Mastering Corneal Surgery : Recent Advances and Current Techniques [1 ed.] 9781630910846, 9781617116407

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Editors Amar Agarwal, MS, FRCS, FRCOphth Dr. Agarwal's Eye Hospital and Eye Research Centre Chennai, India

Thomas John, MD Clinical Associate Professor Department of Ophthalmology Loyola University at Chicago Maywood, Illinois

www.Healio.com/books

Copyright © 2015 by SLACK Incorporated All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher, except for brief quotations embodied in critical articles and reviews. The procedures and practices described in this publication should be implemented in a manner consistent with the professional standards set for the circumstances that apply in each specific situation. Every effort has been made to confirm the accuracy of the information presented and to correctly relate generally accepted practices. The authors, editors, and publisher cannot accept responsibility for errors or exclusions or for the outcome of the material presented herein. There is no expressed or implied warranty of this book or information imparted by it. Care has been taken to ensure that drug selection and dosages are in accordance with currently accepted/recommended practice. Off-label uses of drugs may be discussed. Due to continuing research, changes in government policy and regulations, and various effects of drug reactions and interactions, it is recommended that the reader carefully review all materials and literature provided for each drug, especially those that are new or not frequently used. Some drugs or devices in this publication have clearance for use in a restricted research setting by the Food and Drug and Administration or FDA. Each professional should determine the FDA status of any drug or device prior to use in their practice. Any review or mention of specific companies or products is not intended as an endorsement by the author or publisher. SLACK Incorporated uses a review process to evaluate submitted material. Prior to publication, educators or clinicians provide important feedback on the content that we publish. We welcome feedback on this work. Published by:

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Contact SLACK Incorporated for more information about other books in this field or about the availability of our books from distributors outside the United States. Library of Congress Cataloging-in-Publication Data Mastering corneal surgery : recent advances and current techniques / editors, Amar Agarwal, Thomas John. p. ; cm. Includes bibliographical references and index. I. Agarwal, Amar, editor. II. John, Thomas, 1949- editor. [DNLM: 1. Cornea--surgery. WW 220] RE336 617.7’190598--dc23 2014016227 For permission to reprint material in another publication, contact SLACK Incorporated. Authorization to photocopy items for internal, personal, or academic use is granted by SLACK Incorporated provided that the appropriate fee is paid directly to Copyright Clearance Center. Prior to photocopying items, please contact the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923 USA; phone: 978-750-8400; website: www.copyright.com; email: info@ copyright.com Please note that the purchases of this e-book comes with an associated Web site or DVD. If you are interested in receiving a copy, please contact us at [email protected].

Dedication Dedicated to Professor Harminder Singh Dua, MBBS, DO, DO(London), MS, MNAMS, FRCS, FEBO, FRCOphth., FFMLM, FRCP(Ed), MD, PhD; a clinician, scientist, teacher, trainer, mentor, colleague and friend to many. Amar Agarwal, MS, FRCS, FRCOphth To God of all faiths and religions. I give all credit to God, Jesus Christ, without whom I am nobody. To my wife, Annita and my kids Michelle, Andrea, and Olivia for all their loving support. To my parents for their love and guidance. To all the teachers in this world for their immense contribution to society. Thomas John, MD

Contents Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iii Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii About the Editors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .viii Contributing Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .x Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv Foreword by Alan N. Carlson, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi

Section I

Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Chapter 1

Applied Anatomy and Physiology of the Cornea . . . . . . . . . . . . . . . . . . . . . . . 3 Prafulla K. Maharana, MD and Namrata Sharma, MD

Chapter 2

Penetrating Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Thomas John, MD

Chapter 3

Automated Lamellar Therapeutic Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . 33 Namrata Sharma, MD and Prafulla K. Maharana, MD

Chapter 4

Deep Anterior Lamellar Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Laura Vickers, MD and Terry Kim, MD

Chapter 5

Descemet’s Stripping Automated Endothelial Keratoplasty . . . . . . . . . . . . . . 53 Ian Gorovoy, MD and Bennie H. Jeng, MD, MS

Chapter 6

Ultra-Thin Grafts for Descemet’s Stripping Automated Endothelial Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Vincenzo Scorcia, MD; Elena Albè, MD; and Massimo Busin, MD

Chapter 7

Descemet’s Membrane Endothelial Keratoplasty . . . . . . . . . . . . . . . . . . . . . . 73 Yuri McKee, MD and Francis W. Price Jr, MD

Chapter 8

Endoilluminator-Assisted Descemet’s Membrane Endothelial Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Soosan Jacob, MS, FRCS, DNB, MNAMS and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 9

Corneal Surgery and the Glued Intraocular Lens Technique . . . . . . . . . . . . . 89 Priya Narang, MS and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 10

Pre-Descemet’s Endothelial Keratoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Ashvin Agarwal, MS; Dhivya Ashok Kumar, MD; Priya Narang, MS; Harminder S. Dua, MS, FRCOphth, FRCS, FEBO, PhD; and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 11

Corneal Graft Rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Saima M. Qureshi, MD and Robert A. Copeland Jr, MD

Chapter 12

Femtosecond Laser–Assisted Corneal Graft Surgery . . . . . . . . . . . . . . . . . . 119 Jorge L. Alió, MD, PhD; Felipe Soria, MD; Alfredo Vega-Estrada, MD; and Ahmed Abdou, MD, PhD

Section II

Keratoprosthesis and Ocular Surface Disorders . . . . . . . . . . . . . . . . 129

Chapter 13

Boston Keratoprosthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Bishoy Said, MD and Natalie A. Afshari, MD, FACS

Contents

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Chapter 14

Modified Osteo-Odonto-Keratoprosthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Giancarlo Falcinelli, MD; Paolo Colliardo, MD; Giovanni Falcinelli, MD; Andrea Gabrielli, MD; and Maurizio Taloni, MD

Chapter 15

Foldable Nonpenetrating Artificial Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Yichieh Shiuey, MD and Jose M. Vargas, MD

Chapter 16

Limbal Stem Cell Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Charles L. Thompson, MD and W. Barry Lee, MD

Chapter 17

Amniotic Membrane Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Athiya Agarwal, MD, DO; Soosan Jacob, MS, FRCS, DNB, MNAMS; and Amar Agarwal, MS, FRCS, FRCOphth

Section III

Corneal Surgery Related to Cataract Surgery . . . . . . . . . . . . . . . . . . 195

Chapter 18

Limbal Relaxing Incisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Rachel Kwok, MBBS; Sunil Ganekal, FRCS; and Vishal Jhanji, MD

Chapter 19

Femtosecond Laser Corneal Incisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 H. Burkhard Dick, MD, PhD; Tim Schultz, MD; and Ronald D. Gerste, MD, PhD

Chapter 20

Intrastromal Arcuate Keratotomy to Reduce Corneal Astigmatism With a Femtosecond Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Theresa Rückl, MD; Alexander Bachernegg, MD; Perry S. Binder, MS, MD; and Günther Grabner, MD

Chapter 21

Descemet’s Membrane Detachment: Classification and Management . . . . . 227 Soosan Jacob, MS, FRCS, DNB, MNAMS and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 22

Corneoscleral Pocket Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Richard S. Hoffman, MD; Alejandro Cerda, MD; I. Howard Fine, MD; and Annette Chang Sims, MD

Section IV

Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Chapter 23

Intrastromal Corneal Ring Segments and the Turnaround Technique for Overcoming False Channel Dissection During Intacs Implantation . . . . . . 253 Saraswathy Karnati, MS; Soosan Jacob, MS, FRCS, DNB, MNAMS; and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 24

Corneal Inlays for the Surgical Correction of Presbyopia . . . . . . . . . . . . . . . 263 George O. Waring IV, MD and Fernando Faria-Correia, MD

Chapter 25

Pterygium Surgery: Raising Ocular Surface Surgery to Cosmetic Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 Arun C. Gulani, MD, MS and Aaishwariya Gulani, BS

Chapter 26

Limbal Dermoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Susan Huang, MD; Roy S. Chuck, MD, PhD; and Jimmy K. Lee, MD

Chapter 27

Ocular Surface Squamous Neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Dhivya Ashok Kumar, MD and Amar Agarwal, MS, FRCS, FRCOphth

Chapter 28

Collagen Cross-Linking and Contact Lens–Assisted Collagen Cross-Linking for Corneal Ectatic Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Soosan Jacob, MS, FRCS, DNB, MNAMS; Kaladevi Satish, MS; and Amar Agarwal, MS, FRCS, FRCOphth

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Contents

Chapter 29

Platelet-Rich Plasma in Corneal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Jorge L. Alió, MD, PhD; Francisco Arnalich, PhD; Alejandra E. Rodriguez, MSc; and Alvaro Luque, BSc Financial Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .317

Acknowledgments Nothing in this world moves without HIM, and so also this book was written only by HIM. Amar Agarwal, MS, FRCS, FRCOphth Along with Dr. Amar Agarwal, I acknowledge all those who contributed to this book by taking time from their busy schedules to write their chapter(s). A collective contribution and passion for their surgical pursuits makes this compilation of various surgical techniques valuable for readers all over the world. I wish to acknowledge all my teachers in the Cornea Service, Massachusetts Eye and Ear Infirmary (MEEI), Harvard Medical School, Boston, MA, from whom I have learned immensely both in the clinical and research aspects of “Cornea.” I am thankful to Drs. Kenneth R. Kenyon, Claes H. Dohlman, C. Stephen Foster, Roger F. Steinert, Deborah P. Langston, Mark B. Abelson, Michael D. Wagoner, Jeffrey P. Gilbard, Arthur S. Boruchoff, and Ann M. Bajart for all their dedication and effort in teaching surgical and medical skills relating to cornea and external disease while I was a 2-year Clinical Cornea Fellow at Harvard. I wish to thank Dr. Kenyon, under whose expert guidance I did my research work both at the Schepens Eye Research Institute and at the Massachusetts Institute of Technology (MIT) in Boston. I am fortunate to have worked with my colleagues, cornea fellows and residents at MEEI during my fellowship years, to name a few, Drs. Mitchell C. Gilbert, Eduardo C. Alfonso, Kazuo Tsubota, Scheffer C.G. Tseng, Dimitri T. Azar, John R. Wittpenn, and Oliver D. Schein. Special thanks to Drs. James V. Aquavella and Gullapalli N. Rao for what they taught me in corneal surgery, including epikeratoplasty, refractive surgical procedures, and keratoprosthesis. I am thankful to all my teachers in my formative years during my ophthalmology residency at the University of Pennsylvania. Although not an all inclusive list, I give special thanks to Drs. Ralph C. Eagle, Jr, Myron Yanoff, John H. Rockey, Irving M. Raber, Alexander J. Brucker, David M. Kozart, William C. Frayer, Harold Scheie, and Madeleine Q. Ewing. I am especially thankful to Ralph C. Eagle, Jr, MD, for all his support and professional inspiration, and for teaching me the various pathological basis of disease processes as it relates to the eye. I thank Myron Yanoff for accepting me into the ophthalmology residency program at the University of Pennsylvania. Teachers are one of the greatest assets of any society. I thank all my teachers from kindergarten to completion of my formal education both in the medical and pre-medical years. Without these teachers, I would have been lacking in knowledge and I am indebted to each and every one of my teachers. I wish to acknowledge my wife, Annita, and the kids, Michelle, Andrea and Olivia for putting up with my late night academic work and for all their understanding and loving support. To all my patients, from whom I continue to learn every day. Learning is a continuous and dynamic process that stimulates the mind and makes ophthalmology an even more interesting and challenging field in our life’s journey. Thomas John, MD

About the Editors Amar Agarwal, MS, FRCS, FRCOphth, is the Chairman and Managing Director of Dr. Agarwal’s Group of Eye Hospitals and Eye Research Centre in India, which includes 60 hospitals worldwide; past President of the International Society of Refractive Surgery (ISRS); Secretary General of the Indian Intraocular Implant and Refractive Society (IIRSI); and Professor of Ophthalmology at Ramachandra Medical College in Chennai, India. Dr. Agarwal is the pioneer of phakonit, which is phacoemulsification with needle incision technology. This technique became popularly known as bimanual phaco, microincision cataract surgery (MICS), or microphaco. Dr. Agarwal was the first to remove cataracts through a 0.7-mm tip with the microphakonit technique. He also discovered noanesthesia cataract surgery and FAVIT, a new technique to remove dropped nuclei. Using an aquarium fish pump to increase the fluid into the eye in bimanual phaco and coaxial phaco has helped prevent surge. This formed the basis of various techniques of forced infusion for smallincision cataract surgery. Dr. Agarwal also discovered a new refractive error called aberropia. He was the first to perform a combined surgery of microphakonit (700-μm cataract surgery) with a 25-gauge vitrectomy in the same patient, thus creating the smallest incisions possible for cataract and vitrectomy. He was the first surgeon to implant a new mirror telescopic intraoperative lens (IOL) for patients suffering from age-related macular degeneration. He was the first in the world to implant a glued IOL, in which a posterior-chamber IOL is fixed in an eye without capsules using fibrin glue. He modified the Malyugin ring (MicroSurgical Technology) for small-pupil cataract surgery into the Agarwal modification of the Malyugin ring for miotic pupil cataract surgeries with posterior capsular defects. Dr. Agarwal pioneered the technique of IOL scaffold, in which a 3-piece IOL is injected into an eye between the iris and the nucleus to prevent the nucleus from falling in posterior chamber ruptures. He combined glued IOL and IOL scaffold in cases of posterior chamber rupture where there is no iris or capsular support and termed the technique glued IOL scaffold. Pre-Descemet’s endothelial keratoplasty (PDEK) was also pioneered by Dr. Agarwal. In this procedure, the preDescemet’s layer and Descemet’s membrane with endothelium are transplanted en bloc in patients with a diseased endothelium. The first contact lens–assisted collagen cross-linking procedure, a new technique for crosslinking thin corneas, was performed in Dr. Agarwal’s Eye Hospital, as were the first anteriorsegment transplantation in a 4-month-old child with anterior staphyloma and the first glued endocapsular ring in cases of subluxated cataracts. Endoilluminator–assisted Descemet’s membrane endothelial keratoplasty (E-DMEK) is also performed in Dr. Agarwal’s Eye Hospital. Dr. Agarwal has received many awards for his work in ophthalmology, most significantly the Casebeer Award, Barraquer Award, and Kelman Award. He has performed more than 150 live surgeries at various conferences. His videos have won awards at the film festivals of American Society of Cataract and Refractive Surgery (ASCRS), American Academy of Ophthalmology (AAO), and European Society of Cataract & Refractive Surgeons (ESCRS). He has written more than 60 books, which have been published in various languages, including English, Spanish, and Polish. He trains doctors from all over the world in his center on phaco, bimanual phaco, laserassisted in situ keratomileusis (LASIK), and retina. The website of Dr. Agarwal’s Eye Hospitals is http://www.dragarwal.com.

About the Editors

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Thomas John, MD, was born in India, and lived the majority of his life in the United States. His eye training consisted of an ophthalmology residency at the University of Pennsylvania and a 2-year clinical cornea fellowship at Harvard Medical School, Massachusetts Eye and Ear Infirmary. Dr. John’s academic pinnacle was in Boston, training under Drs. Kenyon, Foster, Steinert, Dohlman, Abelson, Langston, Wagoner, Gilbard, Boruchoff, and Bajart. His corneal research experience stems from Schepens Eye Research Institute and Massachusetts Institute of Technology (MIT), Harvard Medical School. He completed ophthalmic pathology training under Drs. Eagle, Rockey, and Yanoff during his National Institutes of Health (NIH) ophthalmic pathology fellowship. Dr. John was Director of Cornea, External Disease, and Contact Lens Service, Assistant Professor, Seeberger Scholar, Pritzker School of Medicine, University of Chicago. Currently, he is the Clinical Associate Professor at Loyola University at Chicago, and Visiting Professor, Medical Faculty of Military University, Military Medical Academy, Belgrade, Serbia. Dr. John’s private offices are in Oak Brook, Oak Lawn, and Tinley Park, Illinois. He was named Chicago’s Top Doctor by Chicago Magazine; America’s Top Doctor, Castle Connelly Medical, Ltd; and America’s Top Ophthalmologist, Consumer Research Council of America for several consecutive years. A partial list of awards includes the H. J. Memorial Research Prize, St. John’s Medical College, India; Best Resident Paper Award, University of Pennsylvania; Honor Award and Senior Honor Award, American Academy of Ophthalmology (AAO), Best of Show Award for surgical technique videos (first place) twice from AAO; First Place Award, Surgical Video Competition, International Society of Refractive Surgeons (ISRS); First Place Award, Surgical Video Competition, American Society of Cataract and Refractive Surgery (ASCRS); First Place Awards for Poster and Best Paper Presentations, ASCRS; Distinguished Physician Award from Indian American Medical Association; Physician Medal of Distinction from Military Medical Academy, Belgrade, Serbia; and a gold medal from the Indian Intraocular Implant and Refractive Society, Chennai, India. Dr. John is currently on the editorial boards of Ocular Surgery News (OSN), Review of Ophthalmology, and Ophthalmology Management, and was previously on the editorial boards of Annals of Ophthalmology (AO), Expert Review of Ophthalmology, and Optometry Management. He was Chief Editor of the Consultation Section of AO; Associate Editor of AO, Chief Editor, Corneal Dissection Column, OSN; and Editor, Journal Techniques in Ophthalmology. He is widely published in peer-reviewed journals and has edited many books, written many chapters, and made numerous presentations. He served as ASCRS panelist and poster judge and was Chief Film Festival Judge for ASCRS in 2013. He performed live surgery, descemetorhexis with endokeratoplasty, at the International Meeting of the Italian Ophthalmological Society in 2007 in Venice, Italy. He developed numerous surgical instruments and holds a patent on an ophthalmic device. He has delivered numerous surgical video presentations. His present book with Dr. Agarwal is an extension of his surgical interests in ophthalmology. Ophthalmology remains a singular subject in Dr. John’s “report card of life.” Other subjects include family, namely, his wife Annita and children Michelle, Andrea and Olivia, music, drumming (rock and roll), and dancing (ballroom, line, disco). He started ARVO Rock Concert, has been a band leader and drummer for 12 years, and played drums at the Universal Studios, Orlando, in 2014. In his report card of life, he gives all credit to Jesus Christ without whom he is nobody.

Contributing Authors Ahmed Abdou, MD, PhD (Chapter 12) Ophthalmology Department Assiut University Hospital Assiut, Egypt

Perry S. Binder, MS, MD (Chapter 20) Gavin Herbert Eye Institute University of California Irvine, California

Natalie A. Afshari, MD, FACS (Chapter 13) University of California San Diego Shiley Eye Center La Jolla, California

Massimo Busin, MD (Chapter 6) Department of Ophthalmology University of “Magna Graecia” Catanzaro, Italy Department of Ophthalmology “Villa Igea” Hospital Forlì, Italy Fondazione Banca degli Occhi del Veneto Venice, Italy

Ashvin Agarwal, MS (Chapter 10) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India Athiya Agarwal, MD, DO (Chapter 17) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India Elena Albè, MD (Chapter 6) Department of Ophthalmology “Villa Igea” Hospital Forlì, Italy Jorge L. Alió, MD, PhD (Chapter 12, 29) Vissum Corporation Division of Ophthalmology Universidad Miguel Hernández Alicante, Spain Francisco Arnalich, PhD (Chapter 29) Department of Ophthalmology Ramón y Cajal University Hospital IRYCIS Madrid, Spain Alexander Bachernegg, MD (Chapter 20) Department of Ophthalmology Paracelsus Medical University Salzburg, Austria

Alan N. Carlson, MD (Foreword) Professor of Ophthalmology Chief, Refractive and Corneal Surgery Duke Eye Center Durham, NC Alejandro Cerda, MD (Chapter 22) Staff Anterior Segment Surgeon Oftalmoláser Surgery Center Viña del Mar, Chile Roy S. Chuck, MD, PhD (Chapter 26) Department of Ophthalmology and Visual Sciences Albert Einstein College of Medicine Montefiore Medical Center New York, New York Paolo Colliardo, MD (Chapter 14) Azienda Ospedaliera San Camillo-Forlanini Roma, Italy Robert A. Copeland Jr, MD (Chapter 11) Professor and Chairman Department of Ophthalmology Howard University College of Medicine and Hospital Washington, DC

Contributing Authors H. Burkhard Dick, MD, PhD (Chapter 19) Professor and Chairman, Director Institute for Vision Science Ruhr University Eye Hospital Bochum, Germany Harminder S. Dua, MS, FRCOphth, FRCS, FEBO, PhD (Chapter 10) Chair and Professor of Ophthalmology Division of Clinical Neuroscience University of Nottingham Nottingham, United Kingdom Giancarlo Falcinelli, MD (Chapter 14) Osteo-Odonto-Keratoprosthesis Foundation Rome, Italy Bascom Palmer Eye Institute University of Miami Miami, Florida Giovanni Falcinelli, MD (Chapter 14) Azienda Ospedaliera San Camillo-Forlanini Roma, Italy Fernando Faria-Correia, MD (Chapter 24) Refractive Surgery Research Fellow Medical University of South Carolina Storm Eye Institute Charleston, South Carolina Hospital CUF Porto, Portugal Clinica Oftalmologica Dr Horacio Correia Braganca, Portugal I. Howard Fine, MD (Chapter 22) Clinical Professor of Ophthalmology Oregon Health and Science University Eugene, Oregon Andrea Gabrielli, MD (Chapter 14) Osteo-Odonto-Keratoprosthesis Foundation Rome, Italy Sunil Ganekal, FRCS (Chapter 18) Department of Ophthalmology JJM Medical College Davangere, Karnataka, India

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Ronald D. Gerste, MD, PhD (Chapter 19) University Eye Hospital Ruhr University Bochum, Germany Ian Gorovoy, MD (Chapter 5) Ophthalmology Resident University of California, San Francisco San Francisco, California Günther Grabner, MD (Chapter 20) Department of Ophthalmology Paracelsus Medical University Salzburg, Austria Aaishwariya Gulani, BS (Chapter 25) University of Pennsylvania Philadelphia, Pennsylvania Arun C. Gulani, MD, MS (Chapter 25) Chief Surgeon and Director Gulani Vision Institute Jacksonville, Florida Richard S. Hoffman, MD (Chapter 22) Clinical Associate Professor of Ophthalmology Oregon Health and Science University Eugene, Oregon Susan Huang, MD (Chapter 26) Department of Ophthalmology and Visual Sciences Albert Einstein College of Medicine Montefiore Medical Center New York, New York Soosan Jacob, MS, FRCS, DNB, MNAMS (Chapters 8, 17, 21, 23, 28) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India

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Contributing Authors

Bennie H. Jeng, MD, MS (Chapter 5) Professor of Ophthalmology University of California, San Francisco Co-Director, UCSF Cornea Service Chief, Department of Ophthalmology San Francisco General Hospital San Francisco, California Vishal Jhanji, MD (Chapter 18) Department of Ophthalmology and Visual Sciences Prince of Wales Hospital Chinese University of Hong Kong Hong Kong Saraswathy Karnati, MS (Chapter 23) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India Terry Kim, MD (Chapter 4) Professor of Ophthalmology Department of Cornea and Refractive Surgery Duke University Eye Center Durham, North Carolina Dhivya Ashok Kumar, MD (Chapters 10, 27) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India Rachel Kwok, MBBS (Chapter 18) Department of Ophthalmology and Visual Sciences Prince of Wales Hospital Chinese University of Hong Kong Hong Kong, China Jimmy K. Lee, MD (Chapter 26) Department of Ophthalmology and Visual Sciences Albert Einstein College of Medicine Montefiore Medical Center New York, New York

W. Barry Lee, MD (Chapter 16) Cornea, External Disease & Refractive Surgery Section Eye Consultants of Atlanta/Piedmont Hospital Atlanta, Georgia Alvaro Luque, BSc (Chapter 29) R&D Department Vissum Corporation Alicante, Spain Prafulla K. Maharana, MD (Chapters 1, 3) Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi, India Yuri McKee, MD (Chapter 7) Corneal and Refractive Surgeon Price Vision Group Indianapolis, Indiana Priya Narang, MS (Chapters 9, 10) Narang Eye Care & Laser Centre Ahmedabad, Gujarat, India Francis W. Price Jr, MD (Chapter 7) President of the board, Corneal Research Foundation of America Corneal and Refractive Surgery Price Vision Group Indianapolis, Indiana Saima M. Qureshi, MD (Chapter 11) Ophthalmology Resident Department of Ophthalmology Howard University College of Medicine and Hospital Washington, DC Alejandra E. Rodgriguez, MSc (Chapter 29) R&D Department Vissum Corporation Alicante, Spain

Contributing Authors Theresa Rückl, MD (Chapter 20) Department of Ophthalmology Paracelsus Medical University Salzburg, Austria Bishoy Said, MD (Chapter 13) University of California San Diego Shiley Eye Center La Jolla, California Kaladevi Satish, MS (Chapter 28) Dr. Agarwal’s Eye Hospital and Eye Research Centre Chennai, India Tim Schultz, MD (Chapter 19) University Eye Hospital Ruhr University Bochum, Germany Vincenzo Scorcia, MD (Chapter 6) Department of Ophthalmology University of “Magna Graecia” Catanzaro, Italy Namrata Sharma, MD (Chapters 1, 3) Professor of Ophthalmology Cornea & Refractive Surgery Services Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences New Delhi, India Yichieh Shiuey, MD (Chapter 15) Sunnyvale, California Annette Chang Sims, MD (Chapter 22) Affiliate Instructor of Ophthalmology Oregon Health and Science University Eugene, Oregon

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Felipe Soria, MD (Chapter 12) Vissum Corporation Alicante, Spain Maurizio Taloni, MD (Chapter 14) Azienda Ospedaliera San Camillo-Forlanini Roma, Italy Charles L. Thompson, MD (Chapter 16) Cornea, External Disease & Refractive Surgery Section Eye Consultants of Atlanta/Piedmont Hospital Atlanta, Georgia Jose M. Vargas, MD (Chapter 15) CEOVAL Valencia, Venezuela Alfredo Vega-Estrada, MD (Chapter 12) Vissum Corporation Alicante, Spain Laura Vickers, MD (Chapter 4) Chief Resident Duke University Eye Center Durham, North Carolina George O. Waring IV, MD (Chapter 24) Director of Refractive Surgery Department Assistant Clinical Professor of Ophthalmology Medical University of South Carolina Storm Eye Institute Charleston, South Carolina Medical Director, Magill Vision Center Mt. Pleasant, South Carolina Adjunct Assistant Professor of Bioengineering College of Engineering and Science Clemson University Clemson, South Carolina

Preface “In the middle of difficulty lies opportunity” is a line from renowned physicist Albert Einstein that also applies to ocular surgeries. We can master a surgical technique only when we experience its problems and tribulations. Every cornea surgeon undergoes a learning curve for his or her surgical expertise. Some take 2 days, and some take 2 months. Nevertheless, the final destination of mastering the technique is obtained only after continuous exposure to the procedure. This book on surgical maneuvers on the cornea will facilitate surgeons in structuring their varied surgical knowledge. It covers all the recent advances in existing techniques for common and rare corneal conditions presented by the leading authors in their respective fields. Step-bystep approaches to various corneal procedures are well illustrated in 29 chapters, and excellent accompanying surgical videos present the potential intraoperative circumstances surgeons may face. The book highlights novel surgical methods and their differences from existing techniques, including pre-Descemet’s endothelial keratoplasty (PDEK), a recent advancement in endothelial keratoplasty that involves the transplantation of Descemet’s membrane with endothelium along with the pre-Descemet’s (Dua’s) layer. This technique has been performed in collaboration with Dr. Harmindar Dua. Hence, we believe that this book will be helpful to corneal surgeons around the world in improving their surgical dexterity. However, we should not forget that great works that are not completed by strength can be done by perseverance. Amar Agarwal, MS, FRCS, FRCOphth Thomas John, MD

Foreword For several decades, advancements and our approach to corneal surgery would be best characterized as incremental and evolutionary. Remarkably, over the past decade, improvements in surgical techniques and patient outcomes have “accelerated” on a trajectory that is nothing short of revolutionary. We no longer approach corneal scarring, ectasia, and edema with an identical procedure. Also astonishing is the rate at which many of these newer “partial” procedures and techniques have become mainstream—a result of key individuals collaborating and combining their surgical innovation with their skills in communicating and teaching these advances to the mainstream. This is precisely what this new book, Mastering Corneal Surgery, brings to our profession. There is not a single surgeon who will not be challenged by the concepts and techniques meticulously reviewed in this compilation. The spectrum of the latest techniques offered is impressive, including all forms of keratoplasty to complex keratoprosthesis to procedures combining the most advanced techniques in intraocular lens fixation. Mastering Corneal Surgery also brings the latest and very best videos to further enhance understanding and shorten the learning curve around acquiring new surgical techniques. I would like to congratulate the editors, Drs. Agarwal and John, along with the numerous contributing authors, and SLACK Incoroporated for bringing this much needed and comprehensive contribution to our surgical profession. Alan N. Carlson, MD Professor of Ophthalmology Chief, Corneal and Refractive Surgery Duke Eye Center Durham, North Carolina

Introduction Corneal surgery has become very complex and demanding. From the days of simple keratoplasties we have moved to the latest endothelial keratoplasty technique, pre-Descemet’s endothelial keratoplasty. To add to this are cataract surgery and the latest glued intraocular lens surgery. An ophthalmologist would also need to know other aspects of corneal treatment like collagen cross- linking and contact lens–assisted collagen cross-linking for thin corneas. This book has been written to keep all this in mind. The book is divided into 4 sections to make it easy for you, dear reader. The first section covers keratoplasties including lamellar keratoplasties. The second section covers keratoprosthesis and its ramifications. The third section covers corneal surgery related to cataract surgery, which includes limbal relaxing incisions. Finally, the fourth section is the Miscellaneous section. In each section, every chapter is authored by the top surgeons in that field. To make the book easy to understand, there are surgical photos and illustrations but most important of all are the surgical videos. These videos will help you perform any surgery on the cornea from deep anterior lamellar keratoplasty to Descemet’s membrane anterior keratoplasty to pre-Descemet’s endothelial keratoplasty with glued intraocular lenses. All in all, we hope this book will help treat more corneal patients so that corneal blindness becomes a thing of the past. Amar Agarwal, MS, FRCS, FRCOphth

Section I Keratoplasty

1 Applied Anatomy and Physiology of the Cornea Prafulla K. Maharana, MD and Namrata Sharma, MD The cornea is the refractive surface of the eye and, with the sclera, forms the outermost coating of the eyeball. It constitutes up to one-sixth of the entire eyeball. The corneal epithelium is derived from the surface ectoderm, and the mesoderm gives rise to Bowman’s layer, the stroma, Descemet’s membrane, and the endothelium. The average diameter of the cornea varies from 11 to 12 mm horizontally and 9 to 11 mm vertically. The cornea is responsible for 48 diopters of the total power. The posterior surface of the cornea is more spherical than the anterior surface, and the central cornea is thinner (520 μm compared with the peripheral cornea [650 μm or more]). The tear film covers the anterior corneal surface, and the posterior corneal surface is in contact with the aqueous humor.

Precorneal Tear Film The tear film is 7 μm thick and has a volume of 6.5 ± 0.3 μL.1 The tear film is made up of an outer lipid layer (0.1 μm), middle aqueous layer (7 μm), and innermost mucin layer (0.02 to 0.05 μm).2 The tear film keeps the corneal surface moist and prevents the adherence of microbes. More than 98% of the volume of tears is water. The tear film has many essential substances, such as electrolytes, glucose, immunoglobulins, lactoferrin, lysozyme, albumin, and oxygen. It also has many biologically active substances, such as histamines, interleukins, prostaglandins, and growth factors.3 These factors control corneal epithelial migration, proliferation, and differentiation.

Anatomy of the Cornea The cornea has 5 layers: the epithelium, Bowman’s layer, the stroma, Descemet’s membrane, and the endothelium (Figures 1-1 to 1-3).

Epithelium The corneal epithelium has a thickness of 50 to 90 μm and comprises 5 to 7 layers of stratified, squamous, and nonkeratinized cells (see Figure 1-2). The epithelium forms approximately 10% of the total corneal thickness. The cells of the corneal epithelium may be divided into 3 types: squamous cells, which are present superficially; middle wing cells; and deeper basal cells.4

Superficial Layer of Squamous Cells The superficial layer, which consists of squamous cells, forms the outermost 1 to 2 layers of the corneal epithelium. The oldest epithelial cells disintegrate and shed into the tear film by the process of desquamation. These superficial cells are composed of microscopic projections in the form -3-

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Figure 1-1. Histological section of the layers of the cornea (original magnification × 4, hematoxylin and eosin stain).

Figure 1-2. Histological section of the cornea showing the epithelium, basement membrane, and stromal layers (original magnification × 10, hematoxylin and eosin stain).

of microvilli, reticulations, or microplicae. The fibrillar glycocalyx is present on these ramifications, which interacts with the mucinous tear film. The epithelial cells are replaced approximately every 7 to 14 days.5 The superficial cells adhere to each other by the presence of desmosomes and junctional complexes. These complexes consist of tight junctions that circumvent the entire cell and resist the flow of fluid through the epithelial surface.

