperatively. This, together with the prolonged presence of corneal sutures, increases the risk that ocular surface complications will interfere with recovery.6, 7 Moreover, the PK wound never heals back to the full strength of a virgin cornea, so a PK eye is forever at increased risk of loss from a traumatic injury.8 In contrast, EK involves selective removal of dysfunctional recipient corneal endothelium and replacement with donor tissue consisting of posterior stroma and healthy endothelium.9, 10 EK is performed through a small incision and spares the majority of the host cornea so corneal strength and surface topography are minimally altered and the technique is essentially refractive-neutral.10–14 Furthermore, corneal innervation is retained and corneal sutures are not required, so ocular surface complications are minimal.15 Finally, the small incision allows rapid healing and many patients achieve rapid visual recovery after surgery.

EVOLUTION OF EK TECHNIQUES

366

The concept of selective endothelial replacement was pioneered in the 1960s by Jose Barraquer, who created and retracted an anterior flap, ­trephined out posterior stroma, and replaced it with a posterior lamellar button prepared from a donor cornea. This technique suffered from some

of the same limitations as penetrating keratoplasty (PK), including induction of irregular astigmatism, unpredictable corneal topography, loss of the tectonic strength of the cornea, and suture-related problems. In addition, interface haze was a problem, and this technique never gained widespread acceptance. In 1993, Ko et al. performed endothelial replacement through a scleral-limbal approach in rabbits, thus eliminating the flap but still utilizing sutures to secure the donor tissue to the recipient cornea.16 In 1998, Melles reported successful replacement of dysfunctional endothelium through a scleral-limbal approach, without use of any sutures to secure the donor tissue, in a technique he called posterior lamellar keratoplasty (PLK).9 The following year, he reported successfully using this technique to treat pseudophakic bullous keratopathy.17 PLK required lamellar dissection of the recipient and donor corneal tissue. Visualization of dissection depth was quite challenging using standard methods, so Melles came up with the clever idea of injecting an air bubble into the anterior chamber because this created a light reflection that helped the surgeon judge the depth of the blade and dissection plane.18 Melles initially laid the donor tissue on a viscoelastic material-coated spatula for insertion through a 9 mm incision. Later he demonstrated that the donor tissue could be folded in half for insertion through a 5 mm incision.19 Terry renamed the procedure deep lamellar endothelial keratoplasty (DLEK), and undertook a prospective clinical study.14 The most difficult aspect of the PLK/DLEK procedure was excision of the posterior recipient tissue using small scissors with or without a trephine. Melles eventually eliminated this challenging step by showing that Descemet’s membrane and dysfunctional endothelium could simply be stripped from the recipient cornea before implanting the donor tissue, and this EK modification became known as Descemet’s stripping with endothelial keratoplasty (DSEK).10, 12, 15, 20 When a microkeratome is used to perform the donor lamellar dissection the technique is also called Descemet’s stripping automated endothelial keratoplasty (DSAEK).21

SURGICAL TECHNIQUE Anesthesia and Recipient Preparation

EK still requires a completely different skill set compared with that used in standard PK. DSEK is usually performed with topical or local anesthesia, whereas PLK and DLEK are usually performed with local or general anesthesia. With local anesthesia (using a retrobulbar or peribulbar block) it is important to ensure that there is no back pressure from periorbital swelling because back pressure can lead to forceful shallowing of the anterior chamber while the donor tissue is being inserted and may even push the donor tissue back out of the eye. A Honan balloon (the Lebanon Corporation, Lebanon, IN), or similar device, can be applied for 1 hour after injecting a retrobulbar block to ensure that the eye is soft before beginning the procedure. Traction sutures can be placed in the sclera peripheral to the limbus at 6 and 12 o’clock to help stabilize the eye during the procedure. The recipient horizontal corneal diameter should be measured with calipers to help the surgeon select an appropriate trephine size. A 4–5 mm clear corneal or scleral tunnel incision (Fig. 4-30-1) is made in the recipient eye.19 Temporal placement of the incision has several advantages compared with superior placement: donor button insertion is facilitated because the corneal diameter is longer horizontally; the

4.30

Fig. 4-30-3  Stripping of Descemet’s membrane using a 90-degree angled stripper.

to ­ facilitate visualization.15 After the membrane is removed it can be spread on the surface of the cornea to determine whether removal was complete or whether some fragment might remain in the eye. Alternatively, instead of using an infusion of balanced salt solution to maintain the anterior chamber, the anterior chamber can be filled with either air or a cohesive viscoelastic material. However, when using a viscoelastic material, great care should be taken that all viscoelastic material is removed from the anterior chamber and back surface of the cornea as retained viscoelastic material on the stromal surface can prevent attachment of the donor tissue.

Donor Tissue Preparation

Fig. 4-30-2  Scoring of Descemet’s membrane with a modified Sinskey hook around the perimeter of the area to be stripped.

superior conjunctiva is preserved for future glaucoma surgery if needed; and orbital anatomy, such as large brows or sunken globes, is not as important.10 If the recipient epithelium is hazy or scarred it can be removed and this will generally improve the view into the eye.

PLK/DLEK Recipient Dissection and Excision

The trephine used to punch the donor tissue can be used to lightly mark the recipient epithelium to help indicate the area of posterior recipient tissue to be removed. The PLK and DLEK recipient dissection methods differ somewhat. In PLK, the anterior chamber is filled with air to provide a reflection to help the surgeon judge the dissection depth.18 A series of curved blades of increasing length (DORC International, Zuidland, the Netherlands) are used to extend a deep scleral-corneal lamellar dissection just beyond the edges of the trephine mark on the epithelium. In DLEK, the anterior chamber is filled with a cohesive viscoelastic material and the freehand dissection is made with direct visualization, as lamellar dissections have traditionally been done.14 In both PLK and DLEK, the posterior deep stromal button is excised freehand using small curved scissors with or without a trephine.

DSEK Recipient Preparation

A blunt Sinskey hook is used to score Descemet’s membrane in a ­circular pattern to outline the area of planned membrane removal (Fig. 4-30-2).10 The far edge of Descemet’s membrane is grasped with a stripping ­instrument or infusion/aspiration tip and is carefully peeled off and removed from the eye (Fig. 4-30-3).20 Trypan blue can be injected into the ­anterior chamber immediately prior to stripping Descemet’s ­membrane

Donor tissue preparation involves 3 steps: lamellar dissection, sizing to the appropriate diameter with a trephine, and preparation for insertion. Preparing the donor button before opening the patient’s eye allows the surgeon to make sure that the donor button will be suitable for transplantation. Lamellar dissection can be done manually, similar to the PLK or DLEK recipient dissection, or with the aid of a microkeratome. Some eye banks provide pre-dissected donor corneas for an additional fee. Manual dissection is suitable for use with whole donor globes or with corneal/scleral shells that have been mounted on an artificial anterior chamber. Corneal/scleral shells should have a diameter of 16–17 mm to ensure firm and air-tight fixation on an artificial anterior chamber. Excess tissue should be trimmed from the edges if necessary to ensure firm ­fixation. The surgeon should also carefully examine the tissue to ensure that there are no divots or cuts through the peripheral cornea to the limbus because these could allow the tissue to slip or depressurize during the dissection. Estimating the dissection depth can be a challenge with manual dissection, so some surgeons prefer the Melles technique of filling the anterior chamber with air, because the reflection between the air/endothelium interface and the tip of the dissecting blade is indicative of the dissection depth.18 Other surgeons prefer to use viscoelastic material on the donor cornea with tissue storage solution or balanced salt solution in the artificial anterior chamber (AAC) to help protect the endothelium, but this makes it harder to estimate the dissection depth.14 Also, if viscoelastic material is used on a reusable AAC, it needs to be thoroughly removed before autoclaving the AAC, or toxic by-products will be created that could lead to toxic anterior segment syndrome (TASS) in subsequent cases. During the dissection, the AAC should be pressurized so that the donor cornea is firm. Manual dissection begins with a small one-third-depth incision in the peripheral cornea, and the dissection plane is extended across the cornea using series of curved blades of increasing length.9 Alternatively, a Barron suction recipient trephine can be placed over the donor tissue for trephination to about 60% depth and then a dissection plane can be extended across the donor tissue.14 With either method, the surgeon should aim for a dissection depth of approximately 80%. Extremely deep dissections may cause endothelial damage, plus very thin donor buttons are more difficult to manipulate and are more prone to develop wrinkles that can be very difficult to remove when pressed against the recipient cornea.12 For microkeratome dissection, a donor corneal/scleral shell is mounted on an artificial anterior chamber designed to accompany the microkeratome being used. The artificial anterior chamber can be filled with air,

Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

Fig. 4-30-1  Creation of 5 mm scleral tunnel incision for endothelial keratoplasty.

367

4 CORNEA AND OCULAR SURFACE DISEASES

Fig. 4-30-4  Lamellar dissection of the donor tissue with a microkeratome.

Fig. 4-30-5  Placement of the donor tissue with endothelial side upward on a suction trephine block.

viscoelastic material, balanced salt solution, or tissue storage solution. The latter three choices allow the donor thickness to be measured using ultrasonic pachymetry. Donor tissue thickness can vary substantially but typically ranges from 0.45 to 0.70 mm after epithelial removal for donor corneas stored in tissue storage solution (Optisol (XX) typically supplied by American eye banks). After determining the donor thickness, the surgeon can choose a microkeratome head of appropriate depth to provide a posterior donor button of approximately 0.12–0.20 mm thickness (Fig. 4-30-4). After dissection, the donor tissue is carefully transferred from the artificial anterior chamber and placed endothelial side up on a standard punch trephine block, where it is punched to the desired diameter (Fig. 4-30-5). EK donor diameters are usually between 8 and 9 mm. A specific diameter within that range is selected after measuring the horizontal white-to-white dimensions of the recipient cornea with calipers while the patient is lying down. The donor tissue can be covered with tissue storage solution while the recipient eye is being prepared.

Donor Implantation

368

Once the recipient eye is ready to receive the donor tissue, a small drop of cohesive viscoelastic material is placed in the center of the endothelial side of the donor, and the posterior tissue is gently separated from the anterior tissue. The posterior donor button can be folded over on itself like a “taco” for insertion into the recipient eye (Fig. 4-30-6).19 The tissue can either be folded in half or slightly over-folded with approximately 60% anterior and 40% posterior. This type of overfolding has the disadvantage of exposing some peripheral endothelium during tissue insertion, but it can make it easier for the posterior portion of the donor tissue to unfold by sweeping across the iris once it is in the eye, particularly if the anterior chamber is relatively shallow.

Fig. 4-30-6  Separating the posterior donor tissue from the anterior portion and folding of the posterior portion into a taco configuration with endothelial side inward.

Fig. 4-30-7  Insertion of the folded donor tissue into the recipient eye with special forceps that only compress the tissue at the tip.

The folded donor tissue is gently grasped with forceps and inserted into the recipient eye (Fig. 4-30-7); use of forceps that just compress the tissue at the tip may help minimize endothelial damage. The anterior chamber is inflated with balanced salt solution or air to allow the posterior portion of the donor tissue to unfold (Fig. 4-30-8). An alternative method to insert the donor is to fixate the edge of the donor with a suture and then thread the suture across the anterior chamber and out through a stab incision nasally or to insert retina/vitreal intraocular forceps through a nasal stab incision and grasp the donor through the 5 mm temporal incision. Then the donor tissue is pulled into the eye either through the wound with the aid of a guide, which helps fold the tissue endothelial side inward, or through an insertion cartridge into the eye. Once the tissue in the eye is unfolded stromal side up, the anterior chamber is then completely filled with air to press the donor button up against the recipient cornea. While the anterior chamber is completely filled with air, a Lindstrom LASIK roller (BD Medical) can be used to help center the donor tissue and massage fluid out of the donor/recipient interface (Fig. 4-30-9).15 Four small incisions can be made in the recipient cornea down to the graft interface to help drain any fluid trapped between the donor and recipient tissue; these can be made ­ before or after donor tissue insertion (Fig. 4-30-10).15 After 8–10 minutes, many surgeons remove most of the air to prevent pupillary block, and leave the anterior chamber approximately one third full.10 Some surgeons then have the patients lay face up with a partial air bubble for 30–60 ­minutes.10 Other surgeons leave the anterior chamber completely filled for 1–2 hours.21 At the completion of surgery, antibiotics, steroids, dilating drops, and nonsteroidal anti-inflammatory drugs (NSAIDs) are applied to the treated eye.

4.30

Fig. 4-30-10  Using a diamond blade to make a small stab incision down to the graft interface to release any fluid entrapped between the donor tissue and host cornea.

iridocorneal endothelial syndrome,24 posterior polymorphous dystrophy, or failed prior penetrating grafts.25 If anterior stromal scarring from long-standing corneal edema is significant, replacement of the full corneal thickness with a PK may provide better visual acuity. However, in many cases, patients who have tolerated long-standing corneal edema also have other visual limitations (for example, from retinal problems). In such cases, EK is an attractive alternative because it will quickly resolve the corneal edema and bullae while maintaining much of the structural integrity of the eye.

OUTCOME AND COMPARISON TO PK

Fig. 4-30-9  Massaging the surface of the recipient cornea to center the donor tissue and remove fluid from the donor/recipient interface, while the anterior chamber is completely filled with air.

Postoperative Care

Sometimes the donor tissue detaches in the early postoperative period. When this happens, air can be injected into the anterior chamber to again press the donor tissue firmly against the recipient cornea.15 To help prevent graft rejection, patients should be maintained on the corticosteroid regimen the surgeon typically uses after PK.

COMBINED PROCEDURES EK can be combined with other intraocular surgeries such as phacoemulsification, IOL implantation, IOL exchange, secondary lens implant, pars plana vitrectomy, or anterior vitrectomy.15 However, it is often preferable to perform these other surgeries ahead of time and perform EK as a separate procedure, especially for the less experienced EK surgeon. Combining EK with surgeries that require a larger incision can complicate wound closure and air tightness of the incision after placement of the donor. Whereas cataract extraction and IOL implantation is usually performed after PK to help address some of the unpredictable refractive outcomes, it is preferable to perform cataract extraction before EK because this deepens the anterior chamber and facilitates donor unfolding. EK is essentially refractive neutral so there is usually no need to correct significant refractive problems after the procedure.10, 12

INDICATIONS Endothelial keratoplasty provides a targeted method for treating most types of endothelial dysfunction, including Fuchs’ endothelial corneal dystrophy,10, 14, 22 pseudophakic or aphakic bullous keratopathy,10, 14, 17, 23

EK provides a number of significant advantages compared with PK. The eye is completely open during a PK, whereas EK is performed through a small 5 mm incision that can be readily closed during surgery should the patient cough or develop a suprachoroidal hemorrhage. Also, the full-thickness PK incision, typically 20–25 mm long, permanently weakens the eye and renders it susceptible to loss from traumatic injury throughout the remainder of the patient’s life.8 A second major advantage is that EK should minimize the risk of ocular surface complications. In a series of almost 4000 PKs, ocular surface complications were the most prevalent cause of graft failure in the first year after surgery, and accounted for 25% of the graft failures in the first 5 years postoperatively.6, 26 PK cuts all the corneal nerves, resulting in a neurotrophic eye that is more susceptible to dryness, epithelial defects, and infection. The long-standing sutures after PK also increase the risk of infection. In contrast, after EK the corneal nerves are retained and there is no need for corneal sutures.15 These features may be particularly important in developing regions of the world, where patients may have more difficulty getting back to a clinic quickly if they develop a loose suture, and where sanitation challenges may increase the risk of infection. A third major advantage is that EK is essentially refractive neutral (Table 4-30-1). EK does not significantly alter corneal topography, so mean refractive cylinder remains similar to the preoperative level, and hard contact lenses are not required for best vision. In contrast, after PK, mean refractive cylinder is 4–5 D, and 10–15% of patients can only achieve best vision with a hard contact lens.4, 5, 27 Furthermore, the relaxing incisions commonly used to try to correct astigmatic problems after PK can lead to ocular surface complications. A fourth significant advantage is that visual recovery is relatively rapid after EK (see Table 4-30-1). While fewer patients may achieve 20/20 vision after EK compared with PK, overall the visual results are more predictable. For example, in a large DSAEK series, 79% of patients without retinal or amblyopia problems achieved visual acuity of 20/40 or better in the treated eye within 6 months of surgery and no eyes had vision worse than 20/80.12 In contrast, after PK high astigmatism can prevent functional success in 10–20% of treated eyes.1 DSEK increases corneal thickness because posterior donor stroma is implanted without removal of any recipient stroma. In a large DSEK

Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

Fig. 4-30-8  Air injection to unfold the donor tissue.

369

4

   TABLE 4-30-1  VISUAL AND REFRACTIVE OUTCOMES AFTER ENDOTHELIAL KERATOPLASTY OR PENETRATING KERATOPLASTY PROCEDURES

CORNEA AND OCULAR SURFACE DISEASES

Investigator Year (Reference)

Graft Procedure

No. of Eyes

Diagnosis

20/40 or Better

Postop Refractive Cylinder (Diopters, Mean ± SD)

Postop Time

Koenig et al. 200733

DSAEK

34

65% PBK 32% Fuchs 3% ABK

62%

1.8 ± 1.1

6 months

Price & Price 200612

DSAEK

100

90% Fuchs’ 10% PBK

69%

1.5 ± 1.2

6 months

Gorovoy 2006

DSAEK

16

56% Fuchs’ 44% PBK

80%

1.5 ± 1.2

3 months

Price & Price 200510

DSEK

50

90% Fuchs’ 10% PBK

62%

1.5 ± 0.94

6 months

Terry & Ousley 200514

DLEK

100

89% Fuchs’ 10% PBK

49%

1.3 ± 0.86

6 months

Claesson et al. 20023

PK PK

71 96

Fuchs’ PBK

54% 31%

4.2 ± 2.9 4.7 ± 2.6

2 years 2 years

Pineros et al. 19965

PK

130

Fuchs’

64%

3.9 ± 1.9

8 years

Price et al. 19914

PK PK

173 374

Fuchs’ PBK

65% 40%

Not reported Not reported

6 months 6 months

Australian Corneal Graft Registry 200434

PK PK

539 1864

Fuchs’ PBK

47% 20%

Not reported Not reported

Variable Variable

DLEK, deep lamellar endothelial keratoplasty; DSAEK, Descemet’s stripping automated endothelial keratoplasty; DSEK, Descemet’s stripping with endothelial keratoplasty; PBK, pseudophakic bullous keratopathy; PK, penetrating keratoplasty.

COMPARISON OF PATIENT AGE (YEARS) WITH BEST SPECTACLE-CORRECTED VISUAL ACUITY

BEST SPECTACLE-CORRECTED VISUAL ACUITY 900 90

800

80 700

Patient age (years)

Central corneal thickness

100

600 500

60 50 40 30 20

400 0

0.1

Snellen equivalent : 20/20 20/25

370

70

0.2

0.3

0.4

0.5

0.6

10 0

20/30

20/40

20/50

20/60

20/70

0.1

0.2

0.3

0.4

0.5

0.6

Snellen equivalent : 20/20 20/25

0

20/30

20/40

20/50

20/60

20/70

Fig. 4-30-11  Best spectacle-corrected visual acuity (expressed as logarithm of the minimum angle of resolution, LogMAR, and the Snellen equivalent) compared with central corneal thickness (μm). Measurements were taken 6 months after Descemet’s stripping endothelial keratoplasty. Eyes with documented preoperative retinal problems or amblyopia were excluded. Correlation was not statistically significant (P = 0.75).

Fig. 4-30-12  Comparison of patient age (years) with best spectacle-corrected visual acuity (expressed as logarithm of the minimum angle of resolution, LogMAR, and the Snellen equivalent), measured 6 months after Descemet’s stripping endothelial keratoplasty. Eyes with documented preoperative retinal problems or amblyopia were excluded. Correlation was statistically significant (P  =  0.001).

series, Snellen acuity was not statistically significantly correlated with corneal thickness (P value  =  0.75, Fig. 4-30-11).12 In general, younger patients are likely to achieve better visual acuity after DSEK than older patients, even when considering only those who have no known retinal problems (P value  =  0.001, Fig. 4-30-12).12 These findings, together with the EK advantages listed above, are causing a paradigm shift in deciding when to treat patients with endothelial dysfunction. Whereas PK was often postponed until after retirement or at least until visual problems were quite disabling, EK is now being performed earlier, when visual problems begin to interfere with daily activities, such as reading or driving.10 In fact, it is preferable to perform EK before long-standing

corneal edema results in anterior stromal scarring, because the anterior stroma is not replaced. Most EK patients are able to return to work within a week of surgery and it is not uncommon for them to ask to have their second eye treated within a month of having the first eye grafted.10 Compared with PK, EK involves more donor tissue manipulation, including lamellar dissection and folding, which could potentially damage donor endothelium. On the other hand, EK grafts are usually larger (8–9 mm diameter compared with typical PK diameters of 7–8 mm), and provide a larger reservoir of healthy donor endothelium. Several reports now suggest that endothelial cell loss in the first few years after EK is similar to that experienced after PK.22, 28–30

OUTLOOK

REFERENCES   1. Riddle HK Jr, Parker DA, Price FW Jr. Management of postkeratoplasty astigmatism. Curr Opin Ophthalmol. 1998;9:15–28.   2. Binder PS, Waring GO. Keratotomy for astigmatism. In: Waring GO, ed. Refractive keratotomy for myopia and astigmatism. St Louis, MO: Mosby–Year Book;   1992:1157–86.   3. Claesson M, Armitage WJ, Fagerholm P, Stenevi U. Visual outcome in corneal grafts: a preliminary analysis of the Swedish Corneal Transplant Register. Br J Ophthalmol. 2002;86:174–80.   4. Price FW Jr, Whitson WE, Marks RG. Progression of visual acuity after penetrating keratoplasty. Ophthalmology. 1991;98:1177–85.   5. Pineros O, Cohen EJ, Rapuano CJ, Laibson PR. Long-term results after penetrating keratoplasty for Fuchs’ endothelial dystrophy. Arch Ophthalmol. 1996;114:15–8.   6. Price FW Jr, Whitson WE, Collins KS, Marks RG. Five-year corneal graft survival. A large, single-center patient cohort. Arch Ophthalmol. 1993;111:799–805.   7. Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol. 2003;121:1087–92.   8. Elder MJ, Stack RR. Globe rupture following penetrating keratoplasty: how often, why, and what can we do to prevent it? Cornea. 2004;23:776–80.   9. Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea. 1998;17:618–26. 10. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a refractive neutral cornea transplant. J Refract Surg. 2005;21:339–45. 11. Melles GR, Lander F, van Dooren BT, et al. Preliminary clinical results of posterior lamellar keratoplasty through a sclerocorneal pocket incision. Ophthalmology. 2000;107:1850–6; discussion 1857. 12. Price MO, Price FW Jr. Descemet’s stripping with endothelial keratoplasty comparative outcomes with microkeratome-dissected and manually dissected donor tissue. Ophthalmology. 2006;24:24.

13. Fogla R, Padmanabhan P. Initial results of small   incision deep lamellar endothelial keratoplasty (DLEK). Am J Ophthalmol. 2006;141:346–51. 14. Terry MA, Ousley PJ. Deep lamellar endothelial keratoplasty visual acuity, astigmatism, and endothelial survival in a large prospective series. Ophthalmology. 2005;112:1541–8. 15. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: early challenges and techniques to enhance donor adherence. J Cataract Refract Surg. 2006;32:411–8. 16. Ko W, Freuh B, Shield C, et al. Experimental posterior lamellar transplantation of the rabbit cornea. Invest Ophthalmol Vis Sci. 1993;34:1102. 17. Melles GR, Lander F, Beekhuis WH, et al. Posterior lamellar keratoplasty for a case of pseudophakic bullous keratopathy. Am J Ophthalmol. 1999;127:340–1. 18. Melles GR, Rietveld FJ, Beekhuis WH, Binder PS. A technique to visualize corneal incision and lamellar dissection depth during surgery. Cornea. 1999;18:80–6. 19. Melles GR, Lander F, Nieuwendaal C. Sutureless, posterior lamellar keratoplasty: a case report of a modified technique. Cornea. 2002;21:325–7. 20. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23:286–8. 21. Gorovoy M. Descemet’s stripping automated endothelial keratoplasty (DSAEK). Cornea. 2006;25:886–9. 22. Van Dooren B, Mulder PG, Nieuwendaal CP, et al. Endothelial cell density after posterior lamellar keratoplasty (Melles techniques): 3 years follow-up. Am J Ophthalmol. 2004;138:211–7. 23. Price MO, Price FW Jr, Trespalacios R. Endothelial keratoplasty technique for aniridic aphakic eyes. J Cataract Refract Surg. 2007;33:376–9. 24. Price MO, Price FW Jr. Descemet’s stripping endothelial keratoplasty for treatment of iridocorneal endothelial syndrome. Cornea. 2007;26:493–7. 25. Price F, Price M. Endothelial keratoplasty to restore clarity to a failed penetrating graft. Cornea. 2006;25:895–9.

26. Thompson RW Jr, Price MO, Bowers PJ, Price FW Jr. Long-term graft survival after penetrating keratoplasty. Ophthalmology. 2003;110:1396–402. 27. Davis EA, Azar DT, Jakobs FM, Stark WJ. Refractive and keratometric results after the triple procedure: experience with early and late suture removal. Ophthalmology. 1998;105:624–30. 28. Patel SV, Hodge DO, Bourne WM. Corneal endothelium and postoperative outcomes 15 years after penetrating keratoplasty. Am J Ophthalmol. 2005;139:311–9. 29. Ousley PJ, Terry MA. Stability of vision, topography, and endothelial cell density from 1 year to 2 years after deep lamellar endothelial keratoplasty surgery. Ophthalmology. 2005;112:50–7. 30. Price MO, Price FW. Endothelial cell density after Descemet’s stripping endothelial keratoplasty: influencing factors and 2-year trend. Ophthalmology. 2007;  13 Sept [Epub ahead of print]. 31. Sarayba MA, Juhasz T, Chuck RS, et al. Femtosecond laser posterior lamellar keratoplasty: a laboratory model. Cornea. 2005;24:328–33. 32. Sumide T, Nishida K, Yamato M, et al. Functional human corneal endothelial cell sheets harvested from temperature-responsive culture surfaces. FASEB J. 2006;20:  392–4. 33. Koenig SB, Covert DJ, Dupps WJ, Meisler DM. Visual acuity, refractive error, and endothelial cell density six months after Descemet stripping and automated endothelial keratoplasty (DSAEK). Cornea. 2007;26:670-4 34. Williams KA, Hornsby NB, Bartlett CM, et al., eds. The Australian Corneal Graft Registry: 2004 Report. Adelaide: Snap Printing; 2004:154.

4.30 Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

Endothelial keratoplasty techniques are still evolving. For example, Walters has used a trifold “burrito” configuration, Melles and Gorovoy have worked with tissue inserters, and Busin has been pulling the tissue in through a funnel glide with sutures or forceps (personal communications). The effect of different donor insertion methods on long-term endothelial cell survival is an important consideration. Various groups are working to optimize femtosecond laser ­parameters to create smooth posterior lamellar dissections.31 The programming flexibility and precision of the femtosecond laser is quite appealing because it should also allow the surgeon to match the donor curvature

to that of the host posterior cornea and more accurately control donor thickness. Ex vivo generation of corneal endothelium could allow more patients to benefit from EK despite a chronic worldwide shortage of donor corneas. Cultured endothelial cell sheets have been generated using cells harvested from donor corneas.32 Eventually, it may be possible to eliminate graft rejection concerns by implanting autologous corneal endothelium derived from recipient stem cells. In conclusion, current EK techniques have significantly increased the benefits and reduced the risks of grafting for patients with endothelial dysfunction, and future EK developments are expected to continue that beneficial trend.

371

PART 4 CORNEA AND OCULAR SURFACE DISEASES SECTION 9 Surgery

Surgical Ocular Surface Reconstruction

4.31

Vahid Feiz and Ivan R. Schwab

Definition:  The devastating visual consequences of corneal stem

cell deficiency have motivated clinicians to look for sources of ocular ­surface stem cells and to develop surgical techniques to restore the ocular surface in the hope of improving visual function.

Key features n n n

T issue harvested from the cornea–scleral area contains immunogenic cells. Surgical approach depends on degree of ocular pathology and whether ocular damage is unilateral or bilateral. Long-term systemic immunosuppression is necessary for survival of allografts.

to this area. Use of potent topical and systemic ­immunosuppressive agents is an essential aspect of ocular surface reconstruction when an immune-compatible source of tissue is not available. 2. The environment and the extracellular matrix on the surface of the eye on which corneal stem cells are transplanted have a profound effect on the success of the procedure. 3. Corneal and conjunctival stem cells may be harvested from: a. The contralateral eye when the condition leading to stem cell failure is unilateral (autografting). b. Cadaver tissue or from a living related donor, and directly transplanted onto the diseased ocular surface (allografting). c. The normal fellow eye, then grown in culture and transplanted back onto the diseased eye to improve the ocular surface (autografting with stem cell expansion). d. A cadaver eye or from a living related donor eye, then grown in tissue culture and subsequently transplanted onto the ocular surface (allografting with ex vivo expanded tissue).

PREOPERATIVE CONSIDERATIONS Associated features n

n

 oncurrent ocular pathologies need to be addressed as well as C possible prior to undertaking ocular surface reconstruction in order to improve the success of the procedure. Amniotic membrane has been shown to have a variety of desirable effects on the ocular surface.

INTRODUCTION The maintenance of the ocular surface is the result of a delicate balance between cell death and regeneration by two rapidly renewing tissues, the corneal and conjunctival epithelia. This capacity is dependent on a reservoir of stem cells with the ability to provide young epithelial cells to replace the dying or damaged cells. Corneal stem cells are widely believed to be located mainly in the limbal cornea rim, with the highest concentration in the superior and inferior limbus.1 Damage to the corneal stem cells can occur as a result of a variety of insults, including mechanical and chemical insults.2–4 Stem cell deficiency can lead to a variety of ocular surface diseases, ranging from mild ocular discomfort to nonhealing corneal defects, which can result in corneal blindness.

OPERATIVE PROCEDURES Partial Stem Cell Failure

The first modern limbal stem cell transplant was reported by Kenyon and Tseng in 1990.5, 6 Since then reports have appeared utilizing different methods of ocular surface reconstruction for a variety of surface pathologies.4, 5, 7–9

The surgical treatments are more successful in this group of patients since there are already some reserves of stem cell present. Examples ­ include entities such as mild chemical burn with persistent ocular inflammation, partial conjunctivalization of the cornea, or persistent epithelial defects. Other entities include pterygium and pseudo-­pterygium. If the patient is asymptomatic or minimally symptomatic and the central visual axis is clear with fairly normal epithelium, some partial peripheral conjunctivalization of the cornea can be well tolerated for long periods of time.6, 7 In these cases, simple lubrication with ­preservative-free artificial tears, topical anti-inflammatory drops, and close follow-up may be sufficient. There are three sets of surgical options for the group of symptomatic patients, which can be efficacious either individually or in combination. These include mechanical débridement, application of amniotic membrane, and autologous limbal stem cell transplant.

GENERAL CONCEPTS

Mechanical débridement

HISTORICAL PERSPECTIVES

372

Some of the important aspects of preoperative evaluation are listed in Table 4-31-1. Preoperative evaluation can guide the surgeon to the most appropriate modality of treatment. For example, a patient with a unilateral alkali burn and a completely normal contralateral eye would be an ideal candidate for autologous stem cell transplant, while a patient with bilateral ocular cicatrical pemphegoid would not be. Patients with ocular surface disorders can be divided into two main groups: those with total stem cell deficiency and those with partial stem cell deficiency. Each group can then be further divided based on bilateral or unilateral disease.

Some of the main principles of ocular surface reconstruction are listed below: 1. Tissue harvested from the cornea–scleral area includes corneal stem cells, fibroblasts, and Langerhans’ cells. The limbus is a highly vascular part of the ocular surface allowing the immune cells to have access

If the visual axis or a larger portion of the peripheral cornea is covered by conjunctival tissue, simple mechanical débridement of this tissue may allow the remaining corneal stem cells to repopulate the central cornea with normal or near-normal epithelium. The procedure can be done with topical anesthesia and a surgical blade followed by ­application of a bandage contact lens. The goal of this procedure is to provide the

   TABLE 4-31-1 ­PREOPERATIVE CONSIDERATIONS FOR OCULAR SURFACE RECONSTRUCTIVE SURGERY Clinical Finding or Significance

Establishment of the diagnosis

Loss of palisades of Vogt, persistent epithelial defects, corneal pannus, etc.

Determination of the etiology of ocular surface disease

Primary (aniridia, ectodermal dysplasia, etc.); secondary (chemical injury, OCP, Stevens-Johnson syndrome, etc.)

Extent and severity of the disease

Cornea only or conjunctival involvement

Extent of ocular inflammation

Conjunctival inflammation, intraocular inflammation, etc.

Status of the fellow eye

If normal may be a source of tissue for autografting

Coexistent ocular pathology

Glaucoma, tear film insufficiency, adnexal pathology (e.g., exposure, trichiasis, etc.)

General health of the patient

Renal, cardiac, hepatic status if systemic immunosuppression is required

OCP, ocular cicatricial pemphegoid.

patient with a fairly clear visual axis and not to make the entire ­corneal surface normal. Some investigators have reported success with as little as two clock hours of normal limbal cells.6, 7 The procedure may also be repeated if the conjunctival tissue regrows with advancement involving the visual axis.

Application of amniotic membrane

The most important properties of amniotic membrane harvested from the innermost layer of the placenta include the anti-inflammatory effect through downregulation of fibroblasts and providing a substrate for proliferation of the corneal and conjunctival epithelial cells.10, 11 These properties are only useful when there is some reserve of stem cells present as the amniotic membrane itself is not a source of stem cells. Work by Tseng and others has shown that the application of amniotic membrane to eyes with partial stem cell deficiency can improve ocular surface health and, in some cases, even restore a near-normal corneal epithelium.12–16 Examples include acute and chronic chemical injuries and iatrogenic stem cell deficiency. In these cases, application of the amniotic membrane resulted in decreased ocular inflammation and allowed the remaining corneal stem cells to repopulate the ocular surface.17 Other entities with partial stem cell deficiency include eyes with nonhealing epithelial defects and ptreygia.18–23 While not always successful, in many of these instances amniotic membrane allowed healing of epithelial defects and decreased the recurrence rate of pterygium after excision. In cases of pterygium removal, however, success mainly relies upon careful technique and may not require amniotic membrane. Currently, amniotic membrane is commercially available in two main forms: preserved amniotic membrane that is wet; and a dry form (AmbioDry), which can be reconstituted and applied to the ocular surface. Experience with the dry form of amniotic membrane is fairly limited.24, 25 The amniotic membrane is placed on the eye with the epithelial side up to cover the area of interest. The membrane can then be secured with 10-0 nylon sutures passed through the corneal stroma or episclera. In cases of nonhealing epithelial ulcer or pterygium, a membrane with the same size as the defect or larger can be used (Fig. 4-31-1). When amniotic membrane is used for stem cell deficiency secondary to acute or chronic chemical injury, the membrane can cover the entire cornea and even the conjunctiva. If there is conjunctivalization of the cornea, mechanical débridement as described above can be performed prior to application of the amniotic membrane.12

Autologous limbal stem cell transplant

When there is relative or sectoral stem cell deficiency and the condition is unilateral, the unaffected part of the eye or the contralateral eye can serve as a donor for stem cells. The stem cells can be harvested along with conjunctiva from the unaffected eye or the unaffected part of the eye with sectoral stem cell deficiency, and then transplanted to the area of stem cell deficiency. Examples of these kinds of entities include

Fig. 4-31-1  Amniotic membrane application after pterygium excision.

unilateral mild chemical burn and pterygium. The use of conjunctival autografting using limbal tissue following pterygium excision was first described by Kenyon et al. in 1985.26 Since then, a number of investigators have reported variable success rates with transplantation of autologous conjunctiva, including stem cells harvested from superior or inferior limbus of the same eye after pterygium excision.27–30 The surgical technique involves dissection of the pterygium body and the head off the cornea followed by harvesting of limbal tissue from the superior or inferior cornea. The limbal–conjunctival autograft is usually slightly larger than the exposed scleral bed, in all dimensions. The graft is then secured using interrupted 10-0 nylon sutures for the limbal margin and Vicryl sutures for the conjunctival margins. It should be noted that if the correct technique is utilized, a conjunctival graft from the superior bulbar area without limbal tissue can be used in the same manner. In cases of unilateral chemical injury, a rim of tissue containing limbal cells from the contralateral, unaffected eye can be harvested in a similar fashion and transplanted onto the injured eye. Prior to transplantation of the limbal tissue, a clean limbal bed needs to be created by carefully dissecting conjunctival tissue off the cornea–scleral area. The limbal–conjunctival graft can then be secured as described above (Fig. 4-31-2A–C).

Surgical Ocular Surface Reconstruction

Examination Element

4.31

Total Stem Cell Failure

Entities that can result in total stem cell failure include severe ­chemical injuries, Stevens-Johnson disease, ocular cicatricial pemphegoid (OCP), and aniridia. Eyes with total stem cell deficiency may have a variety of different clinical presentations including conjunctivalization of the cornea with symblepheron formation, persistent epithelial defects with possible tissue necrosis and thinning, and chronic inflammation (Fig. 4-31-3). Furthermore, many of the eyes with total stem cell deficiency have other concurrent pathologies, such as exposure, tear film insufficiency, glaucoma, or intraocular inflammation. Prior to attempting ocular surface reconstruction, the concurrent diseases need to be addressed and maximally treated. These entities have been divided into two groups: unilateral disease and bilateral disease.

Unilateral disease

The prototypical example is unilateral chemical injury. Many of the treatment modalities discussed above for relative stem cell deficiency may be applicable to eyes with total stem cell deficiency with some modifications. For example, application of amniotic membrane may be helpful in terms of decreasing ocular surface inflammation but, when solely used, it does not help reconstitute the ocular surface, as it contains no stem cells. The main advantage in cases of unilateral stem cell deficiency is that the contralateral, unaffected eye can be a source of immunologically compatible conjunctival and corneal cells, which may allow reconstitution of the ocular surface.

Autologous limbal stem cell transplant

The surgical technique is similar to the approach described above, with the exception that more tissue needs to be harvested from the unaffected eye to reconstitute the ocular surface.8, 31–33 The surgical approach ­involves careful dissection of the conjunctival tissue from the

373

4 CORNEA AND OCULAR SURFACE DISEASES

A

Fig. 4-31-3  Total stem cell failure with corneal pannus due to severe alkali burn.

Prior to undertaking the harvesting of limbal tissue for stem cell transplant, it should be clearly established that the fellow eye is not affected even slightly and that there is an ample reservoir of stem cells present. A risk does exist of inducing relative stem cell deficiency to the donor eye if too much tissue is harvested. Most clinicians avoid taking more than 6 clock hours of tissue from the donor eye. When there is concern about the health of the fellow eye, allografts may be considered (see below).

Bilateral disease

B

The conditions in this group are the most difficult to address, as the surgical options to rehabilitate the ocular surface are hindered by the lack of an immunologically compatible source of stem cells. This necessitates the use of either living related donor tissue or cells harvested from cadaver eyes and aggressive systemic and topical ­immunosuppression.

Keratolimbal allograft (KLAL)

C

Fig. 4-31-2  (A) Partial stem cell failure with pseudo-pterygium after alkali burn. (B) Autologous limbal transplant after removal of pseudo-pterygium. (C) Ocular surface appearance after application of autologous stem cells.

374

limbal area of the affected eye. A rim of keratolimbal tissue from the contralateral eye, including a conjunctival rim and anterior cornea, can be harvested. Several tissue grafts can be harvested from the fellow eye. The superior and the inferior limbus offer the highest concentration of corneal stem cells. This tissue can then be carefully transported to the prepared bed with the maintenance of correct orientation. The tissue can be sewn into place using nylon or Prolene sutures taking care not to pass the sutures through the harvested stem cell area. A bandage contact lens is then applied to the eye. Postoperatively, patients are treated with antibiotics and corticosteroids, as well as preservative-free artificial tears. The bandage contact lens can be removed when the ocular surface is stable. No need exists for long-term systemic immune suppression in these patients.

Keratolimbal tissue can be harvested from either a whole globe or from corneal tissue. This allograft can then be transplanted directly onto the injured eye. The advantage of this technique, as opposed to harvesting cells from a normal living eye, is that a much larger quantity of cells can be harvested from one or more donor eyes. This theoretically improves the success of the ocular surface reconstruction, especially in eyes with severe stem cell deficiency. During the procedure, the recipient eye is prepared by dissecting conjunctival tissue off the limbus by performing peritomy. Superficial keratectomy to remove fibrovascular tissue off the cornea is then performed with care not to violate the deep layers of the cornea. The donor tissue can be prepared from a donor cornea by ­punching the central corneal button out using a 7.5–8.0  mm trephine. The ­residual cornea–scleral ring containing the limbus is then cut into two half rings. The excess sclera is removed leaving a small scleral rim posteriorly and a small corneal rim anteriorly containing the limbus. The rims are thinned using lamellar dissection. This removes the posterior sclera as well as the posterior cornea. The donor tissue then can be placed on the recipient eye in the correct orientation and secured to the eye by 10-0 nylon sutures. The previously dissected conjunctiva can be advanced and secured to the posterior aspect of the allograft using 8-0 Vicryl sutures. Given that the donor limbus is slightly posterior to the recipient limbus, the circumference of the host limbus to be covered is larger than can be covered by one donor tissue. This will leave gaps in the limbus that may allow fibrovascular tissue access to the cornea. Using cornea or sclera from the donor eye can fill this gap. Some investigators advocate the use of more than one donor eye to allow complete coverage of the limbus.34 Penetrating or lamellar keratoplasty can be performed at the same time, or at a later setting when the ocular surface is more stable32, 34 (Fig. 4-31-4). Postoperatively, patients are treated with topical antibiotics, corticosteroids, and systemic immunosuppression. Because of the relative abundance of Langerhans’ cells and human lymphocyte antigen (HLA)DR antigens in the limbus, a high rate of immunological reaction can be expected, which may lead to recurrence of stem cell failure, ­necessitating aggressive and long-term immunosuppression. Oral ciclosporin is the

4.31

Fig. 4-31-5  Application of amniotic membrane covered by ex vivo expanded corneal stem cells to an eye with stem cell deficiency.

most commonly used agent, although other agents such as systemic corticosteroids and systemic tacrolimus have also been utilized.35–37 The necessary length of time for immunosuppression is not known but at least 1  year of suppressive therapy probably is needed. The reported outcomes of KLAL are variable depending on the disease entities and the duration of follow-up. Investigators have reported short-term improvement in ocular surface varying from 57% to 83.3%.12, 36, 38, 39 However, the long-term follow-up trials have shown a trend toward progressive decline of stem cell population and destabilization of the ocular surface in up to 70% of patients despite systemic immunosuppression.40–41 Given these findings, systemic immune modulation past 1  year may not be necessary.

and Langerhans’ cells, which may in turn have a profound effect on long-term survival of allografted cells. This concept has been used for burn patients where cultured human epidermal cells have been used for reconstructive surgery.45–46 Similar culture techniques have been applied to corneal limbal stem cells in an attempt to amplify these cells. In this approach, a minimal amount of limbal tissue (1–2  mm) is harvested either from an eye with relative stem cell deficiency, or the normal contralateral eye of a patient with unilateral total stem cell deficiency. In cases where there is severe and total bilateral stem cell deficiency, cells can be harvested from either a living related donor or cadaver eyes. Given the small amount of tissue needed, the risk to the donor eye is expected to be minimal. These cells are then amplified in culture media on a carrier, which will be utilized for transport and transplant of the cells onto the diseased eye. The amplified cells may be mounted on petrolatum gauze or a bandage soft contact lens. More recently, de-epithelialized amniotic membrane has been used experimentally as a carrier.47–50 The recipient eye is then prepared in a similar manner to the method described for keratolimbal grafting. The cultured stem cells and their carrier are transferred onto the recipient bed, anchored to the limbus with 10-0 nylon sutures and to the surrounding conjunctiva with 8-0 Vicryl sutures (Fig. 4-31-5). A bandage contact lens is often placed on the eye and kept in place until the ocular surface stabilizes. Postoperative treatment is similar to that for patients with keratolimbal grafts, and if the cells used are allogenic, systemic immunosuppression is needed as described above. Schwab et al. found improvement in the ocular surface of 60% of patients with autologous cells, and in all of the patients (total of 4) with allogenic cells combined with immunosuppression, with a mean follow-up period of 13  months.48 Shimazaki et al., on the other hand, found only a 46.2% success rate in achieving a stable and healthy ocular surface in allografted patients.51 Furthermore, in this report, the authors did not find a difference in success rate between this technique and cadaveric limbal transplantation combined with amniotic membrane. The long-term results of ocular surface reconstruction utilizing ex vivo expanded stem cells are unknown and much work remains to be done.

Living related allograft

In patients with bilateral stem cell deficiency, or in patients with ­unilateral stem cell failure where the fellow eye cannot be used as a donor source due to patient unwillingness to undergo a surgical procedure in a good eye, a living related conjunctival limbal allograft might be a viable option. The advantage of this approach is that a more immunologically compatible tissue may be harvested from a living ­donor, especially if HLA matching is performed. This may in turn allow longer survival of the transplanted cells. The disadvantage is that even with HLA ­matching, postoperative systemic immunosuppression is required. Furthermore, there is a limited amount of tissue that can be harvested from the donor eye, and there is the possibility of inducing an ocular surface disorder in the healthy eye of a donor. The donor tissue is harvested from a healthy donor under peribulbar anesthesia, similar to what has been described above for conjunctival limbal autograft. A total of 4 clock hours of tissue may be harvested, equally divided from the upper and lower limbus. This donor tissue can then be placed onto the recipient eye after peritomy and superficial keratectomy have been performed to prepare the limbus. The donor tissue is secured to the cornea anteriorly using 10-0 nylon sutures and posteriorly to the episclera. Amniotic membrane can be transplanted at the same time, although it is not known whether this is beneficial.42 Systemic immunosuppression is needed similar to that outlined above for keratolimbal allografting. Limited and short-term results reported by several investigators show some success in terms of improving ocular surface, especially when HLA-matched tissue was utilized. There are also indications that the addition of systemic immunosuppression increased the longterm survival of the graft. However, in many cases after an initial period of improvement, the ocular surface deteriorated with recurrence of corneal fibrovascular tissue.42–44 This may be due to the insufficient supply of the tissue. Based on these limited findings, the role and success of this approach in ocular surface reconstruction remains to be determined.

Ex vivo expanded limbal stem cells

Expansion of stem cells by culturing them in vitro theoretically provides a large supply of stem cells that can be used for surface reconstruction. Furthermore, modulation of the culture may allow removal of fibroblast

Surgical Ocular Surface Reconstruction

Fig. 4-31-4  Ocular surface of an eye with total stem cell deficiency after application of cadaveric kerato-limbal tissue and penetrating keratoplasty along with systemic immunosuppression.

SPECIAL CONSIDERATIONS IN OCULAR SURFACE RECONSTRUCTION Other concurrent pathologies need to be addressed fully prior to undertaking ocular surface reconstruction in order to improve the success of the procedure. These may include the involvement of other subspecialties, such as oculoplastics to address eyelid abnormalities and glaucoma to maximize pressure control. The ocular surface needs to be lubricated using treatments such as preservative-free artificial tears and punctal occlusion. Furthermore, the ocular inflammation needs to be maximally and aggressively treated with the use of topical and possibly systemic immune-modulating agents. Some of these issues are discussed below.

375

4

Corneal Transplantation

CORNEA AND OCULAR SURFACE DISEASES

Patients with stem cell failure often have corneal pathology, which may necessitate lamellar or penetrating keratoplasty. Performing keratoplasty in eyes with stem cell failure carries a very poor prognosis for graft survival due to chronic inflammation, vascularization of the ocular surface, and poor epithelial healing after surgery. Corneal transplantation, however, may be more successful when the ocular surface has been reconstituted using some of the approaches outlined above. The optimal timing for cornea transplant is not well known. Some authors indicate that a stepwise approach, starting with stem cell transplantation followed by keratoplasty when the ocular surface is stable, may improve the graft survival.52–53 The largest study of penetrating keratoplasty after cultivated limbal epithelial transplantation was reported by Sangwan et al. where the authors reported a 93% success rate in terms of graft clarity, with a mean follow-up time of 8.3  months. Currently, no data on long-term survival of keratoplasty after ocular surface reconstruction are available. However, other investigators have reported short-term success when performing cornea transplantation combined with stem cell transplant and amniotic membrane in the same setting.44, 54

Systemic Immunosuppression

Without the proper use of immunosuppression, the survival of transplanted cells is poor. Long-term immunosuppressive therapy is needed. The agents utilized for this purpose can carry potential systemic side effects. Usually, collaboration with other medical specialists who have expertise in managing systemic immunosuppression is necessary.

FUTURE CONSIDERATIONS

focusing on utilizing better extracellular matrices for ex vivo ­expansion and transport of stem cells. While the actual clinical application of these approaches is some time away, some novel approaches have already been tried with limited short-term success.

Nonocular Tissue as a Source of Corneal Stem Cells

Cultivated autologous cells harvested from oral mucosa have been used to reconstruct ocular surface. Inatomai et al. and Nishida et al. have both reported short-term and midterm success with this approach.9, 55 In this method, a small amount of oral mucosa is harvested and the epithelial cells are expanded in vitro, followed by transplantation onto the ocular surface. Amniotic membrane can be used as a substrate for cell expansion and transport.9 In both studies, the corneal surface and visual acuity improved. The long-term results of this modality are not yet known.

Ex vivo Expanded Ocular Surface Stem Cell with Bioengineered Extracellular Matrix

Different substrates have been utilized as carriers for the transport of cultivated corneal epithelial cells that can in turn be transplanted onto a diseased eye. These have included collagen, contact lenses, and amniotic membrane.48, 56 Recently, Han et al. reported successful growth of human epithelial cells in fibrin gel in the laboratory.57 They observed that the sheets of epithelium were easily maneuverable, which in turn may increase the ease of transport of the cells and adhesion of the stem cells when transplanted. While this is of interest, no actual clinical data related to this type of bioengineered tissue is available.

The limited supply of stem cells in cases of autografting and the ­immunologic issues in cases of allografting have led investigators to look for alternative sources of stem cells. Furthermore, some ­investigators are

REFERENCES

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28. Dekaris I, Gabric N, Karaman Z, et al. Limbal-conjunctival autograft transplantation for recurrent pterygium. Eur J Ophthalmol. 2002;12:177–82. 29. Al Fayez MF. Limbal versus conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology. 2002;109:1752–5. 30. Shimazaki J, Kosaka K, Shimmura S, Tsubota K. Amniotic membrane transplantation with conjunctival autograft for recurrent pterygium. Ophthalmology. 2003;110:119–24. 31. Meallet MA, Espana EM, Grueterich M, et al. Amniotic membrane transplantation with conjunctival limbal ­autograft for total limbal stem cell deficiency. Ophthalmology. 2003;110:1585–92. 32. Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc. 1996;94:677–743. 33. Tsai RJ, Li LM, Chen JK. Reconstruction of damaged ­corneas by transplantation of autologous limbal epithelial cells. N Engl J Med. 2000;343:86–93. 34. Holland EJ, Djalilian AR, Schwartz GS. Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology. 2003;110:125–30. 35. Tan DTH, Ficker LA, Buckley RJ. Limbal transplantation. Ophthalmology. 1996;103:29–36. 36. Tsubota K, Toda I, Saito H, et al. Reconstruction of corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology. 1995;102:1486–96. 37. Dua HS, Blanco AA. Allolimbal transplantation in patients with limbal stem cell deficiency. Br J Ophthalmol. 1999;83:414–9. 38. Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea. 1996;15:549–56. 39. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal surface reconstruction. Cornea. 1994;13:389–400. 40. Solomon A, Ellies P, Anderson DF, et al. Long-term outcome of keratolimbal allograft with and without penetrating keratoplasty for total limbal stem cell deficiency. Ophthalmology. 2002;109:1159–66. 41. Ilari L, Daya SM. Long-term outcomes of keratolimbal allografts for the treatment of severe ocular surface disorders. Ophthalmology. 2002;109:1278–84.

48. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea. 2000;19:421–8. 49. Grueterich M, Tseng SC. Human limbal progenitor cells expanded on intact amniotic membrane ex vivo. Arch Ophthalmol. 2002;120:783–90. 50. Meller D, Pires RTF, Tseng SCG. Ex vivo preservation and expansion of human limbal epithelial stem cells on amniotic membrane cultures. Br J Ophthalmol. 2002;80:463–71. 51. Shimazaki J, Aiba M, Goto E, et al. Transplantation of human limbal epithelium cultivated on amniotic membrane for the treatment of severe ocular surface disorders. Ophthalmology. 2002;109:1285–90. 52. Croasdale CK, Schwartz GS, Malling JV, Holland EJ. Keratolimbal allograft: Recommendations for tissue procurement and preparation by eye banks, and standard surgical technique. Cornea. 1999;18:52–8.

53. Sangwan VS, Matalia HP, Vemuganti GK, et al. Early results of penetrating keratoplasty after cultivated limbal epithelium transplantation. Arch Ophthalmol. 2005;123:334–40. 54. Theng JT, Tan DT. Combined penetrating keratoplasty and limbal allograft transplant for severe corneal burns. Ophthalmol Surg Lasers. 1997;28:765–8. 55. Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351:1187–96. 56. Schwab IR. Cultured corneal epithelia for ocular surface disease. Trans Am Ophthalmol Soc. 1999;97:891–986. 57. Han B, Schwab IR, Madsen TK, Isseroff RR. A fibrin-based bioengineered ocular surface with human corneal epithelial stem cells. Cornea. 2002;21:505–10.

4.31 Surgical Ocular Surface Reconstruction

42. Gomes JA, Santos MS, Ventura AS, et al. Amniotic membrane with living related corneal limbal/conjunctival allograft for ocular surface reconstruction in StevensJohnson syndrome. Arch Ophthalmol. 2003;121:1369–74. 43. Daya SM, Ilari FA. Living related conjunctival limbal allograft for the treatment of stem cell deficiency. Ophthalmology. 2001;108:126–33; discussion 133–4. 44. Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting from related live donors for corneal surface reconstruction. Ophthalmology. 1999;106:822–8. 45. Phillips TJ, Gilchrest BA. Clinical applications of cultured epithelium. Epith Cell Biol. 1992;1:39–46. 46. Rheinwald JG, Green H. Serial activation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975;6:331–44.16. 47. Pellegrini G, Traverso CE, Franzi AT, et al. Long term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349:990–3.

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PART PART 4 CORNEA 4 CORNEA AND AND OCULAR OCULAR SURFACE SURFACE DISEASES DISEASES SECTION 9 Surgery SECTION TITLE

Management of Corneal Thinning, Melting, and Perforation

4.32

Nicoletta Fynn-Thompson and Michael H. Goldstein

Definition:  Management of full-thickness or partial-thickness loss   of corneal tissue.

Key features n n n

T here must be concurrent, aggressive treatment of the underlying infectious or inflammatory condition. Multiple treatment options depending on the clinical situation. Primary goal is to re-establish the tectonic integrity of the globe.

Associated features n n

T rue ophthalmic emergency. Surgical management often warranted. 

INTRODUCTION The integrity of the cornea can be compromised by both inflammatory and noninflammatory conditions, which may lead to stromal thinning, melting, and perforation. Progression may be slow over months to years, or may be rapid over hours to days. Rapid, proper recognition and management of these conditions is crucial to restore vision and to re-establish the integrity of the eye.

CORNEAL THINNING FROM NONINFLAMMATORY DISORDERS Noninflammatory corneal thinning disorders cause progressive ectasia due to thinning of the stroma. The most common of these disorders include keratoconus, pellucid marginal degeneration, keratoglobus, and posterior keratoconus. Progressive corneal thinning (ectasia) is a rare but serious complication after laser refractive surgery. These conditions are generally slowly progressive; therefore, the primary goal is to maintain functional vision (see Chapter 4-19 for more information).

CORNEAL THINNING AND MELTING FROM INFLAMMATORY DISORDERS

378

Inflammatory corneal disorders can cause thinning with stromal melting. These conditions are often associated with pain, epithelial defects, corneal neovascularization, and other inflammatory changes. Progression is fast and emergent treatment is warranted upon diagnosis. Noninfectious inflammatory causes include peripheral ulcerative keratitis, Mooren’s ulcer, Terrien’s marginal degeneration, and collagen vascular disorders. Infectious inflammatory causes include viral herpetic keratitis, bacterial keratitis, and fungal keratitis. Peripheral ulcerative keratitis suggests an autoimmune-mediated process and often is associated with rheumatoid arthritis. Peripheral ulcerative keratitis (see Chapter 4-17) is also seen with Wegener’s granulomatosis, systemic lupus erythematosus, polyarteritis nodosa, ulcerative colitis, and relapsing polychondritis.

Medical treatment is directed both locally at the cornea and systemically to address the underlying systemic inflammatory process. The goals of local (ocular) treatment are to: (1) provide local supportive therapy to decrease corneal melting; and (2) promote re-epithelialization of the corneal surface. These goals are accomplished using the following modalities: aggressive lubrication with preservative-free eyedrops and ointments, punctal occlusion, placement of a bandage contact lens, patching, oral doxycyline (or equivalent), and tarsorrhaphy. Topical collagenase inhibitors and steroids are of some value, but may also delay healing and cause perforation by initiating stromal melting. The goal of systemic therapy is to suppress the underlying systemic disorder with immunosuppressive or immunomodulatory therapy. If the underlying autoimmune disease is not treated, the corneal pathology will not improve.1–3 Inflammatory corneal disorders caused by infectious organisms (viral, bacterial, or fungal) also cause thinning and melting of the corneal stroma. Treating the pathogen aggressively with both topical and oral medication is most important to reduce further destruction of stromal tissue. Some advocate the use of concomitant steroid drops once the infection is controlled but this is controversial. If, despite aggressive therapy, stromal keratolysis progresses with development of descemetocele, impending perforation, or frank perforation, the goal becomes maintaining the eye’s integrity.

SURGICAL TREATMENT OF CORNEAL PERFORATIONS Tissue Adhesives

Descemetoceles or impending perforations can be stabilized or temporized by application of tissue adhesive and placement of a bandage contact lens with close follow-up. Studies have shown this procedure arrests the process of ulceration in noninfectious eyes. Application of tissue adhesive is much easier to perform in impending perforations than in frank perforations.4 Frank corneal perforations can, however, be successfully treated with application of tissue adhesives. Although perforations measuring 1–2  mm are most successfully treated, those measuring up to 3  mm have been closed. Cyanoacrylate tissue adhesive traditionally has been used (Fig. 4-32-1), 5 and its use to seal corneal perforations was first reported in 1968.6 Cyanoacrylate adhesive prevents re-epithelialization into the zone of damaged stroma and prevents collagenase production, which leads to stromal melting.7 A common technique is described below, although several other excellent techniques exist. A thorough examination of the eye prior to application of the glue must be performed, with attention to the extent of perforation, possible lenticular damage, and possible uveal prolapse at the perforation site. Placing the patient in the supine position under an operating microscope is easier than having the patient at the slit lamp. A topical anesthetic and lid speculum should be placed in the eye. Débridement of necrotic tissue from the ulcer crater is performed. This removed material is plated onto culture media to identify a possible infectious etiology. The tissue adhesive adheres best to basement membrane so débridement of 1–2  mm of normal epithelium surrounding the ulcer allows for proper adhesion of the glue. A methylcellulose spear is used to dry the site. The tissue adhesive is then placed in microaliquots on the site of perforation with an applicator. The applicator can be a needle from a tuberculin syringe,8 a 23 gauge Angiocath catheter (with the needle removed),9 or a micropipette.10 Alternatively, ­ ophthalmic

to avoid incarceration of uveal tissue or the lens, viscoelastic material may also be injected into the anterior chamber.14 Postoperatively, the patient may be placed on an aqueous suppressant, if medically tolerated. Patients with noninfectious perforations should receive a prophylactic broad-spectrum antibiotic four times daily, and a protective shield should be kept in place at all times. Preservative-free artificial tears applied frequently will aid in lubrication with a bandage lens in place. Patients also benefit from oral doxycycline due to its ability to inhibit collagenase. Depending on the etiology, infected perforations are treated with frequent fortified antibacterial, antiviral, or antifungal therapy. Initially, patients should be examined daily and any complaints of decreased vision, pain, tearing, or photophobia should be followed up immediately. If the bandage lens falls out, it must be replaced. If the glue becomes dislodged, reapplication is often necessary. Corneal glue remains in place for weeks to months. It is recommended to leave it in place until it loosens and dislodges on its own, leaving behind a more healthy-appearing stromal tissue. The reported potential complications for corneal tissue adhesive ­application includes cataract formation,15 corneal infiltrates, increased intraocular pressure,16 giant papillary conjunctivitis,17 retinal toxicity,18 keratitis,19 and iridocorneal and iridolenticular adhesions.20 The application of fibrin glue has shown some promising early results when compared with cyanoacrylate adhesive. Studies have shown fibrin glue to cause less neovascularization; however, a longer time is required for the adhesive plug to form.21 Application of fibrin glue has also been shown to be successful with the additional placement of amniotic ­membrane grafts for structural support of a perforated cornea.22, 23

Penetrating Keratoplasty

Fig. 4-32-1  Corneal perforation sealed with cyanoacrylate glue. (Courtesy of Michael H. Goldstein, MD.)

A

B

If the corneal perforation is not amenable to treatment with corneal glue, then tectonic grafting is indicated (either a full-thickness or lamellar graft).8 The smallest trephination capable of incorporating the site of perforation is chosen. Trephination of a soft eye is very difficult but is aided by the judicious use of viscoelastic materials. Alternatively, the temporary application of cyanoacrylate adhesive and sodium hyaluronate to create a normotensive eye has been described.24 A customized hard contact lens applied with tissue adhesive to the corneal perforation has also been reported to stabilize the eye and allow for trephination.25 For some cases, a handheld trephination may be needed. Care must be taken to avoid protrusion of ocular contents or damaging the iris or lens. The donor cornea should be secured with interrupted 10-0 nylon sutures.

4.32 Management of Corneal Thinning, Melting, and Perforation

ointment can be placed on the end of a sterile wooden applicator and the glue placed directly on top and applied to the site of perforation (Fig. 4-32-2). A polyethylene disk can be made and attached to a sterile wooden stick with ophthalmic ointment, and glue placed on the disk. Both are directly applied to the site of perforation. The disk can then be removed or left in place.11, 12 The goal is to create a controlled method of placement of the smallest amount of glue to seal the perforation. The glue will solidify via polymerization over the next few minutes. A large, heaped mound over the crater is not necessary and can cause irritation and discomfort for the patient after the procedure. The eye should be checked for evidence of leakage. If secure, then a bandage contact lens is applied, and the patient is checked at the slit lamp to confirm that the anterior chamber is forming and the glue is in place. Application of tissue adhesive in frank corneal perforations is more challenging, as preparation of the site is more difficult secondary to the constant flow of aqueous from the perforation. In challenging cases, unless contraindicated, an air bubble can be placed into the anterior chamber to temporarily occlude the perforation by surface tension. Larger air bubbles risk pupillary block and increased intraocular pressure, so caution must be taken.13 In eyes with flat anterior chambers, in order

C

Fig. 4-32-2  Technique for application of cyanoacrylate glue for treatment of larger corneal perforation. (A) Apply ointment to end of Q-tip. (B) Place small circular disc from cut drape onto Q-tip and adhere with ointment. (C) Place corneal glue onto disc and then place onto eye. (Courtesy of Michael H. Goldstein, MD.)

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4

Patch Graft

CORNEA AND OCULAR SURFACE DISEASES

If the perforation is too large for a tissue adhesive, but too small for a full-sized penetrating keratoplasty procedure, then a corneal patch graft can be helpful (Fig. 4-32-3). These procedures can temporarily stabilize a perforation or descemetocele, or may be a permanent treatment. It is ideal for peripheral pathology, and care should be taken when used for central pathology as it can interfere with visual outcome.

Miscellaneous Treatments

Multilayered amniotic membrane grafts alone have been shown to be successful in treating nontraumatic corneal perforations. More favorable outcomes are limited to perforations measuring less than 1.5  mm in diameter.13, 26 Conjunctival flaps are useful for thinning due to ulcerations or descemetocele formation, but are contraindicated in corneal perforations. Conjunctival resection may be a useful adjuvant therapy in appropriate cases of corneal melting secondary to peripheral ulcerative keratitis. Fig. 4-32-3  Corneal perforation secondary to acute hydrops treated with patch graft. (Courtesy of Michael H. Goldstein, MD.)

CONCLUSION

Postoperative care is challenging. A balance between reducing inflammation and the possibility of graft rejection, without significantly reducing the host’s immunity, must be reached. Topical steroids four times daily are usually required. Aggressive antibiotic, antiviral, or antifungal treatment is continued as indicated for infectious cases. For noninfectious cases, a broad-spectrum antibiotic is used four times daily.

Corneal thinning, melting, and perforation can be caused by both inflammatory and noninflammatory conditions. Identification and treatment of these conditions is critical in the successful management of these patients. If impending or actual perforation occurs, immediate action must be taken to restore the integrity of the eye. This can be done with tissue adhesives, patch grafts, penetrating keratoplasty, or amniotic membrane grafts.

REFERENCES   1. Wagoner MD, Kenyon KR, Foster CS. Management   strategies in peripheral ulcerative keratitis. Int   Ophthalmol Clin. 1986;26:147–57.   2. Shiuey Y, Foster CS. Peripheral ulcerative keratitis and collagen vascular disease. Int Ophthalmol Clin. 1998;38:21–32.   3. Foster CS, Forstot SL, Wilson LA. Mortality rate in   rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression. Ophthalmology. 1984;91:1253–63.   4. Nobe JR, Moura BT, Robin JB, et al. Results of penetrating keratoplasty for the treatment of corneal perforations. Arch Ophthalmol. 1990;108:939–41.   5. Leahey AB, Gottsch JD, Stark WJ. Clinical experience with N-butyl cyanoacrylate (Nexacryl) tissue adhesive. Ophthalmology. 1993;100:173–80.   6. Webster RG Jr, Slansky HH, Refojo MF, et al. The use of adhesive for the closure of corneal perforations. Report of two cases. Arch Ophthalmol. 1968;80:705–9.   7. Vote BJ, Elder MJ. Cyanoacrylate glue for corneal   perforations: a description of a surgical technique and review of the literature. Clin Exp Ophthalmol. 2000;28:437–42.   8. Vanathi M, Sharma N, Titiyal JS, et al. Tectonic grafts for corneal thinning and perforations. Cornea. 2002;21:792–7.   9. Foster CS. Tissue adhesives. Smolin and Toft’s the cornea: Scientific foundations and clinical practice, 4th ed. Philadelphia: Lippincott Williams and Wilkins;   2005:939-43.

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10. Wessels IF, McNeill JI. Applicator for cyanoacrylate tissue adhesive. Ophthalmic Surg. 1989;20:211–4. 11. Lin DT, Webster RG Jr, Abbott RL. Repair of corneal lacerations and perforations. Int Ophthalmol Clin. 1988;28:69–75. 12. Boruchoff SA, Donshik PC. Medical and surgical   management of corneal thinnings and perforations. Int Ophthalmol Clin. 1975;15:111–23. 13. Rodriguez-Ares MT, Tourino R, Lopez-Valladares MJ,   et al. Multilayer amniotic membrane transplantation in the treatment of corneal perforations. Cornea. 2004;23:577–83. 14. Hirst LW, DeJuan E Jr. Sodium hyaluronate and tissue adhesive in treating corneal perforations. Ophthalmology. 1982;89:1250–3. 15. Hyndiuk RA, Hull DS, Kinyoun JL. Free tissue patch and cyanoacrylate in corneal perforations. Ophthalmic Surg. 1974;5:50–5. 16. Weiss JL, Williams P, Lindstrom RL, et al. The use of tissue adhesive in corneal perforations. Ophthalmology. 1983;90:610–5. 17. Carlson AN, Wilhelmus KR. Giant papillary conjunctivitis associated with cyanoacrylate glue. Am J Ophthalmol. 1987;104:437–8. 18. Hida T, Sheta SM, Proia AD, et al. Retinal toxicity of cyanoacrylate tissue adhesive in the rabbit. Retina. 1988;8:148–53. 19. Ferry AP, Barnert AH. Granulomatous keratitis resulting from use of cyanoacrylate adhesive for closure of perforated corneal ulcer. Am J Ophthalmol. 1971;72:538–41.

20. Markowitz GD, Orlin SE, Frayer WC, et al. Corneal endothelial polymerization of histoacryl adhesive: a report of a new intraocular complication. Ophthalmic Surg. 1995;26:256–8. 21. Sharma A, Kaur R, Kumar S, et al. Fibrin glue versus   N-butyl-2-cyanoacrylate in corneal perforations.   Ophthalmology. 2003;110:291–8. 22. Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin glue in the management of corneal ulcers and perforations: a review of 33 cases. Cornea. 2005;24:369–77. 23. Duchesne B, Tahi H, Galand A. Use of human fibrin glue and amniotic membrane transplant in corneal perforation. Cornea. 2001;20:230–2. 24. Maguen E, Nesburn AB, Macy JI. Combined use of sodium hyaluronate and tissue adhesive in penetrating keratoplasty for corneal perforations. Ophthalmic Surg. 1984;15:55–7. 25. Kobayashi A, Shirao Y, Segawa Y, et al. Temporary use of a customized glued-on hard contact lens before penetrating keratoplasty for descemetocele or corneal perforation. Ophthalmic Surg Lasers Imaging. 2003;34:226–9. 26. Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology. 2002;109:694–703.

PART 5 THE LENS

5.1

Basic Science of the Lens Eric Dai and Michael E Boulton

Definition:  The lens is a highly organized transparent structure that

GROSS ANATOMY OF THE ADULT HUMAN LENS

has evolved to alter the refractive index of light entering the eye.

Key features n���� n���� n���� n����

n���� n���� n����

T he lens comprises three parts: (1) the capsule, (2) the lens ­epithelium, and (3) the lens fibers. α-, β- and γ-crystallins constitute 90% of the total protein content of the lens. Lens function is dependent on the metabolism of glucose to produce energy, protein synthesis, and a complex antioxidant system. Lens transparency is dependent on the highly organized ­structure of the lens, the dense packing of crystallin, and the supply of appropriate nutrients. The ability to change its focusing power occurs by a process called accommodation. The lens exhibits age-related changes in structure, light ­transmission, metabolic capacity, and enzyme activity. Secondary cataract occurs when remnant lens cells following ­cataract extraction cause opacification in the visual axis.

INTRODUCTION

proliferative capacity increases

anterior pregerminative zone germinative zone

epithelial central zone cells

cortex

pregerminative zone germinative zone

equator

equator

transitional zone embryonic nucleus fetal nucleus infantile nucleus adult nucleus

transitional zone

posterior

capsule

bow

Fig. 5-1-1  Gross anatomy of the adult human lens. Note the different regions are not drawn to scale.

The lens is a vital refractive element of the human eye. In 2002, the World Health Organization estimated that lens pathology (cataract) was the most common cause of blindness worldwide, affecting over 17 million people across the globe.1 Not surprisingly, cataract surgery is the most common surgical procedure performed in the developed world.2 An understanding of the basic science of the lens provides valuable insight into the various pathologies involving the lens, as well as the continually evolving techniques used to treat them.

of the capsule depends upon the region of the capsule being measured (Fig. 5-1-2) and, except for the posterior capsule, increases with the age of the individual.4–6 The lens capsule is composed of a number of lamellae stacked on top of each other. The lamellae are narrowest near the outside of the capsule and widest near the cell mass.7 Major structural proteins and a small amount of fibronectin are found within the lamellae.8 This structure is continuously synthesized and represents one of the thickest basement membranes in the body. The capsule is produced anteriorly by the lens epithelium and posteriorly by the elongating fiber cells.

ANATOMY OF THE LENS

Epithelial Cells

The adult human lens is an asymmetric oblate spheroid that does not possess nerves, blood vessels, or connective tissue.3 The lens is located behind the iris and pupil in the anterior compartment of the eye. The anterior surface is in contact with the aqueous on the corneal side; the posterior surface is in contact with the vitreous. The anterior pole of the lens and the front of the cornea are separated by approximately 3.5 mm.4 The lens is held in place by the zonular fibers (suspensory ligaments), which run between the lens and the ciliary body. These zonular fibers, which originate from the region of the ciliary epithelium, are a series of fibrillin-rich fibers that converge in a circular zone on the lens. Both an anterior and a posterior sheet meet the capsule 1–2 mm from the equator and are embedded into the outer part of the capsule (1–2 μm deep). It also is thought that a series of fibers meets the capsule at the equator.5, 6 Histologically the lens consists of three major components – capsule, epithelium, and lens substance (Fig. 5-1-1).

Capsule

The lens is ensheathed by an elastic acellular envelope, which serves to contain the epithelial cells and fibers as a structural unit and allows the passage of small molecules both into and out of the lens. The thickness

The lens epithelium arises as a single layer of cells beneath the anterior capsule and extends to the equatorial lens bow. These cells have a cuboidal shape, being approximately 10 μm high and 15 μm wide. Their basal surface adheres to the capsule, whereas their anterior surface abuts the newly formed elongating lens fibers. Lens epithelial cells have large, indented nuclei and a normal array of organelles. They also contain dense bodies and glycogen particles. The lateral membranes of epithelial cells (membranes in contact with the adjacent epithelial cells) are highly tortuous and attachment to adjacent cells occurs by adhesion complexes located in the lateral membranes that include both desmosomes and tight junctions.3, 8–10 Lens epithelial cells contain the three main groups of cytoskeletal elements, which are microfilaments (actin), intermediate filaments (vimentin), and microtubules (tubulin). These cytoskeletal elements form a network that provides structural support, controls cell shape and volume, ensures intracellular compartmentalization and movement of organelles, enables cell movement, distributes mechanical stress, and mediates chromosome movement during cell division. Epithelial cell density is greatest in the central zone, a region in which cells normally do not proliferate. Cells in this zone are the largest epithelial cells found in the lens. The proliferative capacity of epithelial

381

5

THICKNESS OF THE LENS CAPSULE

THE LENS

21�m

LENS WEIGHT AND CELL NUMBERS WITH AGE

anterior pole 14�m

21�m

weight 250 (mg)

c. 761,184 epithelial cells c. 3,045,100 fibers

17�m

17�m

200 23�m

c. 1,009,312 epithelial cells c. 3,546,100 fibers

23�m 150

4�m posterior pole

100

Fig. 5-1-2  Changes in thickness of the adult lens capsule with location.

birth c. 402,595 epithelial cells c. 1,662,010 fibers

50

cells is greatest at the equator (see Fig. 5-1-1). Cells in the germinative equatorial zone are dividing constantly; newly formed cells are forced into the transitional zone where they elongate and differentiate to form the fiber mass of the lens.3, 11

0

0

20

40

60

Lens Substance

The lens substance, which constitutes the main mass of the lens, is composed of densely packed lens cell cytoplasm (fibers) with very little extracellular space. The adult lens substance consists of the nucleus and the cortex, two regions that often are histologically indistinct. Although the size of these two regions is age dependent, studies of lenses with an average age of 61 years indicate that the nucleus accounts for approximately 84% of the diameter and thickness of the lens and the cortex for the remaining 16%.12 The nucleus is further subdivided into embryonic, fetal, infantile, and adult nuclei (see Fig. 5-1-1). The embryonic nucleus contains the original primary lens fiber cells that are formed in the lens vesicle. The rest of the nuclei are composed of secondary fibers, which are added concentrically at the different stages of growth by encircling the previously formed nucleus. The cortex, which is located peripherally, is composed of all the secondary fibers continuously formed after sexual maturation. The region between the hardened embryonic and fetal nuclear core and the soft cortex (i.e., the fibers added to form the infantile and adult nuclei) sometimes is referred to as the epinucleus. Fibers are formed constantly throughout life by the elongation of lens epithelial cells at the equator. Initially, transitional columnar cells are formed but, once long enough, the anterior end moves forward beneath the anterior epithelial cell layer and the posterior end is pushed backward along the posterior capsule. The ends of this U-shaped fiber run toward the poles of both capsular surfaces.3–6 Once fully matured, the fiber detaches from the anterior epithelium and the posterior capsule. Each new layer of secondary fibers formed at the periphery of the lens constitutes a new growth shell. Lens fibers are held together by the interlocking of the lateral plasma membranes of adjacent fibers to form ball-and-socket and tongue-andgroove joints. These joints, which are found at regular intervals along the length of their membranes, are characterized by square array membranes. Both desmosomes and tight junctions are absent from mature lens fibers, although desmosomes are found between elongating fibers.3, 8, 9

Sutures

Sutures are found at both the anterior and the posterior poles. They are formed by the overlap of ends of secondary fibers in each growth shell. No sutures are found between the primary fibers in the embryonic nucleus. Each growth shell of secondary fibers formed before birth has an anterior suture shaped as an “erect Y” and a posterior suture shaped as an “inverted Y.” The formation of sutures enables the shape of the lens to change from spherical to that of a flattened biconvex sphere.3, 9, 13

Growth

382

The growth of the lens throughout life is a unique characteristic not shared with any other internal organ. The growth rate, which is greatest in the young, diminishes with increasing age. During an average life­ span the surface area of the lens capsule increases from 80 mm2 at birth to 180 mm2 by the seventh decade.5, 7 The rate of increase in cell numbers parallels the increase in both mass and dimensions of the lens, and therefore decreases dramatically after the second decade. Numbers of

80 age (years)

Fig. 5-1-3  Increase in lens weight and cell numbers with age. Note the   correlation between these two parameters. (Lens weight data from Phelps Brown N, Bron AJ. Lens growth. In: Phelps Brown N, Bron AJ, Phelps Brown NA, eds. Lens disorders. A clinical manual of cataract diagnosis. Oxford: ButterworthHeinemann; 1996:17–31. Cell number data from Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec FA, eds. Principles and practices of ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994:82–96.)

both epithelial cells and fibers increase by approximately 45–50% during the first two decades (Fig. 5-1-3). After this, the increase in cell numbers is reduced, with the proportional increase in fibers being very small.3

Mass

The weight of the lens rapidly increases from 65 mg at birth to 125 mg by the end of the first year. Lens weight then increases at approximately 2.8 mg/year until the end of the first decade, by which time the lens has reached 150 mg. Thereafter, the mass of the lens increases at a slower rate (1.4 mg/year) to reach about 260 mg by the age of 90 years (see Fig. 5-1-3).14 The lenses of men are heavier than those of women of the same age, the mean difference being 7.9 ± 2.47 mg (once adjusted for age).15

Dimensions

The equatorial diameter of the human lens increases throughout life, although the rate of increase is reduced significantly after the second decade. The diameter increases from approximately 5 mm at birth to 9–10 mm in a 20-year-old. The thickness of the lens increases at a much slower rate than does the equatorial diameter. The distance from the anterior to the posterior poles, which is 3.5–4 mm at birth, increases throughout life, reaching up to 4.75–5 mm (unaccommodated).4, 14 The thickness of the nucleus decreases with age, as the result of compaction, whereas cortical thickness increases as more fibers are added at the periphery. Because the increase in cortical thickness is greater than the decrease in size of the nucleus, the polar axis of the lens increases with age.16 The radius of curvature of the anterior surface decreases from 16 mm at the age of 10 years to 8 mm by the age of 80 years as this surface becomes more curved. There is very little change in the radius of curvature of the posterior surface, which remains at approximately 8 mm.

PHYSIOLOGY OF THE LENS Permeability, Diffusion, and Transport

After involution of the hyaloid blood supply to the lens (tunica ­vasculosa lentis), the metabolic needs of the lens are met by the aqueous and the vitreous humors. The capsule is freely permeable to water, ions, other small molecules, and proteins with a molecular weight up to 70 kDa. The tight junctions between the epithelial cells do not restrict greatly the

SODIUM AND POTASSIUM CURRENT LOOPS

5.1

TRANSMITTANCE OF THE LENS

Basic Science of the Lens

transmittance 100 (%) 80

K+

Na+

lens transmittance: total, 4½ years direct, 4½ years direct, 53 years direct, 75 years

60 40 20

Fig. 5-1-4  Sodium and potassium current loops. (Adapted from Patterson JW. Characterization of the equational current of the lens. Ophthalmic Res. 1998;20:139–42.)

movement of molecules into the fiber mass. Epithelial cells and fibers possess a number of different channels, pumps, and transporters that enable transepithelial movement to and from the extracellular milieu.

Transport of ions

Fiber cells contain large concentrations of negatively charged crystallins. As a result, a large number of positively charged cations enter the lens cell to maintain electrical neutrality, and therefore the osmolarity of the intracellular fluid becomes greater than that of the extracellular fluid. Fluid flow and swelling is minimized by the resting potential of the plasma membrane being set at a negative voltage using, principally, potassium (K+)-selective channels. An equilibrium is reached when the electrical force that attracts these ions is balanced by the outward leak of K+ down its concentration gradient. The Na+ ions that leak into the cells are exchanged actively for K+ ions, which diffuse through the lens down their concentration gradient and leave through ion channels in both the epithelial cells and surface fibers. There is a net movement of Na+ ions from posterior to anterior and of K+ ions from anterior to posterior (Fig. 5-1-4).17 Although a pH gradient exists, which increases from the central nucleus to the peripheral layers, the intracellular pH of the lens is ­approximately 7.0. Lens cells need to continually extrude ­intracellular protons that are generated from lactic acid, as a result of anaerobic glycolysis, and by the continuous inward movement of positive ions from the extracellular space. The pH is regulated by mechanisms capable of increasing and decreasing intracellular acid levels. Molecules, especially proteins, with the capacity to act as buffers also play a role.

Amino acid and sugar transport

Although amino acids can enter the lens across both the anterior and posterior surfaces, most amino acids are transported into the lens from the aqueous. The lens contains most, if not all, amino acids and also can convert keto acids into amino acids. The lens acts as a “pump–leak” system: amino acids are “pumped” into the lens through the anterior capsule and passively “leak” out through the posterior capsule. Although glucose has the capacity to enter via both the anterior and the posterior surfaces, most enters from the aqueous humor.

BIOPHYSICS Light Transmission

The cornea and lens act as spectral filters absorbing the more energetic wavelengths of the electromagnetic spectrum (i.e., ultraviolet (UV) radiation) that have the potential to damage the retina. The cornea absorbs wavelengths below 295 nm while the lens absorbs strongly in the long UV-B (300–315 nm) and most of the UV-A (315–400 nm) wavelengths. However, in children under 10 years there is a transmission band centered around 320 nm of about 8% which is reduced to 0.1% by age 22 years and by age 60 years no UV radiation transmits across the lens. The total transmittance of the young lens begins increasing rapidly at about 310 nm and reaches 90% at 450 nm, compared with the older lens (e.g., 63 years), which begins transmitting at 400 nm but

0

300

400 500 600

800 1000 1200

1600 2000

wavelength (nm)

Fig. 5-1-5  Changes in transmission (UV and visible) of the normal aging human lens. (From Boettner and Wolter. Transmission of the ocular media. Invest Ophthalmol Vis Sci. 1962;1:776–83.)

does not reach 90% total transmittance until 540 nm (Fig. 5-1-5). The ­overall transmission of visible light decreases with increasing age, a ­feature that arises largely from age-related changes and brunescence in the lens (see Fig. 5-1-5).18, 19

Transparency

During the early stages of embryonic development the lens is opaque, but as development continues and the hyaloid vascular supply is lost the lens becomes transparent. The young lens is transparent because of the absence of chromophores able to absorb visible light and the presence of a highly organized structure that gives minimal light scatter (less than 5% in the normal human lens). The amount of light scatter is minimized in fiber cells once the fibers have elongated fully and matured and their organelles have degenerated. Although the epithelial cells contain large organelles that scatter light, the combined refractive index of this layer and the capsule is no different from the refractive index of the aqueous, so light scatter in this area is very small.

Refractive Indices

Refractive index increases from 1.386 in the peripheral cortex to 1.41 in the central nucleus of the lens. Because both the curvature and refractive index of the lens increase from the periphery toward the center, each successive layer of fibers has more refractive power and, therefore, can bend light rays to a greater extent.20 The anterior capsular surface of the lens has a greater refractive index than the posterior capsular surface (1.364–1.381 compared with 1.338–1.357). The change in refractive index from the surface of the lens to the center results from changes in protein concentration; the higher the concentration, the greater the refractive power. This increase must ­occur as a result of both packing and hydration properties, because protein synthesis in the nucleus is minimal.18, 21

Chromatic Aberration

When visible light passes through the lens it is split into all the colors of the spectrum. The different wavelengths of these colors result in different rates of transmission through the lens and some deviation. As a consequence, yellow light (570–595 nm) normally is focused on the retina; light of shorter wavelengths, for example blue (440–500 nm), falls in front because of the slower transmission and increased refraction ­compared with yellow light; and light of longer wavelengths, for example red (620–770 nm), falls behind because of the faster transmission and less refraction (Fig. 5-1-6). However, although the lens is not designed to correct this chromatic aberration, yellow is normally the ray of greatest intensity. Because the amount of dispersion between the red and the blue images is approximately 1.5–2 D, very little reduction occurs in the clarity of the image that is formed on the retina. As the lens accommodates, refraction increases as a result of the increasing power of the lens and, therefore, the amount of chromatic aberration also increases.20, 22–24

383

5

PRINCIPAL ABERRATIONS OF THE LENS Sperical aberration

THE LENS Chromatic aberration

A

Fig. 5-1-6  Principal aberrations of the lens.

Spherical Aberration

Light rays that pass through the periphery of an optical lens have a ­focal length shorter than that of light rays that pass through the center. This occurs because the refractive power is greater at the periphery, so the light rays are refracted to a greater degree as they pass through this ­region. The lens of the human eye is designed to minimize this spherical aberration since: (1) refractive index increases from the periphery to the center of the lens; (2) curvature of both the anterior and the posterior capsule increases towards the poles; and (3) curvature of the anterior capsule is greater than that of its posterior counterpart. As a result of these structural features the focal points of the peripheral and central rays are similar, which ensures that the reduction in the quality of the image is minimal (see Fig. 5-1-6). The pupil diameter also affects the amount of spherical aberration, because light rays do not pass through the periphery of the lens (unless the pupil is dilated). The optimal size of the pupil needed to minimize this imperfection is 2–2.5 mm.20, 22–24

Accommodation

384

The lens, through its ability to change shape, has the capacity to change the focusing power of the eye. This process is known as accommodation and enables both distant and close objects to be brought to focus on the retina. At rest the ciliary muscle is relaxed and, therefore, the zonules pull on the lens, which keeps the capsule under tension. In this state the capsule is stretched and the lens flattens, enabling the eye to focus on distant objects. Light rays from close objects are divergent and, therefore, are focused behind the retina with the lens in this shape. The lens accommodates these objects by contraction of the ciliary muscles, which relaxes the zonules thus increasing the curvature of the anterior surface and decreasing the radius of curvature from 10 mm to 6 mm. The increase in curvature of the anterior surface increases the refractive power, so that the light rays from close objects are refracted toward each other to a greater extent and, therefore, converge on the fovea. Because the front of the lens has moved forward, the depth of the anterior chamber decreases from 3.5 mm to 3.2–3.3 mm. Very little change occurs in

B

Fig. 5-1-7  Change in form of the lens on accommodation in a person of age 29 years. (A) Relaxed. (B) Accommodated. (Grid squares 0.4 mm.) Note the change in curvature of the anterior surface. (From Phelps Brown N, Bron AJ. Accommodation and presbyopia. In: Phelps Brown N, Bron AJ, Phelps Brown NA, eds. Lens disorders. A clinical manual of cataract diagnosis. Oxford: ButterworthHeinemann; 1996:48–52.)

the curvature of the posterior capsule, which remains at approximately 6 mm (Fig. 5-1-7). The distance between the cornea and the posterior surface of the lens, therefore, changes very little or not at all. Accommodation is accompanied by a decrease in pupil size (miosis) and convergence of the two eyes. Light rays can pass only through the thickest central parts of the lens and the two images become fused. The mechanisms of accommodation can be divided into both physical and physiological processes. Physical accommodation, a measure of the change in shape of the lens during the accommodative process, is measured in terms of the amplitude of accommodation using the unit diopter. It represents the difference between the contractility of the eye at rest and when fully accommodated and, therefore, a measure of the extent to which objects close to the eye can be focused. Physiological accommodation, a measure of the force of ciliary muscle contraction per diopter, is measured with the unit myodiopter. The myodiopter ­increases during the act of accommodation.25, 26

BIOCHEMISTRY The lens, like most tissues, requires energy to drive thermodynamically unfavorable reactions. Adenosine triphosphate (ATP) is the principal source of this energy within the cell. The majority of ATP produced

MAJOR PATHWAYS OF GLUCOSE METABOLISM IN THE LENS

Polyol dehydrogenase

5% Aldose reductase

Sorbitol pathway

Fructose

Glucose

Hexokinase

5%

Gluconic acid

90% 10%

Glucose-6-phosphate Phosphofructokinase

Basic Science of the Lens

Sorbitol

5.1

Glycolysis

6-phosphogluconate

Pentose phosphate pathway

Ribulose-5-phosphate

80% Glyceraldehyde-3-phosphate Glycercaldehyde3-phosphate dehydrogenase

Lactate

Lactate dehydrogenase

C6

C4

Pyruvate kinase Pyruvate

Acetyl CoA

Tricarboxylic acid cycle

C5

3% C4

Fig. 5-1-8  Overview of the major pathways of glucose metabolism in the lens. Percentages represent the estimated amount of glucose used in the   different pathways.

within the lens comes from the anaerobic metabolism of glucose. Other important components required by the lens include the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), which is produced principally by the pentose phosphate pathway and acts as a source of readily available reducing agent used in the biosynthesis of many essential cellular components, such as fatty acids and glutathione. Because the lens is susceptible to oxidative damage, it also must maintain sufficient antioxidant defenses to protect against the accumulation of this damage and the development of cataract.

Sugar Metabolism

Approximately 90–95% of the glucose that enters the normal lens is phosphorylated into glucose-6-phosphate in a reaction catalyzed by hexokinase. Although this enzyme exists as three different isoforms (types I–III), only two have been found in the lens. Because type I has a greater affinity for glucose, it is found in the lens nucleus where glucose levels are low. Type II, which accounts for 70% of the total soluble lens hexokinase but has a lower affinity for glucose, is found predominantly in the epithelium and cortex, where glucose levels are higher. Glucose6-phosphate is used either in the glycolytic pathway (80% of total glucose) or in the pentose phosphate pathway (hexose monophosphate shunt; 10% of total glucose) (Fig. 5-1-8). Because hexokinase is saturated by the normal concentrations of glucose found in the lens, this enzyme is working to maximal capacity and, therefore, limits the rate of both glycolysis and the pentose phosphate pathway. Glycolysis also is regulated by phosphofructokinase and pyruvate kinase.27, 28 Owing to its avascularity and location in the ocular humors, the lens exists in a hypoxic environment. This results in at least 70% of lens ATP being derived from anaerobic glycolysis, a relatively inefficient mechanism for the production of ATP (two net molecules of ATP per molecule of glucose). However, although only a very small amount, approximately 3% of lens glucose, passes into the tricarboxylic acid cycle (see Fig. 5-1-8), this aerobic metabolism generates 25% of lens ATP (36 net molecules of ATP per molecule of glucose). Glycolysis and the tricarboxylic acid cycle generate two energy-rich molecules, the reduced form of nicotinamide adenine dinucleotide (NADH) and the reduced form of flavin adenine dinucleotide (FADH2). These donate their electrons to oxygen, which releases large amounts of free energy that is subsequently used to generate ATP. This cycle, which is restricted to the

epithelial layer, also provides carbon skeleton intermediates for biosynthesis, such as amino acids and porphyrins.27, 29 The bulk of the pyruvate produced by the glycolytic pathway is reduced to lactate in a reaction catalyzed by lactate dehydrogenase (see Fig. 5-1-8), which is concentrated mostly in the cortex. The formation of lactate results in the reoxidation of the cofactor NADH to NAD+. Glyceraldehyde-3-phosphate dehydrogenase, an enzyme used in the glycolytic pathway, regulates the activity of lactate dehydrogenase by controlling the rate of conversion of glyceraldehyde-3-phosphate into 1,3-diphosphoglycerate and, therefore, the availability of NADH.27–29 The 5–10% of glucose that is not phosphorylated into glucose-6­phosphate either enters the sorbitol pathway or is converted into gluconic acid (see Fig. 5-1-8). Although the precise function of these pathways is still unknown, the activity of the sorbitol pathway increases if glucose levels are increased above normal. Glucose is converted into sorbitol by aldose reductase, an enzyme localized to the epithelial layer. This enzyme uses NADPH supplied by the pentose phosphate pathway as a cofactor. Sorbitol then is converted by polyol dehydrogenase into fructose, a suboptimal, but usable, substrate for glycolysis. This enzyme is inactive at low concentrations of sorbitol and metabolizes sorbitol into fructose only if sorbitol has accumulated. Because both sorbitol and fructose have the potential to increase osmotic pressure, and so cause water to enter cells, these sugars may help to regulate the volume of the lens.27–29

Protein Metabolism

The protein concentration within the lens is higher than that of any other tissue in the body. Because the lens grows throughout life, protein synthesis also must occur throughout life. Most of this synthesis is concerned with the production of the crystallins and major intrinsic protein 26 (MIP26). It is assumed that protein synthesis occurs only in the epithelial cells and surface cortical fibers, which contain the organelles needed.30 Lens proteins remain stable for long periods because the majority of the degradative enzymes normally are inhibited. The lens controls the breakdown of proteins by marking those to be degraded with a small 8.5 kDa protein called ubiquitin. This system, which is ATP dependent, is most active in the epithelial layer. Lens proteins are broken down into peptides by endopeptidases and then into the constituent amino acids by exopeptidases. Neutral endopeptidase, previously called neutral proteinase,

385

5

THE �-GLUTAMYL CYCLE Enzymes

THE LENS

1. Membrane-bound �-glutamyltransferase

Amino acid

2. �-glutamylcyclotransferase

�-Glutamyl amino acid

3. 5-oxoprolinase 4. �-glutamylcysteine synthetase

ATP

5-Oxoproline

2

3

5. Glutathione synthetase 6. Dipeptidase Amino acid

Cysteinylglycine 1

ADP + Pi

6

Glycine

Glutamate ATP

Cysteine 4

Glutathione

ADP + Pi

5 �-Glutamyl cysteine

extracellular

intracellular

ADP + Pi

ATP

Fig. 5-1-9  The γ-glutamyl cycle. (From Harding JJ, Crabbe MJC. The lens: development, proteins, metabolism and cataract. In: Davson H, ed. The eye. 3rd ed. London: Academic Press; 1984:207–492.)

is activated by both calcium and magnesium, and is optimally active at pH 7.5 (the pH of the lens is approximately 7.0–7.2). The principal substrate of this enzyme is α-crystallin. The calpains (I and II), which mainly are localized in the epithelial cells and cortex, are used to degrade crystallins and cytoskeletal proteins. They are cysteine endopeptidases, the activities of which are regulated by calcium (Ca2+). These enzymes are inhibited by calpastatin, a natural inhibitor found at higher concentrations than the calpains. The lens also contains a serine proteinase (with trypsin-like activity) and a membrane-bound proteinase.28, 29, 31 The main exopeptidase is leucine aminopeptidase, an enzyme that is optimally active at pH 8.5–9.0, which catalyzes the removal of amino acids from the N-terminal of peptides. Aminopeptidase III, another endopeptidase found in the lens, has an optimal pH of 6.0 and as a result has a greater activity than leucine aminopeptidase in the normal lens.28, 29, 31

Glutathione

Glutathione (L-γ-glutamyl-L-cysteinylglycine) is found at high concentrations in the lens (3.5–5.5 mmol/g wet weight), especially in the epithelial layer (in which levels are higher than in the nucleus; the cortex contains an intermediate concentration). Glutathione has many important roles in the lens, including the following:28, 29, 32 l Maintenance of protein thiols in the reduced state, which helps to maintain lens transparency by preventing the formation of highmolecular-weight crystallin aggregates l Protection of thiol groups critically involved in cation transport and permeability; for example, oxidation of the –SH groups of the Na+,K+ATPase pump, which results in an increased permeability to these ions l Protection against oxidative damage (see below) l Removal of xenobiotics; glutathione-S-transferase catalyzes the conjugation of glutathione to hydrophobic compounds with an electrophilic center

Amino acid transport

386

Glutathione has a half-life of 1–2 days and, therefore, is recycled constantly by the γ-glutamyl cycle; its synthesis and degradation occur at approximately the same rate (Fig. 5-1-9). Glutathione is synthesized from L-glutamate, L-cysteine, and glycine in a two-step process that uses 11–12% of lens ATP.28, 29, 32 Reduced glutathione also can be taken into the lens from the aqueous humor. A reduced glutathione transporter that ­allows the uptake of glutathione by the lens epithelial cells has been characterized.33 The breakdown of glutathione releases its constituent amino acids, which subsequently are needed to synthesize more glutathione.

Antioxidant Mechanisms

Reactive oxygen species is a collective term for highly reactive oxygen radicals (including free radicals) that have the potential to damage ­lipids, proteins, carbohydrates, and nucleic acids. Such radicals include the superoxide anion, the hydroxyl free radical, hydroperoxyl radicals, lipid peroxyl radicals, singlet oxygen, and hydrogen peroxide (H2O2). Reactive oxygen species generally have two origins in tissues: cell metabolism and photochemical reactions. Photochemical damage occurs when light is absorbed by a photosensitizer, a chromophore, that upon photoexcitation to photoexcited singlet state undergoes intersystem crossing and forms a transient excited triplet state. The excited triplet state is long lived, allowing for interaction with other molecules producing free radicals via electron (hydrogen) transfer, or singlet oxygen via transfer of excitation energy from the photosensitizer in the triplet state to molecular oxygen. The continuous entry of optical radiation into the lens, in particular the preferential absorption of shorter wavelengths (295–400 nm), makes lens tissue particularly susceptible to photochemical reactions. The major ultraviolet (UV) absorbers in the lens are free or bound aromatic amino acids (e.g., tryptophan), numerous pigments (e.g., 3-hydroxykynurenine), and fluorophores. Reactive oxygen species also can enter the lens from the surrounding milieu (e.g., H2O2 is present at high levels in the aqueous humor (30 mmol/L in humans)).29,34 Highly reactive oxygen species have the capacity to damage the lens in several ways:29, 35 l Peroxidizing membrane lipids results in the formation of malondialdehyde, which in turn can form cross-links between membrane lipids and proteins. l Introducing damage into the bases of the DNA, such as base modifications (8-hydroxyguanosine), plana-lesions (cytosine glycols) and lesions leading to major helical distortions of the DNA (8,5’ cyclo­ purine deoxyribonucleosides), initiates DNA repair mechanisms. l Polymerizing and cross-linking proteins result in crystallin aggregation and inactivation of many essential enzymes, including those with an antioxidant role (e.g., catalase and glutathione reductase). Although these reactions would result rapidly in lens damage, the ­presence of a complex antioxidant system offers considerable protection. This system, however, is not 100% efficient and a low level of cumulative damage occurs throughout life. Protection against damage induced by reactive oxygen species in the lens is achieved in a number of ways. The superoxide anion undergoes dismutation by superoxide dismutase or interaction with ascorbate (see below), which results in the formation of H2O2. This, along with the

COUPLING OF THE ASCORBIC ACID AND GLUTATHIONE SYSTEMS

Ascorbate

+

GSSG Nonenzymatic

H2O2 + O2

Dehydroascorbate

Catalase

H2O + 1/2O2

NAD(P)H2 Glutathione reductase

GSH

NAD(P)

Basic Science of the Lens

–

2O2 + 2H

5.1

Glutathione peroxidase

2H2O + GSSG

Fig. 5-1-10  Coupling of the ascorbic acid and glutathione systems.

high levels of exogenous H2O2, is detoxified by the enzyme catalase or glutathione peroxidase or both (Fig. 5-1-10).36 Catalase is present in epithelial cells but is found at very low levels in fibers. Glutathione peroxidase, however, is found in significant amounts in both epithelial cells and fibers, although the highest levels are found in the epithelial cells. The glutathione system, therefore, is thought to provide the most protection against H2O2. In addition to neutralizing H2O2, the glutathione system provides important protection against the lipid free-radical chain reaction by the neutralization of lipid peroxides.29, 32, 34, 35 Ascorbic acid (vitamin C) appears to play a major role in the antioxidant system in the lens, although this may be species dependent, because the human lens is rich in ascorbate (1.9 mg/kg wet weight or 1.1 mmol/kg), while it is almost absent in the rat lens (0.08 mmol/kg). Ascorbate is present at high levels in the outer layers of the lens and virtually absent from the nucleus. It rapidly reacts with superoxide anions, peroxide radicals, and hydroxyl radicals to give dehydroascorbate. It also scavenges singlet oxygen, reduces thiol radicals, and is ­important in the prevention of lipid peroxidation. The ascorbic acid and glutathione systems are coupled in that dehydroascorbate reacts with the reduced form of glutathione to generate ascorbate and GSSG (oxidized ­glutathione).31, 34, 37, 38

LENS CRYSTALLINS Crystallin Structure

Up to 60% of the wet weight and most of the dry weight of the human lens is composed of proteins. These lens proteins can be divided on a laboratory basis into water-soluble (cytoplasmic proteins) and waterinsoluble (cytoskeletal and plasma membrane) fractions. The watersoluble crystallins constitute approximately 90% of the total protein content of the lens.39, 40 The three groups of crystallins found in all vertebrate species can be divided into the α-crystallin family and the β/γ-crystallin superfamily. The properties of these crystallins are summarized in Table 5-1-1. The α-crystallins have the largest molecular size of the crystallins. The β-crystallins are composed of light (βL) (c. 52 kDa) and heavy (βH) (150–210 kDa) fractions, which can be separated by gel chromatography. The light fraction can be further subdivided into two fractions, βL1 and βL2.39–43 The smallest of the crystallins are the γ-crystallins. Six members of this family, known as γA–γF, have a molecular weight of 20 kDa.

Crystallin Gene Expression During Lens Growth

The α-, β-, and γ-crystallins are synthesized in the human lens during gestation, and the absolute quantities of these three families increases during development. The first crystallin to be synthesized is α-crystallin,

which is found in all lens cells. The β- and γ-crystallins are first detected in the elongated cells that emerge from the posterior capsule to fill the center of the lens vesicle.44 Throughout life the same pattern of synthesis is maintained, with the result that the α-crystallins are found in both lens epithelial cells and fibers, whereas the β- and γ-crystallins are found only in the lens fibers. α-Crystallin synthesis is far greater in the lens epithelium than in the fibers. The α-crystallins are found in both dividing and nondividing lens cells, whereas the β- and γ-crystallins are found only in nondividing lens cells. Differentiation of a lens epithelial cell into a fiber, therefore, may be one of the factors that triggers a decrease in translation of the α-crystallin gene and stimulates the ­synthesis of the β- and γ-crystallins.45

Crystallin Function

The high concentration of crystallins and the gradient of refractive index are responsible for the refractive properties of the lens. The short-range order of these proteins ensures that the lens remains transparent. The crystallins also have other functions within the lens. The α- and βB1crystallins are able to bind to cell membranes and the cytoskeleton. The importance of this binding is not clear, but is thought to be needed for the change in shape observed during the differentiation of an epithelial cell into a lens fiber. α-Crystallins also may be involved in the assembly and disassembly of the lens cytoskeleton. Similarities in structure between the small heat shock proteins (sHSPs) and αB-crystallin suggest that this crystallin family may provide the lens with stress-resistant properties.40, 41, 46 α-Crystallins have chaperone-like functions that enable them to prevent the heat-denatured proteins from becoming insoluble and facilitate the renaturation of proteins that have been denatured chemically.47 They also act as chaperones under conditions of oxidative stress and, therefore, may help to maintain lens transparency.48 Although the function of the β-crystallins is unknown, their structural similarities with the osmotic stress proteins suggests that they also may act as stress proteins in the lens.46 The γ-crystallins (with the exception of γs-crystallin) are found in the regions of low water content and high protein concentration, such as the lens nucleus. The presence of this family of crystallins correlates with the hardness of the lens. Concentrations are higher in those lenses that do not change shape during accommodation, as in fish, than in those that do, as in the human.40

AGE CHANGES Morphology

Increases in both the mass and dimensions of the lens, which occur throughout life, are greatest during the first two decades. These increases result from the proliferation of lens epithelial cells and their

387

5 THE LENS

388

   TABLE 5-1-1  PROPERTIES OF DIFFERENT CRYSTALLINS α

β

γ

γs

Subunits

αA, αAI, αB, αB1, up to nine minor subunits

Basic: βB1, βB2, βB3 Acidic: βA1, βA2, βA3, βA4

γA–γF

γs

Subunit molecular weight

20 kDa

Basic: 26–32 kDa Acidic: 23–25 kDa

20 kDa

24 kDa

Native molecular weight

600–900 kDa

βH: 150–200 kDa βL: c. 50 kDa

20 kDa

24 kDa

Number of subunits

30–45

βH: 0–8 βL: 2

1

1

Thiol content

Low

High

High

High

N-Terminal amino acid

Masked

Masked

Glycine or alanine

Masked

Secondary structure

Predominantly β-pleated sheet

β-pleated sheet

β-pleated sheet

β-pleated sheet

Three-dimensional structure

Unknown

Two domains with four “Greek key” motifs

Two domains with four “Greek key” motifs

Two domains with four “Greek key” motifs

Chromosome

αA: 21

βB1–βB4: 22

2 αB: 11

3 βA1/βA3: 17 βA2: ?

differentiation into lens fibers. As a consequence of the unique pattern of growth of the lens, it contains cells of all ages. The oldest epithelial cells are found in the middle of the central zone under the anterior pole. Because cells are added to the periphery of this zone throughout life, the age of the cells decreases from the pole toward the outer units of this region so that the newest cells always are found near the pregerminative zone. Because newly formed fibers are internalized as more are added at the periphery of the lens, the oldest fibers are found in the center of the nucleus and the newest fibers in the outer cortex. Each growth shell, therefore, represents a layer of fibers that are younger than those in the shell immediately preceding.49 As the lens ages many morphological changes occur to the epithelial cells, fibers, and capsule. Epithelial cells become flatter, flatten their nuclei, develop electron-dense bodies and vacuoles, and exhibit a dramatic increase in the density of their surface projections and cytoskeletal components. As a result of cellular flattening, the basal surface area of the cell increases; thus the number of cells needed to cover a region of the growing anterior capsule is less than that needed to cover a region of the same size in a younger lens. This, in combination with the decrease in proliferative capacity, means that epithelial cell density decreases as the lens ages.49, 50 Lens fibers show partial degradation or a total loss of a number of plasma membrane and cytoskeletal proteins as the lens ages. The most significant degradation is that of MIP26. Early in life spectrin, vimentin, and actin are present in both the outer cortical fibers and the epithelial layer; however, they are degraded as the fibers age and are further internalized. By 80 years of age expression of these cytoskeletal proteins is restricted to the epithelial cells. The cholesterol-to-phospholipid ­ratio of fiber cell plasma membranes increases throughout life, and consequently membrane fluidity decreases and structural order increases. These changes, which are known to occur from the second decade, are greatest in the nucleus and are therefore partially responsible for the increase in nuclear sclerosis (hardening).51, 52 Furthermore, it is thought that the changes in structure of the plasma membrane and the degradation of cytoskeletal components may contribute to the increase in the number of furrowed membranes and microvilli found on the fiber surface.49 From the fourth decade onward, ruptures are found in the equatorial region of cortical fiber plasma membranes (Fig. 5-1-11). Reparation of these ruptures often prevents the formation of opacities. Any opacities which do develop become surrounded by deviated membranes and therefore isolated from the remainder of the lens. The lens capsule thickens throughout life. It also increases in surface area as a result of the growth of the lens. Ultrastructural changes include the loss of laminations and an increase in the number of linear densities. Although the young lens capsule is known to contain collagen type IV and the aged capsule collagen types I, III, and IV, the presence of types I and III collagen in the young capsule has yet to be confirmed; however, their synthesis may be age related.53

ant

eq

nu

Fig. 5-1-11  Scanning electron micrograph of equatorial region of cortical fiber plasma membranes. Note the circular shade with the fracture of fibers in the deep equatorial cortex (eq) (arrows) and folding fibers in the anterior deep cortex (ant) (arrowheads). (nu, lens nucleus). (From Vrensen GFJM. Aging of the human eye lens – a morphological point of view. Comp Biochem Physiol A Physiol. 1995;111:519–32.)