Middle Layer of Wing Cells The middle layer of the corneal epithelium consists of wing cells, which have lateral, thin, wing-like projections protruding from a more rounded cell body. The wing cells are connected to each other by desmosomal junctions and gap junctions.

Applied Anatomy and Physiology of the Cornea

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Figure 1-3. Histological section of Descemet s membrane and the endothelium (original magnification × 20 hematoxylin and eosin stain).

Deep Layer of Basal Cells The deep layer of the corneal epithelium consists of basal cells, which are cuboidal to columnar in shape and have a diameter of 8 to 10 μm. Posteriorly, the cells are flat and have a basal lamina to which they anchor with the help of hemidesmosomes. The basal cells are metabolically active and are responsible for division, and they form the wing and the superficial cells. The corneal epithelium acts as a tough protective shield against microorganisms and foreign bodies; however, it is partially permeable to small molecules such as glucose, sodium oxygen, and carbon dioxide.

Basement Membrane The basal cells of the corneal epithelium are anchored with the help of hemidesmosomes to the basement membrane, which is located between the corneal epithelium and Bowman’s membrane. It is primarily made up of type IV and VII collagen and glycoproteins and has 2 parts: the superficial lamina lucida layer and the deeper lamina densa layer.

Bowman’s Layer Bowman’s layer is an acellular membrane-like zone with a thickness of approximately 8 to 14 μm. It has numerous pores for the passage of corneal nerves into the corneal epithelium. On examination with electron microscopy, it is made up of a fine meshwork of uniform type I and III collagen fibrils.

Corneal Stroma The corneal stroma, with a thickness of approximately 500 μm, is responsible for 90% of the thickness of the cornea. It is located between Bowman’s layer and Descemet’s membrane (see Figure 1-2). It is composed of lamellae, which are formed from flattened bundles of collagen, stromal keratocytes, and ground substances like keratan sulphate. The major structural component of the corneal stroma is collagen (type I is the major constituent, and types III and VI are also present). There are 200 to 250 bundles of collagen fibrils, and each bundle has a fibril 2 μm thick and 9 to 260 μm wide. The collagen fibers are arranged in a regular manner, parallel to the corneal surface. Such a uniform arrangement and equal spacing of collagen fibers creates a lattice or 3-dimensional diffraction grating, which is responsible for the ability of the cornea to scatter 98% of incoming light rays. The lamellae in the posterior part of the

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Figure 1-4. A 30-gauge needle connected to a syringe with air enters the corneal stroma. This is the top with the endothelial side up. (Reprinted with permission from Dr. Agarwal s Eye Hospital.)

stroma have an orthogonal layering (ie, the bundles are at right angles to each other). In the anterior one-third of the stroma, the lamellae have a more oblique layering. The arrangement of the anterior and posterior lamellar stromal fibers is different. The fibers are more compact anteriorly so that their compactness and their oblique arrangement make lamellar dissection more difficult anteriorly. On the other hand, the arrangement of the fibers is less oblique and loose posteriorly so that manual dissection is simpler in the posterior part. The primary glycosaminoglycans of the stroma are keratin sulfate and chondroitin sulfate, which occur at a ratio of 3:1. The lamellar stroma is secreted and maintained by stromal fibroblasts called keratocytes, which occupy 3% to 5% of the stromal volume. They are responsible for the maintenance of stromal components, and they synthesize collagen degradative enzymes such as matrix metalloproteinases (MMPs).4 MMPs play a role in the pathogenesis of ulcerative keratitis as they accumulate in the tears and trigger an autoimmune response involving the ocular tissue. Keratocytes undergo cellular differentiation in response to injury, converting them into fibroblasts. Keratocytes usually lie between the lamellae and are flat with long, attenuated processes extending from a central cell body in all directions.

Descemet’s Membrane Descemet’s membrane is the basement membrane of the corneal endothelium and is synthesized by the endothelium.6 At birth, the human Descemet’s membrane is 3 μm wide, but in adulthood, the width increases to 12 μm (see Figure 1-3). There are 2 distinct regions in Descemet’s membrane: the anterior one-half to one-third, which is banded; and the posterior two-thirds, which are nonbanded.4 Recently, another layer of the cornea, called Dua’s layer, has been described. This is a novel, well-defined, acellular, strong layer in the pre-Descemet’s cornea. It separates along the last row of keratocytes in most cases with the big bubble technique (Figures 1-4 to 1-6). Its recognition will have a considerable impact on posterior corneal surgery and the understanding of corneal biomechanics and posterior corneal pathology, such as acute hydrops, descemetocele, and pre-Descemet’s dystrophies.5

Endothelium The corneal endothelium is a single-layered, low cuboidal endothelium. It has approximately 400,000 cells and a thickness of 4 to 6 μm. The endothelial cells have a hexagonal shape and are 20 μm wide. They have tight lateral interdigitations, which prevent seepage of the aqueous humor into the stroma. Specific functional complexes are also present near the apical membranes. The number of endothelial cells decreases with age at the rate of 0.3% to 0.6% per year. At birth, cell densities range from 3500 to 4000 cells/mm 2 , whereas an adult’s cell densities range from 1400 to 2500 cells/mm 2. As cells decrease in number, they become thinner and attenuated. The cornea loses it clarity when the endothelial cell densities reach 400 to 700 cells/mm 2 , below which corneal edema occurs.

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Figure 1-5. Air is injected into the space between the pre-Descemet s layer (Dua s layer) and the stroma. (Reprinted with permission from Dr. Agarwal s Eye Hospital.)

Figure 1-6. A type-1 big bubble is created in the space between the pre-Descemet s layer (Dua s layer) and the stroma. (Reprinted with permission from Dr. Agarwal s Eye Hospital.)

Unlike the corneal epithelium, endothelial cells cannot undergo mitosis after birth. The endothelial cells are linked to each other by junctional complexes and gap junctions, but no desmosomes are present. The endothelial cells do not replicate in human beings. They decrease in density with increasing age, raised intraocular pressure, and inflammation and after intraocular surgery. The corneal endothelium plays a major role in maintaining stromal hydration (normally 78%) through the sodium potassium–activated adenosine triphosphotase (ATPase) present in the basolateral borders of the cells. Endothelial cell loss varies from 2% to 7% after anterior lamellar keratoplasty and from 20% to 30% after posterior lamellar keratoplasty depending on the surgeon’s skill. In cases of Descemet’s membrane endothelial keratoplasty (DMEK), endothelial cell loss is higher due to the difficulty in performing this technique. However, in the hands of an experienced surgeon, endothelial cell loss after Descemet’s stripping endothelial keratoplasty and DMEK may be similar.

Nerve Supply of the Cornea The cornea is supplied by the sensory nerves derived from the ciliary nerves of the ophthalmic branch of the trigeminal nerve. The long ciliary nerves supply the perilimbal nerve ring. Nerve fibers penetrate the cornea in the deep peripheral stroma radially and then course anteriorly, forming a terminal subepithelial plexus.7 The nerve fibers lose their myelination soon after penetrating the clear cornea, enter Bowman’s layer, and terminate at the level of the wing cells. An autonomic sympathetic supply is also present in the cornea.

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The physiologic role of corneal innervation is unclear. The presence of corneal sensation is vital to the maintenance of the integrity of the cornea. In cases of herpes simplex, herpes zoster, and diabetes mellitus, corneal sensation is diminished, and this may lead to persistent epithelial defects or delayed epithelial wound healing. Corneal sensation may be altered after anterior lamellar keratoplasty but is preserved after posterior lamellar keratoplasty. This has a bearing on the healing of epithelium postoperatively.

Blood Supply of the Cornea The cornea is one of the few avascular tissues in the body. The normal healthy cornea does not have any blood vessels. The anterior ciliary artery derived from the ophthalmic artery forms an arcade at the limbus.

Oxygen and Nutritional Supply of the Cornea Oxygen is supplied primarily from the diffusion of oxygen from the atmosphere into the tear film. Oxygen from the air is also dissolved in the tear fluid. To a lesser extent, oxygen is also obtained from the aqueous and limbal vessels.

Applied Physiology of the Cornea The basis of corneal physiology consists of an understanding of the corneal epithelial barrier, the endothelial barrier, and metabolic pump functions. The factors that affect hydration of the cornea include the corneal epithelial barrier, the endothelial barrier, the metabolic pump functions, evaporation, and intraocular pressure. If any of these mechanisms function suboptimally, it manifests as corneal edema. A greater increase in corneal thickness occurs when endothelial cells are compromised as compared with damage to the epithelial cells. Metabolic pump functions also play an important role because the corneal stroma swells due to increased tonicity of the stromal components, which contain collagen, salts, and proteoglycans. Corneal stromal swelling pressure is 60 mm Hg, and it occurs if the endothelial barrier is disrupted as the intraocular pressure of 15 mm Hg is unopposed and the aqueous seeps into the stroma. Both the anterior and the posterior surfaces of the cornea contribute to its optical function. The total refractive index of the cornea consists of the total refraction at the 2 interfaces, as well as the transmission properties of the tissue. The refractive indexes of the air, tear, cornea, and aqueous humor are 1.0, 1.336, 1.376, and 1.336, respectively. The refractive power at the curved surface is determined by the refractive indices and the radius of curvature. Refractive power at the central cornea is approximately + 43 diopters, which is the total of the refractive power at the airtear (+ 44 diopters), tear-cornea (+ 5 diopters), and cornea-aqueous humor (– 6 diopters) interfaces.

Differentiation of the Anterior and Posterior Corneal Stroma There are various differences between the anterior and posterior stroma, and a corneal surgeon who performs lamellar keratoplasty should be aware of these differences.8-10 • The anterior corneal stroma has less water (3.04 g H2O/g dry weight) as compared with the posterior stroma (3.85 g H 2O/g dry weight). • The anterior stroma has less glucose (3.8s9 μM/g H 2O) as compared with the posterior stroma (4.93 μM/g H 2O) because the glucose is derived from the aqueous. • Dermatan sulphate, which has greater water retentive property, is located more in anterior stromal layers, whereas keratin sulphate is located more in posterior stromal layers; hence, clinically, edema restricted to the posterior layers resolves more easily.

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Factors Responsible for the Transparent Cornea The factors responsible for the presence of the transparent cornea include its avascular status, the peculiar arrangement of collagen fibers, the absence of a myelin sheath in its nerves, and the corneal endothelial pump. According to the lattice theory, the cornea maintains its transparency because the collagen fibrils are of equal diameter (36 nm) and are equidistant from each other.8 Thus, the incident ray scattered by each collagen fiber is cancelled by the interference of other scattered rays, which allows it to pass through the cornea. Corneal decompensation due to corneal hydration occurs as the proteoglycans within the corneal lamellae absorb water and this equilibrium is disturbed, leading to a loss of transparency. The biochemical and physical properties of the stroma are normally maintained by the presence of a functional epithelial and endothelial barrier and a metabolic pump function so that the water content is maintained at 78%.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Scherz W, Doane MG, Dohlman CH. Tear volume in normal eyes and keratoconjunctivitis sicca. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1974;192(2):141-150. Holly FJ, Lemp MA. Tear physiology and dry eyes. Surv Ophthalmol. 1977;22(2):69-87. Ohashi Y, Motokura M, Kinoshita Y, et al. Presence of epidermal growth factor in human tears. Invest Ophthalmol Vis Sci. 1989;30(8):1879-1882. Nishida T. Cornea. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea: Fundamentals, Diagnosis and Management. 2nd ed. Philadelphia, PA: Elsevier Mosby; 2005:3-20. Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human corneal anatomy redefined: a novel preDescemet’s layer (Dua’s layer). Ophthalmology. 2013;120(9):1778-1785. Hanna C, Bicknell DS, O’Brien JE. Cell turnover in the adult human eye. Arch Ophthalmol. 1961;65:695-698. Johnson DH, Bourne WM, Campbell RJ. The ultrastructure of Descemet’s membrane. I. Changes with age in normal corneas. Arch Ophthalmol. 1982;100(12):1942-1947. Hogan MJ, Alvarado JA, Weddell JE. The sclera. In: Hogan MJ, Alvarado JE, eds. Histology of the Human Eye. Philadelphia, PA: WB Saunders; 1971:114-119. Maurice DM. The cornea and sclera. In: Davison H, ed. The Eye. Vol. IB. 3rd ed. Orlando, FL: Academic Press; 1984. Jafarinasab MR, Rahmati-Kamel M, Kanavi MR, Feizi S. Dissection plane in deep anterior lamellar keratoplasty using the big-bubble technique. Cornea. 2010;29(4):388-391.

Please see video on the accompanying website at

www.healio.com/books/cornealvideos

2 Penetrating Keratoplasty Thomas John, MD Penetrating keratoplasty (PK), or full-thickness corneal transplantation, refers to the removal of the full-thickness recipient cornea and replacement with a similar full-thickness donor corneal disc. Such a technique introduces 2 important issues, namely, a full-thickness, circular recipient corneal wound that never completely heals, which represents a weak circle in the patient’s cornea where the surgical wound is located; and the placement of sutures on the patient’s cornea. Such a circular corneal wound may potentially destabilize the recipient cornea due to its direct effect on the corneal biomechanics. Traumatic injury to such a cornea can potentially result in full-thickness corneal wound dehiscence, globe rupture, and vision loss. Additionally, a PK procedure often introduces significant corneal astigmatism. Corneal sutures, although a necessity in PK, can break and may require immediate care because the exposed suture ends will often cause discomfort or pain, adding the risk of secondary infection. One must also keep in mind the open-sky nature of PK, with the potential for intraoperative choroidal bleeding that can result in an expulsive hemorrhage with permanent loss of the eye. The major bifurcation in corneal transplantation is whether it is an en bloc full-thickness PK or partial-thickness lamellar procedure. Although lamellar corneal procedures have gained popularity in recent years, PK remains the king of keratoplasties, with 36,716 such procedures performed in the United States in 20121 compared with 1855 anterior lamellar keratoplasties (ALKs) and 25,025 posterior lamellar keratoplasties (namely endothelial keratoplasty [EK]) performed during the same period. Thus, PK continues to be the most common corneal transplantation procedure currently performed in the United States. Similar numbers were seen for the previous year (2011): total PKs = 36,144; ALKs = 1778; EKs = 23,287.

Historical Perspective Three names to remember are Eduard Zirm from the Czech Republic, Vladimir Filatov from Russia, and Ramon Castroviejo from the United States. Eduard Zirm performed the first corneal transplant (organ transplant) on December 7, 1905, at a hospital in Olomouc, presently in Moravia in the Czech Republic. He transplanted a donor cornea from an 11-year-old boy who had died into a day laborer who had corneal blindness, subsequently restoring his vision. Seven years later, Vladimir Filatov began developing corneal transplantation techniques, culminating in successful corneal transplantation in 1931 using a donor cornea from a deceased person. Shortly thereafter, in 1936, Ramon Castroviejo performed a corneal transplant in a case of advanced keratoconus that resulted in significant improvement in the patient’s vision.2 Additional factors that contributed to advances in corneal transplantation include the introduction of the operating microscope, improved surgical sutures and instruments, and the establishment of eye banks for the procurement and distribution of human donor corneas. - 11 -

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Surgical Indications Surgical indications for PK are different based on the timeline; the geographic region of the world; the potential socioeconomic limitations on the delivery of surgical procedures, especially those that require human donor tissue; and the rules and regulations related to human organ transplantation in a particular country. The indications for PK may be divided into optical, tectonic, therapeutic, and cosmetic, as outlined below: • Optical: A healthy, clear donor cornea is used to replace an opaque, cloudy, or distorted cornea in an attempt to improve vision and hence quality of life. ° Pseudophakic bullous keratopathy ° Keratoconus ° Regraft secondary to allograft rejection ° Regraft unrelated to allograft rejection ° Keratoglobus ° Degenerations ° Dystrophies ° Scar ° Aphakic bullous keratopathy ° Congenital opacities (see pediatric keratoplasty below) ° Chemical injuries ° Refractive indications • Tectonic: A donor cornea is used to restore the recipient corneal anatomy and globe integrity. ° Descemetocele ° Corneal stromal thinning ° Corneal perforation • Therapeutic: Surgical intervention is performed when therapeutic measures have failed and infection continues to progress. Infection may be due to bacteria, virus, parasites, or other cause. • Cosmetic: Corneal transplantation is performed to improve the appearance of the patient and has no bearing on the visual outcome. This could also be done in a nonseeing eye. An opaque cornea with a white or blue-gray hue may be disturbing to the patient, who may request PK. When we review the 3 leading indications for PK, we begin to see the variations in these indications depending on geographic region (Table 2-1).

Tissue Compatibility Currently, tissue matching is not required in human corneal transplantation. Successful corneal transplantation in the absence of human leukocyte antigen typing and systemic immunosuppression has been performed for more than a century, with the majority (approximately 90%) of the allografts being successful,10 and this may be attributed in part to corneal immune privilege. Corneal neovascularization, inflammation, or trauma is thought to negate the immune privilege.11-15 Corneal allograft immune privilege is thought to be multifactorial, including blockage of effector T cell expression and complement activation, immune response blockage, and immune response diversion to a more tolerogenic pathway.11 Contrary to common belief, it has been shown that lymph vessels, not blood vessels, negate the immune privilege of corneal allografts.16 However, the premise that corneal graft neovascularization increases the risk of graft rejection is true. It has been shown that stimuli that induce blood vessel ingrowth (eg, vascular endothelial growth factor C) also stimulate lymph vessel growth.17

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TABLE 2-1

Leading Indications for Penetrating Keratoplasty per Geographic Location COUNTRY

LEADING INDICATIONS

United States3,4

1982-1996: 1. Pseudophakic bullous keratopathy 2. Fuchs corneal dystrophy 3. Keratoconus 2001-2005: 1. Pseudophakic corneal edema 2. Regraft 3. Keratoconus

United Kingdom5

1. Regrafts 2. Keratoconus 3. Fuchs endothelial dystrophy

Israel6

1. Keratoconus 2. Graft failure 3. Pseudophakic corneal edema

India7

1. Corneal scarring 2. Regrafts 3. Active infectious keratitis

China8

1. Active infectious keratitis 2. Keratoconus 3. Bullous keratopathy

Colombia9

1. Bullous keratopathy (pseudophakic and aphakic) 2. Corneal scar 3. Active infectious keratitis

Pre- and Postoperative Management Patients may be treated with topical nonsteroidal anti-inflammatory drugs, corticosteroids, and antibiotic drops starting 3 days preoperatively and continuing postoperatively in a seamless manner. Postoperatively, the frequency of the dosage may be titrated depending on the postoperative course and the amount of inflammation.

Type of Anesthesia Topical,18 peribulbar,19 retrobulbar, 20,21 and general 22 anesthesia have been used for PK. Peribulbar and retrobulbar anesthesia may be combined with monitored anesthesia care. In the United Kingdom, 93% of surgeons are said to use general anesthesia for PK.22 A possible intraoperative complication is suprachoroidal hemorrhage and loss of intraocular contents.23 In a group

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of patients undergoing PK (n= 830), suprachoroidal hemorrhage was less in the general anesthesia group (0.56%) compared with the local anesthesia group (4.3%).23 The increased resistance to venous outflow associated with retrobulbar anesthetic injection may contribute to the risk of massive suprachoroidal hemorrhage.23

Donor Tissue Preparation The donor cornea is trephined from the endothelial or epithelial surface. For epithelial surface trephination, an artificial anterior chamber is required. The 2 major types are suctionless trephines and suction trephines. A cutting block and artificial anterior chamber may also be used for donor corneal disc preparation.

Suctionless Trephines Suctionless trephines are composed of a cylindrical metal blade that is sharp on one end and blunt on the other end. The surgeon uses 2 fingers to hold the trephine, and trephination of the recipient cornea is performed by digital rotation in a clockwise and counterclockwise direction, often using the thumb and index finger. These trephines may also be used with a handle; however, when a handle is used, the central viewing of the recipient cornea through the trephine opening is not possible. The trephination is stopped upon entry into the anterior chamber to prevent any iris or anterior segment tissue damage. The remainder of the cut is completed using corneal microscissors. The blades of the scissors may be held vertical to achieve a perpendicular cut or angulated to provide a posterior lip on the recipient corneal opening, which can serve as a posterior valve mechanism for an effective donor-host corneal seal. It is important to hold the trephine perpendicular to the central corneal surface in line with the visual axis to obtain a perpendicular corneal cut. One distinct advantage of a suctionless trephine over a suction trephine is that it can be used over irregular, scarred host corneas when suction trephines can fail to establish good suction. These trephines are also used to trephine the donor cornea from the endothelial surface with a guillotine-type of corneal punch. Such an approach provides a uniform edge to the donor corneal disc. Manufacturers usually distribute these trephines for single usage, as disposable blades that are individually packaged, and are sterile, and ready for use. Although trephine diameters vary based on the manufacturer, they are available in increments of 0.25 or 0.5 mm.

Suction Trephines As the name implies, suction trephines have a vacuum mechanism that holds the trephine over the recipient cornea, and it is steadied by the surgeon’s fingers. Examples of suction trephines include the Hanna trephine (Moria S.A.) and the Barron radial vacuum trephine (Katena Products, Inc).

Cutting Blocks The donor corneal tissue is prepared using a cutting block. Cutting blocks, like trephines, are available with and without a vacuum device. The vacuum cutting block holds the donor corneal tissue in stable position while the trephination is performed. Also, cutting blocks are available as a corneal punch, where the trephine blade performs a vertical guillotine-type of cut on the donor corneal tissue.

Artificial Anterior Chamber The artificial anterior chamber was initially described by Ward and Nesburn in 1976.24 The artificial anterior chamber facilitates trephination from the epithelial surface of the donor cornea. Hence, if the same diameter trephine is used on both the donor and recipient corneal surface, the donor corneal disc is expected to have a more favorable fit into the recipient corneal opening compared with trephination on the endothelial surface of the donor cornea. The artificial anterior chamber enables the mounting of the donor corneal-scleral tissue within the instrument, forming a seal around the scleral rim of the excised donor cornea while the endothelial surface is bathed

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by the liquid storage medium.24 Since the initial introduction of the artificial anterior chamber, various modifications and improvements have been made, allowing corneal surgeons to trephine the donor cornea to any desired depth.25

Surgical Technique General Penetrating Keratoplasty Procedure The trephine diameter must be determined. This can be done by using a Castroviejo caliper and measuring the recipient cornea. The trephine diameter that is chosen should permit enough corneal tissue outside the trephine mark so that sutures can be placed in a secure fashion on the recipient cornea without being extremely close to the limbus, which can induce postoperative neovascularization and increase the risk of graft rejection. Next, the central corneal dome is marked after measuring with calipers. This is important because any decentration of the corneal graft can augment iatrogenic corneal astigmatism and degrade postoperative vision and visual quality. Next, the donor cornea is trephined using an endothelial approach or an epithelial-side approach. The epithelial-side approach requires an artificial anterior chamber and a special trephine such as the Hanna trephine. The Hanna trephine permits a preset, desired depth of trephination. The trephination is full thickness, and the punched donor corneal disc is then set aside in the corneal storage media (Optisol GS; Bausch + Lomb Surgical), and attention is directed to the patient’s cornea. The trephination of the patient’s cornea can be either full thickness or partial thickness. Prior to trephination, radial markings using a radial keratotomy marker precoated with gentian violet can assist in subsequent corneal suture placement. Alternatively, a suction trephine such as the Barron radial vacuum trephine, which results in corneal impressions after use, may be used. Next, trephination is performed. Partial-thickness trephination of the recipient cornea provides the added advantage of a controlled entry into the anterior chamber. In full-thickness trephination, care should be taken to withdraw the trephine when the anterior chamber is entered to avoid any potential iris damage. Full-thickness trephination contributes to a more vertical cut on the recipient cornea. Once the anterior chamber is entered, the pupil is further constricted by the use of Miostat (carbachol; Alcon Laboratories, Inc), and viscoelastic material is injected to push the iris-lens-diaphragm posteriorly. The cornea is excised using corneal microscissors. The blades of the scissors may be held vertically to get a vertical cut of the cornea or may be angulated to provide a posterior corneal lip that may facilitate good sealing of the donor corneal disc to the recipient cornea. Blade angulation contributes to a slightly smaller posterior than anterior recipient corneal bed opening. The donor corneal disc is then placed on a bed of viscoelastic and sutured in place with a suture pattern and suture material of the surgeon’s choice. The author’s choice is often 8 interrupted sutures with an additional single 10-0 nylon running suture that encompasses 360 degrees of the corneal wound. If there is corneal neovascularization, then avoid running sutures and elect for all interrupted sutures. It is important to move the needle tip anteriorly or posteriorly to match the suture depths in the donor and recipient corneas, keeping in focus the proper surface matching of the 2 corneal tissues without causing any step at the site of the corneal wound. Any unevenness at the wound site can have a destabilizing effect on the corneal tear film postoperatively and contribute to a poorer visual outcome. When tying the sutures, use proper tension to prevent a corneal aqueous leak postoperatively, and avoid excess suture tension that can increase corneal astigmatism and distort the wound architecture. Whenever possible, use intraoperative keratoscopy to help minimize induced corneal astigmatism. During the suturing process, use a corneal light protector to avoid microscope-induced photopic damage to the macula and retina. An intraoperative slit lamp can help in the assessment of donor-recipient corneal surface alignment. Subconjunctival corticosteroid and antibiotic injection is used to decrease postoperative inflammation and prevent infection. Additional topical corticosteroid drops and antibiotic drops may be used at the end of the surgical procedure, and a steroid-antibiotic combination ointment may be applied to the ocular surface. A patch and shield are then taped in place to complete the surgical procedure.

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Figure 2-1. (A) Intraoperative photograph displaying a failed corneal graft with stromal and epithelial edema. Notice that the central failed graft is diffusely cloudy, whereas the peripheral recipient cornea remains clear. The epithelial edema is depicted by the fragmented corneal epithelial light reflex from the operating microscope light. (B) Radial markings are placed on the corneal surface that will guide suture placement with the repeat graft. Both the interrupted and running 10-0 nylon sutures are cut and removed using a 15-degree superblade. The central edematous epithelium is removed to augment anterior segment visualization. (C) Additional marking pen spots are made at the limbus at the 3-, 6-, 9-, and 12-o clock positions. (D) Intraoperative photograph showing that additional sutures have been removed. Any remaining sutures can be removed after the initial partial deep stromal trephination.

Figure 2-2. (A) The donor corneal tissue is mounted within an artificial anterior chamber and pressurized, and trephination is performed from the epithelial surface of the donor cornea using a Hanna trephine and a disposable blade of the desired diameter. Although the Hanna trephine is set for complete trephination, it may result in partial trephination in some regions of the circular cut. (B) The cut is then completed using corneal microscissors.

Figure 2-3. (A) The Hanna trephine is set to 400 µm depth, and trephination is performed on the patient s cornea starting from the epithelial side. (B) The circular cut on the recipient cornea is seen with some bleeding from the corneal neovascularization. Cautery or topical epinephrine 1:1000 may be used as necessary for hemostasis. (C) Following the partial-thickness trephination, any remaining sutures are removed. (D) Hemostasis has been achieved, and all sutures have been removed.

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Adult Penetrating Keratoplasty in a Phakic Eye When performing PK in a phakic eye (Figures 2-1 to 2-9), the surgeon should take every precaution to prevent accidental iatrogenic damage to the crystalline lens during the procedure. Lenticular damage can result in a delayed cataract formation or capsular tear with extrusion of lens material, which will require removal of the lens. Hence, pupillary constriction may be commenced approximately 1 hour preoperatively with topical pilocarpine 2% ophthalmic solution, applied 3 times at 10-minute intervals. This may be supplemented with intraoperative Miostat (carbachol). In addition, the lens-iris-diaphragm can contribute to a shallower anterior chamber, and the surgeon needs to keep this in mind and use viscoelastic material as needed to deepen

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Figure 2-4. (A) The anterior chamber is entered at the 10-o clock position using a super blade and taking care not to damage the iris. (B) Miostat is injected into the anterior chamber to constrict the pupil and protect the underlying crystalline lens. (C) Viscoat is injected into the anterior chamber. Notice that the pupil is now constricted. (D) Recipient corneal excision is begun using corneal microscissors.

Figure 2-5. (A) The recipient cornea is excised using corneal microscissors. The blades of the scissors are held at an angle to create a posterior corneal lip at the recipient wound. This corneal lip will provide a valvelike mechanism for good wound closure. (B) Excess corneal tissue is trimmed at the wound margin using a curved Vannas scissors. (C) Viscoat is injected into the anterior chamber. Notice that the recipient corneal disc is not excised fully; instead, it is left attached at the 3-o clock position as standby tissue in the event that there is an episode of positive posterior vitreous pressure and the need to close the opening in the eye quickly to prevent any potential expulsive hemorrhage during the procedure. (D) The donor corneal disc is placed on the recipient corneal bed with the endothelium facing the anterior iris surface.

Figure 2-6. (A) Part of the donor corneal arcus senilis is seen at the cut margin of the donor corneal disc. (B) This disc is rotated counterclockwise to position the partial white opacity of the arcus senilis to the 12-o clock position. In this position, the upper eyelid usually covers this opacity. (C) The first suture is placed at the 12-o clock position using a double-prong Polack forceps and a 10-0 nylon suture. (D) The second suture, which is the most important suture in PK, is placed at the 6-o clock position. It is important to properly position this second suture because this is the suture that divides the cornea into 2 equal or unequal parts. Notice the partial vertical fold on the donor corneal surface that divides the corneal disc into 2 equal parts.

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Figure 2-7. (A) Four cardinal sutures close the opening in the recipient cornea. Also seen is the recipient corneal disc attached at the 3-o clock position. (B) The recipient corneal disc is excised. (C) Notice the preplaced corneal markings to help place the cardinal sutures. All of the suture knots are buried within the host corneal rim. (D) A completed view of the procedure with 8 interrupted and one continuous running, 360-degree sutures in place.

Figure 2-8. (A) A corneal astigmatic ruler is used, and the corneal reflection is noted to assess the iatrogenically induced corneal astigmatism. (B) Additional suture(s) are placed to steepen the flat meridian of the corneal graft and thus decrease the corneal astigmatism. (C) It is important to take care not to accidentally cut the existing corneal sutures with the needle while placing the additional astigmatism reduction suture(s). (D) Intraoperative slit-lamp view of the cornea showing a smooth wound margin with no step at the donorrecipient margin.

Figure 2-9. (A and B) Completed view of the PK procedure with additional corneal astigmatism‒reducing corneal sutures.

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the anterior chamber by pushing the lens-iris diaphragm posteriorly. Peripheral iridectomy in an uncomplicated phakic PK is usually unnecessary. If there are anterior synechiae, these may be lysed using 0.12 forceps and Weck-Cel spears (Beaver Visitec Inc), a cyclodialysis spatula, or the cannula that is attached to the viscoelastic syringe. When performing any posterior synechiolysis, it is important to avoid potential lens damage.

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Adult Penetrating Keratoplasty in a Pseudophakic and Aphakic Eye The initial steps in the surgical procedure are the same as those described above. A single or double Flieringa ring may be attached to the episclera. The author does not use a Flieringa ring for any PK procedure. This is surgeon preference.

Pseudophakia A stable posterior chamber intraocular lens (PC IOL) can be left in place (Figures 2-10 to 2-14), and a PK is performed as described previously. If a PC IOL is unstable or subluxated, it should be removed and replaced. An anterior chamber intraocular lens (AC IOL) with closed loops or an unstable AC IOL should also be removed and replaced. Usually iris plane lenses are to be removed. A sulcus PC IOL that is not rubbing on the iris may be left in its stable position. Using blunt and sharp dissection can facilitate removal of the IOL. However, the haptics may have to be cut and the IOL then removed, especially when there are significant iris adhesions. Preserve as much iris tissue as possible. Following removal of the IOL, an anterior vitrectomy is often performed to clear all vitreous from the anterior chamber and resting vitreous behind the iris plane. A scleral-fixated PC IOL may be chosen for the new IOL, and the pupil is then constricted and a PK performed as described above. All anterior and posterior synechiae are lysed, and the anterior chamber angle is reformed.

Aphakia If there is an intact posterior lens capsule or sufficient ciliary sulcus support, a PC IOL may be implanted. In the absence of capsular and sulcus support, a scleral- or iris-sutured PC IOL or a flexible, open-loop AC IOL may be chosen. If an AC IOL is chosen, there should be no contraindications such as angle abnormalities or angle recession. Studies comparing PC IOL with AC IOL implantation have shown favorable results with both techniques.26,27 The surgeon should choose the technique that he or she is comfortable performing. With an AC IOL, a peripheral iridotomy is performed. Endothelial cell loss with AC IOL was comparable to iris-sutured PC IOL (11.5% at 1 year, 21.3% at 2 years, and 25% at 3 years).26 If there is vitreous in the anterior chamber following excision of the recipient cornea, an automated vitrectomy procedure is performed to remove the vitreous from the anterior chamber before implanting a secondary IOL and completing the PK. The vitreous may be highlighted using intracameral preservative-free triamcinolone acetonide to facilitate vitreous visualization during anterior vitrectomy.28,29 An open-sky bimanual automated vitrectomy with low suction (4 to 6 mm Hg) and rapid cutting rate (300 to 400 cuts/minute) may be used with sterile balanced salt solution added to the anterior chamber as needed during the procedure. Remove any vitreous strands to the peripheral recipient cornea or the pupil, and remove any secondary membranes that may be present. With an intact vitreous face, an anterior vitrectomy is usually not required.

Penetrating Keratoplasty With Cataract Extraction and a Posterior Chamber Intraocular Lens When corneal decompensation accompanies clouding of the lens secondary to a cataract, the ideal choice is often a triple procedure, namely a corneal transplantation with cataract extraction and a PC IOL implantation in the capsular bag (Figures 2-15 to 2-23). The goal is to achieve clarity within the anterior segment media to provide optimal vision postoperatively. A clear corneal stroma with endothelial decompensation would direct the surgeon to possible endothelial keratoplasty (Descemet’s stripping endothelial keratoplasty or Descemet membrane endothelial keratoplasty); however, if the cornea has central corneal scarring or significant anterior stromal haze or opacity involving the visual axis, the choice would be a PK. If there is a corneal scar centrally and

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Figure 2-10. Donor cornea preparation. (A) Donor corneal tissue is encased in an artificial anterior chamber after filling the concave well with Optisol and trephination of the donor cornea is performed from the epithelial surface. (B) Trephination did not result in a complete 360-degree full-thickness cut. Hence, a superblade is used to create a full-thickness incision. (C) The donor cornea is then excised using corneal microscissors and a 0.12 forceps. (D) The excised donor corneal disc is set aside with the epithelial side down until ready for use.

Figure 2-11. (A) The central corneal dome is marked with a sterile needle in a pseudophakic eye with a previous corneal transplant, corneal scar, and blurred vision. (B) Previous corneal graft diameter is measured using a Castroviejo caliper to help determine the diameter of the trephine to use on the recipient cornea. (C) A Hanna trephine is used to trephine the recipient cornea set to a depth of 400 µm. (D) The trephination coincides with the previous circular corneal wound. Also seen are the corneal radial marking previously placed with a radial keratotomy marker highlighted with a marking pen. The surface of the cornea is dried with a Weck-Cel spear to examine the partial-thickness corneal wound.

Figure 2-12. (A) Trephination has resulted in cutting all the corneal sutures on the previous graft. (B) The anterior chamber is entered with a super-blade. (C) Viscoat (sodium hyaluronate) and Miostat (carbachol) are injected into the anterior chamber. (D) The recipient cornea is excised.

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Figure 2-13. (A) Seen through the corneal opening is a more constricted pupil; a large, peripheral iridectomy at the 11-o clock position; and a posterior chamber IOL. (B) Old 10-0 nylon sutures are removed from the host corneal rim using a jeweller s forceps. (C) Viscoat is injected into the anterior chamber. (D) The donor corneal disc is placed on the recipient corneal opening with the endothelial side down.

Figure 2-14. (A) The first 2 corneal suture needles are placed at the 12- and 6-o clock positions, and the 12-o clock needle is passed through the donor and recipient corneas. The second suture placed at 6 o clock is the most important interrupted suture because it divides the tissue, and having equal tissue distribution along this vertical meridian is important for proper seating of the donor corneal disc into the recipient corneal opening. (B) The 6-o clock suture is passed through the wound juncture. (C) All the interrupted and running 10-0 nylon sutures have been placed, and the tension in the running suture is adjusted before tying the running suture. Notice the near-even surface at the donor-recipient corneal junction with no corneal step. (D) Intraoperative keratoscopy is used to control surgically induced corneal astigmatism. The endpoint is the conversion of an oval central configuration of lights to a circular central ring of lights, as seen in this intraoperative photograph. Figure 2-15. (A) Cloudy cornea and cataract. Corneal edema is secondary to Fuchs corneal dystrophy and endothelial decompensation. (B) The central cornea is marked with a sharp needle and highlighted with a sterile marking pen after measuring with a Castroviejo caliper. Also seen are radial markings placed on the recipient epithelial surface using a radial keratotomy marker to assist in subsequent corneal suture placement. (C and D) Preparation of the donor corneal disc using an artificial anterior chamber and a Hanna trephine with the blade depth set to achieve a fullthickness circular corneal incision.

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Figure 2-16. (A-C) The recipient cornea is almost completely excised, and the corneal disc is laid flat on the ocular surface with the endothelial side up at the 3-o clock position. The host cornea is set in this position for the possibility of quick wound closure in the event of a sudden increase in posterior vitreous pressure and a potential suprachoroidal hemorrhage. (D) The cataractous lens surface is seen. A capsulorrhexis is performed using a Vannas scissors.

Figure 2-17. (A) The excised anterior capsular disc is removed. (B and C) Hydrodissection is followed by removal of the lens nucleus using the tip of the hydrodissection canula. (D) The lens cortical material is removed using an irrigation/aspiration unit, leaving an intact posterior lens capsule.

Figure 2-18. (A) Viscoat is injected into the posterior lens capsule. (B-D) A large optic posterior chamber IOL is placed in the posterior capsular bag, followed by injection of Miostat and Viscoat.

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Figure 2-19. (A) The donor corneal disc is placed over the recipient central corneal opening. (B) The donor corneal disc is secured with 10-0 nylon sutures. (C) Viscoat is placed on the surface to protect the epithelium. (D) Completed view of the triple procedure. Notice the constricted pupil.

Figure 2-20. (A) A cataract is visualized looking through the cloudy cornea with decompensated Fuchs corneal dystrophy. (B) Hydrodissection is performed using a blunt cannula. (C) Phacoemulsification of the nucleus. (D) The cortical lens material is removed.

Figure 2-21. (A) Following phacoemulsification, a foldable acrylic PC IOL is placed in the posterior capsular bag. (B) The donor cornea is seen within an artificial anterior chamber filled with Optisol GS (Bausch + Lomb Surgical). (C) Digital palpation is used to assess the intrachamber pressure prior to trephination. (D) A Hanna trephine is used to trephine the donor cornea from the epithelial side.

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Figure 2-22. (A) Following trephination of the donor cornea, the donor corneal disc is excised. (B) A Hanna trephine is used to trephine the recipient cornea to a depth of 400 µm. (C and D) The recipient cornea is excised. Notice the single 10-0 nylon suture holding the temporal, clear corneal wound closed.

Figure 2-23. (A) The recipient cornea has been excised, the PC IOL is visible through the central corneal opening, and the pupil has been constricted following the phacoemulsification procedure by injecting Miostat. (B and C) The donor cornea is placed in the corneal opening with Viscoat in the anterior chamber. (D) Completed view of the triple procedure with intraoperative keratoscopy using the Mastel keratoscope (Mastel, Inc) displaying a near-circular ring of lights.

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a cataract contributing to compromised vision interfering with the individual’s daily activities, a triple procedure that includes a PK could be performed. Alternatively, a temporal approach phacoemulsification with a foldable PC IOL implantation may be concluded with a suture closure of the temporal, clear corneal wound, and then the surgeon can proceed with the PK during the same procedure. If visualization of the cataract through a cloudy cornea is poor, the corneal epithelium may be removed in an attempt to improve the view. Such an approach decreases the time of the open-sky part of the surgery. However, if the view through the cornea were too poor to adequately visualize the lens, then an open-sky approach would be the route for cataract extraction. The PK part of the surgery is the same as described previously. The pupil is dilated preoperatively to assist in the cataract removal. Capsulotomy is performed using a capsulorrhexis technique or by freehand cutting of the anterior lens capsule using a curved Vannas scissors to create a capsular opening large enough to deliver the cataractous lens nucleus. To augment visualization of the anterior lens capsule, it may be stained using trypan blue. Avoid any iris contact with any of the instruments because it can contribute to premature pupillary constriction. The central cut and freed capsular disc is then removed, leaving a fairly round capsular opening of 6.0 mm or larger diameter. Following adequate hydrodissection, the lens nucleus can be gently prolapsed out of the capsular bag and then delivered with a lens loop, taking care not to accidentally tear the posterior lens capsule. A cleavage plane can be created using a 25-gauge irrigating cannula, and the lens loop can be introduced into this cleavage plane to deliver the nucleus. A counterclockwise rotary motion with the 25-gauge irrigating cannula or similar instrument can spin the nucleus out of the

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posterior capsular bag. Alternatively, a cryoprobe extraction of the nucleus may be used for lens delivery. Often the combination of hydrodissection of the lens with hydroexpression will release the lens from the capsular bag. The lens cortex is removed using an automated irrigation-aspiration system. Alternatively, a mechanical irrigation and aspiration technique can be used. Because it is an open-sky approach, usually a high vacuum level is used for cortical removal. Next, viscoelastic is used to fill an intact posterior capsular bag, the chosen IOL is placed within the capsular bag, and the pupil is constricted using Miostat (carbachol). Additional viscoelastic is placed over the constricted iris, and the donor corneal disc is placed in position and sutured in place as described previously. Whereas a triple procedure is performed in a single stage, proponents of a staged procedure— often in 6- to 12-month intervals, such as an initial PK followed by phacoemulsification and a subsequent PC IOL when the cornea has stabilized (reproducible topographic and keratometric readings)—feel this approach contributes to greater accuracy for the IOL power calculation. However, one must weigh the pros and cons of a staged procedure over a triple procedure with regard to the visual outcome, surgical cost, and waiting time interval between 2 procedures for visual rehabilitation. In addition, performing a phacoemulsification after a PK can contribute to some endothelial cell loss from the grafted cornea. In 1966, Katzin and Meltzer29 reported their combined technique of PK and cataract extraction, and 10 years later IOL was added to this approach.31 Although a triple procedure has been successful, there is no exact formula that would provide the best IOL power calculation to provide emmetropia following the procedure. In a triple procedure, some surgeons use an average corneal curvature power from their PK patient pool, often choosing keratometric readings from 44.00 to 45.00 diopters. In addition, the fellow eye keratometric readings may be considered. However, there is no definitive way to predict the final keratometric readings of the transplanted corneal graft preoperatively. Also to be considered is the iatrogenic introduction of a variable amount of corneal astigmatism following a PK.

Penetrating Keratoplasty With Intraocular Lens Exchange Following removal of an existing IOL, a secondary IOL with or without anterior vitrectomy, depending on the presence or absence of vitreous in the anterior chamber, is placed either in the anterior or posterior chamber depending on the anatomic restraints and the surgeon’s choice. Options include a transclerally sutured PC IOL, an iris-sutured PC IOL, and an open-loop, flexible AC IOL.

Scleral-Fixated Posterior Chamber Intraocular Lens To avoid the ciliary blood vessels and the long posterior ciliary nerve in the horizontal meridian, conjunctival peritomies are created approximately 3.0 mm in length at the oblique meridian at the 2- and 8-o’clock positions or, alternatively, at the 10- and 4-o’clock positions, and hemostasis is achieved using a bipolar cautery. The two methods of scleral fixation are an open-sky method (from the interior of the eye through the pupil, behind the iris, and exiting the sclera), called the ab interno approach, or passing the needles from the outside through the sclera to the interior of the eye, called the ab externo approach. The ab externo approach has less duration of ocular hypotony compared with the ab interno approach. However, in a triple procedure involving a PK, the ab interno approach may be more suitable because it is an open-sky approach. Important considerations include the IOL type and the site of suture fixation. The IOL should have a largediameter optic (7.0 mm) to allow for any decentration and the presence of haptic eyelets to allow fixation sutures to pass through. Examples of IOLs include CZ70BD (Alcon Laboratories, Inc) and C540MC (Ciba Vision, Inc). Sutures with long needles are preferred, such as the CIF-4 and STC-6 (Ethicon, Inc). 10-0 polypropylene sutures are used. Attachment of the suture to the IOL haptic may take various forms, such as tying the suture (to the IOL haptic, proximal to one of the

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eyelets on the haptic, or to the haptics eyelets), using a girth hitch to attach the suture loop to the PC IOL haptic, or passing the suture through the positioning hole.33 With the last technique, the scleral flap may be eliminated and the suture knot can be buried within the sclera because the suture on the other end can slide through the positioning hole. The needle is passed through the corneal opening, via the pupil, behind the iris, through the ciliary sulcus, and exiting the sclera at approximately 0.75 mm from the limbus beneath a previously dissected scleral flap. The second needle exits the sclera approximately 1.5 to 2.0 mm lateral to the exit site of the first needle. The suture is tied, and the scleral flap and conjunctiva are closed. The visual results of secondary scleral-fixated PC IOL are comparable to other techniques; hence, it is the surgeon’s choice based on his or her comfort level performing the procedure.32

Anterior Chamber Intraocular Lens Round-loop or closed-loop AC IOLs are usually removed at the time of PK and replaced with a flexible tripod AC IOL or a scleral-fixated PC IOL because it is often associated with pseudophakic bullous keratopathy.33,34 In addition, any decentered AC IOLs with visual symptoms, AC IOLs with endothelial touch, and AC IOLs with secondary uveitis are also removed. Anglefixated AC IOLs are often removed by cutting the IOL haptics in the far peripheral region and removing the optic first, followed by removal of haptic segments that may be rotated out of any fibrotic cuff encircling the haptic. Small haptic segments encased in the angle may be left behind if removal would cause more tissue damage.

Iris-Fixated Intraocular Lens Iris-fixated IOLs, such as Artisan/Verisyse style (Opthtec Inc/Abbott Medical Optics Inc), can be disenclaved, resulting in significant IOL mobility, corneal endothelial touch, and secondary visual symptoms that may be exchanged with a new IOL at the time of PK.

Penetrating Keratoplasty With Boston Keratoprosthesis The Boston keratoprosthesis is a collar-button–design keratoprosthesis or artificial cornea that consists of a front plate with a stem, a back plate, and a titanium locking c-ring. The optical part of the device is housed within the front plate. This device is assembled with a donor corneal graft that is sandwiched between the 2 plates after performing a central 3.0-mm trephination to allow for the stem to pass through the corneal graft.35 This assembled unit is then transplanted to the recipient corneal opening with interrupted 10-0 nylon sutures.35

Pediatric Penetrating Keratoplasty Pediatric PK is associated with several unique challenges and requires a team comprising the corneal surgeon and a pediatric ophthalmology group for pre- and postoperative management that will contribute to the overall success of the procedure. In the past, corneal surgeons often elected not to recommend surgery in pediatric unilateral corneal opacities due to the surgical challenges, strong postoperative inflammatory response to a PK, secondary glaucoma, amblyopia management, graft rejection, and treatment compliance.36-40 However, to prevent amblyopia, early PK is preferred.

Etiology of Pediatric Corneal Opacities Congenital • Peters’ anomaly • Congenital corneal dystrophies

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Sclerocornea Glaucoma with corneal edema Metabolic disorders Congenital anterior staphyloma

Acquired Nontraumatic • • • • • •

Herpes simplex keratitis Bacterial keratitis Interstitial keratitis Ophthalmia neonatorum Neurotrophic keratitis Keratoconus

Acquired Traumatic • Birth trauma • Lacerations (corneal and corneoscleral) • Nonpenetrating traumatic injury with corneal opacity

Pediatric Penetrating Keratoplasty Technique Surgical challenges including the smaller size of an infant eye, increased elasticity and decreased rigidity of the infant cornea and sclera, positive vitreous pressure with forward displacement of the lens-iris diaphragm, and intraoperative fibrin formation all add to the complexity of pediatric PK.41-45 Also, the cornea is often thinner and more pliable, and lens expulsion is a potential threat, especially in infants. An optimal initial office examination at 7 to 14 days old will help in the planning of surgical management. An examination under anesthesia is often planned at 3 to 6 weeks of age, and a PK, when indicated, is performed at 8 to 12 weeks of age. Considering the risk of amblyopia in bilateral corneal opacities, unlike in an adult PK, the less severe eye may be operated on first. General anesthesia is used for the procedure. Factors to consider include using a pediatric anesthesiologist, positioning the head slightly higher than the feet in an attempt to reduce positive pressure, using a Honan balloon (Ambler Surgical, Inc) (30 mm Hg for 5 minutes or longer) or manual digital ocular massage, using intravenous mannitol (0.5 to 1.5 g/kg/dose) to reduce vitreous pressure, using paralysis with nondepolarizing muscle relaxant monitored with a peripheral nerve stimulator, and performing a lateral canthotomy, especially in cases of small palpebral fissures. Measure corneal diameter to help determine trephine size. The recipient corneal trephination can often range between 5.0 to 7.0 mm, with a 0.5- to 1.0-mm oversized donor corneal graft to decrease the potential for goniosynechiae formation, provide sufficient anterior chamber depth, and possibly lower the incidence of postoperative glaucoma. A Flieringa ring or scleral support ring that is 2 to 3 mm larger than the corneal diameter is attached to the episclera with 4 6-0 Vicryl sutures (polyglactin 910; Ethicon, Inc) to prevent intraoperative scleral collapse. Additional sutures may be used as needed. Avoid any potential pressure on the globe during surgery. As in adult PK, the geometric corneal center is measured and marked to help in the trephine centration. Trephination of the donor cornea is followed by trephination of the recipient cornea. Following anterior chamber entry with a 15-degree superblade, a viscoelastic agent is injected into the anterior chamber, and the recipient cornea is excised using pediatric corneal transplant scissors. Synechia, if any, are lysed. Anterior chamber irrigation with heparin solution (100 U/mL) immediately post-trephination has been recommended to combat intraoperative fibrin formation.46 At this time, there may often be significant positive pressure. Every attempt should be made to prevent lens or vitreous loss. Donor corneal graft is sutured in place with 12 to 16 interrupted

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10-0 nylon sutures placed at 90% corneal depth, with suture knots buried within the cornea. An indirect ophthalmoscopic examination of the posterior segment may be performed while the child is still under general anesthesia. At the conclusion of the procedure, subconjunctival antibiotic and corticosteroid injection is combined with antibiotic-corticosteroid ophthalmic ointment application and the eye is patched with an eye patch, and a shield is taped into place.

Factors to Consider Donor-Recipient Wound Size The donor-to-recipient corneal diameter relationship may change depending on the indication for which the PK is being performed. Often the surgeon may prefer to have a 0.5-mm differential between the donor and recipient corneal diameters, with the donor corneal disc being larger than the opening in the recipient corneal bed. However, for keratoconus it is preferable to have no diameter differential between the donor and the recipient corneas. So, in keratoconus, one often uses the exact same corneal-diameter trephine for both the donor and the recipient corneas. In aphakic eyes, one may prefer to have a 1.0-mm differential in corneal diameters between the donor and the recipient.

Suture Patterns and Suture Materials The suture material of choice for PK is nylon. The spectrum of corneal suturing techniques ranges from a combination of interrupted sutures with a single running suture, to all interrupted sutures, to double-running sutures. Although for the most part 10-0 nylon sutures are used, sometimes with double-running sutures, the first running suture may be 10-0, followed by an 11-0 or 10-0 nylon suture for the second running suture. The initial step with all grafting techniques is the fixation of the graft to the donor cornea with 4 cardinal sutures at the 12-, 6-, 3-, and 9-o’clock positions. The first suture is placed at the 12-o’clock position. The donor corneal disc may be held with a double-prong forceps, such as a Polack forceps (Rumex Inc), for better donor disc stabilization, and the needle is passed between the two prongs of the forceps. For all subsequent sutures, a 0.12 forceps may be used. The second corneal suture is the most important suture because it determines the proper seating of the donor graft. This suture is placed at the 6-o’clock position, and the graft should have equal corneal tissue on either side of this suture. The last two cardinal sutures are placed at the 3- and 9-o’clock positions, and this provides the initial fixation of the donor graft to the recipient corneal bed. Whereas the interrupted sutures are placed deep within the corneal stroma of the donor and recipient corneas, the running sutures are somewhat more superficial. Avoid sutures passing through the full thickness of the donor graft. All suture knots are buried within the cornea to provide patient comfort. Knots may be buried within the donor cornea or the recipient cornea. However, some are of the opinion that knots buried within the host cornea may be more prone to corneal neovascularization. Use of intraoperative keratoscopy can provide optimal suture tension and astigmatism control.

Positive Vitreous Pressure Management General anesthesia often negates any positive vitreous pressure that may occur in association with retrobulbar anesthesia and monitored anesthesia care. Preoperative use of a mechanical balloon along with intravenous mannitol reduces the intraocular pressure; however, it does not always prevent positive vitreous pressure. In some instances, a vitreous tap or limited vitrectomy may be required. If an early choroidal hemorrhage is suspected, quick digital tamponade by placing the surgeon’s thumb into the recipient corneal opening may avert an expulsive choroidal hemorrhage. Quick suturing of the donor cornea in such instances is essential. Sometimes, fast application of four needles to hold the donor cornea in place may then be followed by tying each of the sutures sequentially.

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Complications Intraoperative • • • • • • • •

Eccentric trephination of recipient cornea Donor corneal iatrogenic damage Improper trephination of donor/recipient cornea Damage to iris and lens Hemorrhage Expulsive choroidal hemorrhage and loss of intraocular contents Iris incarceration to surgical wound Vitreous to the wound and anterior chamber

Postoperative • • • • • • • • •

Corneal wound leak Primary endothelial failure Corneal graft rejection Corneal graft failure Primary disease recurrence in graft Persistent epithelial defect, corneal melt, descemetocele Postkeratoplasty glaucoma Microbial keratitis and ulceration: bacterial, fungal, viral, parasitic (acanthamoeba) Endophthalmitis

Conclusion PK remains a viable type of corneal transplant procedure even when challenged by lamellar keratoplasty techniques. Attention to detail during both the donor and recipient parts of the surgical procedure is essential to optimize the surgical outcome. Intraoperative keratoscopy is highly recommended to decrease the iatrogenic corneal astigmatism associated with PK.

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Eye Bank Association of America. 2012 Eye Banking Statistical Report. http://www.restoresight.org/ wp-content/uploads/2013/04/2012_Statistical_Report_FINAL-reduced-size-4-10.pdf. Accessed July 8, 2014. Castroviejo R. Keratoplasty for the treatment of keratoconus. Trans Am Ophthalmol Soc. 1948;46:127-153. Dobbins KR, Price FW Jr, Whitson WE. Trends in the indications for penetrating keratoplasty in the midwestern United States. Cornea. 2000;19(6):813-816. Ghosheh FR, Cremona F, Ayres BD, Hammersmith KM, Cohen EJ, Raber IM, Laibson PR, Rapuano CJ: Indications for penetrating keratoplasty and associated procedures, 2001-2005. Eye Contact Lens. 2008;34:211-214. Al-Yousuf N, Mavrikakis I, Mavrikakis E, Daya SM. Penetrating keratoplasty: indications over a 10 year period. Br J Ophthalmol. 2004;88(8):998-1001. Yahalom C, Mechoulam H, Solomon A, Raiskup FD, Peer J, Frucht-Pery J. Forty years of changing indications in penetrating keratoplasty in Israel. Cornea. 2005;24(3):256-258. Dandona L, Ragu K, Janarthanan M, Naduvilath TJ, Shenoy R, Rao GN. Indications for penetrating keratoplasty in India. Indian J Ophthalmol. 1997;45(3):163-168. Wang JY, Xie LX, Song XS, Zhao J. Trends in the indications for penetrating keratoplasty in Shandong, 2005-2010. Int J Ophthalmol. 2011;4(5):492-497. Galvis V, Tello A, Gomez AJ, Rangel CM, Prada AM, Camacho PA. Corneal transplantation at an ophthalmological referral center in Colombia: indications and techniques (2004-2011). Open Ophthalmol J. 2013;7:30-33.

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10. Qazi Y, Hamrah P. Gene therapy in corneal transplantation. Semin Ophthalmol. 2013;28(5-6):287-300. 11. Niederkorn JY, Larkin DF. Immune privilege of corneal allografts. Ocul Immunol Inflamm. 2010;18(3):162-171. 12. Niederkorn JY. The immune privilege of corneal grafts. J Leukoc Biol. 2003;74(2):167-171. 13. Streilein JW. New thoughts on the immunology of corneal transplantation. Eye (Lond). 2003;17(8):943-948. 14. Yamada J, Yoshida M, Taylor AW, Streilein JW. Mice with Th2-biased immune systems accept orthotopic corneal allografts placed in “high risk” eyes. J Immunol. 1999;162(9):5247-5255. 15. He YG, Niederkorn JY. Depletion of donor-derived Langerhans cells promotes corneal allograft survival. Cornea. 1996;15(1):82-89. 16. Dietrich T, Bock F, Yuen D, et al. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol. 2009;184(2):535-539. 17. Yavitz EQ. Topical and intracameral anesthesia for corneal transplants. J Cataract Refract Surg. 1997;23(10):1435. 18. Muraine M, Calenda E, Watt L, et al. Peribulbar anaesthesia during keratoplasty: a prospective study of 100 cases. Br J Ophthalmol. 1999;83(1):104-109. 19. Aquavella JV. Outpatient corneal surgery. Int Ophthalmol Clin. 1988;28(2):184-187. 20. Collie DM. Outpatient penetrating keratoplasty. Aust N Z J Ophthalmol. 1989;17(4):373-377. 21. Burdon MA, McDonnell P. A survey of corneal graft practice in the United Kingdom. Eye (Lond). 1995;9(Pt 6 Su):6-12. 22. Ingraham HJ, Donnenfeld ED, Perry HD. Massive suprachoroidal hemorrhage in penetrating keratoplasty. Am J Ophthalmol. 1989;108(6):670-675. 23. Ward DE, Nesburn AB. An artificial anterior chamber. Am J Ophthalmol. 1976;82(5):796-798. 24. John T. Corneal trephines, cutting blocks and artificial anterior chambers. In: Brightbill FS, ed. Corneal Surgery: Theory, Technique and Tissue. 4th ed. Philadelphia, PA: Mosby Elsevier; 2009:305-312. 25. Hassan TS, Soong HK, Sugar A, Meyer RF. Implantation of Kelman-style, open-loop anterior chamber lenses during keratoplasty for aphakic and pseudophakic bullous keratopathy. A comparison with iris-sutured posterior chamber lenses. Ophthalmology. 1991;98(6):875-880. 26. Lass JH, DeSantis DM, Reinhart WJ, Hossain TS, Hom DL. Clinical and morphometric results of penetrating keratoplasty with one-piece anterior-chamber or suture-fixated posterior-chamber lenses in the absence of lens capsule. Arch Ophthalmol. 1990;108(10):1427-1431. 27. Kasbekar S, Prasad S, Kumar BV. Clinical outcomes of triamcinolone-assisted anterior vitrectomy after phacoemulsification complicated by posterior capsule rupture. J Cataract Refract Surg. 2013;39(3):414-418. 28. Vasavada AR, Shah S, Praveen M. Safety of intracameral preservative-free triamcinolone acetonide during anterior vitrectomy. J Cataract Refract Surg. 2013;39(9):1452. 29. Katzin HM, Meltzer JF. Combined surgery for corneal transplantation and cataract extraction. Am J Ophthalmol. 1966;62(3):556-560. 30. Taylor DM. Keratoplasty and intraocular lenses. Ophthalmic Surg. 1976;7(1):31-42. 31. Steinert RF, Arkin MS. Secondary intraocular lenses. In: Steinert RF, ed. Cataract Surgery: Techniques, Complications, and Management. 2nd ed. Philadelphia, PA: WB Saunders; 2004:429-441. 32. Mamalis N, Crandall AS, Pulsipher MW, Follett S, Monson MC. Intraocular lens explantation and exchange: a review of lens styles, clinical indications, clinical results, and visual outcome. J Cataract Refract Surg. 1991;17(6):811-818. 33. Kornmehl EW, Steinert RF, Odrich MG, Stevens JB. Penetrating keratoplasty for pseudophakic bullous keratopathy associated with closed-loop anterior chamber intraocular lenses. Ophthalmology. 1990;97(4):407-412. 34. Todani A, Gupta P, Colby K. Type I Boston keratoprosthesis with cataract extraction and intraocular lens placement for visual rehabilitation of herpes zoster ophthalmicus: the “KPro Triple.” Br J Ophthalmol. 2009;93(1):119. 35. Schanzlin DJ, Goldberg DB, Brown SI. Transplantation of congenitally opaque corneas. Ophthalmology. 1980;87(12):1253-1264. 36. Waring GO III, Laibson PR. Keratoplasty in infants and children. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1977; 83(2):283-296. 37. Brown SI. Corneal transplantation of the infant cornea. Trans Am Acad Ophthalmol Otolaryngol. 1974;78(3):OP461-OP466. 38. Beauchamp GR. Pediatric keratoplasty: problems in management. J Pediatr Ophthalmol Strabismus. 1979;16(6):388-394. 39. Stulting RD, Sumers KD, Cavanagh HD, Waring GO III, Gammon JA. Penetrating keratoplasty in children. Ophthalmology. 1984;91(10):1222-1230. 40. Cowden JW. Penetrating keratoplasty in infants and children. Ophthalmology. 1990;97(3):324-328.

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Aasuri MK, Garg P, Gokhle N, Gupta S. Penetrating keratoplasty in children. Cornea. 2000;19(2):140-144. 42. Vajpayee RB, Ramu M, Panda A, Sharma N, Tabin GC, Anand JR. Oversized grafts in children. Ophthalmology. 1999;106(4):829-832. 43. Dana MR, Moyes AL, Gomes JA, et al. The indications for and outcome in pediatric keratoplasty. A multicenter study. Ophthalmology. 1995;102(8):1129-1138. 44. Huang C, O’Hara M, Mannis MJ. Primary pediatric keratoplasty: indications and outcomes. Cornea. 2009;28(9):1003-1008. 45. Frueh BE, Brown SI. Transplantation of congenitally opaque corneas. Br J Ophthalmol. 1997;81(12):1064-1069. 41.

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3 Automated Lamellar Therapeutic Keratoplasty Namrata Sharma, MD and Prafulla K. Maharana, MD Lamellar keratoplasty (LK), which replaces only diseased corneal layers, has evolved as an alternative to penetrating keratoplasty (PK) for the surgical treatment of corneal pathologies not involving the full thickness of the cornea. Over the past decade, innovations in surgical technique and instrumentation in LK have led to visual outcomes as good as those of PK. The major limitations of LK are that it is technically more demanding and time consuming to perform and that interface irregularity or scarring may give rise to suboptimal visual results.1,2 To overcome this, a number of modifications have been made, including the use of microkeratomes, originally designed for laser-assisted in situ keratomileusis (LASIK) surgery and the semiautomated procedure of automated lamellar therapeutic keratectomy (ALTK; Moria S.A.).2,3 ALTK uses a gas turbine–driven microkeratome to perform both the recipient bed lamellar dissection and lamellar dissection of the donor button with the use of an artificial chamber maintainer.2,3

Indications for Automated Lamellar Therapeutic Keratoplasty The indications for ALTK include diseases involving the anterior to midstromal part of the cornea with a normal endothelium: • Superficial corneal dystrophies such as basement membrane dystrophy and early granular dystrophy4 • Early stages of keratoconus when the corneal thickness is 380 μm or greater4,5 • Chemical burns affecting the superficial layers only4 • Superficial corneal scars after trauma, postinfection leucomas, trachoma, Salzmann’s nodular degeneration, band-shaped keratopathy, herpes, and postexcimer surgery corneal haze2,6,7 • Tectonic purposes in patients with significant corneal thinning and impending perforation8 A modified microkeratome with a redesigned head has also been evaluated for limbal stem cell harvest and transplantation.9

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Contraindications for Automated Lamellar Therapeutic Keratoplasty The contraindications for ALTK include the following: • Endothelial dysfunction. The presence of endothelial abnormality is an absolute contradiction to ALTK.1,4 • Disorders of the lids, including ectropion, entropion, trichiasis, lagophthalmos, and severe blepharitis. These abnormalities must be treated before proceeding to ALTK.4 • Tear film abnormality which includes dry eye and keratoconjunctivitis sicca.4 • Associated diseases which include uncontrolled uveitis and glaucoma.4 • Anatomical factors. Deep-set eyes or small palpebral apertures preclude the use of a microkeratome for host bed preparation.4 • Advanced keratoconus. Severe ectasia and thinning are at increased risk of corneal perforation during host bed preparation, and ALTK should be avoided in these cases.4,5 • Posterior segment pathology may preclude attainment of good visual acuity after ALTK. • Impaired wound healing which includes an immunocompromised patient, collagen vascular disorders, and a history of abnormal wound healing (eg, keloid formation).

Preoperative Evaluation Preoperative evaluation of a patient undergoing ALTK is similar to that of a routine manually dissected LK. Pachymetry is of special relevance because the depth of the dissection is dictated by the depth of the pathology as well as the microkeratome head available. Ultrasound pachymetry should be performed for the central and peripheral areas of the cornea to look for significant irregularity in corneal thickness. Anterior segment optical coherence tomography, if available, is of significant help in preoperative planning of ALTK. It can provide the exact depth of scarring and pannus in cases of chemical burns. Thus, it helps in making the decision regarding which size of microkeratome head to use.

Surgical Technique Preparation of the Recipient Bed The recipient lamellar bed is prepared using a suction ring and an automated microkeratome in a manner similar to that for LASIK. The suction ring determines the size of the lenticule obtained. The suction ring is available in sizes + 2, + 1, 0, and – 1, producing smaller to larger lenticules, respectively, for the same keratometry. The automated microkeratome is used as a cutting instrument. The advancement of the microkeratome over the suction ring can be motor driven or manual. The microkeratome is available in a range of heads, such as 120, 180, 250, and 350 μm, which can used depending on the desired depth of the lamellar cut. The goal is to cut a disc with the same diameter (or 0.5 mm undersized) and thickness as the donor disc. Once the disc is removed, the recipient bed is washed with balanced salt solution and dried with a sponge.