Physiological Changes

Changes to the cellular junctions and alterations in cation permeability occur as the lens ages. The major gap junction protein MIP26 loses some of its amino acids to form new variants, which include polypeptides with molecular weights of 15, 20, and 22 kDa.51, 52 The membrane potential of an isolated, perfused human lens may be –50 mV at the age of 20 years, but only –20 mV at the age of 80 years. Although potassium (K+) levels do not alter greatly, remaining at approximately 150 mmol/ L (150 mEq/L), the sodium (Na+) content of the lens increases from 25 mmol/L (25 mEq/L) at the age of 20 years to 40 mmol/L (40 mEq/L) by the age of 70 years. Thus, the Na+:K+ permeability ratio increases approximately sixfold, which results in a proportionately greater increase in the sodium content of the lens.54 The change in the ratio of these two ions correlates with the increase in optical density of the lens.55 This change in ion permeability with increasing fiber age is thought to occur due to a decrease in membrane fluidity as a result of the age-related increase in the cholesterol-to-phospholipid ratio. The lens, therefore, becomes more dependent on the Na+,K+-ATPase in the epithelial cells. The decrease in membrane potential also results from changes in the

MAIN SPECIES IN THE HUMAN LENS WHICH ABSORB LIGHT TRANSMITTAL BY THE CORNEA

PRESBYOPIC CHANGES IN AMPLITUDE OF ACCOMMODATION WITH AGE

5.1 Basic Science of the Lens

amplitude of 14 accommodation (D) 12

relative 1.2 absorbance

10

0.8

8 6

0.4

4 2

0.0 295

345

395

yellow, aged proteins o-�-glucoside of 3-hydroxykynurenine protein-bound tryptophan

445 495 wavelength (nm)

0 10

20

30

40

50

60 70 age (years)

Fig. 5-1-12  Main species in the human lens which absorb light transmitted by the cornea. (From Dillon J. The photophysics and photobiology of the eye.   J Photochem Photobiol B. 1991;10:23–40.)

Fig. 5-1-13  Presbyopic changes in the amplitude of accommodation with age. The different colored symbols represent the data obtained from different publications. (From Fisher RF. Presbyopia and the changes with age in human crystalline lens. J Physiol. 1973;223:765–79.)

free calcium (Ca2+) levels, which increase from 10 mmol/L (0.04 mg/dL) at the age of 20 years to approximately 15 mmol/L (0.06 mg/dL) by the age of 60 years. It is thought that the Ca2+-ATPase may be inhibited by the decrease in membrane fluidity, which decreases the rate at which calcium is pumped out of the cell. It also is possible that the increase in Na+ and Ca2+ permeability may result from the increased activity of nonspecific cation channels.54

the yellowing of the lens. This reaction is initiated by the attachment of a sugar molecule (e.g., glucose) to an amino acid, normally valine or lysine. In young lenses, 1.3% of lysine residues of human crystallins (both soluble and insoluble) are glycated, but by the age of 50 years this increases to 2.7% and to approximately 4.2% in older lenses.51 Yellow fluorescent photoproducts also are formed in the presence of ascorbic acid. Because ascorbic acid is found in the lens at much higher concentrations than glucose, and because the ascorbic acid reaction is faster, it probably plays a role in the formation of these yellow pigments.59

Biophysical Changes

The absorption of both ultraviolet (UV) and visible light by the lens increases with age. Both free and bound aromatic amino acids (tryptophan, tyrosine, and phenylalanine), fluorophores, yellow pigments, and some endogenous compounds (such as riboflavin) are responsible for the absorption properties of the lens.51 Tryptophan (which absorbs more than 95% of the photon energy absorbed by amino acids) is cleaved in the presence of sunlight and air to form N-formylkynurenine and a series of other metabolic products, which includes 3-hydroxykynurenine glucoside (3-HKG). Because more than 90% of the UV radiation that reaches the lens is UV-A (315–400 nm), and 3-HKG absorbs light between 295 and 445 nm whereas tryptophan only absorbs light between 295 and 340 nm, this glucoside has a relative absorbance greater than that of tryptophan in the young human lens (95% compared with 5%) (Fig. 5-1-12). As the lens ages it changes from colorless or pale yellow to darker yellow in adulthood, and brown or black in old age. These changes in coloration, which are limited to the nucleus, are thought to result from the attachment of 3-HKG and its metabolic derivatives to proteins to produce yellow-pigmented proteins that also absorb light. As the concentration of these pigments increases they compete with 3-HKG, but as the concentration of the kynurenines decreases further the yellow, aged proteins become the major absorbing species of the lens.56, 57 Because these yellow proteins are fluorescent species, the wavelength absorbed increases to approximately 500 nm (see Fig. 5-1-12). A blue fluorophore, which absorbs between 330 and 390 nm and fluoresces between 440 and 466 nm, increases as the lens ages. The autofluorescent properties of the lens also change with age. A green fluorophore, which is excited between 441 and 470 nm and emits between 512 and 528 nm, then is formed by oxygen-dependent photolysis of the blue fluorophore.58 This age-related shift in the spectral transmission of the lens explains the change in an artist’s use of colors throughout a lifetime. The increased capacity of the lens to absorb visible light, in combination with the increased scattering properties of the lens (because of the aggregation of lens proteins and possibly the release of bound water), results in a decrease in transparency.50 The increase in the total number of photons absorbed is accompanied by an age-related loss in antioxidant levels which, therefore, increases the amount of photo-oxidative stress. Nonenzymatic glycation of proteins by the Maillard reaction results in the formation of advanced glycation end products, which also increase

Accommodation Changes

The amplitude of accommodation decreases throughout life from 13– 14 D at the age of 10 years to 6 D at 40 years and almost 0 D by the age of 60 years (Fig. 5-1-13). The older subject, therefore, is unable to focus clearly on near objects and is presbyopic. The change in accommodative power is attributable to a number of factors, including those listed below:60–62 l Young’s modulus of capsular elasticity decreases from 700 N/cm2 at birth to 150 N/cm2 by the age of 80 years. l Stiffness of the lens substance increases, which renders the lens less deformable. l Although the cortex increases in thickness throughout life, very ­little change occurs in the thickness of the nucleus. The effect of the rounding of the nucleus on the change in curvature of the anterior surface during accommodation, therefore, is reduced with age. l Radius of curvature of the anterior capsule decreases, which renders the lens rounder. Contraction of the ciliary muscle, therefore, does not greatly alter the shape of the lens. l Distance between the anterior surface of the lens and the cornea decreases. l The internal apical region of the ciliary body moves forward and ­inward with age. The zonules, therefore, no longer put the lens under so much tension in the unaccommodated state. The increases in curvature and thickness of the lens suggest that the refractive power should increase with age, resulting in myopia. This, however, does not happen because these changes are accompanied by small alterations to the gradient of refractive index. This gradient becomes flatter near the center of the lens and steeper near the surface and, therefore, the refractive power of the eye is lowered.63

Biochemical Changes

The overall metabolic activity of the lens, as well as the activity of many glycolytic and oxidative enzymes, decreases with increasing age. This is attributed, in part, to decreasing enzyme activities in the cortex and nucleus. The activity of many enzymes involved in the metabolism of glucose decrease with age. These include glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, aldolase, enolase,

389

5 THE LENS

phosphoglycerate kinase, and phosphoglycerate mutase. Although overall metabolic activity decreases, the lens still maintains the capacity to synthesize proteins, fatty acids, and cholesterol at substantial rates. Decreased metabolic activity, therefore, does not serve as a significant limiting factor for the production of new lens fibers.51, 52 A reduction in the activity or levels or both of many antioxidants occurs with increasing age. Because this decrease is greatest in the nucleus, fibers in this region of the lens are more susceptible to oxidative damage and lipid peroxidation. As a result they rely upon the overlying cortical fibers and epithelial layer to protect them. The activity of both catalase and superoxide dismutase decreases with age. A decrease also occurs in the levels of ascorbate and glutathione.50 The reduced activity of both glutathione synthetase and γ-glutamylcysteine synthetase, accompanied by a decrease in the uptake of L-cysteine (an amino acid needed for glutathione synthesis), decreases the rate of synthesis of reduced glutathione (Fig. 5-1-14).64 In the human lens a very slow decrease occurs in the total activity of glutathione reductase (converts oxidized glutathione into reduced glutathione). Glutathione peroxidase, which is involved in the breakdown of lipid peroxides and hydrogen peroxide, levels increase from birth until approximately 15 years of age and then slowly decrease throughout adulthood.51, 52 This decreased antioxidant activity coupled with increased photon absorption with increasing age will advance photoxidative damage in the lens.

Crystallins

With increasing age there is an increase in both the complexity and the number of crystallin fractions found in the lens. Age-related changes in crystallins include accumulation of high molecular weight (HMW) aggregates, partial degradation of crystallin polypeptides, increased crystallin insolubility, photo-oxidation of tryptophan and the production of

EFFECT OF AGE ON THE CAPACITY TO SYNTHESIZE REDUCED GLUTATHIONE GSHg–1 lens 3000 (cpm 10000–1)

2000

1000

0

0

20

40

60

80

data from one lens overlapping data from two lenses

100 age (years)

Fig. 5-1-14  Effect of age on the capacity to synthesize reduced glutathione. (From Rathbun WB, Murray DL. Age-related cysteine uptake as rate-limiting in glutathione synthesis and glutathione half-life in the cultured human lens. Exp Eye Res. 1991;53:205–12.)

photosensitizers, loss of sulfhydryl groups, and nonenzymatic glycation. These changes can alter the short-range spatial order of the crystallins and therefore decrease transparency.50–52,56 Levels of soluble HMW aggregates (greater than 15 × 103 kDa) increase from approximately 0.16 mg in the lenses of donors between the ages of 16 and 19 years to 2.3 mg by the age of 60 years (Table 5-1-2).65 This increase occurs as the result of many factors, which include the inhibition of proteolytic enzymes that have the capacity to degrade these aggregates. Most of these aggregates are localized to the lens nucleus and are, in the majority of the young, principally composed of α-crystallin.50 As the lens ages these aggregates increase in complexity and are composed of a mixture of crystallins. The major subunits thought to be involved are αA-, αB-, and γs-crystallins. Many of these polypeptides undergo post-translational modifications, such as the formation of an intramolecular disulfide bond within αA-crystallin, glycation of lysine residues, cross-linking, deamidation of αA- and γs-crystallins and loss of the C-terminal end of αA-crystallin. Such modifications to α-crystallin result in a decrease in the capacity of this crystallin to act as a chaperone protein.50, 66 Below the age of 20 years, approximately 6% of the HMW protein is composed of degraded polypeptides, but by the age of 60 years this increases to 27% (see Table 5-1-2).65 It is thought that many of the HMW aggregates act as precursors for the accumulation of insoluble proteins. Below the age of 50 years, approximately 4% of lens proteins are insoluble, but by the age of 80 years this increases to 40–50%.67 This increase in insolubility is approximately the same in the cortex and nucleus before age 30 years, but with increasing age insolubility increases to a greater extent in the lens nucleus. Up to 80% of nuclear proteins of an aged lens may be insoluble and most of the nuclear α-crystallin is insoluble by the age of 45 years.51, 52 This will contribute to the loss of lens transparency and the development of senile cataract. Tryptophan residues in the crystallins are photo-oxidized to produce photosensitizers. This results in a decrease in tryptophan fluorescence and an increase in nontryptophan fluorescence throughout life. The oxidation of sulfhydryl groups results in the formation of disulfides, which may be one of the factors responsible for the age-related decrease in solubility of lens proteins. Because the γ-crystallins have sulfhydryl groups that are more exposed, they are more susceptible to this oxidation than are the α- and β-crystallins.52 Increases in the glycation of crystallins in the presence of glucose or ascorbic acid results in protein cross-linking and the resultant formation of HMW proteins. The α- and βH-crystallins rapidly cross-link; βL-crystallins are slower, but no γ-crystallin cross-linking occurs. One of the modifications that occurs most frequently to aging crystallins is deamidation of asparagine residues. This results in the formation of aspartic acid residues, which can alter the structure, destabilize the protein, and increase its susceptibility to proteolytic degradation. These age-related changes can lead to disorganization of lens structure and opacities that develop into cataract, a topic covered elsewhere in this section of the book. While the surgical management of cataract is discussed extensively elsewhere, the histopathology of one common sequela of cataract extraction is covered in the following section.

SECONDARY CATARACT A major complication of extracapsular cataract extraction (ECCE) is secondary cataract (also known as after cataract). Posterior capsule opacification (PCO) is the most clinically significant type of secondary cataract and develops in up to 50% of patients between 2 months and 5 years

  TABLE 5-1-2  LEVELS OF DEGRADED POLYPEPTIDES IN WATER-SOLUBLE HIGH-MOLECULAR-WEIGHT PROTEINS OF HUMAN LENSES

390

Donor’s Age (years)

HMW Protein/Lens (mg)

HMW Protein-Associated Degraded Polypeptides/Lens (mg)

HMW Protein as Degraded Polypeptides (%)

16–19

0.16

0.009

5.6

38–39

0.93

0.17

18.2

49–51

2.17

0.255

11.75

55–56

2.2

0.42

19.1

60–80

2.3

0.62

26.9

(Adapted from Srivastava OP, Srivastava K, Silney C. Levels of crystallin fragments and identification of their origin in water soluble high molecular weight (HMW) proteins of human lenses. Curr Eye Res. 1996;15:511–20.)

Fig. 5-1-15  Fibrosis of the posterior capsule. This opacification developed in a 5-year-old child 20 days after extraction of a traumatic cataract (perforation with a knife). No intraocular lens was implanted. (From Rohrbach JM, Knorr M, Weidle EG, Steuhl KP. Nachstar: klinik, therapie, morphologic, and prophylaxe. Akt Augenheilkd. 1995;20:16–23.)

Fig. 5-1-16  Elschnig’s pearls. This opacification developed within 3 years of an extracapsular cataract extraction with implantation of a posterior chamber intraocular lens. (From Rohrbach JM, Knorr M, Weidle EG, Steuhl KP. Nachstar: klinik, therapie, morphologic, and prophylaxe. Akt Augenheilkd. 1995;20:16–23.)

Fibrosis-Type Posterior Capsule Opacification

Residual lens epithelial cells that are still attached to the anterior capsule after ECCE are thought to be the predominant cells involved in the formation of fibrous membranes. Although cases of fibrosis tend to appear within 2–6 months of ECCE, many are clinically insignificant.69 Remnant epithelial cells left on the anterior capsule after surgery differentiate into spindle-shaped, fibroblast-like cells (myofibroblasts), which express α-smooth muscle actin (normally only expressed in smooth muscle cells) and become highly contractile. These fibroblastic cells proliferate and migrate onto the posterior capsule to form a cellular layer that secretes extracellular matrix components and a basal laminalike material. Cellular contraction results in the formation of numerous fine folds and wrinkles in the posterior capsule. At this stage the capsule is only mildly opacified. No significant visual loss occurs until the cells migrate into the visual axis.68, 71 More advanced stages of PCO result from further proliferation and multilayering of cells on the posterior capsule, and are associated with additional extracellular matrix production

5.1 Basic Science of the Lens

after the initial surgery. The frequency of PCO is age related; almost all children develop PCO after ECCE, but in adults the incidence is much lower. This is thought to be because of the higher proliferative capacity of lens epithelial cells in the young compared with the old.68, 69 After ECCE the lens is composed of the remaining capsule and the residual epithelial cells and cortical fibers that were not removed at the time of surgery. The lens epithelial cells still possess the capacity to proliferate, differentiate, and undergo fibrous metaplasia. Migration of these cells toward the center of the previously acellular posterior capsule together with the synthesis of matrix components results in light being scattered, and the associated opacification reduces visual acuity. In the minority of cases, PCO results from the deposition of fibrin and other cell types onto the posterior capsule either at the time of surgery or postoperatively.69 The two morphologically distinct types of PCO are fibrosis and Elschnig’s pearls, which occur independently or in combination. In addition, ECCE procedures may result in the formation of a Soemmering’s ring (Figs 5-1-15–18).69, 70

Fig. 5-1-17  Mixture of Elschnig’s pearls and fibrosis on the posterior capsule. This opacification developed in a 64-year-old woman 2 years after uncomplicated cataract surgery. Note the wrinkling of the posterior capsule. (Courtesy of M Knorr.)

Fig. 5-1-18  Soemmering’s ring. Taken from behind the lens of a human eye obtained postmortem. A three-piece, modified J, polypropylene loop posterior chamber intraocular lens is present. (From Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol. 1992;37:73–116.)

391

5 THE LENS

and the appearance of white fibrotic opacities. The majority of the extracellular matrix produced in the fibrosis-type of PCO is composed of types I and III fibrillar collagen with associated proteoglycans (dermatan sulfate and chondroitin sulfate).72 The basal lamina-like material contains both collagen type IV and heparin sulfate proteoglycan.72 In cases in which the cut edge of the anterior capsule rests on the IOL optic, residual anterior capsular cells may proliferate and extend from this cut edge onto the surface of the IOL, which results in the formation of a membranous outgrowth within approximately 1 week postoperatively.73 Detailed studies using polymethylmethacrylate IOLs have shown that cells do not appear to cover the central part of the optic, and migration onto this optic decreases as the cells in the region of the anterior capsule in contact with the optic undergo fibrous metaplasia and begin to opacify. The cells on the IOL completely disappear within 3 months. It is also possible that cells may migrate around onto the posterior surface of the IOL implant and, therefore, contribute to the formation of PCO. Growth factors present in both the aqueous and the vitreous humors have been implicated in the development of fibrosis-type PCO. These include acidic and basic fibroblast growth factors, insulin-like growth factor-I, epidermal growth factor, platelet-derived growth factor, hepatocyte growth factor, and transforming growth factor-β.

Pearl-Type Posterior Capsule Opacification

The pearls formed in this type of PCO are identical in appearance to Wedl (bladder) cells involved in the formation of posterior subcapsular cataracts. Because Wedl cells are known to originate from equatorial lens epithelial cells, it is believed that residual cells in this region of the capsule are the predominant cells involved in the formation of pearls. The possibility that the residual anterior capsular cells also are involved cannot be excluded completely. Clinically, cases of pearl formation occur somewhat later than those of fibrosis (up to 5 years postoperatively).69 Pearls were first observed by Hirschberg74 in 1901 and then by Elschnig75 in 1911; they now are referred to as Elschnig’s pearls. After ECCE the fiber mass of the lens is no longer present and, as a result, no internal pressure exists. Newly formed lens fibers, therefore, are no longer forced in the anterior and posterior directions, which results in the formation of a mass of cells (normally large and globular, but sometimes spindle shaped), loosely connected and piled on top of each other. Each pearl represents the aberrant attempt of one epithelial cell to differentiate into a new lens fiber, possessing characteristics of both epithelial cells and fibers, and may be embedded in an extracellular matrix. Visual acuity is affected only if the pearls protrude into the center of the posterior capsule and therefore into pupillary space.76–78

Soemmerring’s Ring

Soemmerring first noticed PCO in humans in 1828.79 After ECCE, the cut edge of the remaining anterior capsular flap may attach itself to the posterior capsule within approximately 4 weeks postoperatively, through the production of fibrous tissue. Any residual cortical fibers and epithelial cells, therefore, are trapped within this sealed structure. The equatorial cells still retain the capacity to proliferate and differentiate into lens fibers. The increase in the volume of this lenticular material fills the space between the anterior and the posterior capsule, which results in the formation of a ring that often has the appearance of a string of sausages. Proliferating epithelial cells remain attached to the anterior capsule but also are found to a lesser extent on the posterior capsule, where they form small isolated groups. In some cases the epithelial cells escape from the ring and migrate onto the anterior surface of the anterior capsule. Because the ring forms at the periphery of the lens, vision is not affected.76, 80, 81

Fig. 5-1-19  Posterior capsule following a Nd:YAG laser posterior ­capsulectomy. (From Rohrbach JM, Knorr M, Weidle EG, Steuhl KP. Nachstar: klinik, therapie, morphologic, and prophylaxe. Akt Augenheilkd. 1995;20:16–23.)

Prevention and Treatment of Posterior Capsule Opacification

As yet there is no reliable treatment to prevent PCO and posterior capsulotomy is the treatment of choice when PCO does affect the visual field. A posterior capsulectomy removes the central part of the posterior capsule and therefore instantly improves vision. Although this removal used to be achieved surgically, a neodymium:yttrium–aluminum–garnet (Nd:YAG) laser is now used (Fig. 5-1-19). In a number of patients with posterior segment problems, however, massive proliferation of lens epithelial remnants has been observed within months of the capsulectomy. As a result of this proliferation, the size of the capsulectomy decreases, which may in turn reduce visual acuity. It has been postulated that this occurs because of “activation” of the cells, the release of growth factors from the vitreous humor, the direct stimulation of proliferation, or a combination of these factors.82 Removal of the barrier between the posterior chamber and the vitreous cavity increases the risk of complications such as cystoid macular edema, retinal detachment, uveitis, and secondary glaucoma.69 The implantation of a posterior chamber IOL into the capsular bag after ECCE is known to reduce the likelihood that a patient will develop PCO, because the IOL acts as a barrier to the migration of cells around and into the center of the posterior capsule. Posterior convex or biconvex optics sit in the capsular bag with their posterior surface firmly against the posterior capsule. As a result this capsular surface is stretched radically and flattened, so there should be no room for the cells to pass this mechanical barrier and migrate into the center of the posterior capsule. Barrier-ridge optics have a rim on the posterior surface of the IOL, which also should create a barrier to migrating cells. Migration also has been shown to be dependent on the implant biomaterial. Trials have shown that the posterior capsules of patients who were given polyacrylic (AcrySof) implants were significantly clearer 2 years after implantation than the posterior capsules of those given polymethylmethacrylate or silicone implants. Lens epithelial cells also have been shown to regress in eyes implanted with polyacrylic IOLs.83

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62. Phelps Brown N, Bron AJ. Accommodation and   presbyopia. In: Phelps Brown N, Bron AJ, Phelps   Brown NA, eds. Lens disorders: a clinical manual of cataract diagnosis, Oxford: Butterworth-Heinemann; 1996:48–52. 63. Hemenger RP, Garner LF, Ooi CS. Change with age of the refractive index gradient of the human ocular lens. Invest Ophthalmol Vis Sci. 1995;36:703–7. 64. Rathbun WB, Murray DL. Age-related cysteine uptake as rate-limiting in glutathione synthesis and glutathione half-life in the cultured human lens. Exp Eye Res. 1991;53:205–12. 65. Srivastava OP, Srivastava K, Silney C. Levels of crystallin fragments and identification of their origin in water soluble high molecular weight (HMW) proteins of human lenses. Curr Eye Res. 1996;15:511–20. 66. Yang Z, Chamorro M, Smith DL, Smith JB. Identification of the major components of the high molecular weight crystallins from old human lenses. Curr Eye Res. 1994;13:415–21. 67. Lerman S. Composition and formation of the insoluble protein fraction in the ocular lens. Can J Ophthalmol. 1970;5:152–9. 68. Green WR, McDonnell PJ. Opacification of the posterior capsule. Trans Ophthalmol Soc UK. 1985;104:727–39. 69. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol. 1992;37:73–116. 70. Rohrbach JM, Knorr M, Weidle EG, Steuhl KP. Nachstar: klinik, therapie, morphologie und prophylaxe. Akt Augenheilkd. 1995;20:16–23. 71. McDonnell PJ, Stark WJ, Green WR. Posterior capsule opacification: a specular microscopic study. Ophthalmology. 1984;91:853–6. 72. Ishibashi T, Araki H, Sugai S, et al. Detection of proteoglycans in human posterior capsule opacification. Ophthalmic Res. 1995;27:208–13. 73. Pande MV, Spalton DJ, Marshall J. In vivo human lens epithelial cell proliferation on the anterior surface   of PMMA intraocular lenses. Br J Ophthalmol. 1996;80:469–74. 74. Hirschberg J. Einführung in die Augenheilkunde. II.   Hälkft I Abt. Leipzig: Themie; 1901:159. 75. Elschig A. Klinisch-anatomischer Beitrag zur Kenntnis des Nachstares. Klin Monatsbl Augenkeilkd. 1911;49:444–51. 76. Kappelhof JP, Vrensen GFJM. The pathology of aftercataract. Acta Ophthalmol. 1992;70(Suppl 205):13–24. 77. Sveinsson O. The ultrastructure of Elschnig’s pearls in a pseudophakic eye. Acta Ophthalmol. 1993;71:95–8. 78. Kappelhof JP, Vrensen GFJM, de Jong PTVM, et al. An ultrastructural study of Elschnig’s pearls in the pseudophakic eye. Am J Ophthalmol. 1986;101:58–69. 79. Soemmering DW. Beobachtungen von die organischen Veränderungen in Auge nach Staaroperationen. Frankfurt: Wesche; 1913. 80. Kappelhof JP, Vrensen GFJM, de Jong PTVM, et al. The ring of Soemmering in man: an ultrastructural study. Graefes Arch Klin Exp Ophthalmol. 1987;225:77–83. 81. Jongebloed WL, Dijk F, Kruis J, Worst JGF. Soemmering’s ring, an aspect of secondary cataract: a morphological description by SEM. Doc Ophthalmol. 1988;70:165–74. 82. Jones NP, McLeod D, Boulton ME. Massive proliferation of lens epithelial remnants after Nd-YAG laser capsulotomy. Br J Ophthalmol. 1995;79:261–3. 83. Pande M, Ursell PG, Spalton DJ. Lens epithelial cell regression on the posterior capsule with different intraocular lens materials. Br J Ophthalmol. 1998;82:1182–8.

5.1 Basic Science of the Lens

14. Phelps Brown N, Bron AJ. Lens growth. In: Phelps Brown N, Bron AJ, Phelps Brown NA, eds. Lens disorders. A   clinical manual of cataract diagnosis, Oxford: ButterworthHeinemann; 1996:17–31. 15. Harding JJ, Rixon KC, Marriott FHC. Men have heavier lenses than women of the same age. Exp Eye Res. 1977;25:651. 16. Cook CA, Koretz JF, Pfahnl A, et al. Aging of the ­human crystalline lens and anterior segment. Vision Res. 1994;34:2945–54. 17. Patterson JW. Characterization of the equatorial current of the lens. Ophthalmic Res. 1988;20:139–42. 18. Lerman S. Lens transparency and aging. In: Regnault F, Hockwin O, Courtios Y, eds. Ageing of the lens, Amsterdam: Elsevier/North-Holland Biomedical Press; 1980:263–79. 19. Zigman S. Photochemical mechanisms in cataract formation. In: Duncan G, ed. Mechanisms of cataract formation in the human lens, London: Academic Press; 1981:117–49. 20. Duke-Elder S. The refraction of the eye – physiological optics. In: Abrams D, ed. The practice of refraction, 10th ed. Edinburgh: Churchill Livingstone; 1993:29–41. 21. de Jong WW, Lubsen NH, Kraft HJ. Molecular evolution of the eye lens. Prog Retina Eye Res. 1994;13:391–442. 22. Bennett AG, Rabbetts RB. Ocular aberrations. Clinical visual optics, 2nd ed.. London: Butterworths; 1989:331–57. 23. Elkington AR, Frank HJ. Aberrations of optical systems including the eye. Clinical optics, 2nd ed. Oxford:   Blackwell Scientific; 1991:75–82. 24. Moore DC. Geometric optics. In: Coster DJ, ed. Physics for ophthalmologists. Edinburgh: Churchill Livingstone; 1994:29–34. 25. Duke-Elder S. Accommodation. In: Abrams D, ed. The practice of refraction, 10th ed.. Edinburgh: Churchill Livingstone; 1993:85–9. 26. Fisher RF. The ciliary body in accommodation. Trans Ophthalmol Soc UK. 1986;105:208–19. 27. Kador PF. Biochemistry of the lens: intermediary metabolism and sugar cataract formation. In: Albert DM, Jakobiec FA, eds. Principles and practice of ophthalmology. Basic sciences, Philadelphia: WB Saunders; 1994:146–67. 28. Harding JJ, Crabbe MJC. The lens: development, proteins, metabolism and cataract. In: Davson H, ed. The eye.   3rd ed.. London: Academic Press; 1984:207–492. 29. Berman ER. Lens. In: Blakemore C, ed. Biochemistry of the eye. New York: Plenum Press; 1991:201–90. 30. Bassnett S. The fate of the Golgi apparatus and the endoplasmic reticulum during lens fiber cell differentiation. Invest Ophthalmol Vis Sci. 1995;36:1793–803. 31. Harding J. The normal lens. In: Harding J, ed. Cataract: biochemistry, epidemiology and pharmacology, London: Chapman & Hall; 1991:1–70. 32. Reddy VN. Glutathione and its functions in the lens – an overview. Exp Eye Res. 1990;50:771–8. 33. Kannan R, Yi JR, Zlokovic BV, Kaplowitz N. Molecular characterization of a reduced glutathione transporter in the lens. Invest Ophthalmol Vis Sci. 1995;36:1785–92. 34. Augusteyn RC. Protein modification in cataract. In: Duncan G, ed. Mechanisms of cataract formation in the human lens, London: Academic Press; 1981:72–115. 35. Lerman S. Free radical damage and defense mechanisms in the ocular lens. Lens Eye Toxic Res. 1992;9:9–24. 36. Costarides AP, Riley MV, Green K. Roles of catalase and the glutathione redox cycle in the regulation of anterior-chamber hydrogen peroxide. Ophthalmic Res. 1991;23:284–94. 37. Sasaki H, Giblin FJ, Winkler BS, et al. A protective role for glutathione-dependent reduction of dehydroascorbic acid in lens epithelium. Invest Ophthalmol Vis Sci. 1995;36:1804–17.

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PART 5 THE LENS

5.2

Evolution of Intraocular Lens Implantation Liliana Werner, Andrea M. Izak, Robert T. Isaacs, Suresh K. Pandey and David J. Apple

Introduction Cataract is the most prevalent ophthalmic disease. For 1998 the number of persons blind as a result of cataract was estimated to be about 20 million worldwide; this number was expected to double by early in the twenty-first century.1, 2 Although a pharmacological preventive or therapeutic treatment for this blinding disease is being sought actively, the solution still appears to be many years away. Therefore, surgical treatment for cataracts, which increasingly includes intraocular lens (IOL) implantation, remains the only viable alternative. Treatment of cataracts has been practiced for centuries using various surgical and nonsurgical procedures. However, avoidance of complications and attainment of high-quality postoperative visual rehabilitation in the years before the introduction of modern IOLs were difficult problems. Because significant dioptric power resides in the crystalline lens, its removal results in marked visual disability. Aphakic spectacle correction has been prescribed throughout history, but spectacles are less than satisfactory because of the visual distortions inherent in such high-power lenses. It was not until the late 1940s that the tremendous optical advantages that an IOL could provide in visual rehabilitation were understood and acted upon by Harold Ridley.3–7 The implantation of IOLs is now a highly successful operation; the safety and efficacy of the procedure are now well established. For 1998 the number of IOL implants in the United States was estimated to be 1.6 million. Implantation data from other countries are scant, but the total number of implantations per year worldwide is increasing rapidly. Studies are still needed to determine which surgical technique(s) and which IOL design(s) are safest, most practical, and most economic for high-volume use in the less advantaged areas of the world. For general discussions that review the evolution and provide clinicopathologic overviews of IOLs, see Apple et al.7–10 and Binkhorst.11 Posterior chamber IOLs, following a long period of disfavour after the Ridley lens was discontinued, were reintroduced in the mid-1970s and early 1980s. Jaffe and other authors compared posterior chamber lenses with iris-supported lenses and were impressed by the superior results achieved with the former type of lens using an extracapsular cataract extraction technique. The use of posterior chamber IOLs is now clearly the treatment of choice.

Generation I (Original Ridley Posterior Chamber Lens)

A practical application of the concept of IOLs began with Harold Ridley,3–7 and credit for the introduction of lens implants clearly belongs to him. Ridley’s first IOL operation was performed on a 49-year-old woman at St Thomas’ Hospital in London on November 29, 1949. His ori­ ginal IOL was a biconvex polymethyl methacrylate (PMMA) disc designed to be implanted after extracapsular cataract extraction (ECCE) (Fig. 5-2-1). Ridley’s procedure was initially met with great hostility by several skeptical and critical ophthalmologists. However, good results were ­attained in enough cases to warrant further implantation of the ­Ridley IOL, although dislocation of the lens ultimately proved troublesome.

   Table 5-2-1 The Evolution of Intraocular Lenses Generation

Date

Description

I

1949–1954

Original Ridley posterior chamber lens

II

1952–1962

Early anterior chamber lenses

III

1953–1975

Iris-supported lenses

IV

1963–1990

Intermediate anterior chamber lenses

V

1975–1990

Improved posterior chamber lenses

VI

1990 to present

Modern capsular posterior chamber lenses and modern anterior chamber lenses

Lens Design and Fixation

394

In 1967 Binkhorst11 proposed a detailed classification of the various means of fixation for each IOL type. In a 1985 update of this classification, Binkhorst12 listed four IOL types according to fixation sites: l Anterior chamber angle-supported lenses; l Iris-supported lenses; l Capsule-supported lenses; and l Posterior chamber angle (ciliary sulcus)-supported lenses. By common agreement, most surgeons today differentiate lens types as follows: l Iris-supported lenses; l Anterior chamber lenses; and l Posterior chamber lenses. From the time of Ridley’s first lens implantation to the present day, the evolution of IOLs can be arbitrarily divided into six generations (Table 5-2-1).

Fig. 5-2-1  Posterior view of an eye (obtained postmortem) showing the implantation site of a Ridley lens. To the time of death, almost 30 years after implantation, the patient’s visual acuity remained 20/20 (6/6) in both eyes. Note the good centration and clarity of the all-polymethyl methacrylate optic in the central visual axis. The lens was implanted by Dr. W. Reese and Dr. T. Hammdi of Philadelphia.

It is gratifying to note that Ridley, who died in 2001, lived long enough to experience the acknowledgment, respect, and honor he so fully deserved for this innovation. As a consequence of the relatively high incidence of dislocations with the Ridley lens, a new implantation site was considered − the anterior chamber, with fixation of the lens in the angle recess. The anterior chamber was chosen because less likelihood existed of dislocation within its narrow confines. In addition, anterior chamber lenses could be implanted ­after either an intracapsular cataract extraction (ICCE) or an ECCE. Also, anterior chamber placement of the pseudophakos was considered a simpler technical procedure than placement of the lens behind the iris. Although many surgeons worked on the concept of this type of lens, Baron, in France, is generally credited as being the first designer and ­implanter of an anterior chamber lens (Fig. 5-2-2A).10 He first performed this procedure on May 13, 1952. Late endothelial atrophy, corneal decompensation, and pseudophakic bullous keratopathy were observed with the original Baron lens and also developed with many subsequent anterior chamber lens designs. The entity now termed uveitis−glaucoma−hyphema (UGH) syndrome was described first when ocular tissue damage occurred that was clearly the result of poorly manufactured anterior chamber lenses.13 It took many modifications of the haptic-loop configuration and the lens-vaulting characteristics (see Fig. 5-2-2B) to develop an

Generation III (Iris-Supported Lenses)

Relatively frequent dislocation of the Ridley lens and an unacceptably high rate of corneal decompensation associated with the anterior chamber lenses available in the early 1950s caused some surgeons to discontinue implantation of IOLs entirely.14 However, iris-supported or iris-fixated IOLs were introduced subsequently in an attempt to overcome these problems. Cornelius Binkhorst in The Netherlands was an early advocate of iris-supported IOLs.11, 12 His first lens was a four-loop, iris-clip IOL (Fig. 5-2-3A) design. Although Binkhorst initially believed that IOL contact with the iris would not cause problems, he soon noted that iris chafing, pupillary abnormalities, and dislocation developed with the early irisclip lens. Also, in an effort to circumvent dislocation, Binkhorst made the anterior loops of his four-loop lens longer, but this led to increased corneal decompensation from peripheral touch. His initial implantations were done after ICCE, but occasionally he implanted his four-loop lens following ECCE. His positive experience with this procedure prompted him to modify his iris-clip lens design for implantation following ECCE. Binkhorst’s change from ICCE to ECCE and the introduction of his two-loop iridocapsular IOL (see Fig. 5-2-3B) in 1965 were important advances in both IOL design and mode of

5.2 Evolution of Intraocular Lens Implantation

Generation II (Early Anterior Chamber Lenses)

anterior chamber lens that allowed a reasonable prediction of longterm success. This was achieved largely because of the advances in lens design by Dr. Peter Choyce of England and later by Dr. Charles Kelman of New York.

ANTERIOR CHAMBER LENSES Original 1952 Baron lens

Modern anterior chamber lens

A

B

Fig. 5-2-2  Sagittal section of the anterior segment of the eye. (A) The original 1952 Baron anterior chamber lens, with fixation in the angle recess. Because this one-piece lens was rigid, sizing problems were unavoidable. Note the extremely steep anterior curvature of the lens. Such excessive anterior vaulting invariably caused corneal endothelial problems. (B) Placement of a modern anterior chamber lens fixated in the angle recess. Note the more subtle anterior vaulting of the loops and lens optic.

A

B

Fig. 5-2-3  Binkhorst iris-clip lenses. (A) A correctly positioned Binkhorst four-loop, iris-clip lens, well centered in an eye that had good visual acuity. Moderate pupillary distortion and sphincter erosion occur. Note the iris-fixation suture superior to the site of the large iridectomy. (B) Posterior view of an autopsy globe that contains a two-loop iridocapsular intraocular lens. Note the rod that helps to secure the lens to the iris through the iridectomy. An outer Soemmering ring is present, but the visual axis remains clear. The optic is well centered.

395

5 THE LENS

fixation.15 His and others’ experiences with the two-loop lens style and its modifications were influential in the development of modern design concepts of IOLs, including capsular-bag fixated, posterior chamber IOLs. Binkhorst’s innovative lens designs and his advocacy of ECCE came at a time when the entire future of IOL implantation was in jeopardy; they provided the major impetus that set the stage for modern posterior chamber lens implantations. During the early years of iris-fixated IOLs, many clinical and subclinical problems emerged, such as dislocation, pupillary deformity and erosion, iris atrophy with transillumination defects, pigment dispersion, uveitis, hemorrhage, and opacification of the media. Many of these complications were the result of chronic rubbing or chafing of the iris by IOL loops or haptics. Problems were especially severe with metal loop IOLs and also occurred frequently with multiple-looped lenses because uveal contact and chafing against the mobile iris tissues were unavoidable with these designs. An increased incidence of corneal edema occurred in association with iris-supported lens designs. Corneal decompensation and pseudophakic bullous keratopathy became major indications for penetrating keratoplasty. The well-known coexistence of pseudophakic bullous keratopathy and cystoid macular edema (CME) has been termed corneal-retinal inflammatory syndrome by Obstbaum and Galin.16 Binkhorst’s return to ECCE, with the introduction of his two-loop iridocapsular lens in 1965 (see Fig. 5-2-3B),17 brought about an almost immediate reduction in the incidence of many of these complications. Most iris-supported lenses were biplanar, with the optic placed in front of the pupil. In general, biplanar IOLs required a larger limbal wound opening for insertion. The change to capsular fixation after ECCE provided better stability for the pseudophakos. This important modification was a forerunner to capsular sac (in-the-bag) fixation of modern posterior chamber IOLs. At the time when iris-supported lenses were in widespread use, and until the mid-1980s in many cases, manufacturing methods and surgical techniques were less sophisticated. It is now clear that most modern, high-quality anterior and posterior chamber IOLs provide better success than the IOLs that depend on the iris for support. At present, it is the consensus of surgeons that when a patient who has an iris-supported IOL develops late complications, such as inflammation or corneal decompensation that does not respond rapidly to conservative therapy, lens explantation and/or exchange is usually the best treatment.

Generation IV (Intermediate Anterior Chamber Lenses)

396

While iris-supported IOLs underwent major modifications in the early 1950s up to the beginning of the 1980s, several designs of anterior chamber IOLs were introduced. The problems of tissue chafing and difficulties in correct sizing associated with rigid IOLs were addressed by the development of anterior chamber lenses with more flexible loops or haptics (Box 5-2-1). Unlike the ill-fated, nylon-looped lenses introduced by Dannheim in the early 1950s, the fixation elements of these anterior chamber IOLs were made from more stable polymers, usually PMMA and polypropylene. The best lenses were the various rigid18 and flexible, open-loop, onepiece PMMA designs, such as the three- and four-point fixation Kelman IOLs.19 Modifications of the latter have been in use since the late 1970s and are the styles most commonly implanted today (Fig. 5-2-4). These lenses now are well designed, correctly vaulted, and properly sized and can provide excellent long-term results. As with the early generation of anterior chamber IOLs, new lens designs included both haptic (footplate) fixation lenses and small-diameter, round-looped IOLs. Although in the 1950s implantations with early anterior chamber IOLs were often disappointing, some models of anterior chamber lenses provided good success, particularly when the lens was properly sized. Two important factors that led to an improved success rate with ­anterior chamber IOL use are: l Improved lens designs; and l Improved manufacturing techniques. More appropriate lens flexibility has decreased the need for perfect sizing. Increased attention has been given to the anterior-posterior vaulting characteristics of IOLs, which has reduced the incidence of intermittent touch and uveal chafing problems. Design flaws in older lens styles have been identified and these lenses removed from the market in the United States. Tumble polishing of IOLs, ­particularly one-piece, all-PMMA lenses, produces excellent surfaces

Box 5-2-1 Anterior Chamber Lenses Disadvantages of Closed-Loop Anterior Chamber Lenses Lenses may be difficult to size Lenses may have inappropriate vault–compression ratios; when a lens is compressed, it may vault anteriorly or posteriorly − either type of response can cause deleterious effects Small-diameter loops may cause a “cheese-cutter” effect, particularly if the lens is too large; subsequent erosion and chafing can cause uveitis, including cystoid macular edema and pseudophakic bullous keratopathy Some lenses have a large contact zone over broad areas of the angle with the potential for secondary glaucoma The poorly finished, sharp edges of some lens models can cause chafing, which leads to sequelae such as uveitis or the uveitis– glaucoma–hyphema syndrome Synechiae formation around the small-diameter loops may make the lens difficult to remove when necessary; tearing of ocular tissues, hemorrhage, and iridocyclodialysis are possible complications of intraocular lens removal if correct procedures are not used Advantages of Modern, Open-Loop, One-Piece, All-Pmma Flexible Anterior Chamber Lenses Most modern lenses have an excellent finish with highly polished smooth surfaces and rounded edges from tumble polishing; tissue contact with any component of these intraocular lenses is much less likely to result in chafing damage Sizing is less critical with flexible, open-loop designs In contrast to a closed-loop anterior chamber intraocular lens, the vault (a well-designed, open-loop lens) is maintained even under high compression – this minimizes intraocular lens touch against the cornea anteriorly, or against the iris posteriorly Point fixation is possible, since the haptic may subtend only small areas of the angle outflow structures Most open-loop intraocular lens designs are much easier to remove, when necessary, especially those with Choyce-like haptic or footplate fixation; the well-polished surfaces of these lenses usually do not become completely surrounded by goniosynechiae or cocoon membranes, and, therefore, can usually be removed if necessary without undue difficulty or excessive tissue damage

and edges. The elimination of sharp optic or haptic edges is critical in the ­production of anterior chamber IOLs. This is true even more so than for posterior chamber IOLs because anterior chamber IOLs are fixated in a confined space directly adjacent to delicate anterior ­segment tissues. The two major disadvantages of an anterior chamber IOL, as compared with posterior chamber lens styles, are: l The close proximity of the haptics or loops to delicate tissues such as the trabecular meshwork, corneal epithelium, angle recess, and anterior iris surface; and l The difficulty often encountered in IOL sizing, particularly with rigid lens designs. The close proximity of anterior chamber lens components to the corneal endothelium is an obvious disadvantage because of the ­potential for corneal decompensation and/or pseudophakic bullous keratopathy as a result of contact of the cornea with the IOL. In the past, the most common causes of pseudophakic bullous keratopathy were related to anterior chamber IOLs that were sized incorrectly, vaulted too steeply, or designed with an inappropriate amount of ­flexibility.20 Haptics or spatula-like footplates are one of the two types of fixation elements used for anterior chamber IOLs. Haptics or footplates, popularized by Peter Choyce, are often likened to the flattened portion of a spatula and were used originally with the more rigid IOL styles. They now are used with both rigid and flexible modern anterior chamber IOLs. When IOL removal is necessary for any reason, the footplate generally slides out of the eye much more easily than does a smalldiameter loop and with minimal tissue damage. Small-diameter lens loops are the second type of fixation ­element for anterior chamber IOLs. Loops may be of either an open or a closed ­design. Round, small-diameter, closed loops may cause a “cheese-­cutter”

5.2

Fig. 5-2-4  Modern one-piece, all-polymethyl methacrylate, Kelman-style anterior chamber lenses of four-point and three-point fixation designs. Note the excellent polishing and tissue-friendly Choyce-Kelman style footplates. These represent modern, state-of-the-art lenses that should be distinguished clearly from the earlier, unsatisfactory, closed-loop anterior chamber lenses.

effect within the eye and difficulty with removal. A 360° fibrouveal encapsulation, or “cocoon,” often forms around such small-diameter, round loops as the loops become embedded in the tissues of the angle recess. If the correct explantation procedure is not used, these adhesions may result in tissue tears, hemorrhage, and iridocyclodialysis. These anterior chamber IOLs,21–25 often generically classified together as “closed-loop lenses,” do not provide the safety and efficacy achieved by other anterior chamber lens designs, such as finely polished, flexible, one-piece, all-PMMA lenses (see Fig. 5-2-4). By 1987 the Food and Drug Administration had placed IOLs of the closed-loop design on core investigational status. This had the effect of removing them from the market in the United States, although it did not prevent the export of such lenses. The flexible, open-loop designs,24–28 modifications of the original Kelman anterior chamber IOLs (with Choyce-style footplates), can be well finished using tumble polishing, which provides a rounded, ­ “tissue-friendly” surface at points of haptic contact with delicate uveal tissues. One-piece IOLs, particularly those with a footplate design, are usually much easier to explant than IOLs with round, small-diameter loops, of either closed-loop or open-loop design. Iris- or scleral-fixated, sutured posterior chamber IOLs may be used in cases formerly reserved for anterior chamber IOLs. Results are ­encouraging.29, 30 Uncertainty still exists as to whether a retropupillary lens is superior to a modern, well-manufactured, Kelman-style anterior chamber IOL for cases such as intraoperative capsular rupture or vitreous loss or as a secondary or exchange procedure. The technique is more difficult than insertion of a single anterior chamber lens and should, therefore, be carried out only by an experienced surgeon.

Generation V (Improved Posterior Chamber Lenses)

The return to Harold Ridley’s4–7 original concept of IOL implantation in the posterior chamber occurred after 1975. John Pearce31 of England implanted the first uniplanar posterior chamber lens since Ridley.32 It was a rigid tripod design with the two inferior feet implanted in the capsular bag and the superior foot implanted in front of the ­anterior capsule and sutured to the iris. Steven Shearing33 of Las Vegas introduced a major lens design breakthrough in early 1977 with his posterior chamber lens. The design consisted of an optic with two flexible J-shaped loops. William Simcoe of Tulsa publicly introduced his C-looped posterior chamber lens shortly after Shearing’s J-loop design appeared. Eric Arnott of London was an early advocate of one-piece, allPMMA posterior chamber IOLs. The flexible open-loop designs (J-loop, modified J-loop, C-loop, or modified C-loop) still account for the largest number of IOL styles available today (Fig. 5-2-5).

Evolution of Intraocular Lens Implantation

A

B

Fig. 5-2-5  View from behind of an autopsy eye. (A) A Sinskey-style, J-loop posterior chamber intraocular lens implanted within the lens capsular bag. The optic is well centered, the visual axis is clear, and there is only minimal regeneration of cortex in scattered areas. Moderate haziness or opacity occurs at the margins of the anterior capsulotomy, which does not encroach on the visual axis. (B) The placement of the loop of this modified C-style intraocular lens in the capsular bag.

One obvious major theoretical advantage that a posterior chamber IOL has over an anterior chamber IOL is its position behind the iris, away from the delicate structures of the anterior segment. As posterior chamber lens implantation evolved, the type of fixation achieved in the early years depended largely on chance or on the surgeon’s individual preference. As Figure 5-2-6 illustrates, several loopfixation sites are possible with modern, flexible-loop posterior chamber IOLs. In general, the loops were anchored in one of three ways: l Both loops were placed in the ciliary region; l Both loops were placed within the lens capsular sac; or l O ne loop (usually the leading or inferior loop) was placed in the capsular sac and the other loop (usually the trailing or superior loop) in a variety of locations anterior to the anterior capsular flap. These fixation sites have been confirmed histologically by analyses of postmortem globes implanted with posterior chamber IOLs. The return to posterior chamber lenses coincided with the development of improved ECCE surgery. Shearing33 identified four major milestones that have marked the evolution of ECCE surgery: l Microscopic surgical techniques; l Phacoemulsification; l Iridocapsular fixation; and l Flexible posterior chamber lenses.

397

5

POSSIBLE PLACEMENT SITES OF POSTERIOR CHAMBER LENS LOOPS

THE LENS 3 5

1

2

4 6

7

8 Site 1: loop in the ciliary sulcus. Site 2: loop after erosion into the ciliary body stroma in the region of the major iris arterial circle. Site 3: loop in contact with the iris root. Site 4: loop attached to a ciliary process. Site 5: loop in aqueous without tissue contact (can result in ‘windshield wiper’ syndrome because of inadequate fixation). Site 6: loop in the lens capsular sac. Site 7: loop ruptured through the lens capsular sac (a rare occurrence). Site 8: loop in the zonular region between the ciliary sulcus and the lens capsular sac. The loop may penetrate the zonules (zonular fixation) or extend as far posteriorly as the pars plana (pars plana fixation).

Fig. 5-2-6  The possible placement sites of posterior chamber lens loops.

398

Without microscopic surgery, modern IOL implantation would be far more difficult. Although phacoemulsification was promoted originally because it required only a small wound, it became clear that if an IOL were to be inserted, the wound would have to be enlarged after removal of the cataract, and thus nonultrasonic surgical methods were refined. By 1974, implantation of IOLs again began to achieve significant ­acceptability. A natural marriage between phacoemulsification and implantation of IOLs occurred. As noted previously, Cornelius Binkhorst11, 12, 17 was one of the pioneers in the return to the ECCE procedure. Binkhorst recognized that an intact posterior capsule enhanced stability, and he also recognized the many advantages of IOL implantation within the capsular sac. ­Evidence continues to accumulate that CME and retinal detachment occur less frequently with ECCE than with ICCE. The introduction of flexible posterior chamber lenses designed to be implanted following ECCE largely resolved the debate about ECCE ­versus ICCE clearly in favor of the extracapsular procedure. Securing both loops in the lens capsular sac is the only type of fixation in which IOL contact with uveal tissues is avoided.34 Placement of a lens with one or both loops outside the capsular bag is associated with various potential complications, including decentration and uveal erosion.34, 35 The consequences of uveal touch have been learned after experiences with the earlier iris-fixated IOLs. The excellent success rate now achieved with posterior chamber IOL implantation is associated with improved IOL designs and improved surgical techniques, including the meticulous placement of loops (Box 5-2-2). Posterior capsule opacification (PCO; Elschnig pearls, secondary or after cataract) is a significant postoperative complication in IOL implantation. A well-designed posterior chamber lens in the lens capsular sac provides a gentle but taut radial stretch on the posterior capsule. Of the present open-loop flexible IOLs, the one-piece, all-PMMA posterior chamber designs with posterior convex or biconvex optics appear to be especially effective in providing a symmetrical stretch. Symmetrical stretch may help minimize PCO, as it reduces the folds in the capsular sac and holds the posterior capsule firmly against the posterior surface of the IOL optic. This is sometimes termed the “no space, no cells” concept. The quality of surgery and the accuracy of loop placement are important factors that affect the outcome of the cataract operation. Two very

Box 5-2-2 Advantages of Placing Both Loops in the Lens Capsular Sac Intraocular lens is positioned in the proper anatomical site Both loops can be placed symmetrically in the capsular sac as easily as in the ciliary sulcus Intraoperative stretching or tearing of zonules by loop manipulations in front of the anterior capsular leaflet is avoided Low incidence of lens decentration and dislocation No evidence of spontaneous loop dislocation Intraocular lens is positioned a maximal distance behind the cornea Intraocular lens is positioned a maximal distance from the posterior iris pigment epithelium, iris root, and ciliary processes Iris chafing (caused by postoperative pigment dispersion into the anterior chamber) is reduced No direct contact by, or erosion of, intraocular lens loops or haptics into ciliary body tissues Chronic uveal tissue chafing is avoided, and the probability of long-term blood–aqueous barrier breakdown is reduced Surface alteration of loop material is less likely Intraocular lens implantation is safer for children and young individuals Posterior capsular opacification may be reduced Intraocular lens may be easier to explant, if necessary

helpful tools are available to surgeons that make precise loop or haptic placement possible: l Ophthalmic visco-surgical devices (OVDs); and l New methods to control the size, shape, and quality of the anterior capsulotomy. The intercapsular (envelope) technique and its successor, circular continuous tear capsulorrhexis, greatly increase the ability to achieve accurate and permanent loop placement.

Generation VI (Modern Capsular Lenses − Rigid PMMA, Soft Foldable, and Modern Anterior Chamber)

By the end of the 1980s clinical laboratory studies demonstrated clearly that cataract surgical techniques and IOL design and manufacture had shown remarkable advances.36–40 Surgical technique and IOL design and manufacture had advanced to a point at which the older techniques gave way to more modern ones that allowed consistent, secure, and permanent in-the-bag (capsular) fixation of the pseudophakos. A marriage between IOL design and improved surgical techniques has evolved into capsular surgery. The “capsular” IOLs are fabricated from both rigid and soft biomaterials. The many changes in surgical techniques that occurred after 1980 and into the 1990s include the introduction of OVDs,40–43 increased awareness of the advantages of in-the-bag fixation, the introduction of continuous curvilinear capsulorrhexis (CCC)44–51 (Fig. 5-2-7), hydrodissection52 (Fig. 5-2-8), and the increased use of phacoemulsification. This has allowed not only much safer surgery but also implantation through a smaller incision than was possible in the early days of extracapsular extraction. The evolution from can opener toward capsulorhexis (see Fig. 5-2-7) was initiated by Binkhorst, who developed a two-step (envelope) technique that eventually evolved into the single-step CCC. Two clear advantages of CCC exist over the early can-opener techniques. First, the formation of radial tears (Fig. 5-2-9) is reduced,47 which minimizes radial tears of the anterior capsule; these reduce the stability of the ­capsular bag and may allow prolapse of haptics out of the capsular bag through the anterior capsular tear. Second, and less commonly recognized, capsulorhexis provides a stable capsular bag that allows copious hydrodissection, which in turn is very helpful in cortical cleanup. With a frayed, emptier capsular edge, such as seen with the can-opener technique, hydrodissection is difficult without forming unwanted radial tears. Hydrodissection (see Fig. 5-2-8) was a term coined by Faust52 in 1984. This technique, and the many variations thereof (e.g., cortical cleavage hydrodissection, hydrodelineation), makes the surgery much simpler in that mobilization and removal of cells and cortical material

5.2

Fig. 5-2-8  Surgeon’s view (cornea and iris removed) of a human eye (obtained postmortem) showing experimental hydrodissection. In this case the cannula is placed immediately under the anterior capsule (cortical cleavage hydrodissection). Hydrodissection is one of the most important maneuvers to help reduce the incidence of posterior capsular opacification.

are rendered much easier. The long-term risk of PCO is, in turn, clearly minimized because of the more thorough removal of cells in cortical material, especially in the region of the equatorial fornix. Modern phacoemulsification, pioneered by Charles Kelman, has now made possible the removal of lens material through small incisions and the implantation of IOLs through incisions down to 3 mm in length, as opposed to incisions of 11–12 mm length in the early days of ECCE. Many real advantages of small-incision cataract surgery exist, including safer healing (with fewer risks of complications such as inflammation), more rapid healing, and rapid recovery of visual rehabilitation (with less postoperative astigmatism). In accompaniment with the developments of surgical techniques that allow secure in-the-bag implantation, IOLs have evolved that work well with these techniques − both rigid PMMA designs (Figs 5-2-10 and 5-2-11) and foldable IOLs.53 Figure 5-2-10 shows an example of a modern, state-of-the-art, one-piece, all-PMMA IOL that is designed for in-the-bag implantation. These can be inserted through incisions as small as 5.5–6 mm in length and provide an excellent alternative for the surgeon who finds the almost 50-year history of PMMA as a lens biomaterial of comfort. Long-term results with these IOLs are excellent and, indeed, these lenses provide slightly better centration than do some of the more modern foldable lenses at the present time. The ideal diameter for a one-piece IOL design such as that in Fig. 5-2-10 is 12–12.5 mm, which allows it to fit perfectly into the capsular bag (which measures about 10.5 mm in diameter). The diameter of the

Fig. 5-2-9  Surgeon’s view of an experimentally performed can-opener capsulectomy, with typical radial tears to the equator of the anterior capsule. The cornea and iris are removed from a human eye, obtained postmortem. Following clinical can-opener anterior capsulectomy, one to five radial tears ­invariably occur. (Reproduced with permission from Assia EI, Apple DJ, Tsai JC, Lim ES. The elastic properties of the lens capsule in capsulorrhexis. Am J Ophthalmol. 1991;111:628−32.)

Evolution of Intraocular Lens Implantation

Fig. 5-2-7  Surgeon’s view (cornea and iris removed) of a porcine eye showing the capsulorrhexis procedure. Notice the smooth edges of the anterior capsular tear, which is the key feature of this procedure.

Fig. 5-2-10  A modern, one-piece, all-PMMA, capsular IOL implanted experimentally in a human eye: posterior view (Miyake technique) of the eye (obtained postmortem). Note the excellent centration and a perfect fit within the capsular bag.

c­ iliary sulcus is only slightly larger (approximately 11.0 mm)53 and ­actually decreases with age. These rigid PMMA IOL designs have been found to be very satisfactory in pediatric IOL implantation.54, 55 As 90% of the growth of the infantile globe occurs during the first 18 months to 2 years (Fig 5-2-12), it is fair to assume that “adult” 12 mm lenses can be safely implanted in children this age and older, with the achievement of good results (Figs 5-2-12 and 5-2-13). The problem in the past with IOL implantation has been that of PCO. With present techniques, this is best prevented using primary posterior capsulectomy. Improved small-incision surgical techniques and IOL designs have resulted in a natural evolution toward foldable lenses.56–67 Most foldable lenses today are manufactured from silicone, hydrogel, or acrylic material (Figs 5-2-14 to 5-2-16). The earliest designs for which clinical usage was widespread were the plate lenses known as the “Mazzocco taco.” In early years these were manufactured poorly and often not implanted properly into the capsular bag, so many complications ensued. In recent years manufacturing quality has become much better, and these lenses are now satisfactory for clinical usage (Figs 5-2-17 and 5-2-18). The best plate lenses are those with large positioning holes that allow in-the-bag synechia formation, which enhances fixation and stability.64

399

5 THE LENS Fig. 5-2-11  Scanning electron micrograph of a well-designed, tumble­polished, modified C-loop, one-piece, all-PMMA posterior chamber IOL. The total length of this capsular IOL design is 12.0 mm. Note the excellent, smooth finish of this well-polished IOL. (Original magnification ×10.)

Fig. 5-2-13  Posterior view (Miyake technique) of an eye of a 2-year-old child (obtained postmortem). This was implanted experimentally with a 12-mm, one-piece, all-PMMA IOL in the capsular bag. Note the excellent fit in the ­capsular bag. (Reproduced with permission from Wilson ME, Apple DJ, Bluestein EC, Wang XH. Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. J Cataract Refract Surg. 1994;20:584−91.)

GROWTH OF GLOBE AND LENS CAPSULAR BAG

evacuated 11 capsular bag diameter (mm) 10 9 8 7 6

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 age (years) 16–19 22 23 anterior–posterior axial length of globe (mm)

24

Fig. 5-2-12  Growth of the globe and lens capsular bag. These results are based on a study of 50 eyes obtained postmortem and demonstrate that the growth of the globe and lens capsular bag occurs relatively rapidly during the first 18 months to 2 years. (Reproduced with permission from Wilson ME, Apple DJ, Bluestein EC, Wang XH. Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. J Cataract Refract Surg. 1994;20:584−91.)

400

The most commonly implanted designs at present are three-piece lenses that consist of silicone, acrylic, or hydrogel optics. Plate lenses continue to provide excellent results. These lenses can be implanted through incisions smaller than 5 mm in length, and visual rehabilitation is now incredibly fast with various further modifications, such as clear corneal incisions and topical anesthesia. Such surgery is virtually analogous to arthroscopy of the eye. Lens design and manufacture have improved to such an extent that perhaps the most important factor in the achievement of a successful result is not the IOL itself but the quality of surgery. These factors are very important now that there are high standards for results following IOL implantation, especially in this era when IOL implantation is considered not only a means of optical rehabilitation after cataract removal but also a bona fide refractive procedure. The development of bi- and multifocal IOL designs is one example of this evolutionary process. An increased interest in clear lens extraction for myopia and the use of phakic IOLs also exemplifies the evolution toward refractive IOLs. It is of utmost importance to achieve symmetrical capsular-bag fixation and good cortical cleanup to minimize the chance for complications, such as lens decentration and formation of a Soemmerring ring.

Fig. 5-2-14  Posterior view (Miyake technique) of a well-implanted Advanced Medical Optics three-piece, silicone IOL. The lens is implanted following ­excellent cortical cleanup in a human eye obtained postmortem.

Fig. 5-2-15  Posterior view (Miyake technique) of a well-implanted Alcon AcrySof acrylic IOL. The lens is well centered in the capsular bag after thorough cortical removal.

5.2

Fig. 5-2-17  Scanning electron micrograph that shows the marked improvement in plate lens manufacture by the 1990s. Note the excellent overall design and manufacture finish. (Original magnification ×10.)

The development of foldable lenses is one of fine tuning. For example, much effort is now being expended to develop ever more tissue-friendly optic biomaterials. Figure 5-2-19 reveals a complication that may occur occasionally in patients who have silicone lenses and who require subsequent vitreoretinal surgery using silicone oil.68 Work is under way to address this complication by modifications of the biomaterial to change factors such as its surface characteristics.69 Work is also in progress on the attachment of different styles of haptic materials to the optic to achieve better and more stable fixation of the haptics in the capsular bag. Note that the various ultramodern designs of anterior chamber lenses developed for both aphakic and phakic implantations are considered to belong to generation VI. These include the various Kelman-Choyce designs and modifications by Baikoff and Clemente (see Fig. 5-2-4). These are categorized here to separate them from the myriad of generally inferior anterior chamber IOLs that were available in the earlier intermediate period between 1963 and 1990 (generation IV). The ultramodern designs are suitable for specific clinical indications and clearly should not be included in the generic concept that “all anterior chamber IOLs are bad.”

Recent Advances Our line of research at the Center for Research on Ocular Therapeutics and Biodevices, now transferred to the Moran Eye Center in Salt Lake City, Utah and renamed as the David J Apple MD Laboratories for Ophthalmic Devices Research, allows us to be in close contact not only

Fig. 5-2-18  A well-implanted STAAR-Chiron style silicone plate IOL, with excellent cortical removal and centration. Posterior view (Miyake technique) of the eye (obtained postmortem).

Evolution of Intraocular Lens Implantation

Fig. 5-2-16  A STAAR Surgical Corporation three-piece IOL with polyimide haptics: posterior view (Miyake technique) of an eye (obtained postmortem). The lens is well centered and positioned in a clean capsular bag.

Fig. 5-2-19  View of a patient who has silicone IOL and who later required vitreoretinal surgery with silicone oil. Note the dense bubbles that cover the optic surface, which impair both vision and the surgeon’s view into the eye.

with surgeons worldwide but also with virtually all companies manufacturing IOLs and related devices. One of the best means of discerning manufacturers’ trends is to determine where they are investing energy and funds for the future. On the basis of our contacts and relationships with industry and after a close review of the available scientific literature, we have noted some general principles and tendencies with regard to the development of new foldable IOLs. Focusing on IOLs manufactured in the United States, we have identified seven selected innovative directions. Listed in appropriate chronological order of their introduction, they are as follows: 1. Large fixation holes or foramina have been incorporated in the haptic components of one-piece plate designs (Fig. 5-2-20A). Fibrous ­adhesions often occur between the anterior and posterior capsules following ingrowth of fibrocellular tissue through the holes (see Fig. 5-2-20B,C). This helps enhance the fixation and stability of these designs within the capsular bag.70–72 It is important to note that this fibrous growth requires at least 2 weeks and often much more to establish itself and help anchor the IOL. This design feature has been incorporated into lenses manufactured from silicone (including the Staar toric IOL), hydrogel (hydrophilic acrylic IOLs, and Collamer (Staar CC4203VF) materials. 2. For three-piece foldable designs, the preferred haptic materials are the relatively rigid materials with good material memory, such as PMMA, polyimide (Elastimide), or polyvinylidene fluoride (PVDF)73, 74 (Fig. 5-2-21A−D). Examples of major designs of such lenses on the American market include the Advanced Medical Optics (AMO) SI40 NB with PMMA haptics, the Bausch & Lomb SoFlex C31UB and the Staar AQ-1016 with polyimide haptics, and the AMO CeeOn

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Fig. 5-2-20  Gross and light microscopic photographs of a pseudophakic human eye obtained postmortem, implanted with a silicone plate lens, with large fenestrations. (A) Miyake-Apple posterior photographic technique. The arrow indicates the fibrotic tissue growing through one of the large fenestrations. (B, C) Fusion between anterior and posterior capsules promoted by the fibrocellular tissue growing through the fenestration (Masson’s trichrome; original magnification ×100 and ×400, respectively). PC, Posterior capsule. (Reproduced from Apple DJ, Auffarth GU, Peng Q, Visessook N. Foldable intraocular lenses: evolution, clinicopatholgic correlations, complications. Thorofare, NJ: Slack; 2000.)

C

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402

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Edge 911 with PVDF haptics (previously Pharmacia). These haptics have appropriate memory characteristics that help enhance lens centration and stability and provide better resistance to postoperative ­contraction forces within the capsular bag. 3. One of the most important features that have been incorporated in new foldable lenses in terms of decreasing the incidence of PCO

Fig. 5-2-21  Gross photographs of four modern three-piece silicone lenses with different haptic materials. (A) From left to right: PMMA (CeeOn 912, Pharmacia Inc., Peapack, NJ), Elastimide (AQ-2003, Staar Surgical, Inc., Monrovia, CA), polyvinylidene fluoride (PVDF) (CeeOn Edge 911, Pharmacia Inc.), and Prolene (SI-30 NB, AMO, Irvine, CA). (B−D) Details of the optic-haptic junctions of the lenses having loops manufactured from relatively rigid materials (PMMA, Elastimide, and PVDF, respectively). (Reproduced from Izak AM, Werner L, Apple DJ, et al. Loop memory of different haptic materials used in the manufacture of posterior chamber intraocular lenses. J Cataract Refract Surg. 2002;28:1229−35.)

is the square, truncated optic edge. Various experimental animal s­ tudies by Nishi in Japan, analyses of human autopsy globes in our laboratory, as well as several clinical studies with the three-piece AcrySof lens (MA30BA and MA60BM), the first design identified with this geometric characteristic, demonstrated an enhanced barrier effect against cell migration/proliferation on the posterior ­ capsule

5.2

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Evolution of Intraocular Lens Implantation

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Fig. 5-2-22  Light photomicrographs and schematic illustrations showing the subtle differences regarding the barrier effect of an IOL optic with a rounded edge versus a square truncated edge. (A) Photomicrograph of the site of implantation of an IOL optic with a rounded edge. Note the large Soemmering ring on the left (red stain). Note also the migration of cortical material (red material) onto the posterior peripheral surface of the lens optic, a phenomenon that sometimes occurs with a rounded edge. Rarely does such growth extend onto the central visual axis (Masson’s trichrome; original magnification ×100). (B) Round edge: some cells may squeeze behind the posterior peripheral aspect of the optic, creating a paracentral rim of opacification (arrows) but usually sparing the visual axis. (C) Photomicrograph of a case in which the Soemmering ring (red) remains totally confined to the right of the square optic edge, leaving the posterior capsule (lower left) cell-free (Masson’s trichrome; original magnification ×50). (D) Square truncated optic edge seems to provide an abrupt barrier (arrows), leaving the entire optical zone free of cells. AC, Anterior capsule; PC, posterior capsule. (A, B, and D, Reproduced from Peng Q, Visessook N, Apple DJ, et al. Surgical prevention of posterior capsule opacification. Part III. Intraocular lens optic barrier effect as a second line of defense. J Cataract Refract Surg. 2000;26:198−213. C, Reproduced from Werner L, Apple DJ, Pandey SK. Postoperative proliferation on anterior and equatorial lens epithelial cells. In: Buratto L, Werner L, Zanini M, Apple DJ, eds. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002:603−23.)

A

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Fig. 5-2-23  Gross and light microscopy photographs of the first human eye obtained postmortem with a single-piece AcrySof lens (Alcon Laboratories, Forth Worth, TX) accessioned in our center. (A) The lens is well centered and the capsular bag is clear. (B) Light photomicrograph of a histological section from the same eye. The arrow indicates the imprint of the square edge of the lens optic on the capsular bag, causing a barrier effect that prevented retained/regenerative cortical material from the Soemmering ring to migrate onto the posterior capsule, opacifying the visual axis (Masson’s trichrome; original magnification ×400). (Reproduced from Escobar-Gomez M, Apple DJ, Vargas LG, et al. Scanning electron microscopic and histologic evaluation of the AcrySof SA30AL acrylic intraocular lens. J Cataract Refract Surg. 2003;29(1):164−69.)

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toward the ­ visual axis.75–87 This IOL design feature has also been incorporated in other lenses such as the AMO Sensar IOL with the new ­ OptiEdge optic configuration, a square posterior optic edge and a rounded anterior optic edge. Lenses manufactured from other ­ materials, such as silicone (Pharmacia CeeOn Edge 911) and hydrophilic materials (Rayner Centerflex and the Ciba Vision ­MemoryLens), now present this design feature. The Bausch & Lomb Hydroview foldable hydrogel IOL does not yet have the truncated square optic edge technology, but the manufacturer is working to introduce it on updated models (Fig. 5-2-22). 4. Manufacturers have invested heavily and with great success in single-piece designs, all fabricated from the same material as the optic component. The Alcon (SA30AL and SA60AT) AcrySof IOL is a hydrophobic single-piece acrylic design that has provided excellent results (Fig. 5-2-23). 5. Manufacturers are also investing in the development of injector ­systems to be used with the new lens designs. 6. Perhaps the most energy and funding are being spent on new and complex IOLs that not only restore the refractive power of the eye after cataract surgery but also provide special features, including ­multifocality, toric corrections (Fig. 5-2-24A), pseudoaccommodation (Fig. 5-2-24B,C), postoperative adjustment of the IOL refractive power,

A

and ­image magnification (telescopic lenses) (Fig. 5-2-24D).88–91 Itemization of these IOL designs is not yet useful because proof of safety and efficacy is still in great flux. With any IOL, the issue of “biocompatibility” must be assessed. Not only do surgeons today seem to be seeking IOLs that are easy to insert/inject through small incisions − perhaps the main factor influencing manufacturers’ IOL development − but also more attention is being paid to the interaction of each IOL design within the surrounding capsular bag. Issues such as postoperative cell proliferation within the capsular bag, including PCO (Fig. 5-2-25), anterior capsule opacification (ACO) (Fig. 5-2-26), and interlenticular opacification (ILO) (Fig. 5-2-27) with piggyback IOLs, are used as one indication of lens biocompatibility.92–99 This goes far beyond the normal postoperative inflammatory reaction observed after cataract surgery with IOL implantation. Different studies from our laboratory demonstrated that the choice of IOL design and material can largely influence the outcome of these complications, but the role of surgical techniques should not be underestimated. Last but not least, a “perfect” IOL would not be effective in preventing excess cell proliferation within the capsular bag after bad surgery. 7. The renewed interest in phakic IOLs, which we now realize can potentially correct any refractive error, is also progressing rapidly, and itemization of special IOL models as being those of choice is

B

D C

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Fig. 5-2-24  Special intraocular lenses. (A) Gross photograph of a toric lens (AA-4203TF or AA-4203TL Staar Surgical, Inc.). This lens has basically the same design as single-piece, plate silicone posterior chamber lenses with large fenestrations but with an incorporated cylindrical correction. (B,C) Schematic drawings representing two accommodative lenses, the AT-45 lens, manufactured by C&C Vision (Irvine, CA), and the AKKOMMODATIVE 1 CU, manufactured by HumanOptics (Erlangen, Germany), respectively. The first is essentially a plate haptic lens with Elastimide haptics. It is stated that redistribution of the ciliary body mass during effort for accommodation will result in increased vitreous pressure, which will move the optic of this lens anteriorly within the visual axis, creating a more plus powered lens. The second is a one-piece lens, manufactured from a hydrophilic acrylic material. It is stated that the special mechanical properties of this lens also enable it to change power during the contraction of the ciliary muscle. (D) Schematic drawing representing the implantable miniaturized telescope (IMT) (VisionCare Ophthalmic Technologies Inc., Yehud, Israel). This is the only intraocular device available that is designed specifically to improve vision of patients suffering from age-related macular degeneration. The IMT is composed of two parts, an optical cylinder and a carrying device. The optic cylinder is made of pure glass. The carrying device is made of black PMMA. The latter has a general configuration of a posterior chamber intraocular lens, with two modified C-loops or haptics that hold the device in the capsular bag. Once in place, the anterior part of the optic extends anteriorly for approximately 1 mm through the pupil. It is designed to be stabilized approximately 2 mm posterior to the corneal endothelium. (A-D, Reproduced from Werner L, Apple DJ, Schmidbauer JM. Ideal IOL (PMMA and Foldable) for year 2002. In: Buratto L, Werner L, Zanini M, Apple DJ, eds. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002:435−52.)

A

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these phakic lenses, designed to be inserted through small incisions (Figs 5-2-28 and 5-2-29). Although a large spectrum of lenses is available today, the IOL of choice still depends on a surgeon’s personal preference based on multiple ­factors personalized to each individual, largely influenced by different features unique to each patient, such as the patient’s history and clinical status, but also by the occurrence of intraoperative complications.

5.2 Evolution of Intraocular Lens Implantation

not yet possible. In our opinion, it is somewhat ironic that anterior ­chamber IOLs, previously relegated by many surgeons to a wastebasket of discarded devices, are now being resurrected and researched by both major and start-up manufacturers as a possible lens of choice for refractive correction.100–102 Lenses designed for iris fixation and placement in the posterior chamber are also being studied, with good results to date. There is a trend for the use of foldable materials for

B

Fig. 5-2-25  Gross photographs from pseudophakic human eyes obtained postmortem showing different examples of posterior capsule opacification. (A) The eye was implanted with a rigid three-piece PMMA lens, which presents asymmetric fixation (bag-sulcus). Massive opacification of the capsular bag can be observed. (B) Eye implanted with a one-piece PMMA lens, presenting an important Soemmering ring formation and posterior capsule opacification, which required Nd:YAG laser posterior capsulotomy. Note the proliferation of Elschnig pearls around the orifice of the posterior capsulotomy. (C) Eye implanted with a three-piece AcrySof lens. Although there is a significant Soemmering ring formation, the square edge of the lens prevented the retained/regenerative material from opacifying the visual axis. (A, Reproduced from Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol. 1992;37:73−116. B, Reproduced from Apple DJ. Influence of intraocular lens material and design on postoperative intracapsular cellular reactivity. Trans Am Ophthalmol Soc. 2000;98:257−83.)

B

Fig. 5-2-26  Gross and light microscopic photographs of a pseudophakic human eye obtained postmortem implanted with a three-piece silicone lens (SI-30 NB; AMO). (A,B) Opacification of the anterior capsule covering the lens optic from a posterior or Miyake-Apple view and from an anterior or surgeon’s view, respectively.

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Fig. 5-2-26, cont’d  (C,D) Histological sections from the same eye showing the fibrocellular tissue attached to the inner surface of the anterior capsule at the capsulorrhexis edge (Masson’s trichrome and PAS stains, respectively; original magnification ×400). (A, Reproduced from Werner L, Apple DJ, Pandey SK. Postoperative proliferation of anterior and equatorial lens epithelial cells. In: Buratto L, Werner L, Zanini M, Apple DJ, eds. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002:603−23.)

A

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Fig. 5-2-27  Clinical, gross, and light microscopic photographs from a case of interlenticular opacification between two acrylic piggyback lenses implanted in a patient with high hyperopia (case of Dr Johnny L. Gayton, Warner Robins, GA). The opacity observed (A) was caused by a membrane-like material sandwiched between the two lenses, which are practically fused together in the center (B,C). Histological examination demonstrated the presence of retained/regenerative cortical material and pearls (D), similar to what is observed in cases of posterior capsule opacification (hematoxylin-eosin stain; original magnification ×400). (A−D, Reproduced from Gayton JL, Apple DJ, Peng Q, et al. Interlenticular opacification: clinicopathological correlation of a complication of posterior chamber piggyback intraocular lenses. J Cataract Refract Surg. 2000;26:330−36.)

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Evolution of Intraocular Lens Implantation

A

Fig. 5-2-28  Clinical photographs of eyes implanted with different anterior chamber phakic intraocular lenses. (A) ZSAL-4 (Morcher, Stuttgart, Germany). This is a one-piece PMMA angle-fixated lens, which has features similar to those of the ZB 5M model (Baïkoff’s) concerning the haptic design and the angulation. Its optic is flat at the anterior surface and concave at the posterior surface. This allows more distance between the iris plane and the optic of the lens, also reducing the height of the optical edge, which leaves more space between it and the corneal endothelium. The lens is supplied in powers ranging from −10 to −23 diopters. It became available in Europe in January 1995. (B) Vivarte lens, manufactured by IOLTECH (La Rochelle, France). A manufacturing process termed selective polymerization ­allows the obtention of a one-piece IOL with flexible and rigid areas anywhere needed to optimize the mechanical properties of the lens. This angle-fixated lens thus has soft hydrophilic acrylic optic and footplates, while the haptics have rigidity similar to that of PMMA lenses. (C) Kelman Duet lens, manufactured by TEKIA, Inc. (Irvine, CA). This angle-fixated lens has two parts: an independent Kelman tripod PMMA haptic, with an overall diameter of 12.0, 12.5, or 13.0 mm, and a 5.5 mm monofocal silicone optic. The latter is injected into the anterior chamber and then fixated to the haptic by means of the optic eyelets and haptic tabs using a Sinskeytype hook. (D) Artisan lens (Ophtec, Groningen, Netherlands). This is a one-piece, iris-fixated lens manufactured from PMMA. Artisan haptics (fixation arms) attach to the midperipheral, virtually immobile iris stroma, thus allowing relatively unrestricted dilation and constriction of the pupil. Lenses with incorporated cylindrical correction are also available. (A−D, Reproduced from Werner L, Apple DJ, Izak AM. Phakic intraocular lenses: current trends and complications. In: Buratto L, Werner L, Zanini M, Apple DJ, eds. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002:330−36.)

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Fig. 5-2-29  Gross and clinical photographs showing the two currently available posterior chamber phakic lenses. (A,B) Implantable contact lens (ICL) (Staar Surgical). This is a one-piece plate lens manufactured from a proprietary hydrophilic collagen polymer know as Collamer. It can be inserted or injected into the anterior chamber, and then the haptics are placed behind the iris with the help of a spatula. (C,D) Phakic refractive lens (PRL), manufactured by Medennium Inc. (Irvine, CA). This is also a one-piece plate lens, manufactured from silicone. (A–D, Reproduced from Werner L, Apple DJ, Izak AM. Phakic intraocular lenses: current trends and complications. In: Buratto L, Werner L, Zanini M, Apple DJ, eds. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002:759−77.)

References

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  1. Apple DJ, Ram J, Wang XH, Brown S. Cataract surgery in the developing world. Saudi J Ophthalmol. 1995;9(1):2–15.   2. Isaacs R, Ram J, Apple DJ. Cataract blindness in the developing world: is there a solution? J Agromed. 1996;3(4):7–21.   3. Kador PF. Overview of the current attempts toward the medical treatment of cataract. Ophthalmology. 1983;90:352–64.   4. Ridley H. Intra-ocular acrylic lenses. Trans Ophthalmol Soc UK. 1951;71:617–21.   5. Ridley H. Artificial intra-ocular lenses after cataract extraction. St Thomas Hosp Rep. 1952;7(2):12–4.   6. Apple DJ, Sims J. Harold Ridley and the invention of the intraocular lens. Surv Ophthalmol. 1995;40:279–92.   7. Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a historical and histopathological review. Surv Ophthalmol. 1984;29:1–54.   8. Apple DJ, Mamalis N, Brady SE, et al. Biocompatibility of implant materials: a review and scanning electron microscopic study. J Am Intraocul Implant Soc. 1984;10:53–66.   9. Apple DJ, Rabb MF. Ocular pathology: clinical applications and self-assessment, 5th ed. St Louis: CV Mosby; 1998. 10. Apple DJ, Kincaid MC, Mamalis N, Olson RJ. Intraocular lenses: evolution, designs, complications, and pathology. Baltimore: Williams & Wilkins; 1989. 11. Binkhorst CD. Lens implants (pseudophakoi) classified according to method of fixation. Br J Ophthalmol. 1967;51:772–4. 12. Binkhorst CD. About lens implantation. 2. Lens design and classification of lenses. Implant. 1985;3:11–4. 13. Ellingson FT. The uveitis-glaucoma-hyphema syndrome associated with the Mark VIII anterior chamber lens implant. J Am Intraocul Implant Soc. 1978;4:50–3. 14. Drews RC. The Barraquer experience with intraocular lenses: 20 years later. Ophthalmology. 1982;89:386–93. 15. Drews RC. Intracapsular versus extracapsular cataract extraction. In: Wilensky JT, ed. Intraocular lenses. Transactions of the University of Illinois Symposium on Intraocular Lenses. New York: Appleton-Century-Crofts; 1977. 16. Obstbaum SA, Galin MA. Cystoid macular edema and ocular inflammation: the corneo-retinal inflammatory syndrome. Trans Ophthalmol Soc UK. 1979;99:187–91. 17. Binkhorst CD. The iridocapsular (two-loop) lens and the iris-clip (four-loop) lens in pseudophakia. Trans Am Acad Ophthalmol Otolaryngol. 1973;77:589–617.

18. Choyce DP. The Mark VI, Mark VII and Mark VIII Choyce anterior chamber implants. Proc R Soc Med. 1965;58:729–31. 19. Kelman CD. Anterior chamber lens design concepts. In: Rosen ES, Haining WM, Arnott EJ, eds. Intraocular lens implantation. St Louis: CV Mosby; 1984. 20. Duffin RM, Olson RJ. Vaulting characteristics of flexible loop anterior chamber intraocular lenses. Arch Ophthalmol. 1983;101:1429–33. 21. Mamalis N, Apple DJ, Brady SE, et al. Pathological and scanning electron microscopic evaluation of the 91Z intra­ ocular lens. J Am Intraocul Implant Soc. 1984;10:191–9. 22. Reidy JJ, Apple DJ, Googe JM, et al. An analysis of semiflexible, closed-loop anterior chamber intra­ocular lenses. J Am Intraocul Implant Soc. 1985;11:344–52. 23. Waring GO III. The 50-year epidemic of pseudophakic corneal edema. Arch Ophthalmol. 1989;107:657–9. 24. Apple DJ, Brems RN, Park RB, et al. Anterior chamber lenses. I. Complications and pathology and a review of designs. J Cataract Refract Surg. 1987;13:157–74. 25. Apple DJ, Hansen SO, Richards SC, et al. Anterior chamber lenses. II. A laboratory study. J Cataract Refract Surg. 1987;13:175–89. 26. Auffarth GU, Wesendahl TA, Apple DJ. Are there acceptable anterior chamber intraocular lenses for clinical use in the 1990s? An analysis of 4104 explanted anterior chamber intraocular lenses. Ophthalmology. 1994;101:1913–22. 27. Auffarth GU, Wesendahl TA, Brown SJ, Apple DJ. Update on complications of anterior chamber intraocular lenses. J Cataract Refract Surg, Special Issue: Best Papers of 1994 ASCRS Meeting. 1994:70–6. 28. Auffarth GU, Wesendahl TA, Brown SJ, Apple DJ. Update on complications of anterior chamber intraocular lenses. J Cataract Refract Surg. 1995;22:1–7. 29. Apple DJ, Price FW, Gwin T, et al. Sutured retropupillary posterior chamber intraocular lenses for exchange or secondary implantation (The Twelfth Annual Binkhorst Lecture, 1988). Ophthalmology. 1989;96:1241–7. 30. Duffey RJ, Holland EJ, Agapitos PJ, et al. Anatomic study of transsclerally sutured intraocular lens implantation. Am J Ophthalmol. 1989;108:300–9. 31. Pearce JL. Experience with 194 posterior chamber lenses in 20 months. Trans Ophthalmol Soc UK. 1977;97:258–64. 32. Drews RC. The Pearce tripod posterior chamber intraocular lens: an independent analysis of Pearce’s results. J Am Intraocul Implant Soc. 1980;6:259–62.

33. Shearing SP. Evolution of the posterior chamber intraocular lenses. J Am Intraocul Implant Soc. 1984;10:343–6. 34. Apple DJ, Reidy JJ, Googe JM, et al. A comparison of ciliary sulcus and capsular bag fixation of posterior chamber intraocular lenses. J Am Intraocul Implant Soc. 1985;11:44–63. 35. Miyake K, Asakura M, Kobayashi H. Effect of intraocular lens fixation on the blood-aqueous barrier. Am J Ophthalmol. 1984;98:451–5. 36. Apple DJ, Lim ES, Morgan RC, et al. Preparation and study of human eyes obtained postmortem with the Miyake posterior photographic technique. Ophthalmology. 1990;97:810–6. 37. Assia EI, Castaneda VE, Legler UFC, et al. Studies on cataract surgery and intraocular lenses at the center for intraocular lens research. Ophthalmol Clin N Am. 1991;4:251–66. 38. Assia EI, Legler UFC, Apple DJ. The capsular bag after short- and long-term fixation of intraocular lenses. Ophthalmology. 1995;102:1151–7. 39. Apple DJ, Auffarth GU, Wesendahl TA. Pathophysiology of modern capsular surgery. In: Steinert RF, ed. Textbook of modern cataract surgery: technique, complication, and management. Philadelphia: WB Saunders; 1995. 40. Assia EI, Apple DJ, Lim ES, et al. Removal of viscoelastic materials after experimental cataract surgery in vitro. J Cataract Refract Surg. 1992;18:3–6. 41. Auffarth GU, Wesendahl TA, Solomon KD, et al. Evaluation of different removal techniques of a high viscosity viscoelastic (Healon GV). J Cataract Refractive Surg. Special Issue: Best Papers of 1994 ASCRS Meeting. 1994:30–2. 42. Glasser DB, Katz HR, Boyd JE, et al. Protective effects of viscous solutions in phakoemulsification and traumatic lens implantation. Arch Ophthalmol. 1989;107:1047–51. 43. Madsen K, Stenevi U, Apple DJ, Harfstrand A. Histochemical and receptor binding studies of hyaluronic acid and hyaluronic acid binding sites on corneal endothelium. Ophthalmic Pract. 1989;7(3):1–8. 44. Neuhann T. Theorie und operationstechnik des kapsulorhexis. Klin Monatsbl Augenheilkd. 1987;190:542–5. 45. Gimbel H, Neuhann T. Development, advantages and methods of continuous circular capsulorrhexis techniques. J Cataract Refract Surg. 1990;16:31–7. 46. Assia EI, Apple DJ, Tsai JC, Lim ES. The elastic properties of the lens capsule in capsulorrhexis. Am J Ophthalmol. 1991;111:628–32.

67. Apple DJ, Park SB, Merkley KH, et al. Posterior chamber intraocular lenses in a series of 75 autopsy eyes. I. Loop location. J Cataract Refract Surg. 1986;12:358–62. 68. Apple DJ, Tetz M, Hunold W. Lokalisierte Endophthalmitis: Eine bisher nicht beschriebene Komplikation der extrakapsulären Kataraktextraktion. In: Jacobic KW, Schott K, Gloor B, eds. I. Kongress der Deutschen Gesellschaft für Intraokularlinsen Implantation (DGII), I New York: Springer-Verlag; 1988. 69. Piest KL, Kincaid MC, Tetz MR, et al. Localized endophthalmitis: a newly described cause of the socalled toxic lens syndrome. J Cataract Refract Surg. 1987;13:498–510. 70. Kent DG, Peng Q, Isaacs RT, et al. Security of capsular fixation: small- versus large-hole plate-haptic lenses. J Cataract Refract Surg. 1997;23:1371–5. 71. Whiteside SB, Apple DJ, Peng Q, et al. Fixation elements on plate intraocular lens: large positioning holes to improve security of capsular fixation. Ophthalmology. 1998;105:837–42. 72. Kent DG, Peng Q, Isaacs RT, et al. Mini-haptics to improve capsular fixation of plate-haptic silicone intraocular lenses. J Cataract Refract Surg. 1998;24:666–71. 73. Assia EI, Legler UF, Castaneda VE, Apple DJ. Loop memory of posterior chamber intraocular lenses of ­various sizes, designs, and loop materials. J Cataract Refract Surg. 1992;18:541–6. 74. Izak AM, Werner L, Apple DJ, et al. Loop memory of different haptic materials used in the manufacture of posterior chamber intraocular lenses. J Cataract Refract Surg. 2002;28:1229–35. 75. Nishi O, Nishi K, Wickstrom K. Preventing lens epithelial cell migration using intraocular lenses with sharp rectangular edges. J Cataract Refract Surg. 2000;26:1543–9. 76. Apple DJ, Peng Q, Visessook N, et al. Surgical prevention of posterior capsule opacification. Part I. Progress in eliminating this complication of cataract surgery. J Cataract Refract Surg. 2000;26:180–7. 77. Peng Q, Apple DJ, Visessook N, et al. Surgical prevention of posterior capsule opacification. Part II. Enhancement of cortical clean up by focusing on hydrodissection. J Cataract Refract Surg. 2000;26:188–97. 78. Peng Q, Visessook N, Apple DJ, et al. Surgical prevention of posterior capsule opacification. Part III. Intraocular lens optic barrier effect as a second line of defense. J Cataract Refract Surg. 2000;26:198–213. 79. Werner L, Apple DJ, Pandey SK. Postoperative proliferation of anterior and equatorial lens epithelial cells. In: Buratto L, Osher RH, Masket S, eds. Cataract surgery in complicated cases. Thorofare, NJ: Slack; 2000:399–417. 80. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and collagen type IV to intraocular lens materials in human autopsy eyes. Part I: histological sections. J Cataract Refract Surg. 2000;26:1792–806. 81. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and collagen type IV to intraocular lens materials in human autopsy eyes. Part II: explanted IOLs. J Cataract Refract Surg. 2000;26: 1807–18. 82. Ram J, Pandey SK, Apple DJ, et al. Effect of in-thebag intraocular lens fixation on the prevention of posterior capsule opacification. J Cataract Refract Surg. 2001;27:1039–46. 83. Apple DJ, Peng Q, Visessook N, et al. Eradication of posterior capsule opacification. Documentation of a marked decrease in Nd:YAG laser posterior capsulotomy rates noted in an analysis of 5416 pseudophakic human eyes obtained postmortem. Ophthalmology. 2001;108:505–18.

84. Schmidbauer JM, Vargas LG, Peng Q, et al. Posterior capsule opacification. Int Ophthalmol Clin. 2001;41:109–31. 85. Pandey SK, Wilson ME, Trivedi RH, et al. Pediatric cataract surgery and intraocular lens implantation: current techniques, complications and management. Int Ophthalmol Clin. 2001;41:175–96. 86. Pandey SK, Cochener B, Apple DJ, et al. Intracapsular ring sustained 5-fluorouracil delivery system for prevention of posterior capsule opacification in rabbits: a histological study. J Cataract Refract Surg. 2002;28:139–48. 87. Vargas L, Peng Q, Apple DJ, et al. An evaluation of three modern single-piece foldable intraocular lenses: a clinicopathological study in a rabbit model with special reference to posterior capsule opacification. J Cataract Refract Surg. 2002;28:1241–50. 88. Fine IH, Hoffman RS, Packer M. Clear-lens extraction with multifocal lens implantation. Int Ophthalmol Clin. 2001;41:113–21. 89. Avitablie T, Marano F. Multifocal intraocular lenses. Curr Opin Ophthalmol. 2001;12:12–6. 90. Kaskaloglu M, Uretmen O, Yagci A. Medium-term results of implantable miniaturized telescopes in eyes with agerelated macular degeneration. J Cataract Refract Surg. 2001;27:1751–5. 91. Werner L, Kaskaloglu MM, Apple DJ, et al. Aqueous infiltration into an implantable miniaturized telescope. Ophthalmic Surg Lasers. 2002;33:343–8. 92. Werner L, Pandey SK, Escobar-Gomez M, et al. Anterior capsule opacification: a histopathological study comparing different IOL styles. Ophthalmology. 2000;107:463–71. 93. Werner L, Pandey SK, Apple DJ, et al. Anterior capsule opacification: correlation of pathologic findings with clinical sequelae. Ophthalmology. 2001;108:1675–81. 94. Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathological documentation. Trans Am Ophthalmol Soc. 2001;99:95–107; discussion 107–9. 95. Macky TA, Pandey SK, Werner L, et al. Anterior capsule opacification. Int Ophthalmol Clin. 2001;41:17–31. 96. Gayton JL, Apple DJ, Peng Q, et al. Interlenticular opacification: a clinicopathological correlation of a new complication of piggyback posterior chamber intra­ ocular lenses. J Cataract Refract Surg. 2000;26:330–6. 97. Werner L, Shugar JK, Apple DJ, et al. Opacification of piggyback IOLs associated to an amorphous material attached to interlenticular surfaces. J Cataract Refract Surg. 2000;26:1612–9. 98. Trivedi RH, Izak A, Werner L, et al. Interlenticular opacification of piggyback intraocular lenses. Int Ophthalmol Clin. 2001;41:47–62. 99. Werner L, Apple DJ, Pandey SK, et al. Analysis of elements of interlenticular opacification. Am J Ophthalmol. 2002;133:320–6. 100. Visessook N, Peng Q, Apple DJ, et al. Pathological examination of an explanted phakic posterior chamber intraocular lens. J Cataract Refract Surg. 1999;25:216–22. 101. Werner L, Apple DJ, Izak A, et al. Phakic anterior chamber intraocular lenses. Int Ophthalmol Clin. 2001;41:133–52. 102. Werner L, Apple DJ, Pandey SK, et al. Phakic posterior chamber intraocular lenses. Int Ophthalmol Clin. 2001;41:153–74.

5.2 Evolution of Intraocular Lens Implantation

47. Assia EI, Apple DJ, Tsai JC, et al. An experimental study comparing various anterior capsulectomy techniques. Arch Ophthalmol. 1991;109:642–7. 48. Assia EI, Apple DJ, Tsai JC, Morgan RC. Mechanism of radial tear formation and extension after anterior capsulectomy. Ophthalmology. 1991;98:432–7. 49. Wasserman D, Apple DJ, Castaneda VE, et al. Anterior capsular tears and loop fixation of posterior chamber intraocular lenses. Ophthalmology. 1991;98:425–31. 50. Assia EI, Legler UFC, Castaneda VE, et al. Clinicopathologic study of the effect of radial tears and loop fixation on intraocular lens decentration. Ophthalmology. 1993;100:153–8. 51. Auffarth GU, Wesendahl TA, Newland TJ, Apple DJ. Capsulorrhexis in the rabbit eye as a model for pediatric capsulectomy. J Cataract Refract Surg. 1994;20:188–91. 52. Faust KJ. Hydrodissection of soft nuclei. J Am Intraocul Implant Soc. 1984;10(1):75–7. 53. Ohmi S, Uenoyama K, Apple DJ. Implantation of IOLs with different diameters. Acta Soc Ophthalmol Jpn. 1992;96:1093–8. 54. Wilson ME, Apple DJ, Bluestein EC, Wang XH. Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. J Cataract Refract Surg. 1994;20:584–91. 55. Wilson ME, Wang XH, Bluestein EC, Apple DJ. Comparison of mechanized anterior capsulectomy and manual continuous capsulorrhexis in pediatric eyes. J Cataract Refract Surg. 1994;20:602–6. 56. Auffarth GU, Wilcox M, Sims JCR, et al. Analysis of 100 ­explanted one-piece and three-piece silicone intraocular lenses. Ophthalmology. 1995;102:1144–50. 57. Auffarth GU, Wilcox M, Sims JCR, et al. Complications of silicone intraocular lenses. J Cataract Refract Surg, Special Issue: Best Papers of 1995 ASCRS Meeting. 1995;38–41. 58. Auffarth GU, McCabe C, Wilcox M, et al. Centration and fixation of silicone intraocular lenses: an analysis of clinicopathological findings in human autopsy eyes. J Cataract Refract Surg. 1996;22:1281–5. 59. Buchen SY, Richards SC, Solomon KD, et al. Evaluation of the biocompatibility and fixation of a new silicone intraocular lens in the feline model. J Cataract Refract Surg. 1989;15:545–53. 60. Menapace R. Evaluation of 35 consecutive SI-30 phacoflex lenses with high-refractive silicone optic implanted in the capsulorrhexis bag. J Cataract Refract Surg. 1995;21:339–47. 61. Menapace R. English title: Current state of implantation of flexible intraocular lenses [in German]. Fortschr Ophthalmol. 1991;88:421–28. 62. Menapace R, Radax U, Amon M, Papapanos P. No-stitch, small incision cataract surgery with flexible intraocular lens implantation. J Cataract Refract Surg. 1994;20: 534–42. 63. Tsai JC, Castaneda VE, Apple DJ, et al. Scanning electron microscopic study of modern silicone intraocular lenses. J Cataract Refract Surg. 1992;18:232–5. 64. Apple DJ, Kent DG, Peng Q, et al. Verbesserung der befestigung von silikonschiffchenlinsen durch den gebrauch von positionierungslochern in der linsenhaptik, Proceedings of the 10th Annual Deutsche Gesellschaft fuer Intraokularlinsen Implantation Meeting, Budapest, Hungary, March 1996. 65. Percival SP, Pai V. Heparin-modified lenses for eyes at risk for breakdown of the blood-aqueous barrier during cataract surgery. J Cataract Refract Surg. 1993;19:760–5. 66. Apple DJ, Federman JL, Krolicki TJ, et al. Irreversible silicone oil adhesion to silicone intraocular lenses. A clinicopathologic analysis. Ophthalmology. 1996;103:1555–62.

409

PART 5 THE LENS

5.3

Patient Work-up for Cataract Surgery Frank W. Howes

Key features n

n

 iscussion on patient work-up including ophthalmic and  D medical considerations in the preoperative evaluation of lens ­surgery, including: n the morphology of lens opacities, the effects and diagnosis thereof n the optics of the eye including refractive correction modalities n the biometric measurements in standard and postrefractive eyes. The social and legal considerations in final aspects of the work-up are also discussed.

INTRODUCTION Any patient who needs to undergo cataract surgery, whether local or general anesthesia is used, requires an accurate ophthalmological workup and careful anamnesis. Even if a topical anesthetic is used, surgery is stressful for a patient, especially if there is a coexistent medical disorder. Therefore, the patient’s overall welfare is entrusted to a skilled physician, usually the anesthesiologist. The cataract surgeon concentrates on the eye and should not be distracted by the patient’s systemic needs during surgery, even if the surgeon possesses the requisite skills. Although most cataract procedures are uneventful with regard to the patient’s medical condition, any problem or crisis is potentially ruinous, especially if surgery becomes complicated or prolonged. It is therefore incumbent upon the surgical and anesthetic team to be aware of every patient’s medical status. Cataract management is a team affair. The family doctor provides the medical history and current therapeutic information. Nursing members of the team have more contact with the patient than does the surgeon, and they can address the patient’s immediate needs as well as provide a confidence-boosting ambience. Technical and administrative personnel complete the team, along with the anesthesiologist and ophthalmic surgeon.

MEDICAL HISTORY AND CURRENT THERAPEUTIC REGIMEN

410

A history of cardiac, bronchopulmonary, or cerebrovascular incidents, especially if recent, influences the timing and management of ­ surgery. Diabetes mellitus and systemic hypertension are common in the population predisposed to operable cataract formation, and these conditions may adversely influence both the surgery and the postoperative course of events.1 Ram et al.,2 in a study of more than 6000 patients who underwent cataract surgery, discovered multiple morbidities that arose from a variety of conditions. The major causes ­included pulmonary disease, cardiovascular and hypertensive disorders, diabetes mellitus, and significant orodental problems that ­required intervention. Ram et al.2 also noted significant postoperative problems in 1.27% of their patients, nearly half of whom required hospitalization. Thus, they concluded that all patients for whom cataract surgery is planned should undergo evaluation for systemic disease to prevent morbidity, or even mortality, in the preoperative, intraoperative, and postoperative periods. It is not uncommon for thyroid disorders to be associated with

   Table 5-3-1  MORBIDITY IN CATARACT SURGERY PATIENTS Condition

Percentage

Significant medical history

84

Diabetes mellitus

16

Systemic hypertension

47

Ischemic heart disease

38

Hypothyroidism

18

Undiagnosed tumors

3

cataract surgery; they may even be precipitated by the surgical intervention.3 Fisher and Cunningham4 noted an even higher morbidity in their cohort of patients who had cataract surgery (Table 5-3-1). The presence of disorders that might make cooperation difficult during surgery must be determined so that the operating environment can be optimized. These include Parkinson’s disease and other involuntary movement disorders involving the head, face, and lids; communication difficulty; and excessive fear or anxiety. These factors influence both the surgeon’s and the anesthesiologist’s decision about the form of ­anesthetic to use and the sedation required (see Chapter 5.6). The patient’s social history may provide useful information, especially with reference to smoking, because breathing difficulties during surgery and coughing after surgery could compromise the surgical outcome. Similarly, substance abuse may be linked to poor patient compliance during surgery, as well as having implications for postoperative medication and management. Good preoperative assessment and management can minimize the risks associated with operating on these patients. Systemic disorders may provide clues to the existence of an association between the morphology and the corresponding lens opacities (Table 5-3-2). When a systemic disorder is present, ensuring a good understanding of the pharmacological and other therapeutic measures used in its management is an essential component of the preoperative work-up.

GENERAL OPHTHALMIC HISTORY AND EXAMINATION It is important to establish whether there are coexistent ophthalmic conditions that may influence the cataract surgery, postoperative recovery, or outcome. Both eyes are assessed fully by routine ophthalmological work-up, which includes tonometry, slit-lamp biomicroscope examination, and posterior segment observations under mydriasis to estimate the visual outcome and risk category of surgery for the patient. Intercurrent ophthalmic disorders may prejudice the visual outcome; for example, uveitis may be exacerbated,5 herpes zoster may have left an anesthetic cornea,6 atopic disease may predispose the eye to infection,7 Fuchs’ endothelial dystrophy may predispose the eye to corneal edema, and diabetes mellitus increases the prospects of postoperative macular edema.1 Patient counseling on the procedure and postoperative expectations is a vital part of the preoperative work-up. A written explanation of the background and process of cataract surgery is invaluable.

   Table 5-3-2  SYSTEMIC DISORDERS AND LENS OPACITIES Appearance in the Eye

Myotonic dystrophy

Blue dot cortical cataract and posterior subcapsular cataract

Wilson’s disease

Green sunflower cataract (copper)  anterior or posterior subcapsular

Atopic dermatitis

Blue dot cortical cataract and posterior subcapsular cataract

Hypocalcemia

Discrete white cortical opacities

Diabetes mellitus

Snowflake opacities located in anterior and posterior subcapsular cortex

Acute onset diabetes

Cortical wedges caused by lens fiber swelling

Down’s syndrome

Snowflake opacities located in anterior and posterior subcapsular cortex

5.3

Fig. 5-3-1  Nuclear cataract. With continual generation of lens fibers in the equatorial periphery of the lens, the older material is continually compressed and eventually forms a nuclear cataract with changed optical density and altered transparency

Patient Work-up for Cataract Surgery

Systemic Disorder

SPECIFIC OPHTHALMIC EXAMINATION In addition to the above, the assessment of the patient having lens surgery requires an assessment of the lens itself, whether clear (in refractive lens exchange) or cataractous (for cataract surgery), and an assessment of the optics of the eye in order to provide the patient with a refractive outcome as close as possible to their desire.

ASSESSMENT OF LENS OPACITIES8 INTRODUCTION Age-related changes in the crystalline lens induce changes in visual function. The lens functions as an optical element and provides one third of the refractive power of the human eye. The eye’s optical properties depend on the power of the lens, which in turn is determined by its physical dimensions (curvatures and thickness) and its refractive index as well as its transmissibility and the organization of its internal components. The progressive insolubilization of lens protein with age is believed to cause density fluctuations, which scatter light and impair vision. The impact of a patient’s cataract on the retinal image may be appreciated on funduscopic examination, which shows the blur of fine retinal vessels. The clinician is unable to resolve the retinal capillaries directly because of the scattering of light by opacities in the patient’s lens. Light scattering also blurs the images of fine objects viewed by individuals with cataract.

DIAGNOSIS OF LENS OPACITIES Slit-lamp biomicroscopy is the major method used to observe and assess cataracts. However, the image seen often fails to correlate with the patient’s visual acuity or function. The relationship between alterations in the structural proteins, the increase in light scatter associated with conventional biomicroscopy, and the capacity of visual function is not a simple one. For all lens examinations, the pupil is dilated maximally.

Fig. 5-3-2  Cortical cataract.

In certain instances, crystals appear in the adult nucleus (or in the cortex) that, on slit-lamp examination, appear to be of different colors (polychromatic luster).

Cortical Opacities

The changes in transparency involve most of the cortex of the lens (Fig. 5-3-2). The changes evolve as follows: l Hydration of the cortex with development of subcapsular vacuoles; l Formation of ray-like spaces filled with liquid, which is at first transparent and later becomes opaque; l Lamellar separation of the cortex with development of parallel linear opacities; and l Formation of cuneiform opacities that originate at the periphery of the lens and spread toward the center.

Posterior Subcapsular Opacities

Posterior subcapsular opacities may develop as isolated entities or may be associated with other lens opacities. The opacity begins at the posterior polar region and then spreads toward the periphery. Often, granules and vacuoles are detectable in front of the posterior capsule.

Advanced Cataracts

The crystalline lens may swell and increase in volume because of cortical processes (intumescent cataract; Fig. 5-3-3). Complete opacification of the lens is called a mature or morgagnian cataract. If the liquefied cortical material is not, or is only partially, reabsorbed, the solid nucleus may “sink” to the bottom (Fig. 5-3-4). Reabsorption of the milky cortex causes a reduction in the lens volume, resulting in capsular folding (hypermature cataract).

CLASSIFICATION OF LENS OPACITIES

GRADING OF LENS OPACITIES

With age, the transparency of the lens decreases progressively and a wide variety of opacities may occur.9 The morphological types of senile cataract fall into four basic categories: nuclear, cortical, posterior subcapsular cataracts, and advanced. These cataract types can be graded clinically and can be measured photographically.

Gradations and classifications of cataracts are useful in determining the potential difficulty of cataract surgery, in cataract research, in studies to explore causation, and in trials of putative anticataract drugs. Devices designed to quantify lens opacification have been developed10 − these instruments (such as the Kowa Early Cataract Detector and the Scheimpflug Photo slit lamp) appear to be more ­accurate when used to assess the formation of nuclear cataracts than that of cortical cataracts. A rapid method for the gradation of cataract in epidemiological studies has been reported by Mehra and Minassian11 − the area of lenticular opacity is assessed by direct ophthalmoscopy and graded on a scale from 0 to 5. Highly reproducible, validated systems (Lens

Nuclear Opacities

Initially, an increase in optical density of the nucleus occurs (nuclear sclerosis). The fetal nucleus is first involved and then the whole adult nucleus. The increase in density is followed by an opacification (Fig. 5-3-1), which implies a change in color, namely from an initial clear, to yellow, to a subsequent brown (brownish cataract).

411

performed. The Preferred Practice Pattern of the American Academy of Ophthalmology recommends Snellen acuity as the best general guide to the appropriateness of surgery but recognizes the need for flexibility with due regard to a patient’s particular functional and visual needs, environment, and risks, which may vary widely.15 When the cataract is very dense and opaque, visual acuity may be reduced to light perception only (cataract is still the major cause of blindness throughout the world).

5 THE LENS

Contrast Sensitivity Reduction

Fig. 5-3-3  Intumescent cataract. The crystalline lens increases in volume  because of swelling processes that involve the cortex.

Patients with cataracts commonly complain of loss of the ability to see objects outdoors in bright sunlight and of being blinded easily by oncoming headlamps in night-time driving.16 Typically, loss of contrast sensitivity in patients who have cataracts has been reported to be greater at higher spatial frequencies. All cataracts lower contrast sensitivity − the posterior subcapsular opacities have been reported to be the most destructive.

Myopic Shift

The natural aging of the human lens produces a progressive hyperopic shift. Nuclear changes induce a modification of the refractive index of the lens and produce a myopic shift that may be of several diopters or greater. It is possible to predict that an aging person who had emmetropia previously, but who can now read with no correction (“second sight”), is developing nuclear cataract. If the lens structure becomes heterogeneous, with cortical spoke ­cataract for example, the change in refractive index may be uneven and may produce some degree of internal astigmatism.