Preparation of the Donor Lenticule The donor lenticule may be obtained from a corneoscleral rim. The corneoscleral rim should be at least 4 mm wide because the frill of the corneoscleral rim must be positioned on the artificial anterior chamber maintainer. The artificial anterior chamber consists of a stainless steel structure with 3 screw-type safety rings. The lower ring sustains a metal device that covers the superficial sclera and maintains a tight fit on the metal base of the chamber to avoid leakage. A second ring in an intermediate position approximates the chamber on the former structure to tighten the sclera from above. A third ring located superiorly is adjusted to modify the height of the microkeratome plate. This plate is a gearless track to guide the microkeratome head translation at a constant

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Figure 3-1. ALTK microkeratome head.

Figure 3-2. Preparation of donor cornea mounted on artificial chamber.

height along the corneal pass. Depending on the height at which this plate is positioned, more (lower position) or less (higher position) of the cornea is exposed, resulting in a larger or smaller lenticule diameter, respectively. The chamber is connected to the infusion system with a reservoir of saline solution placed 1.2 m above the chamber level. An expansion air chamber is located within the infusion line 10 cm from the connection to the chamber. The pressure should be more than 60 mm Hg and should be checked with a Barraquer tonometer. Pressure as high as 95 mm Hg has been suggested to ensure a donor lenticule with more consistent thickness. We use an LSK microkeratome (Moria S.A.) to perform ALTK. It consists of a single-piece metal head connected to a nitrogen gas–driven hand piece. The blade oscillates at a rate of 15,000 oscillations/min with an orientation of 25 degrees to the cut plane (Figure 3-1). The grooves on the base plate of the artificial anterior chamber are designed to fit into the microkeratome head; hence, its pass along the cornea is uniform. To reduce the number of air bubbles beneath the cornea, rims are placed on the chamber base after the infusion is released. Once the cornea is stabilized and centered and the absence of air bubbles is confirmed, the infusion is closed, the superior metal support is placed and locked by turning the first ring clockwise, and the second ring is turned counterclockwise to elevate the chamber height and tighten the scleral skirt between the support and chamber (Figure 3-2). The applanation lens is then placed on the cornea to determine the plate height for the desired diameter, turning the second ring counterclockwise or clockwise depending on the guiding circle marks on the lenses. Drops of saline solution are placed on the cornea, and keratectomy is performed by passing the microkeratome head with its oscillating blade at a relatively constant speed along the plate (Figures 3-3 to 3-5). The diameter of the flap that has been cut is then measured (Figure 3-6). Behrens et al10 reported that the precision and accuracy of this system varies according to the attempted thickness and diameter. Greater precision is obtained if the diameter of the cut is less than 8 mm or if the flaps are thinner.

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Figure 3-3. Donor cap after a complete microkeratome pass.

Figure 3-4. Microkeratome head on host cornea.

Figure 3-5. Microkeratome pass for host preparation.

Donor-Recipient Apposition The donor lenticule is placed on the recipient bed (Figure 3-7). Although some surgeons leave the donor lenticule adhered to the recipient bed with no sutures, we prefer to use at least 8 interrupted 10-0 monofilament nylon sutures (Figures 3-8 and 3-9). The eye is then patched for 24 hours. The use of fibrin glue instead of sutures has also been suggested for securing the donor lenticule over the host bed.11 Postoperatively, the patient receives topical antibiotics, dilute corticosteroids, and preservative-free artificial tears, which are then subsequently tapered. The femtosecond laser is the latest addition in the armamentarium available for lamellar corneal procedures. Its main advantages over the microkeratome include better safety, reproducibility,

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Figure 3-6. Host bed after a complete microkeratome pass.

Figure 3-7. Placement of donor button on host surface.

Figure 3-8. Placement of initial 4 cardinal sutures.

predictability, and flexibility. Use of a femtosecond laser for ALTK has been reported, although larger studies are required to better understand the full scope of its usefulness.12

Advantages In addition to the advantages of LK over PK, ALTK offers the following advantages over manual LK:

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Figure 3-9. Appearance after completion of the procedure.

• Better visual outcome because an automated microkeratome allows the surgeon to obtain corneal lenticules with parallel faces that are almost identical in the donor and the recipient corneas. These factors result in optical and refractive results that are better than those obtained with manual techniques. The cut made by the microkeratome is regular and homogeneous, producing a smooth surface without significant chatter lines, as seen with a scanning electron microscope.13 This prevents the irregular astigmatism that occurs with a manual procedure because of the horizontal adherence of the disc to the donor tissue. • Shortened surgical time because both donor and host are prepared using the microkeratome.4 • Few suture-related complications because fewer sutures are required for shorter periods of time.14 The procedure may be combined with phacoemulsification if a significant cataract is present. Removal of anterior diseased corneal tissue allows better visualization for phacoemulsification.

Disadvantages The major disadvantage of conventional ALTK surgery is a lack of precision in flap diameter.2 Both host and donor flap diameters are dependent on the variable suction pressures obtained with each microkeratome pass. In addition, host flap diameter depends on the corneal curvature. Variable suction may also result in a decentered cut and, often, in a flap that is not perfectly circular. Thus, a variable flap diameter may be obtained in both recipient and donor dissection, resulting in a donor-recipient mismatch. Also, the shelving edges obtained may result in less precise edge apposition between donor and recipient during graft suturing.2

Complications Complications associated with ALTK are usually microkeratome related. The most dreaded but uncommon complication is corneal perforation during recipient bed preparation.4 It usually occurs in corneas with abnormal keratometry, as with keratoconus, or in corneas with irregular corneal thickness and localized areas of significant corneal thinning. The microkeratome head and suction ring should be carefully chosen according to keratometry and pachymetry to avoid this complication. An incomplete pass of the microkeratome may result in partial flap formation from resistance to the movement of the microkeratome or loss of suction. Patients with deep-set eyes and small palpebral apertures are especially predisposed. Another complication is a significant discrepancy in the size and thickness of the host bed and donor lenticule. It has been shown that almost 85% of recipient beds have a diameter within 0.5 mm of the desired lenticule diameter, but a few cases may have a diameter that is too high or too low due to improper choice of suction ring or abnormal

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keratometry.9 The donor cornea used may have significant edema during preparation of the lenticule. The donor lenticule will then further reduce in thickness during the postoperative period.9 There are several things a surgeon should consider when using this technique. It is important to obtain lenticules with the same diameter and thickness so that the fit is perfect and future epithelial ingrowth is avoided. Epithelial ingrowth can occur after significant trauma, even many years after surgery.15 The epithelium of the donor should be kept intact as much as possible. The donor epithelium is replaced by the recipient epithelium during the first week. Other complications are similar to those encountered with manual LK. The incidence and severity of interface haze is likely to be less in ALTK due to a smoother interface. Although endothelial rejection does not occur, the possibility of stromal or epithelial rejection should always be kept in mind.15

Outcome of Automated Lamellar Therapeutic Keratoplasty ALTK was undertaken in 48 eyes at our center for various indications, including keratoconus, dystrophies, Salzmann’s nodular degeneration, impacted corneal foreign bodies, and healed bacterial and fungal keratitis. Donor button size ranged from 8.5 to 10 mm (thickness, 350 mm), and host cut size ranged from 8 to 9.5 mm (thickness, 250 mm). Sixteen to 24 interrupted 10-0 monofilament nylon sutures were applied. Mean central corneal thickness was 503 mm. From a preoperative visual acuity of ≤ 2/60 in all eyes, a postoperative visual acuity of ≥ 6/18 was achieved in 32 of 48 patients. Mean epithelialization time was 3 days (range, 1 to 10 days). No cases of interface scarring were seen after a follow-up of 6 months. However, the long-term problem of interface scarring still needs to be ascertained. Although we encountered no major complications, the risk of postoperative complications exists, including delays or defects in epithelialization, epithelial ingrowth in the interface, fibrosis, and even vascularization.15 Edema or melting of the lenticule may also occur. Although an endothelial rejection will not occur, an epithelial and stromal rejection may occur.15 Finally, the original disease may recur.

Conclusion Optical LK performed with an automated microkeratome is a simple, accurate technique. It produces good visual results and is a good alternative to PK, especially in the treatment of anterior corneal pathology.

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Arenas E, Esquenazi S, Anwar M, Terry M. Lamellar corneal transplantation. Surv Ophthalmol. 2012;57(6):510-529. Tan DT, Ang LP. Modified automated lamellar therapeutic keratoplasty for keratoconus: a new technique. Cornea. 2006;25(10):1217-1219. Jiménez-Alfaro I, Pérez-Santonja JJ, Gómez Tellería G, Bueno Palacín JL, Puy P. Therapeutic lamellar keratoplasty with an automated microkeratome. J Cataract Refract Surg. 2001;27(8):1161-1165. Vajpayee RB, Vasudendra N, Titiyal JS, Tandon R, Sharma N, Sinha R. Automated lamellar therapeutic keratoplasty (ALTK) in the treatment of anterior to mid-stromal corneal pathologies. Acta Ophthalmol Scand. 2006;84(6):771-773. Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol. 2011;95(8):1044-1050. Chen W, Qu J, Wang Q , Lu F, Barabino S. Automated lamellar keratoplasty for recurrent granular corneal dystrophy after phototherapeutic keratectomy. J Refract Surg. 2005;21(3):288-293. Tan DT, Ang LP. Automated lamellar therapeutic keratoplasty for post-PRK corneal scarring and thinning. Am J Ophthalmol. 2004;138(6):1067-1069. Wiley LA, Joseph MA, Springs CL. Tectonic lamellar keratoplasty utilizing a microkeratome and an artificial anterior chamber system. Cornea. 2002;21(7):661-663. Chuck RS, Behrens A, McDonnell PJ. Microkeratome-based limbal harvester for limbal stem cell transplantation: preliminary studies. Am J Ophthalmol. 2001;131(3):377-378.

40 10. 11. 12. 13. 14. 15.

Chapter 3 Behrens A, Dolorico AMT, Kara DT, et al. Precision and accuracy of an artificial anterior chamber system in obtaining corneal lenticules for lamellar keratoplasty. J Cataract Refract Surg. 2001;27(10):1679-1687. Chen W, Qu J, Lu F, Zhu RY. Sutureless lamellar keratoplasty by microkeratome combined with fibrin tissue adhesive in rabbits [in Chinese]. Zhonghua Yan Ke Za Zhi. 2004;40(5):331-336. Hoffart L, Proust H, Matonti F, Catanèse M, Conrath J, Ridings B. Femtosecond-assisted anterior lamellar keratoplasty [in French]. J Fr Ophtalmol. 2007;30(7):689-694. Victor G, Sousa SJ, Alves MR, Nosé W. Evaluation of a new system for obtaining donor lamellar grafts. Cornea. 2007;26(2):151-153. Wang TJ, Wang IJ, Hou YC, Hu FR. Giant epithelial ingrowth induced by blunt injury after automated lamellar keratoplasty. J Formos Med Assoc. 2005;104(4):279-281. Kawashima M, Mochizuki H, Kawakita T, Hatoh S, Shimazaki J, Yamada M. Presumed stromal graft rejection after automated lamellar therapeutic keratoplasty: case report. J Med Case Rep. 2007;1:10.

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4 Deep Anterior Lamellar Keratoplasty Laura Vickers, MD and Terry Kim, MD Historically, corneal transplantation has been performed through full-thickness grafting, also known as penetrating keratoplasty (PK). Lamellar keratoplasty (LK) is a more recent approach to allow for preservation of unaffected tissue, and specialized procedures allow for preservation of either the anterior or posterior corneal layers. The main determining factor in whether to use an anterior or posterior approach is the health of the corneal endothelium. The first LK was performed more than 150 years ago, although historically the use of anterior LK was limited by worse visual outcomes compared with PK, as well as the technical difficulty of the procedure.1 In the second half of the 20th century, PK was largely favored. However, in the 1970s, there was an increased interest in lamellar procedures. With advances in the technical approach to deep anterior lamellar keratoplasty (DALK), which involves removal of the central corneal stroma with preservation of Descemet’s membrane and the corneal endothelium, there has been a resurgence in interest in this technique.

Deep Anterior Lamellar Keratoplasty DALK has become an alternative to PK for a variety of indications (Figure 4-1). Recent studies have demonstrated equivalent best corrected visual outcomes and superior preservation of endothelial cell density with DALK compared with PK.2 Interest in DALK has been piqued by its advantages, including enhanced structural integrity, decreased recovery time, and lower incidence of rejection and infection.

Increased Structural Integrity The effect of trauma after DALK has been described in prior reports.3-7 There have been few reports on the protective effect of intact Descemet’s membrane in the setting of globe trauma after DALK.3,5 As in Figure 4-1, the structural integrity of the eye may be maintained after trauma by an intact Descemet’s membrane, preventing the serious complications of a ruptured globe injury, such as infection and severe vision loss. Multiple reports have described full-thickness defects resulting from blunt trauma after DALK.4,7,8 Such cases have worse final visual outcomes overall than the few reported outcomes from partial-thickness injuries. Traumatic injury after PK has been described in a significant body of literature, which has shown that globe rupture secondary to traumatic graft dehiscence can occur years after surgery, most often (although certainly not always) with poor visual outcomes.8 - 41 -

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Figure 4-1. A 30-year-old woman presented with severe pain and blurry vision after blunt eye trauma to the left eye. She had undergone DALK for keratoconus 5 weeks prior with excellent visual results. On examination, she was found to have inferior dislocation of the DALK graft with 2 broken sutures but an intact Descemet s membrane with a prominent descemetocele. The area of dehiscence was Seidel negative, and the globe was intact. Two interrupted sutures were replaced, and the graft was well positioned. Her vision was regained, and the additional risks of frank perforation and open globe injury were avoided. (Reprinted with permission from Alan N. Carlson, MD, Duke University Eye Center, Durham, NC).

Therefore, DALK may have benefits compared with PK in certain patient populations such as children and others at high risk for eye trauma and graft dehiscence.

Decreased Rates of Endothelial Rejection A major advantage of DALK over PK is the increased preservation of endothelial cell density. Because the corneal endothelium remains intact in DALK and only the anterior corneal layers are transplanted into the recipient, there is little to no risk of endothelial cell immune rejection in the graft with resulting retention of the recipient endothelial cells. In contrast, there is significantly more endothelial cell loss after PK. Graft survival is critical in many patients undergoing transplantation for anterior stromal scars after trauma or secondary to keratoconus because many of these patients may be young and otherwise healthy.

Decreased Recovery Time The visual recovery time and course of topical steroids are usually shorter in DALK compared with PK, and sutures are usually removed earlier. Less long-term steroid use is a particular advantage in patients who are phakic and those with glaucoma or a history of steroid-response intraocular pressure elevation. Whereas sutures in PK may remain in place for years after surgery, resulting in variable refraction, sutures can be removed between 3 months and 1 year after DALK. This potentially leads to fewer suture-related complications such as suture-related infection and unpredictable suture breakage.

Avoiding Intraocular Surgery DALK, unlike PK, is not an intraocular surgical procedure. Therefore, the risk of subsequent infection, including endophthalmitis, is lower with DALK, although this has not been studied extensively. In addition, the risk of suprachoroidal hemorrhage and other potential complications of the open-sky technique are absent with DALK.

Special Cases Many case reports demonstrate the broad usefulness of DALK, including the use of bilateral DALK for the management of bilateral post–laser-assisted in situ keratomileusis (LASIK) mycobacterial keratitis and successful DALK in a patient with a descemetocele secondary to severe gonococcal keratitis.9,10 A recent review focused on the use of DALK in pellucid marginal degeneration,11 and a randomized clinical trial focused on DALK in patients with macular corneal dystrophy with good results.12

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Patients with ocular surface disease not affecting the endothelium, such as interstitial keratitis and chemical injuries, may be good DALK candidates. Patients with ocular surface disease with immune compromise or high infection risk, such as neurotrophic ulcers, may be better managed with DALK due to decreased reliance on immune suppressive topical medications after surgery. As discussed later in this chapter, most patients with a functioning endothelium may be candidates for DALK. DALK also has the advantage of potential for use of a 2-step technique to achieve grafting up to 11 mm after the initial DALK procedure, which is useful in certain cases of keratoconus for avoiding late ectasia at the graft-host junction. DALK has also been evaluated in children.13,14 In a small case series, DALK was successful in 11 of 13 eyes, whereas 2 eyes were converted to PK. It was noted that children with mucopolysaccharidoses who have large amounts of glycosaminoglycans in the stroma may not be amenable to DALK with viscodissection or the big bubble technique. There was one case of epithelial rejection, which was managed with repeat DALK with good results.

Cost-Effectiveness The relative cost-effectiveness of DALK vs PK has been addressed. A study from the Netherlands concluded that DALK was overall more costly, but when Descemet’s perforation was avoided, the procedure was more effective (based on the National Eye Institute Visual Functioning Questionnaire).15 Theoretically, the relative cost-effectiveness may be greater with longer followup due to greater retention of endothelial cells after DALK vs PK.

Surgical Technique Most surgeons use full-thickness corneal lenticules. Early direct dissection techniques focused on cryolathed donor lenticules. A recent study compared the use of lyophilized vs Optisol-stored (Chiron Ophthalmics) donor corneas used in DALK among 20 patients with keratoconus.16 There were no major differences in visual outcomes. Keratocyte density was higher among the Optisol-stored corneas initially, although density increased over time in the lyophilized corneas. The donor cornea endothelium is removed, and the donor Descemet’s membrane may or may not be removed depending on surgeon preference. When Descemet’s membrane baring is achieved during DALK, the smooth interface of donor stromal tissue against recipient Descemet’s membrane is thought to provide optimal visual results, whereas retained Descemet’s membrane on the recipient cornea may wrinkle and create interface haze. Additionally, donor endothelial cells contain antigens that may increase rates of subsequent vascularization and graft rejection and potentially delay wound healing. Glycerin-preserved corneal grafts are also acceptable for use in DALK. There are few data available, but studies show similar visual results when compared with fresh donor tissue.17 This preserved tissue offers a solution for corneal transplants in remote locations without eye banks or other access to fresh donor tissue.18 Depending on the patient’s corneal diameter and disease, the DALK bed is typically measured with a diameter of 7 to 8.5 mm (Figure 4-2). A trephine is used to cut through the anterior stromal layer without entering the anterior chamber. The depth of trephination depends on surgeon preference and the depth of disease in the stroma. There has been an evolution in the method of dissecting the corneal stroma from the underlying Descemet’s membrane, with most surgeons now favoring a Descemet’s–baring procedure using the big-bubble technique.

Evolution of Deep Anterior Lamellar Keratoplasty Pre-Descemet’s Versus Maximum-Depth Stromal Dissection Initial descriptions of what was initially termed deep lamellar keratoplasty (DLK) involved removing anterior corneal stroma but usually without baring Descemet’s membrane.19 Later,

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Figure 4-2. (A) A bent 27-gauge needle on an air-filled syringe is advanced into the deep periphery of the trephined cornea, followed by a Tan cannula on an air-filled syringe to inject the air with the goal of dissecting Descemet s membrane off the central cornea. (B and C) Partial keratectomy is performed with a crescent blade to dissect off the superior lamellar tissue. (D) Viscoelastic dissection of Descemet s membrane. (continued)

A

B

C

D

Descemet’s membrane baring or maximum-depth DALK was described.20 One advantage of Descemet’s-baring techniques is decreased interface opacity. Although a Descemet’s-baring procedure may be planned, it may not always be achieved due to Descemet’s perforation or other

Deep Anterior Lamellar Keratoplasty

E

F

G

H

45

Figure 4-2 (continued). (E) Severing of the stroma with an iris spatula. (F) Excision of the 4 quadrants of the deep stroma. (G and H) Trimming off the peripheral rim of corneal tissue. (continued)

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Figure 4-2 (continued). (I and J) Donor tissue is cut to the same size, placed on the host bed, and sutured to the host cornea.

I

J

intraoperative factors. The evolution of Descemet’s-baring techniques has made the procedure technically easier and thus accessible to more corneal surgeons.

Direct Dissection The first description of DALK by Anwar21 implemented direct dissection of the corneal stroma from Descemet’s membrane. In this method, trephination of the anterior stroma is first performed to 60% to 80% depth. The superficial stromal layers are then dissected directly by stretching and lifting the layers while sweeping the blade across the stromal bed.

Intrastromal Air Injection Archila, 22 Price, 23 and Chau et al 24 described an alternative approach to direct dissection using intrastromal air injection prior to trephination. The corneal stroma is expanded to several times its initial thickness via air injection into the stroma with a 26-gauge needle and then becomes opaque. Trephination is then performed, usually leaving residual stroma centrally, which can then be removed by manual dissection down to Descemet’s membrane. A full-thickness lyophilized lenticule with Descemet’s membrane removed is most often used.

Hydrodelamination Sugita and Kondo19 described dissection with hydrodelamination. In this technique, trephination to 75% depth is performed, then saline solution is injected through a 27-gauge needle into the deep central stromal bed and a spatula is used to delaminate the central 5 mm down to the level of Descemet’s membrane, fanning out from the central depression. This approach was initially described using full-thickness cryolathed donor lenticules with Descemet’s membrane removed.

Direct Closed Dissection Melles et al 25 first described closed dissection through a limbal incision. This technique depends on visual determination of the depth of the anterior lamellar dissection. First, air is injected into the anterior chamber to facilitate visualization of the corneal depth, then manual

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dissection of a pre-Descemet’s membrane pocket is performed, and a trephine is used to remove the stromal button. Failure to accurately assess the depth of the dissection can lead to perforation of Descemet’s membrane. To avoid this complication, surgeons may leave residual stromal bed.

Dissection With Viscoelastic Manche et al 26 and Melles et al 25 described techniques using viscoelastic dissection. Manche et al 26 performed trephination first, then created a deep pocket into which viscoelastic was injected to open the space between the deep stroma and Descemet’s membrane. In contrast, Melles et al 25 injected air into the anterior chamber, advanced a 30-gauge cannula anterior to Descemet’s membrane and injected viscoelastic to achieve dissection, and then performed trephination.

Big-Bubble Technique The big-bubble technique is a Descemet’s-baring technique initially described by Anwar and Teichmann.27 It has become the most commonly used approach to DALK. In the big-bubble technique, corneal trephination is performed to 80% depth, followed by injection of an air bubble deep into the paracentral corneal stroma just anterior to Descemet’s membrane with a 30-gauge cannula. Anterior keratectomy is then performed, followed by formation of a small opening in the residual posterior corneal stroma, allowing for lifting of the remaining stroma with an iris spatula, and excision. If Descemet’s baring is not successful using the big-bubble technique, manual dissection may be required. The steps of this procedure are illustrated in detail below (see Figure 4-2). 1. Trephination 2. Air injection 3. Partial keratectomy 4. Incision into the anterior wall of big bubble 5. Severing the stroma with an iris spatula 6. Formation of 2 slits into the anterior wall of the collapsed bubble 7. Lifting the deep stroma and excision with scissors 8. Moistening Descemet’s membrane 9. Suturing the donor corneal tissue 10. Special situations and complications ° Failure to form big bubble ° Perforation of Descemet’s membrane

Combination Big-Bubble/Viscoelastic Technique We use a combination of steps from the big-bubble and viscoelastic techniques to produce successful anatomic and visual results with the DALK procedure. The steps of our procedure are as follows (see Figure 4-2): 1. Trephination is performed using the Hessburg-Barron trephine to 80% depth (approximately 300 μm) with 4 to 5 quarter turns of the handle (each quarter turn cuts approximately 60 μm). 2. A paracentesis incision is made to decrease intraocular pressure, and 4 to 6 small air bubbles are injected into the anterior chamber. 3. A bent 27-gauge needle on an air-filled syringe is used to advance the bevel down into the deep periphery of the trephined cornea at the level of the deepest trephination toward the corneal center; this is followed by the Tan cannula on an air-filled syringe to inject the air with the goal of dissecting Descemet’s membrane off the central cornea. 4. Partial keratectomy is performed with a crescent blade to dissect off the superior lamellar tissue.

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5. Viscoelastic dissection of Descemet’s membrane is performed with Healon (Abbott Medical Optics, Inc) on a 27-gauge needle inserted into the corneal center to dissect off Descemet’s membrane all the way past the trephine border. 6. The stroma is severed with an iris spatula. 7. Two slits are formed in the corneal stroma in a cruciate pattern with a Supersharp blade (the viscoelastic helps protect the underlying Descemet’s membrane from traumatic damage and performation). 8. The deep stroma is lifted and the 4 quadrants are excised, then Tan DALK scissors are used to excise these 4 quadrants of tissue and trim off the peripheral rim of the corneal tissue. 9. The donor tissue is cut to the same size. 10. The donor Descemet’s membrane is stained with trypan blue and subsequently stripped and removed using a Weck-Cel sponge (Beaver Visitec International, Inc) and/or smooth tying forceps. 11. The donor corneal tissue is sutured.

Microkeratome and Femtosecond Laser–assisted Deep Anterior Lamellar Keratoplasty Microkeratome and femtosecond laser–assisted DALK are options that may allow for more precise dissection and may make deeper dissection safer.28 Additionally, these instruments may create smoother interfaces between donor and host by matching the surfaces more closely than manual dissection techniques. The femtosecond laser may also be used in DALK to enhance predictability in the graft-host interface and may be combined with preoperative anterior-segment optical coherence tomography (OCT) for surgical planning and determination of the depth of pathology.29,30 Some authors have described sutureless surgery when the femtosecond laser was used to cut both the donor graft and host bed.30

Postoperative Care Suture Management Patients are typically examined on postoperative days 1 or 3 through 5, 7, 14, and 28. The DALK donor graft is usually sutured into place using interrupted 10-0 nylon sutures. These may be removed as early as 3 weeks postoperatively, and if sutures are not contributing to significant astigmatism, irritation, or vascularization, they may be left in place up to 1 year postoperatively.

Medical Management Antibiotics can be stopped when reepithelialization is complete. Early tapering of topical steroids is an advantage in DALK over PK. Typically, steroids can be tapered as early as 2 to 3 months postoperatively, and most patients do not need long-term daily topical steroids, which is more common after PK.

Complications and Contraindications Intraoperative Complications Descemet’s Membrane Split or Perforation Regardless of dissection technique, Descemet’s membrane perforation is the most commonly described complication of DALK, with reported rates ranging widely, from up to 39% early in the evolution of the technique to 9% to 12% more recently.2,19,25,27 It can occur during trephination; air, fluid, or viscoelastic injection; or direct dissection, especially in areas of prior scarring. The

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rates of perforation have been reported to be higher with direct dissection, hydrodelamination, and viscodissection and lower with the big bubble technique.27 Perforations range from microperforations of less than 1 mm to larger macroperforations. Microperforations may not require conversion to PK but can prohibit further dissection of stroma, resulting in the need to retain a deeper stromal bed. Perforation may lead to Descemet’s membrane detachment, which may be tamponaded by an air or gas bubble, leading to potential complications including pupillary block and endothelial damage. Splits in Descemet’s membrane during air, gas, or viscoelastic injection can lead to its thinning and perforation. Larger perforations often necessitate conversion to PK. Double anterior chamber can arise from intraoperative micro- or macroperforation of Descemet’s membrane due to an influx of aqueous between donor and recipient corneas. This may resolve with air injection into the anterior chamber and/or venting incision in the peripheral cornea. A recent systematic review by the American Academy of Ophthalmology found that double anterior chamber leads to reoperation in 2.2% of cases and to delayed PK conversion in 0.4% of cases.2

Pupillary Block Glaucoma Pupillary block glaucoma can result from anterior chamber air injection, which may be inadvertent or purposefully used in the case of Descemet’s detachments, or even from the pre-Descemet’s big bubble itself. This can lead to endothelial cell loss.

Residual Stromal Bed Residual stromal bed more than 10% of the original recipient stromal thickness (or greater than 65 μm) can lead to worse visual outcomes after DALK due to interface haze. Stromal dystrophies may also recur in residual stromal bed. If vision is significantly compromised, the DALK graft can be removed and the residual stroma removed using the big bubble technique or Melles technique.31

Retained Viscoelastic Viscoelastic may be retained in the interface between Descemet’s membrane and the donor stroma when viscodissection techniques are used. Viscoelastic may also be used to enlarge a collapsed air bubble in the big bubble technique. Retained viscoelastic can lead to donor graft edema and resulting decompensation, and thus should be carefully avoided.

Postoperative Complications Descemet’s Membrane Folds Central Descemet’s membrane folds, more common in eyes with advanced keratoconus, can lead to decreased visual acuity outcomes after DALK.32 One study noted a greater incidence of higher-order aberrations after DALK compared with PK, which the authors attribute to Descemet’s membrane folds, found in 23% of their postoperative keratoconus patients.33

Epithelial or Stromal Rejection Whereas endothelial rejection is not a frequent consequence of DALK, stromal or epithelial rejection is a possible complication. Rates of epithelial graft rejection have been reported to be as high as 10.9%; but, this is readily treatable with topical steroids.34 Rates may be higher among patients with a history of vernal keratoconjunctivitis.34 Rates of stromal rejection after DALK have generally been reported to be 1% to 3%.2 Recently, a series of 20 eyes with a stromal rejection rate of 25% was reported, with excellent results after treatment with frequent topical corticosteroids.34

Postoperative Keratitis Infection is a rare complication of DALK, with a reported rate of approximately 2%.36 Candida keratitis is the most commonly reported type.37-42 One case of recurrent interface abscess after treatment of Acanthamoeba keratitis with DALK was reported.39

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Contraindications to Deep Anterior Lamellar Keratoplasty Patients with a damaged endothelium, such as those with pseudophakic bullous keratopathy, Fuchs’ dystrophy, or endothelial damage resulting from infectious keratitis or other causes, should not undergo DALK. Patients with penetrating ocular trauma are also generally not candidates for DALK. Some eyes with deep stromal scarring may not have success with Descemet’s-baring procedures due to the increased difficulty with deep stromal dissection.

Comparison With Penetrating Keratoplasty A recent systematic review by the American Academy of Ophthalmology of 11 clinical comparative DALK/PK studies found visual acuity results between the 2 procedures to be equivalent, although there was a trend toward worse visual outcomes if more than 10% of the recipient stromal bed was retained.2 Rates of both early and late endothelial cell loss are lower in DALK than in PK, and graft survival has been shown to be longer in eyes undergoing DALK with the big bubble technique compared with PK.42 In the same study, better visual acuity results were achieved with the big bubble technique compared with manual-dissection DALK. A recent study focused on outcomes of DALK vs PK from the patient perspective.44 Among 20 patients who had undergone PK in one eye and DALK in the other, there was no significant difference in objective findings, including visual acuity and refractive outcomes. However, patients reported preferring the PK procedure, although there was no further detail available on which aspects of the experience were different between the 2 procedures. Future studies may provide a full picture of the patient experience.

Future Directions in Deep Anterior Lamellar Keratoplasty Anterior-segment OCT can be used intraoperatively in DALK to assess the depth of penetration into the corneal stroma. This has been described with the big-bubble technique.45 Anteriorsegment OCT can be used to guide repositioning of the cannula and to confirm the depth of the cannula in preparation for air injection and avoidance of Descemet’s membrane perforation, although no ideal depth has been identified. In the future, anterior-segment OCT may be used to perform DALK in corneas with opacity to determine cannula depth under conditions where direct visualization is not possible.

Conclusion With increasingly sophisticated techniques, DALK offers an option for corneal transplantation in eyes with a healthy corneal endothelium and is becoming more accessible to corneal surgeons. This technique is generally less traumatic, avoids rejection, provides tectonic support in cases of trauma, and has the advantage of being a largely extraocular procedure. Although perforation of Descemet’s membrane may necessitate conversion to PK, this complication is increasingly rare. DALK should especially be considered in patients with a high rejection or infection risk who require corneal transplantation with a healthier endothelium due to the shorter course of topical steroids required with this technique compared with PK.

References 1.

Muhlbauer F. Ueber Transplantation der Cornea; Gekronte Preisschrift. Munchen, Jos. Lindauer, 1840 (abstract). In: Schmidt CC, ed. Jahrbucher der in und auslandischen gesamten Midizin. Leipzig, Germany: Otto Wigand; 1842:267-268. 2. Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty: a report by the American Academy of Ophthalmology. Ophthalmology. 2011;118(1):209-218.