Monocular Diplopia Fig. 5-3-4  Morgagnian cataract. The nucleus is seen as a “suntan” or a dark shadow in the inferior third of the pupil.

Opacities ­Classification System III; see below) for cataract classification have been developed by Chylack et al.12 to define the effects of specific cataract type and extent very accurately; these enable the effects of specific cataract types on specific visual functions to be quantified.

Lens Opacities Classification System III

For nuclear opalescence (NO), a slit beam is focused on the lens nucleus and the density of the lens is compared with a set of standard photographs (opalescence and color). If the density is equal to or less than that corresponding to the first photograph, NO nuclear cataract (NC) is zero; NO NC is 1 if the density is equal to or less than that for the second photograph, and so on. The photographs represent lens nuclei of increasing density, and the patient’s cataract is graded accordingly. For cortical cataracts, a retroillumination view through the pupil is used to view the lens, focused first at the anterior capsule and then at the posterior capsule. The photographs are compared with standard photographs − each succeeding photograph shows the pupillary area covered by more cortical cataract. For posterior subcapsular cataract, a retroillumination view of the lens is used, focused at the posterior capsule. Again, the patient’s cataract is graded according to standard photographs (Fig. 5-3-5)

EFFECTS OF OPACITIES ON VISION The nature of the effect of opacity on vision varies according to the degree of the cataract and the cataract morphology. No single test adequately describes the effects of cataract on a patient’s visual status or functional ability.13

Visual Acuity Reduction

412

Measurement of visual acuity has been the standard tool by which to estimate the visual disability of patients and by which to detect changes in visual function induced by cataract over time.14 However, it has been found clinically that visual acuity can remain high despite age-related lens opacities: the severity of the visual disability measured using highcontrast Snellen acuity charts is not sensitive to visual disability characterized by loss of contrast sensitivity. Usually, visual acuity testing is conducted under ideal circumstances, which are not normally met in the real world, and so the results may not reflect visual disabilities that occur in less ideal conditions. Although not a definitive measurement of visual dysfunction, simple Snellen ­acuity is the most used index to determine whether cataract surgery should be

Monocular diplopia is common in patients who have lens opacities, particularly cortical spoke cataract and in conjunction with water clefts that form radial wedge shapes and contain a fluid of lower refractive index than the surrounding lens. The patients, in some cases, may complain of polyopia.

Glare

Even minor degrees of lens opacity cause glare because of the forward scatter of light.17 All forms of cataract can cause glare, especially cortical and posterior subcapsular. Such patients often see more poorly in daylight conditions and in the context of night driving. Unlike contrast sensitivity reduction, some glare may be produced by opacities that do not lie within the pupil diameter. The differences between measured visual acuity in a darkened room (and with a high-contrast chart) and acuity in ambient light that produces glare are interesting as subjective criteria for the justification of surgery.

Color Shift

The cataractous lens becomes more absorbent at the blue end of the spectrum, especially with nuclear opacities. Usually patients are not aware of this color visual defect, but it becomes obvious retrospectively after cataract surgery and visual rehabilitation.

Visual Field Loss

According to the morphology, the density, and the location of the opacities, the field of vision may be affected.

ASSESSMENT OF OPTICS AND BIOMETRY 18 Introduction The most common and successful method to replace crystalline lens power is to use an intraocular lens (IOL). The earliest documented IOL implant was performed by Harold Ridley in 1949.19 Ridley’s original IOL was made of polymethyl methacrylate (PMMA) and placed in the posterior chamber, in a manner very similar to that of the present method. Over the past 50 years, improvements in the purity of the PMMA, in the quality of lens manufacturing, and in the surgical techniques used have transformed this technique into one of the most successful surgical procedures performed today.

OPTICS Once surgery is performed, the eye is rendered aphakic. The optics of the aphakic eye is different from the phakic eye, and an aged phakic eye is different from a young phakic eye. The “normal” optics changes with

5.3

Lens Opacities Classification System 111 (LOCS 111)

Nuclear

Colour/ Opalescence

Patient Work-up for Cataract Surgery

N02 NC2

N03 NC3

N04 NC4

N05 NC5

N06 NC6

Cortical

N01 NC1

C2

C3

C4

C5

P1

P2

P3

P4

P5

Posterior

Subcapsular

C1

Fig. 5-3-5  Lens Opacities Classification System III simulation chart.

STANDARDIZED APHAKIC EYE

STANDARDIZED 72-YEAR-OLD PHAKIC EYE ultrasonic axial length (23.45 mm)

corneal vertex plane

corneal vertex plane

optical axial length (23.65 mm)

optical axial length (23.65 mm) spectacle lens (–0.50 D)

2 principal plane of cornea (50 �m)

anterior chamber depth (3.74 mm)

retinal thickness (250 �m)

spectacle lens (+12.50 D)

2 principal plane of cornea (50 �m)

anterior chamber depth (3.74 mm)

retinal thickness (250 �m)

anterior iris plane

anterior iris plane

neye = 1.336

neye = 1.336 vertex distance (14 mm)

ultrasonic axial length (23.45 mm)

lens (4.70 mm)

cornea

iris

vertex distance (14 mm)

optical axis

cornea

retina

rant = 7.704 mm Kker = 43.81D, n = 1.3375 Kref = 43.27D, n = 4/3

rant = 7.704 mm Kker = 43.81D, n = 1.3375 Kref = 43.27D, n = 4/3

nair = 1.000

nair = 1.000

Fig. 5-3-6  Standardized 72-year-old phakic eye. The values shown are the mean values for a phakic eye: keratometric power of the cornea (kker), net refractive power of the cornea (kref ), and anterior radius of the cornea (rant). Indices of refraction (n) are 1.336 for the aqueous and vitreous (neye) and 1.000 for air (nair).

age. With the advent of the IOL (pseudophakic eye) and its ­subsequent further development having reached a high level of sophistication, the optics of a pseudophakic eye can now mimic the optics of younger eyes. The normal 72-year-old human eye has a total dioptric power of approximately 58 D, with nearly 75% of the power from the cornea and 25% of the power from the crystalline lens (Fig. 5-3-6).20 Removal of the crystalline lens leaves the eye extremely deficient in dioptric power, which must be replaced to restore vision. The replacement of the dioptric power can be in the form of spectacles, contact lenses, corneal onlays, corneal implants, or IOLs. Although each modality can restore the patient’s vision, the optical consequences are dramatically different and must be understood by the clinician to avoid unnecessary complications.

optical axis iris

retina

Fig. 5-3-7  Standardized 72-year-old aphakic eye. The values shown are the mean values for an aphakic eye: keratometric power of the cornea (kker), net refractive power of the cornea (kref ), and anterior radius of the cornea (rant). Indices of refraction (n) are 1.336 for the aqueous and vitreous (neye) and 1.000 for air (nair).

APHAKIA Figure 5-3-7 shows the aphakic eye with a spectacle lens at a vertex of 14 mm to correct the patient’s vision. Replacement of the crystalline lens power with a spectacle lens causes the image that is formed on the patient’s retina to be roughly 25% larger than the image formed with the crystalline lens. The actual magnification is determined by the exact power of the aphakic spectacles. There is approximately 2% of magnification for each diopter of power in the spectacles. The average aphakic spectacle is therefore 12.5 D. The magnification from aphakic spectacles causes other optical aberrations, such as a ring scotoma (Fig. 5-3-8), jack-in-the-box phenomenon (Fig. 5-3-9), and a pincushion distortion (Fig. 5-3-10). Because the image through the spectacles is magnified by 25%, the actual field of view through

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5

JACK-IN-THE BOX PHENOMENON

RING SCOTOMA

THE LENS

c b

d

d

c

x

b

a

a

x 3

2 1

entrance pupil a

a

b c

c d

d Fig. 5-3-8  Ring scotoma. Area X on the diagram. This angle increases ­proportionally with the power of the aphakic correction. A +10.00DS aphakic correction subtends an angle of approximately 9˚ depending on the back vertex distance. The reason for the scotoma, as can be seen in the diagram, is the disparity in refraction between the first ray out of the aphakic lens correction (b) and the first ray to pass through the aphakic correction (c). The prismatic effect ray c causes all the imagery at x (ext b-c) to be lost as can be seen by the zero b-c disparity on the retina. This occurs in a ring all the way around the lens rim and retina, hence the term ring scotoma.

b

1

3

Fig. 5-3-9  Jack-in-the-box phenomenon. This is caused by an eye moving ­peripherally across an aphakic correction as seen in the diagram. The ring scotoma as seen in Fig 5-3-8 moves centrally. As the eye moves fixation from d to the peripheral image a, the lost image x (c-b) disappears hence image 2 disappears and on the retina moves directly from 1 to 3 giving the impression of ­disappearance then sudden reappearance – jack-in-the-box! If contact lenses are worn, they move with the eye and hence jack-in-the-box does not occur.

DISTORTION FROM SPECTACLE LENSES WITH OBLIQUE ANGLES OF GAZE Pincushion distortion from plus lenses to correct hypermetropia

a

Barrel distortion from minus lenses to correct myopia

a

a

Normal

Fig. 5-3-10  Distortion from spectacle lenses with oblique angles of gaze.

414

the spectacles is reduced by 25%, which makes it impossible to see the 25% of the peripheral field that would be seen normally through spectacles with no power. The result is an annulus of no vision, or ring scotoma. When the image of an object moves from the extreme visual field toward the center of fixation, as it passes through the ring scotoma it disappears until it moves into the central island of vision. This jumping into and out of the patient’s vision has been referred to as the jack-inthe-box phenomenon.21–23 Driving a motor vehicle thus becomes very

difficult to perform, as does any activity in which objects move rapidly across the visual field. Pincushion distortion is a property of all plus lenses and is proportional to their dioptric power. This distortion makes a square look like a pincushion − the corners of the square have a stretched-out appearance, and the sides are pushed in, as shown in Fig. 5-3-10. Every object viewed through aphakic spectacles is distorted in this way, which makes rectangular objects, such as doors and boxes,

STANDARDIZED PSEUDOPHAKIC SCHEMATIC EYE ultrasonic axial lengh (23.45 mm) optical axial lengh (23.65 mm) spectacle lens (–0.50 D)

2 principal plane of cornea (50 �m) effective lens position (5.25 mm)

anterior chamber depth (3.74 mm)

retinal thickness (250 �m)

anterior iris plane neye = 1.336 vertex distance (14 mm) cornea

optical axis thin intraocular lens (21.19 D) iris

retina

rant = 7.704 mm Kker = 43.81D, n = 1.3375 Kref = 43.27D, n = 4/3 nair = 1.000

Fig. 5-3-11  Standardized 72-year-old pseudophakic eye (thin IOL). The values shown are the mean values for a pseudophakic eye: keratometric power of the cornea (kker), net refractive power of the cornea (kref ), and anterior radius of the cornea (rant). Indices of refraction (n) are 1.336 for the aqueous and vitreous (neye) and 1.000 for air (nair). Using these values, the required thin IOL power is 21.19 D at an effective lens position (ELP) of 5.25 mm.

appear like a pincushion. For an architect or draftsman, these distortions make the job extremely difficult or impossible to perform. The distortions created by aphakic spectacles necessitated the development of other modalities, such as IOL and corneal onlays or inlays.

Corneal Contact Lenses, Onlays, and Inlays

To correct aphakia at the corneal plane involves the use of contact lenses or surgery that adds dioptric power to the cornea. As the position at which the optical correction is made moves closer to the retina, the necessary dioptric power increases but the subsequent magnification decreases. The power at the corneal plane that is equivalent to 12.5 D at a vertex of 12 mm is 14.7 D; a patient who needs 12.5 D in aphakic spectacles would need 14.7 D in a soft or rigid contact lens. At the corneal plane the magnification is 6−8%. This value is near the limit of aniseikonia (image size disparity between the two eyes),24, 25 so most unilaterally aphakic patients can have binocular vision, with the aphakic eye corrected using a contact lens and the other eye phakic. Binocular vision is not possible with one aphakic spectacle and a normal phakic lens. Corneal onlays, such as epikeratophakia, and inlays are not used commonly in clinical settings. The optical effects are no different from those of a contact lens, but onlays and inlays have the advantage that the patient need provide no maintenance. However, the excellent success of contact lenses and IOLs means that surgical techniques to correct aphakia at the cornea are not reasonable clinical alternatives at this time.

Pseudophakia

Figure 5-3-11 shows a posterior chamber lens in-the-bag following cataract extraction. Just as the average spectacle power for aphakia is 12.5 D, the average power of an equiconvex IOL in-the-bag is approximately 21 D. The average magnification of an IOL in this position is 1.5%, compared with the original crystalline lens. For an anterior chamber IOL the average power would be less, approximately 18 D, and the magnification would be approximately 2.0%. Although some discerning patients can detect this disparity by alternately covering each eye, almost everyone can achieve binocular vision with one eye pseudophakic and the other phakic.26

pseudophakic lens design

The IOLs currently available are either biconvex, convexoplano, or meniscus. As a result of clinical performance and optical analysis, the majority of lenses implanted today are biconvex.27, 28 The reasons for

5.3 Patient Work-up for Cataract Surgery

corneal vertex plane

the emergence of this design as the most superior are both optical and mechanical. The quality of the optical design of an IOL is measured on the basis of its performance with respect to tilting, decentration, and spherical aberration. In terms of each of these, the positive meniscus lens performs miserably and rarely is used today. The original design concept was to create a “laser space,” so that the posterior surface of the lens would not be in contact with the posterior capsule; this avoids pitting of the lens with neodymium:yttrium−aluminum−garnet (Nd:YAG) capsulotomy. When a meniscus lens is tilted or decentered, the induced astigmatism and power change are dramatic. A 10°−15° tilt can induce enough regular and irregular astigmatism to make the spectacle correction intolerable and results in a best corrected vision of less than 20/20 (6/6), simply because of the poor optics. Convexoplano IOLs (convex on the front surface and flat on the posterior surface) were the first to be designed. They are the simplest to manufacture, because one surface is flat and all the optical power lies in the other surface. These lenses have performed well over the years, but degradation of the retinal image with lens tilt or decentration is still greater than it is with biconvex lenses. Optical studies to determine the optimal lens design have shown that a biconvex design with a front surface much steeper than the back appears to minimize this aberration for most humans.29 No clinical studies have demonstrated a difference in the spherical aberration of a convexoplano lens with respect to that of a biconvex lens that is steeper on the front surface. The optimal optical and mechanical performance of an IOL in the human eye is that of biconvex lenses. In addition to minimizing the effects of tilt, decentration, and spherical aberrations, a convex posterior surface may reduce the migration of lens epithelial cells, a ­ migration that may lead to opacification of the capsule; this may be an additional������������������������������������������������������������ mechanical ����������������������������������������������������������� advantage of biconvex over convexoplano lenses. The biconvex IOL has become the predominant lens style used today because of its superior optical and mechanical clinical performance.27

Edge design (see Chapter 5.2)

Reflections, shimmering peripheral lights, and flashes usually are related to the edge design of a lens. Flat edges from truncation (oval optics) or flat edges in round optics create unwanted external and internal reflections that the patient may see in low light levels.30 Therefore, in the past most lenses had rounded edges to avoid coherent reflected images. Square edge design more recently has been noted to reduce posterior capsular opacification, hence modifications to optimize the properties of both.

Optical transmission

The optical transmission through the human eye to the retina usually is considered to be in the range 400−700 nm in wavelength. The cornea filters any wavelength shorter than 300 nm, and the crystalline lens filters out any wavelength shorter than 400 nm. When the crystalline lens is removed, wavelengths of 300−400 nm reach the retina. In the late 1970s much discussion ensued as to whether the short unfiltered wavelengths that could reach the retina could cause syneresis of the vitreous, macular degeneration, cystoid macular edema, and erythropsia. The results of research into these questions have led to the development of ultraviolet light filtration in almost all IOLs as well as yellow filters in some lenses to reduce the blue light hazard. Some questions have been raised regarding potential sleep disturbance with these filters as the diurnal rhythm regulating rods in the peripheral retina respond to blue light.31

Material

Commercially available IOLs mainly are made of PMMA, silicone, or acrylic. Silicone and acrylic lenses are foldable, so they can be ­implanted through small incisions (2.2−3.5 mm in length). The ­index of refraction for PMMA is 1.491, that for silicone is in the range 1.41−1.46, depending on the model and manufacturer, and for acrylic it is 1.55. The higher the index of refraction, the flatter the curvatures of the lens needs to be to achieve the same refractive power. For a 20 D biconvex IOL with 10 D on each surface, the acrylic lens has the flattest curvatures and the silicone the steepest. As a consequence of the flatter curvatures, the acrylic lens is thinner than the PMMA lens, which, in turn, is thinner than the silicone lens, provided all else is equal. The velocity of ultrasound for these materials at eye temperature (35°C) is 2658 m/second for PMMA, 980−1090 m/second for silicone,

415

5

and 2180 m/second for acrylic.32 All three lens materials have performed well clinically.

THE LENS

Three other special types of IOLs are manufactured currently − multifocal, toric and aspheric. Multifocal IOLs have enjoyed a success similar to that of multifocal contact lenses. Multifocal IOLs produce two or more focal points, which create a focused and defocused image on the retina. The result is an image that is approximately 30% reduced in contrast with respect to monofocal lenses and unwanted optical images can be seen at night, such as halos or rings around headlights.33 The reduced image quality must be weighed against the patient’s desire to be less spectacle dependent. With (multifocal) contact lens failure, the problem is solved by returning to spectacles. A patient who is dissatisfied with a multifocal IOL is more difficult to deal with, and lens exchange occasionally is required. The success of these lenses is based almost entirely on appropriate patient selection. Toric IOLs are simply spherocylindric lenses, just like spectacles. If the toric lens is aligned properly with the patient’s corneal astigmatism and the magnitude is correct, the patient’s corneal astigmatism can be neutralized. The magnitude of the cylinder in the IOL must be approximately 1.4 times the astigmatism in the cornea to neutralize completely the corneal astigmatism; for corneal astigmatism of 1.0 D, the cylinder in the IOL must be 1.4 D. Manufacturers usually provide two nominal toricities and recommend using the one that best fits the particular patient on the basis of a nomogram. As long as the lens is within 30° of the intended axis, the patient has less astigmatism in the spectacles than in the cornea. If the lens is misaligned by more than 30°, the patient has greater astigmatism in the spectacles than in the cornea. It is obvious that the lens must fixate well and not rotate from the axis of the original correct placement, otherwise the patient’s refraction fluctuates and the benefit of a toric lens diminishes. Aspheric lenses are designed to minimize spherical aberration and mimic more closely the optics of younger eyes to produce better optics. The aging crystalline lens causes loss of total eye asphericity (the prolate cornea contributes significantly to aspheric optimization) and the aspheric lenses are designed to restore the asphericity of younger optics. The major contribution that needs to be made by the IOL, before the niceties of the speciality lenses, is pure dioptric accuracy. Ophthalmic research has led to the development of a number of different formulas for the calculation of the appropriate dioptric power for any given eye. The essence of the measurements for the formulas and methods of ­calculation is given in the following paragraphs.

Specialty IOLs

MEASUREMENTS34 INTRODUCTION Fyoderov et al.35 first estimated the optical power of an IOL using vergence formulas in 1967. Between 1972 and 1975, when accurate ultrasonic “A” scan units became available commercially, several investigators derived and published theoretical vergence formulas.36–41 All of these formulas were identical, except for the form in which they were written and the choice of various constants, such as retinal thickness, optical plane of the cornea, and optical plane of the IOL.42 The slightly different constants accounted for less than 0.50 D in the predicted refraction. The use of different constants arose as a result of differences in lens styles, “A” scan units, keratometers, and surgical techniques used by the investigators.

IOL CALCULATIONS THAT REQUIRE AXIAL LENGTH Theoretical Formulas

416

The theoretical formula for IOL power calculations has not changed since the original description by Fyoderov et al.35 in 1967. Although several investigators presented the theoretical formulas in different forms, the only differences were slight variations in the values of retinal thickness and corneal index of refraction. Six variables in the formula exist: l Net corneal power (K) l Axial length (AL) l IOL power (IOLP)

 ffective lens position (ELP) E Desired refraction (DPostRx) l Vertex distance (V) Normally, IOL power is chosen as the dependent variable and found by using the other five variables, where distances are given in millimeters and refractive powers are given in diopters, as in equation 5-3-1. l l

Equation 5-3-1 IOLP = (1336 /[ AL − ELP ]) − (1336 /[1336 /{1000 /([1000 / DpostRx] − V ) + K } − ELP ]) The only variable that cannot be chosen or measured preoperatively is ELP. The improvements in IOL power calculations over the past 30 years are a result of improvements in the predictability of the variable ELP (see Fig. 5-3-11 for the physical locations of the variables). The term effective lens position (ELP) was adopted by the United States Food and Drug Administration in 1995 to describe the position of the lens in the eye, because the often-used term anterior chamber depth (ACD) is not anatomically accurate for lenses in the posterior chamber and can lead to confusion for the clinician. The ELP used for IOLs before 1980 was a constant of 4 mm for every lens in every patient (first-generation theoretical formula). This value actually worked well in most patients, because the majority of lenses implanted were of iris clip fixation type, in which the principal plane averages approximately 4 mm posterior to the corneal vertex. In 1981, Binkhorst improved the prediction of ELP by using a single variable predictor, the axial length, as a scaling factor for ELP (second-generation theoretical formula).43 If the patient’s axial length was 10% greater than normal (normal being 23.45 mm), the ELP used was increased by 10%. The average value of ELP used was increased to 4.5 mm, because the preferred location of an implant was in the ciliary sulcus, approximately 0.5 mm deeper than the iris plane. Also, most lenses were convexoplano, similar to the shape of the iris-supported lenses. By 1997 the average ELP used had increased to 5.25 mm. This increased distance has occurred primarily for two reasons: 1. The majority of implanted IOLs are biconvex, which moves the principal plane of the lens even deeper into the eye. 2. The desired location for the lens is in the capsular bag, which is 0.25 mm deeper than the ciliary sulcus. In 1988, it was proved2 that the use of a two-variable predictor (axial length and keratometry) could significantly improve the prediction of ELP, particularly in unusual eyes (third-generation theoretical formula). The original Holladay 1 formula was based on the geometric relationships of the anterior segment. Although several investigators have modified the original Holladay 1 formula, no comprehensive studies have shown any significant improvement using only these two variables. In 1995, Olsen et al.44 published a four-variable predictor that used keratometry and axial length, preoperative anterior chamber depth, and lens thickness. Their results showed an improvement over the two-variable prediction formulas, because the more information that is used to define the anterior segment value, the better the ELP can be predicted. (It is well known from prediction theory that the more variables that can be measured to describe an event, the more accurately the outcome can be predicted.) Holladay et al.45 discovered that the anterior segment and posterior segment of the human eye often are not proportional in size, which causes significant error in the prediction of the ELP in extremely short eyes (axial length < 20 mm). The authors found that even in eyes less than 20 mm in axial length, the anterior segment was completely normal in the majority of cases. Because the axial lengths were so short, the two-variable prediction formulas severely underestimated ELP, which explains part of the large hyperopic prediction errors with the two-variable prediction formulas. Once this problem was recognized, the authors began to take additional measurements on eyes that had extremely small or extremely large axial lengths, to determine whether the prediction of ELP could be improved by being able to describe the anterior segment more accurately. Table 5-3-3 shows the clinical conditions that illustrate the independence of the anterior segment size and the axial length. For a year, data cohorts were gathered from 35 investigators around the world. Several additional measurements of the eye were taken, but only seven preoperative variables (axial length, corneal power, horizontal corneal diameter, anterior chamber depth, lens thickness, preoperative refraction, and age) were found to improve significantly the prediction of ELP in eyes of axial length in the range 15−35 mm.

   TABLE 5-3-3  CLINICAL CONDITIONS THAT DEMONSTRATE THE INDEPENDENCE OF THE ANTERIOR SEGMENT SIZE AND AXIAL LENGTH Axial Length Short

Normal

Long

Small

Small eye nanophthalmos

Microcornea

Microcornea

Normal

Axial hyperopia

Normal

Axial myopia

Large

Megalocornea

Megalocornea

Large eye

Axial hyperopia

Buphthalmos Axial myopia

The improved accuracy of the prediction of ELP is not totally because of changes in the formula; it also is a function of the technical skills of surgeons who implant lenses in the capsular bag consistently. A 20 D IOL that is displaced 0.5 mm axially from the predicted ELP results in an error of approximately 1.00 D in the stabilized post­operative refraction. However, when using piggy-back lenses that total 60 D, the same axial displacement of 0.5 mm causes a 3 D refractive error; the error is directly proportional to the power of the implanted lens. This direct relationship is why the problem is much less evident in extremely long eyes, because the implanted IOL is either low plus or minus to achieve emmetropia following cataract extraction. Predictions for patients who have eyes with axial lengths in the range 22−25 mm and corneal ­powers in the range 42−46 D will be accurate using current third-generation formulas (Holladay 1,46 SRK/T,47 and Hoffer Q48). In cases outside this range, the Holladay 2 formula should be used to ensure accuracy.

Normal Cornea with No Previous Keratorefractive Surgery Refractive lens exchange (RLE) for high myopia and hyperopia

The intraocular power calculations for RLE are the same as those for when a cataract is present. The patients usually are much younger, however, so the loss of accommodation should be discussed thoroughly. The actual desired postoperative refraction should be discussed, also, because a small degree of myopia (−0.50 D) may be desirable to someone who has no accommodation so that the dependence on spectacles can be reduced. This procedure usually is reserved for patients who are outside the range of other forms of refractive surgery. Consequently, the values of axial length, keratometry, and other factors usually are quite different from those of the typical cataract patient because of the degree of refractive error. In most cases of high myopia, the axial lengths are extremely long (> 26 mm). In cases of high hyperopia, the axial lengths are very short (< 21 mm).

Myopia

In patients who have myopia that exceeds 20 D, removal of the lens often results in postoperative refractions near emmetropia with no implant. The exact result depends on the power of the cornea and the axial length. The recommended lens powers usually range from −10 D to +10 D, but the correct axial length measurement is very difficult to obtain in these cases because of the abnormal anatomy of the posterior pole. Staphylomas often are present in these eyes and the macula often is not at the location in the posterior pole where the “A” scan measures the axial length. In such cases, a “B” scan is recommended to locate the macula (fovea) and recheck the value determined using the “A” scan. Variations of 3−4 D may occur because the macula is on the edge of the staphyloma, but the “A” scan measures to the deepest part of the staphyloma. Such a variation results in a hyperopic error, because the distance to the macula is much shorter than the distance to the center of the staphyloma. The third-generation theoretical formulas give excellent predictions if the axial length is stable and its measurements are accurate.

Hyperopia

For patients who have axial lengths shorter than 21 mm, the Holladay 2 formula should be used. In such cases, the size of the anterior segment has been shown to be unrelated to axial length.45 In many of

these patients, the anterior segments are normal, only the posterior segment is abnormally short. In a few cases, however, the anterior segment is proportionately small with respect to the axial length (nanophthalmos). The differences in the size of the anterior segment in these cases can cause an average of 5 D hyperopic error when third-generation formulas are used, because they predict the depth of the anterior chamber to be very shallow. Use of the newer formula can reduce the prediction error in these eyes to less than 1 D. Accurate measurements of axial length and corneal power are especially important in these cases, because any error is magnified by the extreme dioptric powers of the IOLs. It is important to note, however, that if piggy-back lenses are used to achieve a high power then the variation in ELP between bag-bag lenses and sulcus-bag lenses can cause a refractive surprise of up to 4 D.

Patient Work-up for Cataract Surgery

Anterior Segment Size

5.3

METHODS TO DETERMINE AXIAL LENGTH Axial length can be determined by optical methods and ultrasonic methods. A comparison of optical, ultrasonic, and immersion biometry methods will reduce the likelihood of outliers. The IOL Master provides accurate axial lengths in clear lenses but cannot provide accurate information with more advanced lens opacities. Ultrasonic measurement, on the other hand, is less dependent on the density of the cataract. Immersion biometry reduces the likelihood of corneal compression but has slightly less control over alignment. An examination of all methods where possible will enhance accuracy.

Patients with Previous Keratorefractive Surgery Background

The number of patients who have had keratorefractive surgery (radial keratotomy (RK), photorefractive keratectomy (PRK), or laser-assisted in situ keratomileusis (LASIK)) has increased steadily over the past 20 years. With the advent of the excimer laser, the number is predicted to increase dramatically. To determine corneal power accurately in such cases is difficult; usually it is the determining factor in the accuracy of the predicted refraction following cataract surgery. Fortunately, the presence of previous corneal refractive surgery makes no significant difference to the accuracy of axial length measurement, or any of the other parameters required for IOL power calculation. Nevertheless, to provide this group of patients with the same accuracy of IOL power calculations as provided for standard cataract patients presents an especially difficult challenge to the clinician.

Methods to determine corneal power

To determine accurately the central corneal refractive power is the most important and difficult part of the entire IOL calculation process. The explanation is quite simple − instruments used to measure corneal power make too many incorrect assumptions for corneas that have irregular astigmatism; the cornea can no longer be compared to a sphere centrally, the posterior radius of the cornea is no longer 1.2 mm steeper than the anterior corneal radius, and so on. As a result of these limitations, the calculation method and the trial hard contact lens method are the most accurate, followed by corneal topography, automated keratometry and, finally, manual keratometry.

Calculation method

For the calculation method, three parameters must be known − the k readings and refraction before the keratorefractive procedure, and the stabilized refraction after the keratorefractive procedure. It is ­important

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5 THE LENS

that the stabilized postoperative refraction be measured before any myopic shifts from nuclear sclerotic cataracts occur. Also, it is possible for posterior subcapsular cataracts to cause an apparent myopic shift, similar to capsular opacification, in which the patient wants more minus in the refraction to make the letters appear smaller and darker. The concept, described in 1989,49 subtracts the change in refraction caused by the keratorefractive procedure at the corneal plane from the original k readings before the procedure, to arrive at a calculated postoperative k reading. This method usually is the most accurate because the preoperative k values and refraction usually are accurate to ±0.25 D. An example calculation is given in Box 5-3-1.

Trial hard contact lens method

The trial hard contact lens method requires a plano hard contact lens with a known base curve and a patient whose cataract does not prevent refraction to approximately ±0.50 D. This tolerance usually requires a visual acuity of better than 20/80. The patient’s spheroequivalent refraction is determined by normal refraction. The refraction then is repeated with the hard contact lens in place. If the spheroequivalent refraction does not change with the contact lens, then the power value for the patient’s cornea must be the same as that for the base curve of the plano contact lens. If the patient has a myopic shift in the refraction with the contact lens, then the power value for the base curve of the contact lens is greater than that of the cornea by the amount of the shift. If there is a hyperopic shift in the refraction with the contact lens, then the power value for the base curve of the contact lens is less than that for the cornea by the amount of the shift. For example, take a patient who has a current spheroequivalent refraction of +0.25 D. With a plano hard contact lens of base curve 35.00 D placed on the cornea, the spherical refraction changes to −2.00 D. Because the patient experiences a myopic shift with the contact lens, the power value for the cornea must be lower than that for the base curve of the contact lens by 2.25 D. Therefore, the cornea must be 32.75 D (35.00−2.25 D), which is slightly different from the value obtained by the calculation method (see Box 5-3-1). This method is compromised by the possible lack of accuracy of the refractions, which may be limited by the cataract.

Corneal topography

418

Current corneal topography units measure more than 5000 points over the entire cornea and more than 1000 points within the central 3 mm. This additional information provides greater accuracy in determining the power of corneas with irregular astigmatism compared with the data yielded by keratometry. The computer in topography units allows the measurement to account for the Stiles-Crawford effect, actual pupil size, and so on. These algorithms allow a very accurate determination of the anterior surface of the cornea. They provide no information, however, about the posterior surface of the cornea. In order to determine accurately the total power of the cornea, the power of both surfaces must be known. In normal corneas that have not been subjected to keratorefractive surgery, the posterior radius of curvature of the cornea averages 1.2 mm less than that of the anterior surface.50 For a person who has an eye with an anterior corneal radius of 7.5 mm and using the standardized keratometric index of refraction of 1.3375, the corneal power would be 45.00 D. Several studies have shown that this power overestimates the total power of the cornea by approximately 0.56 D. Hence, most IOL calculations today use a net index of refraction of 1.3333 (4/3) and the anterior radius of the cornea to calculate the net power of the cornea. Using this lower value, the total power of a cornea with an anterior radius of 7.5 mm would be 44.44 D. This index of refraction has provided excellent results in normal corneas for IOL calculations. Following keratorefractive surgery, the assumptions that the central cornea can be approximated by a sphere (no significant irregular astigmatism or asphericity) and that the radius of curvature of the posterior cornea is 1.2 mm less than that of the anterior cornea are no longer true. Corneal topography instruments can account for the changes in the anterior surface, but they are unable to account for any differences in the relationship to the posterior radius of curvature. In RK, the mechanism of having a peripheral bulge and central flattening apparently causes similar changes in both the anterior and posterior radii of curvature, with the result that using the net index of refraction for the cornea (4/3) usually gives fairly accurate results, particularly for optical zones larger than 4−5 mm. In RKs with optical zones of 3 mm or less,

the accuracy of the predicted corneal power diminishes. Whether this inaccuracy occurs as a result of the additional central irregularity with small optical zones or of the difference in the relationship between the front and back radii of the cornea is unknown at this time. Studies in which the posterior radius of the cornea is measured are necessary to answer this question. In PRK and LASIK, inaccuracies in the measurement of net corneal power are almost entirely due to the change in the relationship of the radii at the front and back of the cornea, because the irregular astigmatism in the central 3 mm zone usually is minimal. In these two procedures, the anterior surface of the cornea is flattened, with little or no effect on the posterior radius. Using a net index of refraction (4/3) overestimates the power of the cornea by 14% of the change induced by the PRK or LASIK; if the patient had a 7 D change in the refraction at the corneal plane from a PRK or LASIK with spherical preoperative k values of 44 D, the actual power of the cornea is 37 D, but the ­topography units give 38 D. If a 14 D change in the refraction occurs at the corneal plane, the topography units overestimate the power of the cornea by 2 D. In summary, corneal topography units do not provide accurate central corneal power following PRK, LASIK, or RKs with optical zones of 3 mm or less. In RKs with larger optical zones the topography units become more reliable. The calculation method and hard contact lens trial always are more reliable. Topography does, however, provide an excellent overview of central and peripheral corneal shape, the preoperative knowledge of which is valuable in the management of actual surgical intervention with respect to the management of the prevention and correction of corneal astigmatism (qv).

Automated keratometry

Automated keratometers usually are more accurate than manual keratometers for corneas of small optical zone (= 3 mm) RKs, because they sample a smaller central area of the cornea (nominally 2.6 mm). In addition, the automated instruments often have additional eccentric fixation targets that provide more information about the paracentral cornea. When a measurement error on an RK cornea occurs, the instrument almost always gives a central corneal power that is greater than the true refractive power of the cornea. This error occurs because the samples at 2.6 mm are very close to the paracentral knee of the RK. The smaller the optical zone and the greater the number of the RK incisions, the greater the probability and magnitude of the error. Most automated instruments have reliability factors given for each measurement to help the clinician decide on the reliability of the measurement. Automated keratometry measurements following LASIK or PRK yield accurate values of the front radius of the cornea, because the transition areas are far outside the 2.6 mm zone that is measured. The measurements still are not accurate, however, because the assumed net index of refraction (4/3) is no longer appropriate for the new relationship of the front and back radius of the cornea after PRK or LASIK, just as with the topographic instruments. The change in central corneal power as measured by the keratometer used in PRK or LASIK must be increased by 14% to determine the actual refractive change at the plane of the cornea. Hence, the automated keratometer overestimates the power of the cornea proportionately to the amount of PRK or LASIK performed.

Manual keratometry

Manual keratometers provide the least accurate measure of central corneal power following keratorefractive procedures, because the area that they measure usually is larger than 3.2 mm in diameter. Therefore, measurements in this area are extremely unreliable for RK corneas that have optical zones less than or equal to 4 mm. The one advantage of the manual keratometer is that the examiner actually is able to see the reflected mires and the amount of irregularity present. To see the mires does not help obtain a better measurement, but it does allow the observer to discount the measurement as unreliable. The manual keratometer has the same problem with PRK and LASIK as topographers and automated keratometers and, therefore, is no less accurate. The manual keratometer overestimates the change in the central refractive power of the cornea by 14% following PRK and LASIK.

Choosing the desired postoperative refraction target

The procedure to determine the desired postoperative refractive target is no different from that used for other patients who have cataracts, in whom the refractive status and the presence of a cataract in the other

BOX 5-3-1 THE CALCULATION METHOD

Step 1 To calculate the spheroequivalent refraction for refractions at the corneal plane (SEQC) using the spheroequivalent refraction at the spectacle plane (SEQS) at a given vertex (V), use equations 5-3-5 and 5-3-6: Equation 5-3-5

SEQS = sphere + 0.5(cylinder)

Equation 5-3-6

SEQC = 1000 /[(1000 / SEQS ) − V ]

Using equations 5-3-5 and 5-3-6, we find the preoperative SEQS and SEQC are: Preop SEQS = − 10.00 + 0.5(1.00) = − 9.50D Preop SEQC = 1000 [(1000 − 9.50 ) − 14.00] = − 8.38 The postoperative spheroequivalent refraction at the corneal plane would be: Postop SEQS = − 0.25 + 0.5 (1.00 ) = + 0.25 Postop SEQC = 1000 1000 0.25 = + 0.25 Step 2 To calculate the change in refraction at the corneal plane, use equation 5-3-7 Equation 5-3-7 Change in refraction = preoperative SEQC − postoperative SEQC = −8..38 − ( + 0.25) = − 8.63 D Step 3 To calculate the postoperative corneal refractive power, use equation 5-3-8 Equation 5-3-8

mean mean         Mean postoperative k =  preoperative  −  refraction at     corneal plane  k     = 42.00 − 8.63 = 33.37 D This value is the calculated central power of the cornea following the  keratorefractive procedure. For IOL programs that require two k readings, this value is entered twice.

eye are the major determining factors. A complete discussion as to how to avoid refractive problems with cataract surgery is beyond the scope of this text (for a thorough discussion see Holladay and Rubin51). A short discussion of the major factors follows. If the patient has binocular cataracts, the decision is much easier because the refractive status of both eyes can be changed. The most important decision is whether the patient prefers to be myopic and read without glasses, or near emmetropic and drive without glasses. In some cases the surgeon and patient may choose the intermediate distance (−1.00 D) for the best compromise. To target for monovision is certainly acceptable, provided the patient has used monovision successfully in the past. Monovision in a patient who has never experienced this condition may cause intolerable anisometropia and require further surgery. Monocular cataracts restrict the choice of postoperative refraction, because the refractive status of the other eye is fixed. The general rule is that the operative eye must be within 2 D of the nonoperative eye in order to avoid intolerable anisometropia. In most cases this means the other eye is matched or a target of up to 2 D nearer emmetropia is set; if the nonoperative eye is −5.00 D, then the target is −3.00 D for the operative eye. If the patient successfully wears a contact in the unoperative eye or has demonstrated already the ability to accept monovision, an exception can be made to the general rule. It must be stressed, however, that should the patient not be able to continue wearing a contact lens, the necessary glasses for binocular correction may be intolerable and additional refractive surgery may be required.

Special limitations of iol power calculation formulas

As discussed previously, the third-generation formulas (Holladay 1, ­Hoffer Q, and the SRK/T) and the newer Holladay 2 are much more accurate than previous formulas the more unusual the eye. Older

IOL CALCULATIONS USING k VALUES AND PREOPERATIVE REFRACTION Formula and Rationale for Using Preoperative Refraction Versus Axial Length

5.3 Patient Work-up for Cataract Surgery

Mean preoperative k = 42.50 × 90° 41.50 × 18 0° = 42.00 Preoperativerefraction = − 10.00 / + 1.00 × 90 ( vertex = 14.00mm) Postoperativerefraction = − 0.25 + 1.00 × 90 ( vertex = 14.00mm)

f­ormulas, such as the SRK1, SRK2, and Binkhorst 1, should not be used in these cases. None of these formulas gives the desired result if the central corneal power is measured incorrectly. The resulting errors almost always are in the hyperopic direction following keratorefractive surgery, because the measured corneal powers usually are greater than the true refractive power of the cornea. To further complicate matters, the newer formulas often use keratometry as one of the predictors to estimate ELP of the IOL. In patients who have had keratorefractive surgery, the corneal power is usually much flatter than normal and certainly flatter than before the keratorefractive procedure. In short, the ELP of a patient who has a 38 D cornea with no keratorefractive surgery would not be expected to be similar to that of a patient who has a 38 D cornea with keratorefractive surgery. New IOL calculation programs are being developed now to handle these situations and will improve predictions for these cases.

In a standard cataract removal with IOL implantation, the preoperative refraction is not very helpful for the calculation of the power of the implant, because as the crystalline lens is removed, so the dioptric power is being removed and then replaced. In cases in which power is not being reduced in the eye, such as secondary implant in aphakia, piggyback IOL in pseudophakia, or a minus IOL in the anterior chamber of a phakic patient, the necessary IOL power for a desired postoperative refraction can be calculated from the corneal power and preoperative refraction-knowledge of the axial length is not necessary. The formula used to calculate the necessary IOL power is given in equation 5-3-2,52 where ELP is the expected lens position in millimeters (distance from corneal vertex to principal plane of IOL), IOLP is the IOL power in diopters, k is the net corneal power in diopters, PreRx is the preoperative refraction in diopters, DPostRx is the desired postoperative refraction in diopters, and V is the vertex distance in millimeters of refractions. Equation 5-3-2 IOLP = 1336 /[1336 /{(1000 /[{1000 / Pr eRx} − V ]) + k} − ELP] −

1336[1336 /{(1000 / [{1000 / DPostRx} − V ]) + k} − ELP ]

Cases in Which to Use the Calculation from Preoperative Refraction

As mentioned above, the appropriate cases for which preoperative ­refraction and corneal power are used include the following: l Secondary implant in aphakia l Secondary piggy-back IOL in pseudophakia l A minus anterior chamber IOL in a high myopic phakic patient In each of these cases dioptric power is not being diminished in the eye, so the problem is simply to find the IOLP at a given distance behind the cornea ELP that is equivalent to the spectacle lens at a given vertex distance in front of the cornea. If emmetropia is not desired, then an additional term, the desired postoperative refraction (DPostRx), must be included. The formulas for calculating the predicted refraction and the back calculation of the ELP are given in Holladay.20 Use of the formula for particular cases is outlined below.

Secondary Implant for Aphakia

The patient discussed here is 72 years old and is aphakic in the right eye and pseudophakic in the left eye. The right eye can no longer tolerate an aphakic contact lens. The capsule in the right eye is intact and a posterior chamber IOL is desired. The patient is −0.50 D in the left eye and would like to be the same in the right eye. The mean keratometric k is 45.00 D, aphakic refraction is +12.00 sphere at vertex of 14 mm, manufacturer’s anterior chamber depth (ACD) lens constant is 5.25 mm, and the desired postoperative refraction is −0.50 D. Each of the values above can be substituted into equation 5-3-2 except for the manufacturer’s ACD and the measured k reading. The labeled values on IOL boxes are primarily for lenses implanted in the bag. Because this lens is intended for the sulcus, 0.25 mm should be

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subtracted from 5.25 mm to give the equivalent constant for the ­sulcus. The ELP, therefore, is 5.00 mm. The k reading must be converted from the measured keratometric value (n = 1.3375) to the net k reading (n = 4/3), for the reasons described previously under corneal topography. The conversion is performed by multiplying the measured k reading by the fraction obtained in equation 5-3-3 and inserting this into equation 5-3-4. Equation 5-3-3

INVESTIGATIONS FOR FURTHER SURGICAL REFINEMENT CORNEAL TOPOGRAPHY53

Conversion fraction = ([ 4 / 3] − 1) / (1.3375 − 1)

Using the mean refractive K, aphakic refraction, vertex distance, ELP for the sulcus, and the desired postoperative refraction in equation 5-3-2, the patient needs a 22.90 D IOL. A 23.00 D IOL would yield a predicted refraction of −0.57 D.20

Over the years many different techniques for the construction and ­closure of incisions for cataract surgery have been proposed, each with its own claimed advantages. More recently, corneal topography has ­provided an objective means by which to compare the effects of various surgical parameters on optical outcome. Nowadays, the aim of cataract surgery is to return patients to good uncorrected vision. This requires that their final refraction be within 1 D of emmetropia or a predetermined ametropic result, and that preexisting and surgically induced astigmatism be minimized.54 To achieve this, the refractive element of each stage of surgery has to be optimized, which, particularly in difficult cases, is facilitated by the use of corneal topography.

Secondary Piggy-Back IOL for Pseudophakia

PREOPERATIVE TOPOGRAPHY

= (1 / 3) / 0.3375 = 0.98765

Equation 5-3-4 Mean refractive k = Mean keratometric K × conversion fraction = 45.00 × 0.98765 = 44.44D

In patients who have a significant residual refractive error following the primary IOL implant, it often is easier surgically and more predictable optically to leave the primary implant in place and calculate the secondary piggy-back IOL power to achieve the desired refraction. This method does not require knowledge of the power of the primary implant or of the axial length; it is particularly important in cases in which the primary implant is thought to be mislabeled. The formula works for plus or minus lenses; however, negative lenses only now are becoming available. The patient discussed here is a 55-year-old man who had a refractive surprise after the primary cataract surgery and was left with a +5.00 D spherical refraction in the right eye. No cataract is present in the left eye, and the lens is plano. The surgeon and the patient both desire postoperative refraction of −0.50 D, which was the target for the primary implant. The refractive surprise is felt to be caused by a mislabeled IOL, which is centered in the bag and very difficult to remove. The secondary piggy-back IOL will be placed in the sulcus. This is very important, because trying to place the second lens in the bag several weeks after primary surgery is very difficult. More importantly, it could displace the primary lens posteriorly, thus reducing its effective power and leaving the patient with a hyperopic error. To place the lens in the sulcus minimizes this posterior displacement. The mean keratometric k is 45.00 D, pseudophakic refraction is +5.00 sphere at vertex of 14 mm, manufacturer’s ACD lens constant is 5.25 mm, and the desired postoperative refraction is −0.50 D. Use of the same style lens and constant as in the case above and modifying the k reading to net power, equation 5-3-2 yields a +8.64 D IOL for a 0.50 D target. The nearest available lens is +9.0 D, which would result in −0.76 D. In these cases extreme care should be taken to ensure that the two lenses are well centered with respect to one another. Decentration of either lens can result in poor image quality and can be the limiting factor in the patient’s vision.

Primary Minus Anterior Chamber IOL in a High Myopic Phakic Patient

420

3.50 and modifying the k reading to net corneal power yields −18.49 D for a desired refraction of −0.50 D. If a −19.00 D lens is used, the patient would have a predicted postoperative refraction of −0.10 D.

The calculation for a minus IOL in the anterior chamber is the same as for the aphakic calculation of an anterior chamber lens, with the exception that the power of the lens is negative. In the past, these lenses were reserved for high myopia that could not be corrected by radial keratotomy or photorefractive keratectomy. Because most of these lenses fixate in the anterior chamber angle, concerns of iritis and glaucoma have been raised. Nevertheless, several cases have been performed with good refractive results. Because successful laser-assisted in situ keratomileusis procedures have been performed in myopias up to −20.00 D, these lenses may be reserved for myopia that exceeds this power. Interestingly, the power of the negative anterior chamber implant is very close to the spectacle refraction for normal vertex distances. Consider a case in which the mean keratometric k is 45.00 D, phakic refraction is −20.00 sphere at vertex of 14 mm, manufacturer’s ACD lens constant is 3.50 mm, and the desired postoperative refraction is −0.50 D. Using an ELP of

The preoperative assessment of corneal topography has two roles in cataract surgery. First, as an alternative to keratometry, it can provide a representative measure of the corneal curvature or power necessary to calculate IOL power. Second, knowledge of the magnitude and location of pre-existing astigmatism is important if it is to be reversed by appropriate placement and construction of the wound during surgery.

CALCULATION OF IOL POWER Prior to cataract surgery, the power of the IOL required to give the desired postoperative refraction is determined using measurements of corneal curvature and axial length in a mathematical formula. The final refractive result is dependent upon the accuracy of the biometric data and its appropriate use in the relevant calculations. For these calculations, the corneal curvature commonly is measured by keratometry, and the mean of the two readings is used in the formula. For the majority of normal corneas, the small variability of the keratometry readings gives an accuracy of IOL power to within the 0.5 D step interval of manufactured lenses. In this group, variability in the measurement of the axial length tends to be the main source of discrepancy in the IOL power prediction. In contrast, this is not necessarily the case for patients who have corneal pathology or who have undergone previous corneal or refractive procedures.55 When the cornea is irregular, a better prediction of the required IOL power can be obtained using corneal topography rather than keratometry to measure the corneal curvature.56, 57 As a result of the generation of many more data points, corneal topography has the advantage that it represents these corneas more accurately; but with it comes the difficulty of knowing which data points to use in the IOL power calculations. Moreover, different sets of data points may be more accurate with different formulas.55 Examples of the data points that may be used include:57 l�� Keratometric equivalent at the 3 mm zone (average of the steepest and flattest meridians) l Average curvature of the 3 mm ring l Average curvature of the 4 mm ring l Mean central corneal power l Centrally weighted mean corneal power On the whole, measurements that use a greater number of data points that are nearer the central cornea are the most useful.

Planning the Incision Corneal topography may be used to assess the magnitude, location, and regularity of pre-existing corneal astigmatism. Vector analysis may be used to calculate the induced astigmatism that needs to be added to the existing astigmatism to produce the desired spherical end result. This may be achieved either by astigmatically neutral cataract surgery combined with a refractive corneal procedure, or by the appropriate modifi-

Incision Location

BOX 5-3-2 ISSUES TO DISCUSS WITH A PATIENT PRIOR TO CATARACT SURGERY l l l

Surgically induced change in corneal contour is less for the more peripheral incisions in the sclera or limbus55 than for those that involve the cornea. Incisions on the periphery of the steep axis ­create a central flattening effect and an associated amelioration of the astigmatism.

l

Incision Length and Proximity to Visual Axis

l

A huge quantity of literature now exists to support the theory that smaller incisions are associated with less surgically induced change in corneal contour, a more stable refraction, earlier visual recovery, and a better uncorrected visual acuity, particularly early after surgery.59–61 Since the introduction of IOLs that have flexible optics and injection apparatus, smaller incisions have been possible. Some IOLs have been shown to pass through an astigmatically neutral 2.2 mm incision. Incisions from 3 mm to 4.1 mm in width can be used for both execution of the surgery and titration of astigmatic correction by flattening the steep axis. In addition, as mentioned above, titration of proximity to the visual axis will vary the power of the astigmatic correction (see Chapter 5.4)

STANDARD KERATOMETRY Keratometry is a widely available alternative to videokeratoscopy for the measurement of corneal curvature or power. However, as discussed above, it makes measurements over a very small area of cornea,62 which is acceptable in most regular corneas, the central portions of which are broadly either spherical or spherocylindrical. However, for more irregular corneas, the additional data provided by videokeratoscopy are preferred.

INDICATIONS FOR SURGERY AND INFORMED CONSENT The indications for surgery vary from patient to patient, especially with the current minimally invasive nature of cataract and lens implant surgery (compared with such surgery performed only a few years ago). The visual needs of patients vary according to their ages, occupations, and leisure interests. A cataract may not be symptomatic. Visual symptoms and outcome expectation affect the benefit−risk ratio. Although the risks of technically well-performed small incision surgery are few in a healthy eye, patients require enough information on which to base the decision to proceed. Most patients are inclined to accept the professional judgment of the ophthalmic surgeon, but it is implicit that an adult of sound mind has the right to determine whether surgery should proceed. Therefore, in the context of cataract surgery, how much information is it necessary for an ophthalmologist to disclose to a patient? To what extent should an ophthalmologist shield a patient from the anxieties that can accompany a full explanation of diagnosis and treatment? An ophthalmologist must strike a balance between providing enough information to enable the patient to give informed consent with respect to treatment and engendering the confidence and trust that encompasses a joint decision to proceed. The surgeon shoulders the major responsibility for this, which should be accepted as a consequence of medical and specialist training. In the application of professional judgment, the consideration of alternative management strategies, risks, and benefits allows a patient to make some sort of informed evaluation of the options. Statistical information based on published data may be confusing: Where does the patient fit into the statistics? What are the personal outcome statistics for the surgeon who offers advice? What guarantees are there that a particular surgeon will perform the surgery? A problem arises if potential material risks and dangers are not ­disclosed to a patient before surgery and a complication occurs. The patient may claim that, with prior knowledge of such a risk, he or she would not have consented to the surgery. A risk is material when a rational patient considers the risk of undergoing a certain type of treatment to be significant.

l

l

l

l

l

T he purpose of the surgery The surgical procedure The anesthetic requirements Commonly experienced visual conditions after the surgery, even if temporary That temporary postsurgical visual conditions may become permanent under certain conditions The serious complications that may follow surgery Potential pain or ocular discomfort The refractive requirements after the surgery (the need to wear and the provision of spectacles and/or contact lenses) The potential need for additional procedures (planned staged procedures) Alternative management of the condition

Problems that arise from consent to perform surgical procedures can be minimized but not completely avoided, because every contingency cannot be reviewed completely. Taking the following steps will ensure that a thorough approach has been used. Appropriate patient education is required − the procedure is described in a manner that allows the patient to appreciate what will be done to treat the eye. Although the decision to proceed has to be the patient’s, the surgeon must not pass all the responsibility on to the patient; rather, the surgeon should communicate the appropriate degree of confidence in the procedure’s outcome. The surgeon has to assume much of the responsibility for treatment advice, because the patient cannot appreciate the intricacies of every surgical situation. Ultimately, the patient has to have faith in the ability of the surgeon not only to carry out the procedure but also to make the judgment that the benefits far outweigh the risks. An analogous ­situation might be that of a passenger contemplating a journey on a commercial airliner. If the passenger inquires of the pilot what the ­potential risks are, common sense suggests that the answer would be that they are high in number but low in expectation. A passenger who decides to make the trip has confidence in the airline and the aircrew to complete a successful journey. So it is with surgery: the patient must have confidence in the ability of the surgeon and the surgical team to carry out a successful procedure without knowing each and every pitfall that exists. Alternative stratagems for the management of an ophthalmic condition are explained to the patient to enable patient participation in the final direction of treatment. When uncertainties exist, the patient is advised of the predictability of the planned procedure, its stability, and its safety. Statistical information on outcome is of limited value when given in a general sense. Few surgeons are in a position to give specific statistical information about the outcome of their own practices or of certain procedures. The patient must be given adequate time to decide. At the end of the consultation, a patient must have an opportunity to consider the treatment that has been advised or to reverse a decision to proceed. It is inappropriate to obtain a patient’s signed consent for a procedure and then proceed on very short notice (the same day) with that treatment. The delay between consent and treatment must be sufficient to allow the patient to consider the matter fully. To ensure that a patient is fully informed with regard to consent for a surgical procedure, the issues listed in Box 5-3-2 should be covered. The patient should sign a consent form that states that the procedure has been explained fully in language that is comprehensible and that there has been sufficient opportunity to ask questions and reconsider consent prior to surgery. A written guide helps patients comprehend the nature of the planned surgery. Any surgical intervention is essentially a matter of trust and confidence − the trust of the patient in the surgeon’s ability and integrity, and the trust of the surgeon in the patient’s ability to comprehend and follow the process and to comply with prescriptions for managing the condition before, during, and after surgery.

5.3 Patient Work-up for Cataract Surgery

cation of the cataract incision.54, 58 In the latter, the incision is centered on the steep meridian, and the wound construction−placement−closu re combination that will produce the required astigmatic correction is carried out. The effect can be further titrated against the topography by selective suture removal under certain circumstances.

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422

REFERENCES   1. W  agner T, Knaflic D, Rauber M, Mester U. Influence of cataract surgery on the diabetic eye: a prospective study. Ger J Ophthalmol. 1996;5:79–83.   2. Ram J, Pandav SS, Ram B, Arora FC. Systemic disorders in age related cataract patients. Int Ophthalmol. 1994;18:121–5.   3. Hamed LM, Lingua DN. Thyroid disease presenting after cataract surgery. J Pediatr Ophthalmol Strabismus. 1990;27:10–5.   4. Fisher SJ, Cunningham RD. The medical profile of ­cataract patients. Geriatr Clin. 1985;1:339–44.   5. Jacquerie F, Comhaire-Poutchinian Y, Galand A. Cataract extraction in uveitis. Bull Soc Belge Ophthalmol. 1995;259:9–17.   6. Lightman S, Marsh RJ, Powell D. Herpes zoster ophthalmicus; a medical review. Br J Ophthalmol. 1981;65:539.   7. Hara T, Hoshi N, Hara T. Changes in bacterial strains before and after cataract surgery. Ophthalmology. 1996;103:1876–9.   8. Chitkara DK, Colin J. Morphology and visual effects of lens opacities of cataract. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St Louis: Mosby; 2004:280–2.   9. Cardillo Piccolino F, Altieri G. Classification of cataract: In: Concepta���������������������������������������������������������� Angellini���������������������������������������� , ed. Cataract. Roma: M Zingirian; ������������� 1985 . 10. Harding JJ. Cataract epidemiology. Curr Opin Ophthalmol. 1990;1:10–15. 11. Mehra V, Minassian DC. A rapid method of grading cataract in epidemiological studies and eye surveys.  Br J Ophthalmol. 1988;72:801–3. 12. Chylack ������ Jr���� LT�������������������� , Wolfe JK, Singer DM, et al. The Lens Opacities Classification System III. Arch Ophthalmol. 1993;111:831–6. 13. Phelps Brown NA. The morphology of cataract and visual performance. Eye. 1993;7:63–7. 14. Lasa MS, Datiles MB, Freidlin V. Potential vision tests in patients with cataracts. Ophthalmology. 1995;102: 1007–11. 15. American Academy of Ophthalmology. Preferred Practice Pattern: Cataract in the otherwise healthy adult eye. San Francisco: American Academy of Ophthalmology; 1989. 16. Regan D, Giaschi DE, Fresco BB. Measurement of glare sensitivity in cataract patients using low-contrast letter chart. Ophthalmic Physiol Opt. 1993;13:115–23. 17. Lasa MS, Podgor MJ, Datiles MB, et al. Glare sensitivity in early cataracts. Br J Ophthalmol. 1993;77:489–91. 18. Holladay JT. Optics of aphakia and pseudophakia. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed.  St Louis: Mosby; 2004:283–6. 19. Ridley H. Intraocular acrylic lenses. A recent development in the surgery of cataract. Br J Ophthalmol. 1952;36:113–22. 20. Campbell CJ, Koester CJ, Rittler MC, Tackaberry RB. The optics of the eye. In: Physiological optics. Hagerstown: Harper & Row; 1974:99–110. 21. Michaels DD. Aphakia and pseudophakia. In:  Michaels DD, ed. Visual optics and refraction.  St Louis: Mosby; 1985:506–27.

22. R  ubin ML. Optics for clinicians. 2nd ed. Gainesville: Triad; 1974:���������� 249–54.� 23. Milder B, Rubin ML. Aphakia. In: Milder B, Rubin ML. The fine art of prescribing glasses, 2nd ed. Gainesville: Triad; 1991:283–309. 24. Milder B, Rubin ML. Anisometropia. In: Milder B,  Rubin ML, eds. The fine art of prescribing glasses,  2nd ed. Gainesville: Triad; 1991:217–53. 25. Burian HM, von Noorden GK. Visual acuity and aniseikonia. In: Binocular vision and ocular motility. St Louis: Mosby; 1974:130–41. 26. Holladay JT, Rubin ML. Avoiding refractive problems in cataract surgery. Surv Ophthalmol. 1988;32:357–60. 27. Holladay JT, Prager TC, Bishop JE, Blaker JW. The ideal intraocular lens. CLAO J. 1983;9:15–9. 28. Holladay JT. Evaluating the intraocular lens optic. Surv Ophthalmol. 1986;30:385–90. 29. Atchison DA. Optical design of intraocular lenses.  I. On-axis performance. Optom Vision Sci. 1989;66: 492–506. 30. Masket S, Geraghty E, Crandall AS, et al. Undesired light images associated with ovoid intraocular lenses.  J Cataract Refract Surg. 1993;19:690–4. 31. Mainster M. Violet and blue light blocking intraocular lenses: Photoreceptors versus photoreception. Br J Ophthalmol. 2006;90:784–92. 32. Yang S, Lang A, Makker H, Azleski E. Effect of silicone sound speed and intraocular lens thickness on pseudophakic axial length corrections. J Cataract Refract Surg. 1995;21:442–6. 33. Holladay JT, Van Dijk H, Lang A, et al. Optical performance of multifocal intraocular lenses. J Cataract Refract Surg. 1990;16:413–22. 34. Holladay JT. Measurements. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St Louis: Mosby; 2004:287–92. 35. Fedorov SN, Kolinko AI, Kolinko AI. Estimation of optical power of the intraocular lens. Vestn Oftalmol. 1967;80:27–31. 36. Fedorov SN, Galin MA, Linksz A. A calculation of the optical power of intraocular lenses. Invest Ophthalmol. 1975;14:625–8. 37. Binkhorst CD. Power of the prepupillary pseudophakos. Br J Ophthalmol. 1972;56:332–7. 38. Colenbrander MC. Calculation of the power of an iris clip lens for distant vision. Br J Ophthalmol. 1973;57:735–40. 39. Binkhorst RD. The optical design of intraocular lens implants. Ophthalmic Surg. 1975;6:17–31. 40. van der Heijde GL. The optical correction of unilateral aphakia. Trans Am Acad Ophthalmol Otolaryngol. 1976;81:80–8. 41. Thijssen JM. The emmetropic and the iseikonic implant lens: computer calculation of the refractive power and its accuracy. Ophthalmologica. 1975;171:467–86. 42. Fritz KJ. Intraocular lens power formulas. Am J Ophthalmol. 1981;91:414–5. 43. Binkhorst RD. Intraocular lens power calculation manual. A guide to the author’s TI 58/59 IOL power module. 2nd ed. New York: Richard D Binkhorst; 1981.

44. O  lsen T, Corydon L, Gimbel H. Intraocular lens power calculation with an improved anterior chamber depth prediction algorithm. J Cataract Refract Surg. 1995;21:313–9. 45. Holladay JT, Gills JP, Leidlein J, Cherchio M. Achieving emmetropia in extremely short eyes with two piggyback posterior chamber intraocular lenses.  Ophthalmology. 1996;103:1118–23. 46. Holladay JT, Prager TC, Chandler TY, et al. A three-part system for refining intraocular lens power calculations. J Cataract Refract Surg. 1988;13:17–24. 47. Retzlaff JA, Sanders DR, Kraff MC. Development of the SRK/T intraocular lens implant power calculation formula. J Cataract Refract Surg. 1990;16:333–40. 48. Hoffer KJ. The Hoffer Q formula: a comparison of  theoretic and regression formulas. J Cataract Refract  Surg. 1993;19:700–12. 49. Holladay JT. IOL calculations following RK. J Refract Corneal Surg. 1989;5:203. 50. Lowe RF, Clark BA. Posterior corneal curvature. Br J Ophthalmol. 1973;57:464–70. 51. Holladay JT, Rubin ML. Avoiding refractive problems in cataract surgery. Surv Ophthalmol. 1988;32:357–60. 52. Holladay JT. Refractive power calculations for intraocular lenses in the phakic eye. Am J Ophthalmol. 1993;116: 63–6. 53. Corbett MC, Rosen ES. Corneal topography in cataract surgery. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed.. St Louis: Mosby; 2004:309–14. 54. Nordan LT, Lusby FW. Refractive aspects of cataract surgery. Curr Opin Ophthalmol. 1995;6:36–40. 55. Koch DD, Haft EA, Gay C. Computerized video­ keratographic analysis of corneal topographic changes induced by sutured and unsutured 4 mm scleral pocket incisions. J Cataract Refract Surg. 1993;19(Suppl):166–9. 56. Sanders RD, Gills JP, Martin RG. When keratometric measurements do not accurately reflect corneal topography. J Cataract Refract Surg. 1993;19(Suppl):131–5. 57. Cuaycong MJ, Gay CA, Emery J, et al. Comparison of the accuracy of computerized videokeratoscopy and keratometry for use in intraocular lens calculations. J Cataract Refract Surg. 1993;19(Suppl):178–81. 58. Nielsen PJ. Prospective evaluation of surgically induced astigmatism and astigmatic keratotomy effects of  various self-sealing small incisions. J Cataract Refract Surg. 1995;21:43–8. 59. Hayashi K, Hayashi H, Nakao F, Hayashi F. The  correlation between incision size and corneal shape changes in sutureless cataract surgery. Ophthalmology. 1995;102:550–6. 60. Martin RG, Sanders DR, Miller JD, et al. Effect of cataract wound incision size on acute changes in corneal topography. J Cataract Refract Surg. 1993;19(Suppl):170–7. 61. Kohnen T, Dick B, Jacobi KW. Comparison of the induced astigmatism after temporal clear corneal incisions of different sizes. J Cataract Refract Surg. 1995;21:417–24. 62. Wilson SE, Klyce SD. Advances in the analysis of corneal topography. Surv Ophthalmol. 1991;35:269–77.

PART 5 THE LENS

Indications for Lens Surgery/ Indications for Application of Different Lens Surgery Techniques

5.4

Frank W. Howes

Key features n n n n n

L ens surgery is the most common eye operation. Technical indications for lens surgery are divided into two main categories: medical and optical. Socioeconomic conditions of a country is another indication for lens surgery. All lens surgery for whatever indication is properly considered refractive surgery. Lens surgery may be divided into four major categories by ­technique: lens repositioning (couching), lens removal, lens replacement, and lens enhancement.

INTRODUCTION The indications for lens surgery today may be classified into two main categories: 1. Medical, which might more properly be called surgical or pathological indication, and 2. Optical, currently referred to as refractive indication. Medical indications arise from pathological states of the lens of varying causes, usually related to lens clarity, lens position, or other lens­related conditions, such as inflammation or glaucoma. Non-lens-related conditions may also be an indication for lens surgery, such as aniridia. Surgical or pathological indications have existed for centuries, if not millennia, and are generally indisputable. Refractive indications for lens surgery, in contrast, include clear-lens ametropic refractive states. These are relatively new indications, only decades old, and they may or may not be considered pathological conditions; in some academic settings, in past decades, surgery for such conditions was considered controversial, if not contraindicated. However, the ophthalmic subspecialty of refractive surgery gained a secure and permanent foothold in the late 1990s. Now, refractive lens surgery is rapidly becoming a common tool in the armamentarium of both cataract and refractive surgeons. The lens plays such a significant role in the visual refractive system of the eye that many, if not all, of the medical conditions of the lens also interfere with its optics. Similarly, surgical removal of the lens immediately and permanently alters the refractive state of the eye. Today, therefore, all lens surgery, for whatever indication, has properly come to be considered refractive surgery.

MEDICAL INDICATIONS FOR LENS SURGERY Lenticular Opacification (Cataract)

The medical indications for lens surgery (Box 5-4-1) are true pathological states, some of which may threaten the integrity of the whole organ (the eye). They also interfere with a major ocular function, focused vision. Lenticular opacification obstructs the pathway of light; reduces the available quantity of light; scatters light off axis; reduces contrast sensitivity; diminishes color intensity; reduces resolution acuity; may alter lens texture in such a way to contribute to a decrease in

Box 5-4-1 Medical Indications for Lens Surgery I. Lenticular opacification (cataract) II. Lenticular malposition A. Subluxation B. Dislocation III. Lenticular malformation A. Coloboma B. Lenticonus C. Lentiglobus D. Spherophakia IV. Lens-induced inflammation A. Phacotoxic uveitis (phacoanaphylaxis) B. Phacolytic glaucoma C. Phacomorphic glaucoma V. Lenticular tumor A. Epithelioma B. Epitheliocarcinoma VI. Facilitatory (surgical access) A. Vitreous base B. Ciliary body C. Ora serrata

a­ ccommodation amplitude, particularly in the case of presenile nuclear sclerosis; and, in the case of progressive nuclear sclerosis, often results in a myopic alteration of a previously stable lifelong refractive state. Cataract, depending on severity, is a condition of the eye that, by interfering with vision, can simultaneously interfere with certain activities in life. It is generally agreed that surgical intervention is indicated when there is “functional” visual impairment. In highly structured societies, governments or third-party health insurance carriers pay for such surgical procedures, and these same institutions often set standards for lens surgery indications. Visual acuity of 20/50 or worse as measured on a Snellen chart in dim ambient (mesopic) illumination with maximal refractive correction is an acceptable level of cataract to indicate surgery, according to the American Academy of Ophthalmology. Visual acuity of 20/50 or worse when tested with bright light imposition on the pupil, or glare testing, is considered a surgical level of cataract dysfunction in many states in the United States. Reduction of contrast sensitivity can be demonstrated and quantified, and the type and degree of lens opacification may be subjectively quantified by slit-lamp examination and categorized according to the Lens Opacification System III (LOCS-III) devised by Chylack et al.1 The degree to which the opacification obstructs light can, additionally, be measured by laser interferometry.2 Progressive changes in cataract density over time can be documented by Scheimpflug photography of nuclear cataracts3 and by Neitz-Kawara retroillumination photography of posterior subcapsular cataracts.4 In developed societies where surgical technology is advanced, perceived economic conditions may be the factors that determine the prevalence and definition of “cataract blindness” for a population, and this changes as conditions change. In many underdeveloped nations, the prevalence of cataract blindness is determined by the availability of care. In structured economic societies, third-party

423

5 THE LENS

payers and governmental regulatory agencies are not very interested in the results of these sophisticated methods of analyzing loss of lens function; they are more interested in how the loss of lens function interferes with life functions. Loss of functional impairment due to visual impairment may range from minor impairment in luxury lifestyles, such as inability to follow a golf ball; to moderate impairment, such as inability to see well enough to drive an automobile; to severe impairment of life support functions, such as inability to see the units on an insulin syringe or the instructions on a bottle of cardiac medication − or even food on the table. Examples of such tests are the Visual Function Index (VF-14)5–8 and the Activities of Daily Vision Scale (ADVS).9, 10

Cataract in the presence of other ocular disorders

The decision whether and when to remove a cataract in an otherwise healthy eye usually depends on the cataract’s impact on the visual function of the eye and the impact of that level of visual impairment on the person’s life. In healthy eyes whose only disorder is cataract, the presumed outcome after uncomplicated surgery is better vision than before surgery. Indeed, in the most technologically advanced societies, patients are requesting emmetropia, restoration of accommodation, and have even engaged in lawsuits when the desired refractive outcome was not achieved. In these “healthy” eyes, however, high-volume cataract surgeons experience a rate of intraoperative and postoperative complications of less than 2% or, conversely, an uncomplicated rate of 98%. Thus, when one applies a risk-benefit ratio with such a high degree of success, surgery is usually the mutually agreed on course. However, such may not be the case when the cataract is associated with other disorders, especially if they are contributing factors to the loss of vision of an eye. Therefore, such conditions as amblyopia, corneal opacification, vitreous opacification, maculopathy, retinopathy, glaucoma, and optic neuropathy may alter or delay the decision to operate, based not so much on the expected risks but rather on the limited benefits. In some cases, lens surgery is indicated to preserve peripheral vision only for functional ambulation. In other cases, a progressive condition of the posterior segment is an indication for lens surgery, even when the expectation for visual improvement may be minimal.11 Systemic conditions may also play a role in deciding whether and when to remove a cataract. Is the patient’s diabetes under control? Has there been a stroke with hemianopia? Is the patient on systemic anticoagulants? Is the patient terminally ill or immunologically suppressed? Does the patient have Alzheimer’s disease or severe mental retardation? Thus, the decision to remove a cataract may become a collaborative endeavor with participation by the patient, the patient’s family, the patient’s primary physician, the surgeon, a governmental agency, and a third-party payer. The decision, thus, is determined not only by technological findings and expectations but also by a “holistic” evaluation of the impact of such a decision on that person’s life, as defined by that society.

A

424

B

Lenticular Malposition

Subluxation, i.e., displacement of the lens within the posterior chamber, and dislocation, i.e., displacement of the lens out of the posterior chamber into the anterior chamber or vitreous, of the lens are different degrees of the same phenomenon and result from dysfunction of the zonule. The zonule may be defective as a result of congenital malformation, total or partial agenesis, or a hereditary metabolic disorder, such as Marfan’s syndrome. Chronic inflammation and pseudoexfoliation have been shown to be associated with a weakness in the zonular fibers or their attachments. Ocular trauma is an obvious cause. Subluxation, in the absence of associated sequelae, may not be visually significant and may not be an indication for lensectomy. Similarly, complete dislocation of an intact lens into the inferior vitreous may be a quiescent event in the absence of inflammation and may simply produce a state of refractive aphakia, correctable nonsurgically with a spectacle or contact lens or surgically with intraocular lens (IOL) implantation. Subluxation to the extent that the equator of the lens is visible in the midsized pupil is usually visually significant, causing glare, fluctuating vision, and monocular diplopia. This symptom complex would qualify for lens surgery.

Lenticular Malformation

These conditions of abnormal lens development are congenital. They may be genetic, hereditary, or the result of intrauterine infection or trauma. These conditions include lens coloboma, lenticonus, lentiglobus, and spherophakia, as well as varieties of congenital cataract. Partial iris coloboma or total aniridia, whether congenital, traumatic, or surgical, may be an indication for lens surgery to improve visual function or for cosmesis. The availability of aniridia IOLs (Fig. 5-4-1A) and opaque endocapsular rings (see Fig. 5-4-1B,C) offers great improvements for such patients. The indications for surgery depend on the degree to which the specific malformation interferes with vision or the integrity of the involved eye. Such abnormalities may be associated with amblyopia. Early detection and surgical intervention should be incorporated with a plan for amblyopia therapy.

Lens-Induced Ocular Inflammation

Phacoanaphylactic endophthalmitis (phacotoxic uveitis) occurs in an immunologically mature and competent host and is related to physical or chemical disruption of the lens capsule. Surgery may be the appropriate treatment for this form of ocular inflammation.

Lens-Induced Glaucoma

Inflammatory glaucoma (phacolytic glaucoma)

Phacolytic glaucoma occurs in an eye with a mature lens in which the lens capsule is intact. Denatured, nonantigenic liquefied lens material leaks out through the intact lens capsule and elicits a macrophagic, inflammatory reaction. The macrophages, engorged with lens ­material,

C

Fig. 5-4-1  Iris defect prostheses. (A) Aniridia intraocular lens with opaque peripheral “pseudoiris.” (B) Aniridia endocapsular ring. (C) Iris coloboma endocapsular ring (diaphragm type 96G). (Courtesy of Morcher, GMBh, Germany.)

clog the open angle, leading to a secondary open-angle glaucoma. ­Removal of the lens is usually curative, obviating the need for other forms of medical or surgical pressure management. Similarly, removal of the lens in this instance is also curative. The growth of the lens with age progressively engulfs anterior segment space, and may ultimately lead to acute angle-closure glaucoma through the mechanism of pupil block. This is more likely in hyperopic eyes due to the short axial length and already crowded anterior segments. Lens removal and replacement with an intraocular lens greatly increases ­anterior segment space and, in most instances, resolves the glaucoma.

REFRACTIVE INDICATIONS FOR LENS SURGERY The refractive indications for lens surgery include all the classic well-known refractive states of the “healthy” eye, which is why these new indications for lens surgery have been somewhat controversial. There may be no true histopathology to most of these eyes; however, some, such as those with extreme axial myopia, may be at risk for true ­pathology following surgical intervention. In addition, the historical development of spectacles and contact lenses, having long antedated the development of modern lens surgery, created a mind-set among academics that “inborn errors of refraction” are not diseases and are therefore not conditions to be treated with medicine or surgery, especially if such treatment might unnecessarily endanger an eye or expose an otherwise “healthy” eye to undue risk. Although there may be merit to that argument, it is a concept that is rapidly losing popularity. In fact, the voice of tradition seems to have become almost silent on this issue. Whether prudent or not, the global anterior segment ophthalmic surgical community has embarked on a new and enticing endeavor − rendering the human population emmetropic. The process began as an idea before its time in the 1950s, with the failed attempts of Sato at endothelial radial keratotomy and Barraquer and others at phakic anterior chamber IOL implantation. The ophthalmic surgical “technical revolution” that ensued over the following decades led to renewed interest in the surgical correction of refractive errors 30 years later in the 1980s, this time as an idea whose time had come. Refinements in ocular anesthesia, incision technology, lensectomy techniques, ophthalmic visco-surgical ­device (OVD) tissue protection, and IOL manufacturing and implantation allowed the successful return of the concept of intraocular correction of refractive errors, including both clear lensectomy and phakic implantation. All this, combined with the multitude of new keratorefractive procedures, has actually led to the development of

A

B

INDICATIONS FOR DIFFERENT LENS SURGERY TECHNIQUES Surgery affecting the human lens can be organized historically by chronology of development (Table 5-4-1) or divided into four major categories by technique (Box 5-4-2): lens repositioning, lens removal, lens replacement, and lens enhancement. Lens repositioning, traditionally known as “couching,” is perhaps the oldest form of lens surgery and is still in use in some developing countries today. In stark contrast, at the other end of the historical spectrum is the most recent category of lens surgery, that of lens functional enhancement. These new investigational techniques involve surgical procedures designed to enhance accommodation in the presbyopic eye.

5.4 Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques

Pupil block and angle closure (phacomorphic glaucoma)

a new, bona fide ophthalmic surgical subspecialty, that of refractive surgery. Almost all the operable tissues and spaces of the eye have, over decades, come under investigation as locations for refractive surgical modulation: corneal epithelial surface, corneal stroma, corneal endothelial surface, anterior chamber, iris, pupil, posterior chamber, lens, and sclera. The lens, therefore, assumes its role among the others as a popular location for surgical refractive modulation for those who prefer a familiar procedure that spares the cornea and saves the economic expense of an excimer laser. Those who decry the lenticular approach emphasize all the potential intraoperative and postoperative complications attendant with invasive intraocular procedures. Despite the controversy, clear lens replacement stands as a viable procedure today for both myopia and hyperopia, and now that it is possible to ameliorate astigmatism (Fig. 5-4-2A), modulate higher order aberration, and reduce presbyopic symptoms (see Fig. 5-4-2B,E), patient demand for these services have increased dramatically in recent times. Aspheric lenses (see Fig. 5-4-2C) have recently been introduced with the expanding knowledge of higher order aberration control. These IOLs can be used to correct, modify, or maintain naturally occurring wave-front detected aberrations. Multifocal IOLs (see Fig. 5-4-2B) represent some of the first attempts at the intraocular correction of presbyopia. Other attempts at the development of a truly accommodative pseudophakos have included the ­intracapsular injection of liquid silicone12–14 and the intracapsular placement of high-water-content poly-HEMA lenses, a liquid siliconefilled intracapsular balloon,15, 16 multiple IOLs (polypseudophakia)17, 18 (see Fig. 5-4-2D), and more recently the flexing haptic accommodative IOLs (see Fig. 5-4-2E).

C

Fig. 5-4-2  Older and modern intraocular lens modifications providing functions additional to pure spherical dioptric correction. (A) Alcon toric IOL with blue light filter (Acryosof IOL). (B) Alcon multifocal IOL with apodized rings also with blue light filter (Acryosof IOL). (C) Bausch and Lomb (B&L) Akreos aspheric IOL.  (Courtesy of B&L Australia.)

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5 THE LENS E

D

Fig. 5-4-2, cont’d  (D) Older style accommodative PMMA polypseudophakic intraocular lens. (Courtesy of T. Hara.) (E) The C&C Vision CrystaLens model  AT-45 silicone multipiece intraocular lens. (Courtesy of C&C Inc.)

   Table 5-4-1  HISTORY OF CATARACT SURGERY TECHNIQUES Year

Technique

Place

Surgeon

800

Couching

India

Unknown

1015

Needle aspiration

Iraq

Unknown

1100

Needle aspiration

Syria

Unknown

1500

Couching

Europe

Unknown

1745

ECCE inferior incision

France

Daviel

1753

ICCE by thumb expression

England

Sharp

1860

ECCE superior incision

Germany

von Graefe

1880

ICCE by muscle-hook zonulysis and lens tumble

India

Smith

1900

ICCE by capsule forceps

Germany

Verhoeff Kalt

1940

ICCE capsule suction erysiphake

Europe

Stoewer I. Barraquer

1949

ECCE posterior chamber IOL and operating microscope

England

Ridley

1951

Anterior chamber IOLs

Italy Germany

Strampelli Dannheim

1957

ICCE by enzyme zonulysis

Spain

J. Barraquer

1961

ICCE by capsule cryoadhesion

Poland

Krawicz

1967

ECCE by phacoemulsification

United States

Kelman J. Shock

1975

Iris-pupil supported IOLs

Netherlands

Binkhorst Worst

1984

Foldable IOLs

United States South Africa

Mazzocco Epstein

ECCE, Extracapsular cataract extraction; ICCE, intracapsular cataract extraction; IOL, intraocular lens.

426

The indications for a particular lens surgery technique may be determined by several factors (Box 5-4-3). Different medical conditions or pathological states of the eye and the lens may favor one technique over another. In some countries, the availability of equipment, as well as the level of training of the surgeon, may be factors that dictate technique. Certain countries have governmental agencies, professional organizations, academic institutions, insurance payers, or surgical facilities that regulate and control the types of surgical techniques surgeons may perform. For the purpose of this text, however, only specific medical or pathological conditions of the eye are discussed as factors determining the choice of surgical technique.

Couching

This is the oldest technique of lens surgery; it has been performed for more than 1000 years and is still in use today in some developing countries. The original method was an extracapsular technique that involved the placement of a sharp needle through the sclera at the pars plana, behind the iris, until the tip of the needle was visible in the pupil in front of the lens. The anterior capsule was then scratched open with the needle tip, and the nucleus was pushed inferiorly until the pupillary space appeared clear. This early extracapsular technique, which was being performed long before the development of topical anti-inflammatory medications, was associated with inflammation, secondary glaucoma, posterior

Box 5-4-2 Lens Surgery Techniques

Box 5-4-3 Lens Removal Techniques: Ocular Indications I. Intracapsular extraction A. Zonular absence/dialysis B. Lens subluxation C. Lens dislocation II. Nuclear delivery A. Status of cornea 1. Low endothelial cell count 2. Guttate dystrophy B. Status of cataract 1. Brunescent nuclear sclerosis 2. Cataracta nigra C. Torn posterior capsule during phacoemulsification D. Zonulodialysis III. Phacosection A. Same corneal, cataract, and capsular indications as nuclear delivery B. Astigmatism management IV. Phacoemulsification A. Status of cornea 1. Normal endothelial cell count 2. No guttate dystrophy B. Status of cataract 1. Immature nuclear sclerosis 2. Cortical or subcapsular cataract C. Astigmatism management

synechiae, pupillary block, Soemmerring’s rings, and capsular opacification, not to mention endophthalmitis. Considering current technology, there may be no indications for extracapsular couching today. Intracapsular couching, however, is another matter. This procedure was (and still is) performed without anesthesia with the patient in the sitting position, sometimes outdoors. However, couching can also be performed safely under an operating microscope in a matter of minutes following enzymatic zonulysis with α-chymotrypsin. Unlike the exposed nucleus and cortex in the extracapsular method, the intact, encapsulated, dislocated crystalline lens in the intracapsular method is immunologically inert. The low skill level required and the low cost of this simple, safe, fast, and effective procedure make it an attractive alternative for economically disadvantaged developing countries, which harbor a large majority of the world’s estimated 18 million cataract blind.

5.4 Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques

I. Lens repositioning (“couching”) A. Extracapsular B. Intracapsular 1. Physical (instrumental) zonulysis 2. Pharmacological (enzymatic) zonulysis II. Lens removal A. Total (intracapsular) 1. Capsule forceps 2. Suction erysiphake 3. Cryoextraction B. Partial (extracapsular) 1. Anterior capsulotomy/capsulectomy a. Discontinuous b. Continuous (capsulorrhexis) c. Linear 2. Nucleus removal a. Assembled delivery (large incision) (1) Expression (“push”) (2) Extraction (“pull”) b. Disassembled extraction (1) Phacosection (2) Phacoemulsification-aspiration (a) Ultrasound (i) linear (ii) torsional (b) Laser (c) Water jet (d) Impeller 3. Cortex removal a. Irrigation b. Aspiration III. Lens replacement (intraocular lens implantation) A. Locations 1. Anterior chamber a. Angle fixation b. Iris fixation 2. Pupil 3. Posterior chamber a. Iris fixation (sutured or enclavated) b. Ciliary sulcus (sutured or unsutured) 4. Lens capsule a. Anterior capsule (1) Haptic sulcus/optic bag (2) Optic posterior chamber/haptic bag b. Intracapsular (“in the bag placement”) c. Posterior capsule (haptic bag/optic Berger’s space) 5. Pars plana (sutured) B. Optic materials 1. Hydrophobic a. PMMA b. Silicone c. Acrylic 2. Hydrophilic a. Poly-HEMA b. Acrylic c. Collagen-copolymer C. Optic types 1. Monofocal a. Spherical (1) Plus (2) Minus b. Toric c. Telescopic d. Prismatic 2. Multifocal 3. Accommodative IV. Lens enhancement: reversal of presbyopia by scleral expansion A. Ciliary cerclage B. Radial anterior ciliary sclerotomy

Intracapsular Extraction

The intracapsular method of lens removal has not been the procedure of choice in industrialized nations since the development of modern extracapsular techniques in the late 1970s, primarily because of lower rates of postoperative posterior segment complications such as hemorrhage, vitreous loss, retinal detachment, and cystoid macular edema. Current indications for planned intracapsular extraction, therefore, are related to intraocular conditions that preclude safe and successful extracapsular surgery. The absence or lysis of a significant number of zonular fibers, which may occur as an isolated congenital anomaly or as a result of Marfan’s syndrome, pseudoexfoliation, trauma, or following pars plana surgery, may be an indication for intracapsular extraction. Significant subluxation or dislocation of the lens may leave no other option except for removal of the lens in its capsule (see Chapter 5.10). Traditionally, intracapsular extraction involved removal of the complete intact lens through a large incision measuring 11−16 mm. In earlier years these eyes were left aphakic with aphakic spectacle correction offered where available. Bilateral surgery was invariably necessary to minimize aniseikonic problems, although contact lens correction was also satisfactory. Many of these eyes have subsequently had secondary IOLs implanted, with the choice of IOL being angle based, iris fixed (anterior or posterior), or sutured to the ciliary sulcus Modern sulcus fixation IOLs now have design features that enable them to fibrose into the ciliary processes and sulcus (Fig. 5-4-3), ­minimizing the chances of posterior dislocation common in previous sulcus fixation IOLs. In addition these lenses are foldable ­ allowing small-incision surgery and adherence to the principles of astigmatism avoidance and correction. In the majority of primary situations

427

5

3

THE LENS

2

3

A

B

1

Fig. 5-4-3  Examples of newer intraocular lens designs for use in eyes without capsular support. (A) Artisan IOL for iris fixation, either anterior or posterior.  (B) FH1000 (Lenstec) hydrophilic acrylic foldable IOL for sulcus fixation by suture with long-term stability by fibrosis through peripheral haptic fibrosis holes shown. The radius of the haptics matches a 13-mm-wide sulcus (3) and the optic is reinforced to counteract any torsional forces. Length of IOL: 13.25 mm (1); optic width:  6.0 mm (2).

for ­intracapsular surgery, the wound needs to be large and hence constructed appropriately for minimization of astigmatism induction (see Chapter 5.10).

Large-Incision Nuclear Expression Cataract Surgery (Extracapsular Extraction)

This technique became popular in the 1980s as surgeons, who had been performing large-incision intracapsular extraction and anterior chamber implantation, desired the benefits derived from an intact posterior capsule and posterior chamber implantation. The technique persists today and is performed in great numbers, particularly in Asian countries, where the more advanced small-incision techniques of phacoemulsification and foldable lens implantation are not yet available for the masses. In those countries where phacoemulsification and foldable lens implantation are rapidly becoming standard, the only ocular indication for planned nuclear delivery may be an advanced nucleus that is too hard to be emulsified safely. Corneas at risk for developing irreversible edema, such as those with low endothelial cell counts or guttate dystrophy, may be relative indications for nuclear delivery. However, small-incision lens surgery in the presence of highrisk corneas remains a viable option, particularly when highly retentive dispersive OVDs are used in combination with endolenticular or intercapsular phacoemulsification. Another indication for nuclear delivery is the occurrence of a tear in the posterior capsule during phacoemulsification. Although it may be possible to continue to emulsify the nucleus over OVD or over a lens glide (Michelson technique), a large capsular tear with presentation of vitreous may preclude safe emulsification, necessitating incision enlargement and nuclear delivery.

Small-Incision Nuclear Expression Cataract Surgery (“Mini-nuc” and Other Techniques)

428

These techniques involve delivering the nucleus not as a single intact unit in one step through a large incision, but in parts through a small incision. The nucleus may be separated concentrically, delivering the smallest endonucleus separately from outer layers of epinucleus. This technique may be performed through a 7−8 mm sutureless scleral incision using side-port irrigation through a chamber maintainer to hydroexpress the nuclear components, which delaminate as they pass through the incision. This has been called the “mini-nuc” technique.19 By bisecting or trisecting the nucleus further by instrumentation, achieving geometrical nuclear division in the anterior chamber and removing the small sections linearly with forceps or by hydrostatic pressure, incisions as small as 3−4 mm may be achieved.20 The indications for these techniques are the same as those for intact nuclear delivery, as a manual extracapsular technique, with the addition

of astigmatism management. Unlike long-incision, single-stage nuclear delivery, small-incision phacosection may induce no change in astigmatism, particularly if a foldable lens is used and all is accomplished through a 3 mm scleral incision. The choice for this type of surgery relates to the surgeon’s experience, socioeconomic factors, and instrumentation availability.

Phacoemulsification

This technique of nucleus removal has been performed through incisions ranging from 3.2 mm down to less than 1.0 mm. Combined with foldable lens implantation, the major advantage of phacoemulsification is the small incision. Current techniques use self-sealing, sutureless scleral and clear corneal incisions measuring 2.3−3.2 mm. These incisions are astigmatically neutral. Corneal incisions can be moved centrally from the limbus and can be grooved as two-plane, two-stage incisions, allowing the reduction of pre-existing astigmatism, especially when used in combination with astigmatic keratotomy.28 Therefore, the presence of corneal cylinder is an indication for phacoemulsification and foldable lens implantation, just as is the absence of corneal cylinder. The status of both the nucleus and the cornea factors into the decision whether to perform phacoemulsification. It has been observed that with certain phacoemulsification techniques there is a greater loss of endothelial cells. This relates to the duration of the ultrasound, the intensity of the ultrasound, and the proximity to the corneal endothelium. The more compromised the endothelium, the more care required, particularly in eyes with denser nuclei requiring increased energy for removal. OVDs do protect the corneal endothelium and techniques such as the “soft shell” technique,21 which retains good endothelial coverage during the procedure, should be used in these eyes. When phacoemulsification was originally performed in the anterior chamber and in the iris plane, high-risk corneas and dense nuclei were considered contraindications, and nuclear delivery was recommended. However, long ultrasound times have been shown to be well tolerated when the ultrasonic energy is confined to the capsular bag. Newer emulsification techniques,22 together with high vacuum, have also been shown to reduce ultrasound times, providing further protection to the cornea (Box 5-4-4). Newer modalities of nuclear emulsification have evolved including torsional phacotip movement combined with the usual axial ultrasound induced movement, as well as the nonultrasound modalities such as neodymium:YAG laser;23–27 erbium:YAG laser;28–30 pulsed water jet; “plasma blade” molecular bond disruption; impeller aspiration-emulsification; and others.

Lens Capsule Surgery

When capsulectomy was first conceived, it was performed in discontinuous fashion, either as multiple punctures (“can-opener”) with a bent needle or cystotome or as triangular (Kelman) or square (Gills) capsulectomies facilitated with scissors (Fig. 5-4-4). Discontinuous openings, being weak, allow easy dislocation of the nucleus anteriorly for either delivery

Box 5-4-4 Phacoemulsification Techniques

5.4

Fig. 5-4-4  Anterior capsulectomy shapes used for extracapsular cataract surgery. (Courtesy of Advanced Medical Optics Inc.)

or emulsification. However, they are also prone to developing multiple radial anterior tears out to the equator, with possible extension around to the posterior capsule.31 Postoperatively, they have a high rate of posterior synechia formation and anterior IOL loop dislocation.32 Plate-haptic lenses are contraindicated in the presence of a discontinuous anterior capsular opening, as they have also been shown to dislocate anteriorly postoperatively. There is, therefore, rarely a current indication for a discontinuous capsulectomy, except possibly in the case of advanced nuclear sclerosis with absence of a red reflex and nonavailability of a biological capsule stain, such as trypan blue or indocyanine green. Continuous curvilinear capsulectomy (CCC), also known as capsulorrhexis,33 is much more desirable than previous discontinuous methods. The continuous anterior capsular opening is stronger and more resistant to radial tearing than are discontinuous openings.34 The ­continuous anterior capsulectomy of the appropriate size and shape has also been shown to retain IOL haptics of all designs and materials within the capsular bag postoperatively virtually 100% of the time. A circular opening of 4−5 mm also readily retains the nucleus for in situ or endolenticular emulsification techniques. Larger openings of 6−7 mm allow nuclear prolapse for intact delivery, phacosection, or anterior chamber emulsification. Continuous openings that are too small may contract postoperatively due to fibrous metaplasia of lens epithelial cells obstructing not only the patient’s vision but also the doctor’s view, precluding examination and treatment of fundus disorders. YAG laser anterior capsulectomy would then be indicated, just as posterior capsulectomy is indicated for posterior capsular opacification. The ideal continuous anterior capsular opening is 1.0 mm smaller than the diameter of the lens optic to be implanted. The capsular contents may also be removed through a linear capsulectomy (see Fig. 5-4-4) rather than a full capsulectomy. Both discontinuous and continuous linear capsulectomy techniques have been employed for nuclear delivery35 and emulsification.36 The advantage of these intercapsular techniques, if the anterior capsule is left intact during surgery, is protection of the cornea. Leaving the anterior capsule in place also offers the postoperative possibility of total encapsulation of an accommodative pseudophakos. The implantation of a pliable ­refractive material into a complete, intact lens capsule may establish the potential for pseudophakic accommodation. Animal experimental trials were begun in the early 1980s, first by Schanzlin’s group, who evacuated the capsular contents through a 3 mm linear capsulectomy and injected liquid silicone in rabbit eyes.37 These procedures worked surgically; however, the resultant optical power of the liquid injectable material could not be controlled, the anterior capsules became opacified by white fibrosis in a few weeks, and accommodative function was not determined. In the late 1980s, Nishi et al.16 developed a liquid silicone-filled intracapsular balloon and placed it in monkey eyes. The power of the IOL was now controllable, and ­ Scheimpflug photography demonstrated 6 D of apparent accommodation. Also in the late 1980s, the first potentially accommodating IOLs were placed in human eyes; they were 66% water, poly-HEMA “full-size” expandable IOLs.38 Unfortunately, none of these first human subjects, approximately 46 in number, demonstrated accommodation. More recent designs are those of flexible hinged haptic silicone and acrylic IOLs (see example Fig. 5-4-2E) that provide some ­accommodation; ­unfortunately, this effect is ­generally

lost with bag fibrosis. Intraocular IOL power adjustment systems are undergoing research at the time of writing (Calhoun Vision)39 giving surgeons the opportunity to modify postsurgical refraction. This will assist with the management of biometric error, monovision induction, reduction, and enhancement. Residual lens epithelial cell activity and visual axis obstruction following cataract surgery continues to be a major concern. The posterior capsule can opacify as a result of lens epithelial cell migration and hyperplasia (Fig. 5-4-5), and the anterior capsule can opacify as a result of lens epithelial cell (LEC) fibrous metaplasia (Fig. 5-4-6). In addition, excessive fibrosis can result in contraction of the entire capsule with deformation of the IOL haptics, decentration of the IOL optic, and zonular dialysis with capsular bag subluxation or dislocation. Efforts to prevent unwanted postoperative LEC activity have included primary posterior capsulotomy40 and methods of mechanically cleaning the capsule, including vacuuming, vacuuming with ultrasound, curettage, and cryosurgery (Box 5-4-5).41 Attempts at pharmacologically disabling the LEC have included hypotonic hydrolavage, antiprostaglandins,42, 43 anti­ metabolites,44 and immunosuppressors.45 These techniques are currently under investigation. In addition, newer IOL materials that are hydrophilic, such as polyHEMA, acrylic, and collagen-copolymer, appear to stimulate very low levels of lens epithelial hyperplasia and almost no fibrous metaplasia. The possibility of using hydrophilic IOLs as drug delivery systems is also very attractive. However, the most recent clinical advancement that has been demonstrated to reduce the incidence of posterior capsular opacification is the use of IOL optics with “square edge design.” These are manufactured in both acrylic and silicone. The square edge has been shown to be a physical barrier to the central posterior migration of LECs.32

Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques

     I. Location A. Anterior chamber (Kelman, Brown) B. Iris plane (Kratz) C. Posterior chamber (supracapsular) (Maloney) D. Capsule (endolenticular, in situ) 1. Anterior capsulectomy (Sinskey) 2. Anterior capsulotomy (intercapsular) (Hara) II. Techniques A. Carousel B. Chip-and-flip (Fine) C. Phacofracture 1. Divide-and-conquer (Gimbel) 2. Four-quadrant pregrooved (Shepherd) 3. Nonstop chop (Nagahara) 4. Stop-and-chop (Koch) 5. Double chop (Kammann)

Zonular Surgery

The preceding discussion of the surgical management of the lens capsule concentrated on endocapsular techniques and management of the viable lens epithelial cells on the interior surface of the lens capsule. The discussion would be incomplete if it did not address a significant, difficult, new area of capsular surgery that deals with an abnormality of the exterior capsule − management of the weak or partially absent zonule. In most cases, the goal of this type of lens surgery is the same as that for eyes without a compromised zonule: to remove the contents of the capsular bag though a CCC and replace the contents with a foldable IOL. However, in these cases, the goal is extended to include performing the surgery without further compromising the zonule, without disrupting the vitreous, without jeopardizing the long-term integrity of the capsulozonular apparatus, and, if possible, to recircularize and recenter a subluxed capsule. To accomplish these surgical goals and avoid a long incision, intra­ capsular extraction, vitrectomy, and anterior chamber IOL, several modifications to the standard procedure are planned for eyes with compromised zonules. In these eyes, there is some zonular support to the capsule (partial zonular absence), enough of a circumference of attached fibers to support CCC and implantation of an endocapsular ring. If only a small percentage of the zonule is attached, or if the zonule is completely absent, intracapsular extraction with anterior chamber IOL or sutured posterior chamber IOL may be the only technique available.

429

5 THE LENS Fig. 5-4-5  Posterior capsular opacification by lens epithelial cell hyperplasia.

A

Box 5-4-5 Lens Epithelial Cell Surgery I. Primary procedures A. Mechanical 1. Capsular polishing 2. Capsular vacuuming 3. Capsular vacuuming with ultrasound 4. Capsular curettage 5. Capsular cryotherapy B. Pharmacological 1. Hypotonic hydrolavage 2. Antimetabolites 3. Antiprostaglandins C. Immunological 1. Monoclonal antibodies D. Prophylactic posterior capsulotomy/capsulectomy (CCC) II. Secondary procedures A. Invasive 1. Capsulotomy/capsulectomy (CCC) 2. Curettage 3. Vacuuming B. Noninvasive 1. Nd:YAG laser capsulotomy/capsulectomy

430

Endocapsular rings were originally conceived in Japan, not for the purpose of supporting the zonule, but for the purpose of placing ­pressure on the equatorial lens epithelial cells to prevent posterior capsular opacification. Two models were manufactured in the early 1990s. A completely closed circular model, made of silicone for foldability and implantability through a 3 mm incision, was designed by Hara (Fig. 5-4-7A), and an open polymethyl methacrylate (PMMA) model was designed by Nagamoto. It was subsequently demonstrated in clinical trials and by phase-contrast videography of living LECs (Nagamoto and Bissen-Miyajima) that the presence of a ring in the capsular equator had no effect on the viability and migratory activity of LECs. Witchell et al. in Germany also designed an open PMMA ring for the purpose of supporting capsules with compromised zonules (see Fig. 5-4-7B), and Cionni (Cincinnati, Ohio) designed modifications to the PMMA capsule tension rings (CTRs) to allow them to be sutured to the eye wall,46 thus creating a synthetic “pseudozonule” attached to an intracapsular skeletal supporting apparatus (see Fig. 54-7C). When surgery on such eyes is planned, if OVD is to be used for the CCC, care must be taken not to overinflate the eye, especially with a dispersive OVD, as this may stress or further tear zonular fibers. A CCC can usually be performed and should be large. This facilitates hydrodissection and allows for the possibility of nuclear hydroexpression or viscoexpression. Complete hydrodissection is essential so that nuclear manipulations place no stress on the remaining zonular fibers. Similarly, expressing the nucleus through the large CCC into the supracapsular space, the pupillary plane, or the anterior chamber allows for nuclear emulsification safely away from the zonulocapsular ­apparatus.

B

Fig. 5-4-6  Anterior capsular fibrosis. (A) Asymmetric and (B) symmetric anterior capsule fibrosis leading to varying degrees of capsular phimosis. (Courtesy of John Shephard MD, Las Vegas, Nevada.)

If the zonule is weak or absent in only a limited meridional arc such that there is no decentration or subluxation of the capsule, a simple CTR can be implanted. These simple rings can be implanted with ­forceps or by injection with a special instrument (Geuder) and can be implanted at any stage in the surgical procedure: l After hydrodissection, before phacoemulsification l During phacoemulsification l After phacoemulsification, before cortical aspiration l During cortical aspiration l After cortical aspiration, before IOL implantation Additionally to minimize zonular stress for any of the manipulations after the creation of a CCC, iris hooks may be used but fixed to the CCC instead of the iris, thus stabilizing the capsular bag/zonular complex. If there is capsular subluxation, a Cionni CTR may be implanted; ideally, the ring is sutured to the sclera in the meridian that is the center of the arc of zonular absence. The ring will recentralize the capsule, and the suture will recentralize the capsule and will re-elevate a posteriorly tilted capsule to the zonular plane. Another modification to the routine technique is that of lowering the infusion bottle to a level that provides the slowest stream of irrigation beyond a drip, such that the phacotip is cooled and the chamber is maintained, but excessive volume with posterior displacement of the lens is avoided. The Cionni ring type of sutured skeletal support of the capsule is often strong enough to support careful endocapsular phacoemulsification techniques. Chopping performed with equicentripetal forces places no lateral stress on the zonule. When choosing an IOL, it would be ideal to implant a material that induces no fibrous metaplasia of the lens epithelial cells and a design that blocks the formation of central posterior capsular opacification. Therefore, PMMA and silicone are not ideal materials for these eyes. Among those currently available, the IOL of choice is one with an acrylic optic

5.4

B

C

Fig. 5-4-7  Solutions past and present for zonular deficiency. (A) Complete closed circular, foldable silicone endocapsular ring. (Courtesy of T. Hara.) (B) Open PMMA endocapsular ring. (Courtesy of Morcher, GMBh, Germany.) (C) Cionni-modified endocapsular ring for suturing to sclera to create a pseudozonule. (Courtesy of Morcher, GMBh, Germany.)

and a square posterior edge. There are now a number of models from various companies that are available (see Fig. 5-4-2A–C, Fig. 5-4-8). Additionally, these hydrophobic acrylics unfold in a very slow, controlled fashion that produces zero stress on the capsule or zonule.

Surgery for Presbyopia

These new and experimental procedures are designed to enhance lens function; that is, they are performed to improve the amplitude of accommodation in a presbyopic eye. These procedures are intended for purely presbyopic noncataractous eyes with no lenticular pathology other than the normal physiological middle-aged loss of accommodative function. Although one could theoretically make a case for clear lens replacement with an accommodative pseudophakos, it has never been conclusively demonstrated that loss of elasticity of the lens is the sole or even the major cause of presbyopia − in fact, more to the contrary. Changes have been shown to occur in the area of insertion of the zonular fibers, as well as in the configuration of the ciliary muscle. With only this limited knowledge, the present procedures represent the first attempts at the surgical correction of presbyopia by altering the ciliary architecture. Scleral expansion over the ciliary muscle by implantation of four circumferential PMMA rods or by radial sclerotomy, restoring tension to the flaccid zonular fibers, has been shown in early clinical studies to have poor success at restoring some accommodative power to the ciliary-zonule-lens mechanism. Surgery is still therefore limited, in the majority, to the induction of monovision (usually corneal but in many instances by lensectomy, modifiable by piggy-back sulcus-placed lenses, single vision, or multifocal).

Monovision

Monovision is the state of anisometropia geared towards emmetropia in one eye (usually the dominant eye) and near weighted ametropia (myopia) usually in the nondominant eye. Strictly optically speaking, a ­ myopic outcome of −3.00 D would provide a near focal point at 33 cm. This amount of anisometropia would in many instances produce asthenopic symptoms. In practice, patients need only small amounts of residual myopia to be able to read and perform near visual tasks. The target refraction, which, in the nondominant monovision reading eye, provides the best reading acuity with the least distance acuity loss with and with least anisometropic asthenopia is between −0.75 DS and −1.50 DS. This amount of ametropia provides the easiest ­rehabilitation for the monovision patient. In spite of these guidelines, patients should still undergo, at the very least, a loose lens (trial frame) demonstration of the monovision and, at best, a prolonged contact lens simulation of the suggested surgical treatment. This route maximizes significantly the number of satisfied patients after the surgery.

Astigmatism

As discussed above, the surgeon attending to the needs of the lensectomy patient, whether of medical or refractive indication, needs to maintain a holistic approach to the correction of their patient’s problem. In order

Fig. 5-4-8  Many intraocular lenses are now produced with squared posterior edges to minimize lens epithelial cell migration towards the visual axis. This example shows the AMO Sensar AR40e, with rounded anterior edge and squared posterior edge. (Courtesy of Advanced Medical Optics Inc.)

to optimize the outcome of the patient, the following items need to be considered: 1. The removal of the opacity or error in the optical system (the cataract or lensectomy); 2. The accurate correction of the optical state of the eye (biometry ­techniques and formulas, astigmatism induction avoidance, and pre-existing astigmatism correction); and 3. The execution of the surgery in the safest possible way in the prevailing circumstances to minimize complication (sterility, incision creation and location, wound closure, peroperative antibiotics, surgical technique, etc.) and while assessing and attending to these items, ensuring that the best combination of techniques provides the optimal solution for the patient and that includes maintaining the ability to readdress nonoptimal outcomes. The management of the astigmatism in lens surgery (or any anterior segment surgery) has become an essential and integral part of the execution of the operation. A number of techniques have been described to control astigmatism, both in minimizing induction and treating pre-existent cylindrical error. The most useful technique that covers the most common astigmatic errors is “on axis” incision for small-incision surgery (i.e., operative incision placement on the periphery of steep axis of the astigmatism). Other schools of thought suggest that the surgery be performed with the smallest incision possible (astigmatically neutral), then placing the on axis incisions in the appropriate meridian, either partial thickness (limbal relaxing incision − LRI, vertical partial thickness corneal incisions)47 or penetrating (penetrating astigmatic keratotomy − PAK, self-sealing, full-thickness, penetrating incisions, obliquely orientated through the cornea). PAK is the most effective means of controlling astigmatism but does implicate corneal penetration, the mechanism of the power of the procedure. Keeping the incisions single pass and thus reducing instrument passage, enhances the watertight closure, minimizes wound leak, and potentially minimizes infective risk. The power of correction in PAK can be enhanced further by creating a ­second

Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques

A

431

5

   Table 5-4-2  PENETRATING ASTIGMATIC SURGERY (PAK) NOMOGRAM

THE LENS

Cyl to Correct

Incision Size (mm)

Distance from Visual Axis (mm)

Opposite Incision Size (mm)

Distance from Visual Axis (mm)

1.00–1.50

3.2

6.0

nil

nil

1.50–2.00

3.5

6.0

nil

nil

2.00–2.50

3.8 mm

Limbal arcades

nil

nil

2.50–3.00

4.1 mm

5.5

nil

nil

2.50–3.00

3.5

5.5

3.5

5.5

3.00–3.50

3.5

5.0

3.5

5.0

3.50–4.00

3.5

4.5

4.1

5.0

4.00–5.00

4.1

4.5

4.1

4.5

5.00–6.00

4.1

4.5

4.1

4.0

6.00–7.00

4.1

4.0

4.1

4.0

> 7.00*

4.1

4.0

4.1

4.0

Initial overcorrection

Incisions may be sutured in first month

Initial undercorrection

Widen pre-exisiting incisions (possible AC cohesive OVD required)

>7.00 (plus regression or undercorrection)*

Secondary peripheral incisions at 3 months (nomogram)

> 4.00 in penetrating keratoplasty

Primary incisions in H/D junction/secondary incisions peripheral (except when combined with lens surgery) Peripheral incisions on merits of residual astigmatic error as per nomogram

*AC, anterior chamber; cyl, cylinder (astigmatism); H/D, host/donor; OVD, ophthalmic viscosurgical device.

keratotomy on the opposite side of the first incision (180° opposed). The effect is greatest with penetration, reaching corrections as high as 6−7 D of astigmatism with a single pair of incisions. The PAK nomogram listed in Table 5-4-2 demonstrates the titration of the astigmatic corrective effect by variation of incision width against the optical zone radius (OZR − the proximity of the incision to the pupil/astigmatic centrum).48 When this surgery is doubled by further peripheral incision pairs, astigmatic ameliorative effects of up to 10−12 D are noted, which is particularly useful in the correction of corneal graft ametropia,49 either stand alone or in conjunction with lensectomy (or any anterior segment procedure). In the execution of high cylinder correction, patients’ axes must be marked prior to lying down for anesthesia, local, topical, or general, to avoid cyclotorsional error.