Deep Anterior Lamellar Keratoplasty 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

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Zarei-Ghanavati S, Zarei-Ghanavati M, Sheibani S. Traumatic wound dehiscence after deep anterior lamellar keratoplasty: protective role of intact Descemet’s membrane after big-bubble technique [published online ahead of print December 16, 2009]. Cornea. Prasher P, Muftuoglu O, Mootha VV. Traumatic graft dehiscence after anterior lamellar keratoplasty. Cornea. 2009;28(2):240-242. Lee WB, Mathys KC. Traumatic wound dehiscence after deep anterior lamellar keratoplasty. J Cataract Refract Surg. 2009;35(6):1129-1131. Kalantan H, Al-Shahwan S, Al-Torbak A. Traumatic globe rupture after deep anterior lamellar keratoplasty. Indian J Ophthalmol. 2007;55(1):69-70. Chaurasia S, Ramappa M. Traumatic wound dehiscence after deep anterior lamellar keratoplasty. J AAPOS. 2011;15(5):484-485. Kawashima M, Kawakita T, Shimmura S, Tsubota K, Shimazaki J. Characteristics of traumatic globe rupture after keratoplasty. Ophthalmology. 2009;116(11):2072-2076. Tong L, Tan DT, Abańo JM, Lim L. Deep anterior lamellar keratoplasty in a patient with descemetocele following gonococcal keratitis. Am J Ophthalmol. 2004;138(3):506-507. Susiyanti M, Mehta JS, Tan DT. Bilateral deep anterior lamellar keratoplasty for the management of bilateral post-LASIK mycobacterial keratitis. J Cataract Refract Surg. 2007;33(9):1641-1643. Al-Torbak AA. Deep anterior lamellar keratoplasty for pellucid marginal degeneration. Saudi J Ophthalmol. 2013;27(1):11-14. Sogutlu Sari E, Kubaloglu A, Unal M, et al. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for macular corneal dystrophy: a randomized trial. Am J Ophthalmol. 2013;156(2):267274.e1. Harding SA, Nischal KK, Upponi-Patil A, Fowler DJ. Indications and outcomes of deep anterior lamellar keratoplasty in children. Ophthalmology. 2010;117(11):2191-2195. Ashar JN, Pahuja S, Ramappa M, Vaddavalli PK, Chaurasia S, Garg P. Deep anterior lamellar keratoplasty in children. Am J Ophthalmol. 2013;155(3):570-574.e1. van den Biggelaar FJ, Cheng YY, Nuijts RM, et al. Economic evaluation of deep anterior lamellar keratoplasty versus penetrating keratoplasty in The Netherlands. Am J Ophthalmology. 2011;151(3):449-459.e2. Farias R, Barbosa L, Lima A, et al. Deep anterior lamellar transplant using lyophilized and Optisol corneas in patients with keratoconus. Cornea. 2008;27(9):1030-1036. Chen W, Lin Y, Zhang X, et al. Comparison of fresh corneal tissue versus glycerin-cryopreserved corneal tissue in deep anterior lamellar keratoplasty. Invest Ophthalmol Vis Sci. 2010;51(2):775-781. Feilmeier MR, Tabin GC, Williams L, Oliva M. The use of glycerol-preserved corneas in the developing world. Middle East Afr J Ophthalmol. 2010;17(1):38-43. Sugita J, Kondo J. Deep lamellar keratoplasty with complete removal of pathological stroma for vision improvement. Br J Ophthalmol. 1997;81(3):184-188. Anwar M, Teichmann KD. Deep lamellar keratoplasty: surgical techniques for anterior lamellar keratoplasty with and without baring of Descemet’s membrane. Cornea. 2002;21(4):374-383. Anwar M. Dissection technique in lamellar keratoplasty. Br J Ophthalmol. 1972;56(9):711-713. Archila EA. Deep lamellar keratoplasty dissection of host tissue with intrastromal air injection. Cornea. 1984-1985;3(3):217-218. Price FW Jr. Air lamellar keratoplasty. Refract Corneal Surg. 1989;5(4):240-243. Chau GK, Dilly SA, Sheard CE, Rostron CK. Deep lamellar keratoplasty on air with lyophilised tissue. Br J Ophthalmol. 1992;76(11):646-650. Melles GR, Lander F, Rietveld FJ, Remeijer L, Beekhuis WH, Binder PS. A new surgical technique for deep stromal, anterior lamellar keratoplasty. Br J Ophthalmol. 1999;83(3):327-333. Manche EE, Holland GN, Maloney RK. Deep lamellar keratoplasty using viscoelastic dissection. Arch Ophthalmol. 1999;117(11):1561-1565. Anwar M, Teichmann KD. Big-bubble technique to bare Descemet’s membrane in anterior lamellar keratoplasty. J Cataract Refract Surg. 2002;28(3):398-403. Jiménez-Alfaro I, Pérez-Santonja JJ, Gómez Tellería G, Bueno Palacín JL, Puy P. Therapeutic lamellar keratoplasty with an automated microkeratome. J Cataract Refract Surg. 2001;27(8):1161-1165. Sarayba MA, Maguen E, Salz J, Rabinowitz Y, Ignacio TS. Femtosecond laser keratome creation of partial thickness donor corneal buttons for lamellar keratoplasty. J Refract Surg. 2007;23(1):58-65. Yoo SH, Kymionis GD, Koreishi A, et al. Femtosecond laser-assisted sutureless anterior lamellar keratoplasty. Ophthalmology. 2008;115(8):1303-1307,1307.e1. Yao Y, Jin Y, Zhang B, et al. Recurrence of lattice corneal dystrophy caused by incomplete removal of stroma after deep lamellar keratoplasty. Cornea. 2006;25(10):S41-46. Mohamed SR, Manna A, Amissah-Arthur K, McDonnell PJ. Non-resolving Descemet folds 2 years following deep anterior lamellar keratoplasty: the impact on visual outcome. Cont Lens Anterior Eye. 2009;32(6):300-302.

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33. Bahar I, Kaiserman I, Srinivasan S, Ya-Ping J, Slomovic AR, Rootman DS. Comparison of three different techniques of corneal transplantation for keratoconus. Am J Ophthalmol. 2008;146(6):905912.e1. 34. Feizi S, Javadi MA, Jamali H, Mirbabaee F. Deep anterior lamellar keratoplasty in patients with keratoconus: big-bubble technique. Cornea. 2010;29(2):177-182. 35. Olson EA, Tu EY, Basti S. Stromal rejection following deep anterior lamellar keratoplasty: implications for postoperative care. Cornea. 2012;31(9):969-973. 36. Sharma N, Gupta V, Vanathi M, Agarwal T, Vajpayee RB, Satpathy G. Microbial keratitis following lamellar keratoplasty. Cornea. 2004;23(5):472-478. 37. Caretti L, Babighian S, Rapizzi E, Ponzin D, Galan A. Fungal keratitis following deep lamellar keratoplasty. Semin Ophthalmol. 2011;26(1):33-35. 38. Fintelmann RE, Gilmer W, Bloomer MM, Jeng BH. Recurrent Lecythophora mutabilis keratitis and endophthalmitis after deep anterior lamellar keratoplasty. Arch Ophthalmol. 2011;129(1):108-110. 39. Bahadir AE, Bozkurt TK, Kutan SA, Yanyali CA, Acar S. Candida interface keratitis following deep anterior lamellar keratoplasty. Int Ophthalmol. 2012;32(4):383-386. 40. Bi YL, Bock F, Zhou Q , Cursiefen C. Recurrent interface abscess secondary to Acanthamoeba keratitis treated by deep anterior lamellar keratoplasty. Int J Ophthalmol. 2012;5(6):774-775. 41. Jafarinasab MR, Feizi S, Yazdizadeh F, Rezaei Kanavi M, Moein HR. Aspergillus flavus keratitis after deep anterior lamellar keratoplasty. J Ophthalmic Vis Res. 2012;7(2):167-171. 42. Jhanji V, Ferdinands M, Sheorey H, Sharma N, Jardine D, Vajpayee RB. Unusual clinical presentations of new-onset herpetic eye disease after ocular surgery. Acta Ophthalmol. 2012;90(6):514-518. 43. Borderie VM, Sandali O, Bullet J, Gaujoux T, Touzeau O, Laroche L. Long-term results of deep anterior lamellar versus penetrating keratoplasty. Ophthalmology. 2012;119(2):249-255. 44. Yeung SN, Lichtinger A, Kim P, Amiran MD, Rootman DS. Retrospective contralateral study comparing deep anterior lamellar keratoplasty with penetrating keratoplasty: a patient’s perspective. Can J Ophthalmol. 2012;47(4):360-364. 45. Scorcia V, Busin M, Lucisano A, Beltz J, Carta A, Scorcia G. Anterior segment optical coherence tomography–guided big-bubble technique. Ophthalmology. 2013;120(3):471-476.

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5 Descemet’s Stripping Automated Endothelial Keratoplasty Ian Gorovoy, MD and Bennie H. Jeng, MD, MS

Brief History of Selective Endothelial Keratoplasties The first successful penetrating keratoplasty (PK) was performed in 1905 by Zirm1 in a patient who was blinded by bilateral chemical lyme injuries. Since this early corneal transplant surgery, a number of innovations have improved our understanding of surgical techniques in corneal transplants. The earliest forms of endothelial keratoplasty (EK) were performed by Barraquer 2 and Polack,3 who created a hinged anterior corneal flap that was retracted for trephination, followed by transplantation of a posterior stromal/endothelial graft with suturing of the anterior corneal flap side. Although innovative, this technique was not popularized because it suffered from many of the pitfalls of PK, including the need for surface corneal suturing. A paradigm shift occurred in 1998, when Dr. Gerrit Melles from the Netherlands pioneered selective EK with posterior lamellar keratoplasty (PLK), in which he created a large 9.0-mm scleral incision, performed a deep manual lamellar dissection of the host stroma, and inserted similarly sized donor tissue.4 PLK is also used for both dissection of the host cornea and stabilization of the donor tissue after insertion, eliminating the need for corneal sutures. Deep lamellar endothelial keratoplasty (DLEK) by Terry and Ousley5 is PLK with a taco-fold delivery technique for the donor tissue, which allows for a smaller, clear corneal incision. Subsequently, Dr. Melles again revolutionized EK with Descemet’s stripping endothelial keratoplasty (DSEK), made possible by his descemetorhexis technique, which eliminated the need for mastery of the technically difficult lamellar dissections of the host and donor corneas on an artificial chamber.6 Descemet’s stripping automated endothelial keratoplasty (DSAEK), pioneered by Gorovoy,7 made use of the ALTK System (Moria, Inc) to create a lamellar dissection of the donor stroma, completely eliminating any manual lamellar dissection and improving visual results with 2 opposed smooth lamellar surfaces. Since the development of DSAEK, faster recovery and superior visual results with selective EK have simultaneously lowered the threshold for surgery and raised patient expectations. Although postoperative management is critical for long-term graft health, meticulous surgical technique and careful attention in the immediate postoperative period is essential. Two of the most important aspects of DSAEK surgery are minimizing endothelial loss intraoperatively and reducing the risk of graft dislocation. In this chapter, we provide step-by-step instruction for successful DSAEK surgery and illustrate multiple techniques that have been described to improve or modify this - 53 -

Agarwal A, John T, eds. Mastering Corneal Surgery: Recent Advances and Current Techniques (pp 53-65). © 2015 SLACK Incorporated.

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evolving surgery, to which many practitioners have made significant contributions since its initial description.

Preoperative Considerations DSAEK is indicated for a number of endothelial diseases and dystrophies, with the large majority of surgical candidates presenting with Fuchs’ endothelial dystrophy, pseudophakic/ aphakic bullous keratopathy, and a history of a failed prior keratoplasty.7 The surgical technique is similar in all of the conditions, except for eyes undergoing a prior PK or EK. A careful preoperative slit lamp examination is necessary to examine for coexisting corneal diseases, such as Cogan’s map-dot-fingerprint dystrophy from recurrent corneal edema and subepithelial fibrosis from Fuchs’ dystrophy. If either condition is present, appropriate patient counseling is essential to inform patients of potential visual limitations from these coexisting conditions. Some surgeons recommend scraping of the corneal epithelium intraoperatively to help treat coexisting epithelial disorders and to facilitate anterior chamber visualization during DSAEK. The potential disadvantages of scraping include more postoperative pain, slower healing, and increased stromal hydration from the tear film, which may perpetuate graft dislocation. The diameter of the cornea should also be measured or estimated to ensure that the proper-sized graft will be used. For example, a 10-mm cornea will require a smaller graft than will a normal-sized eye. Sizing is surgeon dependent, with the vast majority of surgeons using grafts between 7.5 and 9.5 mm. Although DSAEK is perhaps most easily performed in a deep anterior chamber with pseudophakia, it can be performed with a well-positioned anterior-chamber intraocular lens or in a phakic patient. The advantages of a posterior chamber intraocular lens include a deep chamber that provides more room for unfolding of the donor taco and minimization of subsequent anteriorchamber surgery, which would further damage donor endothelial cells. Nonetheless, a triple procedure involving cataract removal with placement of an intraocular lens with DSAEK is also commonly performed. Although this spares the patient an extra trip to the operating room, it risks additional damage to the donor endothelium. Furthermore, viscoelastic on the donor stromal bed after phacoemulsification can hinder graft adherence, especially with the use of dispersive viscoelastics, which are difficult to fully evacuate from the anterior chamber and may cause postoperative reticular interface haze.8 If cataract surgery is to be performed separately, it is generally performed 4 to 6 weeks prior to DSAEK. Given the potential for high intra- and postoperative intraocular pressure (IOP), glaucoma must be well controlled with the appropriate surgery prior to DSAEK. Interestingly, preoperative shunt surgery may promote graft failure, perhaps through immune-mediated mechanisms with disruption of corneal immune privilege or even changes in the nutritional composition of the aqueous.9 Compared with PK, DSAEK donor buttons are considerably more refractively neutral with little effect on cylinder. However, a 0.5- to 1.5-diopter hyperopic shift can occur, which is believed to be secondary to the meniscus shape of the donor graft rather than the increased thickness of the cornea.10,11 This hyperopic possibility should be discussed with the patient when targeting intraocular lens refraction.

Preoperative Management The majority of surgeons recommend initiating a topical antibiotic, usually beginning 1 hour preoperatively, and do not pharmacologically alter the patient’s pupil preoperatively unless a triple procedure is planned. Some surgeons recommend preoperative apraclonidine 0.5% to lower intraocular pressure and reduce conjunctival inflammation. Additionally, some surgeons recommend preoperative 1% or 2% pilocarpine, especially if performing phakic DSAEK. Others recommend placing a few drops of 100% glycerin on the patient’s cornea prior to entering the operating room to deturgesce the stroma, enhancing intraoperative visibility and perhaps graft adherence.12 The patient is draped in the standard fashion for ophthalmic surgery, and 10% ophthalmic povidone-iodine is used to clean the lids and ocular surface. We recommend sitting temporally for the case and using a retrobulbar block for the first few cases prior to transitioning to topical

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anesthesia. During the surgery, we recommend minimizing the use of balanced salt solution on the eye because this drying allows the cornea to partially dehydrate, improving the view during surgery. First, the host corneal epithelium is gently marked with an inked trephination ring of the size that will be later used to cut the graft (between 7.5 and 9.5 mm). In determining the size of the graft to use, it is important to ensure that the donor graft does not impede too closely to the chamber angle, which increases the risk for postoperative glaucoma and peripheral anterior synechiae. This marked outline will later serve as a guide for the stripping of the host endothelium and for graft insertion and centration. In the setting of a prior PK, most surgeons will size the donor graft to be the same or slightly smaller than the existing graft.

Preparation of Donor Graft More and more surgeons today are using corneal tissue that has been precut by the eye bank. However, some surgeons still prepare their own tissue. In these cases, preparation of the donor tissue first allows the surgeon to ensure that the donor button is suitable prior to opening the patient’s eye. It is recommended to use large donor rims (16 mm) to ensure airtight suction on the artificial anterior chamber (AAC) during dissection. It is also important to carefully inspect the graft to ensure that there are no peripheral cuts or divots in the cornea that would preclude a firm hold by the AAC during automated dissection. The donor corneoscleral rim is placed endothelial side down on the AAC, and balanced salt solution is used to inflate the donor cap to more than 60 mm Hg, which can be measured by various methods. We recommend placing viscoelastic on the base of the AAC prior to placing the donor tissue in the keratome to avoid slippage and minimize trauma to the endothelium. At this point, some surgeons recommend debridement of the donor corneal epithelium with a #15 blade to avoid the potential of smearing epithelium under the cap during the microkeratome pass, which can cause slippage during cutting and, theoretically, later ingrowth.12 Next, the epithelium and anterior stroma are dissected from the graft with an automated keratome such as the Automated Lamellar Therapeutic Keratoplasty System. The size of the keratome head is determined by the pachymetry measurement of the donor cornea. In general, most surgeons will use a 350-μm head for donors that measure more than 600 μm thick at the time of cutting. It is important to ensure that the microkeratome head is well seated and moves smoothly prior to cutting the donor tissue. The posterior donor graft is carefully removed from the AAC “hat” and trephined endothelial side up on the cutting block. The air used to pressure the donor tissue prevents the graft from collapsing into the AAC stage when lifting up the hat. The anterior cap is then replaced on the posterior button prior to trephination to allow for a straight cut edge. Generally, grafts are sized between 7.5 and 9.5 mm, with 8.0- to 8.5-mm grafts being most commonly used. Larger grafts are used for large anterior segments, such as buphthalmos, high myopia, and megalocornea. The advantages of these smaller 8.0- to 8.5-mm grafts include fewer complications intraoperatively with handling the graft, less risk of angle closure glaucoma because a smaller air bubble can be left in the eye, and a smaller risk of peripheral anterior synechia formation. A study comparing endothelial cell counts between 8.0 and 8.5 mm grafts at 2 years postoperatively demonstrated no difference.13 Some surgeons have advocated ultra-thin (UT) DSAEK tissue, with a thickness ranging from 50 to 80 μm, compared with the typical thickness of 100 to 200 μm. When cutting tissue for UT-DSAEK, 2 separate microkeratome passes are made, first with a larger head, then, after remeasuring the bed, with a smaller head of 100 μm or less. UT-DSAEK grafts may provide for quicker postoperative recovery and the use of small-incision graft insertion devices, but can be more difficult to properly unfurl and align after insertion into the anterior chamber and may carry an increased risk of optically significant postoperative striae. If the striae induced are microstriae, these will often settle with time, but macrostriae generally require regrafting.14 Some surgeons recommend inscribing a nonreversible letter such as S on the stromal surface with a gentian violet marker prior to trephination or immediately afterward to help ensure proper graft orientation because a backward S will appear if the endothelium is incorrectly opposed with the host stroma.15 Centration of the donor graft on the cutting block is critical to prevent an

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off-centered trephination with a full-thickness graft disc edge. If this occurs, one can recenter the graft tissue and recut to remove any residual full-thickness tissue because a perfectly circular donor may be more aesthetically pleasing to the surgeon postoperatively but is not optically or functionally critical.16 A drop of the transplant medium is then placed on the graft, and attention is directed to the patient.

Host Preparation Different surgeons place paracenteses in different numbers and different locations. However, the basic premise is that paracenteses should be peripheral enough away from where the DSAEK button will be placed to minimize the risk of dislocation during air/fluid exchange or other manipulation. Then a clear corneal or scleral tunnel incision is placed. The advantages and disadvantages to a clear corneal incision vs a scleral tunnel in DSAEK are similar to those in cataract surgery. The anterior chamber is filled with balanced salt solution, which is used during the procedure to maintain the anterior chamber. Several surgeons instead recommend continuous irrigation through much of the case with an anterior chamber maintainer. Through the right-handed port, an irrigating Descemet’s stripper, modified Sinskey hook, or bent needle is used to score the host Descemet’s membrane for 360 degrees for the perimeter of the proposed Descemet’s dissection (Figure 5-1). The circular perimeter to be scored should be the area delineated on the corneal epithelium by the trephine coated with gentian violet. Some surgeons advocate scoring a slightly smaller area than the graft calls for to minimize removal of too much of Descemet’s membrane, which can easily occur, resulting in corneal edema in the uncovered area during the immediate postoperative period.17 Descemetorhexis is then performed using either a customized stripper or an irrigation and aspiration (I&A) handpiece. Descemet’s membrane is stripped for 2 mm for 2 to 3 clock hours. The instrument is used to grab and drag out the loose edges of Descemet’s membrane (Figure 5-2). It may take several passes to remove all of Descemet’s membrane. Descemetorhexis requires a gentle touch because excessive force can dehisce posterior stromal fibers and lead to visually significant postoperative scarring. A light pipe with the microscope light turned off can be held so that sclerotic scatter from the limbus can help define the relucency of the detached Descemet’s membrane. The chamber should be maintained with either intermittent or continuous infusion of balanced salt solution or with viscoelastic. If the latter is chosen, it is critical to aspirate all of the viscoelastic after the descemetorhexis because residual material will impair graft adherence. Trypan blue, which preferentially stains exposed Descemet’s membrane, can be used to visualize any remaining membrane. Some surgeons also recommend laying the stripped Descemet’s membrane on the cornea to approximate the amount of tissue already removed and ensure complete removal.15 If the surgeon plans to roughen the periphery of the posterior stroma for 360 degrees to increase graft adherence, a Terry scraper can be used for this step and to remove any remaining Descemet’s membrane. Descemet’s membrane must be stripped in Fuch’s corneal dystrophy to eliminate the optical effect of the guttata, but it is not necessarily critical for other etiologies of endothelial failure. The most controversial use of host stripping is in cases of endothelial decompensation after a PK given the risk of PK dehiscence. One study reported no difference in graft dislocation in DSAEK after PK whether or not Descemet’s membrane was stripped.18 However, preservation of Descemet’s membrane may decrease final postoperative visual acuity. Surgeons should be cognizant of the fact that high astigmatism (especially changing astigmatism) after PK may represent wound instability and that repeat PK rather than DSAEK should be the surgery of choice for optical rehabilitation.19

Donor Insertion First, the incision is enlarged to the desired size, which is determined by the technique used for insertion but is generally between 4.0 and 5.0 mm. The donor button is placed under the microscope, and excess fluid is balloted with a sponge. Several drops of a moderately cohesive viscoelastic such as Healon (Abbott Medical Optics Inc) are dropped on to the endothelial side

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Figure 5-1. Descemet s scoring is performed through one of the paracentesis sites just inside the desired perimeter, which is marked with an inked trephine. The goal is to avoid exposed stroma outside of the marked area, which would cause peripheral corneal edema. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-2. The I&A tip bevel is used to engage Descemet s membrane to help strip away the tissue. It is removed in a capsulorrhexis-style tear. The edge of Descemet s membrane can be faintly made out perpendicular to the I&A. Usually, maximum settings are used on the I&A for this step. Any loose peripheral tears are removed to avoid a rolled-up Descemet s membrane, which can act as an interface spacer and create graft dislocation. (Reprinted with permission from Mark Gorovoy, MD.)

of the graft, which is then folded into a taco formation with 60% of the graft button on one side with the endothelium facing inward (Figures 5-3 and 5-4).20,21 Although this folding leaves a small area of peripheral endothelium more vulnerable during manipulation, it facilitates the posterior side-to-side sweep and proper unfolding of the graft within the eye. If using the 60/40 taco fold, the folded graft is delicately picked up with forceps (eg, IOL forceps, Charlie I or II forceps [Storz Opthalmic], Goosey inserter forceps [Moria Surgical], or angled Kelman forceps [Storz Ophthalmic]) 1 mm from the button fold and then inserted into the eye near the opposite limbus through the temporal wound (Figure 5-5). Not surprisingly, there are other techniques to fold the graft. Some practitioners recommend a double-fold envelope technique where 30% of the graft on opposite sides is folded into itself again with the endothelium facing inward. A number of inserter cartridges exist on the market but are beyond the scope of this text. Pull-through suture techniques with an incision 180 degrees away and the use of a Tan Endoglide (Angiotech) or a Busin glide (Ambler Surgical) have also been described.22 Obviously, the manipulation and insertion of the graft is responsible for a large percentage of endothelial cell loss so great care is necessary in these steps; however, measurement of the percentage of endothelial cell loss found similar numbers with folding vs injection.23 After insertion and basic positioning, some surgeons place one 10-0 suture to partially close the wound and stabilize the anterior chamber. The anterior chamber is then deepened with balanced salt solution, which may partially unfurl the graft. Unfolding may occur spontaneously, but it generally requires some assistance from the surgeon. The graft can carefully be unfurled by sliding a cannula into the fold and selectively squirting balanced salt solution to unscroll it. Some surgeons also use the I&A to gently grab the

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Figure 5-3. After removing extra storage medium from around the graft, viscoelastic is placed on the superior half of the graft, which is the section to be folded over. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-4. The graft has been folded over in the 60:40 configuration, in this case with 60% composing the top fold. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-5. Gentle placement of the graft into the eye. Notice the relationship of the forceps to the graft and the depth of the forceps into the eye. Forceps may be slow to let go of the tissue, and it is critical to not remove the graft while coming out of the eye. (Reprinted with permission from Mark Gorovoy, MD.)

underside of the taco and unfold it (Figure 5-6). The graft and the area of stripped Descemet’s membrane are carefully aligned through a number of techniques after air injection (Figure 5-7). Sterile air is then injected into the anterior chamber through one of the paracentesis ports (Figure 5-8). There are several variations on the amount of sterile air injected to the anterior chamber, which will be discussed later. In general, most surgeons overfill with air for a period of time to help with graft adherence and then remove some air to decrease the risk of pupillary block.

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Figure 5-6. The graft is moved slightly nasally, and the I&A is introduced into the eye in a dry fashion underneath the graft and then used to pin it to the stroma. Then, the I&A is placed near the stroma, and aspiration is used to unfurl the graft while leaving the eye. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-7. The tissue is centered with ballottement, and the anterior chamber is slightly shallowed to maintain the graft in its central position. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-8. An air bubble is placed under the donor tissue. If there is any movement of the graft at this time, it is recentered with ballottement and/or the use of a roller. (Reprinted with permission from Mark Gorovoy, MD.)

After the injection of air, the surgeon can gently tap the cornea to help grossly center the graft, which will move away from the area of the cornea that is pressed on. It is critical to minimize exposed bare stroma because, without an endothelium, this tissue will imbibe anterior chamber fluid and result in corneal edema. After this gross alignment, the recipient donor cornea is massaged to remove interface fluid and facilitate graft centration (Figure 5-9). A number of rollers have been used for this manipulation,

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Figure 5-9. Once centration is confirmed, a large air bubble is inserted into the anterior chamber. (Reprinted with permission from Mark Gorovoy, MD.)

Figure 5-10. Stroking the cornea can be used to remove any interface fluid. (Reprinted with permission from Mark Gorovoy, MD.)

including the Lindstrom LASIK roller (Visitec). Most surgeons remove a portion of the air after 5 to 10 minutes to minimize the risk of pupillary block, whereas some leave all of the air in the anterior chamber for 1 to 2 hours.7,24 Generally, the air bubble should cover the area of the graft in the beginning, although some surgeons completely fill the chamber initially (Figure 5-10). We will discuss the pros and cons of various residual air bubble sizes in further detail later. We recommend that patients lie supine as much as possible during the first postoperative day, but acknowledge that the first 1 or 2 postoperative hours are the most critical. Some surgeons perform stab wounds in case interface fluid needs to be drained.24 If the graft decenters with instillation of air, the air should be removed, the graft should be grossly recentered, and the air should be reinjected with finer centration. The surgeon should ensure that no air has escaped behind the iris, which most commonly occurs with air–balanced salt solution exchange. A 10-0 nylon suture is placed through the temporal wound, and wounds are then provoked to ensure watertightness. It is important that the wounds are carefully scrutinized for leaks and the maintenance of the anterior chamber is noted because any postoperative hypotony increases the risk of early graft dislocation. We also recommend injection of subconjunctival steroid at the end of the procedure, topical nonsteroidal anti-inflammatory drugs, topical antibiotics, and dilating the pupil with a mydriatic drug to prevent postoperative pupillary block secondary to air escaping behind the iris.

Postoperative Care Immediate It is critical for the patient to remain supine for at least 1 hour to allow the air bubble to press the graft up against the recipient stroma. After this time, the hope is that the endothelium sodium

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potassium–activated adenosine triphosphotase (ATPase) pump of the donor endothelium will be reactivated and the negative pressure generated by deturgescence of the stroma will keep the graft opposed. IOP should be checked and a slit lamp examination performed 1 hour postoperatively. Excess air is then released through one of the side paracenteses, if necessary. The ideal size of the air bubble is debated, but many recommend that the lower air bubble meniscus at the inferior pupil edge will help oppose the graft and reduce the risk of pupillary block.

Day 1 In addition to the usual postoperative examination of IOP, presence of leaking wounds, and signs of infection, the most critical question is whether the donor button has dislocated. If the graft is more than 70% detached, most surgeons recommend rebubbling. Smaller areas of detachment can resolve on their own. Complete detachments need to be rebubbled, and, in some circumstances, they may need to be repositioned and recentered.

Surgical Technique Pearls Steps to Minimize Graft Dislocation Graft dislocations generally occur early in the postoperative course. Dislocations occur more commonly with inexperienced surgeons and can result in donor endothelial cell loss even if it is ultimately properly repositioned.24 Dislocation rates of 1% to 5% have been reported in the hands of the most experienced surgeons.20 The descemetorhexis technique creates a smooth stromal host bed as seen on electron microscopy, which provides for superior optical results but increases the risk of graft dislocation compared with DLEK; the host stroma is much rougher and acts like a hook-and-loop fastener with a greater ratio of surface area compared with the diameter of the graft secondary to the cut stromal collagen fibers in DLEK.25 The basic concepts in promoting graft adherence are to either increase the intrinsic bond between the donor graft and host stromal bed or increase the force (ie, air bubble) anteriorly displacing the graft into the host stromal bed. The ultimate goal is to recreate the suction effect of the graft on the host formed by the endothelial sodium potassium–activated ATPase pump, which functions to deturgesce the corneal stroma. On occasion, the clearing of the host stroma can be noted intraoperatively, which is a good prognosticator of successful surgery. To promote graft adherence, Terry recommends scraping a 1-mm-wide ring in the recipient bed periphery.20 It is critical not to scrape the visual axis because optical aberrations will otherwise be created. He recommends aggressive scraping using a sharp instrument (not a blunt stripper or Sinskey hook) and ensuring that you can see visible changes in the stromal bed. In addition to performing this same roughening of the rim of the recipient stromal surface within the circular surface mark, Dr. Thomas John, MD also uses a bent need to focally disrupt the stroma at 3, 6, 9, and 12 o’clock to act as reinforcement bolts.26 Roughening of the graft edges is not practiced by all corneal transplant surgeons. Dr. Francis W. Price Jr, MD emphasizes the importance of a well-constructed seal for clear corneal wounds because he believes that a slow wound leak and a soft eye, especially combined with eye rubbing, trigger detachment.26 He recommends counseling patients that these activities will increase the likelihood of detachments. Retention sutures are used on occasion in eyes that are at higher risk for graft dislocation (eg, presence of glaucoma tube shunts or filters). These full-thickness 10-0 nylon sutures are entered near the limbus and directed toward the draft, passing their full thickness through the graft. Care must be taken to avoid excessive tension that may induce striae. These sutures should be removed within the first postoperative month, and the wound must be checked for leaks after removal because it is a full-thickness pass.

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What to Do if the Graft Dislocates Postoperatively Eye rubbing or postoperative hypotony may cause decentration of the graft, usually inferiorly secondary to gravity. Surgeons differ on when they believe a graft needs to be rebubbled or repositioned, but in general, when the graft is more than 70% detached or has dislocated out of the visual axis, we recommend rebubbling. This can be done at the slit lamp, in a minor procedure room, or, if necessary, in the operating room, depending on the state of the patient. We recommend performing the rebubbling with the patient supine with sterile techniques similar to those used in the operating room (ie, topical povidine-iodine, draping, and a lid speculum). Rebubbling can be performed at the slit lamp if the graft is well centered and there is no need to reposition. Some surgeons use longer-acting gas, such as an isoexpansile concentration of sulfur hexafluoride, rather than air when rebubbling. Most patients do well with topical tetracaine alone, but anxious patients should receive anxiolytics such as 5 mg of oral diazepam and intracameral lidocaine if necessary. Balanced salt solution is injected into the eye, and the donor button is carefully repositioned through one of the paracentesis ports. In the same manner used intraoperatively, a roller or gentle pressure on the cornea in combination with a small sterile air bubble can be used to help recenter the donor button. After careful centration, balanced salt solution is exchanged for air until the IOP is increased to approximately 30 mm Hg for 15 minutes to help the graft adhere. After 15 minutes has elapsed, the bubble size is reduced to cover approximately 1 mm past the graft, and the patient lies supine for 1 more hour. There are multiple variations on when surgeons will regraft a patient. Rowsey et al12 recommends performing mattress sutures in all 4 quadrants if the graft has been dislocated for 2 weeks. Debate continues regarding how long a graft remains viable after dislocation, but there are reports of successful repositioning several months after dislocation and even spontaneous reattachment.27 Rare reports of dislocation of the graft into the posterior segment have also been reported 28; prompt removal in these cases are associated with better final visual outcomes.

Prevention of Iris BombÉ If air escapes behind the iris, it causes peripheral anterior displacement of the iris, sometimes accompanied by acute angle closure glaucoma and peripheral iridocorneal touch. To prevent postoperative pupillary block, some surgeons will place a peripheral iridotomy (PI). There is a wide variation in practice regarding inferior PIs: some surgeons always use them, some use them selectively, and some never use them at all. The use of microscissors, such as Duet scissors (Microsurgical Technology), or vitrectomy scissors has been described to create a PI. A preoperative Nd:YAG laser PI is also used by some surgeons who worry about bleeding with an intraoperative PI.17,18 Surgeons who never create an inferior PI believe that with careful early management and the use of a smaller air bubble, the risk of pupillary block can be virtually zero.20 Dr. Mark A. Terry, MD recommends the following technique for leaving the appropriately sized air bubble.26 First, he has the patient lay supine for 10 minutes undisturbed with a normal IOP after the tissue is properly in place with no evidence of interface fluid. Then, he turns the patient’s head away from him (nasally) so that the temporal paracentesis is now closest to the ceiling. He then instills balanced salt solution through this port until only a small bubble (2 or 3 mm) is left. He then repositions the patient’s head back to the normal supine position and ensures that the anterior chamber is well formed with nonleaking wounds. He ensures that the pupil is larger than the remaining air bubble, which will provide some central support for the graft.26

Drainage of Fluid at the Interface Fluid in the interface between the graft and host can interfere with the effective pump action of the endothelium and result in graft dislocation. Several techniques have been suggested to remove this fluid, including corneal surface sweeping to squeegee the fluid, performing drainage

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stab incisions, or temporarily increasing the size of the air bubble to more aggressively push fluid out of the interface.26 Surface sweeping is performed after the air bubble is in place. After irrigating the cornea, a roller, such as a Lindstrom LASIK roller or Cindy Sweeper (Storz Ophthalmic), can be used to gently compress the cornea center toward the limbus and past the graft edge for 30 to 60 seconds. Using this technique, any fluid will be squeegeed out into the anterior chamber. The key is to be forceful enough to expel the fluid but not too vigorous as to dislocate or reposition the graft. In fact, slightly more aggressive rolling is effective in centering a misaligned graft. When the interface fluid is eliminated in this manner (usually within 20 to 30 seconds), the graft will stop moving even with continued rolling. If the interface has air bubbles from the insertion process, these bubbles will also move slightly with the rolling if fluid remains. If the fluid is gone, these air bubbles will be pressed up against the stroma and not move with rolling. These air bubbles usually absorb within a couple of hours postoperatively and have no visual significance.26 Price and Price24 recommend the use of 1 to 4 drainage stab incisions to drain any remaining interface fluid. They also recommend the use of incisions parallel to the graft approximately 1 mm inside the graft edge rather than radial because they believe that radial incisions are more likely to extend beyond the graft and risk slow wound leak and graft detachment. They recommend starting temporally because this area has the highest probability of retaining fluid secondary to the temporal wound creating some local stromal edema and displacing the graft slightly. If the temporal stab incision cannot drain any fluid, it is unlikely that the other quadrants will drain any fluid and are therefore not worth completing. Stab incisions carry a small risk of postoperative infection, and there are several reported cases of epithelial ingrowth, a few of which have required regraft.29 The key to minimizing the remote risk of ingrowth is to not use these stab incisions as anything more than drainage incisions with manipulation of the graft through them. In addition, irregular astigmatism can result from the placement of such venting incisions. Using the highest magnification setting on the operating microscope, the hexagonal pattern of the endothelium via specular microscopy can be visualized only when no fluid is present. Otherwise, if any interface fluid is present, the interface will be perfectly smooth without folds or the hexagonal pattern. Because the donor graft always has some mild intrastromal edema, the specular microscopy image is located on the donor fold side.25 Others have recommended using an upright slit lamp attachment built onto the operating microscope to sweep limbus to limbus and identify fluid.25

A Word About Postoperative Steroids A survey by Price et al 30 found a wide practice pattern regarding the use of postoperative topical steroids, ranging from 4 times a day with a rapid taper and discontinuation by postoperative week 6 to surgeons leaving their patients on steroids indefinitely. The overwhelming majority (95%) used prednisolone acetate 1%. Our recommendation in a typical case is to use steroids 4 times per day for 3 months, followed by a taper to once daily out to 1 year. As one might expect from PK studies, a lower rejection rate occurs with longer-term use of steroids to 18 months postoperatively.30 The obvious risks of long-term steroid use are a rise in IOP and graft infection. Price et al 31 found a 3% to 4% risk of a steroid response (defined as an absolute IOP greater than 24 mm Hg or a 10-mm Hg IOP increase) per month in the first 7 months, which was reduced to 1% to 2% with once-daily dosing. They also reported a few cases of presumed steroid response several years postoperatively. Black patients are also much more likely to suffer from graft rejection after EK.31 Topical cyclosporine can decrease the amount of steroid necessary.

Conclusion DSAEK has revolutionized corneal transplant surgery for endothelial diseases. With the advantages of faster visual rehabilitation, more predictable postoperative refractions, and less graft rejection, this surgical technique has become widely adopted in recent years, to the point of being the standard of care for surgical treatment of endothelial disease. Although Descemet’s membrane

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endothelial keratoplasty is becoming more popular, until more reliable methods of handling the Descemet’s membrane tissue in Descemet’s membrane endothelial keratoplasty are worked out, DSAEK will have a prominent position in the corneal surgeon’s armamentarium of procedures.

References 1. Zirm E. Eine erfolgreiche totale Keratoplastik [translated from the German by Chris Sandison, Technical Translations from German, Bath]. Graefes Arch Ophthalmol. 1906. 64580-64593.593. 2. Barraquer JI. Two-level keratoplasty. Int Ophthalmol Clin. 1963;3:515-539. 3. Polack F. Posterior lamellar keratoplasty. Rev Peru Oftalmol. 1965;2:62-64. 4. Melles GR, Eggink FA, Lander F, et al. A new surgical technique for posterior lamellar keratoplasty. Cornea. 1998;17(6):618-626. 5. Terry MA, Ousley PJ. Deep lamellar endothelial keratoplasty in the first United States patients: early clinical results. Cornea. 2001;20(3):239-243. 6. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23(3):286-288. 7. Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea. 2006;25(8):886-889. 8. Anshu A, Planchard B, Price MO, da R Pereira C, Price FW Jr. A cause of reticular interface haze and its management after Descemet stripping endothelial keratoplasty. Cornea. 2012;31(12):1365-1368. 9. Decroos FC, Delmonte DW, Chow JH, et al. Increased rates of Descemet’s stripping automated endothelial keratoplasty (DSAEK) graft failure and dislocation in glaucomatous eyes with aqueous shunts. J Ophthalmic Vis Res. 2012;7(3):203-213. 10. Price MO, Price FW Jr. Descemet’s stripping with endothelial keratoplasty: comparative outcomes with microkeratome-dissected and manually dissection donor tissue. Ophthalmology. 2006;113(11):1936-1942. 11. Koenig SB, Covert DJ, Dupps WJ Jr, Meisler DM. Visual acuity, refractive error, and endothelial cell density six months after Descemet stripping and automated endothelial keratoplasty (DSAEK). Cornea. 2007;26(6):670-674. 12. Rowsey J, Evangelista JA, Williams J, Rouraker BD. Descemet’s stripping automated endothelial keratoplasty: avoiding complications. In: Brightbill FS, McDonnell PJ, McGhee CNJ, Farjo AA, Serdarevic O, eds. Corneal Surgery: Theory, Technique and Tissue. Philadelphia, PA: Mosby Elsevier; 2009:587-595. 13. Terry MA, Li J, Goshe J, Davis-Boozer D. Endothelial keratoplasy: the relationship between donor tissue size and donor endothelial survival. Ophthalmology. 2011;118(10):1944-1949. 14. Busin M, Madi S, Santorum P, Scorcia V, Beltz J. Ultrathin descemet’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique: two-year outcomes. Ophthalmology. 2013;120(6)1186-1194. 15. Fernandez MM, Afshari NA. How to perform Descemet’s stripping automated endothelial keratoplasty. EyeNet Magazine. American Academy of Ophthalmology website. http://www.aao.org/ publications/eyenet/200701/pearls.cfm. Accessed June 21, 2013. 16. Gorovoy MS. Surgical technique for DSAEK– Descemet’s stripping automated endothelial keratoplasty. In: Brightbill FS, McDonnell PJ, McGhee CNJ, Farjo AA, Serdarevic O, eds. Corneal Surgery: Theory, Technique and Tissue. Philadelphia, PA: Mosby Elsevier; 2009:561-565. 17. Price MO, Price FW. Descemet’s stripping with endothelial keratoplasty. In: Brightbill FS, McDonnell PJ, McGhee CNJ, Farjo AA, Serdarevic O, eds. Corneal Surgery: Theory, Technique and Tissue. Philadelphia, PA: Mosby Elsevier; 2009:571-577. 18. Clements JL, Bouchard CS, Lee WB, et al. Retrospective review of graft dislocation rate associated with descemet stripping automated endothelial keratoplasty after primary failed penetrating keratoplasty. Cornea. 2011;30(4):414-418. 19. Goins K. How to manage DSAEK complications. Review of Ophthalmology. September 8, 2011. http://www.revophth.com/content/i/1628/c/29945/. Access June 13, 2013. 20. Terry MA, Shamie N, Chen ES, Hoar KL, Friend DJ. Endothelial keratoplasty a simplified technique to minimize graft dislocation, iatrogenic graft failure, and pupillary block. Ophthalmology. 2008;115(7):1179-1186. 21. Chen ES, Terry MA, Shamie N, Phillips PM, Friend DJ, McLeod SD. Descemet-stripping automated endothelial keratoplasty: insertion using a novel 40/60 underfold technique for preservation of donor endothelium. Cornea. 2008;27(8):941-943. 22. Macsai MS, Kara-Jose AC. Suture technique for Descemet stripping and endothelial keratoplasty. Cornea. 2007;26(9):1123-1126. 23. Terry MA, Saad HA, Shamie N, et al. Endothelial keratoplasty: the influence of insertion techniques and incision size on donor endothelial survival. Cornea. 2009;28(1):24-31.

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24. 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(3):411-418. 25. Terry MA, Hoar KL, Wall J, Ousley P. Histology of dislocations in endothelial keratoplasty (DSEK and DLEK): a laboratory-based, surgical solution to dislocation in 100 consecutive DSEK cases. Cornea. 2006;25(8):926-932. 26. Kent C. The ongoing evolution of endothelial keratoplasty. Review of Ophthalmology. September 23, 2009. http://www.revophth.com/content/d/features/i/1212/c/22847. Accessed June 20, 2013. 27. Hayes DD, Shih CY, Shamie N, et al. Spontaneous reattachment of Descemet stripping automated endothelial keratoplasty lenticles: a case series of 12 patients. Am J Ophthalmol. 2010;150(6):790-797. 28. Afshari NA, Gorovoy MS, Yoo SH, et al. Dislocation of the donor graft to the posterior segment in descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2012;153(4):638-642, 642. e1-2. 29. Suh LH, Yoo SH, Deobhakta A, et al. Complications of Descemet’s stripping with automated endothelial keratoplasty: survery of 118 eyes at one institute. Ophthalmology. 2008;115(9):1517-1524. 30. Price FW Jr, Price DA, Ngakeng V, Price MO. Survey of steroid usage patterns during and after lowrisk penetrating keratoplasty. Cornea. 2009;28(8):865-870. 31. Price MO, Jordan CS, Moore G, Price FW Jr. Graft rejection episodes after Descemet stripping with endothelial keratoplasty: part two: the statistical analysis of probability and risk factors. Br J Ophthalmol. 2009:93(3):391-395.

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6 Ultra-Thin Grafts for Descemet’s Stripping Automated Endothelial Keratoplasty Vincenzo Scorcia, MD; Elena Alb , MD; and Massimo Busin, MD In the past few years, endothelial keratoplasty has established itself as the gold standard for the treatment of endothelial failure of various origins.1 Descemet’s stripping automated endothelial keratoplasty (DSAEK) is by far the most popular technique to replace diseased endothelium; it is an onlay posterior lamellar keratoplasty procedure that precedes transplantation of donor Descemet’s membrane and endothelium attached to a layer of deep stroma.1,2 As a result, a stromal interface is created between donor tissue and recipient stroma, which some authors have held responsible for the suboptimal visual results obtained in a variable percentage of patients undergoing this type of surgery.3,4 Recent reports have shown that grafts consisting of only Descemet’s membrane and endothelium (ie, Descemet’s membrane endothelial keratoplasty [DMEK]) produce 20/25 or better vision in a significantly higher percentage of patients than do DSAEK grafts.5-7 In addition, the time required to achieve this level of vision is shorter for the former type of donor grafts. However, DMEK has not gained popularity over DSAEK because it is technically more demanding than DSAEK and complications both intra- and postoperatively occur more frequently. Additionally, although more than 40% of patients undergoing DMEK in the absence of comorbidities could achieve 20/20 vision, still more than 50% could not do so, thus suggesting that factors other than the presence of a stromal interface are responsible for the final visual performance.6,8,9 In 2011, Neff et al4 reported post-DSAEK visual results to be better than post-DMEK results in patients with grafts thinner than 131 μm, thus correlating for the first time postoperative vision to the morphologic characteristics of the DSAEK tissue transplanted. Whereas surgeons in the past simply removed most of the anterior stroma from the donor cornea and transplanted what was left behind, debate continued regarding whether an attempt should be made to optimize the shape and thickness of DSAEK grafts to minimize postoperative refractive change and, most of all, to maximize postoperative visual performance. Recently, our group proposed a microkeratome-assisted technique to obtain ultra-thin (UT)DSAEK grafts in a simple, standardized, and reproducible manner10; with this technique, thinner grafts are obtained with a double microkeratome pass.

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Figure 6-1. Optical coherence tomography images of donor tissue obtained (A) before the debulking cut, (B) after the debulking cut, and (C) after the refinement cut.

Figure 6-2. Photographs showing tissue (A) being loaded on a modified Busin glide and (B) delivered using the pull-through technique.

Surgical Technique The donor cornea is mounted on an artificial anterior chamber (AAC) of the Automated Lamellar Therapeutic Keratoplasty system (Moria S.A.). The central corneal thickness of the donor is measured intraoperatively using ultrasound pachymetry (SP-3000; Tomey GmbH). An initial debulking cut is performed using a Carriazo-Barraquer microkeratome (Moria S.A.) with a 300-μm head. After turning the dovetail of the AAC by 180 degrees, a second microkeratomeassisted dissection (refinement cut) is performed from the direction opposite the one of the first cut. Previous unpublished experiments conducted at Fondazione Banca degli Occhi del Veneto showed that microkeratome dissection is deeper at the beginning of the cut, when the instrument engages tissue. Performing the 2 cuts from opposite directions is therefore instrumental not only in avoiding perforation but also in evening out the final thickness of the residual lamella. The head used for this step is selected according to a nomogram developed by Busin aimed at leaving behind a residual bed with a central thickness of approximately 100 μm.11 Pressure in the system is standardized by raising the infusion bottle to a height of 120 cm above the level of the AAC and then clamping the tubing at 50 cm from the entrance into the AAC. In addition, maximum care is taken to maintain a uniform, slow movement of the hand-driven microkeratome, requiring a time between 4 and 6 seconds for each of the 2 dissections. Figure 6-1 shows the optical coherence tomography images of the donor tissue before (Figure 6-1A) and after (Figure 6-1B) the debulking and the refinement cut (Figure 6-1C). The DSAEK procedure is performed according to a standard technique previously described,11,12 except for the following modifications. The side platform of a modified Busin glide is used to scoop the tissue floating on a balanced salt solution cushion in the hollow of the punching block (Figure 6-2A); the graft then is delivered into the anterior chamber with the pull-through technique through a 3-mm-wide, 1-mm-long clear corneal tunnel (Figure 6-2B). Because the funnel of the modified glide is smaller than the conventional glide, the tip can be inserted into the wound during delivery, thus preventing squeezing of the tissue while entering

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Figure 6-3. Anterior segment optical coherence tomography 1 month after UT-DSAEK. The graft is already thin and planar.

the anterior chamber through the corneal incision. In patients undergoing a triple procedure, phacoemulsification and intraocular lens implantation are performed before UT-DSAEK surgery. Postoperatively, patients are instructed to lie supine for at least 2 hours and are then examined approximately 3 hours postoperatively at the slit lamp; some air is removed if no aqueous humor has entered the anterior chamber from behind the iris through the peripheral iridotomy. In a recent study, Busin et al reported the 2-year results of UT-DSAEK procedures.11 All grafts were clear at 1-month follow-up, except for 4 cases. Preoperatively, 93% of the patients had visual acuity of less than 20/40. As early as 1 month postoperatively (with all sutures still in place), best corrected visual acuity (BCVA) was 20/20 or better in 11.7% of all eyes and 20/40 or better in 63.8% of all eyes. The BCVA kept improving over time, with 48.8% of patients seeing 20/20 or better 2 years after UT-DSAEK. In particular, phakic patients performed best, with 76.5% of them reaching a BCVA of 20/20 or better as early as 6 months after UT-DSAEK. Mean endothelial cell density in the donor corneas was 2510 ± 154 cells/mm 2 (range, 2100 cells/mm 2 to 3000 cells/mm 2). Mean endothelial cell loss at 3, 6, 12, and 24 months was 29.8% ± 14.3%, 33% ± 15.5%, 35.6% ± 14.1%, and 36.6% ± 16.0%, respectively, showing substantial stabilization of cell loss as early as 1 year after UT-DSAEK. All eyes had a central graft thickness of less than 151 μm: 260 (95.6%) eyes had a central graft thickness of less than 131 μm, and 213 (78.3%) eyes had a central graft thickness of less than 101 μm. Three months postoperatively, mean central graft thickness was 78.28 ± 28.89 μm, and mean peripheral graft thickness was 92.30 ± 38.04 μm nasally and 97.77 ± 35.66 μm temporally. Peripheral graft thickness was significantly higher than central graft thickness but did not differ statistically between the temporal and nasal sides. Examples of postoperative anterior segment OCT and slit-lamp appearance are shown in Figures 6-3 and 6-4. All complications occurred during the second microkeratome pass. In 10 (3.4%) cases, buttonholing caused incomplete central dissection of the donor tissue, which was used anyway in all cases after refinement by hand. Perforation occurred in 9 cases, with tissue being discarded in 6 (2.1%) and used anyway in 3 (1%) by punching the tissue eccentrically on the peripheral site of the perforation. Finally, in 2 cases, dissection was not complete at the end of the cut but was outside of the area required for punching the tissue to the desired size. Postoperatively, complete graft detachment was seen in 11 (3.9%) cases and was always managed successfully by rebubbling. In 2 additional cases, the graft detached in a limited portion of its periphery with no interference with vision and was not treated (Figure 6-5). None of these cases progressed to total detachment or failure during follow-up. Eight grafts failed. Four (1.4%) grafts did not clear the cornea by 1-month follow-up and were considered primary failures. Four (1.4%) additional grafts cleared primarily but showed late endothelial decompensation and had to be exchanged; therefore, there were considered secondary failures. Two of the grafts that failed primarily and 3 that failed at a later stage had necessitated hand refinement during preparation. Kaplan-Meier graft survival probability at 1, 3, 6, 12, and 24 months was 98.6%, 98.2%, 97.8%, 97.8%, and 96.2%, respectively. All failed grafts were regrafted successfully with UT-DSAEK.

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Figure 6-4. Images from an eye with pseudophakic bullous keratopathy (A and B) before and (C and D) after UT-DSAEK. The UT-DSAEK graft is barely visible in its peripheral portion (arrows).

Figure 6-5. Partial graft detachment involving the peripheral edge; it recovered spontaneously without treatment.

Discussion With the introduction of DSAEK, microkeratome-assisted dissection of donor corneas has become the gold standard for the preparation of grafts for endothelial keratoplasty, mainly because of the ease of the technique, the elimination of tissue waste, and the excellent quality of the stromal surfaces obtained this way. The only major limitation of microkeratome-assisted dissection is its poor accuracy in determining the final thickness of the dissected tissue. In particular, microkeratome heads with wider

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slits produce lamellae with a greater variability in thickness.13 For this reason, to prevent perforation, tissue for DSAEK is cut with heads no wider than 300 or 350 μm, often resulting in a donor button with a significant amount of residual deep stroma. The rationale for obtaining donor grafts with a very thin layer of stroma (UT grafts) is based on the DSAEK study by Neff et al4 and on evidence that in deep anterior lamellar keratoplasty (DALK), visual outcome is better if the residual stromal layer in the recipient bed is limited to approximately 100 μm.14 Also, thin grafts may result in a smaller or negligible hyperopic shift. Finally, although irrelevant to the final visual outcome, a very thin layer of residual deep stroma in the endothelial graft allows handling of the donor tissue similar to that allowed with thicker DSAEK grafts, thus maintaining the same ease of delivery and low postoperative detachment rate. If a single cut is performed using microkeratome heads with slits wider than 350 μm, the actual thickness of the excised lamellae can vary from the intended thickness of 100 μm or more. Instead, after decreasing the thickness of donor tissue to less than 200 μm with the first debulking dissection, a second cut can be performed safely using microkeratome heads with narrow slits (130 μm or less), allowing for much more limited variations in the thickness of the excised lamella. Our results indicate that UT-DSAEK is a procedure that shares the improved visual outcome and lower immunologic rejection rate of DMEK over DSAEK while minimizing postoperative complications. Additionally, similar to DSAEK and unlike DMEK, UT-DSAEK can be performed safely in all types of eyes, even in those with complicated anatomic features (eg, free communication between anterior chamber and vitreous cavity as in aphakia or presence of anterior chamber intraocular lenses) or poor anterior chamber visualization. Finally, unlike DMEK grafts, UT-DSAEK grafts can be dissected routinely even by relatively inexperienced eye bank technicians and can be evaluated easily, thus reducing tissue waste and further improving the quality of tissue to be transplanted.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein RM. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology. 2009;116(9):1818-1830. Anshu A, Price MO, Tan DT, Price FW Jr. Endothelial keratoplasty: a revolution in evolution. Survey Ophthalmol. 2012;57(3):236-252. Letko E, Price DA, Lindoso EM, Price MO, Price FW Jr. Secondary graft failure and repeat endothelial keratoplasty after Descemet’s stripping automated endothelial keratoplasty. Ophthalmology. 2011;118(2):310-314. Neff KD, Biber JM, Holland EJ. Comparison of central corneal graft thickness to visual acuity outcomes in endothelial keratoplasty. Cornea. 2011;30(4):388-391. Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEK—the thinner the better? Curr Opin Ophthalmol. 2009;20(4):299-307. Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology. 2009;116(12):2361-2368. McCauley MB, Price MO, Fairchild KM, Price DA, Price FW Jr. Prospective study of visual outcomes and endothelial survival with Descemet membrane automated endothelial keratoplasty. Cornea. 2011;30(3):315-319. Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced with Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2012;119(3):536-540. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011;118(12):2368-2373. Busin M, Patel AK, Scorcia V, Ponzin D. Microkeratome-assisted preparation of ultrathin grafts for descemet stripping automated endothelial keratoplasty. Invest Ophthalmol Vis Sci. 2012;53(1):521-524. Busin M, Madi S, Santorum P, Scorcia V, Beltz J. Ultrathin Descemet’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique: two-year outcomes. Ophthalmology. 2013;120(6):1186-1194. Busin M, Bhatt PR, Scorcia V. A modified technique for Descemet membrane stripping automated endothelial keratoplasty to minimize endothelial cell loss. Arch Ophthalmol. 2008;126(8):1133-1137. Springs CL, Joseph MA, Odom JV, Wiley LA. Predictability of donor lamellar graft diameter and thickness in an artificial anterior chamber system. Cornea. 2002;21(7):696-699.

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14. Ardjomand N, Hau S, McAlister JC, et al. Quality of vision and graft thickness in deep anterior lamellar and penetrating corneal allografts. Am J Ophthalmol. 2007;143(2):228-235.

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7 Descemet’s Membrane Endothelial Keratoplasty Yuri McKee, MD and Francis W. Price Jr, MD Descemet’s membrane endothelial keratoplasty (DMEK) is the latest addition to the recent advances in corneal endothelial replacement therapy.1-19 DMEK exactly replaces dysfunctional host endothelium with healthy donor endothelium without adding any donor stromal tissue. In the same way that Descemet’s stripping automated endothelial keratoplasty (DSAEK) represented a major advance over penetrating keratoplasty (PK), DMEK represents a significant advancement over DSAEK. Visual rehabilitation occurs in days to weeks with DMEK as compared with weeks to months with DSAEK (Figure 7-1). Furthermore, DMEK produces a more normal posterior corneal surface with fewer higher-order aberrations and generally provides patients with an additional line of median best corrected visual acuity (BCVA) compared with DSAEK. Significantly, DMEK was found to have a 15-times lower relative risk of rejection episodes within the first 2 years compared with DSAEK in a single-center study.8 Finally, DMEK requires no additional expensive equipment.

Donor Preparation Giebel was the first to describe the submerged cornea using backgrounds away (SCUBA) technique for DMEK donor preparation. This technique is a reliable and expeditious way to safely harvest Descemet’s membrane and endothelium for DMEK grafts. As with all lamellar corneal procedures, we recommend powder-free gloves and lint-free polyvinyl alcohol sponges during the entire DMEK procedure, including donor preparation. In the SCUBA technique, the corneal donor rim (endothelium up) is placed in a viewing chamber (K55-57007-23; Krolman Corporation) filled with storage media. The scleral rim is secured with toothed forceps, and Descemet’s membrane is scored with a blunt-tipped instrument such as a Y hook. The score line should be propagated for 360 degrees in the peripheral Descemet’s membrane, 0.5 mm central to the trabecular meshwork. Trypan blue is used to stain the scored edge of Descemet’s membrane. A microdissector (Mastel Precision Instruments) is then used to elevate the scored edge of the peripheral Descemet’s membrane (Figure 7-2). Using Tubagen forceps, Descemet’s membrane is gently peeled toward the center of the corneal rim in all 4 quadrants. The central 3 to 4 mm of Descemet’s membrane is not separated at this time. With the tissue still submerged, the separated areas of Descemet’s membrane are laid back in place. Then the donor rim is placed on a cutting block and Descemet’s membrane is punched at the appropriate diameter (usually 8 to 9 mm) within the score line. Trypan blue is used again to highlight the trephination mark. With the donor rim replaced under storage medium in the viewing chamber, the peripheral skirt of Descemet’s - 73 -

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Figure 7-1. Photograph of a cornea with Fuchs dystrophy. Central guttae and early stromal edema are present. These findings are consistent with decreased vision and increasing glare. (Reprinted with permission from The Digital Manual of Opthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-2. A microdissector is used to elevate the scored edge of Descemet s membrane. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-3. Tubagen forceps are used to peel the final graft from the donor rim after central trephination. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

membrane is removed and the central trephinated area of Descemet’s membrane is grasped near the edge and fully separated from the central corneal stroma (Figure 7-3). Often it is convenient to have the donor tissue prepared ahead of time. The donor tissue, which spontaneously curls up with the endothelium facing outward, can be kept in storage medium in a smooth-walled glass vial for several days before being used in surgery, or it can be stored for longer periods in organ culture medium. The SCUBA technique has yielded a donor loss rate of less than 1% at our institution. We prefer to use donor corneas from decedents older than 40 years and with an endothelial cell count above 2500 cells/mm 2. We have found that tissue from younger donors can be more difficult to uncurl in the recipient eye.

Recipient Preparation For the first several cases of DMEK, the surgeon should choose patients with a properly positioned posterior-chamber intraocular lens (PC IOL), an intact iris-lens diaphragm, and tissue

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Figure 7-4. A reverse Price-Sinskey hook is used to remove the central area of diseased Descemet s membrane and endothelium without engaging the soft posterior stromal fibers. Air provides excellent contrast during stripping of Descemet s membrane. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

from a donor between 60 and 70 years old. Once proficiency is attained, the surgeon may consider DMEK in a phakic eye with a clear lens, using appropriate technique modifications. We do not usually recommend DMEK in eyes with prior glaucoma tube placement because the donor could come in contact with the tube during manipulation. We prefer a temporal approach to facilitate graft insertion, and we use scleral bridle sutures superiorly and inferiorly to maintain a level eye. The central corneal epithelium is lightly marked with the trephine used to punch the graft. Next, 2 paracentesis wounds are created 45 degrees on either side of the horizontal meridian. Preservative-free 1% lidocaine is used intracamerally to augment topical anesthesia. The pupil should be constricted preoperatively with topical pilocarpine. Additional intracameral carbachol can be used if further miosis is desired or if DMEK is combined with cataract surgery. Inject air via a paracentesis to achieve an 80% fill of the anterior chamber. Use a reverse Price-Sinskey hook (Moria S.A.) to score the host endothelium using the epithelial trephination mark as a guide (Figure 7-4). Remove the diseased endothelium from the intended area of graft placement without engaging the soft posterior stromal fibers of the recipient cornea. Infusion of trypan blue into the anterior chamber for 20 seconds will highlight any retained islands or tags of Descemet’s membrane that might inhibit graft adhesion or impair vision. A bimanual irrigation-aspiration setup can be used to remove any retained Descemet’s membrane within the intended zone of graft placement (Figure 7-5). Using 23-gauge intraocular scissors (MicroSurgical Technology) (Figure 7-6), create a small inferior peripheral iridotomy (PI). Next, create a self-sealing 2.8-mm keratome wound between the paracentesis wounds. At this point, the central host Descemet’s membrane has been removed, an inferior PI is present, and the clear corneal wounds should be self-sealing at physiologic intraocular pressure (IOP). The eye is now ready to accept the DMEK donor tissue.

Loading and Injecting Descemet’s Membrane Endothelial Keratoplasty Scroll Multiple closed-system IOL injectors, modified Jones tubes, and even handmade glass pipettes have been used successfully for graft insertion. We use a disposable closed-system IOL injector (Viscojet 2.2; Bausch & Lomb) for graft insertion. The graft should be isolated in a sterile glass petri dish suspended in a small bubble of storage medium. A few drops of trypan blue applied to one end of the scroll will advance up the scroll lumen by capillary action to stain Descemet’s membrane located on the inside of the scroll. After 50 seconds of trypan exposure, the graft is transferred to a second petri dish full of balanced salt solution in which the injector cartridge has been submerged. The scroll is guided into the cartridge, which is then loaded into the injector. Insert the cartridge tip into the anterior chamber via the keratome wound and slowly inject the graft. Shallow the anterior chamber before removing the injector to prevent back pressure from expelling the graft from the eye. Immediately secure the keratome wound with a 10-0 nylon suture (Figure 7-7).

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Figure 7-5. Bimanual irrigation and aspiration is used to remove residual tags of Descemet s membrane that may interfere with donor adhesion or degrade final visual quality. Trypan dye has been used to stain the residual tags of Descemet s membrane. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-6. Intraocular 23-gauge scissors are used to create an inferior PI. The irrigation probe of the bimanual irrigation and aspiration setup is used to maintain the anterior chamber. (Reprinted with permission from The Digital Manual of Opthhalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-7. After graft insertion, the main wound is immediately secured with a 10-0 nylon suture. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Unfolding the Donor Tissue in the Host Eye Inside the eye with the anterior chamber at physiologic depth, the DMEK graft assumes a scroll configuration with the endothelium on the outside of the scroll. Very gentle bursts of balanced salt solution directed circumferentially into the angle will cause the graft to rotate. When one end of the scroll lumen is directed at any one of the corneal wounds, a small amount of balanced salt solution should be directed up the scroll lumen. This will result in partial unfurling of the graft. The anterior chamber depth must be gently reduced to maintain the partially open graft configuration. At this point, a handheld slit beam or intraoperative optical coherence tomography (OCT) (iOCT, Haag Streit) may be used to assess the graft orientation (Figures 7-8 to 7-11). If the arcs of the scrolled edges are seen to be above the connecting bridge of Descemet’s membrane, the graft is in the proper orientation, and the endothelium will be directed posteriorly when the graft is fully opened. If the connecting bridge of Descemet’s membrane is above the scrolled edges, the graft must be flipped over. This can be accomplished by deepening the anterior chamber and directing a gentle flow of fluid beneath the graft until it flips over. Repeat the previous steps until the graft is partially open and in the correct orientation. Next, place a small bubble of air (0.05 cc) under the central graft with a 30-gauge needle on a 1-cc syringe. The bubble will hold the donor scroll

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Figure 7-8. The donor scroll is confirmed to be in the correct orientation with a handheld slit beam. With the microscope, light off the slit beam can be directed tangentially at the partially opened scroll. The top line of light is the host corneal section. Two scrolls can be seen resting above a connecting bridge of Descemet s membrane in the anterior chamber. When completely unscrolled, this graft will correctly leave endothelium facing the iris and Descemet s membrane facing the host stroma. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-9. The Eidelon (Eidelon Optical) handheld slit beam. This can be placed in the finger of a sterile glove for handling during surgery. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-10. Intraoperative OCT image of a DMEK scroll in the proper orientation. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

partially open and prevent the graft from returning to the scroll configuration. Using a 27-gauge irrigation cannula, gentle pressure can be placed on the corneal surface above the scrolled edges of the graft (Figure 7-12). Each time the pressure is released, the graft will uncurl slightly more. Once the entire graft is unscrolled and held in place by the small central bubble, the irrigation cannula can be used to stroke the corneal surface to center the DMEK graft perfectly within the epithelial trephination mark (Figure 7-13). The globe should be rotated so the graft will move

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Figure 7-11. OCT attached to the operating microscope. Intraoperative OCT can be useful in a number of applications, including DMEK. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-12. Gentle pressure on the cornea over the scroll will cause partial unfolding as the tension is released. After several maneuvers, the donor scroll will be completely open. Here one-half of the graft is fully opened already. Trypan staining yields excellent visualization of the graft in the anterior chamber. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-13. When the graft is fully open in the proper orientation and held in place with a small air bubble, it can then be precisely positioned with short crisp strokes on the corneal surface in the intended direction of movement. Notice that the eye is abducted here to aid in causing the graft to relocate temporally. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

“downhill” in the direction desired. Short gentle strokes across the corneal surface will move the graft in small increments, allowing for precise final positioning. Once the graft is well centered and fully open, the anterior chamber should be filled 90% with air (Figure 7-14). Using the 30-gauge needle through the limbus, inject 0.5 to 0.7 cc of air until only a small rim of aqueous fluid remains in the anterior chamber. This will cause the IOP to be elevated temporarily. Confirm that the patient has retained light perception vision by blocking the microscope light and asking the patient for visual confirmation of seeing the light go on and off. If the patient does not clearly sense the presence and absence of the light, release a small amount of air to lower the pressure until the vision returns. The value of topical anesthesia is demonstrated here because the patient needs to be able to perceive the microscope light to confirm blood flow to the optic nerve head. Retrobulbar anesthesia or intracameral anesthesia in the setting of prior vitrectomy may cause temporary loss of light perception. This may make determination of proper

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Figure 7-14. With the donor graft open and well centered, a 90% air fill is placed to support the graft. The needle is placed through the clear cornea near the limbus to avoid causing a hyphema. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Figure 7-15. A small peripheral graft detachment without overlying stromal edema is demonstrated. This is likely to resolve without further intervention. If the detachment extends, a repeat air injection is indicated. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

retinal perfusion in the setting of elevated IOP unreliable. Drops of antibiotics, steroids, and cycloplegics are placed and an eye shield is used at the conclusion of the procedure.