Being on the cornea, this form of astigmatic correction is very stable, but astigmatic correction can also be executed by correctly orientated ­toric IOL insertion. A number of these lenses are now available on the market. High toric corrections require custom manufacture (> 3.00 DC).

ACKNOWLEDGMENT This chapter is based on Chapter 42 from the last edition of this book (Grabow HB. Indications for lens surgery and different techniques. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St Louis: Mosby; 2004:315−25)

REFERENCES

432

  1. C  hylack LT Jr, Wolfe JK, Singer DM, et al. The lens opacities classification system. Version III (LOCS-III). Arch Ophthalmol. 1993;111:831.   2. Lasa MSM, Datiles MB III, Freidlin V. Potential vision tests in patients with cataracts. Ophthalmology. 1995;102:1007–11.   3. Datiles MB III, Magno BV, Freidlin V. Study of nuclear cataract progression using the National Eye Institute Scheimpflug system. Br J Ophthalmol. 1995;79:527–34.   4. Lopez JLL, Freidlin V. Datiles MB III. Longitudinal study of posterior subcapsular opacities using the National Eye Institute computer planimetry system. Br J Ophthalmol. 1995;79:535–40.   5. Steinberg EP, Tielsch JM, Schein OD, et al. The VF-14: an index of functional impairment in patients with cataract. Arch Ophthalmol. 1994;112:630–8.   6. Steinberg EP, Tielsch JM, Schein OD, et al. National study of cataract surgery outcomes: variation in 4-month postoperative outcomes as reflected in multiple outcome measures. Ophthalmology. 1994;101:1131–41.   7. Schein OD, Steinberg EP, Cassard SD, et al. Predictors of outcome in patients who underwent cataract surgery. Ophthalmology. 1995;102:817–23.   8. Cassard SD, Patrick DL, Damiano AM, et al. Reproducibility and responsiveness of the VF-14: an index of functional impairment in patients with cataracts. Arch Ophthalmol. 1995;113:1508–13.   9. Mangione CM, Phillips RS, Lawrence MG, et al. Improved visual function and attenuation of declines in healthrelated quality of life after cataract extraction. Arch Ophthalmol. 1994;112:1419–25.

10. M  angione CM, Orav EJ, Lawrence MG, et al. Prediction of visual function after cataract surgery: a prospectively validated model. Arch Ophthalmol. 1995;113: 1305–11. 11. Edwards MG, Schachat AP, Bressler SB, Bressler NM. Outcome of cataract operations performed to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy of retinal disorders. Am J Ophthalmol. 1994;118:440–4. 12. Gindi JJ, Wan WL, Schanzlin DJ. Endocapsular cataract surgery. I. Surgical technique. Cataract. 1985;2(5):6–10. 13. Haefliger E, Parel J-M, Fantes F, et al. Accommodation of an endocapsular silicone lens (Phaco-ersatz) in the nonhuman primate. Ophthalmology. 1987;94:471–7. 14. Haefliger E, Parel J-M. Accommodation of an endocapsular silicone lens (Phaco-ersatz) in the aging rhesus money. J Refract Corneal Surg. 1994;10:550. 15. Nishi O. Refilling the lens of the rabbit eye after endocapsular cataract surgery. Folia Ophthalmol Jpn. 1987;38:1615–8. 16. Nishi O, Hara T, Hayashi F, et al. Further development of experimental techniques for refilling the lens of animal eyes with a balloon. J Cataract Refract Surg. 1989;15:584–8. 17. Hara T, Hara T, Yasuda A, Yamada Y. Accommodative intraocular lens with spring action. Part 1. Design and placement in an excised animal eye. Ophthalmic Surg. 1990;21:128–33. 18. Hara T, Hara T, Yasuda A, et al. Accommodative intraocular lens with spring action. Part 2. Fixation in the living rabbit. Ophthalmic Surg. 1992;23:632–5.

19. B  lumenthal M, Assia EI. Extracapsular cataract extraction. In: Nordan LT, Maxwell WA, Davison JA, eds. The surgical rehabilitation of vision. New York: Gower; 1992: ch 10. 20. McIntyre DJ. Cataract surgery: techniques, complications and management. In: Steinert RF, ed. Phacosection cataract surgery. Philadelphia: WB Saunders; 1995. :119–22. 21. Arsinhoff SA. The viscoelastic soft shell technique. In: Kohnen T, Koch D, eds. Essentials in ophthalmology, Ch 3.10. Berlin, Heidelberg: Springer-Verlag; 2005: 50–6. 22. Fine IH, Packer M, Hoffman RS. Nucleofractis techniques. In: Kohnen T, Koch D, eds. Essentials in ophthalmology Ch 2.5. Berlin, Heidelberg: Springer-Verlag; 2005 :25–32. 23. Dodick JM, Christiansen J. Experimental studies on the development and propagation of shock waves created by the interaction of short Nd:YAG laser pulses with a titanium target. J Cataract Refract Surg. 1991;17:794–7. 24. Grabner G, Alzner E. Dodick laser phacolysis: thermal effects. J Cataract Refract Surg. 1999;25:800–3. 25. Kanellopoulos AJ, Dodick JM, Brauweiler P, Alzner E. Dodick photolysis for cataract surgery. Ophthalmology. 1999;106:2197–202. 26. Huetz WW, Eckhardt B. Photolysis using the Dodick-ARC laser system for cataract surgery. J Cataract Refract Surg. 2001;27:208–12. 27. Kanellopoulos AJ. Laser cataract surgery: a prospective clinical evaluation of 1000 consecutive laser cataract procedures using the Dodick photolysis Nd:YAG system. Ophthalmology. 2001;108:649–55.

36. H  ara T, Hara T. Intraocular implantation in an almost completely retained capsular bag with a 4.5 to 5.0 millimeter linear dumbbell opening in the human eye. Ophthalmic Surg. 1992;23:545–50. 37. Gindi JJ, Wan WL, Schanzlin DJ. Endocapsular cataract surgery. I. Surgical technique. Cataract. 1985;2(5):6–10. 38. Blumenthal M., Clinical evaluation of full-size hydrogel lens − concept and reality. Six years experience. Presented at Symposium on Cataract, IOL, and Refractive Surgery, Boston, April 9, 1991. 39. Werner L, Mamalis N. Adjustable power intraocular lenses. In: Kohnen T, Koch D, eds. Essentials in ophthalmology, Ch 4.4.7, Berlin, Heidelberg: Springer-Verlag; 2005. :80–1. 40. Galand A, Galand A, van Cauenberge F, Moosavi J. Posterior capsulorrhexis in adult eyes with intact and clear capsules. J Cataract Refract Surg. 1996;22:458–61. 41. Hara T, Hara T. Observations on lens epithelial cells and their removal in anterior capsule specimens. Arch Ophthalmol. 1988;106:1683–7. 42. Nishi O, Nishi K, Yamada Y, Mizumoto Y. Effect of indomethacin-coated posterior chamber intraocular lenses on post-operative inflammation and posterior capsular opacification. J Cataract Refract Surg. 1995;21:574–8.

43. T etz M, Ries M, Lucas C, et al. Inhibition of posterior capsule opacification by an intraocular-lens-bound sustained drug delivery system: an experimental animal study and literature review. J Cataract Refract Surg. 1996;22:1070–8. 44. Power WJ, Neylav D, Collum LMT. Daunomycin as an inhibitor of human lens epithelial cell proliferation in culture. J Cataract Refract Surg. 1994;20:287–90. 45. Goins KM, Optiz JR, Fulcher SFA, et al. Inhibition of proliferating lens epithelium with antitransferrin receptor immunotoxin. J Cataract Refract Surg. 1994;20:513–5. 46. Ahmed II, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular tension ring. J Cataract Refract Surg. 2001;207:977–81. 47. Khng C, Fine IH, Packer M, Hoffman RS. Improved precision with the millimeter caliper for limbal relaxing incisions. J Cataract Refract Surg. 2005;31:1671–2. 48. Howes F. Penetrating astigmatic keratotomy. Presentation ESCRS, Paris, France, 2004. 49. Howes F. Penetrating astigmatic keratotomy, nomogram II. Presentation AUSCRS, Hayman Island, Australia, 2006.

5.4 Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques

28. N  eubaur CC, Stevens S. Erbium:YAG laser cataract removal: role of fiber-optic delivery system. J Cataract Refract Surg. 1999;25:514–20. 29. Hoh H, Fischer E. Pilot study on erbium laser phaco­ emulsification. Ophthalmology. 2001;107:1053–62. 30. Duran SD, Zato M. Erbium:YAG laser emulsification of the cataractous lens. J Cataract Refract Surg. 2001;27:1025–32. 31. Assia E, Apple D, Barden O, et al. An experimental study comparing various anterior capsulectomy techniques. Arch Ophthalmol. 1991;109:642–7. 32. Apple D, Park S, Merkley K, et al. Posterior chamber intraocular lenses in a series of 75 autopsy eyes. Part I. Loop location. J Cataract Refract Surg. 1986;12:358–62. 33. Gimbel HV, Neuhann T. Development, advantages, and methods of the continuous circular capsulorrhexis technique. J Cataract Refract Surg. 1990;16:31–7. 34. Assia E, Apple D, Tsai J, Lim E. The elastic properties of the lens capsule in capsulorrhexis. Am J Ophthalmol. 1991;111:628–32. 35. Galand A. A simple method of implantation within the capsular bag. Am Intra-ocular Implant Soc J. 1983;9: 330–2.

433

PART 5 THE LENS

The Pharmacotherapy of Cataract Surgery

5.5

Steve A. Arshinoff and Yvonne A.V. Opalinski

Key features n��� n��� n���

n���

 harmacotherapeutic agents are used in preoperative,  P intraoperative, and postoperative periods of cataract surgery. Preoperative medications are used to dilate the pupils,  as prophylactic antibiotics, and as anesthetics. Intraoperative pharmacotherapeutic agents include irrigating  solutions and additives to irrigating solutions, as well as  ophthalmic viscosurgical devices and intracameral antibiotics. Postoperative medications include antibiotics, corticosteroids,  and nonsteroidal anti-inflammatory drugs.

INTRODUCTION With current ongoing rapid evolution of cataract surgical techniques, corresponding change in the pharmacotherapeutic management of cataract patients is inevitable. In this chapter, current pharmacotherapeutic practices in the pre-, intra-, and postoperative periods are reviewed.

PREOPERATIVE MEDICATIONS Table 5-5-1 provides a summary of commonly used preoperative pharmacotherapeutic routines for cataract surgery.

Pupil Dilatation

434

Sympathomimetic mydriatic agents (such as phenylephrine 2.5%) and parasympatholytic cycloplegics (such as tropicamide or cyclopentolate 1.0%) usually are used together before extracapsular nuclear expression or phacoemulsification. If used in excess, sympathomimetics increase the risk of a severe systemic hypertensive response and the associated systemic risks in the elderly.1 For this reason, phenylephrine 10% is not recommended for routine use. To assist in adequate pupil dilatation, pilocarpine and other cholinergic miotics should be discontinued 12–24 hours before surgery (approximately twice the expected duration of action of the specific agent). Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in cataract surgery to prevent pupillary miosis, reduce surgically induced inflammation, and prevent postoperative cystoid macular edema.2 Administration of NSAIDs decreases prostaglandin synthesis by the inhibition of cyclooxygenase, thus preventing the transformation of arachidonic acid into prostaglandins.2, 3 Prostaglandin E2 (PGE2) enhances the constrictor action of the iris sphincter through a mechanism that is not dependent on cholinergic receptors.4, 5 Topical flurbiprofen 0.03%, the first agent to be used for this indication, was demonstrated to be clinically superior to topical indomethacin 1%.5 Currently, diclofenac 0.1% and ketorolac 0.5% are used for the same indication.6 Although diclofenac and flurbi profen adequately maintain mydriasis during surgery,7 ketorolac appears to inhibit miosis more effectively than either.8 In order to simplify preoperative drop regimens, it is becoming more common practice for centers to mix all preoperative dilating drops together and administer them as a plegett approximately half an hour preoperatively. The specific agents and doses vary among centers. Intracameral mydriatic solutions using cyclopentolate 0.1%, phenylephrine 1.5%, and Xylocaine 1% or tropicamide 0.5%, phenylephrine 5%, and diclofenac 0.1%, in preservative-free solutions, have proven safe

to the corneal endothelium and effective in producing and maintaining pupillary dilatation.9–11 Effective redilatation has also occurred using these mydriatics intracamerally during surgery on contracted pupils.12

Anti-Infective Prophylaxis

Prophylactic antibiotic use in cataract surgery has been an accepted practice for decades. Preoperatively, the most important source of potential infectious organisms is the patient’s own natural conjunctival and skin flora. Intraoperative cultures indicate that 5% of intraocular surgeries result in measurable anterior chamber contamination from indigenous flora, but the vast majority of these patients develop no clinical adverse sequelae.13 Cultures taken from the conjunctiva and anterior chamber of patients who subsequently developed endophthalmitis usually yielded the same bacterial strains. Staphylococci (Staphylococcus epidermidis and S. aureus), diphtheroids (Corynebacterium), streptococci (Streptococcus viridans), and gram-negative bacilli (anaerobic Propionibacterium acnes and others) are the most common infecting agents in decreasing order of occurrence.14 Administered medications should adequately cover the bacteria most likely to cause potential endophthalmitis during the operative and perioperative period, during which bacteria can gain entrance into the anterior chamber. Before cataract surgery, topical anti-infective regimens have included gramicidin−neomycin−polymyxin B sulfate, aminoglycosides such as gentamicin or tobramycin (which provide gram-negative and Pseudomonas coverage), and the fluoroquinolones − ciprofloxacin, norfloxacin, ofloxacin 0.3%,7, 15, 16 or levofloxacin 0.5%. Of these, levofloxacin provided superior coverage and anterior chamber penetration, before fourth generation fluoroquinolone became available.17–20 The fourth generation fluoroquinolones, gatifloxacin 0.3% and moxifloxacin 0.5%, are currently the preferred agents, offering better penetration than previous generations (moxifloxacin appears to be better than gatifloxacin),21 broader spectrum coverage, and lower incidence of bacterial resistance, and are equally safety.22–24 Antibacterial prophylaxis for cataract surgery is an issue that has recently risen to prominence with the confirmation of an increasing incidence of postoperative endophthalmitis since the advent of clear corneal incisions.25 Some authors have suggested that beginning antibacterial antibiotic prophylaxis 3 days preoperatively may yield superior intraocular drug levels at surgery.26–28 There has been considerable concern that the prophylactic use of potent antibiotics in large numbers of healthy cataract patients contributes to the development of resistant bacterial strains; however, recently even the conservative and rather authoritarian voice of the Medical Letter stated that “Medical letter consultants believe that ophthalmic use of antibacterials is much less likely than systemic use to select for resistant organisms.”29 Nevertheless, complete conjunctival sterility, through the elimination of such flora, is not usually possible with the use of preoperative antibiotics alone.7 The topical antiseptic povidone-iodine 5% instilled as a single drop 10–30 minutes before surgery is one of the most effective measures to decrease this bacterial flora30 and appears equal in efficacy to preoperative topical antibiotics.31

Anesthetics

Anesthetics are covered fully in Chapter 5.6. Local injection anesthesia, both retrobulbar and peribulbar, is declining in popularity, while the use of intracameral nonpreserved lidocaine has gained popularity over the last few years, as has topical lidocaine gel. Lidocaine gel is claimed to provide increased corneal hydration and anesthesia equal to that of injections and drops32, 33 while minimizing patient discomfort, but its popularity seems to be decreasing, possibly due to unwanted epithelial side effects, such as decreased clarity and erosions.

   TABLE 5-5-1  COMMONLY USED AGENTS IN THE ROUTINE PREOPERATIVE PHARMACOTHERAPY OF CATARACT SURGERY Concentration

Dosage

Nonsteroidal anti-inflammatory drugs  to prevent miosis

Diclofenac Ketorolac Flurbiprofen Indomethacin

0.10% 0.50% 0.03% 1%

1 drop 4 times over 1 h preceding surgery

Cycloplegics

Tropicamide Cyclopentolace

1% 1%

1 drop 4 times over 1 h preceding surgery

Mydriatics

Phenylephrine

2.50%

1 drop twice over 0.5 h preoperatively

Antibiotic prophylaxis

Gramicidin– neomycin– polymyxin B Gentamicin Tobramycin Ciprofloxacin Ofloxacin Gatifloxacin Moxifloxacin Trimethoprim–polymyxin B

0.025 mg/ml 2.5 mg/ml 10.000 IU/ml 0.30% 0.30% 0.30% 0.30% 0.30% 0.50% 1 mg/ml (10.000 IU/ml)

1 drop 4 times over 1 h preceding surgery

Anesthetic: retrobulbar or parabulbar

Lidocaine Mepivacaine Bupivacaine

1–2% 1–2% 0.25–0.75%

3–9 ml

Anesthetic: intracameral

Isotonic, nonpreserved lidocaine

1–2%

0.1–0.6 ml

Anesthetic: topical

Proparacaine Tetracaine Benoxinate (oxybuprocaine) Lidocaine Bupivacaine

1–2% 0.50% 0.40% 4% 0.75%

1–2 drops prior to surgery, and then every 10 minutes or as needed during surgery

INTRAOPERATIVE MEDICATIONS Additives to Irrigating Solutions, Intracameral Antibiotics, and Other Intraocular Drugs Used During the Surgical Procedure

Table 5-5-2 gives a summary of commonly used intraoperative pharmacotherapeutic routines. In general, the addition of antibiotics, mydriatics, epinephrine (adrenaline), or lidocaine (lignocaine) is not recommended by the companies that produce irrigating solutions for cataract surgery, because any effect on stabilizers and preservatives in the solutions could alter their pH, chemical balance, or osmolarity and influence the potential toxicities of both irrigating solution and additive alike. Caution is therefore advised if any alteration to commercial irrigating solutions is considered. To prevent intraoperative miosis, nonpreserved epinephrine (1:1000) 0.5 mL/500 mL of irrigating solution is added frequently. This concentration appears not to be toxic to the corneal endothelium and allows normal endothelial function.34 The intraoperative use of antibiotics in irrigating solutions is a controversial issue in cataract surgery. It appears that surgical technique may play the most critical role in anterior chamber contamination, and the antibiotics administered in irrigating solutions may contribute minimally to reduce the risk of endophthalmitis.13, 35, A case of coagulase-negative staphylococcal endophthalmitis has been reported despite intraoperative vancomycin (1 mg/0.1 mL) injected intravitreally.36 Nevertheless, vancomycin (20 μg/mL (0.02 mg/mL)) in combination with gentamicin (8 μg/mL (0.008 mg/mL)), added to the irrigating solution, has been reported to eradicate gram-positive, coagulase-negative micrococci,37 with minimal associated complications.38 Gentamicin alone has been used intraoperatively in the dosage range of 8−80 μg/mL added to the irrigating solution, which appears sufficient to avoid retinal toxicity and at the same time decrease the intracameral bacterial load.39 Surgeons recognize that the postsurgical capsular bag is a sequestered avascular site that harbors a foreign body (the intraocular lens) and may act as the nidus for most cases of endophthalmitis. Vancomycin (1 mg in 0.1 mL balanced salt solution (BSS)) was the first agent to be used by injection directly into the capsular bag as the final step in the surgical procedure, and was introduced by James Gills in the early 1990s. This mode of delivery is considered superior to adding antibiotics to the irrigating solution because the concentration achieved in the anterior

5.5 The Pharmacotherapy of Cataract Surgery

Class and Agent

chamber is much higher; furthermore, it is done at the very end of surgery, leaving a high dose in the anterior chamber for the early postoperative period.40 There was considerable discussion among clinicians and researchers about the safety and efficacy of intracameral injections until a large, multicenter, prospective, randomized, controlled European Society of Cataract and Refractive Surgeons (ESCRS) study showed intracameral cefuroxime (first proposed by Montan et al.) to be effective in producing an 80% reduction in endophthalmitis rates, thus settling the argument.41–43 Other intracameral antibiotics (cefazolin,44, 45 gatifloxacin,46 and moxifloxacin47) have been used and have yielded similar, or better, endophthalmitis reduction rates than those achieved by Montan et al. or the ESCRS study. There is general consensus that intracameral antibiotics are effective in dramatically reducing postoperative endophthalmitis, but also a widespread belief that cefuroxime, found to be so effective in the ESCRS study, may not be the best choice of agent.48 This area is, at the time of writing, one of the most actively debated issues in the field of ophthalmology. Rapid miosis can be produced at the end of the surgical procedure using one of two available intraocular parasympathomimetics − acetylcholine chloride 1% or carbachol 0.01%.49 Current preparations have shown no evidence of endothelial toxicity, and the choice of agent depends on the desired clinical features. Acetylcholine 1% has an onset time of less than 1 minute, has a relatively brief duration of action, and results in miosis for 10 minutes, whereas carbachol 0.01% takes 2 minutes to act and its effect has a duration of 2−24 hours. Both agents lower postoperative intraocular pressure spikes.50 Low-molecular-weight heparin, enoxaparin (10 IU/mL added to standard irrigating solution), produces a decreased inflammatory response immediately after cataract surgery with minimal side effects (e.g., hemorrhage).51, 52 Enoxaparin’s potential in cataract surgery requires further evaluation. A preliminary study using ozonated water (4 ppm concentration) in anterior chamber irrigation confirmed its bactericidal effects and may potentially present another tool against endophthalmitis.53

Irrigating Solutions

In the early days of phacoemulsification, the only irrigating solutions available were normal saline, Plasma-Lyte, and lactated Ringer’s solution. The main difficulty with these solutions was endothelial cell toxicity, which resulted in dysfunction and destruction. Irrigating solutions with calcium, glutathione, and bicarbonate form more ­physiologically

435

5

  TABLE 5-5-2  COMMONLY USED AGENTS IN THE ROUTINE PREOPERATIVE PHARMACOTHERAPY OF CATARACT SURGERY Class and Agent

THE LENS

Agents added to irrigating solutions

Concentration

Antibiotics Vancomycin plus Gentamicin Gentamicin Sympathomimetics to prevent miosis Nonpreserved epinephrine

Agents used at the end of the procedure

Antibiotics Vancomycin Cefuroxime Cefazolin Gatifoxacin Moxifloxacin Parasympathomimetrics Acetylcholine Carbachol

Dosage

20 μg/ml 8 μg/ml 8–80 μg/ml

0.3–0.5 ml of 1:1000 nonpreserved ­epinephrine 500 ml irrigating solution 0.1 ml intracapsularly via sideport at end of procedure

1 mg/0.1 ml 1 mg/0.1 ml 1 –2.5 mg/0.1 ml 100 μg/0.1 ml 100 μg/0.1 ml

0.5 ml injected into anterior chamber via sideport to cause miosis

1% 0.01%

  TABLE 5-5-3  CHEMICAL COMPOSITION OF HUMAN AQUEOUS HUMOR, VITREOUS HUMOR, BSS PLUS, AND BSS Ingredient

Human Aqueous Humor

Human Vitreous Humor

BSS Plus

BSS

Sodium

162.9

144

160

155.7

Potassium

2.2–3.9

5.5

5

10.1

Calcium

1.8

1.6

1

3.3

Magnesium

1.1

1.3

1

1.5

Chloride

131.6

177

130

128.9

Bicarbonate

20.15

15

25

–

Phosphate

0.62

0.4

3

–

Lactate

2.5

7.8

–

–

Glucose

2.7–3.7

3.4

5

–

Ascorbate

1.06

2

–

–

Glutathione

0.0019

–

0.3

–

Citrate

–

–

–

5.8

Acetate

–

–

–

28.6

pH

7.38

–

7.4

7.6

Osmolality (mOsm)

304

–

305

298

(Adapted from Edelhauser HF. Intraocular irrigating solutions. In: Lamberts DW, Potter DE, Potter DE, eds. Clinical Ophthalmic Pharmacology. Boston: Little, Brown and Company; 1987, pp. 431–44.)

436

balanced solutions (Table 5-5-3).54 Several comparative studies have found BSS Plus to be ­superior to BSS and other irrigating solutions and protective of the corneal endothelium. Unlike BSS, BSS Plus is physiologically similar to human aqueous and vitreous, especially with regard to calcium concentration and the addition of glucose, glutathione, and bicarbonate. BSS Plus maintains endothelial cell function over periods ranging from 15 minutes to in excess of a few hours.41 The buffer in BSS Plus is bicarbonate, which is an improvement over the sodium acetate and citrate buffers in BSS. Nevertheless, BSS Plus is used much less frequently than BSS, due to the high price of BSS Plus, and the progressive reduction in irrigating fluid volume used in surgery, as techniques improve over time. Corneal surface irrigation to maintain hydration and surgical clarity has traditionally been performed throughout intraocular procedures with BSS. The development of an elastoviscous hylan surgical shield (HSS) 0.45%, which decreases the surgeon’s dependence on manual corneal irrigation, has proved to be an improvement over BSS in maintaining corneal hydration and clarity intraoperatively.55 Some surgeons use a drop of ophthalmic viscosurgical device (OVD) on the cornea at the beginning of surgery to produce this effect; OVD may not be as effective as HSS but it is more readily available.

OPHTHALMIC VISCOSURGICAL DEVICES The introduction of Healon in 1980 for use in ocular surgery ushered in the era of viscosurgery. Because OVDs tend to consist of solutions of long-chain biopolymers (almost always hyaluronic acid or hydroxypropyl methylcellulose) in low concentration, they are all pseudoplastic in their rheological behavior. Their physical properties tend to correlate (i.e., the most viscous solution is also the most elastic and the most cohesive) and are a function of the chain length distribution of the rheologically important constituent polymer and its concentration. Recently, the advent of DisCoVisc, a viscous dispersive OVD, demonstrated that we can escape the strict correlation between viscosity and cohesion in OVDs, resulting in a new classification, based upon zero-shear viscosity and cohesive−dispersive properties (measured as the cohesion−dispersion index, CDI) (Table 5-5-4). It is apparent that OVDs cannot be referred to generically, as each one has different rheologic properties, and are not interchangeable, in that many surgical maneuvers can be achieved more easily with one type of OVD than another. Before the advent of viscoadaptive OVDs, ­superviscous-­cohesive and viscous-cohesive OVDs were recognized as the best for creating, stabilizing, and maintaining spaces (to deepen the anterior chamber in the presence of positive vitreous pressure, to stabilize the anterior chamber to facilitate capsulorrhexis,

  TABLE 5-5-4  NEW CLASSIFICATION OF COMMON OVDs INCLUDING DisCoVisc Cohesive OVDs CDI ≥ 30 (%asp/mmHg)

7 – 8 × 106 (ten millions)

I. Viscoadaptives* – Healon5 – iVisc (MicroVisc) Phaco – BD MultiVisc

Dispersive OVDs CDI < 30 (%asp/mmHg)



II. Higher viscosity cohesives

II.Higher viscosity dispersives

1 – 5 × 106 (millions)

A. Superviscous cohesives – Healon GV –iVisc (MicroVisc, HyVisc) Plus – BD Visc

A. Superviscous dispersives – none

105 – 106 (hundred thousands)

B. Viscous cohesives – Healon – iVisc (MicroVisc, HyVisc) – Viscorneal Plus – Provisc – Opegan Hi – Viscorneal – Biolon Prime – Biolon – Amvisc Plus – Amvisc – Coese – Biocorneal

B.Viscous dispersives – DisCoVisc

III.Lower viscosity cohesives

5.5 The Pharmacotherapy of Cataract Surgery

Zero-Shear Viscosity Range (mPa.s)

III.Lower viscosity dispersives

104 – 105 (ten thousands)

A. Medium viscosity cohesives – none

A. Medium viscosity dispersives – Viscoat – Biovisc – Rayvisc – Opelead – Vitrax – Cellugel

103 – 104 (thousands)

B.Very low viscosity cohesives – none

B.Very low viscosity dispersives – Opegan –OccuCoat, ICell, Ocuvis, Visilon, Hymecel,  Adatocel, Celoftal (HPMCs)

mPa.s, miliPascal seconds; CDI, c��������������������������� o�������������������������� hesion–dispersion index ��� (% �������������������������������������������������������� aspirated/mmHg); OVD, ophthalmic viscosurgical device. *Viscoadaptives, because of their peculiar “adaptive” behavior when exposed to different degrees of turbulence, may behave either as extremely cohesive or pseudo-dispersive OVDs. Similarly, CDI measurements may differ under different conditions of testing.

and to keep the capsular bag open and taut to facilitate foldable intra­ ocular lens implantation). Conversely, medium and lower viscosity­dispersive OVDs are excellent for the selective isolation of areas of the intraocular surgical field and for enabling fluid partition of the anterior chamber (to protect marginal corneas from the turbulence of phacoemulsification, or to keep a frayed piece of iris or bulging vitreous away from the phacoemulsifying or irrigation-aspiration tip).56 Superviscous-cohesive and viscous-cohesive OVDs cannot be used to partition fluid-filled spaces. To achieve the benefits of both types of older OVDs and avoid having to deal with their disadvantages, the “soft shell technique” can be utilized.57–59 Healon5 and MicroVisc Phaco (iVisc Phaco, Hyvisc Phaco, BD MultiVisc) are viscoadaptive OVDs that exhibit either highly viscous cohesive or pseudodispersive properties, depending on fluid turbulence in the anterior chamber. 60 Dispersive behavior of lower viscosity OVDs and pseudodispersive behavior of viscoadaptives are very different.60, 61 These characteristics allow their use for chamber partitioning and yield enhanced versatility over earlier OVDs during phacoemulsification.62–66 The “ultimate soft shell technique” further enhances the scope of utility of viscoadaptive OVDs,67, 68 and enables the benefits of the soft shell technique to be attained using a single viscoadaptive OVD. DisCoVisc is a new viscous dispersive OVD with zero-shear velocity similar to Healon, but resembles Viscoat’s dispersive properties, thus permitting the chamber maintenance properties of Healon and the dispersive endothelial protection of Viscoat using a single OVD syringe.61

POSTOPERATIVE MEDICATIONS Postoperative drugs are listed in Table 5-5-5.

Antibiotics

Postoperative regimens of topical antibiotics vary but generally consist of one drop to the operated eye 4−6 times daily for 1−2 weeks. The duration of treatment varies from 5 days in uncomplicated surgery to weeks if prolonged inflammation occurs. Topical treatment is so efficacious that the use of injections and collagen shields is increasingly ­falling out of favor. Increasing resistance to antibiotics that have been used for decades and the lack of resistance to newer drugs (e.g., gentamicin versus moxifloxacin or gatifloxacin) also influence the selection of postoperative anti-infective prophylaxis. Subconjunctival injections of antibiotics deliver high levels to the aqueous humor but have a greater risk associated with their administration, notably perforation of the eye, macular infarction, and retinal toxicity. Oral or parenteral antibiotics, such as the fluoroquinolones, may reach substantial levels in the anterior chamber but do not provide any advantages over topical routes of administration and are associated with increased side effects.69, 70 Collagen shields, with a dissolution time of 12 hours, have been introduced to decrease the frequency of drop application and to increase the drug concentration, and its duration, in the cornea and anterior chamber. The shields, presoaked in an antibiotic and corticosteroid solution such as tobramycin and dexamethasone, or netilmicin and betamethasone, are placed on the eye immediately after surgery, and have been associated with minimal adverse effects.71 A preoperative 60-minute application of a singleuse collagen shield delivery system, presoaked in ofloxacin for 10 minutes, has also been proposed to achieve superior aqueous drug levels at the onset of surgery.72 Postoperative application of collagen shields appears to be superior to subconjunctival injections of the same antibiotic­−corticosteroid mix in terms of efficacy, toxicity, safety, and reduction of patient discomfort. It has been advised to use caution with collagen shields in the absence

437

5

  Table 5-5-5  COMMONLY USED AGENTS IN THE ROUTINE POSTOPERATIVE PHARMACOTHERAPY OF CATARACT SURGERY

THE LENS

Class and Agent

Concentration

Dosage

Corticosteroids

Dexamethasone Prednisolone Betamethasone

0.10% 1% 0.10%

1 drop 4 times daily for 3–4 weeks  postoperatively

Nonsteroidal anti-inflammatory drugs

Diclofenac Ketorolac

0.10% 0.50%

1 drop 4 times daily for 4 weeks  postoperatively

Antibiotics

Gramicidin–neomycin–polymyxin B Gentamicin Tobramycin Ciprofloxacin Ofloxacin Gatifloxacin Moxifloxacin Trimethoprim–polymyxin B

0.025 mg/ml 2.5 mg/ml 10, 000 1U/ml 0.30% 0.30% 0.30% 0.30% 0.30% 0.50% 1 mg/ml (10, 000 1U/ml)

1 drop 4 times daily for 3–4 weeks  postoperatively

of a well-sealed wound, because concentrations of some antibiotics in the shield may become toxic if they leach into the anterior chamber.13 Furthermore, some combinations of antibiotic and corticosteroid have produced toxic precipitates.50 The use of postoperative collagen shields has not been widely adopted. They have become much less of an issue recently, as the intraocular concentrations of fourth generation fluoroquinolones, the antibiotics currently most commonly recommended perioperatively for cataract patients, achieve sufficient intraocular levels with topical drops alone.

Corticosteroids and Nonsteroidal Anti-Inflammatory Drugs

438

Topical corticosteroids and NSAIDs are used after cataract surgery to reduce postoperative noninfectious inflammation. Corticosteroids and NSAIDs appear to be equally efficacious in decreasing inflam­ mation,6, 73, 74 and there is no difference between them in terms of astigmatic decay. The development of an intraocular biodegradable drug delivery system containing dexamethasone appears to be an effective alternative to topical drops,75 and because a variety of drugs may be bound to the polymer matrix, it may play a role in the long-term prevention or treatment of cystoid macular edema. Topical NSAIDs have a specific advantage over corticosteroids if there are contraindications to corticosteroid use in a particular patient, such as corticosteroid-responsive elevations of intraocular pressure, recurrent herpes simplex infection,76 or concern about delayed wound healing.77 Ketorolac 0.5% has been shown to be equally effective as a single agent in antimiotic and anti­inflammatory activity when compared with an NSAID−prednisolone 1% combination.78 There is, however, an increased risk of corneal or scleral perforation in the presence of an epithelial defect when NSAIDs are used alone, without concomitant administration of topical ­steroids.79, 80 Pretreatment with an NSAID decreases the postoperative level of inflammation, provided the medication is administered over a period of 3 days.81, 82 Both corticosteroids and NSAIDs are used postoperatively, either interchangeably or together, although not as a single solution. The addition of an NSAID to an antibiotic−steroid postoperative regimen has been reported to decrease the incidence of noninfectious postoperative inflammatory conditions.83 The corticosteroids dexamethasone 0.1%, prednisolone 1%, and betamethasone 0.1% are used most commonly. A new steroid, rimexolone 1%, seems equal in efficacy with less potential intraocular pressure increase than either dexamethasone or prednisolone because its lipophilic nature reduces intraocular penetration.84 In a recent study, a single intraoperative sub-Tenon’s injection of triamcinolone (30−40 mg)85, 86 or intracameral triamcinolone (1.8− 2.8 mg)87 seemed to reduce the inflammatory response postoperatively. The most frequently used topical NSAIDs are diclofenac 0.1% and ketorolac 0.5%.88, 89 Corticosteroid and NSAID regimens are the same and consist of one drop to the affected eye four times daily for up to 4 weeks, usually in conjunction with a topical antibiotic. Combination NSAID−antibiotic drops have been formulated to minimize the number of different bottles a patient must use postoperatively, without altering either the drug’s efficacy or penetration.90

LATE POSTOPERATIVE MEDICATIONS Treatment of Endophthalmitis

Endophthalmitis has been treated with antibiotics systemically, intravitreally, and topically. See Chapter 7.9 for details.

Treatment of Cystoid Macular Edema

Cystoid macular edema (CME) usually manifests 1−3 months postoperatively as either decreased visual acuity or changes on fluorescein angiography that result from serous exudate leaking from incompetent intraretinal capillaries into the outer plexiform layer of Henle.91 Most patients spontaneously recover, with full restoration of visual acuity within 6 months; however, it may require 1−2 years for full spontaneous resolution to occur.2 In approximately one third of severe clinically significant macular edema patients, macular edema may persist, ­accompanied by decreased visual acuity. Prophylaxis and treatment have been suggested in the form of systemic and topical NSAIDs. Oral NSAIDs, with regimens of indomethacin 25 mg three times daily 1 week before surgery and 3 weeks postoperatively,2 or ibuprofen 200 mg preoperatively and postoperatively, have received mixed reviews.92 Literature supports the efficacy of topical NSAIDs,93–95 such as flurbiprofen 0.03%, diclofenac 0.1%, and ketorolac 0.5%, used prophylactically and after surgery to reduce inflammation.96 Piroxicam 0.5% solution used postoperatively appears to be as effective as diclofenac, but causes less ocular irritation.97 Usually, preoperatively and postoperatively, one drop is administered four times daily for up to 3 weeks to prevent CME. Frequently, in the acute postoperative period topical corticosteroids are used in conjunction with NSAIDs in the treatment of CME,98 although their combined effect has once again been questioned.99 In chronic cases, management continues until resolution.2 It has been suggested that indefinite NSAID treatment may be required to maintain CME regression,100 which increases interest in the utility of a long-term, intraocular drug delivery system.67 Once established, CME has been treated with oral acetazolamide, topical corticosteroids with NSAIDs, or posterior sub-Tenon’s injection of long-acting corticosteroids (see Chapter 6.33). Single-dose intracameral, intraoperative, and multiple intravitreal postoperative injections of triamcinolone have also safely prompted regression of chronic CME with minimal changes in intraocular pressure.73, 101–103 Recently, oral ­cyclooxygenase-2-inhibitors (10 mg daily) were found to successfully resolve CME that was unresponsive to oral or topical NSAIDS in a small number of patients, with improvement in visual acuity,104 as has high-dose methylprednisolone (1000 mg for 3 days)105 in the past. Antiglaucomatous prostaglandin analogs such as latanoprost may enhance disruption of the blood−aqueous barrier, increasing the incidence of CME after cataract surgery, but this appears to be a response to the drug’s preservative, and not the drug itself. The concurrent application of NSAIDs decreases the incidence of CME secondary to these medications and does not adversely influence the antiglaucoma drug’s effect on intraocular pressure.106, 107

REFERENCES 27. M  ather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463–6. 28. Kim DH, Stark WJ, O’Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5%  ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112:1992–6. 29. Ophthalmic moxifloxicin (Vigamox), gatifloxacin  (Zymar). The Medical Letter. 2004;46(issue 1179):25. 30. Dereklis DL, Bufidis TA, Tsiakiri EP, Palassopoulos SI. Preoperative ocular disinfection by the use of povidoneiodine 5%. Acta Ophthalmol. 1994;72(5):627–30. 31. Chaudhary U, Nagpal RC, Malik AK, Kumar A. Comparative evaluation of antimicrobial activity of polyvinylpyrrolidone (PVP)-iodine versus topical antibiotics in cataract surgery. J Indian Med Assoc. 1998;96(7):202–4. 32. Koch PS. Efficacy of lidocaine 2% jelly as a topical agent in cataract surgery. J Cataract Refract Surg. 1999;25:632–4. 33. Assia EI, Pras E, Yehezkel M, et al. Topical anesthesia  using lidocaine gel for cataract surgery. J Cataract Refract Surg. 1999;25:635–9. 34. Glasser DB, Edelhauser HF. Toxicity of surgical solutions. Int Ophthalmol Clin. 1989;29:179–87. 35. Parkkari M, Paivarinta H, Salminen L. The treatment  of endophthalmitis after cataract surgery. J Ocular Pharmacol Ther. 1995;11:349–59. 36. Townsend-Pico WA, Meyers SM, Langston RH, Costin JA. Coagulase-negative staphylococcus endophthalmitis after cataract surgery with intraocular vancomycin.  Am J Ophthalmol. 1996;121:318–9. 37. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122:1–7. 38. Sobaci G, Tuncer K. Effect of intraoperative antibiotics in irrigating solution on aqueous humor contamination. Eur J Ophthalmol. 2003;13:773–8. 39. Dickey JB, Thompson KD, Jay WM. Intraocular gentamicin sulfate and post cataract anterior chamber aspirate cultures. J Cataract Refract Surg. 1994;20:373–7. 40. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122:1–17. 41. Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime. JCRS. 2002;28:977–81. 982–7. 42. Seal DV, Barry P, Gettinby G, et al. ESCRS study of prophylaxis of endophthalmitis after cataract surgery: Case for a European multicentre study. J Cataract Refract Surg. 2006;32:396–406. 43. Barry P, Seal DV, Gettinby G for the ESCRS Endophthalmitis Study Group, et al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Preliminary report of principal results from a European multicenter study. J Cataract Refract Surg. 2006;32:407–10. 44. Garat M, Moser CL, Alonso-Tarres C, Martin-Baranera M, Alberdi A. Intracameral cefazolin to prevent endophthalmitis in cataract surgery: A 3 year retrospective study. JCRS. 2005;31:2230–4. 45. Romero P, Mendez I, Salvat M, et al. Intracameral cefazolin as prophylaxis against endophthalmitis in cataract surgery. J Cataract Refract Surg. 2006;32:438–41. 46. Donnenfeld E, Snyder R, Kannellopoulos J, et al  Presented at the annual meeting of the American  Society of Cataract & Refractive Surgery, April 2004. 47. Arshinoff SA. Intracameral Vigamox for antibacterial prophylaxis in cataract surgery. A review of my experiences. Cataract Refract Surg Today. 2007;4:1–3. 48. O’Brien TP, Arshinoff SA, Mah FS. Perspectives on antibiotics for postoperative endophthalmitis prophylaxis: potential role of moxifloxacin. J Cataract Refract Surg.2007;33:1790–1800. 49. ��������������������� Roberts CW. Intraocular miotics and postoperative inflammation. J Cataract Refract Surg. 1993;19:731–4. 50. Arshinoff SA, Calogero DX, Bilotta R, et al. The problems associated with OVD use in cataract surgery. Presented by S Senft at the annual meeting of the American  Society of Cataract and Refractive Surgery, San Diego, CA, April 16–22, 1998. 51. Rumelt S, Stolovich C. Intraoperative enoxaparin minimizes inflammatory reaction after pediatric cataract surgery. Am J Ophthalmol. 2006;141:433–7. 52. Kruger A, Amon M. Effect of heparin in the irrigation solution on post-operative inflammation and cellular reaction on the intraocular lens surface. J Cataract Refract Surg. 2002;28:87–92.

53. T akahashi H, Fujimoto C. Anterior chamber irrigation with an ozonated solution as prophylaxis against infectious endophthalmitis. J Cataract Refract Surg. 2004;30:1773–80. 54. McDermott ML, Edelhauser HF, Hack HM, Langston RH. Ophthalmic irrigants: a current review and update. Ophthalmic Surg. 1988;19:724–33. (review). 55. Arshinoff SA, Khoury E. HsS versus a balanced salt solution as a corneal wetting agent during routine cataract extraction and lens implantation. J Cataract Refract Surg. 1997;23:1211–25. 56. Arshinoff SA. Dispersive and cohesive viscoelastics in phacoemulsification. Ophthalmic Pract. 1995;13:98–104. 57. Arshinoff SA. The viscoelastic soft shell technique for compromised corneas and anterior chamber compartmentalization. Presented at the American Society of Cataract and Refractive Surgery Symposium on Cataract, IOL, and Refractive Surgery, Seattle, Washington DC, 1996. 58. Arshinoff SA. “Soft shell” technique uses two types of viscoelastics. Reported by Harvey Black. Ocular Surg News, Int. Ed. 1996;7(10):20. 59. Kim H, Joo CK. Efficacy of the soft-shell technique using Viscoat and Hyal-2000. J Cataract Refract Surg. 2004;30:2366–70. 60. Arshinoff SA, Wong E. Understanding, retaining, and removing dispersive and pseudodispersive ophthalmic viscosurgical devices. J Cataract Refract Surg. 2003;29:2318–23. 61. Arshinoff Steve A, Jafari Masoud. A New Classification  of Ophthalmic Viscosurgical Devices (OVDs) − 2005.  J Cataract Refract Surg. 2005;31:2167–71. 62. Arshinoff SA, Hofman I. Prospective, randomized trial comparing MicroVisc Plus and Healon GV in routine phacoemulsification. J Cataract Refract Surg. 1998;24:814–20. 63. Miller KM, Colvard M. Randomized clinical comparison of Healon GV and Viscoat. J Cataract Refract Surg. 1999;25:1630–6. 64. Rainer G, Menapace R, Findl O, et al. Intraocular pressure after small incision cataract surgery with Healon5 and Viscoat. J Cataract Refract Surg. 2000;26:271–6. 65. Arshinoff SA. Why Healon5. The meaning of  viscoadaptive. Ophthalmic Pract. 1999;17:332–4. 66. Arshinoff SA. Healon5. In: Buratto L, Giardini P, Bellucci R, eds. Viscoelastics in ophthalmic surgery. Thorofare, NJ: Slack Inc.; 2000. :393–9. 67. Arshinoff S. The ultimate soft-shell technique. Ophthalmic Pract. 2000;18:289–90. 68. Arshinoff SA. Using BSS with viscoadaptives in “the ultimate soft shell technique“. J Cataract Refract Surg. 2002;28:1509–14. 69. Bron AM, Pechinot AP, Garcher CP, et al. The ocular penetration of oral sparfloxacin in humans. Am J Ophthalmol. 1994;117:322–7. 70. Mounier M, Ploy MC, Chauvin M. Study of intraocular diffusion of ofloxacin in humans and rabbits. Pathol Biol. 1992;40:529–33. 71. Haaskjold E, Ohrstrom A, Uusitalo RJ, et al. Use of collagen shields in cataract surgery. J Cataract Refract Surg. 1994;20:150–3. 72. Taravella MJ, Balentine J, Young DA, et al. Collagen shield delivery of ofloxacin to the human eye. J Cataract Refract Surg. 1999;25:562–5. 73. Simone JN, Pendelton RA, Jenkins JE. Comparison of the efficacy and safety of ketorolac tromethamine 0.5% and prednisolone acetate 1% after cataract surgery.  J Cataract Refract Surg. 1999;25:699–704. 74. Hirneiss C, Neubaur AS. Comparison of prednisolone 1%, rimexolone 1% and ketorolac tromethamine 0.5% after cataract extraction. Graefes Arch Clin Exp Ophthalmol. 2005;243:768–73. 75. Chang DF, Garcia IH, Hunkeler JD, et al. Phase II results of an intraocular steroid delivery system for cataract surgery. Ophthalmology. 1999;106:1172–7. 76. Masket M. Comparison of the effect of topical corticosteroids and nonsteroidals on postoperative corneal astigmatism. J Cataract Refract Surg. 1990;16:715–8. 77. Barba KR, Samy A, Lai C, et al. Effect of topical anti- inflammatory drugs on corneal and limbal wound  healing. J Cataract Refract Surg. 2000;26:893–7. 78. Snyder RW, Siekert RW, Schwiegerling J, et al. Acular  as a single agent for use as an antimiotic and anti- inflammatory in cataract surgery. J Cataract Refract  Surg. 2000;26:1225–7. 79. Arshinoff SA, Mills MD, Haber S. The pharmacotherapy of photorefractive keratectomy. J Cataract Refract Surg. 1996;22:1037–44. 80. Arshinoff SA, Opalinski Y. The pharmacotherapy of photorefractive keratectomy (PRK). Comp Ophthalmol Update. 2003;4:225–33. Editorial follows on pp 235–236.

5.5 The Pharmacotherapy of Cataract Surgery

  1. H  offman BB, Lefkowitz RJ. Catecholamines and sympathomimetic drugs. In: Hardman JG, Limberg LE, Goodman Gilman A, et al, eds. The pharmacological basis of therapeutics. Toronto: Pergamon Press; 1990:187–220.   2. Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol. 1992;36:259–84.   3. Arshinoff SA, Mills M, Haber S. Pharmacotherapy of photorefractive keratectomy. J Cataract Refract Surg. 1996;22:1037–44.   4. Keates R, McGowan K. Clinical trial of flurbiprofen to maintain pupillary dilation during cataract surgery. Ann Ophthalmol. 1984;16:919–21.   5. Miyake K. The significance of inflammatory reactions following cataract extraction and intraocular lens implantation. J Cataract Refract Surg. 1996;22(Suppl):759–63.   6. Flach AJ, Kraff MC, Sanders DR, Tanenbaum L. The quantitative effect of 0.5% ketorolac tromethamine solution and 0.1% dexamethasone sodium phosphate solution on postsurgical blood-aqueous barrier. Arch Ophthalmol. 1988;106:480–3.   7. Roberts C. Comparison of diclofenac sodium and  flurbiprofen for inhibition of surgically induced miosis.  J Cataract Refract Surg. 1996;22(Suppl):780–6.   8. Srinivasan R. Topical ketorolac tromethamine 0.5% versus diclofenac sodium 0.1% to inhibit miosis during surgery. J Cataract Refract Surg. 2002;28:517–20.   9. Lundberg B, Behndig A. Intracameral mydriatics in phacoemulsification cataract surgery. J Cataract Refract and Surg. 2003;29:2366–71. 10. Bendig A, Eriksson A. Evaluation of surgical performance with intracameral mydriatics in phacoemulsification surgery. Acta Ophthalmol Scand. 2004;82:144–7. 11. Hirowatari T, Kazuhiro T. Evaluation of a new pre­ operative ophthalmic solution. Can J Ophthalmol.  2005;40:58–62. 12. Backstrom G, Behndig A. Redilatation with intracameral mydriatics in phacoemulsification surgery. Acta Ophthalmol Scand. 2006;84:100–4. 13. Samad A, Solomon LD, Miller MA, Mendelson J. Anterior chamber contamination after uncomplicated phacoemulsification and intraocular lens implantation.  Am J Ophthalmol. 1995;120:143–50. 14. Starr MB, Lally JM. Antimicrobial prophylaxis for ophthalmic surgery. Surv Ophthalmol. 1995;39:485–501. 15. Donnenfeld ED, Schrier A, Perry HD. Penetration of topically applied ciprofloxacin, norfloxacin and ofloxacin into the aqueous humor. Ophthalmology. 1994; 101:902–5. 16. Leeming JP, Diamond JP, Trigg R. Ocular penetration of topical ciprofloxacin and norfloxacin drops and their effect upon eyelid flora. Br J Ophthalmol. 1994;78:546–8. 17. Koch HR, Kulus SC. Corneal penetration of fluoroquinolones: aqueous humor concentrations after topical application of levofloxacin 0.5% and ofloxacin 0.3% eyedrops. J Cataract Refract Surg. 2005;31:1377–85. 18. Yamada M, Ishikawa K. Corneal penetration of simultaneously applied levofloxacin, norfloxacin and lomefloxacin in human eyes. Acta Ophthalmol Scand. 2006;84:192–6. 19. Healy DP, Holland EJ. Concentrations of levofloxacin, ofloxacin and ciprofloxacin in human corneal stromal tissue and aqueous humor after topical administration. Cornea. 2004;23:255–63. 20. Yamada M, Mochizuki H. Aqueous humor levels of topically applied levofloxacin, norfloxacin and lomefloxacin in the same human eyes. J Cataract Refract Surg. 2003;29:1771–5. 21. Kim DH, Stark WJ. Aqueous penetration and biological activity of Moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112:1992–6. 22. Price M, Quillin C. Effect of gatifloxicin ophthalmic solution 0.3% on human corneal endothelial cell density and aqueous humor gatifloxicin concentrations. Curr Eye Res.. 2005;30:563–7. 23. Solomon R, Donnenfeld ED. Penetration of topically applied gatifloxacin 0.35, moxifloxacin 0.5% and ciprofloxacin 0.3% into the aqueous humor. Ophthalmology. 2005;112:466–9. 24. McCulley JP, Caudle D. Fourth generation fluoroquinolone penetration into the aqueous humor of humans. Ophthalmology. 2006;113:955–9. 25. Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis following cataract surgery. Arch Ophthalmol. 2005;123:613–20. 26. Solomon R, Donnenfeld E, Perry H, et al Aqueous humor concentrations from topically applied ocular fluoroquinolones. Poster presented at Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, FL, April, 2004.

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81. R  oberts CW. Pretreatment with topical diclofenac sodium to decrease postoperative inflammation. Ophthalmology. 1996;103:636–9. 82. El-Harazi SM, Ruiz RS, Feldman RM, et al. Efficacy  of preoperative versus postoperative ketorolac  tromethamine 0.5% in reducing inflammation after cataract surgery. J Cataract Refract Surg. 2000;26: 1626–30. 83. Arshinoff SA, Strube YNJ, Ning J, Yagev R. Simultaneous bilateral cataract surgery. J Cataract Refract Surg. 2003;29:1281–91. 84. Yaylali V, Ozbay D. Efficacy and safety of rimexolone  1% versus prednisolone acetate 1% in the control of post-operative inflammation following phacoemulsification cataract surgery. Int Ophthalmol. 2004; 25:65–8. 85. Paganell F, Cardillo JA. A single intraoperative sub- Tenon’s triamcinolone acetonide injection for the  treatment of post-cataract surgery inflammation.  Ophthalmology. 2005;112:1481. 86. Negi AK, Browing AC. Single perioperative triamcinolone injection versus standard post-operative steroid drops.  J Cataract Refract Surg. 2006;32:468–74. 87. Gills JP, Gills P. Effect of intracameral triamcinolone to control inflammation following cataract surgery.  J Cataract Refract Surg. 2005;31:1670–1. 88. Flach AJ, Lavelle CJ, Olander KW, et al. The effect of ketorolac tromethamine solution 0.5% in reducing postoperative inflammation after cataract extraction and intraocular lens implantation. Ophthalmology. 1988;95:1279–84. 89. Solomon KD, Cheetham JK, DeGryse R, et al. Topical ketorolac tromethamine 0.5% ophthalmic solution  in ocular inflammation after cataract surgery.  Ophthalmology. 2001;108:331–7.

90. K  iller HE, Borruat FX, Blumer BK, et al. Corneal  penetration of diclofenac from a fixed combination of diclofenac-gentamicin eye drops. J Cataract Refract  Surg. 1998;24:1365–70. 91. Jaffe NS. Cystoid macular edema (Irvine-Gass syndrome). In: Klein E, ed. Cataract surgery and its complications, 4th ed.. Toronto: Mosby; 1984. :426–41. 92. Yanuzzi LA, Klein RM, Wallyn RH, et al. Ineffectiveness of indomethacin in the treatment of chronic cystoid macular edema. Am J Ophthalmol. 1977;84:517–9. 93. Rossetti L, Bujtar E, Castoldi D, et al. Effectiveness of diclofenac eye drops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery. J Cataract Refract Surg. 1996;22(Suppl):794–9. 94. Miyake K, Masuda K, Shirato S, et al. Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: a multicentred prospective trial. Jpn J Ophthalmol. 2000;44:58–67. 95. Holzer MP, Solomon KD. Comparison of ketorolac and loteprednol 0.5% for inflammation after phacoemulsification. J Cataract Refract Surg. 2002;28:93–9. 96. Rho D. Treatment of acute pseudophakic cystoid macular edema: Diclofenac versus ketorolac. J Cataract Refract Surg. 2003;29:2378–84. 97. Scuderi B, Driussi GB. Effectiveness and tolerance of piroxicam 0.5% and diclofenac sodium 0.1% in  controlling inflammation after cataract surgery. Eur  J Ophthalmol. 2003;13:536–40. 98. Heier JS, Topping TM, Baumann W, et al. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema. Ophthalmology. 2000;107:2034–9. 99. Singal N, Hopkins J. Pseudophakic cystoid macular edema: ketorolac alone versus ketorolac and prednisolone. Can J Ophthalmol. 2004;39:245–50.

100. Weisz JM, Bressler NM, Bressler SB, et al. Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction. Ophthalmology. 1999;106:1656–9. 101. Conway MD, Canakis C. Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema. J Cataract Refract Surg. 2003;29:27–33. 102. Jonas JB. Kreissig. Intravitreal triamcinolone for pseudophakic cystoid macular edema. Am J Ophthalmol. 2003;136:384–6. 103. Ozkiris A, Erkilic K. Complications of intravitreal injection of triamcinolone acetonide. Can J Ophthalmol. 2005;40:63–8. 104. Reis A, Birnbaum F. Cyclooxygenase-2-inhibitors: a new therapeutic option in the treatment of macular edema after cataract surgery. J Cataract Refract Surg. 2005;31:1337–40. 105. Abe T, Hayasaka S, Nagaki Y, et al. Pseudophakic cystoid macular edema treated with high-dose intravenous  methylprednisolone. J Cataract Refract Surg. 1999;25:1286–8. 106. Miyake K, Ota I, Mackubo K, et al. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol. 1999;117:34–40. 107. Miyake K, Ota I, Ibaraki N, et al. Enhanced disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema by topical timolol and its preservative in early postoperative pseudophakia. Arch Ophthalmol. 2001;119:387–94.

PART 5 THE LENS

Anesthesia for Cataract Surgery Donna L. Greenhalgh

Key features n n n

n

 onsideration of patient characteristics. C Local anesthesia: considerations, sedatives used, local anesthetics used. Local techniques: topical, intraocular, deep topical fornix nerve block, retrobulbar, peribulbar, and sub-Tenon’s; advantages, disadvantages, and complications. General anesthesia: techniques, advantages, disadvantages, and complications.

5.6

Anticoagulants

Patients on oral anticoagulants and antiplatelet therapy, including aspirin and clopidogrel, should continue with these throughout surgery.5–7 The risks of cardiovascular complications outweigh the risk of hemorrhage, especially if the patient has had a drug-eluting stent inserted. General anesthesia, sub-Tenon’s, or topical local anesthesia is recommended.

Diabetes mellitus

Local anesthesia causes least disruption to diabetic management but with new anesthetic agents recovery is rapid. General anesthesia is well tolerated.

Local anesthesia

INTRODUCTION The advent of small, self-sealing incisions for phakoemulsification has led to a change in anesthetic practice. Akinesis and very low intraocular pressures are not essential, allowing the use of topical and local techniques like peribulbar and sub-Tenon’s blocks. A team approach is necessary, with the surgeon concentrating on the operation and the anesthetist looking after the patient under general or local anesthesia.

MEDICAL ASPECTS OF ANESTHESIA FOR CATARACT SURGERY Cataract Type and Associated Medical Conditions

Cataracts can be either congenital or acquired. They may be an ocular manifestation of a systemic disease. There is a relatively high incidence of uncommon medical conditions in younger cataract patients. Patients with acquired cataracts are usually elderly; the average age is 75 and has associated comorbidities such as ischemic heart disease and chronic obstructive airway disease. One study showed that 84% of patients had at least one concomitant serious medical disease.1 In an audit of 1000 cases in Auckland 43% were ASA3-4.2 There is a significant increase in overall mortality in those with concurrent hypertension (48%), ischemic heart disease (38%), a history of hypothyroidism (18%), diabetes (16%), and a history of a new malignancy (3%).3 The Royal Colleges of Anaesthetists and Ophthalmologists recommend a full history and appropriate investigations on appropriate patients. However, apart from an ECG, unless specifically indicated, preoperative investigations have not been shown to influence the outcome in patients having local anesthesia for cataract surgery.4

Specific conditions

Ischemic heart disease

441

Ischemia can be provoked by stress at the prospect of local or general anesthesia. Neither should be given within 6 months of a myocardial infarction or 3 months following angioplasty or coronary revascularization. Phenylephrine drops can result in a significant rise in blood pressure and should be administered cautiously. The oxidative damage resulting in cataract formation is linked to free radical formation and atherosclerosis, which explains the high proportion of patients with ischemic heart disease.3

Local anesthesia can be classified into topical, retrobulbar block, peri­ bulbar block, and sub-Tenon’s block.

General Considerations

The main advantage of local anesthesia is a conscious and alert patient. Sedation can result in a confused uncooperative patient in the middle of an operation. However, certain patients can become stressed at the thought of being awake, especially during insertion of the block, and short-term sedation with either midazolam (1–3 mg) or propofol (10–30 mg) can be useful.8 To undergo local anesthesia, a patient must be medically fit. Many comorbidities render a local anesthetic unsuitable, especially if the patient is unable to lie flat. Recommendations are that patients having local anesthesia without sedation or low-dosage sedation need not be starved, while standard fasting times should be followed for deeper sedation or general anesthesia.9 It is now accepted that small amounts of clear fluids can be permitted 2 hours prior to surgery. Minimal monitoring should include ECG and pulse oximetry as many elderly patients become hypoxic lying flat, even without sedation. Intravenous access should be secured. The elderly and those with systemic illnesses should be anesthetized in an appropriate environment with back up facilities if inpatient or critical care is required.9 Supplemental oxygen is given to avoid hypoxia and minimize claustrophobia. Rebreathing can occur under the drapes even at 6 L/minute of oxygen. Nonmedical personnel often carry out preoperative assessment prior to surgery. Accurate listing for local or general anesthesia can be a problem as many patients have concomitant disease. A questionnaire filled in by patients has been shown to be a good initial screening tool with supplemental medical input as required.8 Many patients have visual experiences under local anesthesia; in one survey 16% found this distressing.10 Counseling preoperatively has been shown to be beneficial in reducing the distress.11, 12 All operating room personnel must be trained in basic life support and at least one member should have advanced training. The Joint Royal Colleges in the United Kingdom recommend that an anesthetist be present throughout, whether general or local anesthesia is used, and is essential if sharp needle technique or sedation is used. For patients undergoing topical anesthesia or sub-Tenon’s block, an anesthetist does not need to be available in the theatre block,9 unless the site is isolated.13 In various studies intervention by an anesthetist was necessary: in 37%,14 8.1%,15 and 4.0%16 of cases. In another study 50% required intervention for drugs, 41% for antihypertensive therapy, 17% other interventions, and 2.5% for severe cardiovascular complications. The Joint Royal Colleges advise that due to a high intervention rate an ­anesthetist be present.17, 18

5

l l

THE LENS

l l l l l l l

l l l l l

Patients for whom local anesthesia is contraindicated are those: Who are unable to cooperate (e.g., with mental impairment) In whom communication is difficult (e.g., inability to speak the ­language or deafness) Who have involuntary movements (e.g., those with Parkinson’s ­disease) Who are unable to lie flat or still Who have uncontrolled coughing or sneezing Who are severely anxious or claustrophobic Undergoing bilateral surgery For whom prolonged or difficult surgery is likely For whom general anesthesia is preferred, whether by the patient, the surgeon, or the anesthetist The objectives of local anesthesia are as follows:12 Ensure that the block procedure is painless Provide globe and conjunctival anesthesia Obtain maximal akinesia of the globe and orbicularis oculi Obtain a low pressure within the orbit and globe Avoid local and systemic complications

Sedative Agents Commonly Used in Local Anesthesia

Midazolam, a short-acting, water-soluble benzodiazepine with a halflife of 2 hours, has both amnesic and anxiolytic properties, lacks venous sequelae, and allows rapid patient recovery. It is given slowly intravenously in 1 mg increments. Adequate time must be given for it to work in the elderly otherwise oversedation can easily result. Overdoses can be reversed with flumazenil, a benzodiazepine antagonist, but its half-life is 1 hour, so re-sedation can be a problem. Propofol, a short-acting phenol, is an intravenous induction agent suitable for infusion and sedation. It is characterized by a rapid and clear-headed recovery, with a low incidence of nausea and vomiting. It causes respiratory depression and a fall in blood pressure. Propofol and midazolam have been used for patient-controlled sedation. This has been shown to significantly reduce patients’ level of anxiety, and they remain cooperative enough to press the button, eliminating the unpredictability of elderly patients’ reaction to sedation. Midazolam has a greater risk than propofol of stacking doses, resulting in oversedation.19 Dexmedetomidine, an α2 agonist, has been used as a sedative agent with good effect.20 Fentanyl is a potent, short-acting narcotic analgesic with duration of action of about 30 minutes. Given in doses of 25–50 μg, it provides analgesia with minimal sedation. However, it has the side effects of all narcotic analgesics, including respiratory depression, nausea, and vomiting. Remifentanil is an ultra-short-acting analgesic metabolized by esterases, resulting in an elimination half-life of 3–10 minutes and administered by infusion. It produces intense analgesia, but it needs to be supplemented because it also wears off within 3–10 minutes of the infusion being stopped.21 It can cause a marked fall in heart rate and blood pressure, so should be used with caution in elderly, frail patients. It is not recommended for use as a sole agent.

Topical Anesthesia

Sixty per cent of all cataracts are performed under topical anesthesia in the United States. Benoxinate 0.4%, an ester anesthetic, is one of the most frequently used because of its high degree of safety. Other commonly used agents are tetracaine 0.5% or 1% amethocaine and proparacaine (proxymetacaine) 0.5%; both are short acting (20 minutes) and are the least toxic to the corneal epithelium. Lidocaine 4% and bupivacaine 0.5% and 0.75% have a longer duration of action but an increased associated corneal toxicity. Absolute contraindications are true allergy to local anesthetics and nystagmus. The advantages and disadvantages of topical anesthesia are given in Box 5-6-1.22 Topical anesthesia may be combined with subconjunctival anesthesia. This allows subconjunctival and scleral manipulations to be carried out, with good toleration by patients.

Technique

442

The aim is to block the nerves that supply the superficial cornea and conjunctiva; namely, the long and short ciliary, nasociliary, and lacrimal nerves. The patient should be warned that application of the drops on

Box 5-6-1 Advantages and Disadvantages of Topical Anesthesia ADVANTAGES l No risk associated at needle insertion l No risk of periocular hemorrhage or hyphema with clear corneal incisions; systemic anticoagulation can be continued without any worry l Functional vision is maintained; advantageous for uniocular patients l No postoperative diplopia or ptosis l Patients are fully alert DISADVANTAGES l An awake and talkative patient can be distracting for the surgeon l No akinesia of the eye l If difficulties or problems occur the anesthesia may not be adequate ADVERSE EFFECTS OF TOPICAL OCULAR ANESTHETICS l Direct corneal effects – alteration of lacrimation and tear film stability l Epithelial toxicity – healing has been shown to be delayed when an epithelial defect occurs (lidocaine does not appear to affect healing) l Endothelial toxicity – this occurs when penetrating trauma is present and appears to be related to the preservative benzalkonium l Systemic effects – lethal toxicity (this is only a problem with cocaine) l Allergy and idiosyncratic reactions – contact dermatitis is the most common and occurs with proparacaine most frequently SECONDARY ADVERSE EFFECTS l Surface keratopathy

the surface of the cornea stings (except for proxymetacaine). Drops are administered before the placement of the drapes. As visual perception is not lost, the patient is asked to focus on the light, the intensity of which is reduced. The subconjunctival injection of antibiotics can be painful, but this can be avoided by including these in the infusion bottle. Use of this technique is increasing throughout both the United States and Europe (up to 60% of surgeons in the United States choose this method),22 although several studies show inferior analgesia compared to peribulbar and sub-Tenon’s blocks.23, 24 There is no akinesia of the eye with the following techniques, so they are suitable only for experienced surgeons.25

Intraocular lidocaine

Intraocular lidocaine has been used to provide analgesia during surgery. The solution used is 1% isotonic, nonpreserved lidocaine 0.3 mL administered intramurally. At present, no side effects have been reported, except for possible transient retinal toxicity if lidocaine is injected posteriorly in the absence of a posterior capsule. Its use obviates the need for intravenous and regional anesthetic supplementation in most patients. Adequate anesthesia is obtained in about 10 seconds.25 Intrameral bupivacaine has also been used without problems.26

Deep topical fornix nerve block/limbal

This technique has been superceded by topical and sub-Tenon’s block. It does not confer any advantage over these techniques and can be painful to administer, and will not be discussed further.

Retrobulbar Block

With this technique the aim is to block the oculomotor nerves before they enter the four rectus muscles in the posterior intraconal space. This block has been superseded by peribulbar block as the risk of serious complications is greatly reduced with peribulbar block and so only a limited description is given.27 The eye is kept in the neutral position and a sharp 25- or 27-gauge needle less than 31 mm in length is inserted at the lower temporal orbital margin (Fig. 5-6-1). It is directed posteriorly at an angle of 10 degrees to the horizontal until the equator of the globe is passed and then directed slightly upward and medially (Fig. ��������������������������������������������� 5-6-2)��������������������������������� . Local anesthetic (2–4 mL) is injected slowly after aspiration to check intravascular or subdural placement. Any global movement is noted, as this is indicative of sclera puncture. The eye is not moved as this may increase the risk of optic nerve ­ injury. The advantages and disadvantages of retrobulbar block are given in Box 5-6-2.

Box 5-6-2 Advantages and Disadvantage of Retrobulbar Block

INJECTION SITE FOR RETROBULBAR BLOCK

DISADVANTAGE l The main disadvantage of retrobulbar blocks is that the complication rate is higher than for peribulbar blocks – the reason for the development of the peribulbar block

Overall, there is a 1–3% chance that complications will occur with retrobulbar block. These include: l Retrobulbar hemorrhage l Ocular perforation (< 0.1% incidence, but 1 in 140 injections in myopic eyes)28 l Subarachnoid or intradural injection, leading to brainstem anesthesia in 1 in 350–500 patients l Respiratory depression or arrest (0.29% incidence) l Optic nerve contusion and atrophy l Retinal vascular occlusion l Grand mal seizure l Decreased visual acuity l Hypotony (< 8 mmHg) l Contralateral amaurosis l Muscle complications: ptosis from levator aponeurosis dehiscence, entropion and diplopia following extraocular muscle injection l Pulmonary edema l Oculocardiac reflex, usually produced by pressure on the globe (vasovagal bradycardias are more common)

Anesthesia for Cataract Surgery

ADVANTAGES l A retrobulbar block is reliable for producing excellent anesthesia and akinesia l The onset of the block is quicker than with peribulbar; it usually occurs within 5 minutes l Low volumes of anesthetic result in a lower intraorbital tension and less chemosis than with peribulbar blocks l Loss of visual acuity occurs in a greater number of patients compared to peribulbar blocks, though this can be volume dependent; some ­patients may be distressed by being able to see throughout the ­procedure

5.6

site of injection

Fig. 5-6-1  Injection site for retrobulbar block. The injection site through the lower lid lies halfway between the lateral canthus and the lateral limbus. (Adapted from Sanderson Grizzard W. Ophthalmic anaesthesia. Ann Ophthalmol. 1989;21:265–94.)

ADVANCEMENT OF NEEDLE IN RETROBULBAR BLOCK

Peribulbar Block

The principle of this technique is to instill the local anesthetic outside the muscle cone and avoid proximity to the optic nerve. This utilizes high volumes of anesthetic and the application of a pressure device. The local anesthetic agents do not differ from those used in retrobulbar block, but typically shorter needles are used.

Technique

The volume varies from 3 to 10 mL; the average is 5–7 mL. Again, the eye is in primary gaze. Local anesthetic drops are applied for the initial injection. This is at the inferotemporal lower orbital margin, midway between the lateral canthus and the lateral limbus. The 27- or 25-gauge needle is advanced parallel to the plane of the orbital floor. Local anesthetic is injected at a depth of about 2.5 cm from the inferior orbital rim (in an eye of normal axial length). As with retrobulbar blocks, no resistance to injection should be felt, and aspiration should be performed27 (Fig. 5-6-3). After 5 minutes, the amount of akinesia is assessed. Often, a second injection is required to block the superior oblique. A 25-gauge, 2.5 cm needle is inserted between the medial canthus and the caruncle, which is another relatively avascular area; then the needle is directed immediately backward. The medial check ligament often is penetrated, and the medial rectus can be injected at this point. At a depth of 1.5 cm, another 5 mL of solution is injected to produce a more complete block, with akinesia of the orbicularis oculi and levator palpebrae superioris. This avoids the alternative option of injecting the superotemporal region and causing ecchymosis of the eyelid. A Honan balloon or pressure-lowering device is applied for 20–30 minutes. Four milliliters of local anesthetic can increase the intraocular pressure by over 6.2 mmHg; ocular compression can decrease the intraocular pressure by 8.8 mmHg after 5 minutes and by 14.3 mmHg after 40 minutes. A single medial canthus injection has been described at the junction of the caruncle and medial canthus, which is usually at the junction of the

Fig. 5-6-2  Advancement of needle in retrobulbar block. The needle is advanced beyond the equator of the globe and then directed toward an imaginary point behind the macula, with care taken not to cross the midsagittal plane of the eye. (Adapted from Sanderson Grizzard W. Ophthalmic anaesthesia. Ann Ophthalmol. 1989;21:265–94.)

medial two thirds and lateral two thirds of the lower orbital rim. This is easily learned, and fewer injections decrease the complication rate. Both during insertion of the block and the procedure itself, peribulbar block has been reported to be more painful than using topical anesthesia.29, 30 It is important that adequate training is given to decrease complications for all these blocks.31 The advantages and disadvantages of peribulbar block are given in Box 5-6-3.

Local anesthetic agent

The most common mixture used is bupivacaine 0.5% plus lidocaine 2% plus hyaluronidase 150 international units. The mixture (5–8 mL) is injected slowly to avoid patient discomfort. Aspiration prior to injection minimizes the risk of intravascular or subdural injection. Other agents used are mepivacaine 1–2%, lidocaine 1–2% alone, bupivacaine 0.25–0.75% alone or with lignocaine and prilocaine 3%.30 Levobupivacaine 5 mg/mL is better than ropivacaine 0.75%.31, 32 Levobupivacaine is the L-isomer of bupivacaine with a higher safety index, especially in terms of cardiac side effects. A single medial canthus injection of 7–9 mL of 2% articaine has also been used to good effect.33 Articaine is an amide local anesthetic of low toxicity, which has rapid onset and disperses quickly.34, 35

443

5

PERIBULBAR/INFEROTEMPORAL PERICONAL INJECTION

THE LENS site of injection A

B

C

D

Fig. 5-6-3  Inferotemporal periconal injection. (A) The needle enters the orbit at the junction of its floor with the lateral wall, very close to the bony rim. (B) The needle passes backward in a sagittal plane parallel to the orbit floor. (C) It passes the globe equator when the needle-hub junction reaches the plane of the iris. (D) After test aspiration, up to 10 mL anesthetic solution is injected. (Adapted from Hamilton RC. Techniques of orbital regional anaesthesia. Br J Anaesth. 2001;86:473–6.)

Epinephrine 5 μg/mL may be added to improve the onset time, quality, and duration of the block. However, it should be avoided in patients who have ischemic heart disease, tachycardia, and hypertension. Also, epinephrine has been implicated in optic artery thrombosis secondary to vasoconstriction. A 50% decrease in pressure in the ophthalmic artery has been noted, so it should be avoided in patients with generalized atherosclerosis. Hyaluronidase breaks down C1–C4 bonds between glucosamine and glucuronic acid in connective tissue, which enables the local anesthetic to permeate the tissues more effectively. The required quantity of local anesthetic is therefore reduced, and the time to onset is decreased. Hyaluronidase may help prevent damage to extraocular muscles, especially the inferior rectus muscle preventing diploplia.36, However, this anesthetic is an expensive choice. A “painless” local anesthetic to initially anesthetize the skin and subcutaneous tissues can be helpful. The solution is made by adding 1.5 mL of lidocaine 2% to 15 mL of balanced salt solution, altering the pH and pKa of the solution. Amethocaine or Emla cream applied to the skin at least 1 hour preoperatively removes the pain of injection if the needle passes through the skin.

Complications

444

Globe perforation is more commonly associated with retrobulbar and peribulbar local anesthesia. However, there has been a case report following sub-Tenon’s anesthesia in a patient who had had previous retinal surgery. Caution is advised in patients who have had prior surgery, thinned sclera, or excess scar tissue.37 Globe perforation has also been reported following injection of local anesthetic into the lid for removal of a hordeolum.38 Risk factors for globe perforation are: l��� High myopia, axial length greater than 26 mm39, 40 l��� Atkinson gaze l��� Sharp injection needle;10, 40 however, blunt needles do not prevent perforation41 l��� Previous scleral buckling procedure l��� Inexperience in performing local blocks l��� Poor patient compliance. Signs of globe perforation are: l��� Vitreous hemorrhage (100%), usually on the first postoperative day40, 42 l��� Subretinal hemorrhage (76%) l��� Retinal breaks along the inferior vascular arcade (76%) l��� Retinal detachment (14%) Retinal detachment is often associated with poor visual outcome, but it is improved with prompt recognition and referral to specialized centers.43, 44 Treatment with scleral buckling, pars plana vitrectomy, and silicone oil tamponade has been recommended.45

Box 5-6-3 Advantages and Disadvantages of Peribulbar Block ADVANTAGES l The risk of complications associated with peribulbar block is low l Peribulbar block has all the advantages of retrobulbar block DISADVANTAGES l Peribulbar blocks have all the disadvantages of retrobulbar blocks, but they occur less frequently l The quality of akinesia and anesthesia may not be as good as with retrobulbar block l Often more than one injection is required l The block takes much longer to work—it can take up to 30 minutes l The Honan balloon may be uncomfortable for the patient l Chemosis occurs in 80% of cases, which makes operating conditions difficult l In 5.8% of both retrobulbar and peribulbar blocks, ptosis can remain for up to 90 days l One perforation for every 140 peribulbar blocks in eyes > 26 mm axial length

Sub-Tenon’s Block

This involves surface anesthesia and access to the sub-Tenon’s capsule to administer the local anesthetic. In the United Kingdom this is now the commonest technique, comprising 43% of cases.46

Anatomy

This is described fully elsewhere in the book. Briefly, Tenon’s capsule is a facial sheath, a thin membrane enveloping the eyeball and separating it from orbital fat. The inner surface is smooth and shiny, separated from the outer surface of the sclera by a potential space, the episcleral space or sub-Tenon’s. Anteriorly, the sheath is fastened to the sclera approximately 1.5 cm to the corneal scleral junction. Posteriorly, it is fused with the meninges around the optic nerve. It has been suggested that it is a lymph space. There are numerous delicate bands crossing the space.

Technique

The conjunctiva is anesthetized first with drops of the local anesthetic of choice. The commonest approach is by the infranasal quadrant as this allows good distribution of the anesthetic while

Box 5-6-4 ADVANTAGES AND DISADVANTAGES OF SUB-TENON’S BLOCK

Fig. 5-6-4  Incision for sub-Tenon’s block. Arrows point to conjunctiva, Tenon’s capsule, and shining sclera under the Tenon’s capsule. (Reprinted with kind permission from Kumar CM, Williamson S, Manickham B. A review of subTenon’s block: current practice and recent development. Eur J Anaesthesiol. 2005;22:567–7, figure 2c, European Academy of Anaesthesiology, published by Cambridge University Press.)

decreasing the risk of damage to the vortex veins. The eye is cleaned and the patient asked to look upwards and outwards. Aseptically, the conjunctiva and Tenon’s capsule are picked up 3–5 mm away from the limbus using nontoothed forceps (Moorfields forceps)47 (Fig. 5-6-4). A small incision is made through these layers using scissors (Wescott scissors) exposing the sclera. A sub-Tenon’s cannula is inserted: either a 25 mm long cannula, curved posteriorly with a flat profile and a blunt end hole or an anterior sub-Tenon’s cannula (Greenbaum), a 15 G, 1.2 cm long, blunt, flat-bottomed and D-shaped cannula, designed so the opening on the flat bottom faces the sclera after insertion. The cannula is advanced posteriorly halfway between the horizontal and vertical equators of the globe. Some resistance is met at this point as the scleral Tenon bridging fibers are entered. Slow injection allows advancement of the needle and pushes the tissues away. Three to five milliliters of local anesthetic are injected; the greater the volume, the greater the akinesis. Lignocaine 2% is the gold standard; bupivacaine 0.5% and articaine 2% have also been used. Hyaluronidase can be added. Adrenaline is not advised, as discussed previously. A Honan’s balloon can be used to increase dispersal. There is only a small rise in the intraocular pressure, which is insignificant with this type of block.48 Comparison with peribulbar anesthesia shows that sub-Tenon’s block is a suitable alternative with better akinesia, improved consistency, and a quicker onset.27, 49 When compared with topical anesthesia, subTenon’s provides superior pain relief and patient satisfaction.23, 50 The advantages and disadvantages of sub-Tenon’s block are given in Box 5-6-4. Complications are mainly minor, though orbital inflammation, scleral perforation, sight threatening, cardiovascular collapse, and lifethreatening complications have been reported.13, 48, 51

GENERAL ANESTHESIA General anesthesia is performed on those patients who are unsuitable candidates for local anesthesia; it is the method of choice for babies, children, and some young adults. Previously it was necessary to intubate, paralyze, and ventilate the patient. However, with the advent of phacoemulsification and small incision surgery, plus the use of propofol with a laryngeal mask, it is now feasible to have the patient breathing spontaneously. Intubation was needed before because of the competition for space around the operative site. To enable the endotracheal tube to be tolerated, the patient had to be anesthetized deeply with volatile agents of high concentration, or paralyzed. Not intubating the patient allows a lighter anesthetic to be given, decreasing cardiovascular depression and improving recovery. In patients of 80 years or more, psychomotor testing showed that

Disadvantages The local anesthetic agent must be injected into the capsule – double perforation of the capsule results in anesthetic leaking out, which decreases the effectiveness of the block Although it is an advantage that the globe can be moved under instruction, it is important the eye is not moved at other times – the use of stabilizing sutures is advised Dissection of the capsule must be carried out under sterile conditions

Anesthesia for Cataract Surgery

Advantages Less painful than peribulbar block Better analgesia than topical anesthesia Complications rarely serious No increase in intraocular pressure occurs with the administration of local anesthetic Surgery can begin almost immediately Lasts for 60 minutes and supplemental anesthetic agent can be given The globe can be voluntarily moved at the surgeon’s instruction Low dose and low volume of anesthetic agent are used

5.6

Box 5-6-5 Advantages and Disadvantages of General Anesthesia ADVANTAGES l Patient comfort l Ideal operating conditions – a quiet, immobile patient and soft eye l Allows for rapid alterations in intraocular pressure if required l The method of choice for difficult cases l Effective for more patients l No risk of any of the complications associated with local anesthetic blocks l No residual paralysis of the eye when the patient is awake l Bilateral surgery can be performed, which is advantageous in the frail, elderly, and medically “unfit“ l Better conditions for teaching DISADVANTAGES l Slightly slower turnaround times, if only one anesthetist is available l More expensive

total intravenous anesthesia with propofol and remifentanil resulted in significantly faster recovery of cognitive function compared with etomidate-fentanyl-isoflurane.52 A recent study that compared balanced anesthesia with total intravenous anesthesia (TIVA) showed similar cardiovascular effects but decreased nausea and vomiting, faster recovery, better patient satisfaction, and lower costs with TIVA.53, 54

Technique

Spontaneous respiration

A laryngeal mask is inserted and anesthesia is maintained with either a continuous propofol infusion or a volatile agent of choice. Target­controlled infusion regimes are commonly employed. Propofol 4.5 μg/mL bolus for induction followed by 3.26 μg/mL maintenance target infusion levels can be combined with either an alfentanil (target blood concentration 25 ng/mL) or remifentanil (1–1.5 ng/mL) infusion, although propofol plus topical anesthesia is sufficient. The use of a laryngeal mask enables faster turnaround times and reduces the cough associated with extubation. It provides a stable, easily controlled anesthetic with rapid recovery and a low incidence of nausea and vomiting.

Ventilation

The traditional method involves endotracheal intubation, although controlled ventilation is possible with laryngeal masks, combining the benefits of not intubating with a paralyzed patient. Suxamethonium is avoided, if possible, as a transient rise in intraocular pressure occurs

445

5 THE LENS

with its use. Short-acting nondepolarizers are used in preference along with an induction agent. Maintenance consists of using a volatile agent of choice or a propofol infusion. Although changeovers may be slower, especially if single handed, this technique also provides a stable, easily controlled anesthetic and is the method of choice for certain patients for whom spontaneous respiration is inappropriate (e.g., the obese and patients who cough despite adequate anesthetic).

Conclusion

Both spontaneous respiration and ventilation methods are suitable for day-case anesthesia. They are both widely used in all other specialties. Both propofol and the new volatile agents sevoflurane and desflurane provide a rapid and clear-headed recovery. Hypotension needs to be aggressively treated with vasoconstrictors such as ephedrine or metaraminol, to minimize morbidity. The advantages and disadvantages of general anesthesia are given in Box 5-6-5.

POSTOPERATIVE CARE FOR BOTH LOCAL AND GENERAL ANESTHESIA Cataract extraction by phakoemulsifcation is relatively pain free. In the majority of cases, simple analgesics are sufficient. Non-steroidal anti-inflammatory drugs can be used with caution in the elderly. These can be given orally, intravenously, or rectally and topically. Topical nonsteroidal analgesics can decrease pain and inflammation55 and have been shown to be equally effective in reducing the inflammatory response when compared with corticosteroids, with fewer side effects. Corticosteroids can be reserved for cases with more severe inflammation.56 Topical local anesthesia can be used as an adjunct as well, as it reduces systemic anesthetic requirements. This may help reduce postoperative nausea and vomiting by avoiding the use of opiates, although opiates are rarely needed for pain relief with this type of surgery. Propofol also has antiemetic properties.

REFERENCES

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  1. Fisher SJ, Cunningham RD. The medical profile of cataract patients. Geriatr Clin North Am. 1985;1:339–44.   2. Guise P. Aeroplanes rarely crash nowadays, therefore they don’t need pilots: anaesthesia, anaesthetics and cataract surgery. Clin Exp Ophthalmol. 2005;33:451–2.   3. Hu FB, Hankinson SE, Stampfer MJ, et al. Prospective study of cataract extraction and the risk of coronary heart disease in women. Am J Epidemiol. 2001;153:875–81.   4. The Royal College of Anaesthetists & The Royal College of Ophthalmologists. Local anesthesia for intraocular surgery. London: Royal College of Anaesthetists & The Royal College of Ophthalmologists; July, 2001.   5. Jonas JB, Pakdaman B, Saunder G. Cataract surgery under systemic anticoagulant therapy with coumarin. Eur J Opthalmol. 2006;16:30–2.   6. Hirschman DR, Morby LJ. A study of the safety of continued anticoagulation for cataract surgery patients. Nurs Forum. 2006;41:30–7.   7. Ong-Tone L, Paluck EC, Hart-Mitchell RD. Perioperative use of warfarin and aspirin in cataract surgery by Canadian Society of Cataract and Refractive Surgery members: survey. J Cataract Refract Surg. 2005;31:991–6.   8. MacPherson R. Structured assessment tool to evaluate patient suitability for cataract surgery under local ­anaesthesia. Br J Anaesth. 2004;93:521–4.   9. The Royal College of Anaesthetists. Guidance on the Provision of Ophthalmic Anaesthesia Services, Ch 10. London: The Royal College of Anaesthetists; 2004:49–52. 10. Tan CS, Eng KG, Kumar CM. Visual experiences during cataract surgery: what anaesthesia providers should know. Eur J Anaesthesiol. 2005;22:413–9. 11. Voon LW, Au Eong KG, Saw SM, et al. Effect of preoperative counseling on patient fear from the visual experience during phakoemulsification under topical anesthesia: Multicenter randomized clinical trial. J Cataract Refract Surg. 2005;31:1966–9. 12. Leo SW, Lee LK, Au Eong KG. Visual experience during phacoemulsification under topical anaesthesia: a nationwide survey of Singapore ophthalmologists. Clin Exp Ophthalmol. 2005;33:578–81. 13. Ruschen H, Bremner F, Carr C. Complications after subTenon’s eye block. Anesth Analg. 2003;96:273–7. 14. Rosenfield S, Litinski S, Snyder D, et al. Effectiveness of monitored anaesthesia care in cataract surgery. ­Ophthalmology. 1999;108:1256–61. 15. Brymerski J. Loco standby anaesthesia during ophthalmological surgery in local anaesthesia. Klin Oczna. 2004;106:609–11. 16. Zakrzewski PA, Friel T, Fox G, Braga-Mele R. Monitored anesthesia care provided by registered respiratory care practitioners during cataract surgery: a report of 1957 cases. Ophthalmology. 2005;112:272–7. 17. Heindl B. Frequency of intervention and risk factors in monitored anesthesia care in ophthalmic surgery – a retrospective analysis. Anasthesiol Intensivmed Notfallmed Schmerzther. 2005;40:340–4. 18. Eichel R, Goldbery I. Anaesthesia techniques for cataract surgery: a survey of delegates to the Congress of the International Council of Ophthalmology, ��������������������������� 2002. Clin Exp Ophthalmol. 2005; 33:469–72. 19. Pac-Soo CK, Deacock S, Lockwood G, et al. Patientcontrolled; sedation for cataract surgery using peribulbar block. Br J Anaesth. 1996;77:370–4.

20. Abdalla MI, Al Mansouri F, Bener A. Dexmedetomidine during local anesthesia. J Anesth. 2006;20:54–6. 21. Dal D, Demirtas M, Sabin A, et al. Remifentanil versus propofol sedation for peribulbar anesthesia. Middle East J Anesthesiol. 2005;18:583–93. 22. Irle S, Luckefahr MH, Tomalla M. Topical anesthesia as routine procedure in cataract surgery – evaluation of pain and complications in 1010 cases. Klin Monatsbl Augenheilkd. 2005;222:36–40. 23. Srinivasan S, Fern AI, Selvaraj S, Hasan S. Randomised double-blind clinical trail comparing topical and subTenon’s anaesthesia in routine cataract surgery. Br J Anaesth. 2004;93:683–6. 24. Ruschen H, Celaschi D, Bunce C, Carr C. Randomised control trial of sub-Tenon’s block versus topical anaesthesia for cataract surgery: a comparison of patient satisfaction. Br J Ophthalmol. 2005;89:291–3. 25. Nicholson G, Mantovani C, Hall GM. Topical anaesthesia for cataract surgery. Br J Anaesth. 2001;86:900. 26. Anderson NJ, Nath R, Anderson CJ, Edelhauser HF. Comparison of preservative free bupivacaine vs. lidocaine for intrameral anesthesia: a randomized clinical trial and in vitro analysis. Am J Ophthalmol. 1999;127:393–402. 27. Hamilton RC. Techniques of orbital regional anesthesia. Br J Anaesth. 1995;75:88–92. 28. Edge R, Navon S. Scleral perforation during retrobulbar and peribulbar anesthesia: risk factors and outcome in 50 000 consecutive injections. J Cataract Refract Surg. 1999;25:1237–44. 29. Coelho RP, Weissheimer J, Romao E, Velasco e Cruz AA. Pain induced by phacoemulsion without sedation using topical or peribulbar anesthesia. J Cataract Refract Surg. 2005;31:385–8. 30. Deruddre S, Benhamou D. Medial canthus single-injection peribulbar anesthesia: a prospective randomized comparison with classic double-injection peribulbar anesthesia. Reg Anesth Pain Med. 2005;30:255–9. 31. Kleinman B, Perlman J, Anderson C, et al. A collaborative regional ocular anesthesia training program: successes and failures. J Clin Anesth. 1999;11:301–4. 32. Bedi A, Carabine U. Peribulbar anaesthesia: a doubleblind comparison of three local anaesthetic solutions. Anaesthesia. 1999;54:67–71. 33. Di Donato A, Fontana C, Lancia F, Celleno D. Efficacy and comparison of 0.5% levobupivacaine with 0.75% ropivacaine for peribulbar anaesthesia in cataract surgery. Eur J Anaesthesiol. 2006;Mar 1:1–4. 34. Allman KG, McFaden JG, Armstrong J, et al. Comparison of articaine and bupivacaine/lidocaine for single medial canthus peribulbar anaesthesia. Br J Anaesth. 2001;87:584–7. 35. Ozdemir M, Ozdemir G, Zencirci B, Oksuz H. Articaine versus lidocaine plus bupivacaine for peribulbar anaesthesia in cataract surgery. Br J Anaesth. 2004;92:231–4. 36. Hameda S, Devys JM, Xuan TH, et al. Role of hyaluronidase in diploplia after peribulbar anaesthesia for cataract surgery. Ophthalmology. 2005;112:879–82. 37. Frieman BJ, Friedberg MA. Globe perforation associated with subtenon’s anesthesia. Am J Ophthalmol. 2001;131:520–1. 38. Kim JH, Yang SM, Kim HW, Oh J. Inadvertent ocular perforation during lid anesthesia for hordeolum removal. Korean J Ophthalmol. 2006;20:199–200.

39. Modarres M, Parvaresh MM, Hashemi M, Peyman GA. Inadvertent globe perforation during retrobulbar injection in high myopes. Int Ophthalmol. 1997–1998; 21:17–85. 40. Berglin L, Stenkula S Algvere PV. Ocular perforation during retrobulbar and peribulbar injections. Ophthalmic Surg Lasers. 1995;26:429–34. 41. Grizzard WS, Kirk NW, Pavan PR, et al. Perforating ocular injuries caused by anesthesia personnel. Ophthalmology. 1991;98:1011–6. 42. Wearne MJ, Flaxel CJ, Gray P, et al. Vitreoretinal surgery after inadvertent globe penetration during local ocular anesthesia. Ophthalmology. 1998;105:371–6. 43. Duker JS, Belmont JB, Benson WE, et al. Inadvertent globe perforation during retrobulbar and peribulbar anesthesia. Patient characteristics, surgical management and visual outcome. Ophthalmology. 1991;98:519–26. 44. Gillow JT, Aggarwal RK, Kirby GR. Ocular perforation during peribulbal anaesthesia. Eye. 1996;10:533–6. 45. Rosenthal G, Bartz-Schmidt KU, Engels B, et al. Primary use of silicone oil tamponade in the management of perforating globe injury secondary to inadvertent local anaesthesia injection for ophthalmic surgery. Int Ophthalmol. 1997–1998;21:349–52. 46. Eke T, Thompson J. Severe adverse events associated with local anaesthesia for cataract surgery in the UK and Ireland. Abstract presented at the World Congress of Ophthalmic Anaesthesia, 15 April 2004, London. 47. Kumar CM, Williamson S, Manickham B. A review of subTenon’s block; current practice and recent development. Eur J Anaesthesiol. 2005;22:567–77. 48. Alwitty A, Koshy Z, Browning AC, et al. The effect of sub-Tenon’s anaesthesia on intraocular pressure. Eye. 2001;27:1221–6. 49. Ripart J, Lefrant J-Y, Vivien B, et al. Ophthalmic regional anesthesia medial canthus episcleral (sub-Tenon) anesthesia is more efficient than peribulbar anesthesia. Anesthesiology. 2000;92:1278–85. 50. Parkar T, Gogate P, Deshpane M, et al. Comparison of sub-Tenon anaesthesia with peribulbar anaesthesia for manual small incision cataract surgery. Indian J Ophthalmol. 2005;53:255–9. 51. Mukherji S, Esakowitz L. Orbital inflammation after sub-Tenon’s anesthesia. J Cataract Refract Surg. 2005;31:2221–3. 52. Kubitz J, Epple J, Bach A, et al. Psychomotor recovery in very old patients after total intravenous anaesthesia for cataract surgery. Br J Anaesth. 2001;86:203–8. 53. Weilbach C, Scheinichen D, Thissen U, et al. Anaesthesia in cataract surgery for elderly people. Anasthesiol Instensivmed Notfallmed Schmerzther. 2004;39:276–80. 54. Weibach C, Scheinichen D, Raymondos K, et al. Assessment of anesthesia methods in ophthalmologic surgery by patients, surgeons and anesthesiologists. Ophthalmologe. 2005;102:783–6. 55. Goguen ER, Roberts CW. Topical NSAIDS to control pain in clear corneal cataract extraction. Insight. 2004;29(3):10–1. 56. Simone J, Whitacre M. Effects of anti-inflammatory drugs following cataract extraction. Curr Opin Ophthalmol. 2001;12:1263–7.

PART 5 THE LENS

5.7

Phacoemulsification David Allen

Key features n n n n

n

n n

n

TORSIONAL PHACOEMULSIFICATION USING THE KELMAN TIP

 hanging phaco “power” is achieved by changing the stroke length C of needle vibration, not by changing the frequency. It is not possible to directly compare phaco “power” used between different manufacturers’ machines. While still controversial, evidence is accumulating that direct mechanical action is the most important factor in phacoemulsification. Power modulation significantly increases the efficiency of  longitudinal phaco as well as improving the thermal safety. It is  less important with the new torsional phaco. Modern pump systems are very efficient and high vacuums can  be achieved very quickly with modern flow-based (peristaltic)  systems. In a flow-based machine the aspiration flow rate can be adjusted completely independently of the preset vacuum limit. In a vacuum-based (venturi) machine the aspiration flow rate  is generated by the pressure difference between the vacuum chamber and the eye. Therefore, the two cannot be completely  dissociated and a high vacuum will always result in higher flow rates than a lower vacuum. Modern machines use a variety of strategies to minimize post­ occlusion surge. Postocclusion surge potential is directly related to the maximum set vacuum for any given needle/sleeve/tubing complex.

INTRODUCTION As surgical techniques for the removal of cataract and drug modulation of the consequent biological responses have become more refined, the problems of postoperative infection and inflammation are less prominent in the thinking of lens surgeons. As a consequence, it has become possible to concentrate on the further refinement of the actual process of lens removal. Phacoemulsification (phaco) offers the surgeon the possibility to break the nucleus into smaller pieces and even into a fine emulsion of material, all of which can be removed through the probe used to achieve the break-up. As a result, it is now possible to minimize trauma to the structures of the eye and to have minimal impact on its shape as a consequence of modern cataract surgery. Achieving this, however, requires the use of very powerful tools. Unfortunately, many surgeons fail to understand the principles that underlie the machines they use. As a consequence of this relative ignorance, the surgery is sometimes performed less efficiently and possibly more dangerously than necessary.

Historical Review

In February 1965 Charles Kelman propounded the view that the ultrasonic tool used at that time by some dentists to help descale teeth could also be used to fragment the nucleus of the crystalline lens and allow its removal without the need for a large incision. This liberated a powerful force, previously untried within the eye, but the equipment involved was large, inefficient, and extremely heavy. Nevertheless, he and others persevered.1–4 Kelman’s first operation using phaco on a human eye took 3 hours. At that time the patients were either left aphakic or the incision needed considerable enlargement to allow insertion of the then relatively new, rigid intraocular lenses (IOLs). Three developments − the technological progress of

axis of rotation

incision

cutting edge

Fig. 5-7-1  Torsional phacoemulsification using the Kelman tip. Diagram to show how torsion around the center of the shaft is translated into a sweeping  motion at the tip of the Kelman phaco needle. (Drawing courtesy of Alcon Surgical.)

the 1970s and 1980s (particularly in solid-state electronic control mechanisms), new surgical techniques (particularly continuous curvilinear capsulorrhexis5), and the development of high-quality, foldable IOLs6 − acted synergistically to enable the development of modern phaco surgery despite the considerable early resistance to this new technique.7 Surgeons are now presented with increasingly sophisticated equipment that allows much more control of the surgical process. Understanding the basic principles of the equipment allows the surgeon to maximize this potential.

HANDPIECES AND TIPS The phaco handpiece houses an ultrasonic transducer − a device that converts electrical energy into mechanical vibratory energy. Some crystals exhibit a relationship between mechanical stress and electricity − they are piezoelectric. If an electric charge is applied to opposite faces of these crystals, a strain appears in the structure, which results in deformation. Standard handpieces couple the crystal to the phaco-tip in such a way that the tip moves backwards and forwards when the crystals deform. Recently, Alcon Surgical (Fort Worth, TX, USA) have introduced a handpiece (OZil) that can cause the tip to tort or twist when the crystals deform. It is constructed in such a way that when oscillating at 36 kHz the crystals produce torsion and when stimulated at 43 kHz they produce traditional linear movement. If a tip with a bend in the shaft (e.g., Kelman tip) is attached to such a handpiece, then the twisting of the shaft is converted into a sweeping side-to-side motion at the end of the tip (Fig. 5-7-1).

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5 THE LENS

The frequency at which a handpiece is set to work depends on the design and materials used. For each combination of mass and material a particular frequency exists at which the transducer works most efficiently. Adjustment of the power setting on the machine affects the stroke length (the distance traveled by the tip during one cycle) but not the frequency. Power is expressed as a percentage of the maximum travel the crystal-tip complex can produce. It is clear that if the frequency remains constant but the distance traveled in each stroke increases, the acceleration of the tip and the maximum speed it reaches must be greater. It is now possible to have the control unit continually “autotune” the handpiece: small adjustments can be made to compensate for the effects of changes in temperature, in the mass in contact with the tip, etc. Machines that use this principle vary the electrical power delivered to the crystals so that for a given commanded power the stroke length remains constant regardless of whether the tip is in a fluid medium or in contact with a very hard nucleus. It is important to recognize that the power settings on the machine console are indicative only. Some systems have a nonlinear relation between commanded power and stroke length. The smallest stroke (at minimum power setting) also varies among systems. In one commercially available system, 20% power produces tip travel of 50 μm, whereas this travel is reached only at 60% power in another machine. As a consequence, any comparisons between the ‘efficiency’ of different phaco machines based on comparisons of ‘power used’ are spurious. The physical mechanisms that break up nuclear material when a phaco tip is used have been difficult to elucidate, and until recently the relative importance of the various factors has been unclear.8, 9 We now know that the direct mechanical hammer-like effect of the extremely hard titanium tip coming into contact with the lens material is probably the most important. A phaco tip operated at a frequency of 44 kHz has a maximum speed of 66 ft/second (20 m/second) when operated at full power, and the acceleration of the tip is > 168 300 ft/second2 (> 51 000 m/second2). Under these conditions, direct impact of the tip breaks frictional forces within the nuclear material. This direct effect is reduced, however, by the forward-propagating acoustic waves or fluid and particle waves generated by the tip, which tend to push away any piece of nucleus in contact with the tip. However, it is possible that the acoustic shock waves themselves tend to weaken or break some of the bonds that hold nuclear material together. The role of cavitation in breaking down lens material has recently been shown to be insignificant. In a laboratory study of phacoemulsification performed in a hyperbaric chamber, the effectiveness of phaco was seen to be undiminished in conditions were cavitation was suppressed.10 Various tip designs are available for the surgeon, but there are three key design variations. The Kelman tip has a 22° angle in the tip shaft 3.5 mm from the tip. This design is thought to enhance the emulsification action of the tip, as well as allowing the surgeon to use it as a manipulator. Some tips have a flared termination of the tip (i.e., the outer diameter at the end of the tip is greater than that 1–2 mm behind). This again is thought to enhance the emulsification, but also the inner lumen has a restriction behind the flare that helps to suppress postocclusion surge. Some tips have fluting along the outside of the shaft that allows some fluid to continue to inflow, even if the silicone irrigation sleeve is compressed onto the shaft. This reduces the possibility of thermal damage in the incision.

POWER MODULATION

448

While some form of simple power modulation (pulsed phaco) has been available for a long time, the introduction in 2001 of the Whitestar software for the AMO Sovereign phaco machine (Advanced Medical Optics, Santa Ana, CA, USA) marked a paradigm shift in the way surgeons controlled the application of phaco power. Break-up of phaco into pulses or bursts has two advantages. First, the pauses (off period) allow the machine fluidics to pull material back into contact with the tip following repulsion caused by the jack-hammer effect in traditional longitudinal phaco. Second, the pauses prevent significant build-up of heat due to frictional movement within the incision, making thermal damage to the cornea less likely. Several machines now allow almost infinite variation of both duty cycle (the ratio of on-time to off-time) and the length of the on period. It has been shown that such power modulation significantly improves the ‘efficiency’ of phacoemulsification (i.e., quicker surgery and reduced amount of phaco energy used).11 The Whitestar software already mentioned has a specific occlusion mode whereby, if it is selected, the machine can make adjustments to the power modulations when occlusion is detected.

VACUUM RISE-TIME

vacuum 800 (mmHG) 700 600 500 400 300 200 100 0

0

0.5

1

ASP rate 20 mL/minute ASP rate 40 mL/minute ASP rate 60 mL/minute

1.5

2

2.5

3

time (seconds)

Fig. 5-7-2  Vacuum rise-time as a function of aspiration rate. Graph showing  the effect of increasing aspiration rate (pump speed) on the time to reach  certain vacuum levels.

When first introduced, pulses had a fixed duty cycle of 50% (i.e., the period with power on and with power off were equal) but power was variable, while bursts were of fixed width, usually with fixed power also. Now, with the enhanced modulations possible on several platforms, this distinction has become blurred and it is probably no longer helpful to try to distinguish between them in advanced machines.

PUMPS AND FLUIDICS The function of the phaco pump is twofold: to hold the nucleus onto the tip and to remove debris created by the tip. With modern techniques the pump is also increasingly used to aspirate directly the softer parts of the nucleus. There are two pump principles in general use − flow-driven and vacuum-driven. A hybrid type of pump was briefly available in the Concentrix module of the Bausch & Lomb Surgical (Rochester, NY, USA) Millennium phaco machine. At least one manufacturer is developing a vacuum pump that can be used as a flow-driven pump if required.

Flow Based (Peristaltic)

Roller pumps that rotate against compressible tubing or membrane ­generate flow; this “milks” fluid along the lumen and creates a pressure gradient between pump and anterior chamber. Recent design changes in the pumps and sophisticated microprocessor controls have resulted in powerful and well-controlled pump systems. Although the earlier peristaltic systems had a reputation for being unresponsive, modern systems are capable of producing a 500 mmHg (66.5 kPa) vacuum in under 1 second. The rate at which fluid is aspirated through the unoccluded phaco tip is set at the machine console in milliliters per minute. A low value allows events within the anterior chamber to happen slowly; a high value speeds up events and generates more “pulling power.” Fine adjustments of flow, by changing the speed at which the pump turns, allow for personal surgical style or different operating conditions. Recent advanced systems sense when the tip is occluded partially and then make adjustments to the pump to compensate for reduced aspiration. The second pump parameter that can be adjusted is the vacuum level at which, once achieved, the pump stops. When the tip becomes occluded, the pump continues to turn and move fluid into the cassette, lowering the pressure in the tubing between tip and cassette. Once the preset vacuum has been reached, the pump effectively stops for as long as that vacuum level holds. The rate at which the maximum set vacuum level is reached is directly proportional to the flow rate, so that for a particular machine a level of 460 mmHg is reached in 1.0 second when the flow rate is set at 20 mL/min but reaches 470 mmHg in 0.5 seconds when it is set at 40 mL/min (Fig. 5-7-2).

Vacuum Based

Anterior Chamber hydrodynamics

It is important to understand the correct meaning of various terms used to describe the fluid dynamics of phaco. Normally, “flow” is used to mean evacuation flow out of the eye. Fluid also flows out of the eye at a variable rate through the incisions. To avoid confusion, if flow into the eye is being described, it is necessary to use the term “inflow.” The rate of fluid inflow is determined by the height difference between the drip chamber of the fluid reservoir and the eye. Inflow is almost always passive; it is modulated by the resistance of the tubing and by any compression of the inflow sleeve around the phaco tip. It is essential that the inflow potential (the maximum possible under free-flow conditions) at least equals, and if possible exceeds, the maximum transient outflow (combined incisional flow and machine-generated flow), otherwise anterior chamber collapse occurs. “Vacuum” is taken to mean the preset maximum vacuum level indicated on the console. In neither peristaltic nor vacuum-based ­systems is the vacuum present in the anterior chamber. In traditional longitudinal phaco, an active phaco tip (power applied) produces forces that push material away from it. This is countered by the vacuum that holds the material to the tip. The new torsional phaco mode (Alcon) generates a sweeping horizontal movement without repulsion, and lower vacuums can be used. When a surgeon uses a technique that involves sculpting (e.g., “divide and conquer”12 or “stop and chop”13), a relatively low flow (≤ 20 mL/min), with no tip occlusion, is required. The low flow allows sculpting near or even onto the capsule,

5.7 Phacoemulsification

These systems generate an adjustable level of vacuum in a chamber in the machine: usually a Venturi pump is used. It is the pressure difference between this chamber and the tip that generates flow. Once the tip is occluded, fluid continues to be removed from the tubing until the pressure within it equals that in the vacuum chamber. It is possible, however, to introduce a damping effect into the system so that the equilibration of pressures does not take place instantaneously. In a standard vacuum system, because the flow rate is generated by the pressure gradient, increasing the vacuum increases the flow and vice versa. These two parameters cannot normally be modulated independently, although this will be possible with a new vacuum pump in development.

without the risk of drawing the capsule into the port, and a tip slope of 30° or 45° allows the surgeon both to see the tip and to minimize occlusion potential. For subsequent nucleus fragment consumption (or initially in chop techniques), a high flow (20–40 mL/min) is required to pull the nucleus toward the tip, along with high vacuum (200–600 mmHg) to hold it in contact for emulsification. Occlusion in these circumstances is enhanced by rotation of the tip so that the opening is aligned with the edge of nucleus being grasped, or by using a 0° tip. Many phaco systems now offer the surgeon the opportunity to adjust the fluidics performance, particularly vacuum rise-time, once occlusion has been achieved. Some surgeons, for example, continue to prefer relatively low aspiration flow rates during the acquisition of nucleus fragments, but set the machine to significantly increase the flow rate (and hence speed of achieving the preset vacuum) once the tip is occluded. Another example would be the reduction in flow rate on occlusion that some surgeons use when dealing with very soft cataracts or epinucleus. Since 2001 many surgeons have become interested in the concept of micro-incisional phaco. This was first performed in a biaxial mode; the infusion was dissociated from what became a ‘bare’ aspiration tip by use of a separate cannula inserted through a separate incision. Each incision is only 1−1.5 mm wide, and there are a number of IOLs that can be inserted through sub 2 mm incisions. The reduced maximum incision size results in smaller changes to corneal curvature induced by the surgery. Another theoretical advantage is that in coaxial phaco, the infusion ports in the infusion sleeve around the phaco tip are positioned close to the aspiration port and therefore can create turbulent flow that can disrupt the attractive force generated by aspiration. Until recently these forces, which can be disruptive to the attractive aspiration force, have been unavoidable and therefore ignored. However, the main advantage of biaxial phaco is that these forces are now separated. Critics of biaxial surgery point to the degraded fluidics that may be produced by a nonconforming bare solid cannula passing through a corneal incision; either incisional leakage must be significant, or the incision is so tight as to risk significant tearing of corneal stroma and Descemet’s membrane. New sleeves for coaxial microincision phaco have now been developed that allow coaxial phaco to be performed through 2 mm incisions or smaller. This has been achieved by a combination

IOP DURING POSTOCCLUSION CYCLE

lOP

occlusion breaks high outflow reduces lOP

unobstructed flow

partial occlusion

full occlusion

infusion recovers lOP

AC recovery

unobstructed flow

Fig. 5-7-3  Intraocular pressure (IOP) during postocclusion surge. IOP initially maintained by bottle height. Slight rise when tip occluded. When occlusion breaks, large pressure difference between tubing and anterior chamber (AC) results in rapid outflow of fluid causing IOP to drop rapidly until infusion restores “normal” IOP.

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5 THE LENS

of modifications: reduced internal diameter, thinner walls, and an ultra­ smooth external surface reducing resistance to insertion into a small ­incision. Whether using biaxial or coaxial microincision techniques, it is important that surgeons understand the importance of fluidics, and ensure that the inflow potential through the reduced sleeve or the separate infusion instrument is greater than the maximum outflow during postocclusion surge with their particular combination of machine, needle, and vacuum settings.

POSTOCCLUSION SURGE With any pump design, in the occluded state, vacuum is generated in the lumen of the tubing. In an unmodulated system, when the occlusion breaks, fluid rushes into the tubing to equilibrate the pressure difference between the anterior chamber and the lumen − “postocclusion surge” (Fig. 5-7-3). During the period of occlusion, the walls of the ­tubing tend to collapse in proportion to the increase in vacuum. On

r­ elease of the occlusion the tubing re-expands and often rebounds, which results in a larger postocclusion surge. In addition, if the foot pedal is still in position two (i.e., irrigation and aspiration), the pump may immediately begin to turn. The difference between the outflow surge and the compensating inflow from the irrigation bottle determines the stability of the anterior chamber. Modern phaco systems use a variety of strategies to reduce the problems associated with postocclusion surge. The internal diameter of both the phaco needle (and any restrictions such as seen in the flared needle) and outflow tubing modulate the outflow surge. More rigid outflow tubing reduces the rebound effect. The effective inflow diameter (the gap between the outer wall of the tip and the inner wall of the sleeve in coaxial phaco, or the internal diameter and outflow port diameters of the irrigation instrument in biaxial phaco), along with the bottle height, determines the amount of inflow and how well it compensates for surge. Finally, frequent sampling of the pressure in the inflow and outflow lines can be used to predict or immediately detect outflow surge, and pump behavior can be modified.

REFERENCES   1. K  elman C. Phaco-emulsification and aspiration. A new technique of cataract removal. A preliminary report. Am J Ophthalmol. 1967;64:23–35.   2. Kelman C. Cataract emulsification and aspiration.  Trans Ophthalmol Soc UK. 1970;90:13–22.   3. Kraff MC, Sanders DR, Lieberman HL. Total cataract  extraction through a 3-mm incision: a report of 650 cases. Ophthalmic Surg. 1979;10:46–54.   4. Cohen SW, Kara G, Rizzuti AB, et al. Automated  phakotomy and aspiration of soft congenital and  traumatic cataracts. Ophthalmic Surg. 1979;10:38–45.   5. Gimbel HV, Neuhann T. Development, advantages, and methods of the continuous circular capsulorrhexis technique. J Cataract Refract Surg. 1990;16:31–7.

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  6. A  llarakia L, Knoll RL, Lindstrom RL. Soft intraocular lenses. J Cataract Refract Surg. 1987;13:607–20.   7. Illiff CE. Phacoemulsification − why? Trans Am Acad Ophthalmol Otolaryngol. 1977;83:213–15.   8. Pacifico RL. Ultrasonic energy in phacoemulsification: mechanical cutting and cavitation. J Cataract Refract Surg. 1994;20:338–41.   9. Davis PL. Mechanism of phacoemulsification.  Letter to the editor. J Cataract Refract Surg. 1994;20:672–3. 10. Zacharias J. Role of jackhammer effect and  cavitation in phacoemulsification. Presented  at ASCRS Annual Meeting, San Francisco, USA,  March 18–22, 2006.

11. A  llen D. Power modulation with the Alcon Infiniti lens system. Presented at ASCRS Annual Meeting, San Diego, USA, May 1–5, 2004. 12. Gimbel HV. Divide and conquer nucleofractis phacoemulsification: development and variations. J Cataract Refract Surg. 1991;17:281–91. 13. Koch PS, Katzen LE. Stop and chop phacoemulsification. J Cataract Refract Surg. 1994;20:566–70.

PART 5 THE LENS

Refractive Aspects of Cataract Surgery

5.8

Emanuel S. Rosen

Key features n n n n n n

 nderstand corneal shape pre operation. U Value of corneal topography in lens surgery. Prevent induced corneal astigmatism. Treat astigmatism post operation. By incisions. By corneal laser surgery.

INTRODUCTION When Sir Harold Ridley implanted a human eye with a replacement lens (intraocular lens, IOL) in 1949 he initiated the changing role of cataract surgery.1 As IOL implantation technology matured over the following years, cataract surgery became more than just removing a clouding crystalline lens; it allowed the replacement IOL to be varied to adjust the intrinsic refractive error or ametropia. In other words, there are two strategies for surgical intervention: first removing the impediment of a cataractous lens and then simultaneously incorporating an IOL of measured dioptric power to neutralize existing ametropia. Of course, there are many other aspects to the refractive aspects of cataract surgery. Accurate biometry is vital and readers are referred to that aspect of cataract management in general in Chapter 10-12 in this volume. Cataract surgery in eyes that have previously undergone corneal refractive surgery require special formulae to calculate the correct IOL power after keratometric values have been changed by that surgery. Astigmatism management is a fundamental refractive need in cataract surgery and will be considered here. Latterly, with the advent of clinical aberrometers and their application in refractive surgery, cataract ­replacement is now taking advantage of the deeper understanding of the relationship, in a refractive sense, between the cornea and the lens. Near, intermediate and distance vision needs have to be satisfied by lens replacement, a task fulfilled by emergent multifocal IOL technology, pseudo-accommodative IOLs, and the future fulfillment of true accommodating IOLs. The bases for refractive correction as an aspect of cataract surgery are accurate biometry on the one hand and corneal topography on the other.

CORNEAL INCISIONS Tejedor and Murube2 investigated the best location of clear cornea ­incision in phacoemulsification, depending on pre-existing corneal ­ astigmatism in a randomized clinical trial and noncomparative ­interventional case series. Five hundred and seventy-four patients in five stages were assigned to the following types of incision: superior or temporal (n = 89), superior (n = 141), superior or superior plus relaxing (n = 102), nasal or temporal (n = 156), and incisions based on applying the conclusions of preceding and current studies (n = 86). Visual acuity, refraction, biomicroscopy, keratometry, and videokeratography (Fourier analysis) were performed before and after phacoemulsification and intraocular lens implantation through a 3.5 mm incision. In patients without ­corneal astigmatism, corneal changes induced were greater in superior than in temporal incisions. After a superior incision (preoperative steep

­ eridian at 90°), a shift of 90° away was less likely with at least 1.5 D m of astigmatism. A perpendicular, relaxing, limbal incision decreased corneal changes. Nasal incisions induced greater corneal change than temporal incisions (preoperative steep meridian at 180°). A shift of this meridian 90° away was more likely with astigmatism  6 weeks) of the chiasm often leads to nerve fiber layer defects or optic atrophy. When the body of the chiasm is involved, a temporal or “bow-tie” pattern, which corresponds to retinal fibers that originate nasal to the fovea, may occur (Fig. 9-11-17). However, this appearance often is not apparent, because nondecussating fibers frequently are damaged, as well, particularly with compressive lesions. Optic atrophy also may be a late sign of chiasmal compression and is associated with a poorer postoperative visual acuity.

Signs and Symptoms of Parachiasmal Lesions

Parachiasmal involvement manifests with abnormalities of ocular motility, pupillary function, or facial sensation from injury to cranial nerves III, IV, V1, V2, or VI or the ocular sympathetic nerves in the parachiasmal region. Injury to these structures within the cavernous sinus may be associated with complaints of diplopia, ptosis, unequal pupil size, accommodative difficulty, facial pain or numbness, or eye pain. Signs include ocular motor nerve palsies, decreased sensation in the areas innervated by the first and second divisions of the trigeminal nerve, or Horner’s syndrome. Multiple cranial nerve involvement is more suggestive of invasive malignant tumors. Lesions that block the normal cerebrospinal fluid circulation by ­obstruction of the foramen of Monroe may result in hydrocephalus. ­Ocular examination may reveal vertical gaze abnormalities, convergence retraction nystagmus, pupillary light–near dissociation, and papilledema.

Bitemporal hemianopia (pituitary adenoma, sellar meningioma)

Junctional scotomas (sphenoid meningioma)

Central hemianopic scotomas (hydrocephalus, pinealoma, craniopharyngioma)

9.11 Optic Chiasm, Parasellar Region, and Pituitary Fossa

Right eye field

LOCALIZATION AND IDENTIFICATION OF MASSES BY PATTERN OF FIELD LOSS

Fig. 9-11-16  Localization and probable identification of masses by pattern of field loss. Junctional scotomas occur with compression of the anterior angle of the chiasm (sphenoid meningioma). Bitemporal hemianopia results from compression of the body of the chiasm from below (e.g., because of pituitary adenoma, sellar meningioma). Compression of the posterior chiasm and its ­decussating nasal fibers may cause central bitemporal hemianopic scotomas (e.g., because of hydrocephalus, pinealoma, craniopharyngioma).

“BOW-TIE” ATROPHY

atrophic nasal and temporal disc

Fig. 9-11-17  “Bow-tie” atrophy. Chronic compression of the decussating visual fibers of the chiasm leads to atrophy of the corresponding nasal retinal nerve fibers that enter the optic disc nasally and temporally. At the disc, this atrophy appears in a bow-tie pattern.

An unusual form of dissociated nystagmus called see-saw nystagmus occasionally accompanies mass lesions in the chiasmal region and ­diencephalon. Also, it may be seen transiently ­immediately after brainstem stroke, or subsequent to severe head trauma after a delay of weeks to months, or as a variant of ­congenital nystagmus. See-saw ­nystagmus manifests as alternating intorsion and elevation of one eye with ­extortion and depression of the fellow eye and may result in ­complaints of oscillopsia. It ceases when the eyes are closed and does not occur in blind patients, which suggests a role for vision in its pathogenesis. A lesion that involves the interstitial nucleus of Cajal and its ­connections,

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or damage to the ocular counter-rolling mechanism mediated by the inferior olivary nucleus, has been postulated. Chiasmal gliomas in young children have been reported to cause nystagmus, which may be the initial sign of chiasmal or parachiasmal involvement. The nystagmus, which is usually pendular and asymmetrical, may mimic spasmus nutans (even head nodding).

DIAGNOSIS Visual Field Testing

The primary role of the clinician in the diagnosis of chiasmal disorders is to assess visual function accurately, interpret the results correctly, and, thus, localize the anatomical region that is affected. Visual field tests may provide a strong indication of direct chiasmal involvement, and failure to perform and properly interpret visual field tests is a common cause for delay in the diagnosis of chiasmal disorders. It is important to establish that the vertical midline forms the border of the field depression and accordingly to rule out nonchiasmal temporal field loss that does not respect the vertical midline. Although a peripheral hemianopic step along the vertical midline is characteristic, early chiasmal compression often lacks a clear vertical step. Most often, temporal paracentral depression occurs because the chiasm has macular projections through most areas. A good strategy to establish a field defect attributable to chiasmal disease is to test either a single central isopter or static threshold sensitivity within the central 15–20° from fixation and to compare changes in color perception as colored objects pass across the vertical midline through central fixation.

Neuroimaging

Prompt magnetic resonance imaging (MRI) is indicated for the patient who has symptoms or signs referable to the chiasm or parachiasmal region (see Figs 9-11-8 to 9-11-10). It is the study of choice for most sellar and parasellar lesions, but high-resolution computed tomography (CT) with fine cuts (1.5–3 mm) of axial and coronal views is an acceptable alternative. Both modalities provide about equivalent ability to detect lesions in the parachiasmal regions. The advantages of MRI are a better definition of the anatomical relationships to surrounding structures, the absence of artifacts from bone, and the ability to provide axial, coronal, and sagittal views without special image reconstruction. However, CT provides superior abilities in the detection of tumoral calcifications, of bony erosion and destruction by meningiomas and craniopharyngiomas, and of hyperostosis from meningiomas. Intravenous contrast and enhancement agents, such as paramagnetic gadolinium-pentetic acid for MRI and radiopaque iodine for CT, are used to demonstrate lesions that may not be visualized on noncontrast studies.

Other Diagnostic Testing

Complete endocrinological evaluation should be done in assessment of lesions that involve the pituitary–hypothalamic axis. Lumbar puncture also may be required if an inflammatory or infectious cause is suspected. Magnetic resonance angiography or cerebral angiography may be indicated when vascular causes or cavernous sinus invasion are suspected, or to further characterize or delineate mass lesions and their blood supply. The current sensitivity of MRI or CT often obviates the need for angiography. Some clinicians still use arteriography to absolutely rule out a suprasellar aneurysm or to define the position of the carotid arteries prior to surgery. However, trans-sphenoidal resections of pituitary tumors usually are accomplished safely without prior angiography.

DIFFERENTIAL DIAGNOSIS

992

Several conditions may mimic the visual field defects associated with chiasmal syndromes. Retinal conditions (such as nasal ­ sector ­retinitis pigmentosa), optic disc anomalies (such as tilted optic discs), and ­ papilledema with greatly enlarged blind spots may cause bilateral ­ temporal field loss. Bilateral centrocecal scotomas caused by bilateral ­ optic nerve disease may be difficult to differentiate from ­posterior ­chiasmal compression that affects the macular ­projections unless careful attention is paid to the vertical midline. Visual ­obstruction from overhanging redundant lid tissue, refractive scotomas, ­ psychogenic ­ visual loss, and test artifacts also may ­ simulate chiasmal field ­patterns.

SYSTEMIC ASSOCIATIONS Headache, usually frontal in location, frequently accompanies ­pituitary adenomas, pituitary apoplexy, and meningiomas and may be attributable to a stretched diaphragma sellae. Also, lesions that block ­ normal cerebrospinal fluid circulation may lead to headache, gait difficulties, somnolence and, eventually, urinary incontinence (as a result of ­hydrocephalus). Abnormalities of pituitary endocrine dysfunction caused by disruption of the hypothalamic–pituitary axis or pituitary adenomas may lead to hypopituitarism, changes in hand or foot size because of acromegaly, amenorrhea-galactorrhea in women, impotence in men, or changes in body habitus that arise from Cushing’s syndrome. ­Hypothalamic dysfunction also may manifest as urinary frequency as a result of ­diabetes insipidus, heat or cold intolerance caused by a ­ disturbance of temperature regulation, behavioral changes, lethargy, ­decreased libido, or ­disturbance of appetite. In children, delay or ­arrest in sexual development, precocious puberty, or infantile emaciation may occur.

PATHOLOGY Pituitary Adenomas

Adenomas are by far the most common tumors of the pituitary gland, and usually arise as a discrete nodule from the anterior part of the gland, called adenohypophysis; they are soft and vary in color from gray-white to pink or red, depending on the degree of vascularity. ­Necrosis or ­spontaneous hemorrhage often leads to cystic areas. Pituitary adenomas can be classified according to staining ­affinities of the cell cytoplasm, size, endocrine activity, histologic characteristics, hormone production and contents, ultrastructural features, ­granularity of the cell cytoplasm, cellular composition, cytogenesis, and growth pattern.34 Recent classifications, however, omit criteria based on tinctorial stains (i.e., acidophilic, basophilic, and chromophobic) because of the poor correlation between staining affinities of the cell cytoplasm and other pathological features of pituitary tumors, such as the type of hormone produced and cellular derivation. A unifying pituitary ­ adenoma classification incorporates the histological, immunocytochemical, and electron microscopic studies of the tumor cells, and stresses the ­importance of hormone production, cellular composition, and ­cytogenesis. Therefore, pituitary adenomas are named as lactotroph (PRL-producing) adenomas, corticotroph (ACTH-producing) ­ adenomas, ­ somatotroph (GH-producing) adenomas, and thyrotroph (TSH-­producing) adenomas. Other tumors may be found to be ­producers of more than one hormone (plurihormonal adenomas) and up to one third may be composed of endocrinologically inactive cells (null cell adenomas). In a series of 1000 pituitary tumors surgically resected, Wilson35 found that just over 77% were secretory (41% prolactin, 19% growth hormone, 17% adrenocorticotropin, and 0.2% thyrotropin). ­Occasionally, pituitary tumors are associated with other ­endocrine ­tumors in the pancreas and parathyroid gland (multiple endocrine neoplasia type 1).

Meningiomas

Meningiomas probably derive from cap cells that line the outer surface of the arachnoid (where they serve as the interface between the dura and arachnoid) and within the stroma of the choroid plexus. Histologically, meningiomas are categorized into: l Syncytial tumors in which the cell borders are indistinct because the cell membranes intertwine extensively. l Transitional tumors composed of plump polygonal cells and ­concentrically wrapped spindle cells that form whorls. l Fibroblastic meningiomas composed of interlacing bundles of ­elongated cells that simulate fibroblasts. meningiomas in which prominent, thin-walled l Angioblastic ­capillaries are found interspersed between the tumor cells. A characteristic feature of many meningiomas, especially those in which whorls are prominent, is the presence of psammoma bodies. These structures contain concentric layers of calcium salts, which ­appear to be deposited within degenerating whorl cells. Whorls and psammoma bodies, characteristic of transitional meningiomas, also may be found (but to a lesser degree) in fibroblastic meningiomas. ­Malignant meningiomas are rare and usually show cellular pleomorphism and mitoses. However, tumors that appear histologically benign and show rapid growth, local invasion, and metastasis may be determined malignant on the basis of biological behavior.

Craniopharyngiomas

Optic Pathway Gliomas

In children, most gliomas are astrocytomas that consist of pilocytic cells (spindle-shaped cells with hair-like filaments) and stellate cells. Less ­often, the tumors may comprise evenly distributed oligodendrocytes with dark, round nuclei surrounded by clear haloes, which may stain with Alcian blue. These tumors have a benign appearance histologically. Eosinophilic hyalinization of apparently degenerated neuroglial cells may form elongated structures, called Rosenthal fibers. Formation of microcystic, acellular spaces that contain mucoid material is common. The benign tumors, which are more common in children, are distinct from the aggressive, malignant glioblastoma multiforme that predominates in adults.

TREATMENT, COURSE, AND OUTCOME Pituitary Adenomas

The medical treatment of pituitary tumors that are prolactin secreting consists of bromocriptine and other dopamine agonists that suppress further growth and reduce their size. Bromocriptine usually is started at an initial dosage of 1.25–2.5 mg daily and then increased by 2.5 mg ­every few days until a therapeutic response is obtained. A normal prolactin level may be achieved in up to 90% of microadenomas and in more than 70% of macroadenomas.36 After the institution of bromocriptine therapy, shrinkage of tumor volume and reduction in serum prolactin may occur within days, and maximal shrinkage in tumor size appears to be obtained within 6 weeks. Improvements in visual acuity and field defects may be sustained using bromocriptine therapy in 80–90% of patients.37 Unfortunately, about 15% of prolactinomas do not respond adequately to bromocriptine, and withdrawal of bromocriptine almost always results in tumor recurrence in those patients who did respond. Complications of bromocriptine therapy are uncommon but include ­cerebrospinal fluid rhinorrhea and chiasmal herniation. Adenomas that secrete growth hormones also may respond to ­bromocriptine, but usually better results are obtained using octreotide, a somatostatin analog. Response rates of about 80% have been reported.38 Tumors such as corticotropic adenomas and hormonally “inactive” ­pituitary tumors generally do not respond well to medical interventions. Symptomatic pituitary tumors that are intolerant, unlikely to ­respond, or fail to respond to medical therapy usually are treated by surgical resection, most frequently by the trans-sphenoidal route. For prolactinomas, success rates depend on the initial tumor size and prolactin levels. Of patients with intrasellar microadenomas with prolactin levels under 155 ng/mL, 86% were found to have long-term remissions after trans-sphenoidal surgical removal.36 Failure to obtain long-term remission after surgery correlates with higher initial prolactin levels, especially over 200 ng/mL.39 Overall, recurrence of prolactinomas and pituitary adenomas that secrete growth hormone was 15% at 1 year after trans-sphenoidal surgery. Pretreatment with bromocriptine does not seem to improve surgical cure rates, although pretreatment to ­reduce tumor volume has been found to ease surgical removal. ­Improvement in vision after surgery may be delayed, and final visual outcome is not determined until 10 weeks postoperatively. Improvement does not usually extend beyond 3–4 months. For patients who have prolactinomas and who become pregnant or intend to become pregnant, tumor growth must be anticipated. Options include early trans-sphenoidal resection if visual field loss is threatened or close observation of visual fields with resection of the tumor if visual field loss is found. Bromocriptine therapy is not recommended during pregnancy. Incompletely resected tumors and those unresponsive to hormone therapy are considered for postoperative radiation therapy. Fractions must not exceed 200 cGy daily because of the increased incidence of

Pituitary Apoplexy

Pituitary apoplexy, which may be life threatening, is treated with highdose systemic corticosteroids (e.g., dexamethasone 6–12 mg every 6 hours) and hormone replacement, and may require medical management of either diabetes insipidus or inappropriate antidiuretic hormone secretion. If rapid visual loss occurs, decrease in level of consciousness, or no improvement within 24–48 hours, trans-sphenoidal decompression of the sella is indicated. Ischemic necrosis of the pituitary associated with apoplexy may lead to hypopituitarism. This scenario occurs commonly during the partum and postpartum periods (Sheehan’s syndrome). Most patients who have apoplexy require subsequent hormone replacement for pituitary insufficiency.

Meningiomas

The preferred management of meningiomas that involve the intracranial optic nerves and chiasm is surgical removal.42 Surgical debulking alone, radiation therapy alone, or combination therapy may be performed if vital structures are surrounded densely by tumor. Postoperative radiation therapy of incompletely resected tumors appears to extend the period to tumor recurrence. However, because the tumors grow slowly and this treatment carries the risk of radiation vasculopathy, adjunctive radiation therapy is used only in cases in which progression follows incomplete resection. Another option in some patients includes hormone therapy using the progesterone antagonist mifepristone, which has resulted in reduced tumor size as shown by neuroimaging or improved visual fields in 5 of 14 patients.43 Location of the tumor and duration of visual symptoms are the most important predictors of visual recovery after surgical removal. Meningiomas of the tuberculum sellae generally are completely resectable and usually show visual recovery, whereas complete removal of sphenoid wing or diaphragma sellae tumors is most unlikely and visual improvement usually is not achieved. Complete gross excision alone does not rule out recurrence. One study showed a 19% 5-year probability of recurrence or progression of parasellar meningiomas despite “complete excision.”44

9.11 Optic Chiasm, Parasellar Region, and Pituitary Fossa

Craniopharyngiomas may be solid or cystic; the cysts contain an oily fluid, with cholesterol clefts derived from degenerating epithelial cells and keratin. Histologically, the tumor’s solid portions may be composed of areas of trabeculae of stratified squamous epithelium supported by a vascularized connective tissue stroma, and of areas of peripheral, basal palisading cells that surround layers of stratified squamous epithelial cells, which may form “horny pearls” of keratinized cells. Calcification and deposition of lamellar bone are found frequently. The tumors are surrounded by a capsule of stratified squamous epithelium and, often, dense gliosis.

radionecrosis. Extensive extrasellar extensions usually are treated with surgical decompression followed by irradiation of residual tumor, because a 40% incidence of microscopic dural invasion makes complete resections difficult or impossible to obtain with surgery alone.40 Patients who have pituitary adenomas that do not immediately threaten vision may be considered candidates for stereotactic radiosurgery, such as with proton beam, cobalt-60 gamma knife, or linear accelerator therapy.41 Although endocrine deficit commonly is associated with these modalities, other complications are infrequent and tumor recurrence is rare.

Craniopharyngiomas

The preferred treatment of craniopharyngiomas remains controversial. Although surgical resection of craniopharyngiomas usually is ­approached using craniotomy, subdiaphragmatic and cystic ­ craniopharyngiomas may be approached trans-sphenoidally. Intracavitary ­ placement of ­radioactive or chemotherapeutic agents, including phosphorus-32 ­colloid, yttrium-90 colloid, or bleomycin, within cystic ­ tumors, has been attempted with some success.45 Cystic tumors have a reputation of ­being particularly difficult to manage. Recurrence is frequent with craniopharyngiomas and usually occurs during the first 2 years. Aggressive resections may delay recurrences but lead to greater mortality, as well as visual, endocrine, and neurological morbidity. A review of the ambitious attempts at complete surgical removal showed a 25% operative mortality, a 71% 11-year mortality, and residual tumor in over 75% of those autopsied.46 Adjunctive radiation therapy improved median survival after extensive subtotal resection from about 3 years to more than 10 years and may achieve remission rates greater than 90%.47, 48 However, adjunctive irradiation is reserved for patients over 5 years of age because of the complications of severe intellectual impairment and profound growth retardation that occur in children. Visual recovery occurs in only 50% of patients after tumor resection, and the recovery seen within the first month is all that is expected. Lifelong endocrine replacement is expected in most patients after surgery or radiation therapy or both.49

Optic Gliomas

The treatment of optic chiasmatic–hypothalamic gliomas has been controversial.50, 51 Patients with gliomas that involve the chiasm alone have a mortality of 28% because of the eventual involvement of the

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994

­hypothalamus or third ventricle.50 Invasion of the hypothalamus or third ventricle dramatically increases the mortality rate to more than 50% over 15 years (see Fig. 9-11-10).50 Surgical intervention does not constitute a definitive treatment for these tumors once there is chiasmal or hypothalamic involvement and may be associated with significant visual morbidity and potential mortality. However, studies have shown benefit from tumor resection in those who have demonstrated rapid

expansion of the suprasellar mass with visual deterioration or progressive neurological deficits.51, 52 Shunting procedures are of clear benefit when hydrocephalus is present, and hormone replacement is indicated when endocrine dysfunction occurs. Chemotherapy for progressive chiasmal gliomas has shown promise and in children offers a safer alternative to radiotherapy.53 Radiotherapy may be considered in children over the age of 5 years if progression occurs and chemotherapy has been ineffective.

REFERENCES   1. Sadun AA, Rubin RM. Developments in sensory neuroophthalmology. In: Silverstone B, Lang MA, Rosenthal B, Faye EE, eds. The Lighthouse handbook on vision impairment and rehabilitation. New York: Oxford University Press; 2000:175–96.   2. Hoyt WF. Correlative functional anatomy of the optic chiasm – 1969. Clin Neurosurg. 1970;17:189–208.   3. Rhoton AL, Harris FS, Renn WH. Microsurgical anatomy of the sellar region and cavernous sinus. In: Glaser JS, ed. Neuro-ophthalmology: symposium of the University of Miami and the Bascom Palmer Eye Institute, vol. IX.   St Louis: CV Mosby; 1977:75–105.   4. Bergland RM, Ray BS, Torack RM. Anatomical variations in the pituitary gland and adjacent structures in 225 autopsy cases. J Neurosurg. 1968;28:93–9.   5. Warwick R. The orbital vessels. In: Warwick, R ed. Eugene Wolff’s anatomy of the eye and orbit, 7th ed. Philadelphia: WB Saunders; 1976:406–17.   6. Reed H, Drance SM. The essentials of perimetry: static and kinetic, 2nd ed. London: Oxford University Press; 1972.   7. Wollschlaeger P, Wollschlaeger G, Ide C, et al. Arterial blood supply of the human optic chiasm and surrounding structures. Ann Ophthalmol. 1971;3:862–9.   8. Wilbrand HL. Schema des verlaufs der sehnervenfasern durch das chiasma. Ztschr F Augenh. 1926;59:135–44.   9. Hoyt WF, Luis O. Visual fiber anatomy in the infrageniculate pathway of the primate: uncrossed and crossed retinal quadrant fiber projections studied with Nauta silver stain. Arch Ophthalmol. 1962;68:94–106. 10. Hoyt WF. Anatomic considerations of acute scotomata associated with lesions of the optic nerve and chiasm: a Nauta axon degeneration study in the monkey. Bull Johns Hopkins Hosp. 1962;111:57–71. 11. Hoyt WF, Luis O. The primate chiasm: details of visual fiber organization studied by silver impregnation techniques. Arch Ophthalmol. 1963;70:69–85. 12. Horton JC. Wilbrand’s knee 1904–1995 RIP. Paper presented at Update in Neuro-ophthalmology meeting, 1995, San Francisco. 13. Burrow GN, Wortzman G, Rewcastle NB, et al. Micro­ adenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy service. N Engl J Med. 1981;304:156–8. 14. Scheithauer BW, Kovacs KT, Laws ER Jr, et al. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65:733–44. 15. Wakai S, Fukushima T, Teramoto A, et al. Pituitary apoplexy: its incidence and clinical significance. J Neurosurg. 1981;55:187–93. 16. Onesti ST, Wisniewski T, Post RKD. Clinical versus subclinical pituitary apoplexy: presentation, surgical management, and outcome in 21 patients. Neurosurgery. 1990;26:980–6.

17. Cushing H, Eisenhardt L. Meningiomas arising from the tuberculum sellae with the syndrome of primary optic atrophy and bitemporal field defects combined with a normal sella turcica in a middle-aged person. Arch Ophthalmol. 1929;1:1–41, 166–205. 18. Lumenta CB, Schirmer M. The incidence of brain tumors: a retrospective study. Clin Neuropharmacol. 1984;7:332–7. 19. Schulte FJ. Intracranial tumors in childhood: concepts   of treatment and prognosis. Neuropediatrics. 1984;15:3–12. 20. Yu ZY, Wrange O, Haglund B, et al. Estrogen and progesterone receptors in intracranial meningiomas. J Steroid Biochem. 1982;16:451–6. 21. Battersby RD, Ironside JW, Maltby EL. Inherited multiple meningiomas: a clinical, pathological and cytogenetic study of an affected family. J Neurol Neurosurg Psychiatry. 1986;49:362–8. 22. Koos WT, Miller MH. Intracranial tumors of infants and children. Stuttgart: George Thieme; 1971:415 23. Janss AJ, Grundy R, Cnaan A, et al. Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. Cancer. 1995;75:1051–9. 24. Valueza JM, Lohmann F, Dammann O, et al. Analysis of 20 primarily surgically treated chiasmatic–hypothalamic pilocytic astrocytomas. Acta Neurochir. 1994;126:44–50. 25. Taphoorn MJ, de Vries-Knoppert WA, Ponssen H, et al. Malignant optic gliomas in adults: case report. J Neurosurg. 1989;70:277–9. 26. Baskin DS, Townsend JJ, Wilson CB. Lymphocytic adenohypophysitis of pregnancy simulating a pituitary adenoma: a distinct pathological entity. J Neurosurg. 1982;56:148–53. 27. Osher RH, Corbett JJ, Schatz NJ, et al. Neuro-ophthalmological complications of enlargement of the third ventricle. Br J Ophthalmol. 1978;62:536–42. 28. Kirkham TH. The ocular symptomatology of pituitary tumors. Proc R Soc Med. 1972;65:517–8. 29. Senelick RC, Van Dyk HJ. Chromophobe adenoma masquerading as corticosteroid-responsive optic neuritis. Am J Ophthalmol. 1974;78:485–8. 30. Cappaert WE, Kiprov RV. Craniopharyngioma presenting as unilateral central visual loss. Ann Ophthalmol. 1981;13:703–4. 31. Norwood EG, Kline LB, Chandra-Sekar B, et al. Aneurysmal compression of the anterior visual pathways. Neurology. 1986;36:1035–41. 32. Huber A. Eye symptoms in brain tumors. St Louis:   CV Mosby; 1961:192 33. Traquair HM. An introduction to clinical perimetry,   4th ed. St Louis: CV Mosby; 1944. 34. Kovacs K, Horvath E, Vidal S. Classification of pituitary adenomas. J Neurooncol. 2001;54:121–7. 35. Wilson CB. A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg. 1984;61:814–33.

36. Molitch ME, Elton RL, Blackwell RE, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multi-center study. J Clin Endocrinol Metab. 1985;60:698–705. 37. Molitch ME. The pituitary. In: Melmed S, ed. Prolactinomas, Boston: Blackwell Scientific; 1995;443–77. 38. Lamberts SWJ. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocrinol Rev. 1988;9:417–36. 39. Barrow DL, Mizuno J, Tindall GT. Management of prolactinomas associated with very high serum prolactin levels. J Neurosurg. 1988;68:554–8. 40. Selman WR, Laws ER Jr, Scheithauer BW, et al. The occurrence of dural invasion of pituitary adenomas.   J Neurosurg. 1986;64:402–7. 41. Stephanian E, Lunsford LD, Coffey RJ, et al. Gamma knife surgery for sellar and suprasellar tumors. Neurosurg Clin North Am. 1992;3:207–18. 42. Burde RM, Savino PJ, Trobe JD. Chiasmal visual loss. In: Burde RM, Savino PJ, Trobe JD, eds. Clinical decisions in neuro-ophthalmology, 2nd ed. St Louis: Mosby-Year Book; 1992:74–103. 43. Grunberg SM, Weiss MH, Spitz IM, et al. Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg. 1991;74:861–6. 44. Mirimanoff RO, Dosoretz DE, Linggood RM, et al. Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg. 1985;62:18–24. 45. Anderson DR, Trobe JD, Taren JA, et al. Visual outcome in cystic craniopharyngiomas treated with intracavitary phosphorus-32. Ophthalmology. 1989;96:1786–92. 46. Katz E. Late results of radical excision of craniopharyngiomas in children. J Neurosurg. 1975;42:86–93. 47. Manaka S, Teramoto A, Takakura K. The efficacy of radiotherapy for craniopharyngioma. J Neurosurg. 1985;62:648–56. 48. Baskin DS, Wilson CB. Surgical management of cranio­ pharyngiomas: a review of 74 cases. J Neurosurg. 1986;65:22–7. 49. Repka MX, Miller NR, Miller M. Visual outcome after surgical removal of craniopharyngiomas. Ophthalmology. 1989;96:195–9. 50. Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol. 1994;38:427–52. 51. Garvey M, Packer RJ. An integrated approach to the treatment of chiasmatic-hypothalamic gliomas.   J Neurooncol. 1996;28:167–83. 52. Alshail E, Rutka JT, Becker LE, et al. Optic chiasmatic– ­hypothalamic glioma. Brain Pathol. 1997;7:799–806. 53. Petronio J, Edwards MS, Prados M, et al. Management of chiasmal and hypothalamic gliomas of infancy and childhood with chemotherapy. J Neurosurg. 1991;74:701–8.

PART 9 NEURO-OPHTHALMOLOGY SECTION 2 The Afferent Visual System

9.12

Retrochiasmal Pathways, Higher Cortical Function, and Nonorganic Visual Loss Andrew W. Lawton

carrying parallel streams of information diverted to appropriate areas of the brain for identification, storage, and retrieval.

conducting axons predominate superficially, under the pia. These fibers correspond to the magnicellular layers in the lateral geniculate nuclei. The parvicellular axons dominate the center of the optic tract, with fibers from the opposite eye running in the deepest, dorsal regions. The ­ ipsilateral parvicellular fibers sit slightly ventrally. Optic tract axons achieve this ­orientation by the time they arrive during axonogenesis.

Key features

LATERAL GENICULATE BODIES

Definition:  The retrochiasmal pathways are anatomic brain partitions

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L esions of numerous areas of the brain produce characteristic ­interruptions of pathway functions and visual processing.

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 areful analysis of visual fields and function can localize white C ­matter and cortical lesions accurately. Because patients with conversion reactions and malingerers may have complaints that mimic those caused by retrochiasmal pathway and cortical injuries, careful evaluation is necessary to avoid   unnecessary testing, patient discomfort, and incorrect diagnoses.

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RETROCHIASMAL PATHWAYS AND HIGHER ­CORTICAL FUNCTION OPTIC TRACTS The optic tracts connect the optic chiasm to the lateral geniculate nuclei. An injury to an optic tract may yield a relative afferent pupillary ­defect in the contralateral eye. Because of the temporal crescent, the temporal visual field is 50% larger than the nasal field of the contralateral eye. Hence, the nasal retina produces axons that constitute approximately 55% of the contralateral optic tract. The optic tracts do not maintain a strict retinotopic architecture resulting in incongruous visual field defects (Fig. 9-12-1). Fibers from ­corresponding parts of the retinas do not pair in the optic tracts. Larger diameter, ­faster-

The lateral geniculate bodies are the first sites at which information from corresponding axons arising from the retinal ganglion cell layers pair together. Early embryos do not have this orientation of fibers.1 The axons rearrange themselves into regular layers. The retina directs the rearrangement process via generation of electrical impulses even before the system is visually active. These impulses arise from ganglion and amacrine cells prior to the appearance of photoreceptors. Myelinated nerve fibers divide each lateral geniculate body into six neuronal layers (Fig. 9-12-2).2 The layers are numbered ventral to ­dorsal. Axons from the contralateral eye synapse in layers 1, 4, and 6; axons from the ipsilateral eye synapse in layers 2, 3, and 5. The layers of the lateral geniculate body may be categorized by neuronal size. Large, magnicellular neurons (M cells) predominate in layers 1 and 2; small, parvicellular neurons (P cells) constitute layers 3–6. At this level, visual processing is divided into at least two parallel pathways. Primate studies suggest that the parvicellular pathway involves color perception and visual resolution (high spatial frequency contrast sensitivity).3 The magnicellular pathway deals with motion detection and lower contrast, lower spatial frequency. Several authors propose additional parallel pathways.4 Primate research shows that numerous small neurons (koniocellular or K cells) sit in the interlaminar zones and superficial layers of the lateral geniculate. They receive input from the retina and the region of the superior colliculus. The koniocellular pathways apparently modulate information derived from the other two pathways.

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Fig. 9-12-1  Optic tract cross-section. Note that the parvicellular fibers run centrally and the magnicellular fibers peripherally.

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Fig. 9-12-2  Lateral geniculate body section. The layers are numbered from ventral to dorsal in this posterior view. K fibers travel between the lamellae.

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Fig. 9-12-3  Optic tract paths. Fibers that correspond to the inferior retina course rostrally and laterally into the temporal lobes to form Meyer’s loops. The superior retinal fibers take a much more direct course through the parietal lobes.

The lateral geniculate nuclei are organized by retinotopic visual field loci, as well. The macula tends to project to the caudal 75% of the nucleus. These fibers straddle the midline of the nucleus and form a rhombus. The unpaired sections of the visual fields appear to project peripherally within the nucleus. Fibers from the superior retina tend to migrate medially in the lateral geniculate nuclei; those from the lower retina tend to move laterally.

OPTIC RADIATIONS Axons arising in the lateral geniculate nuclei form the optic radiations and project to the calcarine cortex. Superior retinal fibers course inferiorly in the radiations and the inferior retinal fibers migrate superiorly (Fig. 9-12-3). Axons corresponding to central vision travel between the two other bundles.5 The fibers from the inferior retina travel deep within the parietal lobe relatively close to the internal capsule and to a tract that carries pursuit information from both occipital lobes to the ipsilateral paramedian pontine reticular formation. The superior retinal fibers course ventrally into the temporal lobe in an arc (Meyer’s loop) around the temporal horn of the lateral ventricle.6 These geographical relationships gain considerable importance in localizing a lesion of the visual pathways.

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Information from the optic tracts projects to the calcarine cortices of the medial occipital lobes. This visual cortex performs multiple processing functions to prepare information for detailed analysis elsewhere in the brain. The visual cortex (Brodman area 17, V1) straddles the calcarine sulci. The surface area of the visual cortex ranges from 20 to 25  cm2 and ­occupies approximately 3.5% of the surface area of the brain. The neurons of area 17 receive information via the myelinated stripe of ­Gennari. Information from central vision projects to the caudal half of the visual cortex, while peripheral vision projects rostrally. The visual cortex contains multiple identifiable layers of cells. Layer I, the most superficial, contains small granule cells and a few horizontal cells; layer II consists of pyramidal neurons and numerous ­interneurons; and layer III contains pyramidal and granule cells. Layer IV contains three subdivisions – IVa consists of stellate neurons, IVb contains ­ predominantly granule cells, and the deepest stratum, IVc,

contains granule, pyramidal, and stellate cells. Input from the optic tracts tends to terminate in layer IVc.6 Layer V contains numerous pyramidal cells. Layer VI demonstrates fewer neurons but stains darkly because of star pyramids. The calcarine cortex plays a smaller role in visual processing than previously theorized. It is a coordination center, where information from both hemifields is paired into parallel, vertically oriented, ocular dominance columns.7 Small regions of the visual field are analyzed in the primary visual cortex by an array of complex cellular units called hypercolumns. A single hypercolumn analyzes a discrete region of the visual field. Each hypercolumn contains a complete set of the orientation columns, which represents 360°, a set of left and right ocular dominance columns, and several blobs (regions of the cortex where cells are specific for color). These hypercolumns merge data from corresponding points in each retina. Because the temporal field from the contralateral eye is considerably larger than the nasal field from the ipsilateral eye, each calcarine cortex receives unpaired information from the contralateral eye; this forms the “temporal crescent.” This information is processed most anteriorly and aids in the diagnosis and localization of occipital lobe lesions. Connections between the two hemispheres via the corpus callosum allow synchronization and combination of information generated by both fields.8, 9 The visual cortex contains four basic types of cells that respond in specific and characteristic ways to retinal stimuli.10 Circularly symmetrical cells react to small lights independent of movement or orientation. Simple cells respond to a moving light or a dark line or pattern with a specific orientation and direction of motion that projects on the center of their field. Simple cells may turn either “on” or “off” in response to the stimulus. Complex cells respond to linear stimuli almost anywhere in their field but are less specific as to orientation. They also may be “on” or “off” cells. Hypercomplex cells are similar to complex cells but require a linear stimulus of a specific length. The information generated among all these cells is synchronized through the extensive interconnection between visual cortical areas.11 As a result of this exchange of information, certain stimuli in patterns “pop out” and catch an individual’s attention, while other details (small gaps in a large pattern especially outside the central 15º or the defect associated with the blind spot) may “fill in” and disappear into the background.12

TOPOGRAPHICAL DIAGNOSIS OF RETROCHIASMAL DISEASE Lesions involving the visual pathways tend to produce some form of homonymous hemianopia. A total homonymous hemianopia involving the temporal crescent is nonlocalizing. In most cases, however, careful examination of the visual field and associated clinical findings yields clues to the location of a lesion. Lesions isolated to the optic tracts account for less than 5% of patients with a homonymous hemianopia. Injury to the optic tracts tends to produce exceedingly incongruous field defects. Because the optic tracts include fibers of the afferent pupillary pathway, patients with optic tract lesions tend to demonstrate a relative afferent pupillary defect in the contralateral eye and, eventually, optic atrophy on one or both sides. Patients may demonstrate a larger pupil on the side of the hemianopia (Behr’s pupil) or pupillary hemiakinesia (Wernicke’s pupil). Lesions to the lateral geniculate nuclei also tend to produce an incongruous homonymous hemianopia.13 The vascular supply of the lateral geniculate nucleus may include the adjacent thalamus and corticospinal tracts, which provides additional neurological data to localize a ­lesion clinically. Because pupillary fibers leave the optic tracts rostral to the lateral geniculate nuclei, lesions here do not produce afferent papillary defects. Lesions of the deep parietal lobe may involve the superior (superior and peripheral retinal) fibers of the optic radiations. This damage ­ results in a wedge-shaped, inferior, contralateral homonymous hemianopia (Fig. 9-12-4). Because the optic radiation fibers are still orientating themselves for cortical innervation, the hemianopia is incongruous. Because the macular fibers pass between the parietal and temporal ­ fibers, the defect generally spares central vision. The lesion may involve the posterior limb of the internal capsule and produce a contralateral hemiplegia and hemianesthesia. Involvement of the pursuit pathways, headed for the ipsilateral paramedian pontine reticular formation, tends to result in an alteration of optokinetic nystagmus – the patient cannot pursue stimuli moving toward the

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Fig. 9-12-4  Inferior, incongruous, homonymous visual field defect. Injuries to the parietal lobe tend to spare central fixation, as is characteristic of temporal lobe lesions.

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Fig. 9-12-5  Visual field defect, temporal lobe injury. Interruption of this segment of the optic radiations yields an incongruous, superior, homonymous visual field defect, more dense above than below – the “pie-in-the-sky” pattern.

side of the lesion and does not generate optokinetic nystagmus in that direction. Damage to the temporal optic radiations interrupts the inferior (inferior and peripheral retinal) fibers of Meyer’s loop. The typical visual field defect is an incongruous, wedge-shaped, superior homonymous hemianopia sparing central vision (Fig. 9-12-5). Injury to adjacent structures may yield memory loss, hearing loss, and auditory hallucinations. Lesions of the calcarine cortex tend to be silent other than for visual field defects. These defects tend to be highly congruous (Fig. 9-12-6). Preservation of the temporal crescent identifies a defect as cortical. Patients may show sparing of central vision (macular sparing); this phenomenon generally results from separate arterial supply between the occipital pole and the rostral calcarine cortex. Horton and Hoyt14 mapped the visual cortex in depth by correlating magnetic resonance imaging (MRI) findings and visual dysfunction in patients with occipital lobe lesions. Information from the central 10° of vision involves more than 50% of the caudal striate cortex. Lesions that spare only the temporal crescent are unusual; the central 1° of vision and the entire temporal crescent engage an equivalent cortical volume. Improved neuroimaging techniques now simplify the evaluation of patients with homonymous hemianopia.15 MRI is the method of choice for watershed lesions, small-vessel disease, thrombotic ­ infarction, leukodystrophy, primary or secondary neoplasia, demyelinating white matter disease, shear injuries, or contusion. The MRI should include contrast and noncontrast multiplanar T1- and T2-weighted images. Lesions dominated by blood (acute subarachnoid or ­intraparenchymal hemorrhage, for example) show poorly on MRI. Noncontrast CT ­studies are more productive in these cases. A lumbar puncture may be the only conclusive tool for finding blood.

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Fig. 9-12-6  Visual field defect, inferior left calcarine cortex lesion. Note the high congruity and involvement of fixation.

CORTICAL REPRESENTATION OF VISION INTRODUCTION The visual association areas of the brain create an image of the world through complex combinations of information from several parallel pathways. The brain separates information by position and category and correlates this information with surrounding objects and ­associated sounds (Fig. 9-12-7). The brain must maintain a reference library of previously viewed images ready for instantaneous recall that can be ­applied in unfamiliar contexts. An understanding of the relationship of cortical visual processing pathways enables the recognition of characteristic syndromes by clinical features.

OBJECT IDENTIFICATION AND MEMORY Identification of an object requires the ability to retain an image in ­memory and use this image for future comparison. A patient may be able to identify objects by touch but not by sight.16, 17 If asked to take an object, however, the patient may turn her wrist appropriately, open her hand, and grasp the object so that it does not drop. This syndrome comes from damage to the ventrolateral occipital lobes. In contrast, damage to the superior posterior parietal cortex causes difficulty in making the movements needed to manipulate objects despite a preserved ability to describe the objects and their orientation.18 One theoretical basis for this separation of function targets visual ­association areas in the medial occipital lobes.19 Injury to the right occipital lobe results in failure to identify complex objects (including faces, i.e., prosopagnosia) in general. Apparently, in many animals this area helps to sort out various types of visual stimuli.20 A lesion in the left occipital lobe yields impairment of recognition of objects with numerous parts, including words. A second theory concentrates on the connections among lobes of the brain21 and postulates that primate brains separate visual information into dorsal and ventral streams. The ventral stream originates in the primary visual cortex, projects to the inferotemporal region, and carries information needed to identify objects and their positions in space. The dorsal pathway transmits the information on size, shape, and orientation needed to grasp the object. One stream may be damaged without injuring the other. The positron emission tomography (PET) scanner has provided assistance in resolution of these two theories. Sine wave gratings yield activity restricted to the striate and extrastriate cortices.22 Faces stimulate the right parahippocampal region and both fusiform and anterior temporal cortices. Simple objects activate the left occipitotemporal cortex alone. Farah23 provides an excellent synopsis of the theories of image generation. Lack of image recognition, however, does not mean an individual cannot see an image clearly.24 Patients with prosopagnosia fail in selecting two matching faces from a picture set. Invert the faces, however, and the patients fare much better. Inverting the face apparently allows the brain to treat faces as simple objects.

Retrochiasmal Pathways, Higher Cortical Function, and Nonorganic Visual Loss

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The association of alexia with damage to the angular gyrus may represent a Western bias. Sakurai et al.33 reported a patient who had alexia with agraphia for Japanese characters (kanji). The patient also suffered problems with names. Scans indicated an infarct involving the dominant inferotemporal and fusiform gyri from the temporo-occipital junction to the anterior one third of the temporal lobe. The authors postulated a disconnection of fibers to the parahippocampal region. They suggested that pictographs are processed differently from words composed of letters. They questioned whether a similar lesion might have an impact on reading irregular words in English. Dyslexia represents a very special form of alexia.34 By definition, patients with developmental dyslexia have a discrepancy between the acquisition of reading skills and other intellectual abilities, and this ­ disability is not related to environmental conditions, sensory deficits, or acquired neurological disorders. Investigators have failed to determine a specific site for the origin of developmental dyslexia. One proposal postulates that developmental dyslexia results from deficiencies and depletion in magnicellular pathways35 based on decreased numbers of magnicellular neurons in the lateral geniculate nuclei from postmortem studies in dyslexic patients. These patients also had decreased responses to low spatial-frequency patterns. This theory is not universally accepted, however. It has been challenged36 and the definitive answer to an anatomical cause of developmental dyslexia awaits further clinical research. Phonological dyslexia represents a disorder of association between sounds (phonemes) and letters (graphemes). Some evidence now exists that phonological dyslexia may result from abnormal development of the dominant inferior frontal lobe in areas responsible for control of tongue and lip articulator movements.

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Fig. 9-12-7  Distribution of higher order visual processing among different cortical areas. The magnicellular system (inferior stream) is considered generally with the location and motion of objects, while the parvicellular system (superior stream) is concerned with the fine resolution (acuity), form, and color of objects.

When an image is repeated in a series, necessitating the ­ recurrent identification of the same object, the brain adds another region to the loop. The prefrontal cortex becomes active on PET scan during this task.25 Although long-term memory for vision is a temporal lobe ­function, short-term visual memory is a frontal lobe function. The inability to identify objects visually, however, does not necessarily affect a person’s generation of a mental image. Despite a deficit in naming seen objects, patients may copy visual objects, generate accurate pictures from the memory of an object, or draw a picture based upon tactile examination of an object.26 Ironically, when shown these drawings, patients do not recognize them as their own. Stimulation of storage areas may produce accurate visual hallucinations that may occur as a release phenomenon resulting from visual loss27 or abnormal electrical stimulation.28 Visual hallucinations may result in isolated midbrain injury,29 although the exact mechanism ­remains undetermined.

READING AND DYSLEXIA

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Reading represents a very specialized form of visual processing. The ­unimpaired reader can recognize even sloppy and garbled writing. ­Multiple regions of the brain are involved, and injury to any of these areas produces recognizable syndromes. The primary center for reading and writing language appears to be in the dominant angular gyrus in the parietal lobe.30 Alexia (the inability to read) with agraphia (the inability to write) results from destruction of this area; exceptions to this rule do exist.31 Alexia without agraphia results from disconnection of the dominant angular gyrus from input from both occipital lobes.32 This syndrome most ­commonly results from an infarct in the distribution of the left ­posterior cerebral artery.

The pathway for the interpretation of color remains separate from those responsible for object identification.37 PET scanning findings indicate that the lingual and fusiform gyri become stimulated when a normal individual scans for a colored target.38 Patients who have lesions that cause visual agnosia may maintain the ability to identify the color of objects.39 Patients who have acquired, central cerebral achromatopsia (inability to identify colors) may have complete loss or miss only one primary color.40 The isolation of single color defects links with research performed in macaque monkeys, which showed that an area of prestriate cortex, identified as area V4, contains neurons that respond to specific color stimuli.41 Patients with cerebral achromatopsia generally describe objects as “washed out” or “faded.” Patients still may be able to use contrast clues to separate the edge of one intense color from another. If two colors or a color and a shade of gray match pseudoisochromatically, however, patients demonstrate a distinct inability to isolate colored targets. Despite the achromatopsia, other parts of the parvicellular system may remain intact. Patients may have normal visual acuity and contrast sensitivity. Postmortem and radiological studies of these patients reveal bilateral lesions of the inferior occipital cortex.

INTEGRATION OF VISUAL–AUDITORY SPACE The brain frequently receives contradictory information from the ­visual and auditory systems. For example, when an individual watches a movie, an image is seen directly ahead, but sounds are heard from numerous speakers throughout the theater. The brain integrates this information to provide a meaningful and logical integrated experience. The ability to reconcile auditory and visual cues appears to be learned.42 This reconciliation is a complicated task, because visual ­information is received by direct stimulation of an individual retina, while auditory localization requires a binaural triangulation of sound. The complexity heightens when the individual or the target moves. The brain prioritizes visual input.43 If a sound seems to originate from a seen object, the brain transfers the perception of that sound to the visible source. The process of correlation occurs in the midbrain tectum.

MOTION DETECTION Once the brain identifies an object, it must localize that object in relation to the perceiver and the environment, and determine the relative rate of motion of the object to the perceiver. The observer also may be

NONORGANIC VISUAL LOSS Nonorganic (or functional) visual loss represents one of the most difficult challenges faced by ophthalmologists. Patients affected by organic disease demonstrate true concern about their condition, but patients with nonorganic complaints may go out of their way to confuse or mislead the examiner or, alternatively, show no concern for the problem. Nonorganic visual loss represents a visual complaint that is not explained by physical examination or ancillary testing. Purported visual disturbances may vary from mild visual blurring or focal visual field defects to a complete loss of light perception. Nonorganic visual loss falls into one of two categories – conversion reaction or malingering. Patients with a conversion reaction, previously called hysterical blindness, react to environmental stress. Adolescents seem particularly prone to this kind of response. By becoming “blind,” individuals may justify perceived or real failure as no fault of their own; if one cannot see, one cannot perform. Such individuals gain an apparent resolution of psychological conflict. Because a conversion reaction alleviates tension, patients generally show a flat, relaxed affect despite severe visual complaints. Patients with a conversion reaction appear to honestly believe they are disabled, even when initially confronted with evidence to the contrary. They tend to be cooperative with testing. By cooperating, these patients readily display behavior that contradicts their complaints. Malingering patients mimic visual loss consciously to obtain an external secondary gain. Their visual complaints appear out of proportion to the underlying original injury. Such patients may seek medical advice at the behest of an attorney and have received coaching in advance. Malingerers pay close attention to the actions of an examiner and try to circumvent tests. Physicians must take great care, because any conclusions may require documentation for a judge and jury. An accurate visual acuity assessment may not be obtainable for a patient who has nonorganic visual loss. Fortunately, all the examiner must do is to demonstrate that the patient’s vision is significantly ­better than stated. To evaluate patients who have nonorganic visual loss, the examiner starts with the smallest letters possible, in most cases the 20/10 (6/3) line. The physician should pause at each letter and demonstrate concern and confusion that the patient cannot identify these letters. After making the point that the next letters are much larger, the examiner shifts to the 20/15 (6/4.5) line and repeats the process. By the time the patient looks at the 20/20 (6/6) or 20/25 (6/7.5) line, the power of suggestion has set in and the patient generally is convinced the letters are now large enough to read. This technique works well with complaints of either monocular or binocular visual loss. A 4-diopter prism is an indispensable tool in the evaluation of the visual acuity of patients who have nonorganic monocular visual complaints. The examiner occludes the patient’s “bad” eye, then places the prism over the patient’s “good” eye such that the base is up and the apex splits the pupil. If the prism is positioned in just the right spot, the patient experiences monocular vertical diplopia. The examiner asks the patient if both of the perceived lines appear equally clear; the ­answer will be “yes.” Once the patient is certain that this test measures

CHARACTERISTIC ‘TUNNEL’ FIELD OF NONORGANIC VISUAL FIELD LOSS 30

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Fig. 9-12-8  Characteristic “tunnel” field of nonorganic visual field loss. Paradoxically, the visual field appears to expand as the patient approaches the screen. Such a pattern does not correspond to any known ocular or central nervous system lesion.

the function of the “good” eye, the tester simultaneously uncovers the “bad” eye and slides the prism downward to cover the “good” eye completely. The patient now experiences binocular diplopia but intellectually remains convinced of a monocular phenomenon. At this point, the patient often reads well down the eye chart without hesitation, even when asked to attend to the upper line that corresponds to the “bad” eye. A very accurate measure of visual acuity may be obtained for otherwise uncooperative patients. The red–green eyeglasses provided with the Worth four-dot test may be useful. The examiner asks the patient to put on the glasses and then inserts the red–green filter installed in the vision chart projector. The patient sees the letters on the red half of the eye chart with the eye covered by the red lens and the letters on the green half with the eye covered by the green lens. The patient often progresses well down the eye chart before realizing over-achievement has occurred. The red–green eyeglasses may be used with the Ishihara color plate series, as well. If a patient complains of poor vision in one eye, have the patient put on the red–green glasses with the green lens over the “good” eye and the red lens over the “bad” eye. Under normal circumstances, an individual can read the Ishihara numbers through the red lens but not the green lens. If the subject who has nonorganic complaints reads the numbers under the above circumstances, this discrepancy confirms better-than-stated ocular function. Ophthalmologists often use phoropters and trial frames to confuse patients and obtain a measure of visual acuity. These methods generally fail, however, when patients are malingerers. In both circumstances, patients may close an eye surreptitiously and determine that these are tests of deception. Optokinetic nystagmus only helps ascertain that ­vision is grossly intact in each eye. Perimetry remains an excellent tool for the evaluation of nonorganic complaints. Both confrontational and tangent screen techniques yield the best information, because they allow variable test distances. Patients who are determined to produce a factitious visual field defect may confound Goldmann and automated perimetry techniques easily, however. The most common defect discovered during perimetry is a tunnel field. If a visual field is constricted because of organic disease, the absolute size of an isopter for a given test object increases as the distance from the screen increases. Patients who have tunnel fields, however, tend to have field constriction, but they always generate the same absolute size of an isopter on the tangent screen no matter what the test distance (Fig. 9-12-8). The examiner may enhance this tendency by using large, easily discriminated pins to mark the edge of an isopter. Testing at two distances is necessary, however, because several medical conditions (end-stage glaucoma, end-stage papilledema, tapetoretinal degeneration, chiasmal compression, or bilateral occipital lobe infarcts) may produce authentic generalized constriction of the visual field. The tangent screen may prove useful in another way for the evaluation of patients who have unilateral visual complaints. In one method the visual field is tested for the “good” eye and the location of the blind spot determined. The examiner then tests the “bad” eye and elicits the characteristically small tunnel field inside the blind spot. Finally, the physician evaluates the patient with both eyes open. Patients who have

9.12 Retrochiasmal Pathways, Higher Cortical Function, and Nonorganic Visual Loss

moving, and multiple environmental targets may be moving in ­different directions. The brain has developed efficient mechanisms to resolve these factors. Injuries may result in the ability to perceive motion in an otherwise blind field or to lose motion detection while the image of the object is preserved.44, 45 The primary step in motion detection involves neurons in area V1 of the calcarine cortex supplied by the magnicellular pathway. Motionsensitive neurons react to movement in a specific direction.46 The information from these individual neurons then travels to an area (referred to as MT or V5) in the medial temporal lobe. In primates, MT sits in the posterior segment of cortex, bordering the superior temporal sulcus. Almost 100% of the neurons in MT demonstrate directional sensitivity. Evidence suggests that MT represents the first area in which the information related to motion becomes attached to a texture, color, or pattern.47 Unfortunately, for simplistic views of motion detection, a moving object in the environment generates multiple bits of information in the MT region. Some bits may appear contradictory. The brain must integrate these signals to form one coherent, 3-dimensional representation of relative motion. Approximately 25% of neurons in MT do not react just to linear motion in a single direction but react to motion in multiple vectors. These cells may be responsible for motion integration.

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nonorganic complaints frequently lose the blind spot from the “good” eye, even though the claimed field for the “bad” eye was smaller than 10°. Occasionally, patients tested in this manner may yield totally inexplicable and impossible visual field changes under binocular conditions. For example, a patient who has a full field in one eye and a tunnel field in the other may report a hemifield loss on the side of the “bad” eye with both eyes open. Should a patient claim severe bilateral vision loss and be noncompliant on perimetry testing, the examiner must take every opportunity to observe the patient’s behavior. If a call to the patient from a distance results in an accurate fix on the examiner’s location by the patient, a peripheral field much larger than stated is indicated. Patients who have small, bilateral tunnel fields may be able to maneuver easily without bumping into objects. Patients may pick up or take objects held well away to one side, which indicates they can see the objects. Finally, patients who feel no one is watching may perform tasks inconsistent with their level of claimed disability. Tests for stereoscopic vision may assist the evaluation of patients who have nonorganic complaints. Most methods for stereopsis evaluation require good peripheral fields and good visual acuity in both eyes. Patients often become intrigued with the challenge of stereoacuity testing and perform at a level well beyond that claimed under other conditions. The examiner may be able to use motility testing to advantage. If a patient complains of a tunnel field, the tester should evaluate saccades initially with two targets very close together. The examiner gradually ­increases the distance between the two targets and asks the patient to continue to make saccades back and forth. Because a saccade requires voluntary generation to a visible target, patients who have organic ­visual loss do poorly, but those with nonorganic complaints may perform well. Appropriate evaluation of the pupils constitutes a critical part of the examination of patients who have nonorganic disorders. Asymmetrical visual acuity or field loss between the two eyes must result from intraocular disease or lesions of the optic nerves. Although intraocular disease may not cause an afferent pupillary defect, the examiner usually is

able to identify the lesion visually. Unilateral optic nerve disease must produce a relative afferent pupillary defect on the side of the lesion. A patient who complains of markedly poor vision in one eye only, has normal ocular examination findings, and a normal response of the pupils to a light in the “bad” eye is likely to have a nonorganic syndrome. Ancillary testing, in certain circumstances, may prove helpful. If a patient generates complaints or findings that suggest a retrochiasmal lesion, imaging studies may be used to identify or eliminate such a ­lesion as a cause. Should the examiner need further documentation of optic nerve function, visual evoked response testing that gives a normal latency and amplitude essentially rules out organic disease as a cause of serious injury to the optic nerve. Malingering patients, however, may prove uncooperative and thwart the efforts of the electrophysiology technician. Once the examiner has established a patient’s complaints as nonorganic, all appropriate findings must be documented carefully in the patient record. The physician must perform all critical tests in the presence of a reliable witness who can corroborate the results in a courtroom. Patients who have a conversion reaction, in most instances, respond very favorably to a report of a healthy visual system. The physician must remember that these patients’ complaints stem from anxiety; assuaging that anxiety allows the patient to “recover” without stigma. Only in unusual circumstances does the patient require the assistance of a psychiatrist. The patient and family must understand that a conversion reaction represents an adaptation to stress; they must work to alleviate the cause of this stress to prevent the development of other somatic complaints. Malingering patients react poorly to confrontation. Because they seek secondary gain, they immediately challenge anyone who claims they are lying. The physician approaches these patients supportively. A good approach is to state that, because the physician has not examined the patient previously, an organic lesion may have existed at one time. The examiner can then express concern and relief that the patient’s problem has resolved so well. By using this approach, the physician may avoid significant unpleasantness.

REFERENCES

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  1. Shatz CJ. Emergence of order in visual system development. Proc Natl Acad Sci U S A. 1996;93:602–8.   2. von Noorden GK, Middleditch PR. Histological observations in the normal monkey lateral geniculate nucleus. Invest Ophthalmol Vis Sci. 1975;14:55–8.   3. MISSING REF!!   4. Kier EL, Staib LH, Davis LM, et al. MR imaging of the temporal stem: anatomic dissection tractography of the uncinate fasciculus, inferior occipitofrontal fasciculus, and Meyer’s loop of the optic radiation. Am J Neuroradiol. 2004;25:677–91.   5. Meyer A. The connections of the occipital lobes and the present status of the cerebral visual affections. Trans Assoc Am Physicians. 1907;22:7–15.   6. Hubel DH, Wiesel TN. Laminar and columnar distribution of geniculocortical fibers in the macaque monkey.   J Comp Neurol. 1972;146:421–50.   7. Hubel DH, Wiesel TN. Sequence regularity and geometry of orientation columns in the monkey striate cortex.   J Comp Neurol. 1974;158:267–94.   8. Innocenti GM, Aggoun-Zouaoui D, Lehmann P. Cellular aspects of callosal connections and their development. Neuropsychologia. 1995;33:961–87.   9. Salin PA, Bullier J. Corticocortical connections in the visual system: structure and function. Physiol Rev. 1995;75:107–54. 10. Hubel DH, Wiesel TN. Functional architecture of macaque monkey visual cortex. Proc R Soc London Ser B. 1977;198:1–59. 11. Bressler SL. Interareal synchronization in the visual cortex. Behav Brain Res. 1996;76:37–49. 12. Derrington A. Vision: filling in and popping out.   Curr Biol. 1996;6:141–3. 13. Gunderson CH, Hoyt WF. Geniculate hemianopia: incongruous homonymous field defects in two patients with partial lesions of the lateral geniculate nucleus. J Neurol Neurosurg Psychiatry. 1971;24:1–6. 14. Horton JC, Hoyt WF. The representation of the visual field in human striate cortex. A revision of the classic Holmes map. Arch Ophthalmol. 1991;109:816–24. 15. Davis PC, Newman NJ. Advances in neuroimaging of the visual pathways. Am J Ophthalmol. ­  1996;121:690–705. 16. Milner AD, Perrett DI, Johnson RS, et al. Perception and action in “visual form agnosia.” Brain. 1991;114:405–28. 17. Goodale MA. Perceiving the world and grasping it: is there a difference?. Lancet. 1994;343:930–1.

18. Jakobson LS, Archibald YM, Carey DP, et al. A kinematic analysis of reaching and grasping movements in a­ patient recovering from optic ataxia. Neuropsychologia. 1991;29:803–9. 19. Ogden JA. Visual object agnosia, prosopagnosia, achromatopsia, loss of visual imagery, and autobiographical amnesia following recovery from cortical blindness: case MH. Neuropsychologia. 1993;6:571–89. 20. Mehta Z, Newcombe F, De Haan E. Selective loss of imagery in a case of visual agnosia. Neuropsychologia. 1992;30:645–55. 21. Goodale MA, Milner AD. Separate visual pathways for perception and action. Trends Neurosci. 1992;15:20–5. 22. Sargent J, Ohta S, MacDonald B. Functional neuroanatomy of face and object processing. Brain. 1992;115:15–36. 23. Farah MJ. Current issues in the neuropsychology of image generation. Neuropsychologia. 1995;11:1455–71. 24. Farah MJ, Wilson KD, Drain HM, et al. The inverted face inversion effect in prosopagnosia: evidence for mandatory, face-specific perceptual mechanisms. Vision Res. 1995;35:2089–93. 25. Ungerleider LG. Functional brain imaging studies of cortical mechanisms for memory. Science. 1995;270:769–­­­75. 26. Servos P, Goodale MA, Humphrey GK. The drawing of objects by a visual form of agnosia: contribution of surface properties and memorial representations. Neuropsychologia. 1993;31:251–9. 27. Lepare FE. Spontaneous visual phenomena with visual loss: 104 patients with lesions of the retinal and neural afferent pathways. Neurology. 1990;40:444–7. 28. Howard R, David A, Woodruff P, et al. Seeing visual hallucinations with functional magnetic resonance imaging. Dement Geriatr Cogn Disord. 1997;8:73–7. 29. Roser F, Ritz R, Koerbel A, et al. Peduncular hallucinosis: insights from a neurosurgical point of view. Neurosurgery. 2005;57:E1068. 30. Peterson SE, Fox PT, Posner MI, et al. Positron emission tomographic studies of the cortical anatomy of singleword processing. Nature. 1988;331:585–9. 31. Darius P, Boller F. Transcortical alexia with agraphia following a right temporo-occipital hematoma in a righthanded patient. Neuropsychologia. 1994;32:1263–72. 32. Imtiaz KE, Nirodi G, Khaleeli AA. Alexia without agraphia: a century later. Int J Clin Pract. 2001;55:225–6. 33. Sakurai Y, Sakai K, Sukuta M, et al. Naming difficulties in alexia with agraphia for kanji after a left posterior inferior temporal lesion. J Neurol Neurosurg Psychiatry. 1994;57:609–13.

34. Heilman KM, Voeller K, Alexander AW. Developmental dyslexia: a motor-articulatory feedback hypothesis. Ann Neurol. 1996;39:407–12. 35. Livingstone MS, Rosen GD, Drislane FW, et al. Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia. Proc Natl Acad Sci U S A. 1991;88:7943–7. 36. Sadun AA. Dyslexia at The New York Times: (mis)understanding of parallel visual processing. Arch Ophthalmol. 1992;110:933–4. 37. Humphrey GK, Goodale MA, Jakobson LS. The role of surface information in object recognition: studies of   a visual form agnosic and normal subjects. Perception. 1994;23:1457–81. 38. Gulyas B, Heywood CA, Popplewell DA, et al. Visual form discrimination from color or motion cues. Functional anatomy by positron emission tomography. Proc Natl Acad Sci U S A. 1994;91:9965–9. 39. Boyer JL, Harrison S, Ro T. Unconscious processing of orientation and color without primary visual cortex. Proc Natl Acad Sci U S A. 2005;102:16875–9. 40. Heywood C, Cowey A, Newcombe F. On the role of parvocellular (P) and magnocellular (M) pathways in cerebral achromatopsia. Brain. 1994;117:245–54. 41. Kennard C, Lawden M, Morland AB, et al. Colour identification and colour constancy are impaired in a patient with incomplete achromatopsia associated with prestriate cortical lesions. Proc R Soc London. 1995;260:169–75. 42. Miyashita Y. Neuronal correlate of visual associative long-term memory in the primate temporal cortex. Nature. 1988;335:817–20. 43. Meyer GF, Wuerger SM. Cross-modal integration of auditory and visual motion signals. Neuroreport. 2001;12:2557–60. 44. Riddoch G. Dissociation of visual perception due to occipital injuries, with especial reference to appreciation of movement. Brain. 1917;40:15–57. 45. Dnckert J, Rossetti Y. Blindsight in action: what can the different sub-types of blindsight tell us about the control of visually guided actions? Neurosci Biobehav Rev. 2005;29:1035–46. 46. Albright TD, Stoner GR. Visual motion perception. Proc Natl Acad Sci U S A. 1995;92:2433–40. 47. Braddick O. Seeing motion signals in noise. Curr Biol.1995;5:7–9.

PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

Disorders of Supranuclear Control of Ocular Motility

9.13

Patrick J.M. Lavin and Sean P. Donahue

Definition:  Loss of voluntary saccades (fast) and pursuit (slow) eye

movements result from interruption of neural pathways that carry commands from the cerebral cortex to the ocular motor nuclei in the brainstem. n Disconjugate eye movement disorders and gaze palsies result from lesions that involve the prenuclear pathways between the gaze centers and the ocular motor nuclei.

SUPRANUCLEAR CONTROL OF EYE MOVEMENTS frontal eye fields

superior colliculus parietal occipital temporal junction

Key features n n

 bnormality of voluntary saccades, pursuit or vergence eye   A movements. Preservation of reflex eye movements (vestibulo-ocular,   optokinetic, and Bell’s phenomenon).

Associated features n n n

 yramidal signs (e.g., pseudobulbar palsy, limb weakness,   P spasticity, hyperreflexia, and extensor plantar responses). Extrapyramidal signs (e.g., bradykinesia, dystonia, rigidity,   and tremor). Evidence of disorders that cause supranuclear gaze palsies   (e.g., degenerative, demyelinating, neoplastic, or vascular diseases, or traumatic).

INTRODUCTION With the exception of reflex eye movements (vestibulo-ocular and optokinetic) and the fast phases of nystagmus, cerebral structures determine when and where the eyes move, while brainstem centers determine how they move.1 The final common pathways for eye movements are located in “gaze centers” in the brainstem (Fig.9-13-1). The paramedian pontine reticular formation (PPRF) contains the premotor substrate for ipsilateral horizontal gaze. The midbrain reticular formation (MRF) mediates vertical gaze, vergence eye movements, and ocular counter rolling (Fig.9-13-2). The PPRF and MRF receive input from a number of “higher” centers, including the cerebral hemispheres, superior colliculus, vestibular nuclei, and cerebellum (see Fig. 9-13-1); they innervate the three ocular motor nuclei. Supranuclear gaze palsies result from interruption of the neural pathways that carry commands for voluntary saccades and pursuit before they reach the brainstem eye movement “generators.”

ANATOMY OF EYE MOVEMENT Anatomy of Supranuclear Eye Movement Control

Eye movements are divided broadly into the following two types (Box 9-13-1): l Fast eye movements (saccades) move the eyes from one target to another. l Slow eye movements that allow the eyes to follow (hold) a target when either the target, the head, or both are moving.

interstitial nucleus of Cajal oculomotor nucleus trochlear nucleus

abducens nucleus vestibular nucleus

rostral interstitial nucleus of the medial longitudinal fasciculus paramedian pontine reticular formation Fig. 9-13-1  Supranuclear control of eye movements. The pontine horizontal gaze center (blue) and the vertical gaze center in the midbrain (yellow) receive input from the frontal eye fields to initiate saccades, and from the parietal   occipital temporal junction to control pursuit. These gaze centers control   ocular motility by innervating the ocular motor nerve nuclei (III, IV, and VI).

Slow eye movements may be conjugate (e.g., pursuit,) or disconjugate (e.g., vergence).2 The initiation and generation of saccadic and pursuit eye movements is complex and dealt with in greater detail elsewhere;1–3 a simplified overview is given here. The fast phases of nystagmus (Chapter 9-18) also are saccades (see Box 9-13-1).

Horizontal Eye Movements

The contralateral frontal lobe, particularly the frontal eye field, is responsible for generating horizontal saccades. Each frontal eye field projects to the contralateral PPRF, which innervates the abducens nucleus. Pursuit eye movements are triggered by the ipsilateral posterior ­parietal lobe (see Fig. 9-13-1), which projects to the PPRF and then to the ­abducens nucleus. About 60% of the neurons in the abducens nucleus innervate the ipsilateral lateral rectus muscle; the remaining 40% are interneurons that project, via the medial longitudinal fasciculus (MLF), to the contralateral medial rectus subnucleus in the oculomotor nuclear complex (Fig.9-13-3). Thus, activation of the PPRF or the abducens ­nucleus generates ipsilateral horizontal gaze; conversely, damage to either of these structures results in an ipsilateral gaze palsy.

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9

EYE POSITION DURING HEAD TILT Normal ocular counter-rolling reflex

THE VESTIBULO-OCULAR REFLEX AND ITS CONTRIBUTION TO OCULAR MOVEMENTS

NEURO-OPHTHALMOLOGY

gaze left left eye

right eye

medial longitudinal fasciculus Ocular tilt reaction

• VIth cranial nerve

3

3

6

6 •

•

IIIrd cranial nerve paramedian pontine reticular formation •

ampulla horizontal semicircular canal vestibular nuclei

Fig. 9-13-2  Eye position during head tilt. The normal ocular counter-rolling reflex maintains relative eye position when the head is tilted. As the head tilts to the left, the right eye excyclotorts and depresses while the left eye rises and ­incyclotorts. The ocular tilt reaction occurs after stroke and is paradoxical. ­Patients have a head tilt, bilateral torsion, and a sense of a torted vertical   meri­dian, all to the same side.

BOX 9-13-1 TYPES OF EYE MOVEMENTS SACCADES OR FAST EYE MOVEMENTS (VELOCITY UP TO 800/SECOND) Voluntary (internally triggered) Reflexive (externally triggered – by visual or auditory stimuli) Spontaneous (searching, rapid eye movements of sleep) Fast phases of nystagmus (physiological or pathological)

Pursuit Eye Movements

SLOW EYE MOVEMENTS (VELOCITY UP TO 70/SECOND) Smooth pursuit l Foveal pursuit l Full-field pursuit (optokinetic slow phase) Vestibular slow phase (includes torsional movements) Vergence

Pursuit eye movements allow the eyes to track a moving object at velocities up to 70 degrees/second and have a latency of about 125 milliseconds.2 The generation of pursuit eye movement consists of three essential elements:1, 3 l A sensory component driven by an image moving across the fovea. l A motor component generated near the parieto–occipito–temporal junction that projects to the ipsilateral PPRF. l An attentional–spatial component for concentration on selected ­targets, orientation in space.

OTHER OCULAR OSCILLATIONS (E.G., OPSOCLONUS, FLUTTER)

Vestibular System

Vertical Eye Movements

The premotor substrate for vertical gaze lies primarily in the MRF. The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) contains neurons for both upward and downward saccades. Their axons relay to neurons in the interstitial nucleus of Cajal, which discharge in relation to vertical eye position and play a role in vertical pursuit and eye position. The neurons for upward saccades innervate both ­ipsilateral and contralateral oculomotor and trochlear nerve nuclei (Fig. 9-13-4). The neurons that mediate downward saccades only innervate the oculomotor and trochlear nerve nuclei bilaterally (see Fig. 9-13-1). The riMLF and the interstitial nucleus of Cajal also are involved in the generation of ipsilateral torsional eye movements. The supranuclear pathways for vertical saccades travel from both frontal eye fields to innervate the riMLF on each side in the MRF (Fig. 9-13-4). Vertical saccades require simultaneous activation of both frontal eye fields.

Slow Eye Movements

1002

Fig. 9-13-3  Vestibulo-ocular reflex and its contribution to horizontal eye movements. The semicircular canals respond to rotational acceleration of the head by driving the vestibulo-ocular reflex to maintain the eyes in the same direction in space during head movement. Fibers from the horizontal semicircular canal travel first to the vestibular nuclei and then to each paramedian pontine reticular formation. Excitatory projections that travel to the contralateral sixth cranial nerve nucleus and, via the medial longitudinal fasciculus, to the ipsilateral medial rectus subnucleus cause gaze to the left. In a similar manner, inhibitory projections are sent to the antagonist ipsilateral lateral rectus and contralateral medial rectus.

Slow eye movements help maintain fixation on a target in order to ­stabilize the image on the fovea when either the subject or object is moving. Four types of slow eye movements occur, namely pursuit, optokinetic, vestibular, and vergence.

Vestibular eye movements maintain foveation when the head moves in any direction or plane, including the horizontal (yaw), vertical–sagittal (pitch), or vertical–coronal (roll) planes. For example, if the subject’s head turns 10 degrees to the right, the eyes rotate 10 degrees to the left to maintain fixation (see Fig. 9-13-2). The latency for vestibular responses is about 10 milliseconds.

Optokinetic System

The optokinetic system complements the vestibulo-ocular system when it becomes inadequate, such as with sustained head rotation when the eyes reach the limit in the orbit. In humans the optokinetic system is tested predominantly by foveal fixation and pursuit and, to a lesser ­extent, by moving visual field stimulation. The latter is tested ­clinically by rotating an image of the environment around the patient or by ­turning the patient in a revolving chair so the environment appears to be moving relative to the patient.

Vergence System

The vergence system enables eyes to move disconjugately in the horizontal plane and allows binocular fixation of an object that moves ­toward (convergence) or away (divergence) from the subject. The main stimuli for vergence movements are retinal blur (object unfocused) and diplopia (fusional disparity); convergence is associated with a­ccommodation and

Fixation

PATHWAYS FOR VERTICAL GAZE Upgaze aqueduct

INC

RIMLF

RN

RIMLF

RN INC IO SR SO

CNIII

Pursuit

RN

SR

IO

RN SN

CNIV

Downgaze PC

aqueduct

INC

RIMLF

RN

RIMLF

RN INC IR SO

CNIII

RN

IR

Vergence Eye Movements

RN

A target is moved toward (convergence) and then away (divergence) from the patient, who follows it.

SN CNIV

The patient is asked to fixate a small object, such as a pencil, and ­follow it slowly through the extent of horizontal and vertical versions; the patient’s eyes should pursue the target smoothly. If the pursuit system is defective, or the target moves too quickly, the eyes fall behind and make “catch-up saccades” to refixate the target. This produces saccadic or cogwheel pursuit. Pursuit also may be evaluated while testing the patient’s ability to suppress the vestibulo-occular reflex (VOR). Have the patient sit on a rotatable stool and fixate one of his or her own thumbs at arm’s length, then rotate the stool so that the patient’s head, arm, and thumb move as one. A normal patient can suppress the induced VOR by maintaining fixation on the thumb, even in darkness or with the eyes closed – VOR suppression probably involves the same pathways as smooth pursuit.6 Because blind patients also can suppress the VOR, this technique particularly helps to differentiate between real and psychogenic visual deficits – psychogenic patients appear unable to follow a target smoothly.

CNIII

9.13 Disorders of Supranuclear Control of Ocular Motility

PC

The patient looks at a stationary, accommodative target projected in the distance, while the examiner checks fixation both monocularly and binocularly. Fixation should be steady without nystagmus or other significant ocular oscillations. Small eye movements, such as square wave jerks of less than 1–2  degrees, are normal and do not interrupt fixation.5

Ocular Alignment

Ocular alignment is covered in more detail in the section on strabismus (Chapter 11-3). Ocular alignment should be determined by simultaneous prism and cover testing (for tropias) and by alternate cover testing (for phorias, and to measure the basic deviation) while in the proper cycloplegic refraction, and fixating an accommodative target.

SO

Differentiating Supranuclear from Nuclear and Infranuclear Lesions

If the patient has a gaze palsy, the physician determines whether the eyes can be moved reflexively in the direction of the “paresis” in the following two ways: Fig. 9-13-4  Pathways for vertical gaze. Upgaze pathways originate in the rostral interstitial nucleus of the medial longitudinal fasciculus and project dorsally to innervate the oculomotor and trochlear nerves, traveling through the posterior commissure. Lesions to both axon bundles are necessary to produce upgaze paralysis (lesions B or C). Upgaze paralysis is a feature of the dorsal midbrain syndrome as a result of the lesion’s effect on the posterior commissure (lesion A). Downgaze pathways also originate in the rostral interstitial nucleus of the medial longitudinal fasciculus but probably travel more ventrally. Bilateral lesions also are needed to affect downgaze and usually are located dorsomedial to the red nucleus. INC, interstitial nucleus of Cajal; IO, inferior oblique subnucleus; IR, inferior rectus subnucleus; PC, posterior commissure; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; RN, red nucleus; SR, superior rectus subnucleus.

pupillary miosis (the near triad). The pathways that generate vergence eye movements are not known precisely, but the occipital lobe, midbrain, and cerebellum play significant roles.

DIAGNOSTIC TESTING Techniques used in the examination of the ocular motor system fall into six categories, reviewed in detail by Borchert.4

Saccades

The patient is asked to alternate fixation rapidly between two targets, such as a finger and the examiner’s nose. Both horizontal and vertical saccades are tested and observations are made with respect to latency, velocity and accuracy. Abnormalities in saccadic accuracy include overshooting or ­undershooting the target and are referred to as saccadic dysmetria and indicate cerebellar pathology. Gross abnormalities are clinically obvious, but detection of subtle changes require quantitative oculography.3

Oculocephalic (doll’s eyes) reflex

The oculocephalic (doll’s eyes) reflex is performed by tilting the head forward 30 degrees and fixating a distant target. The head is then ­rotated in the direction opposite the gaze palsy. This maneuver uses direct ­projections from the vestibular system to the ocular motor nuclei (see Fig. 9-13-3). Gaze palsies caused by lesions of the cerebral cortex can typically be overcome by vestibulo-ocular testing. In prenuclear, nuclear, or infranuclear lesions, the reflex does not overcome the palsy.

Vestibulo-ocular reflex testing

The patient’s head is tilted back 60 degrees and the external auditory meatus irrigated with either cool or warm water to stimulate the ­horizontal semicircular canal. In normal subjects and patients who have supranuclear gaze palsies, cool water stimulation causes the eyes to ­deviate slowly toward the irrigated side, which results in nystagmus with the fast (corrective) phase to the opposite side. When warm water is used the fast phase is toward the stimulated ear. The mnemonic COWS (cool, opposite, warm, same) refers to the direction of the fast phase of the nystagmus. In comatose patients no corrective (fast) phase occurs, so with cold water the eyes deviate tonically toward the irrigated ear. Simultaneous bilateral caloric testing may be used to evaluate vertical eye movements, but this is less reliable than oculocephalic testing.4

DISORDERS OF SUPRANUCLEAR OCULAR MOTILITY Supranuclear ocular motility disturbances result from interruption of the neural pathways before they reach the eye movement generators. They may be divided into two groups – disorders of gaze and disorders of vergence eye movements. Gaze palsies affect conjugate eye ­movements and are characterized by loss of voluntary gaze, in one or more ­ directions, while sparing reflex movements, such as the VOR,

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9 NEURO-OPHTHALMOLOGY

­ ptokinetic ­ nystagmus (OKN), and Bell’s phenomenon. Disorders of o vergence eye movements are disconjugate. Skew deviation and the ­ocular tilt reaction, which also spare the final common pathway for extraocular eye movements and are technically supranuclear, may also affect reflex eye movements and are referred to in this chapter as prenuclear.1

Congenital Gaze Palsies

Congenital ocular motor apraxia (COMA) or, more correctly, congenital saccadic palsy,5, 7 is more common in boys than in girls; these children find it difficult to initiate saccades and have variable impairment of pursuit. Vertical eye movements remain intact. In early infancy, blindness may be suspected because of the inability to fixate or follow objects. However, after a few months head control is achieved and the patient moves the eyes by thrusting the head in the direction of the target. As the head overshoots the target, the eyes follow the head movement and take up fixation. The head thrusts, usually accompanied with blinks, become less noticeable with time. Confirmation of saccadic palsy is made by spinning the infant around the examiner (Fig. 9-13-5).8 The eyes move conjugately and slowly in the direction of the spin but, ­because of the impaired saccades, no corrective horizontal fast phases are seen. COMA may be associated with abnormalities in the cerebellum and posterior fossa, and may have associated developmental delay. Ocular motor disorders resembling COMA may be seen in a number of conditions, including Aicardi’s syndrome, dysgenesis of the corpus callosum or cerebellum, ataxia telangiectasia, Cockayne’s syndrome, Joubert’s syndrome, Pelizaeus-Merzbacher’s disease, and succinic semialdehyde dehydrogenase deficiency. Congenital vertical ocular motor apraxia is rare9 and must be differentiated from metabolic and degenerative disorders, such as neurovisceral lipidosis, and from stable disorders such as birth injury, perinatal hypoxia,10 and, occasionally, Leber’s congenital amaurosis. Familial horizontal gaze palsy with scoliosis (HGPS) is an autosomal recessive disorder characterized by paralysis of horizontal gaze from birth, progressive scoliosis, impaired optokinetic reflex, and VOR, but intact convergence and vertical eye movements. Some patients may have fine pendular horizontal nystagmus, facial myokymia, facial twitching, hemifacial atrophy, and situs inversus of the optic discs.3, 11

Acquired Gaze Palsies

1004

TEST FOR THE VESTIBULO-OCULAR REFLEX

Acquired horizontal supranuclear gaze palsies may occur with stroke, head injury, tumors, seizures and, rarely, with metabolic disease. This subject is reviewed in detail elsewhere.1 Because these patients have cognitive dysfunction, they can be difficult to examine. Acute hemisphere stroke can cause a transient gaze deviation.12 Usually, the eyes are deviated toward the side of the lesion because of paresis of gaze to the hemiplegic side. After about 5 days the intact hemisphere usually takes over and both the gaze paresis and ocular deviation resolve. Ictal conjugate ocular deviation (seizure activity) occurs as a result of irritative lesions.13, 14 Such lesions “activate” the involved frontal eye field and cause the eyes to deviate away from the damaged hemisphere (adversive gaze deviation). Usually, such ocular deviation is associated with or immediately followed by adversive nystagmoid eye movements. It later is followed by postictal paralytic conjugate ocular deviation, in which gaze is deviated transiently toward the involved hemisphere, as part of Todd’s paralysis. The PPRF may be injured by a variety of lesions including ischemia, hemorrhage, neoplasm, infection, demyelination, and paraneoplastic disorders. A lesion that affects the ipsilateral abducens nucleus or PPRF causes an ipsilateral gaze palsy. A rostral PPRF lesion spares the VOR, whereas a caudal lesion does not. As a result of the proximity of the abducens nucleus and the facial nerve fasciculus, ipsilateral facial weakness typically occurs with caudal PPRF lesions. Rarely, the firstorder (central) sympathetic fibers may be involved, causing an associated ipsilateral Horner’s syndrome.15 Wrong-way eyes is the term given to conjugate eye deviation to the “wrong” (hemiplegic) side, that is away from the lesion and toward the hemiplegic side (contraversive gaze deviation).16 It may occur with ­supratentorial lesions, particularly thalamic hemorrhage and, rarely, with large perisylvian or lobar hemorrhage or irritative lesions (below). Incomplete lesions of the PPRF result in difficulty maintaining ­eccentric gaze and produce gaze-paretic, or gaze-evoked, nystagmus. When the eyes drift back to the primary position, the patient makes corrective saccades back to the eccentric target, which results in gaze-evoked nystagmus.

Fig. 9-13-5  The child is spun around the examiner to test the vestibuloocular reflex. The slow tonic phase produces gaze in the direction of the spin; fast phase corrective saccades occur to drive the eyes back. In congenital ocular motor apraxia (congenital saccadic palsy), fast phases are absent and the eyes are driven tonically in the direction of the spin.

Bilateral lesions of the PPRF may cause complete loss of voluntary horizontal gaze. Large lesions may extend into the ventral pons, injuring the corticospinal pathways, and render the patient quadriplegic; this combination of findings is referred to as the locked-in syndrome.17 Such patients appear unconscious, but volitional vertical eye and lid movements are spared, differentiating the locked-in syndrome from coma. Ocular bobbing can occur in this setting (Chapter 9-18). Slow saccades occur with pontine disease, some forms of cerebellar degeneration involving the pons, and a number of disorders listed in Box 9-13-2.1

Disorders of Pursuit

The horizontal pursuit pathways control ipsilateral tracking. The final common motor pathway extends from the parieto–occipito–temporal junction, via the dorsolateral pontine nuclei, to the ipsilateral gaze center in the PPRF. With rare exceptions, lesions of the pursuit pathways cause impaired ipsilateral tracking; because the pursuit pathways probably decussate twice,18 a unilateral midbrain lesion can cause impaired contralateral pursuit.19 The frontal eye fields, superior colliculi, and cerebellum also contribute to pursuit drive. Pursuit deficits range from absence of tracking eye movements to saccadic (cogwheel) pursuit. Global impairment of smooth pursuit is a common, nonspecific finding. Injury to the pursuit pathways also affects the slow phase of OKN, easily demonstrated by rotating an optokinetic drum so that the stripes move toward the affected hemisphere. Because of the proximity of the pursuit pathways to the afferent visual pathways, lesions here often are associated with a contralateral homonymous hemianopia. Balint’s syndrome is characterized by these essential features: apraxia of gaze (inability to voluntarily look at different parts of the visual field), simultanagnosia (inability to attend simultaneously to different parts of the visual field), and optic ataxia (mislocalization when reaching for, or pointing to, objects). Bilateral hypoperfusion of the parieto-occipital region, usually as a result of a prolonged episode of hypotension, may case watershed (distal territory) infarction.

Internuclear Ophthalmoplegia

Injury to the MLF, between the abducens nucleus and the contralateral medial rectus subnucleus of the oculomotor nerve, interrupts transmission of neural impulses to the ipsilateral medial rectus muscle (see Fig. 9-13-3). This impairs adducting saccades of the ipsilateral eye, which become either slow or absent. On attempted lateral gaze, away from the side of the lesion, the abducting eye overshoots the target (dysmetria), giving the appearance of dissociated (disconjugate) nystagmus. If the internuclear ophthalmoplegia (INO) is bilateral, abduction saccades also may be slow because of impaired inhibition of resting tone in the

BOX 9-13-2 Causes of Slow Saccades

medial rectus muscle. Upward beating and torsional nystagmus are present frequently, particularly if both MLFs are affected. A subtle INO may be demonstrated when the patient makes repetitive horizontal ­saccades, which disclose slow adduction of the ipsilateral eye. Convergence may be preserved. Other clinical features associated with INO include skew deviation, defective vertical smooth pursuit, impairment of the vertical VOR, as well as impaired ability to suppress or cancel the vertical VOR. INO also may occur with a variety of disorders that affect the ­brainstem (vascular, demyelinating, and metastatic) and must be ­ differentiated from the pseudo-INO of myasthenia or a long-standing exotropia. The one-and-a-half syndrome occurs with damage to the caudal pons that involves the ipsilateral MLF and either the ipsilateral PPRF or the abducens nucleus. It results in an ipsilateral gaze palsy with an ipsilateral INO (see Fig. 9-13-3). The only intact horizontal movement is ­abduction of the contralateral eye. If the facial nerve nucleus or fasciculus is involved, oculopalatal myoclonus (a vertical oscillation of the eyes, palate, and other muscles of branchial origin) may develop later.20 The most common causes of the one-and-a-half syndrome are ­multiple sclerosis and brainstem stroke, followed by metastatic and primary brainstem tumors.21 Ocular myasthenia may cause a pseudo-one-and-a-half syndrome.22

Disorders of Vertical Gaze

Isolated midbrain lesions can cause disorders of vertical gaze (see Fig. 9-13-4) and occur with a variety of diseases (Box 9-13-3). Disorders of vertical gaze, particularly downgaze, often are overlooked in patients with brainstem vascular disease, because damage to the nearby reticular activating system impairs consciousness. Supranuclear upgaze palsies occur with lesions at or near the posterior commissure and with bilateral lesions in the pretectal area (see Fig. 9-13-4). Extrinsic compression of the posterior commissure or pretectal region causes loss of the pupillary light reflex, but accommodation and convergence are preserved (light–near dissociation). Paralysis of upgaze, light–near dissociation of the pupils, impaired convergence, lid retraction, and convergence retraction nystagmus are features of the dorsal midbrain (Parinaud’s) syndrome. Convergence-retraction nystagmus is a uniquely localizing sign of injury to the dorsal midbrain region. It is not true nystagmus but a saccadic disorder3 that is elicited best by rotating an optokinetic drum with the stripes moving downward. When the patient attempts to make corrective upward saccades to refixate, the eyes converge and retract in the orbits because of synchronous co-contraction of the extraocular muscles. Downgaze palsy occurs with bilateral lesions of the rostral interstitial nucleus of the MLF or its projections (see Fig. 9-13-4). With the exception of occlusion of the posterior thalamosubthalamic branch of the ­ posterior cerebral artery (Percheron’s artery), such discrete lesions are rare; involvement of the midbrain rather than the thalamus is ­responsible for the paralysis.23 More commonly, bilateral ­involvement

BOX 9-13-3 Disorders of the Midbrain that Affect Vertical Gaze EXTRINSIC LESIONS Pineal region tumors Vascular malformations and aneurysms Hydrocephalus (failed ventricular shunt) Parasitic cysts INTRINSIC LESIONS Primary brainstem tumor (glioma, ependymoma) Metastatic brainstem tumor Third ventricular tumors Pituitary adenomas Stroke l  Infarction l  Hemorrhage (thalamic, pretectal) Trauma (surgery, head injury) Multiple sclerosis Infection (syphilis, encephalitis) Lipid storage disease Transtentorial herniation Kernicterus Wernicke’s syndrome Bassen-Kornzweig’s syndrome Vitamin B12 deficiency Jejunal ileal bypass

of the pathways for downgaze, and also for upgaze, occurs as part of diffuse neurologic disorders. Rarely, a unilateral lesion of the midbrain tegmentum may result in impaired downward, as well as upward, saccades.24 Progressive supranuclear palsy (Steele-Richardson-Olszewski ­syndrome) is a neurodegenerative disorder that appears in about the sixth decade. It is characterized by vertical supranuclear gaze palsy, particularly for downward eye movements, postural instability, and unexplained falls. In addition, nuchal rigidity, Parkinsonism, pseudobulbar palsy, and mild dementia may be present. Early visual symptoms include blurred vision (making it difficult to see food on a plate and to read), diplopia, burning eyes, and photophobia. As the disease progresses, horizontal eye movements become impaired, as well, and eventually a global gaze paresis develops.3 Wilson’s disease, or hepatolenticular degeneration, is associated with a Kayser-Fleischer ring, caused by the accumulation of copper in ­Descemet’s membrane. Eye movement abnormalities are unusual, but saccades may be slowed and a supranuclear upgaze palsy may occur. Kernicterus, or neonatal jaundice, can cause upgaze paresis, which usually is supranuclear.25 Horizontal saccades may be slow. Huntington’s disease also affects eye movements. Patients find it difficult to initiate saccades and frequently use blinks and head thrusts to facilitate eye movements. Vertical saccades are affected more than horizontal saccades. Fixation instability is prominent.26 Tonic upward deviation of gaze, or forced upgaze, is rare but may be seen in unconscious patients.27 Rarely, tonic upward gaze deviation may be psychogenic, but it can be overcome, indeed cured, by cold ­caloric stimulation of the semicircular canals. Benign paroxysmal tonic upward gaze usually starts during the first year of life, lasts about 2 years, and has no known cause. This phenomenon can occur with cystic fibrosis.28 Tonic upgaze also may be seen in normal infants during the first months of life.29 Tonic downward deviation of gaze, or forced downgaze, is associated with medial thalamic hemorrhage, acute obstructive hydrocephalus, severe metabolic or hypoxic encephalopathy, or massive subarachnoid hemorrhage. When associated with lid retraction, the corneas can be buried below the lower lid (sundowning). In this setting, elevated ­intracranial pressure is a major concern. The eyes may be converged, as if looking at the nose.30 Preterm infants with intraventricular hemorrhages also may have tonic downward deviation with a skew and ­esotropia.31 Tonic downward deviation of the eyes may occur as a ­transient ­ phenomenon in otherwise healthy neonates. It also can be induced in infancy by sudden exposure to bright light.

9.13 Disorders of Supranuclear Control of Ocular Motility

Acquired immunodeficiency syndrome dementia complex Amyotrophic lateral sclerosis Anticonvulsant toxicity (consciousness usually impaired) Ataxia and telangiectasia Hexosaminidase A deficiency Huntington’s disease Internuclear ophthalmoplegia Joseph’s disease Lesions of the paramedian pontine reticular formation Lipid storage diseases Lytico-Bodig’s disease Myotonic dystrophy Nephropathic cystinosis Ocular motor apraxia Ocular motor nerve or muscle weakness Olivopontocerebellar degeneration Progressive supranuclear palsy Wernicke’s encephalopathy Whipple’s disease Wilson’s disease

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9 NEURO-OPHTHALMOLOGY

Skew deviation is a vertical divergence of the ocular axes caused by a “prenuclear” lesion of the vertical vestibulo-ocular pathways in the brainstem or cerebellum. Skew deviation usually, but not always, is comitant and frequently is associated with cyclotorsion of one or both eyes. When the skew deviation is noncomitant it can mimic a partial third or fourth cranial nerve palsy. Skew deviations occur most commonly with vascular lesions of the pons or lateral medulla (Wallenberg’s syndrome). With lesions of the midbrain or upper pons, the contralateral eye was lower (contraversive skew), but with lesions of the lower pons or medulla the ipsilateral eye was lower (ipsiversive skew).32 When patients have alternating skew deviation, the hypertropia changes with the direction of gaze. The adducting eye usually is ­hypotropic, thus mimicking superior oblique overaction. Alternating skew deviation occurs with lesions of either the upper midbrain region ­involving the interstitial nucleus of Cajal or the cervicomedullary junction or cerebellum; in the latter situation, ataxia and downbeat nystagmus usually are associated.33 Paroxysmal or periodic alternating skew deviation occurs with midbrain lesions; the hypertropia changes in a regular or irregular manner over periods of seconds to minutes. Ocular counter-rolling is a normal vestibular reflex that allows people to maintain horizontal orientation of the environment while the head tilts to either side (see Fig. 9-13-2). When the head is tilted to the left, the left eye rises and intorts as the right eye falls and extorts. The ocular tilt reaction is a special type of skew deviation associated with cyclotorsion of both eyes, and paradoxical head tilt, all to the same side – that of the lower eye (see Fig. 9-13-2). A tonic (sustained) ocular tilt reaction occurs with lesions of the ipsilateral utricle, vestibular nerve or nuclei, or a lesion in the region of the contralateral interstitial nucleus of Cajal and medial thalamus. A phasic (paroxysmal) ocular tilt reaction occurs with lesions of the ipsilateral interstitial nucleus of Cajal and may respond to baclofen. Dissociated vertical deviation is an asymmetrical, bilateral phenomenon that occurs with early disruption of fusion (congenital esotropia, infantile cataract). Usually, it is manifest during periods of inattention, in which the deviating eye elevates, abducts, and excyclotorts. The cause remains unclear, but it is one of the few exceptions to Hering’s law of equal innervation. When manifest, it is best treated by unilateral or bilateral superior rectus recession.34 Congenital monocular elevator deficiency, previously known as double elevator palsy, is characterized by congenital limitation of elevation of one eye. Most patients are hypotropic in the primary position but use a chin-up head position to allow fusion. A ptosis or ­pseudoptosis, in which the upper lid of the affected hypotropic eye appears ptotic ­because the eye is lower, almost always is present. Monocular elevator deficiency is believed to result from a prenuclear congenital unilateral midbrain lesion because the affected eye usually is elevated by Bell’s reflex. Furthermore, because the elevator muscles of the affected eye (inferior oblique and superior rectus) are innervated by their respective subnuclei within the third cranial nerve nucleus, but on opposite sides of the midline (Chapter 9-14), a single unilateral lesion must be prenuclear rather than nuclear. In long-standing monocular elevator deficiency, the inferior rectus muscle may become tight, which may be treated using recession. If no restriction occurs, a full tendon vertical transposition (Knapp procedure) of the horizontal muscles is recommended.35 Other disorders that may cause inferior rectus restriction, such as thyroid orbitopathy and orbital floor fractures, must be excluded. Monocular supranuclear (prenuclear) elevator palsy is an acquired limitation of elevation of one eye on attempted upgaze. Patients remain orthotropic in primary position and downgaze is intact. This disorder occurs with unilateral vascular36 or neoplastic37 lesions of the midbrain. The affected eye usually is elevated by Bell’s reflex or by vestibular stimulation.

OCULAR MOTILITY DISORDERS AND THE CEREBELLUM

1006

The cerebellum coordinates the different motor and sensory inputs to the ocular motor system and ensures that the eyes move smoothly and accurately. Ocular motility signs indicative of cerebellar ­disease are listed in Box 9-13-4. The dorsal vermis and fastigial nuclei ­determine the accuracy of saccades by adjusting their amplitude. ­ Lesions of the dorsal vermis and fastigial nuclei result in saccadic ­ dysmetria. The ­ flocculus is responsible for the stabilization of images on the ­fovea, particularly after a saccade. Lesions of the flocculus result in

BOX 9-13-4 Ocular Motility Signs Indicative of Cerebellar Disease Saccadic dysmetria (inaccurate saccadic amplitude;   over- or undershooting a visual target) Saccadic pursuit Unstable fixation (square wave jerks) Impaired vestibulo-ocular reflex suppression Gaze-evoked nystagmus Vertical nystagmus Increased vestibulo-ocular reflex gain

gaze-holding ­ deficits, such as gaze-evoked, rebound, or downbeat ­nystagmus, impaired smooth pursuit, inability to cancel the VOR by the pursuit system, and inability to suppress nystagmus (and vertigo) by fixation. The nodulus influences vestibular eye movements and vestibulo-optokinetic interaction. Lesions of the nodulus may produce periodic alternating nystagmus. Posterior fossa tumors may become apparent with strabismus; acute comitant esotropia may be the first sign.38 Children who have such tumors usually are older than those who have infantile or accommodative esotropia, and they develop nystagmus or other neurological signs at a later date.39 Failure to regain fusion after spectacle, prism, or surgical therapy is a universal finding.38 A variety of ocular motility disorders may be associated with congenital or acquired defects of the cerebellum. Patients with COMA may have midline cerebellar defects.40 Chiari malformations may be associated with downbeat nystagmus, gaze-evoked nystagmus, skew deviation, or esotropia. Familial cerebellar degeneration may be associated with vergence disorders.41

OCULAR MOTILITY DISORDERS AND THE VESTIBULAR SYSTEM The vestibular system stabilizes the direction of gaze during head movements by adjusting tonic innervation to the ocular motor nuclei and, consequently, the extraocular muscles, thus maintaining a stable image on the retina. Each vestibular end organ has three semicircular canals, as well as a utricle and saccule. Each semicircular canal projects to the vestibular nuclei and brainstem. Excitatory projections innervate pairs of yoked agonist extraocular muscles via their subnuclei (see Fig. 9-13-3), while inhibitory projections innervate their antagonists. ­Essentially each extraocular muscle subnucleus receives excitatory projections from one semicircular canal and inhibitory projections from the rival semicircular canal. This network is discussed in greater detail elsewhere.42, 43 Disruption of the pathways that subserve the vertical VOR (peripheral vestibular system, vestibular nuclei, cerebellar inputs, MLF, or cranial nerve subnuclei) causes a skew deviation.

VERGENCE DISORDERS Convergence paralysis occurs with midbrain lesions and may be associated with other features of the dorsal midbrain syndrome. Lack of effort, however, is the most common cause of poor convergence. Degenerative disorders, such as cerebellar degeneration, Parkinson’s disease, and progressive supranuclear palsy, also may be associated with poor convergence. The absence of other midbrain signs and the lack of pupillary constriction on attempted convergence may differentiate psychogenic convergence paralysis from organic disease. Convergence insufficiency is an idiopathic condition that also may in part be related to effort. It is seen in young individuals who complain of diplopia in association with prolonged near work.41 Rarely, it may follow closed head injury. Divergence insufficiency is characterized by uncrossed horizontal diplopia at distance in the absence of other neurological symptoms or signs. Patients have intermittent or constant esotropia that is present only at distance. Abduction is full. The origin of divergence insufficiency is unclear, but it may result from a break in fusion later in life, or occur in patients with cerebellar degeneration. The condition is treated ­easily with base-out prisms for the distance correction and rarely ­ requires ­extraocular muscle surgery.

Causes include radiation therapy and, less commonly, compressive lesions such as cavernous sinus meningiomas, pituitary adenomas, and, rarely, dolichoectatic vessels. Occasionally no cause is found. Ocular neuromyotonia responds to carbamazepine and other antiepileptic drugs and must be differentiated from superior oblique myokymia and the spasms of cyclic oculomotor palsy (Chapter 9-18).

DEVELOPMENT OF THE OCULAR MOTOR SYSTEM Maturation of the infant nervous system continues after birth and is particularly rapid during the first few months of life. At birth the vestibular system is the most developed of the ocular motor subsystems and may be tested by rotating the infant (held at arm’s length). The VOR is well developed by the end of the first postnatal week.43 Smooth pursuit movements occur in neonates, but only with large targets (such as a human face) that move at low velocities. The pursuit system does not mature fully until the late teens. The saccadic system also is immature in the neonate. Vertical saccades mature more slowly than horizontal saccades and may not be detected for the first month after birth. Vergence movements are also slow to mature but are seen after about the first month.