Postoperative Management The patient should remain supine for 1 hour in the recovery room and then be checked in the clinic at a slit lamp. The bubble should be 80% of the anterior chamber volume and not cover the inferior PI. The graft should remain fully attached. IOP should be 25 mm Hg or less. Small amounts of air may be injected or removed to remedy inadequate air fills, graft detachments, or complete air fills. High IOP is usually managed with topical ocular hypotensive drops unless a full air fill or pupillary block is present (in which case, remove air). The patient should remain supine at home for as much as possible during the first 24 hours postoperatively. The air bubble should resorb by 50% each day. In 10% to 15% of cases, air may need to be reinjected to address partial graft detachments. Small peripheral graft detachments without overlying edema may be observed (Figure 7-15). Larger detachments with overlying corneal edema or that approach the visual axis should be treated with proper positioning to cause the air bubble to cover the detachment. If too little air remains in the anterior chamber to appropriately cover the partial detachment, then a repeat air injection is indicated. Complete graft detachment is rare and should be managed in the operating room by either repositioning or replacing the graft. Patients should be advised to avoid changing altitude until the air bubble has completely resorbed (usually by postoperative day 5). We remove the nylon suture 1 week after DMEK if the graft is fully attached and against-the-rule astigmatism is present. Topical antibiotics are continued for 7 to 10 days. Brand-name 1% prednisolone acetate is prescribed 4 times per day for 4 months and then slowly tapered to once per day. Steroid-induced pressure elevations are treated with ocular hypotensive drops and by changing to a lower potency steroid, as needed. Patients without significant stromal scarring or long-standing corneal edema often note improved vision within 2 days as the air bubble begins to exit the visual axis. Final refraction can be done within 1 to 3 months depending on the degree of preoperative corneal edema.

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Figure 7-16. Fully healed DMEK grafts may be difficult to discern. In this example, the small inferior PI is one of the only clues that a DMEK has been performed, other than the crystal clear central cornea. Visual results with DMEK are unparalleled in corneal transplant surgery. (Reprinted with permission from The Digital Manual of Ophthalmic Surgery and Theory, Interactive Medical Publishing, Indianapolis, IN.)

Discussion The DMEK procedure is initially challenging to learn, in part due to the fragility of the donor endothelium. There is a steep learning curve and little room for error. A surgeon should be skilled in other corneal transplant techniques to master DMEK. Despite these challenges, DMEK offers such impressive advantages that it is now a necessary skill for corneal transplant surgeons. Decreased rejection rates and superior visual outcomes will drive patients to seek this technique, especially as information becomes more readily available via the Internet. Corneal surgeons should consider DMEK a first-line procedure in cases of uncomplicated endothelial failure. Results from DMEK with experienced corneal surgeons have now exceeded the results of DSAEK. For DMEK, the rate of visual outcomes at 20/20 or better increases with time. Postoperative recovery is 1 to 4 weeks on average.8 Rejection rates are substantially lower than those with DSAEK and PK. DMEK has been shown to have endothelial cell loss rates similar to DSAEK in long-term follow-up.4 We recommend an instruction course for surgeons learning the DMEK procedure. Patient expectations are high. There are too many nuances to the technique than can be described in a single book chapter. Many hours of wet laboratory practice are a prerequisite for the successful transition to DMEK. Ultimately, the time and effort spent by corneal surgeons to learn this technique will pay dividends in superior outcomes and happier patients (Figure 7-16).

References 1. 2. 3. 4. 5. 6. 7.

Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty: prosepective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology. 2009;116(12):2361-2368. Ham L, Balachandran C, Verschoor CA, van der Wees J, Melles GR. Visual rehabilitation rate after isolated Descemet membrane transplantation: descemet membrane endothelial keratoplasty. Arch Ophthalmol. 2009;127(3):252-255. Li JY, Terry MA, Goshe J, Davis-Boozer D, Shamie N. Three-year visual acuity outcomes after Descemet’s stripping automated endothelial keratoplasty. Ophthalmology. 2012;119(6):1126-1129. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011;118(12):2368-2373. Busin M, Scorcia V, Patel AK, Salvalaio G, Ponzin D. Pneumatic dissection and storage of donor endothelial tissue for Descemet’s membrane endothelial keratoplasty: a novel technique. Ophthalmology. 2010;117(8):1517-1520. Lie JT, Birbal R, Ham L, van der Wees J, Melles GR. Donor tissue preparation for Descemet membrane endothelial keratoplasty. J Cataract Refract Surg. 2008;34(9):1578-1583. Kruse FE, Laaser K, Cursiefen C, et al. A stepwise approach to donor preparation and insertion increases safety and outcome of Descemet membrane endothelial keratoplasty. Cornea. 2011;30(5):580-587.

Descemet's Membrane Endothelial Keratoplasty 8. 9. 10. 11.

12. 13. 14. 15. 16. 17. 18. 19.

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Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced with Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2012;119(3):536-540. Zhu Z, Rife L, Yiu S, et al. Technique for preparation of the corneal endothelium-Descemet membrane complex for transplantation. Cornea. 2006;25(6):705-708. Ham L, Dapena I, van Luijk C, van der Wees J, Melles GR. Descemet membrane endothelial keratoplasty (DMEK) for Fuchs’ endothelial dystrophy: review of the first 50 consecutive cases. Eye (Lond). 2009;23(10):1990-1998. Thaler S, Hofmann J, Bartz-Schmidt KU, Schuettauf F, Haritoglou C, Yoeruek E. Methyl blue and aniline blue versus patent blue and trypan blue as vital dyes in cataract surgery: capsule staining properties and cytotoxicity to human cultured corneal endothelial cells. J Cataract Refract Surg. 2011;37(6):1147-1153. Treffers WF. Human corneal endothelial wound repair. In vitro and in vivo. Ophthalmology. 1982;89(6):605-613. Van Dooren B, Mulder PG, Nieuwendaal CP, Beekhuis WH, Melles GR. Endothelial cell density after posterior lamellar keratoplasty (Melles technique); 3 years follow-up. Am J Ophthalmol. 2004;138(2):211-217. Ham L, van der Wees J, Melles GR. Causes of primary donor failure in Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145(4):639-644. Melles GR, Lander F, Rietveld FJ. Transplantation of Descemet’s membrane carrying viable endothelium through a small scleral incision. Cornea. 2002;21(4):415-418. Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. 2006;25(8):987-990. Burkhart ZN, Feng MT, Price MO, Price FW. Handheld slit beam techniques to facilitate DMEK and DALK. Cornea. 2013;32(5):722-724. Feng MT, Burkhart ZN, Price FW Jr, Price MO. Effect of donor preparation-to-use times on Descemet membrane endothelial keratoplasty outcomes. Cornea. 2013;32(8):1080-1082. Guerra FP, Anshu A, Price MO, Price FW. Endothelial keratoplasty: fellow eyes comparison of Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty. Cornea. 2011;30(12):1382-1386.

Please see video on the accompanying website at

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8 Endoilluminator-Assisted Descemet’s Membrane Endothelial Keratoplasty Soosan Jacob, MS, FRCS, DNB, MNAMS and Amar Agarwal, MS, FRCS, FRCOphth Endothelial keratoplasty has evolved from deep lamellar endothelial keratoplasty (DLEK) to Descemet’s stripping automated endothelial keratoplasty (DSAEK) to Descemet’s membrane endothelial keratoplasty (DMEK). DSAEK is popular and has become universally accepted and practiced due partly to the ease of the surgery and the short learning curve. However, DMEK is practiced in few centers, mainly because of the greater difficulty in performing the surgery. This difficulty is often compounded by the low visibility of the graft through a hazy cornea. Moreover, the DMEK graft is transparent, thin, and flimsy. Therefore, it is difficult to visualize the graft clearly in the anterior chamber after insertion. In an attempt to overcome this, the graft can be stained with trypan blue. Despite this staining, good visualization is often still challenging through an edematous cornea. Also, the dye washes off in time, and, in the case of a longer surgical time, the inserted graft becomes too difficult to visualize. One of the authors (Soosan Jacob)1 has described a technique, endoilluminator-assisted DMEK (E-DMEK), to enable easy identification of the orientation and visualization of the graft during all surgical steps. E-DMEK uses oblique light from a vitreoretinal light pipe or an endoilluminator for better visualization.

Background The endoilluminator has been used to provide an oblique source of illumination in anterior segment surgery since 1993.2 It has been used to visualize the anterior capsular flap while performing capsulorrhexis in hypermature cataracts, to perform cataract surgery in the presence of corneal opacity, for irrigation and aspiration during combined 23-gauge sutureless vitrectomy and cataract surgery, and as an endoilluminated infusion cannula for bimanual anterior chamber vitrectomy. Chandelier illumination has been used during DSAEK since 2011 via a chandelier illumination fiber inserted through the corneal side port to provide sclerotic scattering-like illumination from the sclerocorneal margin and endoillumination from the anterior chamber, resulting in excellent visibility for Descemet’s stripping and intraocular manipulation without obstruction from a hazy cornea.3 However, it has not been reported in patients undergoing DMEK. The use of the endoilluminator for DMEK is a logical extension of its previous uses. Because DMEK is more challenging, the use of an endoilluminator is comparatively more valuable in attaining greater ease of surgery. E-DMEK makes surgery simpler by allowing good visualization and better surgeon understanding of graft morphology and dynamics.

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Figure 8-1. (A) The DMEK graft is prepared by keeping the corneoscleral button submerged in storage medium. The edge of Descemet s membrane is held and gently separated from the stroma. (B) The DMEK graft is seen with edges curving toward Descemet s membrane. (C) The spring coil of a Viscoject injector (Medicel) is removed.5 (D) The soft silicone tip is replaced. (E) The DMEK graft is loaded into the Viscoglide cartridge (Medicel) with the correct orientation. (F) The cartridge is closed and loaded onto the injector. (G) The DMEK graft is injected forward to the tip of the cartridge. (H) The graft is injected into the anterior chamber.

Surgical Technique One of the key steps in DMEK is determining the descemetic side of the graft. The descemetic side needs to face the overlying corneal stroma. This will allow the graft to be appropriately apposed to the stroma on injection of an air bubble. The key to being sure about the correct orientation of the graft is to look at the direction toward which the edges of the graft are curling. Because Descemet’s membrane is an elastic structure, the graft edges always curl toward the stroma. Therefore, intraoperatively, the graft must be oriented with the curve facing upward. This is often difficult to confirm with current techniques. Because the graft is transparent, it is difficult to ascertain the direction of the curvature of the edges, even in an eye with good visibility. The graft is prepared as usual using the submerged cornea using backgrounds away (SCUBA) technique described by Giebel et al.4 This allows easy preparation of the graft with less chance of damage and tearing. Our preferred technique is to punch the donor corneoscleral button to the desired size, followed by submerging the button in storage medium. The edge of Descemet’s membrane is then gently grasped with a fine nontoothed forceps and stripped from all sides, carefully avoiding any uncontrolled tears (Figures 8-1A and 8-1B). The graft is sized 0.5 mm smaller than the proposed recipient bed. The recipient bed is prepared by externally marking the surface of the cornea with a blunt trephine. Descemet’s membrane is then scored with a reverse Sinskey hook and stripped. Once this is done, the DMEK graft is stained with trypan blue 0.1%. Following the technique described by Professor Francis Price,5 the spring coil is removed from the Viscoject injector (Medicel) and the silicone tip is replaced (Figures 8-1C and 8-1D). The graft is then placed into the 1.8-mm Viscoglide cartridge (Medicel) (Figures 8-1E and 8-1F). The cartridge is loaded onto the injector (Figure 8-1G). A microincision keratome is used to create a 2.2-mm temporal clear corneal incision, and a paracentesis is created 90 degrees away. A small inferior peripheral iridectomy is created now (it may also have been created preoperatively using an nd:YAG laser). Using the injector, the graft is gently injected into the anterior chamber, and the incisions are sutured (Figure 8-1H). At this point, the microscope light is turned off, and the endoilluminator or light probe (20, 23, or 25 gauge) is used as an oblique source of illumination to enhance visualization. It is held externally by the surgeon or by an assistant while the surgeon continues surgery bimanually. The tangential light provided by the endoilluminator is used to show details of the graft, folds in the grafts, and the position and orientation of Descemet’s membrane in relation to the corneal stroma. The tip of the light probe is moved around the limbus while focusing it tangentially to allow good visualization and 3-dimensional perception. The direction of graft edge curvature, and thereby graft orientation, is confirmed by tapping the host cornea

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Figure 8-2. (A) Media opacity prevents clear and adequate visualization of the DMEK graft under microscope light. (B) In the E-DMEK technique, using an obliquely directed endoilluminator and switching off the microscope light provides 3-dimensional depth perception of the graft while allowing visualization of the entire graft and views from different angles. This allows better surgeon comprehension of graft dynamics, morphology, and positioning, in turn leading to easier and faster surgery while potentially decreasing graft damage due to prolonged surgery and excessive manipulations. (C) The graft viewed under microscope light, which decreases visualization. (D) The graft, when viewed using the E-DMEK technique, is clearer.

Figure 8-3. (A) Graft seen under microscope light after apposition to overlying stroma with an air bubble. (B) In the same eye, the folded edge at the inferior aspect is seen well only with E-DMEK. (C) Folds and edges in the graft bounce light and create reflections, which allows easier perception of orientation. (D) Graft details through an edematous cornea via E-DMEK.

gently and appreciating the reflexes created by the light bouncing off the edges of the graft and by seeing the movement induced in the graft (Figures 8-2 and 8-3). Using endoillumination, the graft is oriented the right way up and centered under the stripped recipient site, after which an air bubble is injected under the graft to float it up against the overlying stroma. At any time during the surgery, the surgeon can switch back and forth between the microscope light and the endoilluminator. Intraocular pressure and light perception are checked before closing the eye. The patient is asked to maintain a strict supine position for the first 24 hours.

Advantages of Endoilluminator-Assisted Descemet’s Membrane Endothelial Keratoplasty The tangential light provided by the endoilluminator details the graft, the folds in the graft, its position, and the orientation of the Descemet’s membrane. Moving the tip of the light probe around the limbus while keeping it tangentially focused allows good visualization and 3-dimensional depth perception. Keeping only the perpendicularly incident operating microscope light on makes it difficult to determine whether the edges are curving upward or downward. It also decreases the clear 3-dimensional depth perception of the surgeon because of the transparent nature of the graft. Even in a nonedematous, clear cornea, it is often difficult to confirm the direction of the curvature of the scrolled edges with the operating microscope light alone, and the surgeon may have to use an instrument inserted under the scroll edge to confirm the direction of the roll. With E-DMEK, the light reflexes that are created by the tangential endoilluminator light falling on the folds and edges of the graft allow confirmation of the direction of the curvature

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Figure 8-4. (A) Appearance of the cornea at 1 month postoperatively. (B) Slit view of the same patient shows a nonedematous cornea and attached graft. The inferior edge of the graft can be seen. (C) Appearance of a clear cornea in a different patient 10 days postoperatively. (D) The attached graft margin is shown (arrowheads).

of the graft edges and thereby graft orientation while maintaining a no-touch technique, thus decreasing cell loss in the graft. E-DMEK also allows movements induced in the graft during various maneuvers to be easily seen by the surgeon. The handheld slit beam technique for DMEK surgery was described by Burkhart et al6 in 2013. However, E-DMEK has the advantages of allowing views of the entire graft rather than only a slit view and not requiring scanning across the graft for a more complete view. The endoilluminator gives a clear view of the entire graft. The strong focused light of the probe is able to pierce through the edematous cornea and allow easy visualization. We prefer holding the endoilluminator close to the corneal surface externally as opposed to inserting it into the anterior chamber, where it produces excessive sclerotic scattering of the light. When directed tangentially, it provides excellent visualization. Inserting the endoilluminator into the anterior chamber also tends to cause wound leakage and shallowing of the anterior chamber, and it occupies space within the anterior chamber, thus interfering with the free movement of the graft and hindering graft flotation.

Conclusion E-DMEK allows better 3-dimensional visualization and depth perception, thereby providing a better understanding of graft morphology, position, orientation, and dynamics. It is a valuable technique to enhance surgical ease, speed, and success for the DMEK surgeon. Potential graft damage caused by excessive handling and maneuvering within the eye is decreased (Figure 8-4). We have also used the E-DMEK technique in pre-Descemet’s endothelial keratoplasty (PDEK) as E-PDEK and obtained similar results and advantages.

References 1.

Jacob S, Agarwal A, Agarwal A, Narasimhan S, Kumar DA, Sivagnanam S. Endoilluminator assisted transcorneal illumination for Descemet’s Membrane Endothelial Keratoplasty (E-DMEK) : A technique for enhanced intra-operative visualization of the graft in corneal decompensation secondary to pseudophakic bullous keratopathy. J Cataract Refract Surg. In press. 2. Mansour AM. Anterior capsulorhexis in hypermature cataracts. (letter). J Cataract Refract Surg. 1993;19:116–117. 3. Inoue T, Oshima Y, Hori Y, Maeda N, Nishida K. Chandelier illumination for use during Descemet Stripping Automated Endothelial keratoplasty in patients with advanced bullous keratopathy. Cornea. 2011;(30) Suppl1:S50-53.

Endoilluminator-Assisted Descemet's Membrane Endothelial Keratoplasty 4.

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Giebel AW, Grandin JC, Price FW. The SCUBA technique for reliable and consistent harvesting of endothelial grafts without stroma. December 1, 2008. American Academy of Ophthalmology ONE Network. http://one.aao.org/annual-meeting-video/scuba-technique-reliable-consistent-harvestingof-. Accessed November 6, 2014. 5. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: early challenges and technique to enhance donor adherence. J Cataract Refract Surg. 2006;32:411-18. 6. Burkhart ZN, Feng MT, Price MO, Price FW. Handheld slit beam techniques to facilitate DMEK and DALK. Cornea. 2013;32(5):722-724.

Please see video on the accompanying website at

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9 Corneal Surgery and the Glued Intraocular Lens Technique Priya Narang, MS and Amar Agarwal, MS, FRCS, FRCOphth The past decade has seen a paradigm shift in the management of corneal disorders—from penetrating keratoplasty (PK) to endothelial keratoplasty (EK)—and in the management of secondary intraocular lens (IOL) implantation—from conventional sutured scleral fixation and iris retro-claw fixation to sutureless glued intrascleral IOL implantation. These advancements offer many benefits to a select group of patients. Posttraumatic cases with corneal opacities and lenticular disruption/dislocation are ideal scenarios in which to perform glued IOL with corneal surgical intervention. Complicated cataract surgeries associated with posterior capsule rupture often lead to corneal decompensation. Corneal edema and decompensation result from failure of the corneal endothelium to maintain deturgescence. The visual function of the 5-layered cornea is dependent on its shape and clarity, and each layer plays a vital role. Corneal decompensation beginning many years after IOL implantation may be due to excessive loss of endothelium at the time of surgery, followed by ongoing normal or accelerated attrition of the remaining endothelium. With the recent surge in keratoplasty techniques for the treatment of corneal diseases, determining when to perform corrective surgery for IOL implantation in the setting of corneal disease is crucial for appropriate surgical planning. Glued IOL has been used in multiple situations, including surgical aphakia, traumatic phacocele, and dislocated in-the-bag IOL, as well as in combination with femtosecond laser–assisted keratoplasty. This chapter discusses considerations for deciding to perform glued IOL implantation and the appropriate corneal procedure to perform for corneal diseases. The past decade has seen a revolutionary shift in the treatment of corneal endothelial disease. Fifteen years ago, the only surgical treatment for pseudophakic bullous keratopathy and Fuchs’ dystrophy was PK. Although used successfully for more than a century, PK requires many months of refractive adjustments before the eye achieves visual stability. Starting with posterior lamellar keratoplasty in the late 1990s, a number of procedures have been developed, refined, and widely adopted, which have given patients faster recoveries and improved globe stability compared with traditional corneal transplantation. Preliminary results of the most recent form of EK—Descemet’s membrane EK (DMEK)—suggest that pure endothelial cell transplantation is on the horizon.1

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Surgical Considerations for Combined Corneal Procedures The main advantage of combining EK and glued IOL surgery is patient convenience. Patients undergo only one surgery, attend fewer appointments, and deal with only one set of postoperative medications. Although a combined surgical procedure is not significantly more complex than EK surgery alone, a few concerns must be addressed, especially for novice surgeons. During the surgery, the surgeon must be prepared for a decreased view secondary to guttata or haze, decreased anterior chamber stability (in cases requiring explantation of a previous IOL), increased chances of graft dislocation (intraoperative miosis is often required), increased intraocular inflammation that may lead to increased endothelial cell damage, and a potential risk of problems with the anterior chamber air fill due to air diversion into the vitreous. The creation of an air bubble in the anterior chamber is an essential element of EK techniques, including Descemet’s stripping EK (DSEK), DMEK, and their respective automated techniques (DSAEK and DMAEK). There are no rules to determine when patients should undergo combined surgery vs glued IOL surgery alone; however, the patient’s preoperative history and examination are important tools for making this decision. Patients who report blurred vision on awakening have corneal edema and are more likely to show corneal decompensation after glued IOL surgery alone. Specular microscopy may show an increased risk for corneal decompensation in severe cases in which the endothelial cell count is low, but this testing modality can be unpredictable in the presence of dense guttata. Corneal pachymetry has been suggested as a method for predicting corneal decompensation.2 Performing IOL implantation before a corneal procedure involves refractive instability and unpredictable keratometry values; therefore, predicting the lens implant power before a corneal procedure can present challenges. Studies of lens power calculations associated with keratoplasty have shown that an effective way of reducing postoperative ametropia is to perform keratoplasty first, followed by lens extraction and IOL implantation at a later date. Flowers et al 3 reported 95% of patients within ± 2.00 diopters of intended postoperative target refraction following PK and cataract extraction with IOL placement performed secondarily. The major advantages of glued IOL surgery combined with EK as opposed to glued IOL surgery combined with PK include improved keratometric stability, decreased astigmatism after keratoplasty, and reduced IOL power errors due to better refractive outcomes. Prior to the introduction of EK procedures, poor postoperative refractive results, with as little as 26% of eyes within ± 2.00 diopters of intended target refraction, were reported.4 In the largest published review, EK was shown to routinely create a hyperopic refractive shift (range, 0.70 to 1.50 diopters; mean, 1.10 diopters) and induce minimal astigmatism (mean, 0.11 diopters).5 Taking these refractive considerations into account, surgeons planning IOL implantation before or combined with EK should aim for 1.00 to 1.25 diopters of myopia to achieve emmetropia. All corneal procedures described herein are combined with glued IOL surgery. A separate detailed description of just the glued IOL technique follows.

Glued Intrascleral Haptic Fixation of an Intraocular Lens Glued IOL is a technique that is universally applicable in cases with a posterior capsule rupture, irrespective of the size of the capsular break.6 Two partial-thickness scleral flaps are created 180 degrees opposite each other, followed by the introduction of infusion in the form of an anterior chamber maintainer or trocar cannula. Sclerotomy is performed with a 20-gauge needle beneath the flaps approximately 1 mm away from the limbus, with the needle directed obliquely downward toward the midvitreous cavity (Figure 9-1A). Vitrectomy is performed with a 25-gauge cutter introduced from the sclerotomy site, and all vitreous strands are thoroughly cut. Visualization of the vitreous strands can be enhanced with the use of triamcinolone acetonide. A corneal tunnel is fashioned, a 3-piece foldable IOL is loaded, and the tip of the haptic is slightly extruded from the cartridge, demonstrating a “lucky 7” sign.7 The IOL is injected, and the tip of the leading

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Figure 9-1. (A) Two partial-thickness scleral flaps are made 180 degrees apart. Trocar infusion is introduced, followed by sclerotomy with a 22-gauge needle approximately 1 mm behind the limbus beneath the scleral flap. The needle is entered into the eye in an obliquely downward direction. (B) Glued IOL forceps are introduced from the left sclerotomy site and grasp the tip of the leading haptic. When the entire IOL unfolds, the haptic is pulled and externalized. (C) Glued IOL forceps are introduced from the right sclerotomy site; the tip of the trailing haptic is caught and externalized. (D) Two scleral pockets are made with a bent 26-gauge needle, one on either side. It is made parallel to the sclerotomy wound at the edge of the flap. (E) The haptic is tucked into the scleral pocket. The haptic is grasped near the tip with the forceps and then introduced into the scleral pocket on either side. The centration of the IOL can be adjusted by the amount of haptic tucked. After both haptics are tucked, vitrectomy is performed at the sclerotomy site to cut any present vitreous strand. (F) Fibrin glue is applied.

haptic is grasped with a glued IOL forceps introduced from the left sclerotomy site (Figure 9-1B). The cartridge is slightly withdrawn so that the trailing haptic lies at the corneal incision. When the entire IOL has unfolded, the tip of the leading haptic is pulled and externalized from the left sclerotomy site with the help of glued IOL forceps. The trailing haptic is grasped and flexed into the eye while the leading haptic is held by an assistant to prevent its slippage into the eye. The handshake technique8 is used for externalization of the trailing haptic, wherein the IOL haptic is bimanually transferred from one glued IOL forceps to another under direct visualization in the pupillary plane. When both haptics are externalized (Figure 9-1C), they are tucked in the scleral pocket created with a 26-gauge needle at the edge of the bed of flap just parallel to the sclerotomy site (Figures 9-1D and E), preventing any further movement of the haptic, reducing pseudophacodonesis, and minimizing slippage and late redislocation. Vitrectomy is performed at the sclerotomy site to ensure there is no vitreous traction postoperatively. Infusion is stopped, air is injected into the anterior chamber, and the flaps are sealed with the application of fibrin glue (Figure 9-1F), although complete scleral wound healing with collagen fibrils may take up to 3 months. Because the haptic is snugly placed inside an intralamellar scleral tunnel, the IOL remains stable from the early postoperative period. This method avoids additional corneal incisions or multiple sclerotomies and reduces surgical time and intraocular pressure (IOP) fluctuation by maintaining a closed system.

No-Assistant Technique The no-assistant technique is a modification of the process of haptic externalization in glued IOL surgery where the leading haptic remains externalized throughout the procedure, eliminating

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Figure 9-2. (A) Two partial-thickness limbal-based scleral flaps of 2.5 x 2.5 mm are created 180 degrees opposite each other, followed by placement of an infusion cannula. (B) After both flaps are made, the cornea is marked with a marking pen at the center of the corneal dome, and an 8.5-mm blunt trephine is used to mark the area concentric to this mark to facilitate Descemet s membrane scoring and stripping. (C) After Descemet s membrane scoring, Descemet s membrane is stripped with a reverse Sinskey hook. (D) The IOL is held with McPherson forceps and inserted through the scleral incision. The leading haptic is grasped with microcapsulorrhexis forceps. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, Agarwal A. Femtosecond-assisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.)

the need for an assistant to hold the haptic.9 The handshake technique for the trailing haptic is performed beyond the mid-pupillary plane, which changes the direction of action of vector forces, thereby facilitating leading haptic externalization. This technique has the advantage of overcoming the difficulties associated with inadequate assistance, including slippage, kink, or breakage of the haptic.

Special Case Consideration The placement of an IOL in its correct position is essential. Routinely in aphakic eyes, a foldable IOL is injected into the anterior chamber and its haptics are externalized through the sclerotomy site behind the iris. However, in cases of a posterior chamber IOL implanted in the anterior chamber, the same IOL can be repositioned in a closed globe manner by exteriorizing its haptics through the sclerotomies. In cases of an anterior chamber IOL, explantation is advised, and a new IOL is implanted by performing the glued IOL technique.

Glued Intraocular Lens Technique With Descemet’s Stripping Endothelial Keratoplasty DSEK is a partial-thickness corneal graft surgery in which the inner endothelial layer is replaced. Two partial-thickness scleral flaps approximately 2.5 by 2.5 mm are made 180 degrees opposite each other. An anterior chamber maintainer is introduced in the inferior quadrant (Figure 9-2A). A circular mark is placed on the patient’s corneal surface, and it serves as a guide

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Figure 9-3. (A) The trailing haptic is externalized via the sclerotomy. (B) The trailing haptic is tucked into the intrascleral lamellar pocket. (C) The donor lenticule is inserted into the eye. (D) The donor lenticule is unfolded with saline injection and adjusted. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, Agarwal A. Femtosecond-assisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.)

for removal of the recipient Descemet’s membrane (Figure 9-2B). The anterior chamber is entered through a peripheral stab incision, and Descemet’s membrane is scored and detached as a single disc (Figure 9-2C). It is important not to damage the inner surface of the patient’s cornea during this step of Descemet’s membrane removal because the inner corneal stroma will form half of the donor/recipient interface. A sclerotomy wound is created with a 20-gauge needle approximately 1 mm away from the limbus beneath the scleral flaps, and the entire glued IOL surgery is performed until the tucking of the haptics in the scleral pockets (Figures 9-2D, 9-3A, 9-3B). An inferior peripheral iridectomy (PI) is performed to prevent a postoperative air bubble–associated pupillary block glaucoma attack. The anterior chamber maintainer helps to maintain the anterior chamber throughout the surgery, and the use of viscoelastic is deterred; it is important not to leave residual viscoelastic in the anterior chamber because it is thought to potentially hamper good adhesion between the donor corneal disc and the recipient corneal stroma. Next, the donor cornea is mounted within an artificial anterior chamber and pressurized. Manual dissection is used to remove the anterior corneal stroma. The dissected donor corneal tissue is then placed with the epithelial side down, and trephination is performed from the endothelial side using a disposable trephine. The diameter of the trephine matches the diameter of the circular mark placed on the corneal epithelium of the recipient cornea made at the beginning of the procedure. The donor disc is approximately 150 μm thick. A small amount of viscoelastic is placed on the endothelial surface of the donor corneal disc. The donor corneal disc is then introduced into the anterior chamber (Figure 9-3C) with a tacofold technique using a forceps or inserted using a surgical glide or an inserter in its unfolded, or partially folded, state (Figure 9-3D). Once within the anterior chamber, the donor disc is attached to the recipient’s inner corneal stroma using a large air bubble (Figure 9-4). The donor-recipient interface is formed between the donor and recipient corneal stromas. The donor disc is then centred to the recipient cornea using the preplaced epithelial circular mark. Approximately 10 minutes is allowed to elapse to facilitate initial donor recipient corneal disc adherence. Postoperatively, the patient is asked to lie flat in the recovery room for 1 hour and to lie flat for the most part during the first postoperative day.

Descemet’s Stripping Automated Endothelial Keratoplasty DSAEK with glued IOL has been documented to be effective.10,11 The surgical steps in DSAEK are similar to those described earlier for the recipient cornea. However, donor corneal dissection is changed from a manual approach to an automated, microkeratome-assisted procedure. Hence, the stromal interface is improved in DSAEK as compared with DSEK. This improved donor-recipient interface is thought to contribute to the improved vision quality in DSAEK. Surgeon preparation of donor tissue allows for some degree of change in the parameters of the donor tissue in the operating room and decreases the overall cost of the procedure.

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Figure 9-4. Air is injected into the anterior chamber to fix the donor lenticule. Fibrin glue is used to seal the scleral flaps.

Femtosecond Laser–Assisted Descemet’s Stripping Automated Endothelial Keratoplasty A freshly prepared corneoscleral button is mounted on a Barron artificial anterior chamber (Katena Products, Inc), making sure the centration is good and the chamber is filled with viscoelastic. After ensuring an adequate and watertight assembly, the assembly is docked with the Intralase applanation cone (Abbott Medical Optics Inc) attached to the laser delivery system. No suction ring is placed. The laser pass is performed in the 60-kHz Intralase-enabled keratoplasty mode. The sequence is as follows: posterior side cut, full lamellar pass, and anterior side cut. The depth of the lamellar cut is calculated as to ensure a 180-mm posterior lenticule. This is based on direct subtraction from the measurement (just before corneoscleral rim creation) on wholeglobe corneal pachymetry on anterior-segment optical coherence tomography (Visante; Carl Zeiss Meditec). After the laser pass, the undissected cornea on the artificial chamber is shifted to the operating room from the femtosecond laser room. It is dissected and repositioned in the operating room. A 10-0 monofilament nylon suture is passed through the periphery of the lenticule from the stromal to endothelial direction to help in unfolding and adjustment of the lenticule later (Video 9-1).