Transient Ocular Motility Abnormalities in Infancy

Several benign transient ocular motility disorders occur in infancy. Neonatal strabismus occurs in up to one third of healthy neonates; an esotropia that persists beyond 3 months, or an exotropia that persists beyond 4 months, postnatally is abnormal.44 Tonic downward ocular deviation occurs in approximately 2% of otherwise healthy neonates45, 46 and is similar to the “sun-setting” sign seen in infants who have hydrocephalus, but resolves spontaneously. Lid retraction, either spontaneous or associated with sudden darkness, may be noted. Tonic upgaze is much rarer than tonic downgaze but is well described31, 47 and, also, usually resolves. Skew deviation occurs in healthy infants and usually resolves;45 however, a substantial number of them develop strabismus. Some neonates may have transient horizontal gaze palsy (Donahue, personal observation, 1995). Premature infants, especially those with intraventricular hemorrhages, may develop tonic downward and esotropic ocular deviations similar to the motility findings in adults who have acquired thalamic lesions. Although the upgaze palsy typically resolves, the esotropia ­persists and requires surgery.28

9.13 Disorders of Supranuclear Control of Ocular Motility

Divergence paralysis is a controversial entity that may be difficult to differentiate from divergence insufficiency and bilateral sixth ­cranial nerve palsies. Such patients usually have horizontal diplopia at distance, but abducting saccades are slow. Patients who have bilateral sixth cranial nerve palsies and who recover gradually may go through a phase in which the esotropia is comitant and versions are full, and thus mimic divergence paralysis. Spasm of the near reflex is characterized by intermittent episodes of convergence, miosis, and accommodation. Symptoms include double or blurred vision. The patient is esotropic, particularly at distance, and has extreme miosis. Spasm of the near reflex is commonly psychogenic in origin. Patients who have psychogenic spasm of the near reflex often have associated somatic complaints and behavioral abnormalities, which ­include blepharoclonus on persistent lateral gaze. Occasionally, a patient with uncorrected high hyperopia will appear to have spasm of the near reflex; however, a careful cycloplegic refraction will reveal an accommodative esotropia that was precipitated or unmasked. In such cases the correct management consists of prescribing the full cycloplegic refraction. Central disruption of fusion, also called post-traumatic fusion ­deficiency, occurs after moderate midbrain injury and causes intractable diplopia, despite the patient’s ability to fuse intermittently and even achieve stereopsis briefly.42 Prism therapy or surgery is ineffective. Central disruption of fusion may also be associated with brainstem tumors, stroke, neurosurgical procedures, removal of long-standing cataracts, and uncorrected aphakia. This condition must be differentiated from psychogenic disorders of vergence and bilateral superior oblique palsies; the latter usually cause intolerable torsion. The hemislide phenomenon occurs when patients who have large visual field defects, particularly dense bitemporal hemianopias, develop diplopia. They have difficulty maintaining fusion because they can no longer suppress any latent deviation as a result of loss of overlapping areas of field. Ocular neuromyotonia is a brief, involuntary, intermittent myotonic contraction of one or more muscles supplied by the ocular motor nerves, most commonly the third cranial nerve. Although the mechanism is unclear, it is included here because it must be differentiated from other vergence disorders. Ocular neuromyotonia usually results in esotropia of the affected eye, with accompanying failure of elevation and depression of the globe, and may be provoked by prolonged eccentric gaze. It may be associated with signs of aberrant reinnervation of the third cranial nerve. Usually, the pupil is fixed to both light and near stimuli.

REFERENCES   1. Lavin PJM, Donahue S. Neuro-ophthalmology: the efferent visual system. Gaze mechanisms and disorders. In: Daroff RB, Fenichel GM, Marsden CD, Bradley WG, eds. Neurology in clinical practice, 5th ed. Boston:   Butterworth Publishing; in press.   2. Sharpe JA. Neural control of ocular motor systems. In: Miller NR, Newman NJ, eds. Walsh & Hoyt’s clinical neuro-ophthalmology, vol 1, 5th ed. Baltimore: Williams & Wilkins; 1998:1101–67 .   3. Leigh RJ, Zee DS. Diagnosis of central disorders of ocular motility. The neurology of eye movements, 4th ed. Oxford: Oxford University Press; 2006:598–718.   4. Borchert MS. Principles and techniques of the examination of ocular motility and alignment. In: Miller NR, Newman NJ, eds. Walsh & Hoyt’s clinical neuro-ophthalmology, vol 1, 5th ed. Baltimore: Williams & Wilkins; 1998: 1169–1188.   5. Leigh RJ, Daroff RB, Troost BT. Supranuclear disorders of eye movements. In: Glaser GS, ed. Neuro-ophthalmology, 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 1999:345–368.   6. Chambers BR, Gresty MA. Effects of fixation and optokinetic stimulation on vestibulo-ocular reflex suppression. J Neurol Neurosurg Psychiatry. 1982;45:998–1004.   7. Cogan DG. A type of congenital motor apraxia presenting jerky head movements. Trans Am Acad Ophthalmol Otolaryngol. 1952;56:853–62.   8. Supranuclear and internuclear gaze pathways. In: Bajandas FJ, Kline LB, eds. Neuro-ophthalmology review manual, 4th ed. Thorofare: Slack; 1996: 43–67.   9. Ebner R, Lopez L, Ochoa S, Crovetto L. Vertical ocular motor apraxia. Neurology. 1990;40:712–3. 10. Hughes JL, O’Connor PS, Larsen PD, Mumma JV. Congenital vertical ocular motor apraxia. J Clin Neuro Ophthalmol. 1985;5:153–7.

11. Sharpe JA, Silversides JL, Blair RDG. Familial paralysis   of horizontal gaze associated with pendular nystagmus, progressive scoliosis, and facial contraction with   myokymia. Neurology. 1975;25:1035–40. 12. Tijssen CC, Schulte BP, Leyten AC. Prognostic significance of conjugate eye deviation in stroke patients. Stroke. 1991;22:200–2. 13. Sharpe JA, Johnson JL. Ocular motor paresis versus apraxia. Ann Neurol. 1989;25:209–10. 14. Pierrot-Deseilligny C, Gautier JC, Loron P. Acquired ­ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol. 1988;23:199–202. 15. Kellen RI, Burde RM, Hodges FJ III, Roper-Hall G. Central bilateral sixth nerve palsy associated with a unilateral preganglionic Horner’s syndrome. J Clin Neuroophthalmol. 1988;8:179–84. 16. Sharpe JA, Bondar RL, Fletcher WA. Contralateral gaze deviation after frontal lobe haemorrhage. J Neurol Neurosurg Psychiatry. 1985;48:86–8. 17. Plum F, Posner JB. The diagnosis of stupor and coma,   3rd ed. Philadelphia: FA Davis; 1980. 18. Daroff RB, Hoyt WF. Clinical disorders of the supranuclear systems for vertical ocular movement. In: Bach-y-Rita P, Collins CC, Hyde JE, eds. The control of eye movements, New York: Academic Press; 1971:196–197. 19. Bolling J, Lavin PJ. Combined gaze palsy of horizontal saccades and pursuit of contralateral to a midbrain haemorrhage. J Neurol Neurosurg Psychiatry. 1987;50:789–91. 20. Wolin MJ, Trent RG, Lavin PJ, Cornblath WT. Oculopalatal myoclonus after the one-and-a-half syndrome with facial nerve palsy. Ophthalmology. 1996;103:177–80. 21. Wall M, Wray SH. The one-and-a-half syndrome – a unilateral disorder of the pontine tegmentum: a study of 20 cases and review of the literature. Neurology. 1983;33:971–80.

22. Davis TL, Lavin PJ. Pseudo one-and-a-half syndrome with ocular myasthenia. Neurology. 1989;39:1553. 23. Siatkowski RM, Schatz NJ, Sellitti TP, et al. Do thalamic lesions really cause vertical gaze palsies? J Clin Neuro Ophthalmol. 1993;13:190–3. 24. Ranalli PJ, Sharpe JA, Fletcher WA. Palsy of upward and downward saccadic, pursuit, and vestibular movements with a unilateral midbrain lesion; pathophysiologic ­correlations. Neurology. 1988;38:114–22. 25. Hoyt CS, Billson FA, Alpins N. The supranuclear disturbances of gaze in kernicterus. Ann Ophthalmol. 1978;10:1487–92. 26. Topical diagnosis of neuropathic ocular motility disorders. In: Miller NR, ed. Walsh & Hoyt’s clinical ­neuro-ophthalmology, vol. 2, 4th ed, Baltimore: Williams & Wilkins; 1985: 652–784. 27. Barontini F, Simonetti C, Ferranini F, Sita D. Persistent upward eye deviation. Report of two cases. Neuro­ ophthalmology. 1983;3:217–24. 28. Gieron MA, Korthals JK. Benign paroxysmal tonic   upward gaze. Pediatr Neurol. 1993;9:159. 29. Ahn JC, Hoyt WF, Hoyt CS. Tonic upgaze in infancy. A report of three cases. Arch Ophthalmol. 1989;107:57–8. 30. Kumral E, Kocaer T, Ertubey NO, Kumral K. Thalamic hemorrhage. A prospective study of 100 patients. Stroke. 1995;26:964–70. 31. Tamura EE, Hoyt CS. Oculomotor consequences of intraventricular hemorrhages in premature infants.   Arch Ophthalmol. 1987;105:533–5. 32. Brandt T, Dieterich M. Skew deviation with ocular torsion: a vestibular brainstem sign of topographic diagnostic value. Ann Neurol. 1993;33:528–34. 33. Hamed LM, Maria BL, Quisling RG, Mickle JP. Alternating skew on lateral gaze. Neuroanatomic pathway and relationship to superior oblique overaction. Ophthalmology. 1993;100:281–6.

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34. Scott WE, Sutton VJ, Thalacker JA. Superior rectus recessions for dissociated vertical deviation. Ophthalmology. 1982;89:317–22. 35. Burke JP, Ruben JB, Scott WE. Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long-term stability. Br J Ophthalmol. 1992;76:734–7. 36. Ford CS, Schwartze GM, Weaver RG, Troost BT. Monocular elevation paresis caused by an ipsilateral lesion. Neurology. 1984;34:1264–7. 37. Munoz M, Page LK. Acquired double elevator palsy in a child with pineocytoma. Am J Ophthalmol. 1995;118:810–1. 38. Williams AS, Hoyt CS. Acute comitant esotropia in children with brain tumors. Arch Ophthalmol. 1989;107:376–8.

39. Simon JW, Waldman JB, Conture KC. Cerebellar astrocytoma manifesting as isolated, comitant esotropia in childhood. Am J Ophthalmol. 1996;121:584–6. 40. Brodsky MC, Baker RS, Hamed LM. Complex ocular motor disorders in children. In: Brodsky MC, Baker RS, Hamed LM, eds. Pediatric neuro-ophthalmology. New York: Springer-Verlag; 1996:251–301. 41. Waltz KL, Lavin PJM. Accommodative insufficiency. In: Margo CE, Mames RN, Hamed L, eds. Diagnostic problems in clinical ophthalmology. Philadelphia: WB Saunders; 1993:862–866. 42. Pratt-Johnson JA, Tillson G. The loss of fusion in adults with intractable diplopia (central fusion disruption). Aust N Z J Ophthalmol. 1988;16:81–5.

43. Leigh RJ, Zee DS. The vestibular-optokinetic system. The neurology of eye movements, 2nd ed. Philadelphia:   FA Davis: 199115–78. 44. Nixon RB, Helveston EM, Miller K, et al. Incidence of strabismus in neonates. Am J Ophthalmol. 1985;100:798–801. 45. Hoyt CS, Mousel DK, Weber AA. Transient supranuclear disturbances of gaze in healthy neonates. Am J Ophthalmol. 1980;89:708–13. 46. Kleiman MD, DiMario FJ, Leconche DA, Zalneraitis EL. Benign transient downward gaze deviation in pre-term infants. Pediatr Neurol. 1994;10:313–6. 47. Deonna T, Roulet E, Meyer HU. Benign paroxysmal tonic upgaze of childhood – a new syndrome. Neuropediatrics. 1990;21:213–4.

PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

Nuclear and Fascicular Disorders of Eye Movement

9.14

Sean P. Donahue

Definition:  Eye movement disorders caused by damage to the ocular motor nerve nuclei (cranial nerve III, IV, or VI) or to the ocular motor nerve fascicles within the brainstem.

LOCATION OF OCULAR MOTOR NERVE NUCLEI AND FASCICLES IN THE BRAINSTEM pineal gland cerebral aqueduct medial longitudinal fasciculus superior colliculus third nerve nucleus inferior colliculus red nucleus fourth nerve

Key features n n n

Diplopia. Incomitant ocular deviation. Other localizing neurological signs.

Associated features n n n

Other cranial nerve palsies. Supranuclear disorders of motility. Long tract signs. 

midbrain

pons

third nerve paramedian pontine reticular formation sixth nerve nucleus seventh nerve facial nerve nucleus

medulla

sixth nerve

INTRODUCTION Eye movement commands are carried from the cerebral cortex and higher brainstem structures to the ocular motor nerve nuclei. These commands are then sent to the individual extraocular muscles by cranial nerves III, IV, and VI. Eye movement abnormalities resulting from damage to the structures that carry commands to the ocular motor nerve nuclei are considered supranuclear or prenuclear in origin (see Chapter 9.13). Abnormalities resulting from damage to the ocular motor nuclei and their respective cranial nerves are considered infranuclear. An infranuclear ocular motor nerve palsy can be caused by damage anywhere from the nucleus to the extraocular muscle. Nuclear ocular motor palsies occur at the level of the ocular motor nucleus; fascicular nerve palsies are caused by lesions to the nerve fibers that travel from the nucleus and exit the brainstem into the subarachnoid space. Nuclear and fascicular ocular motor nerve palsies produce characteristic ocular abnormalities based on the loss of the function of the innervated extraocular muscle. Acute palsies produce an incomitant strabismus that is greatest in the field of action of the paretic muscle. Palsies of the third nerve are also associated with abnormal pupillary and lid function. Fourth nerve palsies are associated almost always with additional complaints of torsion or a head tilt. Nuclear and fascicular nerve palsies often are associated with other ­neurological signs because of the large number of structures located nearby (Fig. 9-14-1). A detailed knowledge of the neuroanatomy of the midbrain and pons enables the clinician to localize these lesions with great accuracy.

EPIDEMIOLOGY AND PATHOGENESIS Ocular motor nerve palsies typically become apparent in one of the ­following four ways:1 l Truly isolated nerve palsies that have no other signs or symptoms. l Isolated nerve palsies that have associated symptoms. l Nerve palsies associated with palsies of other cranial nerves. l Nerve palsies with neurological signs other than cranioneuropathies.

Fig. 9-14-1  Location of ocular motor nerve nuclei and fascicles in the ­brainstem. Note the relationship of the cranial nerve nuclei and fascicles to   the medial longitudinal fasciculus, red nucleus, paramedian pontine reticular formation, and facial nerve nucleus and fascicle. The fourth nerve exits dorsally, while the third and sixth nerves exit ventrally.

Each of these four groups has a different corresponding differential ­ iagnosis. Reports in the literature that consider the causes of ­ ocular d motor nerve palsies2–5 generally do not classify the palsies in this manner. Thus, most of these reports are of limited value to the clinician, who may have either localized the lesion already or formulated a ­differential diagnosis based on the manner of appearance. Because nuclear and fascicular disorders are highly localizable, it is better to localize the lesion and then consider the causes based on the patient’s age and the history (Boxes 9-14-1 to 9-14-3). Most ­nuclear and fascicular disorders of eye movement are caused by vascular ­disease (infarction, hemorrhage from arteriovenous malformation), demyelination, and tumor (metastatic or primary). Infectious, inflammatory, and traumatic causes are less likely. Congenital oculomotor nerve palsy can arise from brainstem disorders in some patients,6–8 who often have other brain anomalies and brainstem syndromes. Although thyroid disease and myasthenia can mimic isolated cranial nerve palsies, neither is associated with neurological deficits of brainstem function.

OCULAR MANIFESTATIONS Palsies of the Third Cranial Nerve

The oculomotor nerve innervates four extraocular muscles (medial ­rectus, inferior rectus, superior rectus, and inferior oblique) in addition to the levator palpebrae and the pupillary sphincter.

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BOX 9-14-1 CAUSES OF NUCLEAR AND FASCICULAR THIRD CRANIAL NERVE PALSIES

BOX 9-14-3 CAUSES OF NUCLEAR AND FASCICULAR SIXTH CRANIAL NERVE PALSIES

Children Congenital l with neurological abnormalities l with aberrant reinnervation l with cyclic oculomotor spasm Vascular (arteriovenous malformation) Primary tumor Metastatic tumor

Vascular disease l Hemorrhage l Infarction (anterior inferior cerebellar artery paramedian perforating arteries) Demyelinating disease Trauma Tumor l Glioma l Astrocytoma l Ependymoma l Medulloblastoma l Metastatic l Infiltrative Other

Young Adults Demyelinating Vascular (hemorrhage or infarction) Tumor Older Adults Vascular (infarction) Tumor

BOX 9-14-2 CAUSES OF NUCLEAR AND FASCICULAR FOURTH CRANIAL NERVE PALSIES Intrinsic Midbrain Lesions Trauma (anterior medullary velum) Tumor l Medulloblastoma l Ependymoma l Metastatic Demyelination Stroke l Ischemic l Hemorrhagic Arteriovenous malformation Extrinsic Midbrain Lesions Tumor l Pinealoma l Metastatic Hydrocephalus Aqueductal stenosis

The degree of involvement of each of these six structures can be quite variable. When the palsy is complete, there is complete ptosis with a dilated pupil that responds neither to light nor near. The eye is deviated out and usually, but not always, down. Function of the other ocular motor nerves can be assessed in this situation by evaluation of abduction (sixth cranial nerve) and by observing incyclotorsion on attempted depression in addition (fourth cranial nerve).

Nuclear Third Cranial Nerve Lesions

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The third nerve nucleus is located in the midbrain near the cerebral ­aqueduct at the level of the superior colliculus (Fig. 9-14-2). The anatomy of the third nerve nucleus was described by Warwick9 in a ­classic paper in 1953. Each extraocular muscle that receives innervation from the third nerve has a corresponding subnucleus (Fig. 9-14-3). A single central nucleus (central caudal nucleus) innervates both levator palpebrae muscles. Distinct, bilateral subnuclei exist for the extraocular muscles. An additional bilateral subnucleus, the Edinger-Westphal ­nucleus, provides parasympathetic input to the pupillary sphincter. Projections from the subnuclei to their targets all are uncrossed (each subnucleus innervates the ipsilateral corresponding extraocular muscle), with two exceptions − the single central caudal nucleus sends projections to both levator muscles, and the superior rectus subnucleus projection is crossed. Thus, the right superior rectus subnucleus innervates the left superior rectus muscle, and vice versa. The evolution of the crossed connections may have occurred to facilitate vestibular innervation. Because the trochlear nerve also undergoes a decussation, each cyclovertical muscle and its corresponding yoked muscle pair have nuclei on the same side of the brain. The right ­inferior

ANATOMY OF MIDBRAIN AT THE LEVEL OF THE THIRD NERVE NUCLEUS periaqueductal cerebral nucleus of medial aqueduct third nerve lemniscus gray medial longitudinal fasciculus

substantia nigra

red nucleus third nerve cerebral peduncle (crus cerebri) posterior communicating arteries superior cerebellar arteries

interpeduncular fossa posterior cerebral arteries third nerve basilar artery

Fig. 9-14-2  Anatomy of midbrain at the level of the third cranial nerve nucleus. The fascicles of the third nerve pass through the red nucleus, substantia nigra, and crus cerebri before they exit into the interpeduncular fossa. The medial lemniscus is nearby. Note the intimate relationship of the oculomotor nerve nuclei to the medial longitudinal fasciculus, periaqueductal gray, and the cerebral aqueduct.

oblique subnucleus and left superior rectus subnucleus are both located on the right; the left inferior rectus subnucleus and right superior oblique subnucleus are both located on the left. This allows the direct innervation of a yoked muscle pair from the corresponding semicircular canal without a decussation; and is important in the vestibular-ocular counter-rolling reflex (see Chapter 9.13). Although the anatomy of the third nerve nucleus is complex, it allows precise localization. Daroff10 has proposed clinical rules that obligate or exclude nuclear involvement (Box 9-14-4). Because the central caudal subnucleus sends projections to both levator muscles, a bilateral third nerve palsy that spares the lid on both sides obligates a rostral nuclear lesion. The crossed projection of the superior rectus subnucleus underlies the observation in that unilateral third nerve lesions with contralateral superior rectus involvement obligate a nuclear lesion, whereas a third nerve palsy with no contralateral superior rectus abnormality cannot be caused by a nuclear lesion. The reader should review Daroff’s rules (see Box 9-14-4) and determine how the neuroanatomy is responsible for each rule. Isolated nuclear third nerve lesions are quite rare. Usually the lesion extends to cause supranuclear disorders of vertical gaze and other neurological signs. However, Warwick’s scheme of nuclear anatomy has received confirmation by magnetic resonance ­ imaging

ANATOMY OF THE THIRD NERVE NUCLEUS Edinger–Westphal subnucleus – to ipsilateral pupillary sphincter to ipsilateral inferior rectus to ipsilateral inferior oblique to ipsilateral medial rectus

third nerve

to contralateral superior rectus

inferior rectus medial rectus superior rectus inferior oblique levator palpebrae Edinger–Westphal subnucleus

Fig. 9-14-3  Anatomy of the third cranial nerve nucleus. The third nerve nucleus consists of a single, central, caudally located nucleus for the levator palpebrae, paired bilateral subnuclei with crossed projections that innervate the superior recti, and paired bilateral subnuclei with uncrossed projections that innervate the medial recti, inferior recti, and inferior oblique muscles. Parasympathetic input to the ciliary body and iris sphincter arises from the Edinger-Westphal nucleus. (From Warwick R. Representation of the extraocular muscles in the ­oculomotor nuclei of the monkey. J Comp Neurol. 1953;98:449–503.)

documentation in patients who have obligatory nuclear third nerve palsies;11–13 ­histopathological confirmation also has been reported.14, 15 Infarction, usually of small branches of the basilar artery, is the cause of most nuclear third nerve palsies. Metastatic, lymphoproliferative, and primary neoplastic disease also can occur.

Fascicular Third Cranial Nerve Palsies

After leaving the nucleus, the axons of the oculomotor neurons travel through the midbrain. Here, they pass near or through two important structures before exiting into the subarachnoid space of the interpeduncular fossa (the red nucleus and the crus cerebri). Lesions that damage the third nerve fascicle within the red nucleus cause a contralateral intention tremor and ataxia. Because the nearby medial lemniscus carries sensory fibers for light touch and proprioception on the contralateral side, these modalities also may be impaired or absent. Lesions of the cerebral peduncle damage corticospinal tract fibers and produce a contralateral hemiparesis. Each of these syndromes has a specific eponym (Table 9-14-1). Classically, fascicular third nerve palsies were thought to affect all functions of the third nerve equally, with the degree of pupil involvement (anisocoria increasing in bright light) being proportional to the lid and motility defects. Recently, however, it has been recognized that isolated extraocular muscle pareses can result from fascicular third nerve lesions.16, 17 Divisional oculomotor paresis also can be caused by brainstem18 or vascular19, 20 disease. The “isolated,” pupil-sparing third nerve palsy seen in adults with vascular disease results from fascicular damage.21 Most fascicular third nerve lesions have vascular causes (hemorrhage, infarction). Metastatic or infiltrative disease is less common; demyelinating disease is rare, even in patients with known multiple sclerosis. Because fascicular third nerve palsies are typically ischemic in nature, they may have varying degrees of recovery. Aberrant regeneration, however, does not occur. Patients who have aberrant regeneration after an acquired third nerve palsy must be considered to have a compressive lesion of the third nerve.

Congenital Third Cranial Nerve Palsies

Congenital oculomotor nerve palsies are rare and are often associated with neurological abnormalities.6–8, 22 Aberrant regeneration is common,23 which, if present, argues against a nuclear lesion. Loewenfeld

Conditions that Obligate Nuclear Involvement Bilateral third nerve palsy without ptosis (bilaterally spared levator ­function) Unilateral third nerve palsy with contralateral superior rectus ­abnormality and bilateral partial ptosis Conditions that Exclude a Nuclear Lesion Unilateral ptosis Unilateral internal ophthalmoplegia Unilateral external ophthalmoplegia associated with normal contralateral superior rectus function Conditions that Neither Exclude nor Obligate a Nuclear Lesion Bilateral total third nerve palsy Bilateral ptosis Bilateral internal ophthalmoplegia Bilateral medial rectus palsy Isolated unilateral single muscle involvement (except levator and superior rectus). From Daroff RB. ­Oculomotor manifestation of brainstem and cerebellar dysfunction. In: Smith JL, ed. Neuro-  ophthalmology: symposium of the University of Miami and Bascom-Palmer Eye Institute, vol 5.   Hallandale: Huffman; 1971:104–21.

9.14 Nuclear and Fascicular Disorders of Eye Movement

central caudal nucleus to bilateral levators

BOX 9-14-4 DAROFF’S RULES FOR NUCLEAR THIRD CRANIAL NERVE PALSIES

 TABLE 9-14-1  SYNDROMES OF THE FASCICULAR THIRD CRANIAL NERVE Location

Eponym

Findings

Red nucleus

Benedikt’s

Intention tremor, ataxia, contralateral sensation loss (if medial lemniscus involved)

Crus cerebri

Weber’s

Contralateral hemiparesis

and Thompson24 speculated that perinatal damage to the third nerve causes retrograde degeneration of the oculomotor nucleus, which then is reinnervated haphazardly. Some patients with congenital oculomotor nerve palsies develop cyclic oculomotor spasm.24 Typical cases have a slow alternation between a paretic phase, in which the lid droops, the pupil dilates, and the eye turns out, and a spastic phase, in which the lid elevates, the pupil constricts, accommodation occurs, and the eye adducts. These cycles usually persist throughout life. Cyclic oculomotor spasm usually is not associated with acquired lesions of the third nerve.

Palsies of the Fourth Cranial Nerve

Superior oblique palsy is the most common cause of acquired vertical diplopia and can be either congenital or acquired. Patients who have acquired superior oblique palsies have diplopia that is often worse in downgaze, and they usually complain of torsion. Subjective image ­separation increases with gaze in the direction opposite the side of the palsy and with head tilt toward the side of the palsy. Motility testing in the acute phase usually demonstrates poor depression in adduction. Orthoptic measurements show a hypertropia of the affected eye that increases with gaze to the side opposite the palsy and with head tilt toward the side of the palsy. The most common cause of an isolated, acquired fourth nerve palsy is trauma (see Box 9-14-2).25–27 Congenital fourth nerve palsies can become apparent at any age. Young children often exhibit abnormal head postures, while older individuals typically experience intermittent vertical diplopia. Patients who have congenital fourth nerve palsies have large vertical fusional amplitudes, and old photographs demonstrate a consistent head tilt. Motility often is full in these patients; overelevation in adduction with a corresponding hypotropia of the abducting eye on alternate cover test (inferior oblique overaction) also is relatively common. Ortho­ptic testing yields results similar to those for acquired fourth nerve palsies. Three unique clinical points exist that need to be remembered about the trochlear nerve. It is the only cranial nerve to exit dorsally. It undergoes an immediate decussation in the anterior medullary velum to

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9 NEURO-OPHTHALMOLOGY

innervate the contralateral superior oblique. Finally, the fourth nerve has the longest intracranial course of any cranial nerve. Although both congenital and acquired fourth nerve palsies usually are isolated, additional neuro-ophthalmologic findings occasionally are present that help to localize the lesion and determine whether ­imaging studies are warranted. Because the fourth nerve fasciculus is quite short, most brainstem fourth nerve palsies usually involve both the nucleus and fasciculus.

abducens medial longitudinal fourth ventricle fasciculus nucleus spinal nucleus seventh nerve and tract of the trigeminal nerve

Nuclear and Fascicular Fourth Cranial Nerve ­Lesions

The fourth nerve nucleus is in the midbrain at the level of the inferior colliculus (see Fig. 9-14-1). It lies just caudal to the third nerve nucleus and receives prenuclear input from the vestibular system, the medial longitudinal fasciculus, and the rostral interstitial medial longitudinal fasciculus (riMLF). The fasciculus of the trochlear nerve travels dorsally to exit the lower midbrain just caudal to the inferior colliculus, near the tentorium. Because the nerve decussates in the anterior medullary velum, nuclear and fascicular fourth nerve palsies are associated with superior oblique dysfunction on the contralateral side. Isolated lesions that affect only the nuclear or fascicular trochlear nerve are very rare. Most lesions of the area that surrounds the fourth nerve nucleus and fasciculus also affect neighboring structures. Both extrinsic (tumor, hydrocephalus) and intrinsic (tumor, stroke, demyelination, arteriovenous malformation) lesions of the brainstem may damage the trochlear nerves or nucleus and often produce an associated upgaze palsy or features of the dorsal midbrain syndrome (see Box 9-14-2). Lesions that damage the fourth nerve within the dorsolateral midbrain also can damage the first-order (descending) sympathetic fibers to produce a contrallateral fourth nerve palsy with an ipsilateral Ho syndrome.28 Damage that extends into the medial longitudinal fasciculus can produce an ipsilateral internuclear ophthalmoplegia in association with a superior oblique palsy. Damage to both trochlear nerve fascicles at their decussation within the anterior medullary velum usually results from trauma and produces a bilateral superior oblique palsy, which is often asymmetrical. These patients can have a V-pattern esotropia, a reversing hypertropias on gaze and tilt, and greater than 10  degrees of subjective excyclotorsion.29 An interesting fascicular syndrome of the fourth nerve involves the brachium of the superior colliculus.30 Through this structure pass pupillomotor fibers as they travel from the optic tract to the pretectum. These fibers subserve the pupillary light reflex from the contralateral visual field. Because the retinogeniculate pathway has already separated from the pupillary pathways, conscious light detection is not affected, but the pupillary light reflex is. Patients who suffer lesions in this area have normal visual fields but a small (0.6–0.9 log unit) relative afferent pupillary defect in the eye contralateral to the lesion, consistent with an optic tract lesion. The fourth nerve palsy is also on the contralateral side (the fascicle is damaged before the decussation).

Palsies of the Sixth Cranial Nerve

The sixth nerve innervates the ipsilateral lateral rectus muscle and produces abduction. Damage to the sixth nerve produces an esotropia that is worse in the field of action of the involved sixth nerve and greater at distance than near. Most patients are able to fuse with a face turn toward the side of the palsy (gaze away from the palsy). The pupil is not affected. Patients who have long-standing sixth nerve palsies can develop tightening and contracture of the medial rectus, which causes a restrictive strabismus with positive forced ductions. Occasionally, patients who have long-standing sixth nerve palsies may have associated vertical diplopia and hypertropia.31 Nuclear and fascicular lesions of the sixth nerve typically have characteristic findings.

Nuclear Sixth Cranial Nerve Palsies

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ANATOMY OF THE SIXTH NERVE NUCLEUS IN THE PONS

The sixth nerve nucleus is in the pons, just ventral to the floor of the fourth ventricle. The fascicle of the facial nerve wraps around the sixth nerve nucleus (Fig. 9-14-4). The sixth nerve nucleus contains bodies of two types of neurons − most project directly to the lateral rectus muscle, but about 40% of the cells in the abducens nucleus are interneurons which project, via the medial longitudinal fasciculus, to the ­contralateral medial rectus subnucleus, and cause adduction of the contralateral eye. Thus, the sixth nerve nucleus, like the paramedian pontine reticular formation, is a gaze center. Damage to the sixth nerve nucleus or to the caudal paramedian pontine reticular formation produces an ipsilateral gaze palsy that cannot be overcome by vestibular testing.32 Because all nuclear sixth nerve palsies produce a gaze palsy, an abduction deficit not associated with contralateral adduction weakness cannot arise from nuclear damage.

nucleus of facial nerve paramedian pontine reticular formation

sixth nerve corticospinal tract third nerve basilar artery

Fig. 9-14-4  Anatomy of sixth cranial nerve nucleus in the pons. The ­abducens nucleus is surrounded by the facial nerve fasciculus after it originates from its nucleus and is associated intimately with the medial longitudinal fasciculus. Abducens fascicles traverse the paramedian pontine reticular formation and the corticospinal tract before leaving the lower ventral pons. The vestibular nuclei and spinal nucleus and tract of the trigeminal nerve are nearby in the lateral pons.

BOX 9-14-5 NUCLEAR AND FASCICULAR SYNDROMES OF THE SIXTH CRANIAL NERVE Nuclear Sixth Nerve Palsies One-and-a-half syndrome (obligate) Foville’s syndrome Gaze palsy Peripheral facial palsy (likely) Fascicular Sixth Nerve Palsies With contralateral hemiplegia (Raymond’s syndrome) Facial weakness (Millard-Gubler syndrome)

The location of the sixth nerve nucleus within the brainstem produces several possible associated deficits when a nuclear sixth nerve palsy is present (Box 9-14-5). The intimate relationship between the facial nerve fasciculus and the sixth nerve nucleus produces an ipsilateral peripheral facial nerve palsy in nearly all cases of abducens nuclear injury (Fig. 9-14-5). The first-order sympathetic fibers travel in the dorsal pons and damage to these fibers produces an ipsilateral preganglionic Horner’s syndrome. Damage to the trigeminal nucleus and tract produces ipsilateral facial analgesia. Damage to the lateral ventral pons can produce loss of taste. Foville’s syndrome results from a dorsal pontine infarct and combines an ipsilateral gaze palsy with an ipsilateral facial palsy, loss of taste, and facial analgesia, Horner’s syndrome, and peripheral deafness. It is rare for a patient to have all characteristics of Foville’s syndrome. When damage from either the sixth nerve nucleus or paramedian pontine reticular formation also involves the ipsilateral medial longitudinal fasciculus, a characteristic motility pattern is produced, consisting of an ipsilateral gaze palsy with an ipsilateral internuclear ophthalmoplegia. The ipsilateral eye cannot adduct or abduct, while the contralateral eye can only abduct. This syndrome is called a one-and-a-half syndrome.33 Most nuclear abducens palsies are caused by infarction (anterior inferior cerebellar or paramedian perforating arteries), demyelination, or compression (intrinsic pontine tumors). Infiltrative disease, hemorrhage, and trauma are less likely causative factors (see Box 9-14-3).

Fascicular Sixth Cranial Nerve Palsies

Nearly all fascicular lesions of the abducens nerve are associated with distinctive neurological findings that result from damage to the surrounding neurological structures of the pons.(Box 9-14-5)

 TABLE 9-14-2  NUCLEAR AND FASCICULAR SYNDROMES OF THE FOURTH ­CRANIAL NERVE

­ oville’s ­syndrome can occur with either nuclear or fascicular lesions. F These can be differentiated by evaluation of contralateral adduction: a ­ nuclear lesion has a gaze palsy, while a fascicular lesion has an ­ipsilateral abduction deficit. Lesions that affect the abducens fasciculus in the ventral pons can cause a contralateral hemiplegia (Raymond’s syndrome). MillardGubler’s syndrome has ipsilateral peripheral facial weakness in addition to the abduction deficit and contralateral hemiplegia. These eponymous syndromes and their findings are listed in Box 9-14-5. Because most lesions can affect both the dorsal and ventral pons, a clinical overlap exists between these syndromes. Common causes of fascicular lesions include infarction, compression (cerebellar pontine angle tumor or glioma), infiltration, and demyelination, and vary with the age of the patient.1, 3, 34 Hemorrhage, trauma, and infection are less likely (see Box 9-14-3). Classic teaching in pediatric ophthalmology held that isolated sixth nerve palsies in childhood should be considered the result of a pontine glioma until proven otherwise.34 However, the definition of isolated palsy used in that study meant that no other cranial nerve palsies existed, and not that the remainder of the neurological examination was normal. Most children with pontine gliomas develop other neurologic findings within a few weeks, and therefore a careful neuro-ophthalmologic examination with close follow-up probably is all that is necessary in children (under age 14 years) who have truly isolated idiopathic sixth nerve palsies.

DIAGNOSIS Palsies of the Third Cranial Nerve

Both nuclear and fascicular third nerve palsies usually can be localized clinically. Attention should be paid to vertical gaze abnormalities, because the centers for vertical gaze are in close proximity to the oculomotor nucleus and also are often damaged. Vestibular testing should be performed in patients who have bilateral vertical gaze abnormalities, to differentiate supranuclear from nuclear and infranuclear causes of these disorders. Bell’s reflex often is preserved with supranuclear lesions. A neurological examination should be directed to identify tremor, contralateral hemisensory loss, contralateral hemiplegia, pronator drift, and contralateral hyperreflexia. Magnetic resonance imaging is the best method by which to assess the integrity of midbrain structures in ­ patients who have acute palsies. The neuroradiologist should be ­informed of the clinical localization so that attention can be directed to this area.

Palsies of the Fourth Cranial Nerve

Management of fourth nerve palsies depends upon the associated ­neurological findings and localization. Older adults with an isolated fourth nerve palsy and predisposing factors for vascular disease need only careful follow-up. Imaging studies should be performed if progression occurs, if additional neurological signs develop, or if recovery

Laterality of Superior Oblique Palsy

Pretectal area

Contralateral

Vertical gaze palsy Dorsal midbrain syndrome

Descending   sympathetic   pathways

Contralateral

Ipsilateral Horner’s ­syndrome

Superior   cerebellar   peduncle

Contralateral

Ipsilateral dysmetria

Medial   longitudinal   fasciculus

Contralateral

Ipsilateral internuclear ophthalmoplegia

Brachium of   superior   colliculus

Contralateral

Contralateral relative   afferent pupillary defect Contralateral pupil ­homonymous hemianopia Normal visual fields

Anterior   medullary   velum

Bilateral

‘V’ pattern esotropia Reversing hypertropias   on side gaze >10° excyclotorsion

Clinical Manifestations

Nuclear and Fascicular Disorders of Eye Movement

Fig. 9-14-5  T2-weighted magnetic resonance image of a 33-year-old woman who has a left abduction deficit, gaze paretic nystagmus on left gaze, and left facial weakness. The cause of this nuclear sixth nerve lesion (long arrow) most likely was demyelinating disease. A second lesion can be seen in the right cerebellum (arrowhead).

Site of Damage

9.14

does not begin to occur within 3 months. Younger individuals who have large fusional amplitudes and photographic documentation of head tilting since infancy or childhood need no further evaluation, because the palsy is likely congenital with recent decompensation. Patients who have acquired fourth nerve palsies with localizing signs should undergo imaging studies, with attention paid to the areas suggested by the clinical findings. Patients who have no risk factors for vascular disease, no history of trauma, and no findings suggestive of a decompensating congenital fourth nerve palsy should undergo imaging studies to rule out small peripheral schwannomas, especially if progression occurs. Inquiry regarding the presence of multiple caféau-lait spots or other stigmata of neurofibromatosis may be useful.

Palsies of the Sixth Cranial Nerve

Management of sixth nerve palsies also depends on the associated ­findings. All patients who have sixth nerve palsies must receive complete neuro-ophthalmologic evaluation. Specific attention should be paid to the function of the facial nerve and to the other cranial nerves that subserve ocular motility and the pupil. The cerebellum vestibular system and tendon reflexes also should be evaluated. The optic nerves must be examined to rule out papilledema. Patients who have brainstem findings need magnetic resonance imaging and appropriate management. Patients who have had strokes need immediate neurological consultation, while patients who have brain tumors need urgent neurosurgical evaluation. Nuclear or fascicular involvement is unlikely in patients with truly isolated sixth nerve palsies. The evaluation and work-up of these ­patients is given in detail in Chapter 9.16.

TREATMENT, COURSE, AND OUTCOME Palsies of the Third Cranial Nerve

Many patients with microvasular oculomotor nerve palsies eventually improve. Ptosis is advantageous, because it prevents diplopia. Strabismus correction and lid surgery are needed to restore binocularity in patients who do not improve spontaneously; the author waits for stable measurements to occur for 6 months before suggesting surgical alignment. Specific techniques for restoring motility in patients who have third nerve palsy (superior oblique tendon transfer) are discussed ­elsewhere.35

Palsies of the Fourth Cranial Nerve

Palsies of the fourth nerve that result from vascular disease or trauma often resolve spontaneously over 3–6 months. During this time, Fresnel prisms can be placed over spectacles to allow fusion. However, this

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often is fraught with difficulty, because the deviation is usually quite incomitant and torsion cannot be corrected. Patients who have fourth nerve palsies that arise from compressive lesions often do not improve and require surgery. Surgical options for the treatment of superior oblique palsy are complex and are beyond the scope of this chapter. Knapp36 and Scott and Kraft37, 38 have proposed surgical classification schemes; this author prefers that of Scott because it is more detailed and has better long-term follow-up. Congenital superior oblique palsies often are associated with abnormalities of the insertion of the superior oblique tendon and have been discussed by Wallace and von Noorden.39

Palsies of the Sixth Cranial Nerve

Nearly all patients who have sixth nerve palsies experience diplopia. During the acute phase, this is best managed by patching the paretic eye or by frosting a spectacle lens. Prisms usually are not well tolerated because of

the magnitude and incomitance of the deviation. Botulinum toxin may prevent secondary contracture of the antagonist medial rectus and allow fusion with a small face turn while recovery of lateral rectus function occurs.40 Botulinum toxin injection probably does not decrease the need for later surgical intervention of unilateral sixth nerve palsy.41, 42 Surgical intervention for sixth nerve palsy is indicated when the ­deviation has been stable for a minimum of 6 months. Preoperative evaluation should include determination of corneal sensation and lid closure; patients may experience corneal damage if the eye is brought to primary position and lid closure is inadequate. The choice of surgical procedure for chronic sixth nerve palsies depends upon the recovery of function of the lateral rectus muscle, which can be assessed by ­determining the saccadic velocity. Patients who have good return of function usually do quite well with an ipsilateral recess−resect procedure. ­Patients who have little or no lateral rectus function need muscle transposition surgery.

REFERENCES   1. Miller NR. Topical diagnosis of neuropathic ocular motility disorders. In: Miller NR, ed. Walsh & Hoyt’s clinical neuro-ophthalmology, 4th ed. Baltimore: Williams & Wilkins; 1985:652–784.   2. Rush JA, Younge BR. Paralysis of cranial nerves III, IV, and VI. Cause and prognosis in 1000 cases. Arch Ophthalmol. 1981;99:76–9.   3. Berlit P. Isolated and combined pareses of cranial nerves III, IV, and VI. A retrospective study of 412 patients.   J Neurol Sci. 1991;103:10–5.   4. Richards BW, Jones FR Jr. Younge BR. Causes and prognosis in 4278 cases of paralysis of the oculomotor, trochlear, and abducens cranial nerves. Am J Ophthalmol. 1992;113:489–96.   5. Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol. 1992;114:568–74.   6. Balkan R, Hoyt CS. Associated neurologic abnormalities in congenital third nerve palsies. Am J Ophthalmol. 1984;97:315–9.   7. Hamed LM. Associated neurologic and ophthalmologic findings in congenital oculomotor nerve palsy. Ophthalmology. 1991;98:708–14.   8. Good WV, Barkovich AJ, Nickel BL, Hoyt CS. Bilateral congenital oculomotor nerve palsy in a child with brain anomalies. Am J Ophthalmol. 1991;111:555–8.   9. Warwick R. Representation of the extraocular muscles   in the oculomotor nuclei of the monkey. J Comp Neurol. 1953;98:449–503. 10. Daroff RB. Oculomotor manifestation of brainstem and cerebellar dysfunction. In: Smith JL, ed. Neuroophthalmology: symposium of the University of Miami and Bascom-Palmer Eye Institute, vol 5. Hallandale: Huffman; 1971:104–21. 11. Bryan JS, Hamed LM. Levator-sparing nuclear oculomotor palsy. Clinical and magnetic resonance imaging findings. J Clin Neuroophthalmol. 1992;12:26–30. 12. Martin TJ, Corbett JJ, Babidian PV, et al. Bilateral ptosis due to mesencephalic lesions with relative preservation of ocular motility. J Neuroophthalmol. 1996;16:258–63. 13. Pratt DV, Orengo-Nania S, Horowitz BL, Oram O. Magnetic resonance imaging findings in a patient with nuclear oculomotor palsy. Arch Ophthalmol. 1995;113:141–2. 14. Barton JJ, Kardon RH, Slagel D, Thompson HS. Bilateral central ptosis in acquired immunodeficiency syndrome. Can J Neurol Sci. 1995;22:52–5.

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15. Keane JR, Zaias B, Itabashi HH. Levator-sparing oculomotor nerve palsy caused by a solitary midbrain metastasis. Arch Neurol. 1984;41:210–2. 16. Warren W, Burde RM, Klingele TG, Roper-Hall G.   Atypical oculomotor paresis. J Clin Neuroophthalmol. 1982;2:13–8. 17. Ksiazek SM, Slamovits TL, Rosen CE, et al. Fascicular   arrangement in partial oculomotor paresis. Am   J Ophthalmol. 1994;118:97–103. 18. Ksiazek SM, Repka MX, Maguire A, et al. Divisional oculomotor nerve paresis caused by intrinsic brainstem disease. Ann Neurol. 1989;26:714–8. 19. Breen LA, Hopf HC, Farris BK, Gutmann L. Pupil-sparing oculomotor nerve palsy due to midbrain infarction.   Arch Neurol. 1991;48:105–6. 20. Fleet WS, Rapcsak SZ, Huntley WW, Watson RT. Pupilsparing oculomotor palsy from midbrain hemorrhage. Ann Ophthalmol. 1988;20:345–6. 21. Hopf HC, Gutmann L. Diabetic 3rd nerve palsy:   evidence for a mesencephalic lesion. Neurology. 1990;40:1041–5. 22. Norman MG. Unilateral encephalomalacia in cranial nerve nuclei in neonates. Report of two cases. Neurology. 1974;24:424–7. 23. Victor DI. The diagnosis of congenital unilateral thirdnerve palsy. Brain. 1976;99:711–8. 24. Loewenfeld IE, Thompson HS. Oculomotor paresis   with cyclic spasms. A critical review of the literature and a new case. Surv Ophthalmol. 1975;20:81–124. 25. von Noorden GK, Murray E, Wong SY. Superior oblique paralysis. Arch Ophthalmol. 1986;104:1771–6. 26. Brazis PW. Palsies of the trochlear nerve: diagnosis and localization – recent concepts. Mayo Clin Proc.. 1993;68:501–9. 27. Keane JR. Fourth nerve palsy: historical review and study of 215 inpatients. Neurology. 1993;43:2439–43. 28. Guy J, Day AL, Mickle JP, Schatz NJ. Contralateral trochlear nerve paresis and ipsilateral Horner’s syndrome.   Am J Ophthalmol. 1989;107:73–6. 29. Tachibana H, Minura O, Shiomi M, Oono T. Bilateral trochlear nerve palsies from a brainstem hematoma.   J Clin Neuroophthalmol. 1990;10:35–7. 30. Eliott D, Cunningham ET Jr, Miller NR. Fourth nerve paresis and ipsilateral relative afferent pupillary defect without visual sensory disturbance. J Clin Neuroophthalmol. 1991;11:169–72.

31. Slavin ML. Hyperdeviation associated with isolated unilateral abducens palsy. Ophthalmology. 1989;96:512–6. 32. Muri RM, Chermann JF, Cohen L, et al. Ocular motor consequences of damage to the abducens nucleus   area in humans. J Neuroophthalmol. 1996;16:191–5. 33. Wall M, Wray SH. The one-and-a-half syndrome − a unilateral disorder of the pontine tegmentum: a study of 20 cases and review of the literature. Neurology. 1983;33:971–80. 34. Robertson DM, Hines JD, Rucker CW. Acquired sixth nerve paresis in children. Arch Ophthalmol. 1970;83:574–9. 35. van Noorden GK, Campos EC. Binocular vision and ocular motility, 6th ed. St Louis: Mosby; 2002. 36. Knapp P. Classification and treatment of superior oblique palsy. Am Orthopt J. 1974;24:18–22. 37. Scott WE, Kraft SP. Classification and surgical treatment of superior oblique palsies: I. Unilateral superior oblique palsies. New Orleans Academy of Ophthalmology. Pediatric ophthalmology and strabismus: transactions of the New Orleans Academy of Ophthalmology. New York: Raven Press; 1986 :15–38. 38. Scott WE, Kraft SP. Classification and treatment of superior oblique palsies: II. Bilateral superior oblique palsies. New Orleans Academy of Ophthalmology. Pediatric ophthalmology and strabismus: transactions of the New Orleans Academy of Ophthalmology, New York: Raven Press; 1986. :265–91. 39. Wallace DK, von Noorden GK. Clinical characteristics   and surgical management of congenital absence of the superior oblique tendon. Am J Ophthalmol. 1994;118:63–9. 40. Repka MX, Lam GC, Morrison NA. The efficacy of botulinum neurotoxin A for the treatment of complete and partially recovered chronic sixth nerve palsy. J Pediatr Ophthalmol Strabismus. 1994;31:79–83. 41. Lee J, Harris S, Cohen J, et al. Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. J Pediatr Ophthalmol   Strabismus. 1994;31:283–6. 42. Archer S. Study needs more statistical power. J Pediatr Ophthalmol Strabismus. 1995;32:142.

PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

9.15

Mark L. Moster Definition:  Dysfunction of one or more of the three cranial nerves that move the eyes.

Key features n n

Diplopia. Dysconjugate gaze.

Associated features n n n n n n

Ptosis. Pupillary abnormalities. Pain. Proptosis. Chemosis. Arterialization of conjunctival vessels.

INTRODUCTION One of the common clinical presentations in neuro-ophthalmology involves dysfunction of the ocular motor nerves, cranial nerves III (oculomotor nerve), IV (trochlear nerve), and VI (abducens nerve). In this chapter the anatomy of the peripheral course of the ocular motor nerves is reviewed, and various clinical syndromes are discussed. The syndromes include isolated involvement of each nerve, involvement of multiple cranial nerves simultaneously, involvement of the third, fourth, and sixth cranial nerves with other neurological or orbital symptoms and signs, and involvement of these cranial nerves with severe pain. An approach to the differential diagnosis of patients who seek treatment for involvement of the ocular motor nerves and guidelines for evaluation and treatment are also given.

ANATOMY The clinical localization and subsequent differential diagnosis of cranial neuropathies requires knowledge of the anatomy of the third, fourth, and sixth cranial nerves. The anatomy within the brainstem is covered in Chapter 9.14; here, the relevant anatomy of the motor nerves from the brainstem exit to the eye is given (Fig. 9-15-1). The third cranial nerve exits the midbrain anteriorly to enter the subarachnoid space. It moves forward and laterally, passes between the posterior cerebral artery and superior cerebellar artery, and then runs alongside the posterior communicating artery. The nerve pierces the dura to enter the cavernous sinus, where it runs along the lateral wall, superior to the fourth cranial nerve. It enters the orbit via the superior orbital fissure. In the anterior cavernous sinus, it divides into the superior and inferior divisions. The superior division ascends lateral to the optic nerve to supply the superior rectus and levator palpebrae superioris muscles. The inferior division divides into branches that supply the inferior rectus, inferior oblique, and medial rectus muscles and the

pupillary sphincter. Parasympathetic preganglionic fibers travel along the branch to the inferior oblique and terminate in the ciliary ganglion near the apex of the extraocular muscle cone. The postganglionic fibers from the ciliary ganglion travel in the short ciliary nerves, along with the sympathetic fibers, to enter the globe at the posterior aspect near the optic nerve. They terminate in the ciliary body and iris, and control pupillary constriction and accommodation via the ciliary muscles. The trochlear nucleus lies in the midbrain, at the level of the inferior colliculus, inferior to the third nerve complex, and anterior to the cerebral aqueduct. The fourth cranial nerve exits the midbrain dorsally and crosses to the opposite side, within the anterior medullary velum, just below the inferior colliculi. The nerve crosses forward within the subarachnoid space around the cerebral peduncle and runs between the posterior cerebral and superior cerebellar arteries, along with the third nerve. The fourth cranial nerve pierces the dura at the angle between the free and attached borders of the tentorium cerebelli to enter the cavernous sinus. It runs within the lateral wall of the cavernous sinus, just below the third cranial nerve and above the first division of the fifth cranial nerve (trigeminal nerve). It enters the orbit via the superior orbital fissure, but runs outside the annulus of Zinn and diagonally across the levator palpebrae superioris and superior rectus muscle to reach the superior oblique muscle. It supplies the superior oblique muscle, the main action of which is to depress the eye in the adducted position. Secondary actions are incyclotorsion and abduction of the eye. The abducens nerve exits the brainstem at the junction of the pons and pyramid of the medulla, and ascends through the subarachnoid space along the surface of the clivus. It runs forward over the petrous apex of the temporal bone and beneath the petroclinoid ligament to enter the cavernous sinus. In the cavernous sinus, it runs lateral to the internal carotid artery, but medial to the third and fourth cranial nerves and first and second divisions of the fifth cranial nerve, which run in the lateral wall. It enters the superior orbital fissure and passes through the annulus of Zinn to innervate the lateral rectus muscle.

OCULAR MANIFESTATIONS General Symptoms

The universal symptom associated with dysfunction of the ocular motor nerves is binocular diplopia. With third cranial nerve dysfunction, ptosis and mydriasis are also symptoms. Diplopia occurs when an object projects onto retinal points that do not correspond in both eyes. The diplopia is worst in the direction of action of the weak muscle(s). However, diplopia may not occur with poor visual acuity, ptosis or in ­patients affected by a suppression scotoma from congenital ­strabismus. On examination, a patient who has binocular diplopia demonstrates an ocular deviation. Numerous examination techniques are available to measure ocular deviations, which include the use of prism lenses with the cover−uncover or alternate cover technique, the red glass test, the Maddox rod, and the Hess or Lancaster screen. The examiner must become familiar and proficient with one or more of these techniques (Chapter 11.13) to adequately assess patients who have diplopia. A tendency toward ocular deviation that variably is present is termed a phoria, whereas a constantly manifest deviation is a tropia. When a measured deviation is similar in all gaze directions, it is a comitant

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CRANIAL NERVES III, IV, AND VI, LATERAL VIEW

NEURO-OPHTHALMOLOGY

IVth nucleus to contralateral superior oblique

IIIrd nucleus

posterior communicating artery

levator superior rectus palpebrae

superior oblique

midbrain

pons

medulla

VIth nucleus to ipsilateral lateral rectus

petroclinoid ligament

VIth nerve

IVth nerve

IIIrd cavernus sinus nerve

lateral medial rectus rectus

inferior oblique

Fig. 9-15-1  Lateral view of cranial nerves III, IV, and VI from the brainstem nuclei to the orbit. The third nerve exits the midbrain anteriorly, crosses near the junction of the internal carotid and posterior communicating artery in the subarachnoid space, and enters the cavernous sinus, where it runs in the lateral wall. The fourth nerve exits the midbrain posteriorly and crosses to the opposite side, to move forward in the subarachnoid space and into the cavernous sinus. The sixth nerve exits the pons anteriorly, ascends along the clivus bone, crosses the petrous apex, and descends below the petroclinoid ligament to enter the cavernous sinus, where it runs between the lateral wall and the carotid artery.

deviation; when it varies by direction it is incomitant. Congenital strabismus most often presents with a comitant deviation. Acquired cranial neuropathies appear with a ductional deficit on examination that corresponds to weakness in the appropriate muscle(s) innervated by the cranial nerve(s) involved. In a more subtle deficit, ductions may appear full, but an incomitant deviation greatest in the direction of action of the paretic muscle is seen. When a cranial neuropathy is chronic, spread of comitance may occur, and the deviation mimics that of congenital strabismus.

Isolated Cranial Neuropathies

In this section, the assessment of patients affected by isolated involvement of the third, fourth, or sixth cranial nerve, with no other neurological or ophthalmologic signs, is discussed.

Isolated sixth cranial nerve palsy

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An isolated sixth nerve paresis appears with a unilateral abduction deficit of variable degree, from a complete inability to abduct past the midline to a mild incomitant esodeviation greatest on lateral gaze. Abduction saccades in the affected eye are slow. The history consists of binocular uncrossed diplopia, worse in the direction of the lesion and worse at distance than near. Figure 9-15-2 demonstrates the deviation seen using a Maddox rod in a patient who has a right sixth nerve paresis. Congenital sixth nerve palsy is rare and may be related to birth trauma. The deficit often is transient, and resolves in the first month of life.1–3 Other congenital abnormalities of the sixth nerve, such as Möbius’ syndrome and Duane’s retraction syndrome, show other findings and are discussed in the section on differential diagnosis. An isolated, acquired sixth nerve paresis may arise from a lesion anywhere in the course of the sixth nerve, from the fascicular portion in the brain to the orbit. Since other symptoms and signs are not present to help localization, the differential diagnosis is extensive. In children, isolated sixth nerve paresis may be a relatively ­ benign occurrence after viral infection, but it is also a presenting sign of

intracranial tumor.2, 3 In old age, isolated sixth nerve paresis is quite common because of ischemic infarction. In young adults, postviral and ischemic lesions are less common, but trauma, neoplasm, and demyelinating disease are more common.4, 5 In the era of magnetic resonance imaging (MRI), demyelinating disease is likely the most common diagnosis eventually made in young adults with an isolated sixth nerve paresis.5 Vincristine toxicity may cause isolated sixth nerve palsy.6 Traumatic sixth nerve injury is often associated with fractures of the petrous bone or clivus. Other clinical findings include mastoid ecchymosis (Battle’s sign) and cerebrospinal fluid otorrhea. Chronic sixth nerve paresis results from many of the same causes as acute sixth nerve paresis but more often arises from a compressive lesion.7–10 A syndrome of benign recurrent sixth nerve paresis may occur,11 particularly in children. However, skull-base tumors also may present in this manner,12 and remission of a sixth nerve paresis is not always a sign of a benign sixth nerve paresis. Although each series reviews patients differently, some generalizations are apparent from reports of isolated and nonisolated sixth nerve paresis.2–5, 13–20 In adults affected by isolated sixth nerve paresis, the cause is more likely to be ischemia, in comparison with those who have nonisolated sixth nerve paresis. Tumor, trauma, or aneurysm are more often present in nonisolated cases. Also, tumor is a more common cause of sixth nerve paresis in young adults and children than in older patients.

Isolated fourth cranial nerve palsy

A fourth nerve or trochlear palsy manifests with an isolated, vertical, diagonal, or cyclotorsional diplopia and is the most common cause of vertical diplopia. The diplopia is usually worse looking down, as in reading, and is worse when looking to the side opposite the lesion. On examination a spontaneous head tilt may occur to the side ­opposite the fourth nerve paresis. In addition, the head may be turned down, with the chin depressed, the eyes up, and the face turned to the side opposite the paresis, to diminish the diplopia.

RIGHT VIth NERVE PARESIS, MADDOX ROD TEST

PARKS–BIELSCHOWSKY THREE-STEP TEST

Eight possible muscles involved: right/left: superior rectus, superior oblique, inferior rectus, inferior oblique

Step 1: Which eye is hypertropic?

Right hypertropia

Step 2: Which lateral direction has worse hypertropia?

Worse in left gaze

Four possible muscles: right: superior oblique, inferior rectus; left: superior rectus, inferior oblique

Esodeviation as the patient looks toward the right

Fig. 9-15-2  Right sixth cranial nerve paresis evaluated by the Maddox rod test. A Maddox rod is placed in front of the patient’s right eye. Subjective deviation between the light and the line is noted by the patient in different positions of gaze. An esodeviation greatest as the patient looks to the right is consistent with a right lateral rectus muscle weakness.

Ductions may be normal or show a mild decrease of depression of the adducted eye. Examination using the Parks-Bielschowsky three-step test (Fig. 9-15-3) shows a hyperdeviation that is worse on contralateral gaze, downgaze, and ipsilateral head tilt. A fourth step that demonstrates the deviation is worse in downgaze than upgaze is confirmatory. With time, spread of comitance may develop. Double Maddox rod testing shows excyclotorsion (Fig. 9-15-4) − if the excyclotorsion is > 10°, fourth nerve paresis is likely to be bilateral. Congenital fourth nerve paresis is common. Patients affected by a congenital paresis may experience acute diplopia at any age, but often they are in the fifth to seventh decades of life. The diplopia may occur as a decompensation during periods of stress. Examination of photographs of the patient at a younger age is important, in that a persistent head tilt to one direction may be demonstrated. In addition, if a fourth nerve paresis is congenital, a large-amplitude vertical fusional capacity of > 6 D, often 10−15 D, is present. The most common cause of acquired fourth nerve paresis is trauma that affects the nerve along the tentorial edge or the anterior medullary velum. In addition, the fourth nerve is the ocular motor nerve most commonly injured by trauma. In this situation, the fourth nerve paresis may be bilateral (discussed below in the section on bilateral ophthalmoplegia). Inflammatory and infectious lesions in the subarachnoid space may also affect the fourth nerve. Pinealoma or tentorial meningioma may compress the fourth nerve. In children with fourth nerve paresis, congenital factors are likely the leading cause (which may appear later in childhood or in adulthood), followed by trauma.2 Structural lesions account for a minority of cases. In elderly patients, particularly those who have hypertension or diabetes, vasculopathic ischemic infarction is a likely cause of fourth nerve paresis. Less common causes include tumor that involves the midbrain or cerebellum, aneurysm, or herpes zoster ophthalmicus.21 The fourth nerve may become involved with herpes zoster ophthalmicus because it shares the same connective tissue sheath as the ophthalmic division of the fifth cranial nerve. The cause of fourth nerve paresis has been studied in numerous series.2, 3, 13, 15, 18–20, 22–25 Causes include trauma, ischemia, tumor, aneurysm, and demyelination. Trauma is a more common cause of a fourth nerve paresis than of third and sixth nerve pareses.

Step 3: In which head tilt direction is it worse?

Step 4: Confirmatory. Is it worse in upgaze or downgaze?

Two possible muscles: right superior oblique, left superior rectus

Worse in right head tilt One possible muscle: right superior oblique

Worse in downgaze Confirms right superior oblique; helps rule out mimickers, such as myasthenia and thyroid disease

Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

Hypertropia

9.15

Fig. 9-15-3  Parks-Bielschowsky three-step test. In a patient who has a vertical deviation because of a weakness in a single muscle, this three-step test determines which muscle is weak. Step four confirms that the correct muscle has been identified and helps to rule out other causes of vertical deviation.

Isolated third cranial nerve palsy

Patients who have third nerve palsy have a history of horizontal and/ or vertical binocular diplopia, ptosis, or complaints of enlarged pupil or difficulty in focusing, with involvement of accommodation (Fig. 9-15-5); various combinations of these may occur. Diplopia may be absent because ptosis effectively occludes one eye. Isolated ptosis or mydriasis usually is not a sign of third nerve palsy. When complete, the eye may be deviated down and out. When the motility defect is more subtle, exotropia on adduction, hypotropia on elevation, and hypertropia on depression occurs in the involved eye. The diagnostic considerations in isolated third nerve palsy depend on the age of the patient, in a similar way to involvement of the fourth or sixth cranial nerves. In a truly isolated third nerve palsy, the presumed location is the subarachnoid space. However, lucencies in the midbrain have been demonstrated by MRI in patients who have isolated third nerve palsies on a vasculopathic basis; these suggest the infarct is in the brainstem itself. The major differential diagnoses in an adult who has isolated third nerve palsy are vasculopathic infarction, vasculitic infarction (as in giant cell arteritis), a compressive lesion (usually from aneurysm), trauma, meningeal inflammation (such as with infection26 or tumor), ophthalmoplegic migraine, or demyelination. Third nerve palsy is a rare complication of internal carotid artery dissection27 or chemotherapeutic toxicity.28

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13 5

NEURO-OPHTHALMOLOGY

DOUBLE MADDOX ROD TEST FOR EXCYCLOTORSION

13 5

9

Several series have looked at the causes of isolated and nonisolated third nerve paresis with similar findings as in fourth and sixth nerve paresis.2, 3, 13, 15, 18–20, 25, 29–32 From these studies, third nerve paresis is associated more frequently with aneurysm than are fourth or sixth nerve pareses. Ophthalmoplegic migraine is only associated with a third nerve paresis. As with the sixth nerve paresis, isolated lesions more often are ischemic than nonisolated ones.

45

60

12

0

13

5

Fig. 9-15-4  Double Maddox rod test for excyclotorsion. A red Maddox rod is placed in front of the right eye and a white Maddox rod in front of the left eye in a trial frame or phoropter. In a patient who has vertical diplopia, one line is above the other. With excyclotorsion, the two lines are not parallel, but cross each other. One of the Maddox rods is then rotated until the two lines appear parallel. The degree of rotation required (in this case about 12 degrees) to make the lines parallel determines the degree of excyclotorsion.

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Patients who have a vasculopathic third nerve palsy often have pain that precedes the ptosis or diplopia. In a vasculopathic lesion, the pupillary reaction is usually spared, and the pupil does not become enlarged. However, in up to 38% of cases, the pupil may be involved, usually with less than 1 mm of anisocoria.33 Clinical associations include diabetes, hypertension, or other risk factors for atherosclerosis. The natural course of a vasculopathic, isolated third nerve palsy is one of recovery over weeks to months, usually 3 months. The pupil is spared because the infarction occurs in the center of the nerve and good collateral supply exists in the nerve periphery, where the pupillary fibers are located. One of the true neuro-ophthalmologic emergencies occurs when compression of the third nerve results from an expanding aneurysm at the junction of the internal carotid and posterior communicating arteries. Such compressions most often, but not always, are painful, and in almost all instances involve the pupil. However, numerous case reports of isolated third nerve palsy caused by expanding aneurysms show that the pupil may be spared initially.34 Often, these patients have only partial ptosis and extraocular muscle involvement, and, with very rare exceptions, the pupil becomes involved within 1 week of symptom onset. This situation is one of the few life-threatening emergencies in neuroophthalmology and one in which appropriate diagnosis and treatment is lifesaving. In contrast to an acute third nerve palsy, a slowly progressive third nerve palsy that involves the pupil usually is a sign of an enlarging cavernous sinus lesion.35 Ophthalmoplegic migraine is a syndrome that becomes apparent with a migraine-type headache and the development of a third nerve palsy; the pupil is usually involved. The pain precedes the oculomotor paresis and is intense, continuous, and located in the orbital region. As the paralysis reaches its maximum, the headache begins to recede. The initial presentation is usually in childhood, multiple attacks may occur, and a family history of migraine is often present. The third nerve palsy may last from hours to weeks, and ­ permanent deficits occur after repeated attacks.36 MRI shows enlargement and ­enhancement of the third nerve as it exits the brainstem, which is more prominent during the attack.37 A rare syndrome in children is a recurrent isolated third nerve palsy, which resolves without deficit. Some patients later develop migraine, and some investigators consider this a variant of ophthalmoplegic migraine.1 A case of recurrent postviral oculomotor paresis at age 11 months and

Fig. 9-15-5  Isolated third nerve palsy in the setting of herpes zoster ophthalmicus. At the time of acute illness. Note the presence of herpes zoster lesions in the distribution of the first division of the fifth nerve. Third nerve palsy consists of ptosis, adduction, elevation, and depression deficit with preserved abduction.

Multiple cranial neuropathies

In contrast with isolated mononeuropathies, which are often benign and vasculopathic in nature, involvement of more than one ocular ­motor nerve rarely results from vasculopathic lesions.46 It is very important to ascertain that multiple nerves are involved, because establishment of this enables localization of the lesion responsible. For the most part, these patients have lesions of the cavernous sinus, superior orbital fissure, or orbital apex. Since the first division of the fifth cranial nerve is also involved in such lesions, pain may be a prominent feature. Causes of multiple cranial nerve involvement have been reviewed in numerous series.15, 18, 19 In contrast to isolated mononeuropathies, ischemia is an infrequent cause, and tumor, inflammation, trauma, and aneurysm are more common. Typically, fourth nerve paresis is associated with hyperdeviation, most noticeable when the eye is adducted. In the presence of a third nerve paresis, the eye does not adduct, which makes it difficult to determine the presence of a coexisting fourth nerve paresis. In this situation, the eye is examined carefully for intorsion of the globe on attempted downgaze, from which secondary action of the fourth nerve is assessed. This is accomplished most easily by visualization of a conjunctival ­vessel for intorsion (Fig. 9-15-6). On occasion, the third and fourth cranial nerves may be involved together in the brainstem, usually with other neurological deficits. These cranial nerves may be involved together in the subarachnoid space also, as discussed below. Because the sixth nerve crosses along the petrous apex, a syndrome that includes sixth nerve palsy, facial pain, hearing loss, and (sometimes) facial paralysis may occur. This is known as Gradenigo’s syndrome and may result from infectious mastoiditis, tumor, trauma, aneurysm of the petrosal segment of the internal carotid artery, or inferior petrosal sinus thrombosis. Petrous bone fractures involve combinations of the fifth, sixth,

9.15 Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

39 months has been described, with steroid response and enhancement of the cisternal portion of the oculomotor nerve during the episodes.38 Other causes of isolated third nerve palsy in the subarachnoid space include trauma and infectious or neoplastic meningitis. Aberrant regeneration refers to an abnormality found on examination, after recovery of the third nerve from damage that caused disruption of the axons as a result of a structural lesion.39 The abnormal activation of one part of the third nerve is found when another part should be in action. For instance, if fibers originally destined for the medial rectus now supply the levator palpebrae superioris, then on adduction of the eye the lid elevates (so-called lid-gaze dyskinesis). If the same fibers now innervate the pupil, on adduction of the eye the pupil constricts. This may give rise to pupillary light−near dissociation. Another common pattern of aberrant regeneration is elevation of the eyelid on downgaze, the pseudo-Von Graefe’s phenomenon, because fibers destined for the inferior rectus now go to the levator palpebrae superioris. Cocontraction of vertically acting muscles may limit vertical excursion of the eye and be associated with retraction of the globe. When aberrant regeneration is found, the diagnosis is not an isolated ischemic lesion, but a structural lesion. Primary aberrant regeneration refers to the findings above, but with no antecedent third nerve palsy. This suggests a compressive lesion of the third nerve that slowly evolves with ongoing recovery to produce the aberrant regeneration without clinical realization of a third nerve palsy. This has been described with lesions that slowly evolve, ­usually in the cavernous sinus. Most often these are internal carotid artery ­aneurysms, intracavernous meningiomas, or neurinomas.40, 41 Occasionally, aberrant regeneration may occur between the sixth and third nerve. For example, on attempted abduction, the lid elevates and the eye adducts. This has been described after trauma with initially complete ophthalmoplegia.42 A rare congenital condition, with unknown cause, is cyclic oculomotor paralysis with spasm. This encompasses a condition that cycles between an oculomotor paresis as described above and periods of oculomotor spasm that occur every 1.5–2 minutes and persists throughout life. During the periods of oculomotor spasm, the eye may be adducted, the lid elevated, the pupil miotic, and accommodation increased. After a 10–60 second interval, the eye becomes deviated outward with ptosis and mydriasis.43 A few patients with brief (30 seconds to 4 hours) recurrent transient oculomotor paresis with negative evaluations have been described.44

Divisional third cranial nerve palsy

The third nerve divides in the anterior cavernous sinus into a superior and inferior division − lesions may affect either division. A superior division third nerve palsy manifests with an isolated elevation deficit and ptosis of one eye. An inferior division third nerve palsy may cause mydriasis, and an adduction and depression deficit without ptosis or elevation deficit. Divisional palsies usually result from a structural lesion in the anterior cavernous sinus or orbit. A characteristic example is a superior division third nerve paresis from an ophthalmic artery aneurysm. However, divisional palsies have been described as far posteriorly as the anterior midbrain, likely because fibers have segregated into different portions of the nerve at this point. In addition, cases exist of benign, remitting pareses of either division of the third nerve.45

A

Nonisolated Cranial Neuropathies

When a patient affected by involvement of an ocular motor nerve has other findings, the approach to evaluation changes. The associated findings are clues to the localization and character of the lesion and may include brainstem neurological deficits, meningeal signs, involvement of other ocular motor or other cranial nerves, and ­orbital signs. Nerve palsies that arise in the brainstem most often are associated with long-tract findings, alterations in consciousness, or other ­cranial neuropathies, and are covered in Chapter 9.14. When ­accompanied by other cranial nerve involvement without brainstem findings, the likely localization includes the subarachnoid space, cavernous sinus, and orbit. Those nerve palsies associated with proptosis, chemosis, and visual loss often arise in the orbit, and are covered in Chapter 12.12. In this section, nonisolated cranial neuropathies are reviewed. They are subdivided into categories of multiple cranial neuropathies, bilateral cranial neuropathies, and lesions in the subarachnoid space that may cause both multiple unilateral or bilateral cranial neuropathies.

B

Fig. 9-15-6  Demonstration of intact fourth cranial nerve in the presence of a third nerve paresis. (A) The patient’s right eye is exotropic from a complete third nerve palsy. (B) However, an intact fourth nerve is noted on attempted downgaze because of incyclotorsion of the eye. This is best seen by comparison of   the conjunctival vessels in (A) with their position in (B) on attempted downgaze.

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ANATOMY OF THE CAVERNOUS SINUS

NEURO-OPHTHALMOLOGY

Coronal view pituitary gland

sympathetic plexus

Lateral view IIIrd cranial IIIrd cranial nerve nerve IVth cranial nerve IVth cranial nerve ophthalmic nerve gasserian VIth cranial ganglion nerve

internal carotid artery

maxillary nerve

abducens internal carotid nerve artery

sympathetic plexus

mandibular nerve maxillary nerve

optic nerve

Fig. 9-15-7  Anatomy of the cavernous sinus. Coronal and lateral views. (From Kline LB. The Tolosa-Hunt syndrome. Surv Ophthalmol. 1982;27:79–95.)

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seventh, and/or eighth cranial nerves and other findings of hemotympanum, Battle’s sign (mastoid hematoma), and cerebrospinal fluid otorrhea. The cavernous sinus consists of a plexus of veins. Within the plexus lies the sixth nerve and within the lateral wall lies the third nerve, fourth nerve, first division of the fifth nerve, and, posteriorly, the second division of the fifth nerve. Within the cavernous sinus, the sympathetic fibers form a plexus along the carotid artery (Fig. 9-15-7). The superior orbital fissure contains the same nerves as the ­anterior cavernous sinus. Therefore, signs and symptoms of cavernous sinus and superior orbital fissure lesions may be identical. The findings include involvement of any of the above cranial nerves in isolation or in various combinations. Therefore, third nerve paresis, fourth nerve paresis, sixth nerve paresis, Horner’s syndrome, and sensory loss of the first division of the fifth nerve all may be present, and, if a lesion is in the posterior cavernous sinus, there may be involvement of the second division of the fifth nerve. The pupil may be involved, spared, or appear spared with concomitant oculosympathetic and parasympathetic involvement. Various degrees of pain may be involved and, if pain is severe, “painful ophthalmoplegia syndrome” is diagnosed.47 Broad categories of diseases that involve the cavernous sinus include neoplasms, inflammation, infection, vascular lesions, and trauma.48–51 Neoplastic lesions include local metastatic disease from nasopharyngeal cancer, olfactory neuroblastoma, adenoid cystic carcinoma, cylindroma, ameloblastoma, and squamous cell carcinoma, or disease that spreads from distant lesions, which includes carcinoma, sarcoma, multiple myeloma, and lymphoma. Local spread of benign tumors includes pituitary adenoma, meningioma, craniopharyngioma, neurilemmoma, and epidermoid tumor. Chordomas, chondromas, and giant cell tumors may also spread in the cavernous sinus. Meningiomas may arise in the cavernous sinus itself. Neuromas, neurofibromas, or schwannomas may occur on the gasserian ganglion or the other cranial nerves.52 Pituitary apoplexy is a clinical syndrome caused by sudden enlargement in a pituitary tumor as a result of acute hemorrhage or edema. The patient may have had previous symptoms or have a clinically silent lesion that appears acutely because of the sudden change. The presentation has variable features that include acute and severe headache, diplopia with ophthalmoplegia from cavernous sinus involvement, visual loss from optic nerve, chiasm, or tract involvement, meningismus from hemorrhage into the subarachnoid space, and endocrine insufficiency. Inflammatory lesions may be both infectious and noninfectious. Bacterial infections may cause cavernous sinus thrombosis, which causes a unilateral or bilateral cavernous sinus syndrome, proptosis, and chemosis associated with signs of fever, depressed mental status, and signs of sepsis. Spread of infection from sinusitis or a mucocele from the paranasal sinuses may cause compression of the cavernous sinus. Mucormycosis is a life-threatening infection that may affect the ­cavernous sinus, superior orbital fissure, or orbit. Multiple cranial neuropathies may occur relatively rapidly in a predisposed patient, such as

a diabetic or an immunosuppressed patient. Often an indicative eschar is seen in the nose in such patients. An occlusive vasculitis may occur with stroke that affects the brain or eye. To make the diagnosis, a high index of suspicion is required in the appropriate patient. Aspergillosis also may involve the orbital apex or cavernous sinus. Rarely, other infections such as syphilis or tuberculosis may affect the cavernous sinus. Herpes zoster, usually ophthalmic but even with cervical involvement, may be followed by abnormalities of the cavernous sinus. Most often this consists of involvement of one cranial nerve − an isolated third, fourth, or sixth dysfunction − after zoster in the first division of the fifth cranial nerve.21, 53 Occasionally, multiple cranial nerves may be involved. Inflammatory, noninfectious lesions include sarcoidosis, Wegener’s granulomatosis, eosinophilic granuloma, and the idiopathic TolosaHunt syndrome; the last causes painful ophthalmoplegia. The pain is described as gnawing or boring and may precede ophthalmoplegia. The ophthalmoplegia arises from combinations of third (most frequently), fourth, or sixth nerve involvement. Other findings include Horner’s syndrome, proptosis, optic nerve involvement, fifth nerve (divisions 1−3) involvement, or seventh nerve paresis.47, 54, 55 The symptoms last for days to weeks and spontaneous remissions occur, with or without residual deficits. Recurrences may occur at intervals of months to years. Vascular causes of a cavernous sinus syndrome include carotid artery aneurysm, cavernous sinus thrombosis, direct carotid artery to cavernous sinus fistula, and dural arteriovenous fistula. Intracavernous carotid artery aneurysms are saccular aneurysms that develop most commonly from atherosclerosis. They cause slowly progressive ophthalmoplegia through enlargement, often with aberrant regeneration, and may cause an acute carotid cavernous fistula if they bleed. The other cause of a ­direct carotid cavernous fistula is a condition resulting from trauma that directly damages the internal carotid artery. A direct carotid cavernous fistula causes a cavernous sinus syndrome, as well as headache, facial pain, severe proptosis, chemosis, and injection of the eye, with arterialization of conjunctival and episcleral vessels. Often pulsatile tinnitus and an orbital bruit occur, and retinal venous engorgement and hemorrhage, central retinal vein occlusion, retinal ischemia, serous retinal or choroidal detachment, and anterior ischemic optic neuropathy may also be seen. Intraocular pressure may be elevated and angle-closure or neovascular glaucoma may develop. A less serious fistula results from a dural arteriovenous connection in which multiple dural vessels that come off the arterial system connect directly with the cavernous sinus. This occurs most often in elderly women and has a subacute or chronic course. The findings include the above cranial neuropathies, as well as proptosis, orbital bruit, and conjunctival injection, none as severe as those associated with a direct internal carotid cavernous fistula. The more subtle clinical picture means that these patients are often misdiagnosed with chronic conjunctivitis, episcleritis, or thyroid ophthalmopathy (Fig. 9-15-8).

9.15

B

Fig. 9-15-8  Dural arteriovenous fistula. (A) Patient had diplopia that resulted from a left sixth nerve paresis, Horner’s syndrome, proptosis, chemosis, and injection with arterialization of the conjunctival vessels. (Pupils are pharma­ cologically dilated.) (B) Arteriogram demonstrates filling of the cavernous sinus and a huge dilated superior ophthalmic vein in the arterial phase of an external carotid artery injection in the same patient.

Involvement of the sixth nerve with loss of tearing and sometimes sensory loss in the second division of the fifth nerve localizes a lesion to the sphenopalatine fossa; such lesions commonly result from metastatic tumor or nasopharyngeal carcinoma. Poliomyelitis may involve one or more cranial nerves, most often the sixth cranial nerve.

Bilateral ophthalmoplegia

Bilateral ophthalmoplegia, a unique variant of the syndrome of multiple cranial neuropathy, refers to involvement of more than one of the above cranial nerves that includes at least one on each side. This implies a lesion that is large enough to cause deficits bilaterally or is situated in a location such that bilateral cranial nerves are involved. Möbius’ syndrome is a congenital syndrome associated with bilateral sixth nerve or horizontal-gaze paresis and seventh nerve (facial nerve) paresis and other deficits, which may include tongue atrophy, hand and face deformities, and other malformations. Bilateral sixth nerve paresis is seen in posterior fossa or clivus lesions. Clivus tumors, such as meningioma, chordoma, chondroma, or chondrosarcoma, or spread of nasopharyngeal carcinoma often cause bilateral sixth nerve palsies because the two sixth nerves run adjacent to each other along the clivus. Increased intracranial pressure of any cause may produce unilateral or bilateral sixth nerve palsy by downward pressure and shift of the brainstem. This is because the sixth nerve is fixed as it exits the pons and as it pierces the dura to enter Dorello’s canal under the petroclinoid ligament and possibly other anatomic relationships.56 Papilledema ­inevitably is present. After myelography, spinal anesthesia, or even lumbar puncture, a bilateral sixth nerve paresis may rarely develop in association with a severe, postlumbar puncture headache syndrome.57 A similar mechanism of downward shift of the brainstem that arises from a pressure differential may be responsible. With this syndrome of intracranial hypotension, diffuse enhancement of the meninges also may be seen on MRI (Fig. 9-15-9). Basilar artery aneurysm or dolichoectasia of the basilar artery also may cause unilateral or bilateral sixth nerve paresis. When the presentation of bilateral sixth nerve paresis is compared with that of unilateral cases, ischemic causes are less frequent and trauma is more common.16, 17 Bilateral fourth nerve paresis may be seen after head trauma. Trauma likely involves the nerves in the area of decussation in the anterior medullary

Fig. 9-15-9  Magnetic resonance image (with gadolinium) of a patient with bilateral sixth cranial nerve palsy. The palsy resulted from intracranial hypotension after lumbar spine surgery. Note the diffuse enhancement of the meninges.

velum. Bilateral fourth nerve paresis also may be seen with hydrocephalus, tumor, arteriovenous malformation, or demyelinating disease. With bilateral fourth nerve paresis, right hyperdeviation in left gaze or right head tilt and left hyperdeviation in right gaze or left head tilt occur. In primary position, depending on the relative symmetry of the bilateral fourth nerve paresis, orthophoria, or right or left hyper­ deviation may occur. An additive effect of excyclodeviation occurs, with the result that greater than 10° of excyclotorsion is often seen. Because a tertiary action of the superior oblique muscle is abduction, loss of action of both superior obliques in downgaze causes a relative esodeviation in downgaze, which results in a characteristic V-pattern horizontal deviation. Rarely, bilateral simultaneous ophthalmoplegia may have a vasculopathic cause.46

Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

A

Subarachnoid involvement

With subarachnoid involvement, signs of multiple cranial nerve involvement may occur on one or both sides and produce the above syndromes, as well as headache, stiff neck, photophobia, and fever. With elevated intracranial pressure, papilledema occurs. In the subarachnoid space, causes of cranial neuropathies include subarachnoid hemorrhage, trauma, infectious or neoplastic meningitis, idiopathic intracranial hypertension (pseudotumor cerebri), tumors on the sixth nerve, or tumors in the clivus that compress the sixth nerve. Infectious meningitis may arise from bacterial, fungal (mainly ­cryptococcal), tuberculous, or syphilitic causes, or from Lyme disease. Inflammatory meningitis occurs with sarcoidosis. Patients with HIV may develop cranial neuropathies, associated with mostly secondary infectious causes (toxoplasmosis and cryptococcal), and with numerous other symptoms and signs. In one series of HIV patients with neurologic involvement, 17% had sixth nerve palsy, 9% third nerve palsy and 1% fourth nerve palsy.58

Nonisolated third cranial nerve palsies

Nonisolated third nerve palsies occur in the subarachnoid space and are accompanied by meningeal signs. The processes are similar to those described above − mainly infectious, neoplastic, or traumatic. However, one additional nonisolated third nerve syndrome occurs with uncal ­herniation through the tentorium, with large hemispheric mass lesions (such as tumor, hemorrhage, or infarct with edema). The patient has a corresponding neurological deficit and is lethargic. The third nerve is compressed against the tentorial edge, petrous ridge, and clivus by the uncus of the temporal lobe. Usually, pupillomotor fibers are involved first. Rarely, upward herniation from a mass in the posterior fossa may cause a third nerve palsy.

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9

DIAGNOSIS

NEURO-OPHTHALMOLOGY

The above histories and examination techniques should allow ­identification of the dysfunctional nerve(s). Although identification of the cranial nerve involved is important in the differential diagnosis, perhaps the most important feature is not the cranial nerve itself but the associated findings (“company it keeps”). The “company it keeps” may include involvement of other cranial nerves, other neurological deficits, or findings suggestive of an orbital process. These other findings help to localize the lesion and differentiate the likely causes. In some instances, the cranial neuropathy is truly isolated and involves only the third, fourth, or sixth nerve. When this occurs, a unique approach to differential diagnosis is undertaken. The evaluation of patients for ophthalmoplegia is dependent on the age of the patient. For infants, a congenital deficit or birth trauma is considered; for children a postviral syndrome, trauma, or posterior fossa tumor; for young adults trauma, multiple sclerosis, aneurysm, or arteriovenous malformation; and for older adults diabetes, hypertension, atherosclerosis, or giant cell arteritis. The character of the onset and progression also is important in ­differential diagnosis. Acute onset is consistent with a vascular, inflammatory, or traumatic cause. Progressive deficits are consistent with mass lesions such as tumor or aneurysm. Intermittent symptoms are suggestive of myasthenia gravis. Although cranial neuropathy commonly results from trauma, such deficits only rarely occur with mild trauma.59 In these instances, an underlying structural lesion, such as aneurysm or tumor, often is present.60, 61

Isolated Cranial Neuropathies

Isolated cranial neuropathies are occasionally seen with intrinsic brainstem lesions. These are discussed in Chapter 9.14.

Isolated sixth cranial nerve palsy

In a child who has an acquired, isolated sixth nerve paresis, early investigation using MRI is reasonable because of the frequent presentation of tumor with sixth nerve paresis. In an elderly person, with or without a history of diabetes or hyper­ tension, an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet count, blood pressure recording, measurement of levels of glucose, antinuclear antibodies (ANA), rapid plasma reagin (RPR), fluorescent treponemal antibodies (FTA), and a Lyme titer are indicated. The patient may be followed with expectant improvement over a few months. Should no improvement occur over a few months or if the early clinical features deviate from the expected course, then neuroimaging, preferably with MRI, is indicated. The imaging must focus on the course of the sixth nerve, which includes the pons, clivus, petrous apex, cavernous sinus, and orbit. Some experts advocate MRI in all patients with isolated cranial neuropathy, because a small percentage will have lesions that may benefit from early treatment, including pituitary apoplexy.13, 62 Cerebrospinal fluid (CSF) and nasopharyngeal examination are considered if no cause is otherwise found. In a young adult, particularly without evidence of hypertension or diabetes, the above serologic tests and neuroimaging are performed and, if negative, a CSF examination is reasonable. If no abnormality is found, the patient is followed at regular intervals and re-evaluated at 6 months if resolution does not occur.

Isolated fourth cranial nerve palsy

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The evaluation of patients affected by isolated fourth nerve paresis ­depends on the age group and setting. A history of significant trauma or evidence of a congenital fourth nerve paresis with decompensation requires no further work-up. In older patients subject to vascular risk factors, an ESR, CRP, and platelet count are obtained to rule out giant cell arteritis (see Chapter 9.22), and the patient may be followed clinically. For the patient who does not have this history, blood pressure is checked, as well as glucose level, Lyme titer, and ESR. If no resolution occurs within 6 months, neuroimaging, preferably MRI, is performed. Examination of CSF may be indicated although, without other neurological symptoms or signs, the diagnostic yield is low. As for sixth nerve palsy, some would advocate early neuroimaging.13 In children and young adults who have no history of trauma or ­evidence to suggest a congenital cause, neuroimaging and a search for vasculitis are indicated. A CSF examination is indicated if no clear cause can be established and if the deficit does not resolve.

Isolated third cranial nerve palsy

In adults of vasculopathic age, the most important issue is whether the pupil is involved or not. If the pupil is spared with otherwise complete involvement of ocular motility and ptosis, and the patient is over 50 years of age, diabetic, or hypertensive, a diagnosis of vasculopathic third nerve paresis may be presumed. Since aneurysms that do not at first involve the pupil have been described, the patient is followed carefully for the first week, and if the pupil becomes involved, further evaluation is indicated.34, 63, 64 If the pupil does not become involved, the patient is presumed to have a vasculopathic third nerve palsy and expected to recover over 3–6 months. At follow-up visits during this period, the patient is evaluated for aberrant regeneration; if present, further work-up for a structural lesion is dictated. Some would perform MRI on all isolated cranial neuropathies at presentation.13 If the pupil is involved, the appropriate evaluation must be pursued until aneurysm is excluded adequately. The initial study is an MRI scan or, if not available, a computed tomography (CT) scan, with and without contrast, is carried out for subarachnoid blood and evidence of aneurysm. If negative, a magnetic resonance angiogram (MRA) or CT angiography (CTA) may show an aneurysm.65 However, in many centers the sensitivity of MRA and CTA is not considered sufficient to exclude an aneurysm. In this situation, urgent catheter angiography must be carried out to exclude aneurysm. If an aneurysm is found, emergency neurosurgery must be performed to prevent subarachnoid hemorrhage.66 A presentation with complete ptosis and ophthalmoplegia and partial pupil involvement (mildly dilated and mildly less reactive) is known as relative pupillary sparing. Although controversial, most neuro-ophthalmologists consider this similar to pupillary sparing and monitor the patient carefully for the first week or perform MRA or CTA. Angiography is indicated if the pupil becomes more involved.66 Another controversial presentation is when partial ptosis and ophthalmoparesis occur, with complete sparing of the pupil. Many investigators consider this condition to be similar to that of a pupil affected by third nerve paresis and make evaluations to exclude an aneurysm, whereas other investigators monitor the patient carefully and evaluate if the pupil becomes involved. It is reasonable to at least evaluate as far as MRA and CTA in this situation.66 Although the initial thought process is focused on aneurysmal compression, it should be remembered that many patients with relative pupillary spared third nerve palsies have other mass lesions.67 Therefore, in addition to MRA or CTA, standard MR or CT imaging is required. If a pupil-sparing third nerve paresis does not resolve within the expected 3–6 month period, further work-up is indicated, which includes MRI scan, vasculitis work-up, and, if no diagnosis can be made, a CSF examination. For children, many cases are congenital and no further work-up is ­indicated. In such patients, the third nerve palsy often is incomplete and associated with signs of aberrant regeneration. With a difficult delivery, trauma is the most likely cause.1 In those conditions that are acquired, angiography is likely indicated. Although the youngest reported age for a child with posterior communicating artery aneurysm is 7 years,68 even infants may have an arteriovenous malformation or cavernous carotid aneurysm causing oculomotor palsy.69 If no clear history of ophthalmoplegic migraine or known trauma is found, evaluation is carried out as above to establish the underlying causes, even if the pupil is spared.29 Numerous recent reports have documented enlargement and enhancement of the third nerve on MRI in patients with ophthalmoplegic migraine.37, 70 In adults below the vasculopathic age, all third nerve palsies are worked up, which includes neuroimaging with MRI, blood tests (ESR, RPR, FTA, Lyme titer, glucose, ANA) to rule out vasculitis or infection, and CSF examination if no other cause is found. For any patient who develops signs of aberrant regeneration, work-up for a structural lesion is initiated, or repeated if previous work-up has been carried out and no lesion found.

Nonisolated Cranial Neuropathies Multiple cranial neuropathies

The management of patients who have cavernous sinus and superior orbital fissure lesions depends on the age of the patient, acuteness of presentation, speed of progression, presence of pain, history of systemic diseases or tumors, and accompanying features. Patients who have ­fever, somnolence, or a toxic appearance must be evaluated rapidly for

BOX 9-15-1 Differential Diagnosis of Painful Ophthalmoplegia Syndrome

9.15

ANEURYSM Intracavernous carotid artery Posterior cerebral artery Basilar artery CAROTID CAVERNOUS FISTULA CAVERNOUS SINUS THROMBOSIS

A

TUMORS Primary intracranial Local or distant metastasis Pituitary apoplexy Meningeal carcinomatosis or lymphomatosis INFECTION Mucormycosis or other fungal infection Herpes zoster Tuberculosis Bacterial sinusitis, mucocele, periostitis Syphilis INFLAMMATION Sarcoid Wegener’s granulomatosis Tolosa-Hunt syndrome Orbital pseudotumor GIANT CELLARTERITIS ISCHEMIC Diabetes Hypertension OPHTHALMOPLEGIC MIGRAINE

evidence of cavernous sinus thrombosis or mucormycosis. Those who seek treatment acutely with prominent vascular features, with arterialization of conjunctival vessels, proptosis, and bruits, must be evaluated for direct carotid cavernous fistula. The work-up includes neuroimaging with MRI, with and without gadolinium, as the procedure of choice. If MRI is contraindicated, CT scans, with and without contrast using very thin axial and coronal sections, is carried out. Most often, the structural lesion is imaged by one of these techniques. For a dural arteriovenous fistula or direct fistula, MRA, as well as conventional angiography, may be performed. In rare instances, CSF examination is helpful. When appropriate, blood tests such as level of ­angiotensin-converting enzyme, Lyme titer, RPR, and FTA are considered. When a mass lesion consistent with tumor is found, a primary tumor source that has metastasized is possible. The diagnosis may be made by biopsy elsewhere, if more accessible lesions are present. With primary tumors, biopsy of the cavernous sinus lesion is often necessary. With the onset of painful ophthalmoplegia consistent with idiopathic inflammation, a course of corticosteroids may be initiated. A positive response to corticosteroids has been used as diagnostic support for ­Tolosa-Hunt syndrome. However, since similar responses may occur in association with tumors, such as chordoma, giant-cell tumor, lymphoma, and epidermoid, the diagnosis must be made with caution and must be considered a diagnosis of exclusion. Differential diagnostic considerations for the presentation of painful ophthalmoplegia are listed in Box 9-15-1.36 Evaluation to exclude the above causes of the cavernous sinus syndrome, as well as numerous other conditions, includes neuro­ imaging, complete blood count, ESR, FTA, ANA, serum protein electrophoresis, and, occasionally, nasopharyngeal and CSF examinations. Neuroimaging may be normal or may show a lesion consistent with inflammation. With recurrent episodes consistent with Tolosa-Hunt syndrome, biopsy of any lesion noted on neuroimaging is indicated to rule out these other entities. In the few cases reviewed pathologically, idiopathic chronic granulomatous inflammation is seen. When a patient who has a known or an occult pituitary adenoma has an acute onset of painful ophthalmoparesis, often pituitary apoplexy is found by demonstration of acute hemorrhage or swelling of the

B

Fig. 9-15-10  Duane’s syndrome (type III). (A) Abduction deficit. (B) Adduction deficit, retraction of globe, and narrowing of palpebral fissure on adduction   of the right eye. (Adapted from Moster ML. Complications of cancer therapies. In: Miller N, Newman NJ, eds. Walsh & Hoyt’s neuro-ophthalmology, 5th ed. Baltimore: Williams & Wilkins; 1997.)

­ ituitary adenoma on neuroimaging. These patients undergo surgery, p using trans-sphenoidal hypophysectomy. To diagnose direct or indirect carotid cavernous fistula, arteriography is the definitive diagnostic procedure. However, MRI and MRA may demonstrate enlargement of the superior ophthalmic vein or the ­actual fistula. Other helpful procedures include CTA, Doppler ultrasound, color Doppler, and measurement of ocular pulse amplitude. Reversal of flow may be demonstrated in the superior ophthalmic vein.71

Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

TRAUMA

Bilateral ophthalmoplegia

Neuroimaging that includes the course of each nerve involved on each side is required for patients who have bilateral simultaneous ophthalmoplegia without obvious cause. If negative, CSF examination is ­carried out and serologic evaluation for collagen vascular disease, arteritis, syphilis, and Lyme disease is obtained.

DIFFERENTIAL DIAGNOSIS Numerous disorders that affect ocular motility may mimic and appear identical to a cranial neuropathy. These processes include restrictive ophthalmopathies, such as thyroid disease; neuromuscular diseases, such as myasthenia or botulism; and polyneuropathies, such as the Miller-Fisher variant of the Guillain-Barré syndrome. The major examination technique used to exclude a restrictive ­process is the forced duction examination, in which a forceps or cottontipped swab is used to overcome the ductional deficit in the eye. A positive sign of restriction is when the deficit cannot be overcome because of resistance. Another sign of restrictive disease is an elevation of intraocular pressure when the eye moves in the direction of the restriction.

Isolated Cranial Neuropathies Isolated sixth cranial nerve palsy

The differential diagnosis of a sixth nerve paresis includes Duane’s retraction syndrome, thyroid or other restrictive ophthalmopathy, myasthenia gravis, spasm of the near reflex, or breakdown of a previous esophoria. Duane’s syndrome is a congenital abnormality that occurs in three different forms. All three forms include narrowing of the palpebral ­ fissure and retraction of the globe when the eye is adducted. Type I consists of an abduction deficit that mimics a sixth nerve paresis, type II consists of an adduction deficit, and type III includes both an abduction and adduction deficit (Fig. 9-15-10). MRI has revealed the absence of the ipsilateral abducens nerve in type I Duane’s syndrome and in some of those with type III. Type II patients had preserved abducens nerves.72 Pathologically, abnormal development of the cells of the abducens nucleus and innervation of the lateral rectus by branches of the oculomotor nuclei occurs. During adduction,

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9 NEURO-OPHTHALMOLOGY

co-firing of the medial and lateral recti produces retraction of the globe. Patients who have Duane’s syndrome do not usually experience diplopia. Duane’s syndrome is bilateral in 18% of cases and familial in 10%.73, 74 Spasm of the near reflex most often is seen as a nonorganic, functional disorder in patients who have psychogenic disease or in malingerers. It presents with an abduction deficit that arises from substitution of convergence for lateral gaze. The diagnosis is made by finding the other features of the near reflex, mainly miosis, on attempted lateral gaze. Ductions tested with the other eye covered usually are normal. Spasm of the near reflex is seen rarely in organic conditions.75 Restrictive ophthalmopathy most often results from thyroid disease. If not already present, the patient soon develops other orbital signs, such as proptosis, injection, chemosis, lid retraction and lag, and has a positive forced duction test. Other restrictive processes of the medial rectus include trauma and orbital myositis. Myasthenia may be differentiated on history and examination by the features of fatigability and variability. Evaluation with office testing (ice test, sleep test, or Tensilon test), acetylcholine receptor antibody, and electromyogram establishes the diagnosis. Patients who have congenital esophoria or compensated esotropia may give a history consistent with sixth nerve palsy, as a result of worsening of the previous deviation, often in times of stress or infection. Features that favor this diagnosis include a relatively comitant deviation and the establishment of an ocular deviation when photographs of the patient at a younger age are reviewed.

Isolated fourth cranial nerve palsy

The differential diagnosis of isolated fourth nerve paresis includes myasthenia gravis, thyroid ophthalmopathy and other orbital restrictive ­processes, Brown’s syndrome, skew deviation, and overaction of the ­inferior oblique muscle associated with congenital strabismus. Thyroid ophthalmopathy is present most often with other orbital signs and features of restriction, as noted above for sixth nerve paresis.76 Myasthenia gravis can be differentiated by its fatigability and variability. Skew ­deviation, a supranuclear vertical deviation that results from brainstem disease, is often associated with other neurological findings that are not present with an isolated fourth nerve paresis. Skew deviation may have a comitant or incomitant pattern of deviation and does not exactly fit with the three-step pattern of a fourth nerve paresis. The ocular tilt reaction, a form of skew deviation that most closely mimics a fourth nerve paresis, appears with hypotropia, head tilt toward the hypotropic eye, and conjugate torsion toward the hypotropic eye.77 In addition, excyclotorsion may not be present with myasthenia, skew deviation, and thyroid disease, but is invariably present with an isolated fourth nerve paresis. Brown’s syndrome causes diplopia because of an elevation deficit in adduction, in which the involved eye is hypotropic; forced duction test is positive. When congenital, this syndrome results from a short or tethered superior oblique tendon, but the acquired syndrome may be a result of tenosynovitis, adhesions, metastasis, or trauma.1, 35 Brown’s syndrome actually mimics an inferior oblique paresis; the latter may be differentiated by concomitant overaction of the superior oblique muscle, an A-pattern horizontal deviation, and a negative forced duction test. Patients affected by overaction of the inferior oblique muscle have a deviation greatest in adduction in upgaze.

Isolated third cranial nerve palsy

The differential diagnosis of isolated third nerve palsy is not as lengthy as for fourth and sixth nerve palsies because of the many structures innervated by the third nerve and the characteristic findings. Nonetheless,

if no pain or pupil involvement exists, myasthenia gravis must be considered. Restrictive ophthalmopathy may mimic parts of a third nerve paresis, but does not involve the pupil, more often presents with lid retraction than ptosis if thyroid ophthalmopathy is the cause, and often has other orbital findings. A supranuclear lesion may involve ­ptosis and an elevation deficit, but usually has other associated deficits that involve midbrain and diencephalic structures.

Nonisolated Cranial Neuropathies

It is important in the diagnosis of simultaneous palsies of the motor nerves of the eye to differentiate these from oculoparesis that arises from orbital inflammatory disease, such as Graves’ ophthalmopathy or orbital pseudotumor, ocular myopathies (such as chronic progressive external ophthalmoplegia), disorders of neuromuscular transmission (such as myasthenia gravis or botulism), and polyneuropathies (such as the Miller-Fisher variant of Guillain-Barré syndrome). Demyelinating disease, basilar artery ischemia or aneurysm, skull base tumors, Wernicke’s encephalopathy, and supranuclear gaze palsies also must be included in the differential diagnosis of nonisolated cranial neuropathies.46

TREATMENT Aside from treatment for the specific cause of the cranial neuropathy, the symptoms of diplopia must be treated. Acutely, occlusion of either eye using a patch or opaque tape over glasses is the best treatment, particularly in patients who are expected to recover. With chronic diplopia, prism therapy is helpful for a subgroup of patients, especially when the deviation is not very incomitant. Eventually, with chronic, stable deviations, strabismus surgery (see Chapter 11-14) may be useful. Some clinicians use botulinum toxin injections early on, particularly for fourth or sixth nerve paresis, to promote earlier fusion while recovery takes place. Ultimate recovery is similar with or without botulinum treatment.78 Botulinum toxin is also a treatment option for a chronic cranial nerve paresis. For instance, in fourth nerve paresis, it may be injected into the ipsilateral inferior oblique or the contralateral inferior rectus.

Nonisolated Cranial Neuropathies

The Tolosa-Hunt syndrome is exquisitely sensitive to corticosteroids − pain resolves almost immediately and ophthalmoplegia resolves subacutely with 60–80  mg/day of prednisone. However, recurrences may not respond as well. Direct internal carotid cavernous fistulas are treated by occlusion carried out by an interventional neuroradiologist, with balloon occlusion of the connection between the carotid artery and cavernous sinus. Occasionally, neurosurgery is required, with occlusion of the carotid artery both above and below the site of the fistula. Dural arteriovenous fistulas may be followed clinically if no threat to vision exists. In over 50% of patients, the fistula spontaneously ­undergoes thrombosis and resolves, particularly after angiography.76 In addition, the patient may be trained to perform occlusion of the carotid artery intermittently during the day by the application of pressure using the finger tips (provided no serious cerebrovascular disease is present); this may allow for spontaneous thrombosis to occur. On some occasions, spontaneous thrombosis may be associated with retinal vein ­occlusions and visual loss. In cases in which a threat to vision occurs, selective arteriography with occlusion of the feeder vessels is performed by an interventional radiologist. Catheter angiography is also important to assess the presence of cortical venous drainage, which is associated with an increased risk of intracranial hemorrhage.

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  5. Peters GB 3rd, Bakri SJ, Krohel GB. Cause and prognosis of nontraumatic sixth nerve palsies in young adults. Ophthalmology. 2002;109:1925–8.   6. Lash SC, Williams CP, Marsh CS, et al. Acute sixthnerve palsy after vincristine therapy. J Aapos. 2004;8:67–8.   7. Currie J, Lubin JH, Lessell S. Chronic isolated abducens paresis from tumors at the base of the brain. Arch   Neurol. 1983;40:226–9.   8. Sakalas R, Harbison JW, Vines FS, Becker DP. Chronic sixth nerve palsy. An initial sign of basisphenoid tumors. Arch Ophthalmol. 1975;93:186–90.

  9. Savino PJ, Hilliker JK, Casell GH, Schatz NJ. Chronic sixth nerve palsies. Are they really harbingers of serious intracranial disease? Arch Ophthalmol. 1982;100:1442–4. 10. Galetta SL, Smith JL. Chronic isolated sixth nerve palsies. Arch Neurol. 1989;46:79–82. 11. Knox DL, Clark DB, Schuster FF. Benign VI nerve palsies in children. Pediatrics. 1967;40:560–4. 12. Volpe NJ, Lessell S. Remitting sixth nerve palsy in skull base tumors. Arch Ophthalmol. 1993;111:1391–5. 13. Chou KL, Galetta SL, Liu GT, et al. Acute ocular motor mononeuropathies: prospective study of the roles of neuroimaging and clinical assessment. J Neurol Sci. 2004;219:35–9.

36. Friedman AP, Harter DH, Merritt HH. Ophthalmoplegic migraine. Arch Neurol. 1962;7:320–7. 37. Carlow TJ. Oculomotor ophthalmoplegic migraine: is it really migraine?. J Neuroophthalmol. 2002;22:215–21. 38. Nazir SA, Murphy SA, Siatkowski RM. Recurrent para-  infectious third nerve palsy with cisternal nerve enhancement on MRI. J Neuroophthalmol. 2004;24:96–7. 39. Sebag J, Sadun AA. Aberrant regeneration of the third nerve following orbital trauma. Synkinesis of the iris sphincter. Arch Neurol. 1983;40:762–4. 40. Schatz NJ, Savino PJ, Corbett JJ. Primary aberrant oculomotor regeneration. A sign of intracavernous meningioma. Arch Neurol. 1977;34:29–32. 41. Cox TA, Wurster JB, Godfrey WA. Primary aberrant   oculomotor regeneration due to intracranial aneurysm. Arch Neurol. 1979;36:570–1. 42. Buckley EG, Ellis FD, Postel E, Saunders T. Posttraumatic abducens to oculomotor nerve misdirection. J Aapos. 2005;9:12–6. 43. Friedman DI, Wright KW, Sadun AA. Oculomotor palsy with cyclic spasms. Neurology. 1989;39:1263–4. 44. Lee MS, Egan RA, Shults WT, Lessell S. Idiopathic repetitive oculomotor nerve palsies in otherwise normal patients. Ophthalmology. 2005;112:2225–6. 45. Derakhshan I. Superior branch palsy of the oculomotor nerve with spontaneous recovery. Ann Neurol. 1978;4:478–9. 46. Sergott RC, Glaser JS, Berger LJ. Simultaneous, bilateral diabetic ophthalmoplegia. Report of two cases and discussion of differential diagnosis. Ophthalmology. 1984;91:18–22. 47. Kline LB. The Tolosa-Hunt syndrome. Surv Ophthalmol. 1982;27:79–95. 48. Keane JR. Cavernous sinus syndrome. Analysis of 151 cases. Arch Neurol. 1996;53:967–71. 49. Thomas JE, Yoss RE. The parasellar syndrome: problems in determining etiology. Mayo Clin Proc. 1970;45:617–23. 50. Kline L. Cavernous sinus/orbital apex syndrome. In: Tusa R, Newman S, eds. Neuro-ophthalmological disorders, New York: Marcel Dekker; 1995:291–8. 51. Jefferson G. Concerning injuries, aneurysms and tumors involving the cavernous sinus. Trans Ophthalmol Soc UK. 1953;73:117–52. 52. Nakagawa T, Uchida K, Ozveren MF, Kawase T. Abducens schwannoma inside the cavernous sinus proper: case report. Surg Neurol. 2004;61:559–63. discussion 63. 53. Karmon Y, Gadoth N. Delayed oculomotor nerve palsy after bilateral cervical zoster in an immunocompetent patient. Neurology. 2005;65:170. 54. Tolosa E. Periarteritic lesions of the carotid siphon with the clinical features of a carotid infraclinoidal aneurysm. J Neurol Neurosurg Psychiatry. 1954;17:300–2. 55. Hunt WE, Meagher JN, Lefever HE, Zeman W. Painful ophthalmoplegia. Its relation to indolent inflammation of the carvernous sinus. Neurology. 1961;11:56–62. 56. Hanson RA, Ghosh S, Gonzalez-Gomez I, et al. Abducens length and vulnerability?. Neurology. 2004;62:  33–6. 57. Miller EA, Savino PJ, Schatz NJ. Bilateral sixth-nerve palsy. A rare complication of water-soluble contrast myelography. Arch Ophthalmol. 1982;100:  603–4. 58. Mwanza JC, Nyamabo LK, Tylleskar T, Plant GT. Neuroophthalmological disorders in HIV infected subjects with neurological manifestations. Br J Ophthalmol. 2004;88:1455–9.

59. Levy RL, Geist CE, Miller NR. Isolated oculomotor palsy following minor head trauma. Neurology. 2005;  65:169. 60. Chrousos GA, Dipaolo F, Kattah JC, Laws ER Jr.. Paresis   of the abducens nerve after trivial head injury. Am   J Ophthalmol. 1993;116:387–8. 61. Walter KA, Newman NJ, Lessell S. Oculomotor palsy from minor head trauma: initial sign of intracranial aneurysm. Neurology. 1994;44:148–50. 62. Warwar R, Bhulla S, Pelstring R, Fadell R. Sudden death from pituitary apoplexy in a patient presenting with an isolated sixth cranial nerve palsy. J Neuro-Ophthalmol. 2006;26:95–7. 63. Bartleson JD, Trautmann JC, Sundt TM Jr. Minimal oculomotor nerve paresis secondary to unruptured intracranial aneurysm. Arch Neurol. 1986;43:  1015–20. 64. O’Connor PS, Tredici TJ, Green RP. Pupil-sparing third nerve palsies caused by aneurysm. Am J Ophthalmol. 1983;95:395–7. 65. McFadzean RM, Teasdale EM. Computerized tomography angiography in isolated third nerve palsies.   J Neurosurg. 1998;88:679–84. 66. Jacobson DM, Trobe JD. The emerging role of magnetic resonance angiography in the management of patients with third cranial nerve palsy. Am J Ophthalmol. 1999;128:94–6. 67. Jacobson DM. Relative pupil-sparing third nerve palsy: etiology and clinical variables predictive of a mass. Neurology. 2001;56:797–8. 68. Branley MG, Wright KW, Borchert MS. Third nerve palsy due to cerebral artery aneurysm in a child. Aust N Z J Ophthalmol. 1992;20:137–40. 69. Tamhankar MA, Liu GT, Young TL, et al. Acquired, isolated third nerve palsies in infants with cerebrovascular malformations. Am J Ophthalmol. 2004;138:484–6. 70. O’Hara MA, Anderson RT, Brown D. Magnetic resonance imaging in ophthalmoplegic migraine of children.   J Aapos. 2001;5:307–10. 71. Golnik K. Cavernous sinus arteriovenous fistula. In: Tusa R, Newman S, eds. Neuro-ophthalmologic disorders. New York: Marcel Dekker; 1995. 72. Kim JH, Hwang JM. Presence of the abducens nerve according to the type of Duane’s retraction syndrome. Ophthalmology. 2005;112:109–13. 73. Raab EL. Clinical features of Duane’s syndrome. J Pediatr Ophthalmol Strabismus. 1986;23:64–8. 74. DeRespinis PA, Caputo AR, Wagner RS, Guo S.   Duane’s retraction syndrome. Surv Ophthalmol. 1993;38:257–88. 75. Moster ML, Hoenig EM. Spasm of the near reflex   associated with metabolic encephalopathy.   Neurology. 1989;39:150. 76. Moster ML, Bosley TM, Slavin ML, Rubin SE. Thyroid ophthalmopathy presenting as superior oblique paresis. J Clin Neuroophthalmol. 1992;12:94–7. 77. Donahue SP, Lavin PJ, Hamed LM. Tonic ocular tilt reaction simulating a superior oblique palsy: diagnostic confusion with the 3-step test. Arch Ophthalmol. 1999;117:347–52. 78. Holmes JM, Beck RW, Kip KE, et al. Botulinum toxin   treatment versus conservative management in acute traumatic sixth nerve palsy or paresis.   J Aapos. 2000;4:145–9.

9.15 Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

14. Shrader EC, Schlezinger NS. Neuro-ophthalmologic evaluation of abducens nerve paralysis. Arch ­Ophthalmol. 1960;63:84–91. 15. Rucker CW. The causes of paralysis of the third, fourth and sixth cranial nerves. Am J Ophthalmol. 1966;61:1293–8. 16. Johnston AC. Etiology and treatment of abducens paralysis. Trans Pac Coast Otoophthalmol Soc Annu Meet. 1968;49:259–77. 17. Keane JR. Bilateral sixth nerve palsy. Analysis of 125 cases. Arch Neurol. 1976;33:681–3. 18. Richards BW, Jones FR Jr, Younge BR. Causes and prognosis in 4278 cases of paralysis of the oculomotor, trochlear, and abducens cranial nerves. Am J Ophthalmol. 1992;113:489–96. 19. Rush JA, Younge BR. Paralysis of cranial nerves III, IV, and VI. Cause and prognosis in 1000 cases. Arch Ophthalmol. 1981;99:76–9. 20. Tiffin PA, MacEwen CJ, Craig EA, Clayton G. Acquired palsy of the oculomotor, trochlear and abducens nerves. Eye. 1996;10:377–84. 21. Archambault P, Wise JS, Rosen J, et al. Herpes zoster ophthalmoplegia. Report of six cases. J Clin Neuro­ ophthalmol. 1988;8:185–93. 22. Burger LJ, Kalvin NH, Smith JL. Acquired lesions of the fourth cranial nerve. Brain. 1970;93:567–74. 23. Younge BR, Sutula F. Analysis of trochlear nerve palsies. Diagnosis, etiology, and treatment. Mayo Clin Proc. 1977;52:11–8. 24. Khawam E, Scott AB, Jampolsky A. Acquired superior oblique palsy. Diagnosis and management. Arch ­Ophthalmol. 1967;77:761–8. 25. Harley RD. Paralytic strabismus in children. Etiologic incidence and management of the third, fourth, and sixth nerve palsies. Ophthalmology. 1980;87:24–43. 26. Huang P, Tai CT. Tuberculous meningitis with initial manifestation of isolated oculomotor nerve palsy.   Acta Neurol Taiwan. 2005;14:21–3. 27. Campos CR, Massaro AR, Scaff M. Isolated oculomotor nerve palsy in spontaneous internal carotid artery   dissection: case report. Arq Neuropsiquiatr. 2003;61  :668–70. 28. Nakamura A, Tojo K, Takasu K, et al. Unilateral ­oculomotor nerve palsy induced by combination therapy of interferon-alpha2b and ribavirin. Intern Med. 2005;44:682–3. 29. Ng YS, Lyons CJ. Oculomotor nerve palsy in childhood. Can J Ophthalmol. 2005;40:645–53. 30. Goldstein JE, Cogan DG. Diabetic ophthalmoplegia with special reference to the pupil. Arch Ophthalmol. 1960;64:592–600. 31. Green WR, Hackett ER, Schlezinger NS. Neuro-  ophthalmologic evaluation of oculomotor nerve   paralysis. Arch Ophthalmol. 1964;72:154–67. 32. Miller NR. Solitary oculomotor nerve palsy in childhood. Am J Ophthalmol. 1977;83:106–11. 33. Jacobson DM. Pupil involvement in patients with   diabetes-associated oculomotor nerve palsy. Arch   Ophthalmol. 1998;116:723–7. 34. Kissel JT, Burde RM, Klingele TG, Zeiger HE. Pupil-sparing oculomotor palsies with internal carotid-posterior communicating artery aneurysms. Ann Neurol. 1983;13:149–54. 35. Newman S. Disorders of ocular motility. In: Slamovits T, Burde R, eds. Textbook of ophthalmology. Neuro-  ophthalmology, London: Mosby-Yearbook Europe;   1997. :7.1–28.

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PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

Disorders of the Neuromuscular Junction

9.16

Deborah I. Friedman

Definition:  A disorder of the neuromuscular junction, caused by an

antibody-mediated autoimmune attack on postsynaptic acetylcholine receptors or the altered presynaptic release of acetylcholine.

Key features n

Ocular or generalized muscle weakness.

Associated features n n n n n

 tosis and ocular motility disturbances. P Facial, trunk, and limb weakness. Speech and swallowing dysfunction. Respiratory compromise. Autonomic nervous system dysfunction.

MYASTHENIA GRAVIS INTRODUCTION Of all the disorders of the neuromuscular junction (Table 9-16-1), myasthenia gravis is the most common.1 It is a disorder caused by an antibody-mediated autoimmune attack on the acetylcholine (ACh) receptors at the neuromuscular junction. The hallmark of myasthenia gravis is fluctuating muscle weakness that worsens with exertion and improves with rest. Ocular manifestations, such as ptosis and diplopia, are present frequently at onset and eventually are present in most patients.

EPIDEMIOLOGY AND PATHOGENESIS

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The prevalence of myasthenia gravis is rising, largely as a result of longer lifespan. An estimated 15 cases occur per million population.2, 3 Women are affected twice as frequently as men. The incidence has one peak in the second and third decades, affecting mostly women, and another in the sixth and seventh decades, which involves mostly men. However, the disease can occur at any age. Myasthenia gravis rarely is familial, but heredity might be a risk factor. Young female patients who have thymic hyperplasia often have human lymphocyte antigen (HLAB8 and HLA-DR3 patterns). An association exists with HLA-B7 and HLA-DR2 in patients over 40 years of age. The neuromuscular junction is composed of the motor axon terminal, the synaptic cleft, and the postsynaptic surface of the muscle cell (Fig. 9-16-1), in which deep infoldings occur. Acetylcholine (ACh) is stored in vesicles in the cytoplasm of the nerve terminal and mediates neuromuscular transmission. Depolarization of the axon by an action potential causes release of ACh into the synaptic cleft by calcium-­dependent, voltage-dependent exocytosis. Ordinarily, more ACh is released than is needed to produce neuromuscular transmission, which creates a safety factor. Once released, the ACh diffuses across the synaptic cleft to the postsynaptic folds.

The postsynaptic folds contain the ACh receptors and acetylcholinesterase, the enzyme that hydrolyzes ACh. In general, the receptors are located on the tips of the folds and acetylcholinesterase is concentrated deeper within the synaptic folds. When two ACh molecules bind to a receptor, conformational changes occur and an ion channel opens, which results in a local depolarization and subsequent muscle contraction. An additional safety factor exists at this level, because the potential generally exceeds the threshold required for depolarization of a muscle fiber (end-plate potential). Innervated receptors undergo continuous turnover, with a half-life of 8–11 days. In myasthenia gravis, the major pathological changes are found at the postsynaptic membrane, with loss and simplification of the postjunctional folds, reduced numbers of ACh receptors, and a widened synaptic cleft. New receptors are synthesized, but they are not incorporated into the damaged postsynaptic membrane, which results in loss of receptors at the junction. The synapses of patients with myasthenia gravis contain about one third the number of ACh receptors found in those of healthy controls. The number of receptors seems to parallel the severity of weakness. With a reduced number of receptors, the end-plate potential is inadequate to generate contraction of some muscle fibers; this produces the characteristic muscle weakness. Normally, a decline (“rundown”) occurs in the amount of ACh released by successive muscle contractions. At myasthenic junctions, the rundown produces progressive failure of neuromuscular transmission, because of the reduced number of receptors. This accounts for the muscular fatigability that is the hallmark of the disease. The muscular abnormalities in myasthenia gravis result from an antibody-mediated process that likely originates in the thymus gland. The antibodies both accelerate the rate of degradation of ACh receptors and block ACh binding sites. B cells produce the autoantibodies, but T cells also are important in the autoantibody response of myasthenia gravis. In myasthenia gravis, the T and B cells produced by the thymus gland are more responsive to the ACh receptor than are their counterparts in the peripheral blood. Of patients who have myasthenia gravis, 75% have thymic abnormalities; of these, 85% have thymic hyperplasia and 15% have thymomas. Perhaps the strongest evidence for the ­importance of the thymus gland in the pathogenesis of myasthenia is the effectiveness of thymectomy.

OCULAR MANIFESTATIONS Ocular symptoms, ptosis and diplopia, are present at onset in about 70% of patients and eventually are present in 90%. Ptosis, either ­isolated or associated with extraocular muscle involvement, often is the first ­symptom. The ptosis may be unilateral or bilateral, symmetrical or asymmetrical, and often it is more pronounced as the day progresses. Involvement of the extraocular muscles varies from single-muscle paresis to total ophthalmoplegia. Myasthenia gravis may simulate ocular motor nerve palsy, unilateral or bilateral internuclear ophthalmoplegia, or gaze palsy. When the levator palpebrae superioris also is involved, the disease may mimic pupil-sparing third nerve palsy. Patients ­experience diplopia, which usually fluctuates throughout the day; sometimes the disease produces vertical separation of the images, at other times it causes horizontal diplopia. The diplopia may be intermittent. Other motility abnormalities include saccadic dysmetria and decreased final saccadic velocity, small “quiver” eye movements, and gaze-evoked nystagmus.4 Nystagmus occurs because of muscle fatigue; isolated nystagmus as a sign of myasthenia gravis is rare. For practical purposes, the

   TABLE 9-16-1  DISORDERS OF NEUROMUSCULAR TRANSMISSION Cause

Location

Defect

Symptoms

Treatment

Myasthenia gravis

Autoimmune

Postsynaptic

Antibodies to ACh receptor

Ptosis, diplopia Weakness, improves with rest

Pyridostigmine (Mestinon), corticosteroids, immunosuppressants; thymectomy

Botulism

Clostridium botulinum infection

Presynaptic

Impaired ACh release

Ptosis, diplopia, tonic pupils, accommodative impairment, bulbar weakness, cholinergic blockade

Respiratory support Antitoxin

Lambert-Eaton myasthenic syndrome

Paraneoplastic

Presynaptic

Impaired Ach release

Rarely ptosis, diplopia Proximal muscle weakness Autonomic dysfunction

Treat malignancy – diaminopyridine, corticosteroids, immunosuppressants

Organophosphate toxicity

Insecticides Chemical warfare

Synaptic

Inhibits acetylcholinesterase

Rapid respiratory failure Muscle twitching then paralysis Mental status changes Pupillary miosis

Atropine, pralidoxine

Black widow spider (Latrodectus mactans) bite

α-Larotoxin

Presynaptic

Increased ACh release

Autonomic hyperactivity Vasoconstriction Painful, rigid abdomen

Calcium, magnesium, atropine, antivenin; warming

Tick paralysis

Toxic

Presynaptic

Impaired ACh release

Irritability, pain, paralysis Respiratory paralysis Late signs – unreactive pupils, ophthalmoplegia

Remove tick, supportive measures

Scorpion toxin

Toxic

Presynaptic

Increased ACh release

Agitation, respiratory failure, blurred vision, abnormal eye movements, jerking of extremities, autonomic dysfunction

Calcium, atropine, antivenin, supportive measures

9.16 Disorders of the Neuromuscular Junction

Disorder

ACh, Acetylcholine.

NEUROMUSCULAR JUNCTIONS NORMAL

MYASTHENIA GRAVIS

axon mitochondrion vesicle nerve terminal

release site

synaptic nerve

acetylcholine receptors acetylcholinesterase muscle

Fig. 9-16-1  Neuromuscular junctions. In myasthenia gravis, acetylcholine is released from presynaptic vesicles and diffuses across the synaptic cleft to the postsynaptic receptors. Acetylcholinesterase, located deep within the synaptic folds, hydrolyzes acetylcholine. There is also a simplification of the postsynaptic site with a reduced number of receptors. (From Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–810.)

pupils are normal in myasthenia gravis. Although anisocoria, impaired accommodation, and sluggishly reactive pupils have been described, the abnormalities are subtle and not clinically significant.

DIAGNOSIS The diagnosis of myasthenia gravis usually is suspected from the patient’s symptoms and the physical examination. The presence of ptosis and ­extraocular muscle weakness that either fluctuates or does not conform

to any pattern of ocular motor nerve paresis raises the suspicion of myasthenia gravis. Many ocular signs may be present on the examination. With unilateral ptosis, the other eyelid may appear retracted, exhibiting Hering’s law of equal innervation. If the ptotic eyelid is lifted manually, the ptosis worsens on the contralateral side (Fig. 9-16-2). This finding is not exclusive to myasthenia but frequently is present in patients who have the condition. Cogan’s lid twitch sign demonstrates the rapid recovery and easy fatigability of the levator. When the patient looks down for 10–20 seconds and then rapidly looks up to primary position, the upper eyelids often overshoot (retract) and then settle back into a stable position; a downward drift of the lids or several twitches may be observed. Prolonged upgaze produces muscle fatigue, with eyelid droop or downward drift of the eyes. As the patient attempts repeated largeamplitude saccades, slowing of the eye movements may occur with repetition. Ice placed on a ptotic lid may prolong the time for which the ACh receptor channels open and produce clinical improvement. The ice test is a sensitive and specific test for myasthenia gravis.5–7 With generalized myasthenia gravis, muscle strength testing reveals weakness, usually more prominent proximally. Individual muscles weaken with repetitive testing; the strength improves after a brief period of rest. No specific laboratory test exists to confirm the diagnosis of myasthenia gravis. A combination of physical examination, pharmacological tests, blood tests, and electrodiagnostic tests often is needed to confirm the diagnosis. If a demonstrable, measurable abnormality is present on the examination, administration of an acetylcholinesterase inhibitor produces increased strength of myasthenic muscles.8 The most commonly used agent is intravenous edrophonium (Tensilon), because of its rapid onset of action (30 seconds) and short duration of action (5 minutes). Baseline readings are taken for the pulse, blood pressure, and the physical sign to be measured. For ocular manifestations, this may include measurement of the palpebral fissures and levator function or quantitation of subtle motility deficits using a Maddox rod or Hess screen.9 The patient should be warned of potential side effects, including diaphoresis, abdominal cramping, nausea, vomiting, salivation, and light-headedness. Although the complication rate is very low, the most dangerous complication is heart block, and atropine sulfate should be made available immediately (0.4–0.6 mg, adult dose).10 Alternatively, patients may be pretreated with intramuscular or subcutaneous atropine. An assistant

1027

9 NEURO-OPHTHALMOLOGY

1028

A

C

B

Fig. 9-16-2  Myasthenia gravis. (A) Right ptosis and compensatory left upper lid retraction. (B) On looking right note right abduction deficit and left lid retraction to compensate for right ptosis. (C) On sustained upgaze, right upper lid becomes fatigued.

is required to monitor the patient’s pulse and blood pressure during the test. Ten milligrams is drawn into a tuberculin syringe. After administration of an initial test dose of 2 mg intravenously, the patient is observed for 1 minute while the pulse is monitored. Some patients improve with the test dose. If no improvement and no adverse reaction occur, an additional 4 mg is administered. The remaining 4 mg can be used if no effect is seen. The presence of eyelid fasciculations indicates that an adequate dose was injected. The response to edrophonium often is dramatic. Intramuscular neostigmine (Prostigmin) is useful in children who may not cooperate with intravenous injections. Neostigmine (1.5 mg for adults or 0.04 mg/kg for children, mixed with 0.6 mg atropine sulfate) produces observable effects within 15 minutes; peak action occurs 30 minutes after injection. A safe alternative to the edrophonium test is the sleep test.11 After the baseline deficit has been documented, the patient rests quietly with eyes closed for 30 minutes. The measurements are repeated immediately after the patient “wakes up” and opens the eyes. Alternatively, an ice pack is placed over closed lids for a few minutes. Improvement after rest is characteristic of myasthenia gravis. A serum assay for anti-ACh receptor antibodies should be obtained for all patients who have suspected myasthenia gravis. Antibody titers do not correlate with the severity of the disease. The binding antibody is obtained most commonly, being detected in approximately 90% of patients who have generalized myasthenia gravis and 70% of patients who have ocular myasthenia. Blocking antibodies are present in approximately 60% of patients who have generalized myasthenia and 50% of patients who have ocular disease, and rarely are present (1%) without binding antibodies. Muscle specific kinase (MuSK) antibodies are present in 30% of patients with generalized myasthenia when other ­antibodies are not detected. However, MuSK antibodies are rarely ­detected in purely ocular disease.12 Electrophysiological tests are useful for the diagnosis of myasthenia gravis if other tests are inconclusive. Repetitive supramaximal motor nerve stimulation (1–3  Hz) produces a progressive decremental response of the compound muscle action potentials during the first four or five stimuli. The amplitude of the response then either levels off or increases slightly because of post-tetanic potentiation. This technique shows abnormalities in 40–90% of patients who have myasthenia gravis and results are more likely to be positive with severe disease. Single fiber electromyography (SFEMG) demonstrates “jitter,” which indicates the variability of propagation time to individual muscle fibers supplied by the same motor neuron. Intermittent “blocking” caused by failure of conduction at the neuromuscular junction also may occur. The sensitivity of SFEMG is approximately 90%.13 In particular; SFEMG of the superior rectus and levator palpebralis muscles is extremely sensitive for the detection of ocular myasthenia gravis.14 Conversion from ocular to generalized disease is less likely with normal SFEMG findings of the upper extremities.15 Because 10–15% of patients who have myasthenia gravis have a thymic tumor, high-quality radiographic imaging of the chest (computed tomography or magnetic resonance imaging) is mandatory, even for patients with solely ocular findings (Fig. 9-16-3). A plain chest radiograph alone is not adequate for this purpose. Fullness of the thymus gland typically is seen up to age 30  years. The persistence of a thymus gland in a patient over 40  years of age or an increase in size on serial imaging studies raises the suspicion that a thymoma is present. Other testing is directed toward associated systemic diseases and treatment. It is not unusual for patients who have myasthenia to have another autoimmune disease. Because 5% of patients who have myasthenia gravis have coexistent thyroid disease, thyroid function tests should be obtained for all patients. Complete blood count, antinuclear antibody analysis, and

aortic arch superior vena cava

calcification thymoma

descending aorta

Fig. 9-16-3  Computed tomography of the chest with contrast enhancement. Shown is a large, multilobulated thymoma in a 32-year-old man with ocular myasthenia gravis. The mass is in proximity to the aortic arch and the ascending aorta. A focal calcification is present anteriorly. The patient’s ptosis and diplopia remitted following removal of the thymoma.

erythrocyte sedimentation rates typically are drawn in patients who have confirmed myasthenia gravis. If treatment with corticosteroids is planned, diabetes and tuberculosis should be excluded. Neuroimaging of the brain is not required routinely but may be considered for atypical cases that are antibody negative and refractory to treatment (Table 9-16-2).

SYSTEMIC ASSOCIATIONS Generalized myasthenia gravis develops in 75% of patients. The nonocular symptoms include facial weakness, weakness of the jaw when chewing, dysarthria, and dysphagia. Nuchal muscular weakness produces inability to hold the head up. Weakness of the limbs is common. If the erector spinae muscles are involved, the patient may be unable to maintain an erect posture. Most patients feel tired with reduced stamina. In severe cases, weakness of the muscles of the chest and diaphragm produces dyspnea. A pronounced drop in the vital capacity leads to myasthenic crisis, which requires mechanical ventilation and aggressive treatment. Approximately 12% of neonates born to myasthenic mothers develop transient neonatal myasthenia gravis, as a result of maternal transmission of autoantibodies through the placenta; these trigger independent antibody production by the infant. Affected neonates have generalized weakness with difficulty eating, respiratory weakness, a poor cry, and facial weakness, which are noticed shortly after birth. The symptoms last for several weeks and then resolve without recurrence. Thymic enlargement and thymoma frequently are present in patients who have myasthenia gravis. Other autoimmune disorders, such as thyroid disease, systemic lupus erythematosus, and pernicious ­anemia, are found with increased frequency in patients with myasthenia gravis.

TREATMENT The major therapies for myasthenia gravis are: l Acetylcholinesterase inhibitors l Immunosuppression

   TABLE 9-16-2  DIFFERENTIAL DIAGNOSIS OF THE NEUROMUSCULAR JUNCTION Pupils

Ocular Motility

Lids

Other Ocular Findings

Other Systemic Findings

Myasthenia gravis

Normal

Fluctuating ophthalmoparesis

Ptosis Cogan’s lid twitch sign

—

Fluctuating weakness that improves with rest

Graves’ ophthalmopathy

Normal

Restricted EOM Positive forced duction testing

Lid retraction Lid lag

Conjunctival infection Keratoconjunctivitis sicca Exophthalmos Optic neuropathy

Symptoms of hyperthyroidism may be present

Botulism

Dilated, poorly reactive Light–near dissociation

Ophthalmoparesis

Ptosis

—

Limb weakness Bulbar signs Respiratory failure Urinary retention Constipation

Lambert-Eaton myasthenic syndrome

Usually normal

Usually normal

Usually normal

Keratoconjunctivitis sicca

Autonomic and sensory symptoms

Guillain-Barré syndrome

Normal or poorly reactive

Normal or ophthalmoparesis

Ptosis

—

Facial diplegia Limb weakness Areflexia Respiratory failure

Progressive external ophthalmoplegia

Normal

Slowly progressive Symmetrical ophthalmoparesis

Slowly progressive Ptosis

May have pigmentary retinopathy

None unless coexisting mitochondrial disorder

9.16 Disorders of the Neuromuscular Junction

Disorder

EOM, Extraocular movement.

 ymptomatic treatment of ocular abnormalities S Avoidance of agents that worsen neuromuscular transmission Acetylcholinesterase inhibitors raise the safety factor for neuromuscular transmission by preventing the degradation of ACh. Although these agents provide symptomatic improvement in muscle weakness, they do not treat the disease directly. However, because of their rapid effectiveness and lack of long-term side effects, they often are the first agents used in the treatment of myasthenia. Pyridostigmine (Mestinon), the most commonly used drug, has a duration of action of 2–8 hours. It is most useful for the treatment of systemic weakness of myasthenia gravis and may not improve the diplopia. The usual starting dose is 30–60 mg every 4 hours while awake. Larger doses or more frequent dosing intervals may be used as needed. Above 120 mg every 3 hours, no additional effectiveness is likely and a risk exists of cholinergic crises. A delayed release preparation taken at bedtime is useful for patients who have profound weakness upon awakening in the morning. The most common side effects from these agents are gastrointestinal disturbances (nausea, diarrhea) and muscle twitching. Overdosage results in sialorrhea, blurred vision, and worsening weakness (cholinergic crisis). It may be difficult to differentiate cholinergic crisis as a result of medication from worsening of the disease that is myasthenic crisis. Diplopia often does not improve with pyridostigmine and may be treated with immunosuppressive agents.16 Thymectomy is indicated for all patients who have a thymoma and may be beneficial for some patients who do not have one.17 Thymectomy produces improvement in almost all cases with no thymoma present and results in complete remission in 35–45% of patients. The benefits of thymectomy may not be apparent for 2–3 years, yet some patients respond almost immediately after surgery. It usually is recommended for patients under the age of 55 years who have generalized disease.17 The presence or absence of ACh receptor antibodies does not seem to influence the efficacy of the surgery. A trans-sternal approach is preferable, to allow adequate visualization of the thoracic cavity and total thymus removal. Ectopic rests of thymic tissue may be undiscovered if the less invasive transcervical technique is used. The morbidity and mortality rates from thymectomy are quite low. Because any surgical procedure may worsen myasthenia, some patients benefit from a short course of plasmapheresis preoperatively. Alternative methods of direct thymic suppression, such as radiation therapy, are not effective. Immunosuppressants, mainly cytotoxic agents and corticosteroids, treat the disease directly and generally are employed in patients who do not improve satisfactorily with acetylcholinesterase inhibitors. It may be several weeks to months before these medications take effect. Prednisone is used most frequently, and various dosing strategies are employed. Daily administration of high doses (60–100 mg) may ­produce substantial worsening within the first 2 weeks of treatment and should be used with l

l

caution. Other regimens use increasing, daily, low doses of prednisone, or alternate-day dosing. Alternate-day dosing has the advantage of fewer side effects, and many patients who have purely ocular symptoms improve on a low dosage (20–30 mg) of alternate-day therapy. The risks of long-term prednisone administration include peptic ulcer, osteoporosis, femoral neck fracture, diabetes, skin breakdown, weight gain, and cushingoid features. Appropriate medical precautions and monitoring are required. To minimize the complication rate, the lowest dosage of prednisone possible should be used, and other immunosuppressant agents added, if needed. Mycophenolate mofetil, azathioprine, cyclophosphamide, and ­cyclosporin are effective for the long-term management of myasthenia gravis and may be used in combination with prednisone and pyridostigmine.18, 19 These medications have fewer long-term side effects than prednisone. Blood counts must be taken, and liver and renal function must be monitored, and a small possibility exists that a neoplasm will develop after many years of treatment. Plasmapheresis effectively reduces circulating autoantibodies. It typically is reserved for patients in myasthenic crisis or is used preoperatively for thymectomy in patients who have severe weakness. Improvement is rapid, but transient. Like plasmapheresis, intravenous immune globulin produces rapid improvement through a difficult period of myasthenic weakness (400 mg/kg per day for 5 days).20, 21 Patients in myasthenic crisis require aggressive pulmonary treatment, often need intubation and mechanical ventilation, and are best managed in the intensive care unit. As a rule, ptosis typically responds to treatment and diplopia may be refractory. Ocular symptoms can be treated symptomatically as other therapies are initiated, or when these are ineffective. Lid crutches may be beneficial for patients who have ptosis, but ptosis surgery should be reserved for patients who are stable and refractory to other treatments. Diplopia is managed using patching or prisms; strabismus surgery is inappropriate for patients who have active myasthenia gravis. Medications that lower the safety factor of neuromuscular transmission should be avoided in patients who have myasthenia. Penicillamine causes a myasthenic syndrome that may be associated with autoantibody production. Many antibiotics decrease the production or release of ACh, including the aminoglycoside agents (streptomycin, neomycin, kanamycin, gentamicin, tobramycin, amikacin, viomycin), bacitracin, polymyxins (polymixin A and B, colistin), and the ­monobasic amino acid antibiotics (lincomycin and clindamycin). Rarely, worsening of myasthenia occurs with erythromycin or following iodinated contrast dye administration. All neuromuscular blocking agents, such as curare and depolarizing agents, should be used with caution. Chloroquine, lithium, and magnesium affect both presynaptic and postsynaptic transmission. Antiarrhythmic agents, including procainamide and quinidine, can cause or worsen myasthenia gravis. Phenytoin, β-­blockers, cisplatin, phenothiazines, and tetracyclines may have similar effects.

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9 NEURO-OPHTHALMOLOGY

COURSE AND OUTCOME

DIAGNOSIS

Despite its ominous name, myasthenia gravis is seldom fatal; most patients experience remission or good control of their symptoms with treatment. Of those patients who have only ocular symptoms and signs at onset, 10–20% undergo spontaneous remission and 50–80% develop generalized disease, almost always within 2 years of onset of the disorder.22 Patients who have ocular myasthenia who are over the age of 50 years are more likely to progress to generalized myasthenia, while a younger age at onset carries a better prognosis. In adults, the disease is most labile during the first 10 years; most deaths occur during the first year. After 10 years, the course becomes more stable. The long-term prognosis is poorer when a thymoma is present.23 When death occurs from myasthenia gravis, usually it is ­because of respiratory failure with secondary cardiac dysfunction.

The diagnosis is based on the symptoms and signs, the circumstances of infection, electrophysiological studies, and isolation of the organism or toxin. When botulism is suspected, stool, gastric aspirate, and at least 20  ml of serum should be collected for analysis. If the source of contaminated food is available, it may be submitted to the relevant health department for evaluation. Identification of botulinum toxin in serum and stool is performed using a mouse bioassay. A Tensilon test result is almost always negative. Electrophysiological studies are very helpful and show changes similar to those seen in the Lambert-Eaton syndrome.

BOTULISM INTRODUCTION Botulism is a potentially life-threatening disorder caused by the toxin of Clostridium botulinum. Three types exist – food-borne, wound, and infantile. The clinical picture is characterized by rapidly evolving cranial nerve and respiratory weakness with autonomic dysfunction. Associated symptoms include hyposalivation, dysphagia, dysarthria, respiratory failure, mus­ cular weakness, constipation, urinary retention, nausea, and vomiting.

EPIDEMIOLOGY AND PATHOGENESIS Botulism, caused by the neurotoxin elaborated by Cl. botulinum, may take many forms. Its site of action is the presynaptic nerve terminal, where it prevents the release of ACh. The preformed toxin may be ­ingested, as in food-borne botulism, or gain access by wound infection. Alternatively, the bacterium or spore may colonize the gastrointestinal tract, as in infant botulism. At least eight types of toxin have been described, but only three forms commonly affect humans. Type A botulism is usually the most severe form of the disease. The most common food sources of botulism are vegetables, meat, and fish. Commercially canned foods account for only 3% of cases; 97% arise from consumption of home-preserved foods. Restaurant outbreaks are rare but represent 42% of cases. About 10 outbreaks occur yearly, with a mean of 2.2 persons affected per outbreak. Historically, classic or food-borne botulism was caused by inadequately cleaned, smoked, salted, or dried fish or meat. Contemporary risk factors include commercial or home-prepared condiments, vegetables, nonacid foods, and preserved raw fish.24 Plastic food storage bags and containers provide a near-perfect anaerobic environment for growth of Cl. botulinum. Home-canned vegetables and garlic (particularly when coated in oil), canned fruit, fish, and condiments (especially garlic and peppers) accounted for most outbreak reports in the 1980s. The risk increases when foods are held for long periods at ambient temperatures or are reheated inadequately before serving. Because the spores of Cl. botulinum are ubiquitous in the soil, they also contaminate foods that are harvested from the ground (e.g., onions, potatoes). Wound botulism always has been the least common form of botulism but is increasing in incidence as a result of intravenous drug abuse and cocaine abuse associated with necrotic nasal passages.25 Infant botulism occurs during the age range 2–6  months in previously healthy infants. The course is subacute and may be difficult to diagnose until the child becomes severely ill. The classic source of infection is honey. Transmission of spores from adults to infants is possible from soil contamination of clothing. A similar infection can be seen in adults who have achlorhydria, following gastrointestinal operations, and who have blind loops of the bowel.

OCULAR MANIFESTATIONS

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Ophthalmic manifestations are not likely to occur in isolation but are part of a systemic illness. Diplopia and ptosis occur with varying degrees of ophthalmoparesis. Internal ophthalmoplegia with accommodation paresis produces blurred vision. The pupils often are abnormal, with a poor reaction to light. Pupillary light–near dissociation may be observed during the acute infection and occasionally persists after recovery.26 Quivering eye movements have been described. Hypolacrimation is found often.

DIFFERENTIAL DIAGNOSIS The Guillain-Barré syndrome, Miller-Fisher syndrome, and poliomyelitis resemble botulism clinically. Myasthenia gravis spares the pupils and is more gradual in onset. Tick paralysis, diphtheria, organophosphate toxicity, shellfish toxicity, and hypokalemic periodic paralysis are other diagnostic considerations.

SYSTEMIC ASSOCIATIONS Symptoms of food-borne botulism begin 12 hours to 8 days after ingestion of the toxin. Typically, the patient is conscious and afebrile. The characteristic systemic symptoms include hyposalivation and respiratory failure, urinary retention, constipation, and vomiting. Limb weakness may resemble that of Guillain-Barré syndrome, with ascending or descending paralysis. The reflexes are often normal. Prominent bulbar symptoms and cranial nerve palsies may develop. At worst, the patient is “locked in,” unable to move or respond, but fully awake. In wound botulism, symptoms begin 4–18 days after injury and are identical to those of food-borne botulism. Infant botulism causes constipation and weakness, with descending paralysis.27 The infant has a poor suck, a weak cry, and becomes hypotonic. Impairment of extraocular movement, facial weakness, and cranial nerve palsies are common. Dilated pupils, respiratory arrest, and death may ­follow. The course often is insidious and mistaken for failure to thrive.

TREATMENT The most important aspect of treatment is supportive, with mechanical ventilation when necessary. If the patient is not allergic to horse serum (pretesting for hypersensitivity is required), trivalent acute bacterial endocarditis antitoxin is administered, although its efficacy is uncertain. Guanidine is no longer recommended. Recovery occurs spontaneously as new synapses develop; this may take 6–12 months.

LAMBERT-EATON MYASTHENIC SYNDROME INTRODUCTION First described in 1953 as a triad of muscle weakness, autonomic dysfunction, and hyporeflexia, the Lambert-Eaton myasthenic syndrome (LEMS) shares clinical features with myasthenia gravis. Unlike myasthenia gravis, LEMS is a presynaptic disorder of neuromuscular transmission affecting calcium channels.28 This rare disorder is associated with a malignancy, such as oat cell carcinoma of the lung, in at least 50% of cases.29 Symptoms of LEMS typically precede the diagnosis of the neoplasm.

Epidemiology and Pathogenesis

Most patients who have the paraneoplastic form are over 40  years of age. Smoking is a risk factor because of the high association with bronchogenic carcinoma. About 3% of patients who have small cell carcinoma of the lung have LEMS.30 The non-neoplastic form is associated with pernicious anemia, thyroid disease, Sjögren’s syndrome, and other autoimmune disorders. A personal or family history of autoimmune disease is found in 34% of patients who have primary LEMS.31 Myasthenia gravis and LEMS may occur concurrently. Symptoms are caused by impaired release of ACh from the nerve terminal. End-plate potentials are too small to generate an action potential. Striated muscle, glands, and smooth muscle are affected. Calcium and guanidine increase neurotransmitter release, which results in improved strength.

SYSTEMIC ASSOCIATIONS

In contrast to myasthenia gravis, ocular manifestations are not prominent. Decreased lacrimation leads to keratoconjunctivitis sicca, which is the predominant ocular complaint. Ptosis and intermittent diplopia may occur. Sluggishly reactive pupils and tonic pupils are infrequent.32 Slow, saccadic velocities that normalize after exercise have been described. There is one report of a patient with ophthalmoparesis and pseudoblepharospasm.33

More than 80% of the associated malignancies are small cell carcinomas of the lung. Other tumors associated with LEMS include small cell carcinoma of the cervix or the prostate, adenocarcinoma, and lymphoma. The myasthenic syndrome may precede the detection of the malignancy by up to 7  years and rarely follows detection of the tumor.27 If no malignancy is found, repeated investigations are warranted. Other laboratory testing includes thyroid function tests, complete blood count, erythrocyte sedimentation rate, antinuclear antibodies, anti-Ro, and anti-La (SS-A, SS-B) to evaluate for the association of the non-neoplastic form with pernicious anemia, thyroid disease, Sjögren’s syndrome, and other autoimmune disorders.

DIAGNOSIS Rapid onset and progression of symptoms over weeks to months is common in the paraneoplastic form. The non-neoplastic variety has an insidious onset with mild, stable symptoms. Patients generally have proximal muscle weakness and leg pain. Autonomic involvement is present in 50% of cases, which results in dry mouth, constipation, hypo­ hidrosis, impotence, orthostatic hypotension, and urinary retention. Unlike myasthenia gravis, muscle strength improves following voluntary contraction or repetitive testing. Paradoxical lid elevation may ­occur after prolonged upgaze.34 The deep tendon reflexes are hypoactive or absent at rest and increase with voluntary muscle contraction. Electrophysiological studies confirm the diagnosis. Low rates of nerve stimulation (2–3  Hz) produce a decremental response, but high rates (20–50  Hz) cause a two- to tenfold incremental increase in the compound action potential. SFEMG shows changes similar to those found in myasthenia gravis. The Tensilon test is negative and anti-ACh ­receptor antibodies are not present, although calcium channel anti­ bodies have been found in about 50% of patients.

TREATMENT

Guanidine is effective, but it has potentially severe side effects, including bone marrow depression, paresthesias, renal and hepatic impairment, confusion, atrial fibrillation, and hypotension. Typically, anticholinesterases are tried as first-line therapy. 3,4-Diaminopyridine is a more direct treatment; it works by blocking potassium channels and enhancing the release of ACh from the presynaptic nerve terminal. A definite and sustained response to aminopyridines occurs in most patients.35 Treatment with plasmapheresis, intravenous immunoglobulin, corticosteroids, and azathioprine usually leads to improvement in strength.36 Immunosuppressants may take several months to be effective. Magnesium should be avoided, because it worsens the weakness. Other medications that decrease neuromuscular transmission should be used with caution. Treatment of the underlying carcinoma may produce improved strength.

DIFFERENTIAL DIAGNOSIS

COURSE AND OUTCOME

Disorders that produce proximal muscle weakness may resemble the myasthenic syndrome. Myasthenia gravis usually can be excluded clinically, with its prominent ocular and facial involvement. Guillain-Barré syndrome, polymyositis, lumbosacral plexopathies, and polyradiculopathies can be excluded by electrophysiological testing and neuroimaging.

The presence or absence of malignancy largely determines the prognosis. Those patients who have lung cancer should be screened regularly for recurrence within the first 4  years of diagnosis and advised to stop smoking. Most patients can lead a moderately active lifestyle with treatment but should avoid vigorous exercise.

9.16 Disorders of the Neuromuscular Junction

OCULAR MANIFESTATIONS

REFERENCES   1. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–810.   2. Phillips LH, Torner JC. Has the natural history of myasthenia gravis changed over the past 40 years? A metaanalysis of the epidemiological literature. Neurology. 1993;43:A386.   3. Christensen PB, Jensen TS, Tsiropoulos I, et al. Incidence and prevalence of myasthenia gravis in western ­Denmark. Neurology. 1993;43:1779–83.   4. Schmidt D, Dell’Osso LF, Abel LA, Daroff RB. Myasthenia gravis: dynamic changes in saccadic waveform, gain and velocity. Exp Neurol. 1980;68:365–7.   5. Ellis FD, Hoyt CS, Ellis FJ, et al. Extraocular muscle responses to orbital cooling (ice test) for ocular myasthenia gravis diagnosis. J AAPOS. 2000;4:271–81.   6. Kubis KC, Danesh-Meyer HV, Savino PJ, Sergott RC. The ice test versus the rest test in myasthenia gravis. Ophthalmology. 2000;107:1995–8.   7. Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 2000;107:622–3.   8. Seybold M. The office Tensilon test for ocular myasthenia gravis. Arch Neurol. 1986;43:842–3.   9. Coll GE, Demer JL. The edrophonium-Hess screen test in the diagnosis of myasthenia gravis. Am J Ophthalmol. 1992;114:489–93. 10. Ing EB, Ing SY, Ing T, Ramocki JA. The complication rate of edrophonium testing for suspected myasthenia gravis. Can J Ophthalmol. 2000;35:141–4. 11. Odel JG, Winterkorn JM, Behrens MM. The sleep test for myasthenia gravis. A safe alternative to Tensilon. J Clin Neuro Ophthalmol. 1990;35:191–204. 12. Bennett DLH, Mills KR, Riordan-Eva P, et al. Anti-MuSK antibodies in a case of ocular myasthenia gravis. J Neurol Neurosurg Psychiatry. 2006;77:564–5. 13. Oh SJ, Kim DE, Kuruoglu R, et al. Diagnostic sensitivity of laboratory tests in myasthenia gravis. Muscle Nerve. 1992;15:720–4.

14. Rivero A, Crovetto L, Lopez L, et al. Single fiber electromyography of extraocular muscles: a sensitive method for the diagnosis of ocular myasthenia gravis. Muscle Nerve. 1995;18:943–7. 15. Weinberg DH, Rizzo JF III, Hayes MT, et al. Ocular myasthenia gravis: predictive value of single-fiber electromyography. Muscle Nerve. 1999;22:1222. 16. Evoli A, Batocchi AP, Minisci C, et al. Therapeutic options in ocular myasthenia gravis. Neuromuscul Disord. 2001;11:208–16. 17. Romi F, Gilhus NE, Aarli JA. Myasthenia gravis: disease severity and prognosis. Acta Neurol Scand Suppl. 2006;183:24–5. 18. Tindall RSA, Rollins JA, Pillips JT, et al. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med. 1987;316:719–24. 19. Schneider-Gold C, Hartung HP, Gold M. Mycophenolate mofetil and tacrolimus: New therapeutic options in neuroimmunological diseases. Muscle Nerve. (31 Mar 2006, Epub ahead of print). 20. Thornton CA, Griggs RC. Plasma exchange and intravenous immunoglobulin treatment of neuromuscular disease. Ann Neurol. 1994;35:260–8. 21. Brannagan TH III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin in neurologic disease. Neurology. 1996;47:647–77. 22. Bever CT Jr. Aquino AV, Penn AS, et al. Prognosis of ocular myasthenia. Ann Neurol. 1983;14:516–9. 23. Palmisani MT, Evoli A, Batocchi AP, et al. Myasthenia gravis associated with thymoma: clinical characteristics and long-term outcome. Eur Neurol. 1994;34:78–82. 24. Barrett DH. Endemic food-borne botulism: clinical experience, 1973–1986 at Alaska Native Medical Center. Alaska Med. 1991;33:101–8. 25. Mitchell PA, Pons PT. Wound botulism associated with black tar heroin and lower extremity cellulitis. J Emerg Med. 2001;20:371–5.

26. Friedman DI, Fortanasce VN, Sadun AA. Tonic pupils as a result of botulism. Am J Ophthalmol. 1990;109: 236–7. 27. Schreiner MS. Infant botulism: a review of 12 years’ experience at the Children’s Hospital of Philadelphia. Pediatrics. 1991;87:159–65. 28. Greenberg DA. Neuromuscular disease and calcium channels. Muscle Nerve. 1999;22:1341–9. 29. Argov Z, Shapira Y, Averbuch-Heller L, Wirguin I. Lambert-Eaton myasthenic syndrome (LEMS) in association with lymphoproliferative disorders. Muscle Nerve. 1995;18:715–9. 30. Elrington GM, Murray NM, Spiro SG, et al. Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective study of 150 patients. J Neurol Neurosurg Psychiatry. 1991;54:764–77. 31. Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment. Neurology. 2000;54:2176–8. 32. Clark CV. Ocular autonomic nerve function in LambertEaton myasthenic syndrome. Eye. 1990;4:473–81. 33. Kanzato N, Motomura M, Suehara M, Arimura K. Lambert-Eaton myasthenic syndrome with ophthalmoparesis and pseudoblepharospasm. Muscle Nerve. 1999;22:1727–30. 34. Breen LA, Gutmann L, Brick JF, Riggs JR. Paradoxical lid elevation with sustained upgaze: a sign of LambertEaton syndrome. Muscle Nerve. 1991;14:863–6. 35. Sanders DB, Masseuy JM, Sanders LL, Edwards LJ. A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome. Neurology. 2000;54:603–7. 36. Bain PG, Motomura M, Newsome-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47:678–83.

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PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

9.17

Ocular Myopathies Richard M. Rubin and Alfredo A. Sadun

Definition:  Ocular myopathies involve pathology of the extraocular

muscles that results in ophthalmoplegia and other disorders of ocular motility.

Key features n n n n n

L imitations of motility. Inflammation. Exophthalmos. Pain. Diplopia.

Associated features n n n

S ome myopathies are acquired and of known mechanism   (Graves’ disease). Some myopathies are acquired and consequent to other processes (certain forms of myositis). Some myopathies are congenital but may not manifest until late adulthood (mitochondrial). 

INTRODUCTION Diseases that involve metabolic abnormalities, atrophy, infiltration, or inflammation of the ocular muscles may appear as weakness or restriction. Except for Graves’ dysthyroid ophthalmopathy, most of these conditions are uncommon or rare. Graves’ dysthyroid ophthalmopathy, orbital myositis, and infiltrative myopathies are covered in Part 11, and other orbital diseases and trauma that may cause restrictive eye syndromes are discussed in Chapters 12.12 and 12.13. The four sections of this chapter independently cover mitochondrial myopathies, dystrophic myopathies, Graves’ dysthyroid ophthalmopathy, and other inflammatory and infiltrative myopathies.

MITOCHONDRIAL DISORDERS EPIDEMIOLOGY AND PATHOGENESIS

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Mitochondria are cytoplasmic organelles that produce energy for cell functions, maintenance, repair, and growth through the enzymatic processes of oxidative phosphorylation. A group of neurodegenerative and myopathic syndromes result from disorders of mitochondrial metabolism that cause defects in the energy cycle of susceptible tissues.1 For reasons that remain unclear, the tissues most reliant on mitochondrial energy are those of the central nervous system, heart, muscles, kidneys, and endocrine organs. Hence, these tissues are most likely to show ­various clinical manifestations of mitochondrial dysfunction. Each mitochondrion possesses 2–10 mitochondrial DNA genomes made up of a closed circle of 16 569 nucleotide base pairs. The ­mitochondrial

DNA encodes for 13 polypeptides essential in oxidative phosphorylation and for ribosomal and transfer ribonucleic acids essential in the production of mitochondrial proteins. Nuclear DNA encodes for an additional 56 subunits of the electron transport chain and for genes required for replication, transcription, and translation of the mitochondrial genes. Mitochondrial DNA has unique genetics for several reasons, which include its cytoplasmic location and the multiple DNA copies that ­exist in each cell. Mitochondrial DNA is inherited maternally because it is transmitted via oocyte cytoplasm. In addition, new mutations often result in heteroplasmy, a mixed intracellular population of normal and mutant DNA molecules. Also, multiple random and asymmetrical ­mitochondrial divisions lead to replicative segregation and eventually homoplasmy, such that each cell possesses only pure mutant mitochondrial DNA. Thus, the relative proportion of normal and mutant mitochondrial DNA may vary from cell to cell and from individual to individual. The variable phenotypic expressions of mitochondrial dysfunction likely arise from interplay of the unique features of mitochondrial ­inheritance that cause heteroplasmy and homoplasmy, the modifying contribution of nuclear DNA under the influence of mendelian ­genetics, the deterioration of mitochondrial function with aging, and the ­different energy requirements of specific tissues. The most common mitochondrial disorder to affect muscles is chronic progressive external ophthalmoplegia (CPEO) and its best known subtype, Kearns-Sayre syndrome.2 Less common ­mitochondrial myopathies of ophthalmic importance include ­mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome ­(MELAS), myoclonic epilepsy with ragged red fibers (MERRF, Fukuhara’s syndrome), and mitochondrial neurogastrointestinal encephalopathy.3, 4 Mitochondrial disorders that affect tissues other than muscle during early childhood include Alpers’ disease, Menkes’ disease, and Leigh’s disease; one that manifests later in life is Leber’s hereditary optic ­neuropathy (LHON).5

OCULAR MANIFESTATIONS Patients who have CPEO often exhibit initial bilateral ptosis followed by limitation of ductions in all directions and marked delay of saccades. Downward gaze may be spared until late in the disease course. Curiously, despite ocular misalignment, these patients rarely complain of diplopia. Weakness of the orbicularis oculi and facial muscles is found commonly, and pigmentary retinopathy may be associated. Kearns-Sayre syndrome, in particular, is characterized by the triad of external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction block during the first or second decade of life (early-onset CPEO). ­Peripapillary pigment atrophy and salt-and-pepper retinal pigment ­epithelial changes are most striking in the macula. True bone spicule pigmentary retinopathy as seen in retinitis pigmentosa is not typical in Kearns-Sayre syndrome. The MELAS syndrome manifests with ptosis and external ophthalmoplegia, in addition to the commonly associated visual disturbances, which may include hemianopia or cortical blindness.6 Eventually, MERRF develops into progressive optic atrophy.

DIAGNOSIS The possibility of muscle disease should be considered whenever ophthalmoplegia does not correspond to the pattern of a cranial nerve palsy and when there is acquired ptosis. Most diagnoses are made through a process of exclusion and imaging studies.

SYSTEMIC ASSOCIATIONS Systemic findings of CPEO include short stature, peripheral neuropathy, ataxia, spasticity, somatic muscle weakness, vestibular dysfunction, and deafness.8 Lactic acidosis is found often because of defective aerobic metabolism. Abnormalities of cardiac conduction and of the central nervous system, which include cerebellar dysfunction and elevated CSF protein exceeding 100 mg/dL, are associated with Kearns-Sayre syndrome.9 The cardiac conduction disturbances have an onset typically 10 years after ptosis appears and may result in sudden death. Endocrine dysfunction may include hypoparathyroidism, diabetes mellitus, hypogonadism, or growth hormone deficiency. In CPEO and Kearns-Sayre syndrome, the brain eventually may undergo spongiform degeneration, with the clinical picture of dementia. Basal ganglia calcifications may occur. The association of progressive ophthalmoplegia with peripheral neuropathy, leukoencephalopathy, and gastrointestinal dysmotility in mitochondrial disease has been reported.10 It is likely that additional multiorgan system, mitochondrial syndromes will be elucidated. Seizures, vomiting, lactic acidosis, episodes of hemiparesis, and stroke-like events during childhood or early adulthood characterize MELAS. Although partial recovery from these stroke-like episodes is the rule, severe neurological damage eventually results. Typically, MERRF occurs during the second decade of life with myoclonus, followed by ataxia, weakness, and seizures.

A

PATHOLOGY Biopsy of skeletal muscle reveals “ragged red fibers” that stain red or purple using a modified Gomori trichrome stain (Fig. 9-17-1). The mitochondria of the involved muscle fibers are concentrated ­peripherally and may show increased staining for the mitochondrial enzyme ­succinate dehydrogenase. Biochemical abnormalities of oxidative phosphorylation, such as patchy cytochrome-c oxidase deficiency, may be detected by muscle biopsies as well. The ultrastructural appearances of skeletal muscle mitochondria are varied and may show enlarged mitochondria that contain crystal-like inclusions; changes in the number, shape, or regularity of cristae; or emptiness, vacuolization, or triglyceride accumulation within mitochondria (Fig. 9-17-2). The mitochondria often are increased in number and size. Such morphological changes are not necessarily unique and may be found in other muscle disorders, such as the muscular dystrophies or polymyositis. Histopathologically, the retinal findings in Kearns-Sayre syndrome suggest retinal pigment epithelial dysfunction rather than photoreceptor disease.11

9.17 Ocular Myopathies

Diagnoses of mitochondrial disorders often are supported by histopathological and biochemical evidence of mitochondrial dysfunction. Specific identification of an enzyme defect may confirm the diagnosis. Generally, to show abnormalities in patients who have mitochondrial cytopathies, substrates of oxidative phosphorylation from serum and cerebrospinal fluid (CSF), which include glucose, lactate, and pyruvate, and the pH of venous blood during fasting all are measured. Elevation of CSF protein levels also may help in the diagnosis of CPEO and MELAS syndrome. Electrocardiograms should be obtained for all patients suspected of mitochondrial cytopathies, to detect any life-threatening cardiac conduction abnormalities. Neuroimaging may help in the assessment for other causes of neurological deficits. In CPEO, magnetic resonance imaging (MRI) of the brain often shows hyperintensity in the thalamus and globus pallidus on T2-weighted images. Kearns-Sayre syndrome was shown in one case to have MRI findings indistinguishable from those of multiple sclerosis.7 Posterior cerebral cortical abnormalities that correspond to focal neurological deficits commonly are found on neuroimaging in MELAS syndrome. Genetic analysis for mitochondrial DNA mutations from blood leukocytes or muscle biopsy may show a characteristic mutation in MELAS syndrome. Poor correlation exists between specific mitochondrial DNA mutations and CPEO, because CPEO may exhibit a clinical picture related to a final common pathway of impaired mitochondrial energy production in muscle from a variety of mutations. Diseases of glycolipid metabolism, lysosomal or glycogen storage, peroxisome dysfunction, and acquired viral, toxic, and endocrine myopathies and encephalopathies also must be ruled out. Electromyography helps to differentiate myopathic from neuropathic causes of muscle weakness.

TREATMENT Coenzyme Q10, essential for normal mitochondrial function and deficient in a proportion of patients who have CPEO and Kearns-Sayre syndrome, administration has been associated with improved exercise tolerance, cardiac function, and ataxia in some patients with KearnsSayre syndrome.12 Other treatments, such as thiamine, also aim to bypass or enhance oxidative phosphorylation but only occasionally have been shown to improve exercise tolerance, cardiac conduction, or lactic acidosis. However, coenzyme Q10 and these other treatments do not improve the ophthalmoplegia, retinopathy, or ptosis in patients who have CPEO or Kearns-Sayre syndrome. Complaints that arise from ptosis often are handled by ptosis crutches or a careful surgical approach, in which the lid is raised minimally by addressing the visual obstruction rather than the cosmetic appearance. Overly aggressive attempts to treat the ptosis may result in exposure keratopathy and corneal ulceration because of weak orbicularis oculi muscles and a poor Bell’s reflex. Symptomatic ocular deviations may be treated successfully with strabismus surgery. Periodic evaluation by a cardiologist is indicated in Kearns-Sayre ­syndrome. In some instances, placement of a pacemaker for prophylactic pacing or for treatment of symptomatic cardiac block is necessary to prevent sudden death. The systemic use of corticosteroids is contraindicated in Kearns-Sayre syndrome because of the possible precipitation of coma and death from hyperglycemic acidosis.13 Genetic counseling should be offered to all patients who have mitochondrial cytopathies.

COURSE AND OUTCOME Chronic progressive external ophthalmoplegia is a slowly progressive loss of lid and extraocular motor function. The diplopia may or may not worsen, because the symmetry of the ophthalmoplegia may prevent strabismus. However, small ptosis correction may be required as

B

Fig. 9-17-1  MELAS syndrome. (A) Complete external ophthalmoplegia in a 20-year-old woman. (B) Microscopic section of degenerated extraocular muscles stained with trichrome shows “ragged red fibers.”

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9 NEURO-OPHTHALMOLOGY Fig. 9-17-2  Viewed with an electron microscope, the abnormal mitochondria in a case of chronic progressive external ophthalmoplegia show as electron dense and globular. The normal arrangement of cristae is not seen. Fig. 9-17-4  Front view of a patient who has myotonic dystrophy. The muscle wasting gives the characteristic drawn appearance of “hatchet facies.”

forms above, in Fukuyama’s syndrome the manifestations and death occur in early childhood.

OCULAR MANIFESTATIONS

Fig. 9-17-3  Slit-lamp view of a “Christmas tree” cataract in myotonic dystrophy. Note the iridescent or colored refractile flecks.

described above. In severe cases that have more generalized manifestations, such as in Kearns-Sayre syndrome, retinopathy and cardiac problems may develop. Patients who have MELAS and MERRF may develop several neurological deficits, which include ataxia, weakness, and seizures.

DYSTROPHIC MYOPATHIES EPIDEMIOLOGY AND PATHOGENESIS

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Three forms of muscular dystrophy of ophthalmologic importance exist, all of which involve progressive weakness of the skeletal muscles. Myotonic dystrophy, like the other three forms, involves difficulties with relaxation of skeletal muscles after contraction. Myotonic dystrophy is an autosomal dominant condition in which the first symptoms usually appear during the teenage years or in young adulthood. Several large pedigrees have been identified. Oculopharyngeal dystrophy usually develops a little later, in young or middle-aged adults. The first symptoms often are difficulty in swallowing, with ptosis later. A large French Canadian autosomal dominant pedigree has been identified, in which the original ancestor immigrated to Quebec in 1634.14 Autosomal recessive and sporadic inheritances also have been reported. Fukuyama’s syndrome (MERRF) is an autosomal recessive condition most often found in people of Japanese descent. Unlike the other two

In myotonic dystrophy, abnormalities in the extraocular muscles are ­accompanied by involvement of other muscles, which include the ­levator, and result in slowly progressive bilateral ptosis. Other ocular findings include cataracts, described as Christmas tree cataracts (Fig. 9-17-3) for their multiple refractile colors.15 In oculopharyngeal dystrophy, dysphagia is followed soon by bilateral ptosis which, over a period of years, is followed by external ophthalmoplegia and weakness of the orbicularis. The patient, despite a remarkable lack of ocular motility, may not complain of diplopia, because often the limitations of eye movement are very symmetrical so that no strabismus occurs. In Fukuyama’s syndrome, in addition to the weakness of the orbicularis and a strabismus, nystagmus, anterior polar cataracts, optic nerve atrophy, and a chorioretinal degeneration with retinoschisis or detachment occur also.16

DIAGNOSIS The electromyogram, with characteristic spontaneous, high-frequency bursts, is diagnostic for all forms of dystrophic myotonias. Furthermore, all dystrophic myotonias are evident clinically by blepharospasm or the inability of the patient to open the eyes after they have been forcibly closed for some time. Only myotonic dystrophy has intraocular findings such as the Christmas tree cataract (see Fig. 9-17-3). Both myotonic dystrophy and oculopharyngeal dystrophy have external ophthalmoplegia, but Fukuyama’s syndrome does not. In all three dystrophies, biopsy reveals characteristic histopathology.

SYSTEMIC ASSOCIATIONS In myotonic dystrophy, involvement of the muscles of the head and neck gives the characteristic narrow, drawn facial appearance or “hatchet ­facies” (Fig. 9-17-4). Involvement of the cardiac muscles may result in congestive heart failure. Dysphagia, constipation, and incontinence are not uncommon. In some cases mental retardation occurs, and in males testicular atrophy and premature baldness are frequent. In oculopharyngeal dystrophy, the bulbar musculature is affected ­frequently and temporalis wasting occurs. Patients have difficulty swallowing without aspirating. Other bulbar and limb girdle muscles become involved later. In Fukuyama’s syndrome, the proximal muscle groups are involved most. Mental retardation, seizures, severe motor development delay, and cortical blindness are common.

PATHOLOGY

9.17 Ocular Myopathies

In myotonic dystrophy, findings from histopathological examination of the extraocular muscles are similar to those seen in the skeletal muscles.17 Down the centers of muscle fibers run rows of nuclei. The myofilaments and sarcoplasmic reticulum are disrupted, and accumulations of impaired mitochondria may be found. In oculopharyngeal dystrophy, tubulofilamentous intranuclear inclusion bodies are seen on ultrastructural examination of muscle biopsies. In Fukuyama’s syndrome, the same changes are seen, confined largely to the proximal muscle groups.

TREATMENT For all three muscular dystrophies, treatment consists of symptomatic support. The cataracts of myotonic dystrophy may be removed. Foot braces and other devices are available to help support footdrop or other skeletal muscle weakness. All patients affected by dystrophic myopathies need to be referred to neurologists.

A

COURSE AND OUTCOME Progressive atrophy of the skeletal muscles leads to a variety of systemic difficulties. In myotonic dystrophy the patient develops difficulty climbing stairs and, eventually, even with walking and holding the head up. Vision may be maintained after cataract surgery. In oculopharyngeal dystrophy, dysphagia is most problematic.

GRAVES’ DYSTHYROID OPHTHALMOPATHY EPIDEMIOLOGY AND PATHOGENESIS Graves’ dysthyroid ophthalmopathy is the most common cause of ­exophthalmos − it probably accounts for more than 50% of cases. Prevalence, although uncertain, has been estimated in studies in the United States at 0.4% and in the United Kingdom at 1.1–1.6%.18 Women are affected 3–10 times more frequently than men.19 The mean age of appearance for Graves’ thyroid disease is 41 years, and the orbital disease occurs an average of 2.5 years afterward.19 Even though the disease is more common in women, the severity of disease tends to be greater in men and in patients above 50 years of age.19 Graves’ ophthalmopathy is presumed to result from autoimmune processes that include extraocular muscle myositis, fibroblast proliferation, glycosaminoglycan overproduction, and orbital congestion. Both humoral and cell-mediated immune mechanisms have been ­implicated.20 The hyperthyroidism in Graves’ disease may run an independent course and has been attributed to stimulation of thyrotropin receptors on the thyroid cell plasma membrane by immunoglobulin. These thyroid-stimulating immunoglobulins (previously called long-acting thyroid stimulator proteins) are demonstrable in 50% of patients who have active Graves’ disease. However, orbital changes have not been found to occur directly in response to these thyroidstimulating antibodies. Other immunoglobulins have been identified in the stimulation of collagen synthesis by fibroblasts and myoblast proliferation, although it remains uncertain whether these antibodies are primarily pathogenic or occur secondarily because of local inflammatory processes. Immunohistochemical analysis and histological findings have shown orbital infiltration with mononuclear cells sensitized to retro-orbital antigens. Abnormal helper-to-suppressor T-cell ratios and reductions in the number of T-suppressor cells are thought to be associated with a proliferation of B lymphocytes that produce autoantibodies directed against the orbital tissues. The expression of immunomodulatory ­proteins, such as histocompatibility antigen molecules, intercellular adhesion molecules, and heat-shock proteins, may play a role in the presentation and recognition of antigenic epitopes specific to orbital and thyroid tissues. Cytokines released by the infiltrating monocytes may stimulate immunomodulatory protein expression, glycosaminoglycan production, and proliferative activity from orbital fibroblasts. Differences between orbital and pretibial fibroblasts and fibroblasts from other locations may explain why connective tissue involvement in Graves’ disease is limited largely to these regions. Orbital venous congestion also has been suggested to contribute significantly to the pathogenesis of many of the clinical findings of Graves’ ophthalmopathy.21 Both genetic and environmental risk factors have been identified, which may predispose toward or act as triggers for the abnormal auto­ immune disturbance in Graves’ disease.22 Population studies show

B

Fig. 9-17-5  Graves’ disease. (A) In Graves’ disease, exophthalmos often looks more pronounced than it actually is because of the extreme lid retraction that may occur. This patient, for instance, had minimal proptosis of the left eye but marked lid retraction. (Courtesy of Shaffer DB. In: Yanoff M, Fine BS. Ocular pathology, 4th ed. London: Mosby; 1996.) (B) A histological section shows both fluid and inflammatory cells separating the muscle bundles. The inflammatory cells are predominantly lymphocytes, plus plasma cells.

linkage to certain histocompatibility antigens, which include HLA-B8 and HLA-DR3 in White, HLA-BW46 in Chinese, and HLA-BW35 in Japanese patients. Environmental factors such as stress, smoking, and infection with certain gram-negative organisms (e.g., Yersinia enterocolitica) may increase the risk or severity of Graves’ ophthalmopathy.23

OCULAR MANIFESTATIONS The eye manifestations of Graves’ ophthalmopathy typically are selflimited. An active phase of inflammation and progression tends to stabilize spontaneously 8–36 months after onset. Initial symptoms of Graves’ ophthalmopathy may be complaints of foreign-body sensation, tearing, or photophobia, often accompanied by signs that include lid retraction, lid lag, lagophthalmos, prominence of the episcleral vessels over the horizontal rectus muscles, and lid edema (Fig. 9-17-5A). Exophthalmos reflects an increase in soft tissue mass within the bony orbit and may result from enlargement of the extraocular muscles or increased orbital fat volume24 (Fig. 9-17-5B). Exophthalmos is almost always bilateral and usually relatively symmetrical. Attempts to push the globe back into the orbit (retropulsion) typically are met with firm resistance because of the inflammatory orbital changes that preclude displacement of the fat. Limitation of ocular motility is the direct consequence of pathological changes that affect the extraocular muscles. The inferior rectus muscle is involved most commonly, followed by the medial rectus and the superior rectus. Clinical complaints associated most frequently with muscle restriction are nontorsional, vertical, or oblique diplopia, which may be noticed only on awakening. Patients often are bothered by the feeling of orbital fullness and the pulling sensation experienced on gaze away from a restricted muscle. Also, increased intraocular pressure may occur on gaze in the opposite direction of the restricted muscle. In ­particular, this is seen on upgaze with inferior rectus restriction. Patients with Graves’ disease may have sore eyes from exposure keratopathy or superior limbic keratitis. Dry eye is common because of disturbances in tear quantity and, especially, tear film constitution,

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9 NEURO-OPHTHALMOLOGY Fig. 9-17-6  Fundus view of a case of Graves’ ophthalmopathy. The patient   was losing vision as a consequence of optic neuropathy. Note the congested appearance of the optic nerve head. (Courtesy of Dr. S. Feldon.)

Fig. 9-17-7  Computed tomography scan of the orbit in a case of Graves’ ophthalmopathy. Note the enlarged muscles (medial recti more than lateral recti). (Courtesy of Dr. M. Yanoff.)

 TABLE 9-17-1  “NO SPECS” AND “RELIEF” CATEGORIZATION OF GRAVES’ DISEASE Class

Signs

0

No signs nor symptoms

1

Only signs are upper eyelid retraction,   lid lag, stare

2

Soft tissue signs and symptoms: l   Resistance to retropulsion l   Edema of conjunctiva and caruncle l   Lacrimal gland enlargement l   Injection over the horizontal rectus muscle insertions l   Edema of the eyelids l   Fullness of the eyelids

3

Proptosis

4

Extraocular muscle involvement

5

Corneal involvement secondary   to exposure

6

Sight loss secondary to optic nerve   compression

as well as because of the increased exposure. Acute disease is associated with conjunctival and periorbital edema. With quiescence of the disease, the swelling may reduce, although motility disturbances and exophthalmos tend to remain. Optic nerve involvement also may occur because of compression of the optic nerve at the orbital apex by the enlarged muscles (Fig. 9-17-6). This is more likely to be associated with superior rectus enlargement and no gross exophthalmos (which is a form of self-decompression). Optic nerve compression may be associated with decreasing visual acuity, color loss, afferent pupillary defect, and visual field loss. On examination, the optic disc may be swollen, normal, or atrophic. In 1969, Werner proposed the “NO SPECS” classification for signs of Graves’ ophthalmopathy.25 In 1981, Van Dyke refined the class 2 NO SPECS soft tissue findings with the mnemonic RELIEF26 (Table 9-17-1). Although the mnemonics help to remember the manifestations of Graves’ disease, not uncommonly, the order of signs and symptoms does not follow the order of the classification but consists of combinations of findings from various classes.

DIAGNOSIS

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In 1995, Bartley and Gorman proposed diagnostic criteria for Graves’ ophthalmopathy as eyelid retraction with objective thyroid dysfunction, or either eyelid retraction or objective thyroid dysfunction in

Fig. 9-17-8  Ultrasonographic image (“B” scan) of the orbit in a case of Graves’ ophthalmopathy. Two enlarged muscles (dark shadows) are seen behind the globe. (Courtesy of Dr. S. Feldon.)

association with exophthalmos, optic neuropathy, or extraocular muscle involvement.27 The clinical signs must not be attributable to other causes. In Graves’ ophthalmopathy, muscle tendons are relatively spared on computed tomography (CT) scans (Fig. 9-17-7; see Fig. 9-9-2).28 The non-contrast-enhanced coronal orbital CT scan is most helpful in the assessment of the size of the extraocular muscles. Bilateral enlargement is strongly suggestive of thyroid ophthalmopathy, even when the ­thyroid function study results are normal. The differential diagnosis includes orbital tumors, which may be primary (hemangioma, meningioma, glioma, lymphoma) or metastatic (breast, lung, colon, prostate), as discussed in Chapter 9.22. The distinction from Graves’ ophthalmopathy usually is apparent, both by the lid findings (such as lid lag) characteristic of Graves’ ophthalmopathy and by the distinct neuroimages of orbital tumors. One exception may be lymphoma, which may be differentiated by its propensity to involve the lacrimal gland and by its lack of clinical manifestations. Orbital inflammations, such as orbital pseudotumor, may be more difficult to differentiate. However, ultrasonography (Fig. 9-17-8) and CT may be used to note the sparing of the muscle tendons seen only in Graves’ ophthalmopathy. Furthermore, ultrasonography may be used to distinguish the characteristic, widely separated, and fairly highamplitude spikes seen in Graves’ ophthalmopathy (Fig. 9-17-9) from those found in diseases such as orbital myositis. Neuroimaging and possibly biopsy of nasal mucosa may help to exclude diseases such as Wegener’s granulomatosis. Scanning also helps to differentiate orbital infections, such as preseptal or orbital cellulitis; however, the classic clinical characteristics of infections must be recognized (Chapter 9.22).

The orbital congestion consequent to carotid-cavernous sinus or dural shunt fistulas also may be differentiated clinically (they do not ­produce an increase in orbital resistance to retropositus or lid lag) and ­particularly by MRI.

SYSTEMIC ASSOCIATIONS Ophthalmopathy is clinically evident in 25–50% of patients with Graves’ hyperthyroidism. Occasionally, Graves’ ophthalmopathy occurs in patients affected by Hashimoto’s thyroiditis or in patients who have no evidence of thyroid disease. Thyroid hormone levels may be elevated, normal, or even low. Although unnecessary to confirm a diagnosis of Graves’ ophthalmopathy, measurements of tri-iodothyronine, thyroxine, and thyroid-stimulating hormone levels are performed. Systemic manifestations of Graves’ disease may include nervousness, emotional lability, tremor, weakness, fatigue, heat intolerance, sweating, dyspnea, palpitations, goiter, leg swelling, increased appetite, weight loss, and hair thinning.

PATHOLOGY Generally, as in other forms of inflammatory myositis, the early histopathology in Graves’ ophthalmopathy consists of inflammatory cell infiltration, mucopolysaccharide deposition, and increased water content. In the later stages, the muscles undergo atrophy and fibrosis (see Fig. 9-17-5B). These changes are associated with enlargement of the extraocular muscles and relative sparing of the tendinous insertions. More particularly, the cellular infiltrate is hypocellular and polymorphous, and consists primarily of mature lymphocytes, plasma cells, and macrophages.

TREATMENT The management of Graves’ ophthalmopathy is largely independent of the management of the concomitant endocrinopathy. Such patients require at least two specialists to manage both aspects of the disease. The short-term goal of therapy in Graves’ ophthalmopathy is to conserve useful vision, which may mean the provision of artificial tears or improvement of lid coverage for an exposed cornea. In rare cases, it may mean the treatment of Graves’ optic neuropathy (see Fig. 9-17-6). The long-term goal of therapy is restoration of the orbital anatomy. If possible, this should entail postponement of reconstructive surgery until lack of progression has been established. In general, several tools exist in the management of Graves’ ophthalmopathy. The use of glucocorticoids in Graves’ ophthalmopathy is controversial. Without question, an immediate benefit occurs, but this seems to decay with time.29 Hence, many investigators believe that glucocorticoids should be reserved for use in patients who have optic neuropathy, and in such cases are given in large dosages (over 100 mg prednisone per day). Radiation as a nonspecific immunosuppressant does lead to improvement in Graves’ ophthalmopathy. However, the effect may take a few months to maximize, and in the interim visual loss from an ­optic

9.17 Ocular Myopathies

Fig. 9-17-9  Ultrasonographic image (“A” scan) of the orbit in a case of Graves’ ophthalmopathy. Note the high-amplitude spikes characteristic of such muscles. Courtesy of Dr. S. Feldon.

­ europathy may become permanent. Complications (short and very n long term) arise from radiation therapy that suggest it should not be employed except in cases of optic neuropathy. Some investigators use radiation therapy in cases of severe visual loss from an optic neuropathy in conjunction with corticosteroids. Immunosuppressant agents such as azathioprine or cyclophosphamide have been advocated.29 The combined use of prednisone and ­ciclosporin has been suggested as well.29 The common surface problems of ocular irritation, foreign-body ­sensation, and tearing usually are treated best with artificial tears and other lubricants. However, eyelid surgery for severe lid retraction is also of benefit.30 Diplopia may be managed early with spectacle prisms. However, the variable nature of Graves’ ophthalmopathy-induced diplopia and its noncomitance make prism use, Fresnel as well as standard, ineffectual. Eventually, most patients who have diplopia require strabismus surgery. The most frequent procedure is a recession of the inferior rectus muscle to compensate for restriction. Surgery also is an option to address the common problems of exophthalmos and lid retraction. Some investigators, however, argue that orbital decompression surgery be reserved for cases that involve optic neuropathy, because this type of surgery carries a higher risk than the strabismus or lid surgeries described above, and the cosmetic problem can be addressed, at least partly, with combined upper and lower lid and lateral canthoplasty procedures. Orbital decompression may be performed from lateral, medial, and floor approaches (or combinations). Surgical decompression is reserved for when the patient does not respond to medical treatment. However, the optic neuropathy of Graves’ ophthalmopathy can be serious, and the clinician must be prepared to identify the problem at the earliest stage and approach it by medical, surgical, or radiation therapy.

COURSE AND OUTCOME As described above, most cases of Graves’ ophthalmopathy stabilize or even regress partially within 8–36 months. Once stable, the condition is reviewed for the need for additional surgery. Most patients do well, but may continue to complain of dry eye symptoms and require the continued use of artificial tears.

OTHER INFLAMMATORY AND INFILTRATIVE ­MYOPATHIES EPIDEMIOLOGY AND PATHOGENESIS Orbital Myositis

The most common cause of primary muscle dysfunction is inflammation. Inflammation or secondary ischemia related to swelling (tissue compartment syndrome) may lead to fibrosis and scarring within an extraocular muscle. Orbital congestion may cause a restrictive component. Such orbital inflammation, or orbital pseudotumor, is usually idiopathic, although the cause may sometimes be determined. Idiopathic orbital myositis refers to nonspecific orbital inflammation. However, a variety of conditions, such as Crohn’s disease, or more localized diseases, such as sinusitis and asthma, have been reported to incite an attack of orbital myositis. This orbital inflammation may extend anteriorly to involve the posterior globe (posterior scleritis) or lacrimal gland (dacryoadenitis), or posteriorly as an orbital apex syndrome. When orbital pseudotumor involves primarily the muscles (myositis), it tends to occur unilaterally (although bilateral involvement may occur up to 25% of the time) in young adults, with women involved more frequently than men. A variety of granulomatous, infectious, neoplastic, and vasculitic disorders may masquerade as myositis also. Infectious myositis may result from trichinosis, but more commonly the cause is never determined.31 Orbital cellulitis may be bacterial and originate from the paranasal sinuses, or fungal in association with metabolic acidosis or diabetes mellitus. Myositis may be associated with systemic or distant inflammatory disease such as Crohn’s disease. Other inflammatory syndromes, such as Wegener’s granulomatosis and giant cell arteritis, also may affect the extraocular muscles directly.32

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9

Amyloidosis and Infiltrative Myopathies

NEURO-OPHTHALMOLOGY

Other infiltrative processes (amyloidosis and lymphoma) may limit ­extraocular muscle relaxation.33 Neoplasms may extend locally into or metastasize directly to a muscle.34

OCULAR MANIFESTATIONS Idiopathic and other forms of orbital inflammatory disease or orbital pseudotumor (orbital myositis) are associated with significant extraocular muscle involvement.35, 36 The myositis may be isolated to a single muscle, but most often it affects several. Even though the disease process often is bilateral, most often symptoms are reported as unilateral and typically include some degree of discomfort in almost all patients. The pain often is most severe when ductions away from the most affected muscle are attempted. Patients also frequently experience gaze-evoked diplopia. Local orbital signs such as exophthalmos and injection are common. Children are more apt to have bilateral orbital involvement, may develop spontaneous orbital ­ hemorrhage, and are less likely to have an associated systemic ­disease.

DIAGNOSIS In orbital myositis, the involved extraocular muscle usually is enlarged on orbital imaging. Enhancement of the muscle, and particularly its insertion into the globe, may help to separate myositis from thyroid ophthalmopathy.37 Crohn’s disease, vasculitis, serum sickness, herpes zoster, sarcoidosis, Lyme’s disease, and trichinosis all are considered part of the review of systems and investigated by special studies. The diagnosis of orbital pseudotumor or idiopathic orbital myositis is one of exclusion and can be made only after the appropriate investigations have been carried out, as described above. If a meticulous history and physical examination are followed by appropriate studies, which include orbital imaging, and no diagnosis can be confirmed, tissue biopsy is usually considered. In many cases, the clinical picture is sufficiently clear and a trial of glucocorticoids may be initiated, but often an orbital biopsy is indicated, especially if the orbital inflammation is refractory to glucocorticoids or returns after the glucocorticoids have been tapered.

SYSTEMIC ASSOCIATIONS An unclear relationship exists between idiopathic orbital pseudo­ tumor, or orbital myositis, and paranasal sinus disease, sinusitis, or even a concomitant upper respiratory infection. Systemic conditions associated with myositis include trichinosis, tuberculosis, aspergillosis, Lyme’s disease, and other infections, distant inflammatory disease such as Crohn’s disease, sarcoidosis, amyloidosis, acromegaly, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, and lithium therapy.

PATHOLOGY In addition to the general changes described above, various specific causes of myositis have their own characteristic histopathological features. For example, in cases of foreign bodies, granulomatous inflammation with multinucleated giant cells are found. Polymorphonuclear leukocytes are seen in association with various infections. Eosinophilic infiltration is seen in trichinosis. In idiopathic orbital myositis, nonspecific and non-neoplastic inflammatory lesions occur in the orbit with diverse pathological appearances − most often they display a polymorphous, chronic inflammatory infiltration. In chronic forms of idiopathic pseudotumor, large amounts of ­fibrovascular stroma also may be seen. The pathological differentiation between orbital pseudotumor, benign lymphoid hyperplasia, monomorphous lymphoid lesions, and malignant lymphoma may be difficult. Immunological cell markers and gene rearrangement studies can help in the differentiation of these entities. However, 15–20% of patients who have polyclonal cell markers eventually may develop a monoclonal malignant lymphoma. In orbital myositis with plasma cell or lymphoproliferative infiltration an associated amyloidosis may occur. This amyloid shows on hematoxylin and eosin staining as an eosinophilic hyaline accumulation that often surrounds the blood vessels. It also may accumulate in round globules within the extraocular muscles.

TREATMENT In myositis, the issue often comes down to whether to treat with glucocorticoids. High-dose, daily glucocorticoids usually reverse the disease process effectively and eliminate the pain. Inadequate treatment may result in recurrence, but once the desired effect occurs, the glucocorticoids must be tapered slowly over several weeks or months and discontinued. Nonsteroidal anti-inflammatory drugs are less effective than glucocorticoids but have fewer side effects. In those patients who do not respond or who become glucocorticoid dependent, low-dose radiation therapy (2000 cGy) may induce a remission effectively. However, many inflammatory and infiltrative myopathies initially respond to such treatment, only to recur. Furthermore, treatment may not only obfuscate the natural history of the disease, but may make the diagnosis by biopsy more difficult. Hence, it often is prudent to complete the diagnostic work-up, which includes orbital biopsy, prior to anti-­inflammatory treatment.

COURSE AND OUTCOME Idiopathic orbital myositis usually responds very well to systemic glucocorticoids. In most cases, the diagnostic work-up does not yield any causative factor and recurrences are not very common. Such patients do well and show no evidence of any ophthalmologic ­sequelae.

REFERENCES

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  1. DiMauro S, Moraes CT. Mitochondrial encephalopathies. Arch Neurol. 1993;50:1197–207.   2. Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989;320:1293–9.   3. Holt IJ, Harding AE, Cooper JM, et al. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989;26:699–708.   4. Hirano M, Silvestri G, Blake DM, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology. 1994;44:721–7.   5. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic ­neuropathy. Science. 1992;242:1427–30.   6. Fang W, Huang CC, Lee CC, et al. Ophthalmologic manifestation in MELAS syndrome. Arch Neurol. 1993;50:977–80.   7. Crisi G, Ferrari G, Merelli E, Cocconcelli P. Magnetic resonance imaging in a case of Kearns-Sayre syndrome confirmed by molecular analysis. Neuroradiology. 1994;36:37–8.

  8. Drachman DA. Ophthalmoplegia plus. The neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch Neurol. 1968;18:654–74.   9. Kearns TP. External ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy: a newly recognized syndrome. Trans Am Ophthalmol Soc. 1965;63:559–625. 10. Uncini A, Servidei, Silvestri G, et al. Ophthalmoplegia, demyelinating neuropathy, leukoencephalopathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name. Muscle Nerve. 1994;17:667–74. 11. McKechnie NM, King M, Lee WR. Retinal pathology in the Kearns-Sayre syndrome. Br J Ophthalmol. 1985;69:  63–9. 12. Goda S, Hamada T, Ishimoto S, et al. Clinical improvement after administration of coenzyme Q10 in a patient with mitochondrial encephalopathy. J Neurol. 1987;234:62–9. 13. Bachynski BN, Flynn JT, Rodrigues MM, et al. Hyperglycemic acidotic coma and death in Kearns-Sayre syndrome. Ophthalmology. 1986;93:391–6. 14. Johnson CC, Kuwabara T. Oculopharyngeal muscular dystrophy. Am J Ophthalmol. 1974;77:872–9.

15. Burian HM, Burns CA. Ocular changes in myotonic dystrophy. Am J Ophthalmol. 1967;63:22–34. 16. Tsutsumi A, Uchida Y, Osawa M, et al. Ocular findings in Fukuyama-type congenital muscular dystrophy. Brain Dev. 1989;11:413–9. 17. Kuwabara T, Lessell S. Electron microscopic study of extraocular muscles in myotonic dystrophy. Am J Ophthalmol. 1976;82:303–8. 18. Tumbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Wickham survey. Clin Endocrinol (Oxf ). 1977;7:481–93. 19. Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves’ orbitopathy vary with age and sex. Arch Ophthalmol. 1993;111:197–201. 20. Bahn RS, Heufelder AE. Mechanisms of disease: pathogenesis of Graves’ ophthalmopathy. N Engl J Med. 1993;329:1468–75. 21. Saber E, McDonnell J, Zimmerman KM, et al. Extraocular muscle changes in experimental orbital venous stasis: some similarities to Graves’ orbitopathy. Graefes Arch Klin Exp Ophthalmol. 1996;234:331–6. 22. Levine MR, Tomsak RL, El-Toukhy E. Thyroid-related ophthalmopathy. Ophthalmol Clin North Am. 1996;9:645–58.

29. Kahaly G, Schrezenmeir J, Schweikert B, et al. Remission­-maintaining effect of cyclosporin and   endocrine ophthalmopathy. Transplant Proc. 1986;18:844–5. 30. Martinuzzi A, Sadun AA. Marginal myotomies of ­levator with lateral-tarsal canthoplasty in the ­treatment of Graves’ lid retraction. Ital J Ophthalmol. 1991;5:23–9. 31. Bouree P, Bouvier JB, Passeron J, et al. Outbreak of trichinosis near Paris. BMJ. 1979;i:1047–9. 32. Pinchoff BS, Spahlinger DA, Bergstrom TJ, Sandall GS. Extraocular muscle involvement in Wegener’s ­granulomatosis. J Clin Neurol Ophthalmol. 1983;3:  163–8.

33. Katz B, Leja S, Melles RB, Press GA. Amyloid ­ophthalmoplegia: ophthalmoparesis secondary to primary systemic amyloidosis. J Clin Neurol Ophthalmol. 1988;9:39–42. 34. Slamovits TL, Burde RM, Sedwick L, et al. Bumpy muscles. Surv Ophthalmol. 1988;33:189–99. 35. Kennerdell JS, Dresner SC. The nonspecific orbital ­inflammatory syndromes. Surv Ophthalmol. 1984;29:93–103. 36. Rootman J, Nugent R. The classification and management of acute orbital pseudotumors. Ophthalmology. 1982;89:1040–8. 37. Trokel SL, Hilal SK. Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography. Am J Ophthalmol. 1979;87:503–12.

9.17 Ocular Myopathies

23. Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA. 1993;269:479–82. 24. Liu D, Feldon SE. Thyroid ophthalmopathy. Ophthalmol Clin North Am. 1992;5:597–622. 25. Werner SC. Classification of the eye changes of Graves’ disease. Am J Ophthalmol. 1969;68:646–8. 26. Van Dyk HJ. Orbital Graves’ disease. A modification of the “NO SPECS” classification. Ophthalmology. 1981;88:  479–83. 27. Bartley GB, Gorman CA. Diagnostic criteria for Graves’ ophthalmopathy. Am J Ophthalmol. 1995;119:792–5. 28. Trokel SL, Jakobiec FA. Correlation of CT scanning and pathologic features of ophthalmic Graves’ disease.   Ophthalmology. 1981;88:553–64.

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PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

Nystagmus, Saccadic Intrusions, and Oscillations

9.18

Peter A. Quiros and Robert D. Yee

Definition:  Fixation instabilities that usually are involuntary and

rhythmic. Nystagmus arises from inability to maintain fixation due to slow drift. Saccadic intrusions and oscillations result from spontaneous rapid eye movement instability.

Key features n n n

Inability to maintain or achieve proper fixation. Decreased visual acuity. Oscillopsia.

Associated features n

Central nervous system abnormalities. Strabismus.

n

Albinism.

n

INTRODUCTION Nystagmus, saccadic intrusions, and saccadic oscillations are fixation instabilities that usually are involuntary and rhythmic. They may impair vision, and many are signs of neurologic disease. By recognizing the specific type of nystagmus or instability, the ophthalmologist can localize central nervous system (CNS) as well as peripheral lesions, determine which follow-up tests are appropriate (such as magnetic resonance imaging (MRI)), and often initiate treatment.

EPIDEMIOLOGY AND PATHOGENESIS The application of bioengineering principles, the use of electronic recordings of eye movements in humans, and neurophysiological studies in animals have led to many hypotheses about the pathophysiology of nystagmus. Abnormalities of the vestibulo-ocular, otolithic-ocular, smooth pursuit, optokinetic, vergence, and eccentric gaze-holding ­systems have been postulated.1 However, the causes of most types of nystagmus are still not known.

OCULAR MANIFESTATIONS

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Nystagmus is caused by an abnormality in a slow eye movement system or in the system that holds fixation. Abnormal slow eye movements cause a drift away from the intended fixation target or direction of gaze. A more rapid eye movement in the opposite direction is then initiated to carry the eyes back to the intended position. Nystagmus waveforms can be jerk or pendular (Fig. 9-18-1). If the corrective movements are reflexive, the waveform is termed jerk. The slow movements are the slow phase, and the refixation saccades are fast phases. The direction of jerk nystagmus is designated by the direction of the fast components; for example, fast components to the right indicate “right-beating” jerk nystagmus. When the corrective movements also are slow eye movements, the waveform is pendular. These represent the two main types of nystagmus. Nystagmus by definition must have a slow phase, thus differentiating it from saccadic intrusions

Saccadic intrusions are caused by abnormalities in the saccadic eye movement system. Abnormal saccades move the eyes away from the intended direction of gaze, and corrective saccades carry the eyes back. In saccadic intrusions, such as square-wave jerks and macrosquare-wave jerks, brief pauses occur, or intersaccadic intervals, between the opposing saccades (Fig. 9-18-2). In ocular flutter and opsoclonus, no intersaccadic intervals occur. These are not true nystagmus, as these conditions have no slow phase. Normal visual acuity requires a stationary retinal image on the fovea. If fixation instabilities cause movement of the retinal image across the fovea at speeds of a few degrees per second or greater, visual acuity is diminished. Therefore, many types of nystagmus and saccadic oscillations without intersaccadic intervals cause deceased visual acuity. During volitional saccades, images move across the retina, but there is no sensation of movement of the visual surround. In contrast, most types of nystagmus and saccadic oscillations without intersaccadic intervals cause illusory, back-and-forth movements of the visual surround, called oscillopsia.

DIAGNOSIS Most types of nystagmus and saccadic instabilities can be detected and identified without the aid of eye movement recordings and other specialized equipment via careful attention to characteristics of the oscillations. While the patient fixates on a stationary target at distance and near, the following questions should be addressed: l Is the drift away from the target a slow eye movement (nystagmus) or a saccade (saccadic instabilities)? l Do slow movements occur in one direction and fast movements in the opposite direction (jerk nystagmus), or are the opposing movements of equal speed (pendular nystagmus)? l What is the direction of the instability (horizontal, vertical, oblique, or torsional)? l What is the effect of blocking fixation? Does it increase the nystagmus intensity (vestibular nystagmus), or does it decrease the intensity (congenital nystagmus)? Frenzel goggles to block fixation or electronic equipment to record eye movements in the dark usually are not readily available. Viewing the fundus of one eye with a direct ophthalmoscope while the patient covers the other eye blocks fixation and magnifies motion of the fundus caused by eye movements. The fundus moves in the direction opposite to that of the eye. The direct ophthalmoscope is an excellent instrument with which to detect small-amplitude oscillations such as voluntary “nystagmus” and superior oblique myokymia. Further questions to address are: l What is the effect of different gaze positions? Acquired jerk nystagmus generally worsens in the direction of the fast phase. l Does eccentric gaze change the intensity or the direction of the instability? Congenital nystagmus changes the direction of the fast phase with the position of gaze, i.e., right-beating in right gaze, left-beating in left gaze. l Is the instability present only in eccentric gaze (gaze-evoked nystagmus)? l Are the oscillations in both eyes symmetrical, or are they asymmetrical with different amplitudes or directions in each eye (disconjugate nystagmus)? l If no instability occurs in the sitting upright position, is it present in other positions of the body and head (vestibular nystagmus of benign paroxysmal positional vertigo (BPPV))?

NYSTAGMUS WAVEFORMS

SACCADIC INTRUSIONS AND OSCILLATIONS

eye position A

A

B

B

C

C

D

D

E

E

time

Fig. 9-18-1  Nystagmus waveforms. The horizontal dashed lines indicate the intended position of gaze. (A) Jerk nystagmus with slow components of constant velocity. (B) Jerk nystagmus with slow components of exponentially increasing velocity. The flat, slow component portions near the intended gaze position ­follow the fast components and represent extended foveation periods typical   of congenital nystagmus. (C) Jerk nystagmus with slow components of ­exponentially increasing velocity. Extended foveation periods follow slow ­movements that bring the eye toward the intended gaze position. (D) Pendular nystagmus. Note that foveation periods are brief compared with those in B and C. (E) Jerk nystagmus with slow components of exponentially decreasing ­velocity.

The answers to these questions and information from the patient’s history and other physical findings will allow the ophthalmologist to identify the instability. Figures 9-18-3 to 9-18-6 are flowcharts that can be used to identify the different types of nystagmus.

DIFFERENTIAL DIAGNOSIS Congenital Nystagmus

Congenital nystagmus is the most common form of nystagmus, accounting for about 80% of all nystagmus. It is also one of several common types of nystagmus that occur in children (Table 9-18-1); it is a high-frequency, horizontal nystagmus that begins in the first few months of life. Congenital nystagmus is not pathogenetically associated with other CNS disorders, although it is found frequently in patients who have certain systemic and ocular disorders that impair vision, such as oculocutaneous albinism and ocular albinism. It can be an X-linked recessive, autosomal dominant, or autosomal recessive disorder. The nystagmus waveforms are pendular, jerk, or a combination of the two, and many are complex. Often brief intervals occur when the retinal image is relatively stationary on the fovea, called extended foveation periods, which allows better visual acuity. Unlike in vestibular nystagmus, fixation increases the nystagmus intensity, while staring and blocking fixation decrease the nystagmus. In contrast to patients who have acquired types of nystagmus, patients who have congenital nystagmus rarely complain of oscillopsia. Patients who have congenital nystagmus often exhibit a head turn, which places their eyes into the so-called null point, in which nystagmus intensity is minimized, foveation periods are long, and visual acuity is best. High-frequency, low-amplitude head nodding is seen commonly. The head nodding usually does not improve vision. Congenital nystagmus remains horizontal in vertical gaze and usually is decreased at near with convergence. The dampening of nystagmus with

Nystagmus, Saccadic Intrusions, and Oscillations

eye position

9.18

time

Fig. 9-18-2  Saccadic intrusions and oscillations. Dashed lines indicate the intended gaze position. (A) Square-wave jerks with intersaccadic intervals.   (B) Macrosquare-wave jerks with intersaccadic intervals. (C) Single saccadic pulse and double saccadic pulses. (D) Ocular flutter with no intersaccadic ­intervals. (E) Macrosaccadic oscillations following a refixation saccade.

convergence improves vision, which is one reason why many children who have congenital nystagmus do not need schoolbooks with largesize print. In one form of the nystagmus blockage syndrome, excessive convergence produces an esotropia, fixation of the distant target with the adducted eye, a decrease in nystagmus, and improved vision.2 In another form, a switch occurs from a congenital nystagmus waveform to a manifest latent nystagmus (MLN) waveform (see the next section) when the adducted eye fixates. In such patients, vision is better with the latter nystagmus.

Latent and Manifest Latent Nystagmus

Latent nystagmus is always associated with strabismus, usually infantile esotropia. In true latent nystagmus, no nystagmus is present with both eyes open. When either eye is occluded, a horizontal jerk nystagmus occurs, the slow components of which are toward the occluded eye and the fast components of which beat toward the uncovered, fixing eye. The shift of fixation is the stimulus for the nystagmus. Electronic eye movement recordings have shown that true latent nystagmus is rare. In most instances, a low-intensity jerk nystagmus (MLN) exists that beats toward the fixing eye without occlusion. Nystagmus intensity increases with occlusion of the nonfixing eye, and the jerk nystagmus reverses direction when the eye that preferentially fixes is occluded. Gaze in the direction of the fast component increases nystagmus intensity, and gaze in the opposite direction decreases the intensity (Alexander’s law). Patients who have MLN can have a habitual face turn toward the direction of the fast component, which places the eyes in the opposite direction and improves vision. Congenital nystagmus patients who have jerk nystagmus also can show reversal of the nystagmus direction when each eye is occluded, as a result of a shift in the position of the null point. Rarely, patients who have congenital nystagmus also have MLN.

Spasmus nutans

Spasmus nutans occurs in the first year of life and is a triad of pendular nystagmus, head nodding, and torticollis. The nystagmus often is dissociated (both eyes are not beating together), and in individual patients it can vary from conjugate to disconjugate to monocular over a few minutes. Its direction is primarily horizontal, but it can have vertical

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9

IDENTIFICATION OF TYPES OF GAZE-EVOKED NYSTAGMUS

IDENTIFICATION OF TYPES OF NYSTAGMUS

NEURO-OPHTHALMOLOGY

Primary position with fixation? Yes Conjugate movements? Yes Long history, high frequency, no oscillopsia? Yes

Present with block fixation?

No

No

Dissociated nystagmus

Yes

No

Yes

Present with occlusion of one eye? Yes

Yes

Decays, reverses on return to primary gaze?

Congenital nystagmus

Long history, high frequency, no oscillopsia?

No

Yes

Fixation nystagmus

No

No

Congenital nystagmus

Yes

Manifest latent

Yes

No

Gaze-paretic nystagmus (nonlocalizing)

Fig. 9-18-5  Identification of types of gaze-evoked nystagmus.

IDENTIFICATION OF TYPES OF DISSOCIATED NYSTAGMUS

Vestibular nystagmus in upright position?

Dissociated nystagmus in primary gaze?

No

Acute onset vertigo, fixation decreases?

Yes Present with static positioning?

No

No

Central vestibular nystagmus

Present with rapid positioning?

Yes Sustained positional nystagmus

Yes Oculopalatal myoclonus

No

Yes

Superior oblique myokymia

Present in eccentric gaze?

No

Yes

Monocular torsional high frequency? Yes

Transient, intense upbeat, dissociated?

No

Pendular, palate, face?

Yes

Abducting nystagmus begins with fatigue? No

No Monocular visual loss?

Internuclear ophthalmoplegia

Central paroxysmal positional nystagmus

Benign paroxysmal positional nystagmus

Fig. 9-18-4  Identification of types of vestibular nystagmus.

and torsional components. In most patients, the syndrome seemingly resolves spontaneously over 1–2 years. However, electronic eye movement recordings show that a small-amplitude, intermittent, dissociated, pendular nystagmus can persist at least until age 5–12 years.3 Characteristically, the nystagmus frequency is higher (3–11 Hz) and its amplitude more variable than in congenital nystagmus. Head nodding is found in most patients who have spasmus nutans. It induces vestibulo-ocular responses that transform the nystagmus into larger-amplitude, slower, binocularly symmetrical, pendular oscillations with improved vision. Spasmus nutans must be differentiated from other disorders that cause head nodding and nystagmus, such as visual loss in children, intracranial tumors, and congenital nystagmus. Children with bilateral vision impairment can have rapid, horizontal,

Yes Myasthenia gravis

No

Yes

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Gaze-paretic nystagmus (lateralizing)

IDENTIFICATION OF TYPES OF VESTIBULAR NYSTAGMUS

Yes

Peripheral vestibular nystagmus

Symmetric in right, left gaze?

Myasthenia gravis

Dissociated nystagmus

Fig. 9-18-3  Identification of types of nystagmus.

Yes

Rebound nystagmus

No

No

Gaze- evoked nystagmus

Yes

Begins with fatigue?

Yes

Latent Conjugate Congenital nystagmus movements? nystagmus

Dissociated nystagmus

No

Yes Long history, high frequency, no oscillopsia?

No

Long history, high frequency, no oscillopsia?

Vestibular nystagmus

No

Increased by occlusion of one eye?

Yes

Yes

Present in eccentric gaze?

No

Congenital nystagmus

Gaze-evoked nystagmus conjugate?

No

Optic glioma and other causes of visual loss

Young child, head nodding, torticollis? Yes

Spasmus nutans

No Vertical, torsional? Yes See-saw nystagmus

Fig. 9-18-6  Identification of types of dissociated nystagmus.

pendular head oscillations; horizontal or vertical nystagmus; and ­intermittent head tilting during attempts to fixate.4 The nystagmus can be pendular or jerk, with slow components of constant, increasing, or decreasing velocity.5 The head shaking seems to be a voluntary, learned adaptation that can improve vision. The diagnostic signs from careful examination of eye and head movements, including electronic

 TABLE 9-18-1  CHARACTERISTICS AND LOCALIZATIONS OF NYSTAGMUS IN CHILDHOOD

 TABLE 9-18-2  CHARACTERISTICS AND LOCALIZATIONS OF VESTIBULAR ­NYSTAGMUS

Characteristics

Localization

Nystagmus

Characteristics

Localization

Idiopathic congenital

Complex waveforms, jerk (increasing velocity slow components), pendular, horizontal, null zone, (face turn, head nodding, no oscillopsia)

Coexisting ocular,   visual pathway lesions (not pathogenetic)

Spontaneous peripheral vestibular

Jerk, horizontal, small torsional, inhibited by fixation

Labyrinth, eighth nerve (acute)

Central vestibular   (fixation) nystagmus

Brainstem, cerebellum

Latent/manifest latent

Jerk (decreasing velocity slow components), horizontal, fast components beat toward fixing eye

Coexisting infantile esotropia

Jerk, pendular, horizontal, vertical, torsional, not inhibited by fixation

Sustained positional vestibular

Labyrinth, eighth nerve   or brainstem, cerebellum

Spasmus nutans

Pendular, horizontal, small vertical, torsional, dissociated, high frequency, (torticollis, head nodding), onset in first year, resolution in 1–2 years

No signs of visual pathway lesions

Jerk, horizontal, small torsional, direction fixed, direction changing (static positioning)

Benign paroxysmal positional

Jerk, dissociated upbeat, latency, not inhibited by fixation, fatigue (Nylen-  Barany maneuver)

Posterior vertical canal

Monocular visual loss

Pendular, vertical, horizontal, monocular, high frequency, intermittent, (occasional head nodding)

Gliomas of optic nerve, chiasm or third ventricle, and other causes of   visual loss

Central paroxysmal positional

Jerk, symmetric, upbeat, downbeat

Brainstem, cerebellum

r­ ecordings, can differentiate spasmus nutans from congenital nystagmus but do not reliably separate spasmus nutans from nystagmus and head nodding due to CNS lesions.6 Visual loss, optic atrophy, abnormal growth and development, signs and symptoms of CNS disorders, or an older age of onset warrants MRI studies.7 Some clinicians obtain neuroimaging for all patients who have spasmus nutans. Others do not, because the prevalence of CNS tumors in patients without other signs of CNS masses is low.8

Optic glioma in infants

Tumors of the optic nerve, optic chiasm, or third ventricle can produce a high-frequency, pendular nystagmus in infants. Its direction is usually vertical, and it is often monocular. A careful examination to detect visual loss, optic atrophy, and signs of neurofibromatosis type 1 is required to differentiate this type of pendular nystagmus from spasmus nutans. MRI of the orbits and brain is warranted.

Vestibular Nystagmus

Vestibular nystagmus is the most common type of acquired nystagmus. The characteristics and localizations of several types of vestibular ­nystagmus are shown in Table 9-18-2.

Peripheral Vestibular Nystagmus

Peripheral vestibular nystagmus is caused by an acute imbalance of tonic innervation to the brainstem from the vestibular labyrinths and the eighth nerves. Destructive disorders, such as labyrinthitis and vestibular neuritis, decrease innervation from the affected ear and produce jerk nystagmus with slow components toward that ear and fast components beating toward the opposite side. Irritative disorders, such as Meniere’s disease, increase innervation from the affected ear and generate jerk nystagmus with fast components toward that ear and slow components toward the opposite ear. Because the vestibular nerve conveys tonic innervation from a horizontal semicircular canal, a pair of vertical canals, and otoliths (saccule and utricle), the nystagmus is mainly horizontal but has vertical and torsional components as well (rotary nystagmus). The slow component has a constant-velocity waveform. Gaze in the direction of the fast component increases the nystagmus intensity (amplitude X frequency), and gaze in the direction of the slow component decreases the intensity (Alexander’s law). Nausea and vertigo with the sensation of rotation of the environment or self-rotation in the direction of the fast component are usually present. Tinnitus, hearing loss, and ear pain also may be present. The nystagmus intensity is high during the first few days but spontaneously decreases. At this time, fixation might inhibit the nystagmus. However, blocking fixation reveals the nystagmus. Imbalance of tonic inputs from the otoliths can cause a transient skew deviation (hypotropic eye ipsilateral to the damaged ear).

Head-Shaking Nystagmus

Rapid head oscillations can produce head-shaking nystagmus. The head is shaken horizontally and vigorously by the patient for 10–15 seconds, and then fixation is blocked. In patients who have peripheral vestibular lesions, a transient, horizontal jerk nystagmus with the fast components to the side opposite the damaged side is induced. Vertical head-shaking can produce a less intense horizontal nystagmus with fast components beating toward the damaged side. In patients who have central vestibular lesions, horizontal head-shaking can induce a downbeat nystagmus or a horizontal nystagmus.

Nystagmus, Saccadic Intrusions, and Oscillations

Nystagmus

9.18

Central Vestibular Nystagmus

Lesions of the vestibular nuclei, the cerebellum, or the connections between the flocculonodular lobes and the brainstem can cause central vestibular nystagmus. In contrast to peripheral vestibular nystagmus, fixation does not greatly inhibit the nystagmus, which leads to the synonymous term fixation nystagmus. Central vestibular nystagmus can be purely horizontal, torsional, or vertical, because horizontal and vertical vestibulo-ocular pathways begin to separate in the vestibular nuclei. Jerk nystagmus in primary gaze that is predominantly torsional is associated with lesions of the vestibular nuclei on the side contralateral to the fast component.9

Positional Vestibular Nystagmus

Positional vestibular nystagmus is not present in the sitting upright position but is induced by the supine and lateral positions or by rapid movements of the head and body into head-hanging positions. ­Fixation suppresses the nystagmus when the cause is a peripheral vestibular ­lesion but does not suppress it when a central vestibular lesion is ­present. The nystagmus direction can remain the same in the right and left lateral positions (direction fixed), or it can change (direction changing). The fast components may beat toward the down ear (geotropic) or toward the up ear (apogeotropic). Both peripheral and ­central vestibular lesions can cause direction-fixed and direction-changing ­positional nystagmus.

Benign Paroxysmal Positional Nystagmus

Rapid positioning of the head and body into the right or left headhanging position (Nylen-Barany or Dix-Hallpike maneuver) induces benign paroxysmal positional nystagmus (BPPN). After a delay of 1–2 ­seconds, an intense vertical nystagmus develops. Fixation does not ­suppress the nystagmus, and the patient usually complains of vertigo after the maneuver. Characteristic binocular asymmetry exists in which the nystagmus primarily upbeats in the higher eye (i.e., the eye opposite to the head-hanging position) and is oblique and torsional in the lower eye. The asymmetry is explained by the primary and secondary ­actions of the vertical extraocular muscles stimulated by the posterior ­semicircular canals (contralateral inferior rectus and ipsilateral superior oblique). The nystagmus dies away over several seconds. Repetition of the maneuver soon after the initial positioning generates a less intense nystagmus (fatigue).

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9 NEURO-OPHTHALMOLOGY

The cause of BPPN is otoconia that have become dislodged from the otoliths (utricular macule) and either are attached to the cupula of a posterior semicircular canal (cupulolithiasis) or freely move in that ­canal (canalithiasis). Endolymph flow in the posterior canal produces an abnormally prolonged deflection of the hair cells in the crista of the canal. Positional exercises, such as the Epley maneuver, can move the granules back into the utricle and eliminate the positional nystagmus and vertigo.10 Canalithiasis and paroxysmal positional nystagmus of the horizontal and anterior posterior canals can occur spontaneously or can be produced by repositioning for the posterior canal form of BPPN.11 The Nylen-Barany maneuver can induce paroxysmal positional nystagmus other than BPPN, such as downbeat nystagmus and other types of central vestibular nystagmus.12 Therefore, the typical features of BPPN must be present to confirm the diagnosis; it can result from viral labyrinthitis, head injury, and infarction of the inner ear. Most often it is an isolated disorder in the elderly.

Gaze-Evoked Nystagmus

Several types of gaze-evoked nystagmus exist that are present in eccentric gaze but not in primary gaze (Table 9-18-3). In gaze-paretic nystagmus, no nystagmus occurs in primary gaze, but a jerk nystagmus occurs in about 30° of eccentric gaze. The slow components move the eyes toward primary gaze and have waveforms with exponentially decreasing velocities (see Fig. 9-18-1). Fast components beat toward the intended eccentric gaze position. The drift toward primary gaze results from impairment of gaze-holding mechanisms that involve the nucleus prepositus hypoglossi and medial vestibular nucleus (the “neural integrator”) and their connections with the flocculonodular lobe of the cerebellum. The eye position signal cannot hold the eyes eccentrically in the orbits, so they drift back toward primary gaze. Normal, physiological, endpoint nystagmus is present in the ­extremes of horizontal and upward gazes of about 45–50°. Therefore, nystagmus at only 30° is likely to be a pathological finding. Endpoint nystagmus is irregular and might be slightly dissociated (larger amplitude in the abducting eye), which mimics the dissociated nystagmus associated with internuclear ophthalmoplegia. However, the other eye movement abnormalities associated with internuclear ophthalmo­ plegia are absent. Generally, physiologic endgaze nystagmus dampens within 6 seconds. Symmetrical gaze-paretic nystagmus in which the nystagmus intensity is the same in right gaze and left gaze usually is not a localizing sign. It is produced by mental fatigue; CNS depression from barbiturates, tranquilizers, anticonvulsants, alcohol, and other drugs; and disorders of the cerebral hemispheres, brainstem, and cerebellum. Asymmetrical, horizontal, gaze-paretic nystagmus often is lateralizing. A lesion of the brainstem or cerebellum is generally on the side of greater nystagmus intensity.  Table 9-18-3  CHARACTERISTICS AND LOCALIZATIONS OF GAZE-EVOKED ­NYSTAGMUS Nystagmus

Characteristics

Localization

Physiologic, endpoint

Jerk, small amplitude, intermittent, extremes   of horizontal and up gaze

Physiologic

Gaze-paretic (symmetric)

Jerk (decreasing velocity slow components) at   30° eccentric gaze

Nonlocalizing (drugs, mental fatigue)

Jerk (decreasing velocity slow components), horizontal, at 30° eccentric gaze, larger amplitude toward side of lesion

Lesions of brain-stem, cerebellum, cerebral hemisphere

Jerk, horizontal, decreases and direction can reverse ineccentric gaze, transient jerk nystagmus on return to primary gaze, fast components beating-toward eccentric gaze

Cerebellum

Jerk, horizontal or vertical, gradual onset in prolonged eccentric gaze

Myoneural junction (fatigue – increasing   transmission block)

Gaze-paretic (asymmetric)

Rebound

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Myasthenia gravis

Myasthenia gravis can produce a horizontal or upbeat gaze-paretic nystagmus. Initially, little or no nystagmus exists, but as the ­extraocular muscles fatigue, nystagmus develops. In horizontal gaze, the amplitude of the fast component in the abducting eye is often larger than that in the adducting eye as a result of the greater fatigue of the medial rectus muscle. Normal subjects can have an endpoint nystagmus of very small amplitude that increases with fatigue.

Rebound Nystagmus

Rebound nystagmus is a type of horizontal, gaze-paretic nystagmus in which the jerk nystagmus gradually decreases in amplitude as the eyes remain in eccentric gaze for many seconds. In some instances, the nystagmus direction actually reverses (centripetal nystagmus); for example, it becomes left-beating in right gaze. On return to primary gaze, a jerk nystagmus occurs that beats in the direction opposite to that of the previous gaze-paretic nystagmus. The secondary nystagmus decreases and disappears after several seconds. Rebound nystagmus usually is ­associated with disorders of the cerebellum. Vertical rebound ­nystagmus occurs less often. Normal subjects can have a few beats of rebound nystagmus after prolonged eccentric gaze if no fixation target is present on return to primary gaze (lights turned off).

Alternating Nystagmus

The direction of jerk nystagmus changes spontaneously in alternating nystagmus (Table 9-18-4). In periodic alternating nystagmus (PAN), a repetitive cycling of right-beating and left-beating nystagmus occurs in primary gaze. The amplitude of nystagmus gradually increases and ­decreases over a period of about 90 seconds, followed by a short period of about 10 seconds in which there is no nystagmus, small-amplitude vertical or torsional nystagmus, or square-wave jerks (null period). Nystagmus that beats in the opposite direction then ensues increasing and decreasing over 90 seconds and followed by a null period. The cycle continues and is not affected by other eye movements, except for strong rotational vestibular stimuli, which can reset the cycle. During periods of jerk nystagmus, patients have horizontal oscillopsia and blurred vision. They might spontaneously turn their heads in the direction of the fast component. This moves the eyes to a position of minimal nystagmus and better vision (null position). The null position moves gradually to the right, back to primary gaze, to the left, and back to primary gaze. This type of alternating nystagmus is almost always associated with cerebellar disorders. Ablation of the nodulus and uvula in the monkey produces periodic alternating nystagmus. Alternating nystagmus also occurs in congenital nystagmus, in MLN, and in association with severe binocular visual loss from many causes (e.g., chronic papilledema, vitreous hemorrhage, cataract). In congenital nystagmus and MLN, the change in nystagmus direction can be caused by a shift of fixation from one eye to the other. However, congenital nystagmus and periodic alternating nystagmus can coexist, for example, in patients with albinism.13 The periods of alternating nystagmus are not as symmetrical or regular as in periodic alternating nystagmus ­associated with cerebellar disorders, although shifting of the null ­positions also occurs.  TABLE 9-18-4  CHARACTERISTICS AND LOCALIZATIONS OF OTHER TYPES OF FIXATION NYSTAGMUS Nystagmus

Characteristics

Localization

Periodic alternating

Jerk, horizontal, in primary position, regular phases of right-beating, null, left-beating (shifting null position)

Cerebellar nodulus   and uvula

Alternating (irregular)

Jerk, horizontal, in   primary position, variable, asymmetric phases

Congenital nystagmus, severe, binocular   visual loss

Upbeat

Jerk, fast components beat upward

Only in upgaze–part of symmetric gaze–paretic nystagmus; in primary gaze–lower pons

Downbeat

Jerk, fast components beat downward, vertical intensity increases in horizontal gaze

Cerebellum, lower   brainstem

Upbeat Nystagmus

Downbeat Nystagmus

Acquired pendular nystagmus in adults

Acquired pendular nystagmus usually has horizontal, vertical, and torsional components and is often disconjugate. Lesions of the pons, medulla, midbrain, and cerebellum, often caused by multiple sclerosis or infarction, produce oscillations with a typical frequency of 3–4 Hz. MRI studies show large or multiple lesions, which suggests that more than one pathway must be damaged to produce pendular nystagmus.16 A head tremor might be present. The nystagmus trajectory also can be elliptical or circular. When acquired pendular nystagmus is associated with similar movements of the soft palate, tongue, facial muscles, pharynx, and larynx, it is called ocular myoclonus; this syndrome has also been called oculopalatal myoclonus. The cause usually is an infarction that affects the structures of Mollaret’s triangle and their connections (red nucleus in the midbrain, inferior olive in the medulla, and contralateral dentate nucleus of the cerebellum). Hypertrophy of the inferior olive and the pendular oscillations begin several months later. Extensive hemorrhage in the pons can produce a large-amplitude, vertical, pendular nystagmus and bilateral horizontal gaze palsies.

Downbeat nystagmus in primary gaze usually is caused by a structural lesion in the posterior fossa at the level of the craniocervical junction (see Table 9-18-4). The nystagmus intensity characteristically increases in horizontal eccentric gaze and may be increased by convergence. Convergence also can convert an upbeat nystagmus in primary gaze to a downbeat nystagmus. Lesions of the cerebellum and pons are associated most often with downbeat nystagmus, and the most common causes are infarction, cerebellar degeneration, multiple sclerosis, and congenital malformations.15 Downbeat nystagmus may be part of an acquired syndrome in adulthood consisting of cerebellar ataxia, lower brainstem dysfunction, or cranial nerve palsies caused by Arnold-Chiari malformations (types 1 and 2). Although such malformations are not the most common cause of downbeat nystagmus, a magnetic resonance study of the posterior fossa should be obtained, because surgical decompression can diminish the nystagmus and the other abnormalities in the syndrome. Rarely, a variety of other disorders can cause downbeat nystagmus, including lithium toxicity, magnesium deficiency, vitamin B12 deficiency, midbrain infarction, brainstem encephalitis, Wernicke’s encephalopathy, increased intracranial pressure with hydrocephalus, syringobulbia, cerebellar tumor, and anticonvulsant medication. Downbeat nystagmus has been reported to occur as an inherited congenital disorder. The slow components can have constant velocity, increasing velocity, and decreasing velocity waveforms.

Children who have monocular visual loss from causes other than optic nerve glioma can have a monocular, high-frequency, small-amplitude, pendular nystagmus.17 They do not have intracranial tumors, spasmus nutans, or signs of damage to the optic nerve or optic chiasm. The nystagmus can disappear after successful treatment for the monocular visual loss. Adults who have acquired, severe monocular visual loss (e.g., dense cataract) can have a very low-frequency, irregular, vertical drift and jerk nystagmus (Heimann-Bielschowsky phenomenon), which can also be abolished with recovery of vision. Bilateral blindness results from a number of causes and can produce large-amplitude oscillations with small-amplitude ones superimposed. Both oscillations are horizontal and vertical and can have jerk and pendular waveforms. The direction of the jerk nystagmus varies over time (shifting null position). Vestibuloocular responses are impaired; volitional saccades and the fast components of vestibular nystagmus may be absent. Head nodding is usually present. Children who have congenital stationary night blindness and rod monochromatism may have small-amplitude, high-frequency, disconjugate, pendular nystagmus similar to that seen in spasmus nutans.

Dissociated Nystagmus

See-saw nystagmus

Several types of dissociated nystagmus occur in which the eye movements are strikingly disconjugate (Table 9-18-5). Nystagmus might be present in only one eye (spasmus nutans, optic glioma, and uniocular visual loss), larger in one eye than the other (abduction nystagmus in

 TABLE 9-18-5  CHARACTERISTICS AND LOCALIZATIONS OF DISSOCIATED NYSTAGMUS Nystagmus

Characteristics

Localization

Acquired pendular   in adults

Pendular, horizontal, vertical, torsional, disconjugate (coexisting palatal myoclonus)

Brainstem, cerebellum

Superior oblique   myokymia

Pendular, jerk,   torsional, vertical,   high frequency, small amplitude, monocular

Trochlear nucleus

See-saw

Pendular, vertical, torsional, rising eye intorts, falling eye extorts; rarely jerk

Midbrain (interstitial nucleus of Cajal)

Abducting “nystagmus”   of internuclear   ophthalmoplegia

Jerk, horizontal, decreasing velocity slow components, larger in abducting eye in horizontal gaze

Medial longitudinal   fasciculus in pons,   midbrain

Abducting nystagmus   of myasthenia gravis

Gaze-paretic nystagmus in horizontal gaze, greater paresis of medial rectus muscle

Myoneural junction –  myasthenia gravis

Monocular visual loss and bilateral visual loss

9.18 Nystagmus, Saccadic Intrusions, and Oscillations

Upbeat nystagmus in primary gaze is caused by lesions that affect the brainstem, especially the lower pontine tegmentum (see Table 9-184).14 Lesions of the medulla, midbrain, thalamus, and cerebellum also can cause upbeat nystagmus. Common causes of these lesions are ­multiple sclerosis, infarction, intra-axial tumor, Wernicke’s encephalopathy, brainstem encephalitis, and cerebellar degeneration. Rarely, upbeat nystagmus can be a form of congenital nystagmus and might be seen as a transient finding in normal infants. Upbeat nystagmus that is present only in upgaze and is associated with symmetrical, horizontal, gaze-paretic nystagmus is usually a type of gaze-paretic nystagmus that might not have a localizing significance. Patients with upbeat nystagmus may have slow components with constant velocity, decreasing velocity, or increasing velocity waveforms. Nicotine can produce a small-amplitude upbeat nystagmus seen in the dark in normal subjects.

internuclear ophthalmoplegia), or in different directions (see-saw ­ ystagmus). Dissociated nystagmus present in the primary position is n often pendular and is often jerk nystagmus in eccentric gaze.

See-saw nystagmus is a disconjugate, vertical, pendular nystagmus. In one half of a cycle, the rising eye also intorts and the falling eye extorts. The movements are reversed in the other half cycle. See-saw nystagmus is caused most often by large parasellar tumors that cause bitemporal hemianopsia (optic chiasm) and impinge on the third ventricle. Less ­often, head trauma and infarction of the upper brainstem are the causes. Congenital forms occur, including those in infants who have albinism. In the congenital forms, the rising eye extorts and the falling eye intorts. See-saw nystagmus might be caused by damage to otolithic pathways involving the interstitial nucleus of Cajal, which participate in the ocular tilt reaction. Stereotactic ablation of the interstitial nucleus of Cajal, clonazepam, and baclofen abolish the nystagmus. Rarely, see-saw nystagmus has a jerk waveform, in which case it arises from a unilateral midbrain lesion. The lesion hypothetically damages the ­interstitial nucleus of Cajal (torsional eye velocity generator) and spares the adjacent rostral interstitial nucleus of the medial longitudinal fasciculus (MLF; torsional fast component generator).18

Abducting nystagmus in internuclear ophthalmoplegia

In internuclear ophthalmoplegia, horizontal gaze in the direction opposite to the lesion in the MLF in the midbrain or pons induces a jerk nystagmus in the abducting eye and a smaller (or no) nystagmus in the paretic, adducting eye. This abducting nystagmus is the most common type of dissociated nystagmus. It might be simply a gaze-paretic nystagmus with superimposed paresis of the medial rectus muscle ipsilateral to the MLF lesion. However, in many patients, the speed of the exponentially velocity-decreasing waveform of the centripetal slow component is much higher than that found in gaze-paretic nystagmus. The abducting saccade has a characteristic overshooting waveform with a rapid, postsaccadic drift. The hypermetria may be a consequence of an adaptive increase in innervation in response to the weakness of ­adduction. The

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9 NEURO-OPHTHALMOLOGY

saccadic pulse is increased, but the step is not increased proportionately (pulse-step mismatch) or is absent, which results in a rapid centripetal drift. Therefore, the abducting nystagmus might be caused by a train of hypermetric saccades.19 Physiological endpoint nystagmus also can be dissociated slightly (larger amplitude in the abducting eye), but the other ocular motor abnormalities that are characteristic of internuclear ophthalmoplegia are absent. These abnormalities consist of limitation of adduction, slow adducting saccades, hypermetric abducting saccades, upbeat nystagmus, and skew deviation.

Down Syndrome

Patients who have Down syndrome frequently have nystagmus. The nystagmus types include dissociated pendular nystagmus, horizontal nystagmus of high frequency, and small-amplitude and latent nystagmus or MLN.20

 Table 9-18-6  CHARACTERISTICS AND LOCALIZATIONS OF SACCADIC INSTRUSIONS AND OSCILLATIONS Type

Characteristics

Localization

Square-wave jerks

Horizontal, 1–5°, 200 ms intersaccadic intervals

Not localizing

Macrosquare-wave jerks

Horizontal, 10–40 , 100 ms intersaccadic intervals

Cerebellum

Macrosaccadic oscillations

Horizontal saccadic dysmetria, series of hypermetric saccades, 200 ms intersaccadic intervals

Cerebellum

Voluntary “nystagmus”

Horizontal, high frequency, low amplitude, intermittent, no intersaccadic intervals

Volitional

Saccadic pulses

Horizontal, single or double saccades with   no steps

Cerebellum,   lower brainstem

Ocular flutter

Horizontal, large amplitude, linear and curvilinear trajectories, no intersaccadic intervals

Cerebellum,   lower brainstem

Opsoclonus

Multidirectional, large amplitude, linear and curvilinear trajectories,   no intersaccadic intervals

Cerebellum,   lower brainstem

Lid Nystagmus

Upward twitches of the upper eyelids (lid nystagmus) sometimes can exceed the amplitude of the upward fast components in upbeat nystagmus. Wallenberg’s syndrome (lateral medullary syndrome) has a variety of ocular motor abnormalities,21 including horizontal, gaze-paretic nystagmus with lid nystagmus. Convergence can induce lid nystagmus in patients who have lesions in the medulla or cerebellum.

Epileptic Nystagmus

Involuntary head turns, tonic deviation of the eyes, and nystagmus can be caused by a variety of seizures. In general, when an epileptic focus occurs in the parietal-temporal-occipital lobe, the eyes deviate to the ­contralateral side, and a horizontal jerk nystagmus is seen with fast components beating toward that side. The fast and slow components are ­confined to the contralateral field of gaze, and the nystagmus might occur as a result of activation of cortical saccadic regions in the cerebral cortex.22 Ipsiversive deviation of the eyes and nystagmus with ipsiversive slow components might arise from an epileptic focus in the temporal-occipital cortex that activates a cerebral cortical area for smooth pursuit.23 Pendular, torsional, or convergence nystagmus also can occur with epilepsy.

Ocular Bobbing

Stupor and coma are associated with several ocular abnormalities, including ocular bobbing. Intermittent, irregular, conjugate, downward saccades are followed by slower, upward drift movements. Patients who have ocular bobbing have extensive damage to the pons from hemorrhage ­or compression or have toxic or metabolic encephalopathies. Several ­variants of ocular bobbing exist. In inverse bobbing, or ocular dipping, downward, slow movements are followed by upward saccades back toward the primary position. In converse bobbing, or reverse ocular dipping, largeamplitude, upward saccades are followed by downward drifts.

Saccadic Intrusions

Reflex saccades to objects that enter the visual field are mediated through pathways from the visual association areas of the parietal lobes and temporal lobes, and from ocular motor fields in the frontal lobes. They project to the superior colliculi and the saccade-related areas of the brainstem. Normally, reflex saccades to these sites can be inhibited voluntarily. Pathways from the frontal lobes to the basal ganglia (pars reticularis of the substantia nigra) and superior colliculus might be important for the inhibition of reflex saccades. Patients who suffer frontal lobe diseases, including Alzheimer’s disease, Huntington’s disease, progressive supranuclear palsy, and schizophrenia, have inappropriate saccades that interrupt fixation. These saccadic intrusions have been called the “visual grasp reflex” (see Fig. 9-18-2 and Table 9-18-6). Saccadic intrusions do not represent true nystagmus as these disorders do not exhibit a slow phase.

Superior oblique myokymia

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Superior oblique myokymia is a very high-frequency, torsional, and oblique oscillation of one eye that causes monocular oscillopsia and, occasionally, vertical diplopia. Careful observation of the conjunctival blood vessels with a slit lamp or of the fundus with an ophthalmoscope reveals the extremely high-frequency, low-amplitude, pendular oscillations, as well as the occasional jerky nystagmoid movements as well as tonic intorsion and infraduction that produce diplopia. Electromyogram of the superior oblique muscle has shown abnormal discharges at a frequency of 35 Hz. Superior oblique myokymia usually occurs in otherwise healthy adults, can remit spontaneously, and may recur. Rarely, it is associated with brainstem disorders, such as multiple sclerosis or a pontine tumor.

Convergence-Retraction Nystagmus and Convergence Nystagmus

Voluntary or reflex upward saccades in Parinaud’s syndrome (dorsal midbrain syndrome) are hypometric and show simultaneous adduction and retraction of both eyes. Co-contraction of antagonist muscles causes the retraction. Optokinetic stimuli that move downward elicit upward, reflex saccades and the pattern of convergence-retraction nystagmus. Convergence nystagmus has been caused by an Arnold-Chiari type 1 malformation, which resolved with surgical decompression of the foramen magnum.24 It can also be caused by Whipple’s disease, which produces contractions of the masticatory muscles (ocular masticatory myorhythmia) and a vertical gaze palsy.25 Antibiotics can resolve the oculofacial-skeletal myorhythmia.

Square-wave jerks

Normal subjects have infrequent, small-amplitude (less than one to a few degrees), horizontal saccades that move the eyes away from the fixation target and then back to the target, called square-wave jerks (see Fig. 9-18-2). Pause occurs between the to-and-fro saccades (intersaccadic interval) of about 200 milliseconds, which allows sufficient foveation time for normal visual acuity with no oscillopsia. The frequency of square-wave jerks increases in the dark. Larger (1–5°) and more frequent ( > 2 Hz) square-wave jerks are abnormal and are associated with cerebellar disorders, progressive supranuclear palsy, Huntington’s disease, and schizophrenia. They occur sporadically or in bursts.

Macrosquare-wave jerks

Macrosquare-wave jerks are horizontal and large (10–40°) and have ­intersaccadic intervals of about 100 milliseconds. They are found in cerebellar disorders (e.g., multiple sclerosis and olivopontocerebellar ­atrophy) and occur sporadically or in bursts.

Macrosaccadic oscillations

Macrosaccadic oscillations are a type of saccadic dysmetria. A hypermetric saccade overshoots the target and is followed by a series of hypermetric, corrective saccades that straddle the target and gradually decrease in size until the target is fixated. The intersaccadic intervals are 200 milliseconds long. Macrosaccadic oscillations are associated with cerebellar disorders.

Voluntary “nystagmus”

Normal subjects can voluntarily produce bursts of high-frequency (10–20 Hz), small-amplitude (a few degrees), horizontal, saccadic oscillations, called voluntary “nystagmus.” This is not a true nystagmus,

Saccadic pulses

Saccadic pulses are saccadic intrusions in which saccades move the eyes away from the fixation target, followed by a rapid drift back to the target (glissade). They represent saccadic pulses without steps; they can occur ­singly, in a series, or in a train (saccadic pulse train) that mimics nystagmus (abducting nystagmus of internuclear ophthalmoplegia). Saccadic pulses occur in normal subjects, patients who have myoclonus, and patients who have multiple sclerosis. Double saccadic pulses are pairs of saccadic pulses that move in opposing directions and occur back-to-back with no intersaccadic intervals. They are part of a continuum of other saccadic oscillations with no intersaccadic intervals (ocular flutter and opsoclonus).

Ocular flutter

Ocular flutter consists of bursts of moderately large-amplitude, horizontal, back-to-back saccades without intersaccadic intervals. Blurred vision and oscillopsia usually are present. Ocular flutter can occur in the primary position and after a refixation saccade (flutter dysmetria); it is associated with the same disorders of the brainstem and cerebellum that produce opsoclonus (see next section). Eyelid blinks induce bursts of large-amplitude flutter in neurodegenerative disorders and a few beats of low-amplitude flutter in normal subjects.

Opsoclonus

In opsoclonus, a series of large-amplitude, back-to-back, multidirectional saccades interrupt fixation. The directions of the to-and-fro saccades can be horizontal, vertical, or oblique; their trajectories can be linear or curvilinear, and the frequency is high (10–15 Hz). The chaotic appearance of the oscillations has led to the use of the term “saccadomania.” In its severe form, opsoclonus is nearly continuous and persists even in some stages of sleep. With improvement, or in its milder form, the oscillations are intermittent. During fixation, saccadic burst cells in the pontine paramedian reticular formation (horizontal saccades) and in the rostral interstitial nucleus of the MLF (vertical saccades) are inhibited by tonic activity in pause cells in the nucleus raphe interpositus in the midbrain. Pause cell activity is momentarily inhibited during saccades, which allows the burst cells to fire and generate the saccadic pulse signal. An abnormal decrease in pause cell activity as a result of direct damage to these cells or abnormal input to them from other ­neurons might produce opsoclonus and ocular flutter. Opsoclonus often is associated with cerebellar ataxia and limb myoclonus. The disorders that cause opsoclonus damage the brainstem or cerebellum; they include benign brainstem encephalitis in children and adults following viral illnesses, myoclonic encephalopathy of infants (dancing eyes and dancing feet), paraneoplastic brainstem and cerebellar syndromes in children (neuroblastoma) and adults (small cell lung carcinoma, breast carcinoma, ovarian tumors), and multiple sclerosis.26, 27 Opsoclonus and ocular flutter have been reported in association with drug toxicities, exposure to toxic chemicals, and hyperosmolar coma and as transient findings in normal neonates. Adrenocorticotropic hormone can diminish the saccadic oscillations of infantile myoclonic encephalopathy and neuroblastoma, and corticosteroids can be effective in paraneoplastic syndromes in adults. Some normal subjects can produce saccadic oscillations volitionally, including many of the characteristics of opsoclonus and ocular flutter.28

TREATMENT Drug Treatment

The goal of treating vestibular nystagmus is mainly to diminish the associated vertigo. The large number of medications that are used is an indication that no optimal drug therapy exists for most patients. The classes of drugs include anticholinergics (scopolamine (hyoscine)), antihistamines (meclizine), monoaminergics (ephedrine), benzodiazepines (diazepam), phenothiazines (prochlorperazine), and butyrophenones (droperidol). Unfortunately, drowsiness from many of these drugs limits their efficacy for chronic, recurrent vertigo. An exception is acetazolamide, which is very effective for the treatment of familial periodic ataxia with nystagmus.29

The goal in the treatment of nonvestibular forms of nystagmus and saccadic oscillations is to improve vision by ameliorating the associated blurring and oscillopsia. As in vestibular nystagmus, many medications have been tried, but few have been found to be consistently effective.30 Only a few double-blind studies have been carried out: anticholinergics for acquired pendular nystagmus,31 and muscarinic antagonists for acquired pendular and downbeat nystagmus.32 Baclofen is an analog of γ-aminobutyric acid and was developed to treat skeletal muscle spasm. It consistently decreases the symptoms and signs of periodic alternating nystagmus.33 To diminish the side effect of drowsiness, the initial dosage is low, 5 mg by mouth three times a day, and is increased gradually. Patients perceive a return of symptoms after a few hours. The drug is not taken at bedtime, because the beneficial effects are not appreciated. Some patients who have congenital nystagmus report that their vision improves with baclofen, and in a few patients, nystagmus has been found to decrease slightly with an increase in the null zone of least nystagmus intensity. Baclofen decreases the slow component velocity and oscillopsia in some patients who have upbeat and downbeat nystagmus.34 Its therapeutic effect might result from augmentation of the physiological inhibitory effect of γ-amino­ butyric acid on the vestibular nuclei in the vestibulocerebellum and on the velocity storage mechanism. Clonazepam is an antiepileptic agent that has been shown to decrease downbeat nystagmus in some patients.35 Its most common side effect is drowsiness. The initial dosage of 0.5 mg by mouth three times a day is increased gradually. Recently, gabapentin (900–1500 mg/day) has been shown to decrease, but not abolish, acquired pendular nystagmus in a few patients.36 Adrenocorticotropic hormone can diminish ocular flutter and opsoclonus in infantile myoclonic encephalopathy and neuroblastoma. Corticosteroids can decrease these saccadic oscillations in paraneoplastic, cerebellar ataxia syndromes in adults. Carbamazepine, baclofen, and clonazepam have been used to treat superior oblique myokymia; gabapentin also seems to be effective and has a better ­side-effect profile than the other agents.37 Isoniazid in dosages of 800–1000 mg/day decreased acquired pendular nystagmus in two patients who had ­multiple sclerosis.38

9.18 Nystagmus, Saccadic Intrusions, and Oscillations

because it consists of to-and-fro, back-to-back saccades. Because no intersaccadic intervals occur, visual acuity is poor, and oscillopsia is present during the oscillations. Voluntary “nystagmus” cannot be sustained for more than several seconds; subjects show signs of intense effort, such as squinting, facial muscle contractions, and convergence.

Optical Treatment

In congenital nystagmus, convergence and eccentric gaze often decrease the nystagmus and improve vision. To induce convergence, 7 D (prism) of base-out prism can be placed in each spectacle lens. If the patient is young, − 1.00 D can be added to the spherical correction. If the null zone is in horizontal eccentric gaze, the spectacle prism powers can be modified to incorporate a prism effect in which the eyes conjugately rotate toward the null zone (prism apices toward the null zone). Contact lenses have fewer optical aberrations and usually correct the refractive errors in patients who have congenital nystagmus more effectively than do spectacles. In addition, tactile sensory feedback from the contact lenses might diminish the nystagmus intensity. One congenital nystagmus patient reported transient oscillopsia when contact lenses were removed after a short therapeutic trial.39 The combination of a high plus spectacle lens and a high minus contact lens for one eye has been devised to stabilize retinal images in that eye and improve vision.40 This combination places the image at the eye’s center of rotation. However, because vestibulo-ocular eye movements and volitional eye movements do not cause retinal image movement with these lenses, walking is difficult. A patient who had ocular myoclonus was found to have vertical pendular nystagmus in one eye and horizontal pendular nystagmus in the other. Patching the eye that had vertical nystagmus caused an esotropia of that eye but resulted in disappearance of the horizontal nystagmus in the other.41 In patients who have MLN, spectacle treatment for an accommodative component of their esotropia can transform MLN to latent nystagmus or decrease MLN, each of which leads to an improvement of binocular visual acuity.42

Surgical Treatment

An eccentric null zone in congenital nystagmus often produces a habitual face turn. If marked, the face turn can cause difficulties when viewing at distance or reading; in addition, it can be a ­ cosmetic ­ problem. Resections and recessions of the four horizontal rectus muscles can move the null zone toward the primary position (Anderson-Kestenbaum procedure), which improves vision in the primary position.43, 44

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9 NEURO-OPHTHALMOLOGY

However, months after the surgery, the null zone may become ­eccentric again. If convergence decreases congenital nystagmus significantly, surgery to induce a greater convergence effort can be combined with the Anderson-Kestenbaum procedure.45 Large recessions of all four horizontal rectus muscles are designed to symmetrically weaken the muscles and can reduce nystagmus intensity. Diplopia and limitation of ductions reportedly have not been significant problems.46, 47 Occasionally, bilateral vertical rectus recessions or bilateral, combined vertical rectus recession-resections are performed to correct vertical head postures in congenital nystagmus.48 Rarely, surgery of the oblique muscles is used to correct a head tilt.49 In patients who have strabismus and MLN, strabismus surgery can change the MLN to latent nystagmus and improve binocular visual acuity.42 In Arnold-Chiari malformations, suboccipital decompression can diminish downbeat nystagmus if permanent damage to the midline ­cerebellum and lower brainstem has not occurred. Procedures to weaken

the superior oblique and ipsilateral inferior oblique muscles have been used to treat superior oblique myokymia.

Other Treatments

A variety of other therapies have been used to treat nystagmus. Of these, the Epley maneuver for BPPN is by far the most effective.10 Tactile stimulation of the face and neck,50 auditory biofeedback, and acupuncture have been shown by electronic recordings to decrease congenital nystagmus. However, their efficacy outside of the laboratory setting has not been established. Retrobulbar injections or intramuscular injections of botulinum A toxin decrease nystagmus by paralyzing the extraocular muscles. They have been used to treat congenital nystagmus,51 latent nystagmus,52 and acquired nystagmus.53 The paralysis is temporary, requiring repetition of the injection every few months. The side effects are diplopia, ptosis, filamentary keratitis, and increased nystagmus in the noninjected eye from plastic-adaptive changes in response to the paresis of the injected eye.54, 55

REFERENCES   1. Leigh RJ. Clinical features and pathogenesis of acquired forms of nystagmus. Baillières Clin Neurol. 1992;1:  393–416.   2. Ciancia AD. On infantile esotropia with nystagmus in abduction. J Pediatr Ophthalmol Strabismus. 1995;32:280–8.   3. Gottlob I, Wizov SS, Reinecke RD. Spasmus nutans. A long-term follow-up. Invest Ophthalmol Vis Sci. 1995;36:2768–71.   4. Jan LE, Groenveld M, Connolly MD. Head shaking by visually-impaired children: a voluntary neurovisual   adaptation which can be confused with spasmus   nutans. Dev Med Child Neurol. 1990;32:1061–8.   5. Gottlob I, Wizov SS, Reinecke RD. Head and eye movements in children with low vision. Graefes Arch Clin Exp Ophthalmol. 1996;234:369–77.   6. Gottlob I, Zubcov A, Catalano RA, et al. Signs distinguish­ ing spasmus nutans (with and without central nervous system lesions) from infantile nystagmus. Ophthalmology. 1990;97:1166–75.   7. Newman SA, Hedges TR, Wall M, Sedwick A. Spasmus nutans – or is it?. Surv Ophthalmol. 1990;34:453–6.   8. Arnoldi KA, Tychsen L. Prevalence of intracranial lesions in children initially diagnosed with disconjugate nystagmus (spasmus nutans). J Pediatr Ophthalmol Strabismus. 1995;32:296–301.   9. Lopez L, Bronstein AM, Gresty MA, et al. Torsional nystagmus. A neuro-otological and MRI study of thirty-five cases. Brain. 1992;1115:1107–24. 10. Epley JM. The canalith repositioning procedure: for treatment of benign paroxysmal positional nystagmus. Otolaryngol Head Neck Surg. 1992;107:399–404. 11. Herdman SJ, Tusa RJ. Complications of the canalith repositioning procedure. Arch Otolaryngol Head Neck Surg. 1996;122:281–6. 12. Brandt T. Positional and positioning vertigo and nystagmus. J Neurol Sci. 1990;95:3–28. 13. Abadi RJ, Pascal F. Periodic alternating nystagmus in humans with albinism. Invest Ophthalmol Vis Sci. 1994;35:4080–6. 14. Hirose G, Kawada J, Tsukada K, et al. Upbeat nystagmus: clinicopathological and pathophysiological considerations. J Neurol Sci. 1991;105:159–67. 15. Yee RD. Downbeat nystagmus: characteristics and   localization of lesions. Trans Am Ophthalmol Soc. 1989;87:984–1032. 16. Lopez LI, Gresty MA, Bronstein AM, et al. Acquired   pendular nystagmus: oculomotor and MRI findings. Brain. 1996;119:265–72. 17. Good WV, Koch TS, Jan JE. Monocular nystagmus caused by unilateral anterior visual-pathway disease. Dev Med Child Neurol. 1993;35:1106–10. 18. Halmagyi GM, Aw ST, Dehaene I, et al. Jerk-waveform see-saw nystagmus due to unilateral mesodiencephalic lesion. Brain. 1994;117:789–803.

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19. Thomke F, Hopf C. Abduction nystagmus in internuclear ophthalmoplegia. Acta Neurol Scand. 1992;86:365–70. 20. Wagner RS, Caputo AR, Reynolds RD. Nystagmus in Down’s syndrome. Ophthalmology. 1990;97:1439–44. 21. Brazis PW. Ocular motor abnormalities in Wallenberg’s lateral medullary syndrome. Mayo Clin Proc. 1992;67:365–8. 22. Kaplan PW, Tusa RJ. Neurophysiologic and clinical correlations of epileptic nystagmus. Neurology. 1993;43:2508–14. 23. Tusa RJ, Kaplan PW, Hain TC, Naidu S. Ipsiversive eye deviation and epileptic nystagmus. Neurology. 1990;40:662–5. 24. Mossman SS, Bronstein AM, Gresty MA, et al. Convergence nystagmus associated with Arnold-Chiari malformation. Arch Neurol. 1990;47:357–9. 25. Adler CH, Galetta SL. Oculo-facial-skeletal myorhythmia of Whipple’s disease. Ann Intern Med. 1990;112:467–9. 26. Fisher PG, Wechsler DS, Singer HS. Anti-Hu antibody   in a neuroblastoma-associated neoplastic syndrome. Pediatr Neurol. 1994;10:309–12. 27. Digre K. Opsoclonus in adults. Report of three cases and review of the literature. Arch Neurol. 1986;43:1165–75. 28. Yee RD, Spiegel PH, Yamada T, et al. Voluntary saccadic oscillations, resembling ocular flutter and opsoclonus.   J Neuroophthalmol. 1994;14:95–101. 29. Van Boggert P, Van Nechel C, Goldman S, Szliwowski HB. Acetazolamide-responsive hereditary paroxysmal ataxia: report of a new family. Acta Neurol Belg. 1993;93:268–75. 30. Leigh RJ, Averbuch-Heller L, Tomsak RL, et al. Treatment of abnormal eye movements that impair vision: strategies based on movement – current concepts of physiology and pharmacology. Ann Neurol. 1994;36:129–41. 31. Leigh RJ, Burnstine TH, Ruff RL, Kasmer RJ. Effect of anticholinergic agents upon acquired nystagmus: a double blind study of trihexyphenidyl and tridihexethyl chloride. J Clin Neuroophthalmol. 1991;11:166–8. 32. Barton JJ, Huaman AG, Sharpe JA. Muscarinic antagonists in the treatment of acquired pendular and downbeat nystagmus. Ann Neurol. 1994;35:319–25. 33. Troost BT, Janton F, Weaver R. Periodic alternating oscillopsia: a symptom of alternating nystagmus abolished by baclofen. J Clin Neuroophthalmol. 1990;10:273–7. 34. Dieterich M, Straube A, Brandt T, et al. The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psychiatry. 1991;54:627–32. 35. Currie JN, Matsuo V. The use of clonazepam in   the treatment of nystagmus-induced oscillopsia.   Ophthalmology. 1986;93:924–32. 36. Stahl JS, Rottach KG, Avercuh-Heller L, et al. A pilot study of gabapentin as a treatment for acquired nystagmus. Neuroophthalmology. 1996;16:107–13. 37. Tomsak RL, Kosmorsky GS, Leigh RJ. Gabapentin attenuates superior oblique myokymia. Am J Ophthalmol. 2002;133:721–3.

38. Traccis S, Rosati G, Monaco MF, et al. Successful   treatment of acquired pendular nystagmus with   isoniazid and base-out prisms. Neurology. 1990;40:  492–4. 39. Safran AR, Gambazzi Y. Congenital nystagmus: rebound phenomenon following removal of contact lenses.   Br J Ophthalmol. 1992;76:497–8. 40. Yaniglos SS, Leigh RJ. Refinement of an optical device that stabilizes vision in patients with nystagmus. Optom Vis Sci. 1992;69:447–50. 41. Herishanu YO, Zigoulinski R. The effect of chronic   one-eye patching on ocular myoclonus. J Clin   Neuroophthalmol. 1991;11:116–8. 42. Zubcov AA, Reinecke RD, Gottlob I. Treatment of manifest latent nystagmus. Am J Ophthalmol. 1990;110:160–7. 43. Pratt-Johnson JA. Results of surgery to modify the null-zone position in congenital nystagmus. Can J Ophthalmol. 1991;26:219–23. 44. Kraft SP, O’Donoghue EP, Roarty JD. Improvement of compensatory head postures after strabismus surgery. Ophthalmology. 1992;99:1301–8. 45. Zubcov AA, Stark N, Weber A, et al. Improvement   in visual acuity after surgery for nystagmus. Ophthalmology. 1993;100:1488–97. 46. Helveston EM, Ellis FD, Plager DA. Large recession of the horizontal recti for treatment of nystagmus. Ophthalmology. 1991;98:1302–5. 47. von Noorden GK, Sprunger DT. Large rectus muscle recessions for the treatment of congenital nystagmus. Arch Ophthalmol. 1991;109:221–4. 48. Sigal MB, Diamond GR. Survey of management strategies for nystagmus patients with vertical or torsional head posture. Ann Ophthalmol. 1990;22:134–8. 49. Prakash P, Arya AV, Sharma P, Chandra VM. Torsional Kestenbaum in congenital nystagmus with torticollis. Indian J Ophthalmol. 1990;38:70–3. 50. Sheth NV, Dell’Osso LF, Leigh RJ, et al. The effects of afferent stimulation on congenital nystagmus foveation periods. Vision Res. 1995;35:2371–82. 51. Carruthers J. The treatment of congenital nystagmus with Botox. J Pediatr Ophthalmol Strabismus. 1995;32:306–8. 52. Liu C, Gresty M, Lee J. Management of symptomatic latent nystagmus. Eye. 1993;7:550–3. 53. Ruben ST, Lee JP, O’Neil D, et al. The use of botulinum toxin for treatment of acquired nystagmus.   Ophthalmology. 1994;101:783–7. 54. Leigh RJ, Tomsak RL, Grant MP, et al. Effectiveness of botulinum toxin administered to abolish acquired nystagmus. Ann Neurol. 1992;32:633–42. 55. Tomsak RL, Remler BF, Averbuch-Heller L, et al.   Unsatisfactory treatment of acquired nystagmus with retrobulbar injection of botulinum toxin. Am J Ophthalmol. 1995;119:489–96.

PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

The Pupils Randy H. Kardon

Definition:  Pupillary disorders may be classified into two major   categories – afferent and efferent.

n Afferent pupillary defects interfere with the input of light to the

­ upillomotor system by light blockage or deficits in any of the p retinal layers, into the optic nerve, chiasm, optic tract, or midbrain pretectal area. All of these result in a symmetrical decrease in the contraction of both pupils to light given to the damaged eye, ­compared with light given to the other less damaged or normal eye. n E  fferent pupillary defects interfere with contraction or dilatation of the pupil due to damage in the midbrain, in the peripheral nerve that supplies the iris muscles, or in the iris muscles themselves, often leading to asymmetrical pupils (anisocoria).

Key features n

n

 elative afferent pupillary defects cause a reduction in pupil   R contraction when one eye is stimulated by light compared with when the opposite eye is stimulated by light. Efferent pupillary defects cause anisocoria, a difference in pupil size between the right and left eyes, the extent of which depends on the condition of lighting or near effort.

Associated features n

n

 elative afferent pupillary defects may be associated with visual R field or electroretinographic asymmetries between the two eyes. Asymmetrical differences in retinal appearance or optic nerve appearance may occur. Efferent pupillary defects may be associated with either damage   to the parasympathetic or sympathetic nerves that supply the iris or direct damage to the iris sphincter or dilator muscles that results in immobility of the pupil.

INTRODUCTION In this chapter the pupil is discussed from a practical, clinical standpoint. The focus is on features of pupil examination that enable effective diagnosis and management of a variety of diseases of the afferent visual system and of diseases that affect pupil size. The chapter is divided into two main portions – one on the use of pupil examination to assess afferent visual input and the second on the diagnostic implications of abnormal integration of the efferent output to the pupils. Abnormal integration may result in pupils of unequal diameter (anisocoria), pupils that do not dilate well in darkness, or a light–near dissociation, in which pupil contraction to a near reflex greatly exceeds the pupil constriction to a light reflex.

RELATIVE AFFERENT PUPILLARY DEFECTS In general, the most important clinical use of the pupil is in the assessment of afferent input from the retina, optic nerve, and subsequent anterior visual pathways (chiasm, optic tract, and midbrain pathways). Because the pupillary light reflex represents the sum of the entire neuronal input (photoreceptors, bipolar cells, ganglion cells, and axons of

9.19 ganglion cells), damage anywhere along this portion of the visual pathway reduces the amplitude of pupil movement in response to a light stimulus.1, 2 Thus, the clinician can establish any asymmetrical damage between the two eyes by a simple comparison of how well the pupil contracts to a standard light shone into one eye compared with the same light shone into the other eye.3 Observation of pupil movement in response to alternating the light back and forth between the two eyes is the basis for the alternating light test, or “swinging flashlight” test, used to assess the relative afferent pupillary defect (RAPD).4, 5 Another important aspect of pupil movement in response to light is that the pupillary light reflex summates the entire area of the visual field, with some increased weight given to the central 10°.2 Thus, in general terms, the pupillary light reflex is roughly proportional to the amount of working visual field. Damage to peripheral portions of the retina and visual field defects outside the central field reduce the amplitude of the pupillary light reflex. Such damage may not be established by other objective tests of visual function, such as the electroretinogram and visual evoked potential. Standard flash electroretinogram findings are affected very little by focal retinal damage that produces a visual field defect. For example, a patient who has a disciform scar caused by aged-related macular degeneration or a branch artery occlusion gives a normal flash electroretinogram result. However, in such an example, the pupillary light reflex is reduced compared with that of the other eye, and an RAPD is obvious. In addition, optic nerve disease or damage to the retinal ganglion cells is not detected by standard flash electroretinography. Assessment of the pupillary light reflex readily enables the detection of such damage. Because the visual evoked potential primarily samples the occipital pole or tip, which represents the central 5–10° of visual field, it is not affected to any great extent by peripheral visual field defects. In addition, cooperation of the patient is required to fixate on the center of a computer monitor while the visual stimulus is presented. A patient who chooses not to fixate properly or who has media opacities that reduce the clarity of the checkerboard pattern may produce an abnormal result, even if the retina and optic nerve function are normal (i.e., a falsepositive test result). Similarly, peripheral visual field defects caused by glaucoma or anterior ischemic optic neuropathy may yield a normal visual evoked potential, or false-negative result, but the pupillary light reflex is reduced.6 Therefore, the pupillary light reflex is one of the few objective ­reflexes that can be used as a clinical test for the detection and quantification of abnormalities of the retina, optic nerve, optic chiasm, or optic tract. Because the amount of RAPD is correlated, to a large extent, with the amount of asymmetry of visual field deficit between the two eyes, it also may be used to help substantiate abnormal results of perimetric­ ­testing;7–10 this often helps the clinician to determine whether a ­patient’s report of visual field defects is believable and trustworthy. The correlation between visual field asymmetry and RAPD also is a useful monitor of the course of disease for a worsening or improvement in function. RAPDs are, by definition, relative to the input of one eye compared with that of the other. Bilateral symmetrical damage does not produce RAPDs. Thus, a definite RAPD in one eye on the first visit but no RAPD on follow-up may represent improvement in the previously damaged eye or the development of damage in the previously better eye. Therefore, it is always important to remember that the RAPD is, indeed, relative to the other eye. Estimation of the amount of RAPD in log units (asymmetry between the two eyes) provides an idea of how much visual field damage is present and whether it is consistent with the results of the visual field test. In addition, the amount of RAPD may indicate whether the cause of damage is consistent with the results of the pupil examination. For

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   TABLE 9-19-1  COMMON DISEASES THAT PRODUCE RELATIVE AFFERENT PUPILLARY DEFECTS

NEURO-OPHTHALMOLOGY

Log Unit Relative Afferent Pupillary Defect

Condition

Site

Intraocular hemorrhage

Anterior chamber or vitreous (dense) Anterior chamber (diffuse) Preretinal (central vein occlusion   or diabetic)

0.6–1.2 0.0–0.3 0.0

Density of hemorrhage Density of hemorrhage Preretinal location does not significantly reduce light

Diffusing media opacity

Cataract or corneal scar

0.0–0.3 in opposite eye

Dispersion of light produces increase   in light input

Unilateral functional visual field loss

None (nonorganic)

0.0

No real visual field loss

Central serous retinopathy or cystoid macular edema

Retina (fovea)

0.3

Area of retina involved, depth   of scotoma

Central or branch retinal vein occlusion

Inner retina

0.3–0.6 (nonischemic) ≥ 0.9 (ischemic)

Area of visual field defect and degree   of ischemia

Central or branch retinal artery occlusion

Inner retina

0.3–3.0

Area and location of retina involved

Retinal detachment

Outer retina

0.3–2.1

Area and location of detached retina   (e.g., 0.6–0.9 log units for macula +0.3 log units for each quadrant)

Anterior ischemic optic neuropathy

Optic nerve head

0.6–2.7

Extent and location of visual field defect

Optic neuritis (acute)

Optic nerve

0.6–3.0

Extent and location of visual field defect

Optic neuritis (recovered)

Optic nerve

0.0–0.6

No visual field defect, residual relative afferent pupillay defect

Compressive optic neuropathy

Optic nerve

0.3–3.0

Extent and location of visual field defect, other eye involvement

Chiasmal compression

Optic chiasm

0.0–1.2

Asymmetry of visual field loss, unilateral central field involvement

Optic tract lesion

Optic tract

0.3–1.2 in the eye with temporal   field loss

Incongruity of homonymous field defect, hemifield pupillomotor input asymmetry

Postgeniculate damage

Visual radiations Visual cortex

0.0

Stimulus light size (no residual relative   afferent pupillary defect but definite pupil perimetry defects)

Midbrain tectal damage

Olivary pretectal area of pupil light input region of midbrain

0.3–1.0

Similar to optic tract lesions, but no visual field defect

Influencing Factors

The expected magnitude of defect is given as well.

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example, a patient affected by a small amount of macular degeneration in one eye and not the other is expected to have only a 0.3–log unit RAPD, but if that patient has a 1.0–log unit RAPD, then some other cause of visual loss is likely, such as a previous branch retinal artery ­occlusion or optic neuropathy (Table 9-19-1). In general, with unilateral visual loss, loss of the central 5° of the visual field results in an RAPD of approximately 0.3 log units. Loss of the entire central area of field (10°) causes an RAPD of 0.6–0.9 log units. Each visual field quadrant outside of the macula is worth about 0.3 log units, but the temporal field loss seems to result in more loss of pupillary input compared with loss in the nasal field quadrants. The correlation between the relative afferent defect and the area and extent of visual field loss, however, is only approximate. Differences between the two may be important clues as to the cause and extent of damage to the anterior visual system. Studies that used computerized pupillography to quantify the RAPD more precisely showed that some subjects who have normal visual fields and examination results can have a small (0.3–log unit) RAPD.11, 12 The amount of pupillomotor input asymmetry (the RAPD) may be estimated roughly using the alternating light test (without any neutral density filters) and the subjective grades +1, +2, +3, or +4 for asymmetry of pupillary response. This subjective grading also may be categorized according to the amount of “pupil escape,” or dilatation of the pupils, as the light is alternated between the eyes.13 However, most subjective grading of RAPDs has serious limitations, such as some large-scale errors that arise from age variations in pupil size and pupil mobility. For example, a patient who has small pupils and small pupillary contractions to light may have a large RAPD, but this may appear deceptively small on the basis of small differences in pupil excursion observed as the

light is alternated between the two eyes. However, the amount of neutral density filter needed to dim the better eye until the small contractions are equal represents substantial input damage. To estimate the size of RAPDs without using filters is very much like the estimation of an ocular deviation “by Hirschberg” without a prism cover test. More accurate quantification of RAPDs is accomplished by determination of the log unit difference needed to “balance” the pupil reaction between the two eyes.4, 5 Photographic neutral density filters (49 mm, screw mount, 0.3 log, 0.6 log, and 0.9 log) often are available through local photography stores.

Measurement of the Relative Afferent Pupillary Defect

Measurement of RAPDs is the most important part of the pupil examination, because it may give the most valuable clinical information. The alternating light test for an afferent defect is based on the assumption that the irises are a matched pair – each has sphincter and dilator muscles of good shape and properly innervated – so that the light reactions can be compared. Therefore, it is important to first establish whether an anisocoria is present, which may indicate an efferent defect.

Evaluation of anisocoria

Pupillary inequality usually results from an iris innervation problem, so to evaluate anisocoria the iris sphincter and dilator muscles must be checked. In the office, the best way to decide whether the sphincter muscle or dilator muscle is weak is to compare the amount of anisocoria in darkness and in light, which can be carried out without any special equipment. The examiner must be able to change the lighting and still view the pupils. Of course, usually no anisocoria is found in

Fig. 9-19-1  Checking for an RAPD using the “tilt test.” If there seems to be no input asymmetry, the “tilt test” can confirm this by inducing an RAPD of the same magnitude in each eye by holding a   0.3 –log unit neutral ­density filter over one eye during the ­alternating light test and then repeating it with the filter over the other eye.

The Pupils

darkness or in light, in which case the efferent arm of the light reflex arc is presumed intact, and the examiner proceeds to check for an afferent defect. When anisocoria is present, the examiner needs to establish whether it increases in darkness or in light. If one sphincter is weak, the investigator may still check for an afferent defect in the pupil that still works by comparison of its direct and consensual reactions. If no asymmetry of input is apparent, and hence no RAPD, this impression may be confirmed using the “tilt test” described below (Fig. 9-19-1). Anisocoria may influence the estimate of pupillary input asymmetry. Small pupils allow less light to pass and large pupils more. However, if neither pupil is less than 3.0 mm wide in light, then any anisocoria less than 2.0 mm difference may be disregarded – at least with respect to a false afferent defect induced by the pupillary inequality. Only very large anisocorias cause enough difference in retinal illumination between the two eyes to produce an apparent asymmetry of pupillomotor input.

9.19

Fig. 9-19-2  Demonstration of a large afferent defect in the right eye. This is best demonstrated when the light is alternated from eye to eye at a steady rate. The light is kept just below the visual axis and 1–2 inches (3–5 cm) from each eye. Each eye is illuminated for about 1 second and then the light switched quickly to the other eye; this allows comparison of the initial direct pupil ­contraction with light in each eye. Fig. 9-19-3  Balancing pupillary response using filters. A dark iris appears even darker behind the filter so it may be difficult to view the pupil, in which case it helps to peek behind the filter to obtain   a better view of the iris.

Establishment of relative afferent pupillary defect

To check for RAPD, the light is alternated from one eye to the other (Fig. 9-19-2). If the light is too bright, the pupils do not redilate promptly, and very little pupil movement is seen as the light is alternated to the other eye. The problem may be solved by a direct reduction in stimulus intensity or if the light is moved 3–4 inches (8–10 cm) away from the eyes and alternated between them.

efforts, the afferent asymmetry may still fluctuate slightly with time, even when carefully recorded using computerized pupillography.

Observe the illuminated eye

Small children

If the pupils react relatively weakly when one eye is stimulated and ­better when the other is stimulated, an afferent defect relative to the better eye (RAPD) has been identified.

Balance the responses using filters

To balance the response, a filter is held over the good eye and the alternating light test repeated. If the input asymmetry is still visible, the density of the filter over the good eye is increased until the amplitudes of the direct light reactions of the two eyes are balanced. To be certain of the measurement, the balance point may be overshot deliberately and then back titrated. When a dense filter is used, it may be necessary to look behind the filter to see the pupil (Fig. 9-19-3).

“Tilting” – the dubious relative afferent pupillary defect

If a very small asymmetry is suspected, such as a defect of less than 0.3 log units in the left eye, it may be just the result of noise in the system (e.g., “hippus”). An effort must be made to confirm the asymmetry by “tilting” the RAPD to the right and to the left using a 0.3 –log unit filter (see Fig. 9-19-1). If no RAPD exists, the examiner should be able to induce the same amount of input asymmetry by holding a 0.3 –log unit filter over the right eye during the alternating light test and then repeating the test with the filter switched to the left eye. If a small RAPD is present, it will become more apparent when the filter is held over that eye.

Moment-to-moment variability

Unfortunately, the pupillary response to a repeated light stimulus is far from constant; it changes from moment to moment.11, 12 A common ­error is to judge the apparent asymmetry of the light reflex too quickly. It is important to alternate the light back and forth at least 3 times to obtain a mental average of any asymmetry. In this way, moment-to-moment fluctuations in the pupillary response are “averaged out.” Despite such

Infants and small children may appear to have weak pupillary responses to light, largely because of the excitement and apprehension that inhibit the pupillary light reflex at the supranuclear level in the midbrain. Usually, after the light stimulus has been repeated several times, the light reaction begins to improve and “loosen up,” especially as the child becomes less anxious. A baby’s pupils are checked at about 3 ft (1 m) away with a direct ophthalmoscope. In a dark room, the brightest light and smallest spot are used, focus is on the red reflex, and the light is alternated from eye to eye. The baby usually is fascinated, and a filter sometimes can be placed in the beam to one eye.

Only one working pupil

When the input defect is in an eye that has an injured iris or a dilated pupil, the pupillary responses of the uninjured eye must be observed. The direct and consensual responses of the working pupil may be compared by alternation of the light from one eye to the other. While a measurement is made, the good eye is behind the filter and it may be hard to see the pupil. Sometimes it is necessary to use a side light on the healthy iris in order to see its consensual pupil reaction. Because this may corrupt the measurement, an infrared video system is used, if possible.

Instrumentation

Instruments are available that give a more precise evaluation of the ­pupillary light reflex; these include infrared video recording equipment and a computerized interface to present controlled light stimuli and quantify the dynamics of pupil movement in response to each light stimulus.

Infrared videography

Sometimes it is important to view the magnified movement of both pupils at once. Infrared videography (Fig. 9-19-4) enables the ­examiner to see both pupils clearly in the dark, which is particularly

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9 NEURO-OPHTHALMOLOGY

helpful when difficult afferent pupillary defects need to be checked for (e.g., one pupil is fixed, or both irises are pigmented very darkly). Because melanin reflects infrared light, dark irises appear light and so the black pupils stand out in contrast and are viewed easily. Videography also is used to establish the dilatation lag of a Horner’s pupil, to catch the brief paradoxical constriction in patients who have some retinal abnormalities (found when lights are turned out), to transilluminate the iris in pigment dispersion syndrome,14 and in Adie’s syndrome.

EFFERENT PUPILLARY DEFECTS Anisocoria

As discussed above, a pupillary inequality usually indicates that one of the four iris muscles, or its innervation, is damaged (Fig. 9-19-5). To establish which is the weaker muscle, it is useful to know how the anisocoria is influenced by light. An anisocoria always increases in the ­direction

Computerized pupillometry

Various computerized infrared-sensitive pupillometers are available commercially and can record precisely the dynamics of pupil movement in the light or in the dark; the results are analyzed by sophisticated software. Such systems provide quantitative information about the pupillary light reflex and, in the future, may help to automate the clinical determination of pupillary input deficits that result from retinal and optic nerve diseases.11, 12, 15–17 In addition, information obtained using computerized pupillography provides evidence that a number of different types of visual stimuli can produce changes in the pupillary light reflex, related to color, form, movement, and acuity.18–24

Pupil perimetry

An automated perimeter may be modified to record pupillary responses. A video camera is pointed at the pupil and the amplitude of each light reaction is measured and stored in the computer, which is helpful as an objective form of perimetry and to localize lesions in the pupillary pathways.25, 26 Pupil perimetry is also useful in cases of nonorganic, functional visual loss to show objectively that messages are, indeed, going normally into the brain from parts of the visual field in which the patient claims to see nothing.

Fig. 9-19-4  The infrared video-pupillometer. The infrared sources (clusters of light-emitting diodes) are mounted in gooseneck lamps. The double base-out prisms bring the pupils close together on the screen, allowing increased magnification from the infrared videocamera and telephoto lens.

PARASYMPATHETIC AND SYMPATHETIC INNERVATION OF THE IRIS MUSCLES

arousal! sphincter pupillae

optic tract

iris

(input from homonymous hemiretinas)

ACh NE

inhibitory impulses pupil

ciliary ganglion

short ciliary nerve ACh

NE

'postganglionic neuron' long ciliary nerve

'postganglionic neuron'

hypothalamus

ACh

ACh

Edinger–Westphal nucleus oculomotor nucleus

'preganglionic neuron'

Parasympathetic pathway pons

'central neuron'

carotid plexus superior cervical ganglion

dilator iridis ACh

cervical cord cervical sympathetic

ACh – acetylcholine NE – norepinephrine

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Fig. 9-19-5  Parasympathetic and sympathetic innervation of the iris muscles.

(excitatory impulses)

midbrain

oculomotor nerve

Sympathetic pathway

pretectal nucleus

'preganglionic neuron'

ciliospinal center (Budge) C8–T1 ACh

of action of the paretic iris muscle, just as an esotropia increases when gaze is in the direction of action of a weak lateral rectus muscle.

Pupillary Inequality that Increases in the Dark

Pupil dilatation rate

9.19 The Pupils

In patients who have a pupillary inequality that increases in the dark (Fig. 9-19-6), the problem is to differentiate Horner’s syndrome from a simple anisocoria (or physiological anisocoria) – in which the inequality also is greater in dim light. A simple anisocoria may vary from day to day, or even from hour to hour, and is visible in about one fifth of the normal population; it is not related to refractive error. Clinically, Horner’s syndrome is recognized by associated signs such as ptosis, “upside-down ptosis” of the lower lid and, in an acute case, conjunctival injection and lowered intraocular pressure. Simple anisocoria is common (about 10% of normal subjects, examined in room light, have an anisocoria of 0.4 mm or more) and is not associated with disease. Simple anisocoria also, like Horner’s syndrome, decreases slightly in light, but it does not show a dilatation lag of the smaller pupil. It is believed that simple anisocoria most likely arises from asymmetrical inhibition at the Edinger-Westphal nucleus in the midbrain. Normally, during wakefulness some inhibition from the reticular activating formation keeps the pupils midsize or larger.

During sleep, this inhibition fades and allows the neurons in the Edinger-Westphal nucleus to discharge, which results in miotic pupils. If, during wakefulness, the inhibition is greater to the right EdingerWestphal nucleus than the left, the right pupil is larger, especially in dim light. When light is added or a near reflex is generated, this inhibition is overcome and the pupils become smaller and any asymmetrical inhibition diminishes. A reduction of the anisocoria results as the ­pupils become smaller. The characteristic “dilatation lag” of the pupil in Horner’s syndrome is seen easily in the office using a handheld light shone from below. The room lights are switched off and the smaller pupil examined for an apparent reluctance to dilate. Pupil dilatation is normally a combination of sphincter relaxation and dilator contraction, a combination that produces a prompt dilatation. The patient who has Horner’s syndrome has a weak dilator muscle in one iris and, as a result, that pupil dilates more slowly than the normal pupil. If the sympathetic lesion is complete, the affected pupil dilates only by sphincter relaxation. The resultant asymmetry of pupil dilatation produces an anisocoria that is largest 4–5 seconds after the lights have been turned out – the process is much

DIAGNOSIS OF PUPILLARY ABNORMALITIES IN WHICH ANISOCORIA INCREASES IN DIM LIGHT Patient has anisocoria Is the inequality greatest in dim light? YES

NO

The anisocoria increases in bright light

YES

Is this a tonic pupil associated with Adie's syndrome?

Go to Figure 9-19-8

Use clinical observation or Polaroid flash photograph Does the anisocoria reverse in bright light because the small pupil does not constrict or dilate very well? NO Use clinical observation or Polaroid flash photograph Does the smaller pupil show a 'dilation lag' when the lights are turned out? Probable diagnosis of Horner’s syndrome, but confirmation is needed

YES

NO

Drug test Instill cocaine HCI 5% or 10% in each eye and wait 40–60 minutes

The anisocoria decreases because both pupils dilate to cocaine eye drops

The anisocoria increases because the smaller pupil dilates poorly

Although increased, the anisocoria is still ≤0.8 mm

The anisocoria becomes ≥0.8 mm in room light

Drug test Instill phenylephrine 1% in each eye at the end of the cocaine test and wait 30–40 minutes The small pupil dilates widely and becomes the largest pupil

Horner’s syndrome Damage to the oculosympathetic pathway produces Horner’s syndrome. Is the lesion in the postganglionic neuron?

This is an equivocal result. Is the pupil resistant to dilatation because the iris is damaged or inflamed?

Drug test Instill hydroxyamphetamine 1% in each eye and wait 40–60 minutes. (Do this test at least 48 hours after the cocaine test.) Both pupils dilate

Both pupils dilate; Horner’s pupil becomes the larger pupil

Central neuron Horner’s syndrome

Preganglionic Horner’s syndrome

The small pupil dilates poorly

Horner’s pupil dilates poorly (less than the other pupil) or not at all Postganglionic Horner’s syndrome

Structural anisocoria

Physiologic anisocoria

Fig. 9-19-6  Diagnosis of pupillary abnormalities in which anisocoria increases in dim light. If the anisocoria is greatest in dim light and diminishes in bright light, then the pupillary inequality is either physiological (a simple anisocoria) or arises from the loss of sympathetic innervation to the dilator muscle (Horner’s syndrome). A few other conditions need to be considered, but this chart is concerned only with acute damage to a single intraocular muscle or its innervation. (Material adapted and figure created from L eaman S. Focal points: Clinical modules for ophthalmologists Phototoxicity: Clinical Considerations, Vol. V, Number 8, American Academy of Opthalmology, 1987.)

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9 NEURO-OPHTHALMOLOGY

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slower than is generally thought. At 10–20 seconds after the lights have been put out, the anisocoria lessens as the sympathectomized pupil gradually catches up, a process referred to as dilatation lag. The test is a quick and simple way to differentiate Horner’s syndrome from simple anisocoria, and it does not require pupillary drug tests. It works well most of the time, particularly in young people who have mobile pupils, but if the dilatation lag is inconclusive, cocaine eye drops may be used to confirm the diagnosis of Horner’s syndrome.

Diagnosis of Horner’s syndrome – cocaine and apraclonidine testing

The action of cocaine is to block the reuptake of norepinephrine (noradrenaline) normally released from the nerve endings. If, because of an interruption in the sympathetic pathway, norepinephrine is not released, cocaine has no adrenergic effect. The affected pupil in a patient with Horner’s syndrome dilates less with cocaine than does the normal pupil, regardless of the location of the lesion. Cocaine drops are placed in both eyes and after 60 minutes the anisocoria has increased clearly, because the normal pupil has dilated more than the Horner’s pupil. The author recommends cocaine hydrochloride 10% in both eyes (not more than two drops) to ensure that even the darkest iris receives a full mydriatic dose; corneal epithelial defects will not result from this dose. Cocaine 2%, 4%, and 5% also have been used in diagnostic tests for Horner’s syndrome and work well. Anisocoria is measured after 50–60 minutes have elapsed. If very little dilatation of the pupil occurs, even though an oculosympathetic defect is suspected, and the pupil did not dilate well in darkness even after 30 seconds before the cocaine test, then a false-positive cocaine test result must be considered. A false-positive result may occur if the iris is held in a miotic state, through either scarring or aberrant reinnervation of the iris sphincter. In such cases, the addition of a direct-acting sympathomimetic agent to both eyes (e.g., 2.5% phenylephrine) at the conclusion of a positive cocaine test should dilate the suspected eye easily and eliminate the cocaine-induced anisocoria almost immediately. For the reasons stated above, pseudo-Horner’s syndrome results in inadequate dilatation to direct-acting sympathomimetic agents. The likelihood of Horner’s syndrome increases steadily as the degree of pupillary inequality (measured after the instillation of ­cocaine) increases. Unlike in the hydroxyamphetamine test, calculation of the change in anisocoria from before to after cocaine application is unnecessary. If there is at least 0.8 mm of pupillary inequality after ­cocaine administration, Horner’s syndrome is highly likely.27 Recently, it has been proposed that a new pharmacologic test using 0.5% apraclonidine be used for the diagnosis of Horner’s syndrome in place of cocaine.28–33 Typically, 30 minutes following topical apraclonidine administered to both eyes, the miotic eye with the oculosympathetic defect dilates and the anisocoria reverses. In patients with anisocoria of other causes, such as physiologic anisocoria, no mydriasis occurs. If topical apraclonidine is found to be as sensitive and specific as cocaine in differentiating Horner’s syndrome from other causes of anisocoria, then it ought to replace cocaine, which is expensive, not readily available in most doctors’ offices, and, as a controlled substance, must be kept under lock and key. Finally, apraclonidine has an advantage over cocaine in that it will actively dilate the affected eye and not the normal eye, making its action a positive (mydriatic) one in the affected eye rather than a negative one in the affected eye and a positive (mydriatic) one in the unaffected eye. As an α2-adrenergic agonist, apraclonidine has been used to lower intraocular pressure after yytrium–aluminum–garnet (YAG) laser treatment. Stimulation of the presynaptic α2 receptor is thought to inhibit release of norepinephrine and reduce aqueous production. In one study,31 apraclonidine 1% had the same pressure-lowering effect in the affected eye of six patients with Horner’s syndrome as it did in the contralateral eye. During that study, an unexpected mydriatic effect in the eyes with Horner’s syndrome was noticed. This effect is attributed to the drug’s weak α1 agonist property, which acts on the denervated, supersensitive iris dilator muscle. Apraclonidine did not appear to have any significant effect on the pupil of the unaffected eye. Unlike phenylephrine, whose corneal penetration varies widely among individuals, apraclonidine readily penetrates the cornea and gains access to the iris, so the limiting factor to its mydriatic effect is whether α1 supersensitivity is present in the iris dilator muscle. As early as 1989, the mydriatic effect of topical clonidine in patients with Horner’s syndrome was described in the German literature.34 Apraclonidine has potential advantages over phenylephrine, not only in its ease of corneal penetration, but also in the fact that it does not need to be diluted. Further studies will clarify the diagnostic efficacy of apraclonidine for the diagnosis of oculosympathetic defects.

Location of damage to the sympathetic pathway

Whether the damage to the sympathetic pathway is in the postganglionic neuron is a question of considerable clinical importance, because many postganglionic defects are caused by benign, vascular headache syndromes or carotid dissections, and a preganglionic lesion sometimes results from the spread of a malignant neoplasm. Hydroxyamphetamine eye drops help to localize the lesion in Horner’s syndrome. The clinician needs to know where the lesion is to direct the radiographic work-up, for example, to the internal carotid artery rather than to the pulmonary apex. Horner’s syndrome sometimes manifests so characteristically that further efforts to localize the lesion are not needed, as with patients who have cluster headaches. Hydroxyamphetamine releases norepinephrine from storage in the sympathetic nerve endings. When the lesion is postganglionic, the third order nerve is dead and no norepinephrine stores are available for ­release at the iris. When the lesion is complete, the pupil does not dilate at all. However, the dying neurons and their stores of ­norepinephrine may last for almost 1 week from the onset of damage. Therefore, a hydroxyamphetamine test administered within 1 week of a postganglionic lesion may give a false preganglionic localization if some of the norepinephrine stores remain. When Horner’s syndrome is caused by preganglionic or central lesions, the pupils dilate normally, because the postganglionic third order neuron and its stores of norepinephrine, although disconnected, are still intact; when the lesion is in the preganglionic neuron, the involved pupil often becomes larger than the normal pupil after hydroxyamphetamine administration, apparently because of “decentralization supersensitivity.”

Interpretation of the hydroxyamphetamine test

The test is simple – the pupil diameters are measured before and 40–60 minutes after hydroxyamphetamine drops have been placed in both eyes. The change in anisocoria in room light is noted. If the affected pupil – the smaller one – dilates less than the normal pupil, an increase in anisocoria occurs, and the lesion is in the postganglionic neuron. If the smaller pupil now dilates so much that it becomes the larger pupil, the lesion is preganglionic and the postganglionic neuron is intact. The examiner must wait at least 2 days after cocaine has been used before the administration of hydroxyamphetamine; cocaine seems to block its effectiveness. In about one half of ambulatory patients with Horner’s syndrome, the location of the lesion is identified satisfactorily by the nature and location of the injury or disease. The other half of these patients offer no clues as to the location of the damage – a pharmacological localization of the lesion in these patients can be most helpful. The author has attempted to apply the results of hydroxyamphetamine mydriasis in those patients with a known lesion location to those in whom the lesion location is unknown. It appears that postganglionic lesions (along the carotid artery) can be separated from the nonpostganglionic lesions (in the brainstem, spinal cord, upper lung, and lower neck) with a degree of certainty that varies with the amount of anisocoria induced when the drops are placed in both eyes.35

Congenital Horner’s syndrome

When a child is observed to have a unilateral ptosis and miosis, the first question is to ascertain whether Horner’s syndrome is present. The ptosis of Horner’s syndrome is moderate, never complete. Sometimes the elevation of the lower lid is helpful. A child who has congenital Horner’s syndrome and naturally curly hair has, on the affected side of the head, hair that seems limp and lank. The shape of the hair follicles apparently depends on intact sympathetic innervation, as does the iris pigment. A child who has blond, straight hair and very pale, blue eyes does not have any visible hair straightness or iris heterochromia. A weaker solution of cocaine (two drops of cocaine 2% in each eye) is used in children. The most telling symptom is the hemifacial flush (blanch on the affected side) that occurs with nursing or crying. Generally, the affected side is pale. In an air-conditioned office, it may be hard to decide whether decreased sweating on the affected side is present. A cycloplegic refraction sometimes produces an atropinic flush ­everywhere except on the affected face and forehead and, thus, provides additional evidence toward diagnosis because of lack of sympathetic innervation to the skin vasculature. In infants, hydroxyamphetamine drops do not help to localize the lesion, because orthograde trans-synaptic dysgenesis takes place at the superior cervical ganglion after early interruption of the preganglionic oculosympathetic neuron. Fewer postganglionic neurons result, even

though no direct postganglionic injury has occurred, which produces weak mydriasis and ambiguous results in children.36 A patient with Horner’s syndrome clearly acquired in infancy must be evaluated for neuroblastoma – a treatable tumor (Fig. 9-19-7).

9.19 The Pupils

Pupillary Inequality that Increases with Light

For a patient who has pupillary inequality that increases with light, several problems must be addressed (Fig. 9-19-8).

Slit-lamp examination of the iris

Trauma to the globe usually results in a torn sphincter and an iris border that transilluminates at the slit lamp. The pupil often is not round and other evidence of ocular injury may be present. Naturally, such a pupil does not constrict well to light. The residual reaction often is segmental in a traumatic iridoplegia. An atrophic sphincter caused by previous herpes zoster iritis also may reveal transillumination defects, as seen with the slit lamp, that arise from previous ischemic insults to the iris. If, however, the iris looks normal, further investigation is required, as outlined below.

Residual light reaction

If no residual light reaction is present, the possibility of pharmacological mydriasis must be explored.37 However, a completely blocked light reaction sometimes may occur when the sphincter is denervated by either a preganglionic lesion (third cranial nerve palsy) or a postganglionic lesion (acute, complete tonic pupil), in acute angle closure (iris ischemia), or with an intraocular iron foreign body (iron mydriasis). If the dilated pupil still has some response to light, the dilatation may result from partial denervation of the sphincter, incomplete atropinization, or adrenergic mydriasis. When the light reaction is poor because the dilator muscle is in spasm (as a consequence of adrenergic mydriatics such as phenylephrine), then the pupil is very large, the conjunctiva is blanched, and the lid is retracted. In such cases, any decrease in the amplitude of accommodation is minor and is the result of spherical aberration and a shallow depth of field – both optical results of the dilated pupil, or from the small inhibitory effect of sympathetic receptor activation or accommodation.

Segmental paralysis of the iris sphincter

When some residual light reaction occurs, the iris sphincter is examined for sector palsy using the slit lamp. When the dilator is in a druginduced adrenergic spasm or when the cholinergic receptors in the iris sphincter are blocked by an atropine-like drug, the entire sphincter muscle (all 360°) is less effective. This does not happen when postganglionic parasympathetic nerve fibers have been interrupted. In patients with Adie’s syndrome, all pupils that have a residual light reaction (about 90%) show segmental contractions of the sphincter (so-called vermiform movements). Thus, a pupil that has a weak light reaction and no segmental palsy usually indicates a drug-induced mydriasis, but signs of a third cranial nerve paresis (preganglionic parasympathetic nerve) must also be sought.

Pupillary supersensitivity to cholinergic drugs

If weak pilocarpine (about 0.1%) or weak methacholine (2.5%) is applied to both eyes (with both corneas healthy and untouched), and the affected (dilated) pupil constricts more than the normal pupil to become the smaller pupil, that iris sphincter is denervated. It seems likely that with a postganglionic denervation (ciliary ganglion to the eye), the sphincter will show a little more supersensitivity than in the preganglionic case (third cranial nerve palsy); however, the differences are not great. Cholinergic supersensitivity of the iris sphincter is considered now to be only a weak sign of Adie’s syndrome. As the iris sphincter is reinnervated by cholinergic accommodative fibers and becomes smaller over time, supersensitivity can be lost.31 Ptosis or diplopia must be re-evaluated, because it is very rare for an ambulatory patient to have an isolated sphincter palsy from damage to the intracranial third nerve. If the normal pupil constricts a little and the dilated pupil not at all, the mydriasis may result from a local dose of an anticholinergic drug such as atropine. A stronger concentration of pilocarpine is needed to establish this.

Pupillary response to a miotic dose of pilocarpine

If, on application of pilocarpine 1% in each eye, the affected pupil ­reacts little or not at all and the unaffected pupil constricts normally, the ­pupil was not dilated because of innervation problems but because

Fig. 9-19-7  Horner’s syndrome clearly acquired in infancy must be evaluated for neuroblastoma, a treatable tumor. This baby, with a right ptosis and miosis, developed a flush during cycloplegia that made the vasomotor abnormality very clear – the Horner’s side remained pale. The baby had no sign of Horner’s syndrome during her first 8 months, but at 16 months Horner’s syndrome is obvious (ptosis, miosis, and upside-down ptosis). Because the syndrome was acquired, a chest radiograph was ordered; it showed a mass in the pulmonary apex. Magnetic resonance imaging confirmed the lesion. Surgery showed it to be a neuroblastoma.

of a ­ problem in the sphincter muscle, itself. Non-neuronal causes of mydriasis are: l Anticholinergic mydriasis (e.g., scopolamine (hyoscine), cyclopentolate, atropine). l Traumatic iridoplegia (sphincter rupture, pigment dispersion, angle recession). l Angle-closure glaucoma (ischemia of the iris sphincter). l Fixed pupil after anterior segment surgery. l Bound down iris (synechia) after iritis. The cause for complete loss of function of the iris muscles after ­anterior segment surgery is unknown. Sometimes an excessive rise in intraocular pressure during or after surgery can cause ischemic damage to the iris sphincter.

Tonic Pupil of Adie’s Syndrome

Young adults (more women than men) may discover that one ­ pupil is large or that they cannot focus up close with one eye. Slit-lamp ­examination usually shows segmental denervation of the iris sphincter. Within the first week, supersensitivity to cholinergic substances may be demonstrated. After about 2 months, nerve regrowth is active and fibers originally bound for the ciliary muscle (they outnumber the sphincter fibers by 30:1) start to arrive (aberrantly) at the iris sphincter, which produces the characteristic light–near dissociation of Adie’s syndrome. Eventually, the affected pupil becomes the smaller of the two pupils, especially in dim light, because of the aberrant reinnervation by accommodative fibers (“little old Adie’s pupil”). The segmental palsy of the iris sphincter is seen particularly well using infrared video recording of transillumination of the iris.38

Fixed, Dilated Pupil

When a pupil is dilated by an atropinic medication, the resultant condition can be differentiated with confidence from an innervational palsy by its tendency to resist the miotic effects of cholinergic drops such as pilocarpine. Pilocarpine 1% is a sufficient miotic dose for any eye, but a sphincter with all its cholinergic receptors blocked by atropine or tropicamide does not constrict with pilocarpine 1%. If the anticholinergic drug starts to wear off such that a small light reaction begins to return, pilocarpine 1% may only cause minimal constriction compared with the normal pupil.

Third Cranial Nerve Palsy

An old clinical rule of thumb states that if the pupillary light reaction is spared, the third cranial nerve palsy probably does not result from compression or injury, but more likely from small-vessel disease such as might be seen in diabetes. The rule still applies, but a very small number of ­pupil-sparing third cranial nerve palsies arise from midbrain infarcts.

Aberrant Regeneration of the Third Cranial Nerve

The third cranial nerve carries instructions to several different muscles, so when the nerve is injured and the fibers regrow, they may grow into the wrong place. This most commonly occurs when the glial scaffolding, which normally segregates nerve bundles, is disrupted by trauma or external compression by a tumor. For example, the eye may inappropriately turn in when the patient is trying to look down, or the pupil may inappropriately constrict with depression, adduction, or supraduction of the globe.

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9

DIAGNOSIS OF PUPILLARY ABNORMALITIES IN WHICH ANISOCORIA INCREASES IN BRIGHT LIGHT

NEURO-OPHTHALMOLOGY

Patient has anisocoria Is the inequality greatest in bright light? Go to Figure 9-19-6

More anisocoria in dim light

YES

NO

Is there any consistent iris sphincter movement in response to the light?

Is there partial segmental paralysis of the iris sphincter? YES

Adrenergic? Partial atropinic? Partial third nerve?

NO

YES

Suspect damage to the innervation of the intraocular muscles

Suspect pharmacologic mydriasis

Use clinical observation or Polaroid flash photographs to decide whether pupil reacts more to a near stimulus than it does to light

Could still be acute Adie’s syndrome or a third nerve palsy

NO

Is the iris structurally normal? YES

NO

Could still be acute Adie’s syndrome. Third nerve palsies seldom present with an isolated weakness of the iris sphincter, especially not in an ambulatory patient

Is there a light–near dissociation (LND)? YES

Examine the iris using the slit lamp, and a broad, tangential beam. Switch the light off and on

NO

The light–near dissociation suggests a denervated and reinnervated sphincter; most likely Adie’s syndrome or an old third nerve injury with aberrant reinnervation. A midbrain light–near dissociation is usually bilateral Use eye drops to test for cholinergic supersensitivity Is the sphincter supersensitive to weak pilocarpine drops (0.1%), so that the pupil with a weak light reaction becomes the smaller pupil in darkness? YES

Use eye drops to test for anticholinergic blockade

NO

True of postganglionic denervation and, perhaps to a lesser extent, also of preganglionic damage

Does the pupil constrict to a miotic dose of pilocarpine (1.0%)? YES

Adie’s syndrome tonic pupil 90% of Adie’s syndrome pupils have some remaining light reaction. Residual light reaction is segmental. 90% of Adie’s syndrome patients have abnormal deep tendon reflexes. Light–near dissociation is the rule

NO

Third nerve palsy Many partial third nerve palsies Atropinic mydriasis The entire with aberrant reinnervation show a segmental palsy sphincter is palsied (over 360). of the iris sphincter (due to diabetic neuropathy). Pilocarpine miosis is blocked An isolated dilated pupil, in office practice, does not usually reflect an early third nerve palsy

Iris damage Any history of trauma? Tears of the pupillary margin? Pigment granules on the stromal surface? Transillumination of the iris? Angle recession? Choroidal rupture? Accommodative paresis? Angle-closure glaucoma? Iron mydriasis (siderosis: nerve damage)? Urrets–Zavalla mydriasis (iris sphincter damage following intra-ocular surgery – cause Adrenergic mydriasis The pupil is unusually large, the palpebral fissure is widened, and the conjunctiva may be blanched. Accommodation is not impaired. Very bright light can overcome the mydriasis

Fig. 9-19-8  Diagnosis of pupillary abnormalities in which anisocoria increases in bright light. Initial pupillary inequality greater in bright light than in the dark indicates that the sphincter of the large pupil is weak or that a parasympathetic lesion is present on that side.

LIGHT–NEAR DISSOCIATION: EVALUATION OF THE NEAR RESPONSE The pupillary contractile response to a near effort is observed as a standard part of the pupil evaluation. If the light reaction seems a little weak, the examiner must check whether the pupils constrict better to near than to light. If they do, this is called light–near dissociation, the causes of which are summarized in Table 9-19-2.

How to Test for a Pupillary Near Response

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The pupillary near reaction usually is weak when tested in dim light or in the dark. The patient needs a clear view of an object before it can be brought into focus. The examiner must not induce a near response at the slit lamp unless magnification is required to view segmental contractions of the iris sphincter; the room usually is dark and too much equipment is close to the patient’s face in this situation.

The near response is examined in moderate room light, such that the patient’s pupils are midsize and the near object is clearly visible. The patient is given an accommodative target to view – something with fine detail on it. Sometimes a better response is obtained if some other sensory input is added to the stimulus, such as a ticking watch or clicking fingernails; or something proprioceptive, for example, the patient’s own thumbnail can be brought into the patient’s view (perhaps, in the case of a child, with a little face drawn on it). Convergence indicates how hard the patient is trying. The near response, although it may be triggered by blurred or disparate imagery, has a large volitional component, and the patient may need encouragement. If, for some reason, the patient has not made a near effort recently (for example, because stereopsis is not achieved at near), then a few practice runs may be needed. Often, on the third or fourth try, a good near response is obtained. Sometimes the near effort must be generated for 5 to 10 seconds to see a good near reaction of the pupil.

   TABLE 9-19-2  CAUSES OF LIGHT−NEAR DISSOCIATION OF THE PUPIL Location

Mechanism

Severe loss of afferent light input to both eyes

Anterior visual pathway (retina, optic nerves, chiasm)

Damage to the retina   or optic nerve   pathways

Loss of pretectal light input to Edinger-Westphal nucleus

Tectum of the midbrain

Infectious (Argyl   Robertson pupils) or   compression (pinealoma)

Adie’s syndrome

Iris sphincter

Aberrant reinnervation of sphincter by accommodative neurons

Third cranial nerve aberrant reinnervation

Iris sphincter

Aberrant reinnervation   of sphincter by   accommodative neurons or medial rectus   neurons

   TABLE 9-19-3  CAUSES OF POOR PUPIL DILATATION IN DARKNESS Cause

Location

Mechanism

Past inflammation   or surgical trauma

Posterior iris surface   or sphincter

Scarring or synechiae of the iris because of past iritis

Acute trauma

Sphincter

Prostaglandin release causes sphincter spasm

Adie’s syndrome tonic pupil  Third nerve aberrant reinnervation

Sphincter

Aberrant regeneration of iris sphincter by accommodative or extraocular motor neurons that are not inhibited in darkness

Pharmacologic miosis

Iris sphincter

Cholinergic influence

Unilateral episodic spasm of miosis

Postganglionic   parasympathetic   neuron

Uninhibited episodic activation of postganglionic neurons

Congential miosis   (bilateral)

Sphincter

Developmental   abnormality

Fatigue, sleepiness

Edinger-Westphal nucleus

Loss of inhibition at midbrain from reticular activating formation

Lymphoma, inflammation, infection

Periaqueductal gray matter

Interruption of inhibitory fibers to the Edinger-  Westphal nucleus

Central-acting drugs

Reticular activating   formation, midbrain

Narcotics, general   anesthetics

Old age (bilateral miosis)

Reticular activating   formation, midbrain

Loss of inhibition at midbrain from reticular activating formation

Oculosympathetic defect

Sympathetic neuron   interruption

Horner’s syndrome

A lack of near response usually indicates that the patient (or the doctor) is not trying hard enough, or not enough time is given at the peak of convergence for the pupil to constrict maximally. A patient who is completely blind and has no pupillary reaction to light sometimes provides a good near response when asked to “cross your eyes like you did when you were a child.” If a patient cannot produce a near response, the lid closure reflex is tried: the patient faces the examiner with eyes squeezed shut while the examiner tries, with both hands, to hold one of the patient’s eyes open. This often produces a surprisingly strong near response, and is called the eye closure pupil reaction.

Recognition of Light–Near Dissociation

Sometimes it is difficult to establish whether the near response is clearly greater than the light reaction. In such cases, when the examiner faces the patient with pocket light in hand, three levels of light are used:

l

9.19 The Pupils

Cause

 arkness, with a light shining tangential on the pupils from below. D Room light. l Room light with an additional bright light shone in the eyes. With the patient looking in the distance, the bright light is shone in the eye for 1–2 seconds 3 or 4 times, which indicates how small the pupils may become using a light stimulus only. The near response must not be judged by the addition of a near stimulus to a bright light stimulus, which almost always produces an apparent light–near dissociation, because the near stimulus inevitably adds something to the light stimulus. A real light–near dissociation is present only if the near response (tested in moderate light) exceeds the best constriction that bright light can produce. l

POOR PUPIL DILATATION When one or both pupils stay small and miotic, even in darkness, a number of factors may be responsible (Table 9-19-3). To better understand the different mechanisms possible it is important to understand the normal process in darkness that allows the pupil to dilate. When a light stimulus is terminated, two mechanisms cause the pupil to dilate. The greater part of pupil dilatation arises from inhibition to the Edinger-Westphal nucleus in the midbrain, which reduces the firing of the preganglionic parasympathetic neurons in the Edinger-Westphal nucleus and results in relaxation of the iris sphincter. Within a few seconds, sympathetic nerve firing increases, which augments the pupil dilatation by active contraction of the dilator muscle. The combined inhibition of the iris sphincter and stimulation of the iris dilator is a carefully integrated neuronal ­reflex. Therefore, inability of the pupil to dilate in darkness may occur because of a sympathetic nerve palsy, but also from mechanical limitations of the pupil (scarring), pharmacological miosis, aberrant reinnervation of cholinergic neurons to the iris sphincter that are not normally inhibited in darkness (accommodative or extraocular motor neurons), or inhibitory input signal not received by the Edinger-Westphal nucleus.

RECENT DISCOVERIES IN THE RETINAL ORIGIN OF THE PUPIL LIGHT REFLEX – THE ­MELAnOPSIN-CONTAINING RETINAL GANGLION CELL New evidence in the last few years has shown that the rod and cone input to the pupil light reflex is mediated by a special class of retinal ganglion cells containing the primitive visual pigment melanopsin found in the retina of lower animals.39–50 Besides being activated by rod and cone input causing a transient pupil response, the melanopsin retinal ganglion cell is itself also directly sensitive to light, providing a sustained steady-state pupil constriction to light. This intrinsic, direct activation pathway of the melanopsin-containing retinal ganglion cells causes the cell to discharge in a sustained way and is directly proportional to steady-state light input, similar to a DC light meter, which does not show classical light adaptation properties. In genetically altered mice that completely lack functional rods and cones, it was discovered that a rather robust pupil light reflex was still present. This unexpected finding was followed by a series of studies to identify what retinal element could be contributing to the pupil light reflex in the absence of rod and cone input. Through clever labeling experiments, a specific ganglion cell was identified containing melanopsin, which was itself photosensitive, with a broad spectral peak centering on about 490 nm. These melanopsin ganglion cells have been found to project both to the suprachiasmatic nucleus in the hypothalamus and also to the pretectal nucleus (the site of the first midbrain interneuron synapse for the pupil light reflex pathway). Elegant electrophysiologic recordings coupled with the study of response properties of these ganglion cells have revealed that the ­ melanopsin­containing retinal ganglion cells provide the midbrain pathway for the pupil light reflex and also provide light sensing information for the diurnal regulating areas of the hypothalamus that modulate the circadian rhythm. These melanopsin ganglion cells also receive rod and cone input to the pupil light reflex, but are also capable of transduction of light directly, without photoreceptor input, and may be responsible for providing more steady-state light input information to the brain. This helps to explain why some patients blind from photoreceptor loss still exhibit both a pupil light reaction to bright blue light and also maintain a circadian rhythm, while patients blind from optic nerve lesions (loss of melanopsin ganglion cell input) are often lacking a normal circadian rhythm.

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REFERENCES   1. Lowenstein O, Kawabata H, Loewenfeld I. The pupil as indicator of retinal activity. Am J Ophthalmol. 1964;57:569–96.   2. Loewenfeld IE. The pupil: anatomy, physiology, and clinical applications. Ames, Iowa: Iowa State University Press; Detroit: Wayne State University Press; 1993.   3. Levatin P. Pupillary escape in disease of the retina or optic nerve. Arch Ophthalmol. 1959;62:768–79.   4. Thompson HS, Corbett JJ, Cox TA. How to measure the relative afferent pupillary defect. Surv Ophthalmol. 1981;26:39–42.   5. Thompson HS, Corbett JJ. Asymmetry of pupillomotor input. Eye. 1991;5:36–9.   6. Cox TA, Thompson HS, Hayreh SS, Snyder JE. Visual evoked potential and pupillary signs. A comparison in optic nerve disease. Arch Ophthalmol. 1982;100:1603–7.   7. Thompson HS, Montague P, Cox TA, Corbett JJ. The relationship between visual acuity, pupillary defect,   and visual field loss. Am J Ophthalmol. 1982;93:681–8.   8. Brown RH, Zillis JD, Lynch MG, Sanborn GE. The afferent pupillary defect in asymmetric glaucoma. Arch Ophthalmol. 1987;105:1540–3.   9. Johnson LN, Hill RA, Bartholomew MJ. Correlation of afferent pupillary defect with visual field loss on automated perimetry. Ophthalmology. 1988;95:1649–55. 10. Kardon RH, Haupert C, Thompson HS. The relationship between static perimetry and the relative afferent   pupillary defect. Am J Ophthalmol. 1993;115:351–6. 11. Kawasaki A, Moore P, Kardon RH. Variability of the relative afferent pupillary defect. Am J Ophthalmol. 1995;120:622–33. 12. Kawasaki A, Moore P, Kardon RH. Long-term fluctuation of relative afferent pupillary defect in subjects with normal visual function. Am J Ophthalmol. 1996;122:875–82. 13. Bell RA, Waggoner PM, Boyd WM, et al. Clinical grading of relative afferent pupillary defects. Arch Ophthalmol. 1993;111:938–42. 14. Haynes WL, Alward WLM, McKinney K, et al. Quantitation of iris transillumination defects in eyes of patients with pigmentary glaucoma. J Glaucoma. 1994;3:1106–13. 15. Fison PN, Garlick DJ, Smith SE. Assessment of unilateral afferent pupillary defects by pupillography. Br J Ophthalmol. 1979;63:195–9. 16. Cox TA. Pupillography of a relative afferent pupillary defect. Am J Ophthalmol. 1986;101:320–4. 17. Cox TA. Pupillographic characteristics of simulated relative afferent pupillary defects. Invest Ophthalmol Vis Sci. 1989;30:1127–31.

18. Young RSL, Han B, Wu P. Transient and sustained components of the pupillary responses evoked by luminance and color. Vision Res. 1993;33:437–46. 19. Young RSL, Kennish J. Transient and sustained components of the pupil response evoked by achromatic spatial patterns. Vision Res. 1993;33:2239–52. 20. Barbur JL, Harlow AJ, Sahraie A. Pupillary responses to stimulus structure, colour, and movement. Ophthalmic Physiol Opt. 1992;12:137–41. 21. Slooter JH, van Noren D. Visual acuity measured   with pupil responses to checkerboard stimuli. Invest Ophthalmol Vis Sci. 1980;19:105–8. 22. Ukai K. Spatial pattern as a stimulus to the pupillary system. J Opt Soc Am A. 1985;2:1094–100. 23. Barbur JL, Thomson WD. Pupil response as an objective measure of visual acuity. Ophthalmic Physiol Opt. 1987;7:425–9. 24. Cocker KD, Moseley MJ. Visual acuity and the pupil   grating response. Clin Vision Sci. 1992;7:143–6. 25. Kardon RH, Kirkali PA, Thompson HS. Automated pupil perimetry. Pupil field mapping in patients and normal subjects. Ophthalmology. 1991;98:485–96. 26. Kardon RH. Pupil perimetry. Curr Opin Ophthalmol. 1992;3:565–70. 27. Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine test in the diagnosis of Horner’s syndrome. Arch Ophthalmol. 1990;108:384–7. 28. Kardon RH. Are we ready to replace cocaine with apraclonidine in the pharmacologic diagnosis of Horner syndrome? J Neuro-ophthalmology. 2005;25:69–70. 29. Freedman KA, Brown SM. J Neuro-ophthalmology. 2005;25:83–5. 30. Morales J, Brown S, Abdul-Rahim AS, Crosson C.   Ocular effects of apraclonidine in Horner’s syndrome. Arch Ophthalmol. 2000;118:951–4. 31. Brown SM, Aouchiche R, Freedman KA. The utility   of 0.5% apraclonidine in the diagnosis of Horner   syndrome. Arch Ophthalmol. 2003;121:1201–3. 32. Chen PL, Chen JT, Lu DW, Chen YC, Hsiao CH. Comparing efficacies of 0.5% apraclonidine with 4% cocaine in the diagnosis of Horner syndrome in pediatric patients.   J Ocul Pharmacol Ther. 2006;22:182–7. 33. Koc F, Kavuncu S, Kansu T, Acaroglu G, Firat E. The sensitivity and specificity of 0.5% apraclonidine in the diagnosis of oculosympathetic paresis. Br J Ophthalmol. 2005;89:1442–4. 34. Gmunder HP, Girke W. Clonidin zur Diagnostik beim Horner Syndrom. Nervenarzt. 1989;60:299–301. 35. Cremer SA, Thompson HS, Digre KB, Kardon RH.   Hydroxyamphetamine mydriasis in Horner’s syndrome. Am J Ophthalmol. 1990;110:71–6.

36. Weinstein JM, Zweifel TJ, Thompson HS. Congenital Horner’s syndrome. Arch Ophthalmol. 1980;98:1074–8. 37. Thompson HS, Newsome DA, Loewenfeld IE. The fixed dilated pupil: sudden iridoplegia or mydriatic drops? A simple diagnostic test. Arch Ophthalmol. 1971;86:21–7. 38. Kardon RH, Corbett JJ, Thompson HS. Segmental denervation and reinnervation of the iris sphincter as shown by infrared videographic transillumination. Ophthalmology. 1998;105:313–21. 39. Hannibal J, Hindersson P, Knudson SM, Georg B, Fahrenkrug J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci. 2002;22. RC191. 40. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. 2002;295:1065–70. 41. Fu Y, Liao HW, Do MTH, Yau KW. Non-image-forming ocular photoreception in vertebrates. Curr Opin   Neurobiol. 2005;15:415–22. 42. Berson DM. Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci. 2003;26:314–20. 43. Lucas RJ, Freedman MS, Lupi D, et al. Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav Brain Res. 2001;125:97–102. 44. Gamlin PDR, McDougal DH, Pokorny J, et al. Human and macaque pupil responses driven by melanopsin-  containing retinal ganglion cells. Vision Res. 2007;47:946–54. 45. Dacey DM, Liao HW, Peterson BB, et al. Melanopsinexpressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature. 2005;433:749–54. 46. Van Gelder RN. Non-visual ocular photoreception.   Ophthalmic Genetics. 2001; 195–205. 47. Peirson S, Foster RG. Melanopsin: another way of   signaling light. Neuron. 2006;49:331–9. 48. Gooley JJ, Lu J, Fischer D, Saper CB. A broad role for melanopsin in nonvisual photoreception. J Neurosci. 2003;23:7093–106. 49. Provencio I, Rollag MD, Castrucci AM. Photoreceptive net in the mammalian retina. Nature. 2002;415:493. 50. Hattar S, Lucas RJ, Mrosovsky N, et al. Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature. 2003;  424:76–81.

PART 9 NEURO-OPHTHALMOLOGY SECTION 3 The Efferent Visual System

9.20

Presbyopia and Loss of Accommodation Sean P. Donahue

Definition:  Accommodation is the ability to increase the refractive

power of the eye’s optical system. Loss of accommodation may occur   as a result of presbyopia, the age-associated decrease in elasticity of the natural lens, or from other less common causes.

Key feature n

Blurred vision at near.

Associated features n n n

Advanced age. Drug use (cholinergics, botulism). Other rare causes.

accommodation) is always associated with mydriasis (pupil dilatation). Five muscarinic antagonists are commonly used in ophthalmology (Table 9-20-1). Tropicamide (Mydriacyl) has a very short half-life and should not be used to determine the cycloplegic refraction. Cyclopentolate has sufficient half-life to be the standard in pediatric ophthalmology. Homatropine, scopolamine (hyoscine), and atropine are generally used for therapeutic purposes. Phenylephrine (adrenaline), a sympathomimetic, causes mydriasis but has no significant effect on accommodation. Accommodative ability decreases with age. Although a great deal of variability occurs in the normal levels of accommodation, children have remarkable accommodative capabilities and presbyopia is rare prior to age 35. Normal valves for accommodative amplitudes are illustrated in Table 9-20-2.4

OCULAR MANIFESTATIONS Because accommodation is part of the near reflex, it is linked closely with convergence and pupillary miosis. Clinically, it is very difficult to separate these components, and the presence of pupillary miosis is a good indicator of accommodative effort.

INTRODUCTION Accommodation is the ability to increase the refractive power of the optical system of the eye. It occurs to produce a clearer image of near objects. To bring about accommodation, the ciliary body contracts, the lens zonules relax, and the crystalline lens assumes a more spherical shape, which increases its refractive power. Presbyopia is the most common disease to affect accommodation and is caused by an age-associated loss of elasticity of the lens and lens capsule. Disorders other than presbyopia that affect accommodation are quite rare. Regardless of cause, symptoms of blurred vision at near and of eye strain with prolonged near work result.1

EPIDEMIOLOGY AND PATHOGENESIS The neural pathway for accommodation probably begins in the midbrain. Attempts at accommodation are associated with convergence and pupillary miosis (the “near triad”). These areas receive input from the cerebral cortex and pretectum; complex pathways project symmetrically to the portion of the third nerve nucleus responsible for accommodation, probably in the caudal segment of the Edinger-Westphal parasympathetic nucleus.2 These fibers then travel from the third nerve nucleus to the ciliary ganglion, where they synapse with postganglionic parasympathetic fibers destined for the ciliary body and iris sphincter. They reach the intrinsic muscles of the eye via the short ciliary nerves. It is possible that a direct (nonsynapsing) pathway from the midbrain to the ciliary body also exists. Several experiments have shown that the ciliary body also receives sympathetic input. This is evidenced clinically by the increased accommodative amplitude seen in the affected eye of patients with Horner’s syndrome. However, the parasympathetic control is of much greater clinical importance.3 Because accommodation is mediated almost exclusively via parasympathetic pathways, it is antagonized best with muscarinic blockers. For the muscarinic antagonists used clinically, cycloplegia (paralysis of

 TABLE 9-20-1  STANDARD CYCLOPLEGIC AGENTS

Agent

Available Concentrations (%)

Maximum Effect for Cycloplegia (minutes)

Duration of Cycloplegia (hours)

Tropicamide

1, 2

15

4–6

Cyclopentolate

0.5, 1, 5

20–45

24

Homatropine

2, 5

45–60

72

Scopolamine

0.25

30–60

168 (7 days)

Atropine

0.25, 0.5, 1

120

360 (15 days)

 TABLE 9-20-2  ACCOMMODATIVE AMPLITUDES AT GIVEN AGES

Age (years)

Amplitude of Accommodation (D)

Near Point When Emmetropic (cm)

20

11

9.1

32

8

12.5

40

6

16.7

44

4

25.0

48

3

33.3

56

2

50.0

64

1

100.0

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Disorders of accommodation typically present with blurred vision at near. Patients who have latent hyperopia must use a portion of their accommodative reserve to focus at distance, and may present with premature presbyopia. Mild myopia, in contrast, may delay symptoms of presbyopia. Most disorders of accommodation are bilateral. Thus, if the patient is corrected to emmetropia, the amount of near blurring should be similar in each eye. Disorders that present as a unilateral loss of accommodation localize to the infranuclear third nerve, the ciliary ganglion (Adie’s syndrome), or the effector organ (ciliary body) itself (Horner’s syndrome or pharmacological cycloplegia).

DIAGNOSIS Accommodation can be measured by determining the accommodative amplitude or the accommodative range.4 In all tests, it is important that refractive error be corrected properly to put the far point at infinity and render the ocular system emmetropic at distance. Three methods are used to determine monocular accommodative amplitude. The first method involves a small target being brought forward toward the eye until it blurs. This is the near point of accommodation. The reciprocal of the distance at which the target blurs is the accommodative amplitude. A second method uses the Prince rule, a scaled ruler combined with a near add of +3 D, which puts the far point of an emmetrope at 33 cm. The target on the Prince rule is brought forward until it blurs; this distance is then converted into the diopters of accommodative amplitude, taking into account the +3 add. A third test uses a distance target and lenses of increased minus sphere to induce accommodation. More minus sphere is added until the subject can no longer overcome the minus lenses with accommodation. The amount of minus sphere that can be overcome represents the accommodative amplitude. The accommodative range refers to the range of distances that can be viewed clearly by using accommodation. Typically, it is expressed without correction for emmetropia. A +2 hyperope with 4 D of accommodation would have an uncorrected accommodative range from infinity to 50 cm, whereas a −2 myope with a similar accommodative amplitude would have an accommodative range from 50 cm to 17 cm.

DIFFERENTIAL DIAGNOSIS The most common cause of accommodative dysfunction is presbyopia. Symptoms of bilateral, progressive blurred vision at near with eye strain, in a patient of appropriate age, are usually enough to make the diagnosis. When presbyopic symptoms or decreased accommodative amplitudes

are seen in an individual younger than 40 years, the patient is most likely a latent hyperope; a cycloplegic refraction confirms the diagnosis. Accommodative problems also can be caused by lesions anywhere along the neuroanatomical pathway that subserves accommodation.5 These, however, are relatively rare. Trauma to the parasympathetic nuclei in the midbrain, to supranuclear structures, or to the third nerve can produce asthenopic symptoms. Adie’s syndrome is usually associated with decreased accommodation. Pharmacological cycloplegia also produces temporary accommodative dysfunction. A fascinating case of temporary loss of accommodative power associated with eating has been reported.6 Systemic medications can cause decreases in accommodation. These medications often have anticholinergic side effects. Phenothiazines, and antiparkinsonian drugs, such as trihexyphenidyl (benzhexol, Artane), are typical offenders. Whether accommodative dysfunction occurs in otherwise healthy children is a subject of controversy in the optometry and pediatric ophthalmology literature. Some authorities believe that decreased accommodative amplitudes in children are effort related (as evidenced by lack of pupillary constriction to an attempted near target); others believe that such an entity is real and can be treated successfully with orthoptic exercises.7, 8 Increased accommodation is seen rarely. Patients who have acute Horner’s syndrome may notice an increased accommodative range on the affected side. More often, an abnormally proximal near point is caused by miotic agents, such as pilocarpine. Accommodative spasm is a functional disorder with episodic esotropia, diplopia, blurred vision at distance, miosis, and an abnormal near point of accommodation. These patients do well with either reassurance or daily drops of a mild cycloplegic until the symptoms cease.

TREATMENT Treatment of presbyopia involves the use of plus lenses for near work either in a bifocal or as reading glasses. Several methods can be used to determine the proper add. Most problems with reading adds result from overcorrection for the near distance. Correction to emmetropia and the use of trial frames (rather than the phoroptor) to determine the proper add yield the best results.9

COURSE AND OUTCOME Most patients with asthenopic symptoms do well with plus-power spectacles for reading. Plus-power requirements increase until patients reach their early 60s, and then stabilize.

REFERENCES 1.  Weale R. Presbyopia toward the end of the 20th century. Surv Ophthalmol. 1989;34:15–30. 2.  Bender MB, Weinstein EA. Functional representation in the oculomotor and trochlear nuclei. Arch Neurol Psychiatry. 1983;49:98–106. 3.  Miller NR, ed. Walsh and Hoyt’s clinical neuro-  ophthalmology, vol. 2, 4th ed, Baltimore: Williams & Wilkins; 1985:442–57.

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4.  Milder B, Rubin ML. Accommodation. In: The fine art of prescribing glasses without making a spectacle of yourself, Gainesville: Triad Scientific Publishers; 1978. :18–41. 5.  In: Miller NR, ed. Walsh and Hoyt’s clinical neuro-  ophthalmology, vol. 2, 4th ed, Baltimore: Williams & Wilkins; 1985:469–556. 6.  Hudson HL, Rismondo V, Sadun AA. Prandial presbyopia: the muffin man. Br J Ophthalmol. 1991;75:707–9.

7.  Slamovitz TL, Glaser JS. The pupil and accommodation. In: Tasman W, Jaeger EA, eds. Duane’s clinical ophthalmology, vol. 2, Philadelphia: Lippincott-Raven; 1995:1–26. 8.  Raskind RH. Problems at the reading distance.   Am J Orthoptics. 1976;26:53–8. 9.  Stein HA. The management of presbyopia with contact lenses: a review. CLAO J. 1990;16:33–8.

PART 9 NEURO-OPHTHALMOLOGY SECTION 4 The Brain

Headache and Facial Pain Joel M. Weinstein

Definition:  Chronic, intermittent, or episodic pain that involves the head, skull, scalp, or face.

Key features n n

 ost headaches fall into specific rubrics (e.g., tension headache, M migraine) that involve fairly common patterns of symptoms. Most headaches do not reflect serious organic disease.

Associated feature n

T hough usually benign, the pain from headaches can be   devastating and interfere with routine activities.

INTRODUCTION Headache and facial pain are among the most common complaints seen in medical practice. From the perspective of the ophthalmologist, the critical tasks are to: l Diagnose correctly and treat painful intraocular and orbital disorders. l Recognize various benign syndromes that cause headache and ­facial pain, including migraines, tension headaches, and cluster headaches. l Identify the minority of patients who have headache caused by ­serious intracranial or systemic pathology. In this chapter a working plan is developed to facilitate the diagnosis of patients in the last two categories. This requires both a knowledge of various nonophthalmological disorders and a new methodology with which to elicit the relevant clinical history.

EPIDEMIOLOGY AND PATHOGENESIS Headache and facial pain are common symptoms of many processes, some of which are not completely understood. They are seen with great frequency in patients of both sexes, of all ages, and from all around the world. Specific forms of headache have their own prevalence, as described later.

OCULAR MANIFESTATIONS By their nature, headache and facial pain are nonspecific symptoms that may be associated with a variety of disorders. In some of these disorders, visual or neurological signs and symptoms may point to a specific diagnosis. These signs and symptoms are discussed under the appropriate diagnostic headache categories.

DIAGNOSIS AND TESTING Headaches and facial pain, more than any other disease category, are diagnosed through a thorough and intelligent history taking. Hence, the focus in this chapter is on how to take a good history.

9.21

The Art and Science of Taking a Headache History

A thorough history is the key to making the correct diagnosis in a headache patient. To elicit the pertinent clinical information, patients are given the opportunity to describe the symptom complex in detail. Some measure of knowledgeable guidance is required, however, to extract the relevant clinical details and to avoid irrelevant minutiae. Some patients who have headache and facial pain enter the medical care system with firm preconceptions about the cause of their pain. For example, many have been told by well-meaning friends or relatives that “sinus headaches” or “eye strain” (e.g., because of ­uncorrected refractive errors) is the source of their discomfort. These misconceptions are reinforced by the over-the-counter market, which strongly promotes analgesic and sympathomimetic preparations for the treatment of “sinus headaches.” However, it rarely is helpful, and often counterproductive, to point out these apparent misconceptions at the outset. The relevant objective facts should be ­elicited in a nonchallenging and supportive manner, and a formulation should be deferred until the end of the examination. It is ­ important to keep these preconceptions in mind, however, ­because they may color the patient’s description of the symptoms; for ­example, the patient may try to relate all headaches to reading and overlook other contributory factors. To sort out the multitude of factors that can contribute to or cause headaches, it is essential to obtain a relevant past medical history, a basic neurological review of systems (Box 9-21-1), and a directed headache history (outlined in the next section and in Box 9-21-2).

Basic Outline of the Headache History

Date of onset, age at onset, and frequency of symptoms

The length of time that a patient has suffered from headaches is the first guidepost in differentiating benign headaches from those that signify a progressi