Complications of Descemet’s Stripping Endothelial Keratoplasty and Descemet’s Stripping Automated Endothelial Keratoplasty Flattening of the Anterior Chamber Flattening of the anterior chamber can occur with excessive air injection with retro-iris air bubble formation. This can be reversed by sterile balanced salt solution injection into the anterior chamber. It is important to perform an inferior PI to avoid air bubble–associated angle closure postoperatively.

Decentration of the Donor Disc Decentration of the donor disc should be corrected intraoperatively by gentle exterior corneal massage as needed or by using a reverse Sinskey hook to reposition the donor corneal disc. Venting corneal incisions are usually not necessary to perform into the donor-recipient corneal interface. Postoperative donor disc detachment can be reattached with repeat air injection with the usual intraoperative sterile precautions.

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Figure 9-5. Pseudophakic bullous keratopathy. (A) A posterior-chamber IOL is implanted in the anterior chamber. (B) The DMEK graft is prepared. (C) The posterior-chamber IOL implanted in the anterior chamber led to corneal decompensation. The same posterior chamber IOL is relocated into the posterior chamber using a closed-globe glued IOL technique. The haptic is grabbed from over the iris using a glued IOL forceps and is transferred with the handshake technique between 2 hands until the tip of the haptic is held. (D) The haptic is externalized through the sclerotomy made under the scleral flap. The same procedure is followed for the second haptic, which is externalized through a sclerotomy under a second scleral flap created 180 degrees away from the first. Each haptic is then tucked into a scleral tunnel created at the edge of the scleral flap. (E) The DMEK graft is loaded into a Staar ICL injector and injected into the anterior chamber. (F) The DMEK graft is unrolled, and an air bubble is used to appose it against the overlying stroma. (Reprinted with permission from Kumar DA, Agarwal A. Glued intraocular lens: a major review on surgical technique and results. Curr Opin Ophthalmol. 2013 Jan;24(1):21-29.)

Retention of Interface Fluid If there is retention of interface fluid that is loculated, allowing time for fluid resorption is the correct option. However, if there is an open communication of aqueous from the interface to the anterior chamber, repeat air injection may be the only choice in most cases to seal and reattach the donor corneal disc to the recipient inner corneal stroma.

Iatrogenic Graft Failure Although new inserter devices have reduced the rates of graft failure, it cannot be ruled out.

Glued Intraocular Lens Technique With Descemet’s Membrane Endothelial Keratoplasty DMEK is the latest iteration of EK and the latest innovation in minimally invasive corneal transplantation. It replaces only Descemet’s membrane and the endothelium and leaves the patient’s cornea closer to its original condition than any other transplant technique. It involves transplanting a delicate sheet of corneal cells 1/100 mm thick, which is 10 times thinner than previously required. In patients with a compromised endothelium (Figure 9-5A), it has a tremendous potential for faster recovery. The recipient corneal dissection in DMEK is similar to the aforementioned 2 procedures, resulting in exposure of the patient’s uncut inner corneal stroma. An inferior PI is performed as

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in DSEK and DSAEK procedures. The donor Descemet’s membrane is scored, partially detached under fluid, and trephined from the endothelial side. A Sinskey hook is used to lift up the edge of the cut Descemet’s membrane. Once an adequate edge is lifted, a nontoothed forceps is used to gently grab Descemet’s membrane at its edge (Figure 9-5B) and it is separated from the underlying stroma in a capsulorrhexis-like circumferential manner. Descemet’s membrane with the healthy donor corneal endothelium is removed as a single donor disc with no donor corneal stroma; hence, there is no need for an artificial anterior chamber or microkeratome in the donor tissue preparation. This donor Descemet’s membrane/endothelial complex is stained with a vital dye such as trypan blue for visualization. An anterior chamber maintainer is introduced, and all steps of glued IOL surgery are followed consecutively, beginning from the 180-degree opposite scleral marking to the externalization and tucking of haptics (Figures 9-5C and 9-5D). The graft is then carefully loaded into a STAAR Implantable Contact Lens injector (STAAR Surgical Company) (Figure 9-5E) with the cartridge tip held occluded with a finger. It is injected gently into the anterior chamber by plunging the soft-tipped injector, taking care not to fold the graft. Wound-assisted implantation is avoided, and the anterior chamber maintainer flow is titrated carefully to prevent backflow and extrusion of the graft through the incision. The default shape of the donor disc is a coiled circular tube. This donor disc is then uncoiled using fluidics, and the surgeon must avoid any direct instrument contact to the donor endothelium. Proper orientation is essential prior to attaching the donor Descemet’s membrane to the exposed recipient bare corneal stroma. The graft orientation is then checked, and it is unfolded gently using a small air bubble as described by Melles.12 Once unfolded, an adequately tight air bubble is injected under the graft to float it up against the stroma (Figure 9-5F). Finally, fibrin glue is used to seal the lamellar scleral flaps, conjunctiva, and clear corneal incisions.

Complications Inability to Harvest a Viable Graft Dr. Art Giebel described harvesting the graft manually under water using his SCUBA technique. Nevertheless, a back-up cornea for DMEK should be kept available because it can be used if the harvest is unsuccessful.

Poor Adherence of the Graft Postoperatively Postoperative detachments are usually partial and can be managed with repeat air injections. Ensure that Descemet’s membrane is properly oriented before injecting air into the anterior chamber for Descemet’s membrane attachment. Also, confirm that the tip of the cannula is between the unrolled Descemet’s membrane and the iris before injecting air to attach Descemet’s membrane to the patient’s cornea. If there is any postoperative Descemet’s membrane separation, reinject air into the anterior chamber to attach Descemet’s membrane to the patient’s cornea.

Glued Intraocular Lens Technique With Penetrating Keratoplasty The donor tissue is prepared using a manual trephine from a freshly prepared corneoscleral button by punching on a Teflon block. The scleral flaps and the scleral pockets are created before the PK procedure is begun, followed by sclerotomy with a 20-gauge needle. This ensures adequate globe tautness before the eye is completely opened up. The host cornea is trephined, and a 3-piece IOL is held at the pupillary plane. The leading haptic is externalized from the left sclerotomy site, and the trailing haptic is externalized from the right sclerotomy site. The haptics are tucked in the scleral pockets, followed by suturing of the donor lenticule on the host tissue. The reconstituted fibrin glued is injected under the sclera flaps, and local pressure is applied for approximately 10 to 15 seconds to allow firm adhesion between the flap and the scleral bed.

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Figure 9-6. (A) Preoperative photograph showing pseudophakic bullous keratopathy with an anterior-chamber IOL in situ. (B) Femtosecond laser‒ created top-hat configuration. (C) Femtosecond laser‒assisted top-hat configuration showing the predictable and uniform wound formation. (D) An inferior straight sclerotomy is made with a 20-gauge needle 1.5 mm from the limbus under the existing scleral flaps. Note the diametrically opposite scleral flaps. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, et al. Femtosecondassisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.).

Figure 9-7. (A) Augmentation of the top-hat configuration in areas that had poor laser penetration because of overlying opacity. (B) The posterior uncut tissue is dissected with a Vannas scissors. (C) An anterior-chamber IOL is explanted after removal of the host button. (D) The leading haptic is grasped with the microcapsulorrhexis forceps and pulled through the inferior sclerotomy following the haptic curve. Note the diametrically opposite scleral flaps. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, et al. Femtosecondassisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.)

Glued Intraocular Lens Technique With Femtosecond Laser–Assisted Penetrating Keratoplasty Femtosecond laser–assisted PK with anterior chamber IOL explantation and glued IOL (Figures 9-6 to 9-9) has been documented in a peer-reviewed journal.13 Donor buttons are prepared from whole globes after application of the suction ring. Adequate vacuum and centration is achieved and a top-hat configuration is created using a femtosecond laser. For the host cut, a topical anesthetic agent is instilled into the patient’s eye. The suction ring is similarly applied, and, after adequate vacuum and centration, a top-hat configuration is created. The donor corneal tissue and patient are then shifted to the keratoplasty operating room, and the rest of the surgery is performed under peribulbar anesthesia. As previously explained, 2 partialthickness scleral flaps are made, followed by sclerotomy. The top hat is inspected for completeness. After the host button is removed, limited open-sky anterior vitrectomy is performed. The haptics are then externalized, followed by tucking in the scleral pockets. The graft is placed, and cardinal sutures are applied. The reconstituted fibrin glue is injected through the cannula of the syringe delivery system under both the scleral flaps. The same glue can be applied in the area between the sutures at the entire graft-host junction. The conjunctiva is also apposed with the glue.

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Figure 9-8. (A) The leading haptic is externalized completely under the inferior scleral flap. (B) The trailing haptic is externalized through the superior sclerotomy under the scleral flap. (C) The graft button is placed, and cardinal sutures are applied. (D) A scleral tunnel is created along the curve of the externalized haptic in the superonasal area at the edge of the scleral bed of the flap. Note the diametrically opposite scleral flaps. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, et al. Femtosecond-assisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.)

Figure 9-9. (A) The superior haptic is tucked into the superonasal tunnel. (B) The tucking is shown at higher magnification. (C) Reconstituted fibrin glue is injected through the cannula of the syringe delivery system under the inferior scleral flap. (D) The glue is applied at the graft-host junction. Note the diametrically opposite scleral flaps. (Reprinted with permission from Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, et al. Femtosecond-assisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.).

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Glued Intraocular Lens Technique With the Boston Keratoprosthesis A keratoprosthetic device is intended to provide a transparent optical pathway through an opacified cornea in an eye that is not a reasonable candidate for a corneal transplant. The Boston Keratoprostheis (KPro, Massachusetts Eye and Ear Infirmary) is a permanent keratoprosthetic device that has been proposed for individuals when attempts at corneal transplant have failed. Keratoprosthetic devices differ in design but basically consist of a special tube that acts as a visualization channel that is anchored to the front surface of the cornea. Implantation techniques differ, and success rates are variable and highly dependent on the skill of the surgeon. The device is available in 2 formats: type I and type II. The type I Boston KPro is available in either a single standard pseudophakic plano power or customized aphakic powers (based on axial length) with adult-sized (8.5-mm diameter) and pediatric-sized (7.0-mm diameter) back plates. The type II format is similar to the type I format but is reserved for severe end-stage ocular surface disease desiccation that requires a permanent tarsorrhaphy to be performed, through which a small anterior nub of the type II model protrudes. Primary keratoprosthesis surgery is often combined with other procedures, including iridoplasty, glaucoma filtration devices, IOL and lens capsule removal, and core vitrectomy. The Boston KPro has its own indications for use, and when combined with glued IOL, the indications become more constrained. A combined procedure can be considered for any condition associated with secondary IOL implantation and where the Boston KPro is the only indication.

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Indications for Surgery The Boston KPro is a proven primary treatment option for the following: • Repeat graft failure herpetic keratitis • Pediatric congenital corneal opacities, including Peter’s anomaly • Cicatrizing conditions, including Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe ocular burns • Failed corneal graft with poor prognosis for further grafting • Vision less than 20/200 in the affected eye and compromised vision in the opposite eye The prerequisites for surgery are as follows: • No end-stage glaucoma or retinal detachment • Easy access to hospital and/or health care team • Commitment of the patient for a regular follow-up schedule

Surgical Technique The keratoprosthesis is assembled by creating a sandwich composed of the KPro front plate, the donor cornea, and the KPro back plate, which are secured with a locking ring. A donor cornea is trephined to create an 8.75-mm button with a central 3-mm opening. This tissue is then inserted between the front plate of the keratoprosthesis (with the optical cylinder passing through the center 3-mm opening) and the fenestrated back plate. The back plate is tightened in nut-and-bolt fashion, and a locking titanium ring is applied. Before the host cornea is trephined, 2 partial-thickness scleral flaps are created as in a glued IOL surgery, followed by sclerotomy and creation of scleral pockets. The host cornea is then trephined and cut, and open-sky vitrectomy is performed. The haptics of a 3-piece IOL are externalized from the sclerotomy sites and tucked. The assembled device is inserted in an 8.0-mm recipient bed and sutured in standard fashion with 9-0 nylon. A bandage contact lens is placed. The scleral flaps are then adhered to the base by application of fibrin tissue glue.

Postoperative Regime Indefinite placement of a bandage contact lens is needed to maintain adequate ocular surface hydration and prevent stromal melt, dellen formation, tissue melt, and necrosis. Daily topical antibiotic prophylaxis is necessary, as are lifelong topical steroids. Close follow-up with an ophthalmologist is essential, and the follow-up required after KPro placement is often lifelong.

Postoperative Complications The most common postoperative complications include retroprosthetic membrane, elevated IOP, infectious endophthalmitis, and vitritis. Retinal detachment and vitreous hemorrhage are rarely seen.

Prognosis The preoperative condition of the eye influences the clinical outcome after KPro surgery. The most favorable outcomes are achieved in noncicatrizing conditions, followed by ocular burns and ocular cicatricial pemphigoid, with the worst outcomes in Stevens-Johnson syndrome patients. In patients with severe neurotrophic keratopathy, traditional PK is fraught with problems, including poor epithelial healing and corneal ulceration. The Boston KPro can provide rapid visual rehabilitation, despite corneal anesthesia in these patients, and is currently our treatment of choice as a primary procedure for Herpes zoster ophthalmicus patients who need corneal transplantation.

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Glued Intraocular Lens Technique With Deep Anterior Lamellar Keratoplasty Glued IOL associated with deep anterior lamellar keratoplasty (DALK) raises concerns different from those associated with EK. Simultaneous surgery increases the difficulty of the DALK dissection due to altered visualization and decreased chamber stability due to the fresh incisions, which renders the trephination process difficult. For these reasons, we believe that glued IOL surgery either before or after DALK is preferable.

Conclusion Glued IOL surgery combined with corneal procedures is a viable option, although surgical expertise is required for achieving the maximum benefits of the combined procedures.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Fernandez MM, Afshari NA. Endothelial keratoplasty: From DLEK to DMEK. Middle East Afr J Ophthalmol. 2010;17(1):5-8. Ventura ACS, Wälti R, BÖhnke M. Corneal thickness and endothelial density before and after cataract surgery. Br J Opthalmol. 2001;85(1):18-20. Flowers CW, McLeod SD, McDonnell PJ, Irvine JA, Smith RE. Evaluation of intraocular lens power calculation formulas in the triple procedure. J Cataract Refract Surg. 1996;22(1):116-122. Van Meter WS, Lee WB, Katz DG. Corneal edema. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology. Vol.4. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein RM. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology. 2009; 116(9):1818-1830. Agarwal A, Kumar DA, Jacob S, Baid C, Agarwal A, Srinivasan S. Fibrin glue-assisted sutureless posterior chamber intraocular lens implantation in eyes with deficient posterior capsules. J Cataract Refract Surg. 2008;34(9):1433-1438. Agarwal A, Agarwal A, Jacob S, Narang P. Comprehending IOL signs and the significance in glued IOL surgery. J Refract Surg. 2013:29(2):79. Agarwal A, Jacob S, Kumar DA, Agarwal A, Narasimhan S, Agarwal A. Handshake technique for glued intrascleral haptic fixation of a posterior chamber intraocular lens. J Cataract Refract Surg. 2013;39(3):317-322. Narang P. Modified method of haptic externalization of posterior chamber intraocular lens in fibrin glue-assisted intrascleral fixation: no-assistant technique. J Cataract Refract Surg. 2013;39(1):4-7. Sinha R, Shekhar H, Sharma N, Tandon R, Titiyal JS, Vajpayee RB. Intrascleral fibrin glue intraocular lens fixation combined with Descemet-stripping automated endothelial keratoplasty or penetrating keratoplasty. J Cataract Refract Surg. 2012;38(7):1240-1245. Prakash G, Agarwal A, Jacob S, Kumar DA, Chaudhary P, Agarwal A. Femtosecond-assisted descemet stripping automated endothelial keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation. Cornea. 2010;29(11):1315-1319. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the Descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23(3):286-288. Prakash G, Jacob S, Ashok Kumar D, Narsimhan S, Agarwal A, Agarwal A. Femtosecond-assisted keratoplasty with fibrin glue-assisted sutureless posterior chamber lens implantation: new triple procedure. J Cataract Refract Surg. 2009;35(6):973-979.

Please see video on the accompanying website at

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10 Pre-Descemet’s Endothelial Keratoplasty Ashvin Agarwal, MS; Dhivya Ashok Kumar, MD; Priya Narang, MS; Harminder S. Dua, MS, FRCOphth, FRCS, FEBO, PhD; and Amar Agarwal, MS, FRCS, FRCOphth With the introduction of posterior lamellar keratoplasty (PLK) by Melles et al1 in 1998, corneal endothelial transplantation techniques have evolved at a rapid pace. Terry and Ousley 2 subsequently modified it as deep lamellar endothelial keratoplasty (DLEK), where a folded, taco-shaped 9.0- to 9.5-mm-diameter posterior transplant is inserted through a self-sealing 5.0mm scleral tunnel incision. The techniques required difficult lamellar dissections and resulted in lamellar interface problems. Following this, Descemet’s stripping endothelial keratoplasty (DSEK) was introduced, in which the patient’s Descemet’s membrane is stripped and a donor posterior transplant containing Descemet’s membrane along with a portion of lamellar stroma is transplanted.3-6 Postoperative interface opacification along with altered posterior corneal curvature caused refractive issues thereby limiting the light transmission and potential improvement in visual acuity of patients after DSEK. Later, Price and Price6 introduced the use of a mechanical microkeratome for smooth donor graft dissection and termed it Descemet’s stripping automated endothelial keratoplasty (DSAEK). In 2006, Tappin7 first performed the true endothelial cell (Tencell) transplantation of Descemet’s membrane using a carrier device. Later, Melles et al8,9 reported the first clinical results of transplanting isolated Descemet’s membranes in human eyes and called the procedure Descemet’s membrane endothelial keratoplasty (DMEK). Early evidence to support the existence of a distinct pre-Descemet’s layer (Dua’s layer) of tissue was presented by Dua et al10 in 2007 and followed by a study wherein evidence was presented to further support the presence of the distinct pre-Descemet’s layer.10 Addition of a 10-μm (mean value) pre-Descemet’s layer to the endothelial graft can generate tissue for endothelial transplant, allowing easier handling and insertion of the tissue because it does not tend to scroll as much as Descemet’s membrane, with the pre-Descemet’s layer splinting Descemet’s membrane.10 Pre-Descemet’s endothelial keratoplasty (PDEK) is the term we have given a technique in which the donor endothelium–Descemet’s membrane complex with the additional pre-Descemet’s layer is transplanted.

Surgical Technique Donor Preparation A corneoscleral disc with an approximately 2-mm scleral rim is dissected from the whole globe or obtained from an eye bank. A 30-gauge needle attached to a syringe is inserted from the - 101 -

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Figure 10-1. Pre-Descemet s endothelial keratoplasty (PDEK) donor graft preparation. (A) A 30-gauge needle is inserted at the limbus on the endothelial side. (B) The needle is advanced into the stroma. (C) Intrastromal air injection is performed. (D) A central dome-shaped type 1 big bubble is formed. (E) Trephination of the endothelial graft is performed. (F) The endothelium-Descemet s membrane complex with the pre-Descemet s layer is stained with trypan blue and cut with corneoscleral scissors.

limbus into the midperipheral stroma (Figure 10-1A and 10-1B). Air is slowly injected into the donor stroma until a type 1 big bubble10 is formed, which is a well-circumscribed, central domeshaped elevation measuring 7 to 8.5 mm in diameter (Figure 10-1C and 10-1D). It always starts in the center and enlarges centrifugally, retaining a circular configuration. Trephination of the donor graft is performed along the margin of the big bubble (Figure 10-1E). The bubble wall is penetrated at the extreme periphery, and trypan blue is injected into the bubble to stain the graft, which is then cut all around the trephine mark with corneoscleral scissors (Figure 10-1F) and covered with the tissue culture medium. The graft is loaded into an injector when ready for insertion.

Recipient Bed Preparation After administering peribulbar anesthesia, the recipient corneal epithelium is debrided (if grossly edematous) for better visualization (Figure 10-2A). A trephine mark is made on the recipient cornea respective to the diameter of Descemet’s membrane to be scored on the endothelial side (Figure 10-2B). A 2.8-mm tunnel incision is made at the 10-o’clock position near the limbus. The anterior chamber is formed and maintained with saline injection or infusion. The margin of Descemet’s membrane to be removed is scored initially from the endothelial side with a reverse Sinskey hook (Figure 10-2C). Once an adequate edge is lifted, a nontoothed forceps is used to gently grab Descemet’s membrane at its edge, and the graft is separated from the underlying stroma in a capsulorrhexis-like circumferential manner. The peeled Descemet’s membrane is then removed from the eye.

Donor Lenticule Implantation The donor lenticule (endothelium–Descemet’s membrane–pre-Descemet’s layer) roll is inserted in the custom-made injector (Figure 10-2D) and slowly pushed up the lumen of the nozzle. The injector is improvised from an intraocular lens implant injector by removing the sponge tire and spring and reattaching the sponge tire to prevent any back suction and inadvertent damage to the donor graft. Using the injector, the graft roll is injected in a controlled fashion into the anterior chamber. The donor graft is oriented endothelial side down and positioned on the recipient posterior stroma by careful, indirect manipulation of the tissue with air and fluid (Figure 10-2E). Once the lenticule is unrolled, an air bubble is injected underneath the donor graft lenticule to lift it toward the recipient posterior stroma. The anterior chamber is completely filled with air for the

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Figure 10-2. Recipient bed preparation and graft insertion. (A) Preoperative image of the eye with endothelial decompensation as epithelium debridement is performed. (B) Trephine marking is performed on the cornea. (C) Descemet s membrane is scored and stripped with a reverse Sinskey hook. (D) The graft lenticule is loaded into an injector. (E) Intraoperative manipulation of the graft is performed for proper positioning. (F) Air is injected underneath the donor graft lenticule to lift it toward the recipient posterior stroma. The anterior chamber is filled with air.

next 30 minutes, followed by an air-liquid exchange to pressurize the eye (Figure 10-2F). The eye speculum is removed and the anterior chamber is examined for air position. The patient is advised to lie in a strictly supine position for the next 3 hours.

Discussion Dissection of the endothelium-Descemet’s membrane complex in endothelial keratoplasties has been widely modified.11-14 Tearing of the delicate DMEK graft can render the tissue unusable for transplantation. Thus, techniques like automated donor tissue preparation using a microkeratome or pneumatic dissection have been introduced for donor graft separation. The most popular Descemet’s membrane–baring technique is the big-bubble method, where the big bubble forms a cleavage plane, leaving Descemet’s membrane bare for dissection in lamellar keratoplasty. Recently, Dua et al10 reported the presence of a distinct layer in the pre-Descemet’s cornea that differs from the rest of the corneal stroma by several features. In the PDEK procedure, this layer is included with the endothelium–Descemet’s membrane complex, thereby providing additional support to the graft. Presence of this layer, with its characteristics of relative rigidity and toughness, allows easy intraoperative handling and insertion of the tissue because it does not tend to scroll as much as Descemet’s membrane alone. Although DMEK provides a significantly higher rate of 20/20 and 20/25 vision, with comparable endothelial cell loss compared with DSAEK procedure; a 63% air reinjection rate for partial detachments and 8% rate of graft failure, which requires a repeat DMEK or DSAEK, have been reported.15 It has failed to gain widespread acceptance mainly because of difficulty in donor preparation resulting in a significant loss of donor tissue, loss of endothelial cells after Descemet’s membrane removal, and difficulty in positioning the donor tissue within the eye. In PDEK, the pre-Descemet’s layer serves as a splint, which facilitates easy manipulation of the entire graft. Because the endothelium–Descemet’s membrane complex remains adherent to the underlying pre-Descemet’s layer, tight rolling of the thin, delicate tissue is prevented. The splinting effect provided by the additional layer reduces inadvertent tears or endothelial damage during tissue harvesting and intraoperative maneuvers. Pre-Descemet’s layer has been noted to be tough and rigid compared with Descemet’s membrane; therefore, the endothelium-Descemet’s membrane complex is thicker than DMEK donor graft and reduces the likelihood of upside-down transplantation.16

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Chapter 10 TABLE 10-1

Comparison of Different Endothelial Keratoplasty Techniques DSEK

DMEK

PDEK

Surgical layers

Stroma + DM + Endo

DM + Endo

Pre-Descemet s + DM + Endo

Technical difficulty

Easy

Difficult

Moderate

Type of procedure

Tissue additive

Tissue neutral

Minimal tissue additive

Artificial anterior chamber

Required

NR

NR

Microkeratome

Required (DSAEK)

NR

NR

Induced hyperopia

Yes

No

No

Corneal thickness

Increased

Normal

Minimal

Intrastromal interface

Yes

No

Minimal

Cost

Costly

Cost-effective

Cost-effective

Eye bank‒prepared donor tissue

Available

No

Can be made available

Graft unrolling

Easy

Difficult

Moderate

Tissue handling

Good

Difficult

Good

Visual recovery

Slow

Fast

Fast

Abbreviations: DM, Descemet s membrane; DMEK, Descemet s membrane endothelial keratoplasty; DSAEK, Descemet s stripping automated endothelial keratoplasty; DSEK, Descemet s stripping endothelial keratoplasty; Endo, endothelium; NR, not required; PDEK, Pre-Descemet s endothelial keratoplasty.

In ultrathin DSAEK, mean central graft thickness recorded 3 months postoperatively was 78.28 ± 28.89 μm.17 Spectral domain optical coherence tomography (SD-OCT) in vivo analysis of PDEK grafts showed a mean graft thickness of 28 ± 5.6 μm 1 month postoperatively, which is greater than the conventional DMEK graft and less than the DSAEK or ultrathin DSAEK graft.17,18 Onlay procedures such as DSEK create a stromal interface between donor tissue and recipient stroma, which has been held responsible by some authors for the suboptimal visual results in a variable percentage of patients undergoing those procedures.19 There is also a risk of significant hyperopic shift depending on the graft thickness added to the patient’s posterior stroma in onlay procedures. A comparison of some aspects of different endothelial keratoplasty techniques is shown in Table 10-1. Mean graft diameter obtained in PDEK is 7.6 ± 0.22 mm, which is less than the 8- or 9-mm diameter of DMEK grafts.20 The probable reason for the smaller graft size is the difficulty in separating the pre-Descemet’s layer in the peripheral cornea.10 However, it is known that the endothelial cells are capable of proliferation and acquire morphological adaptations to compensate for the peripheral cornea.21 This has been observed by the clinical clearance of peripheral corneal edema and fluid reabsorption, indicating efficient endothelial pump function after 8- to 7.5-mm PDEK grafts.20 SD-OCT pictures of PDEK cases show a graft that is close and well attached to the recipient bed (Figure 10-3). A comparison of pre- and postoperative clinical slit lamp pictures of the eye show a clear graft on postoperative day 1 (Figure 10-4). In an attempt to improve donor preparation, air dissection for separation of the posterior lamellae, a concept initially described by Anwar and Teichmann 22 in their big-bubble technique of deep anterior lamella keratoplasty, has been studied for endothelial graft preparation.23,24 The presence

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Figure 10-3. Postoperative SD-OCT image of 4 cases after PDEK showing closely apposed and well-attached grafts.

A

B

Figure 10-4. (A) Preoperative, (B) postoperative, and (C) OCT images (day 1) of a PDEK case.

C

of residual stroma, along with the endothelium-Descemet’s membrane complex, has also been reported, demonstrating the existence of a stromal layer along with DMEK grafts.23 In a light microscopic analysis of a DMEK donor graft, McKee et al 23 noted residual stroma remaining on Descemet’s membrane for the entire length of the section. Average central stromal thickness has been observed to be 12.4 μm.23 No electron microscopic or immunohistochemistry study has been performed to identify the variations of the stromal layer attached to the endothelium–Descemet’s membrane complex in DMEK grafts. After the recent work by Dua et al10 on the separation of the pre-Descemet’s layer by the big-bubble technique, the utility of the pre-Descemet’s layer in endothelial graft harvesting has been applied in PDEK. The absence of cells (nuclei) in the pre-Descemet’s layer has also been reported. This may be an advantage in relation to scarring of the transplanted pre-Descemet’s layer as against transplant of deep stroma with a complement of keratocytes as is inevitable in DSEK, DSAEK, and their ultra-thin variations.

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Figure 10-5. (A) Pseudophakic bullous keratopathy. (B) Type 1 bubble formed in the donor cornea. (C) Two partial thickness scleral flaps are fashioned 180 degrees opposite to each other. Anterior chamber maintainer is introduced in the eye. (D) Haptics of the IOL being externalized. (E) Pupilloplasty being done. (F) Well-shaped pupil formed.

Pre-Descemet’s Endothelial Keratoplasty With Glued Intraocular Lens: Two to Tango Cases with decompensated corneas due to endothelial disorders requiring secondary IOL implantation or an IOL exchange are potential candidates for undergoing PDEK with glued IOL surgery. The main advantage of combining PDEK and glued IOL surgery is that patients undergo a single surgery, attend fewer appointments, and deal with a specific set of postoperative medications. Alternatively, both the surgeries can be performed sequentially, wherein glued IOL is performed as an initial procedure followed by PDEK in a second stage. Pupil disfigurement is often encountered in patients requiring these procedures. Pupil reconstruction forms an important element to avoid the chances of air diversion into the vitreous following the surgery, as this might enhance the chances of graft dislocation postoperatively. Pupilloplasty is thereby performed along with PDEK and the glued IOL procedure in cases with pupil disfigurement.

Technique The initial step involves successful harvesting of the donor lenticule, then the glued IOL procedure (minus the application of glue to seal the scleral flaps), followed by recipient bed preparation and donor lenticule insertion (Figures 10-5, 10-6, and 10-7). Application of fibrin glue to seal the scleral flaps is then ensued so as to ensure that the fluids emanating and egressing from the eye do not wash it off. In PDEK, a major shortcoming is the size of graft, which is approximately 8 mm, limiting the amount of donor Descemet’s membrane endothelium complex as compared with other techniques. However, a type 1 bubble can be created in donor eyes younger than 50 years, allowing tissue with a greater endothelial cell density to be used for transplantation. This may compensate for the smaller donor graft size. For DMEK, it is recommended that younger donor eyes be avoided due to the tighter adhesion between Descemet’s membrane and posterior stroma resulting in a higher incidence of Descemet’s membrane tears during tissue harvesting. Another drawback of PDEK can be the occasional creation of a type 2 bubble (pre-Descemet’s membrane) instead of a type 1 bubble (pre-PDL), necessitating the conversion of PDEK to DMEK to avoid wasting donor tissue. The viability of the donor corneal endothelium in the management of endothelial disorders remains an important consideration. Surgeon training, skill, and experience deserve special mention because they can affect the surgical outcomes and subsequent reporting of complication rates.

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Figure 10-6. (A) Epithelium is debrided and the endothelium is scored. (B) Graft is loaded on to the cartridge of a foldable IOL injector. (C) Graft seen in anterior chamber. (D) Unrolling of the graft done with fluidics and air. (E) Air injected beneath the graft for proper apposition. (F) Stable IOL with well-formed anterior chamber and good graft apposition seen one month postoperatively.

A

B

Figure 10-7. (A) Preoperative photograph demonstrating pseudophakic bullous keratopathy with the lens in the anterior chamber. (B) Post-operative photograph at 3 months. (C) Anterior segment OCT demonstrating 28 μ of graft thickness.

C

The immediate short-term outcomes suggest that it is a promising new corneal transplantation procedure that provides rapid visual recovery.

References 1. 2. 3. 4. 5. 6.

Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea. 1998;17(6):618-626. Terry MA, Ousley PJ. Replacing the endothelium without corneal surface incisions or sutures: the first United States clinical series using the deep lamellar endothelial keratoplasty procedure. Ophthalmology. 2003;110(4):755-764. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the Descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23(3):286-288. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a refractive neutral corneal transplant. J Refract Surg. 2005;21(4):339-345. Price MO, Price FW. Descemet’s stripping endothelial keratoplasty. Curr Opin Ophthalmol. 2007;18(4):290-294. 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(3):411-418.

108 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Chapter 10 Tappin M. A method for true endothelial cell (Tencell) transplantation using a custom-made cannula for the treatment of endothelial cell failure. Eye (Lond). 2007;21(6):775-779. Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. 2006;25(8):987-990. Melles GR, Ong TS, Ververs B, van der Wees J. Preliminary clinical results of Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145(2):222-227. Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human corneal anatomy redefined: a novel preDescemet’s layer (Dua’s layer). Ophthalmology. 2013;120(9):1778-1785. Schlötzer-Schrehardt U, Bachmann BO, Laaser K, Cursiefen C, Kruse FE. Characterization of the cleavage plane in Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2011;118(10):1950-1957. McCauley MB, Price FW Jr, Price MO. Descemet membrane automated endothelial keratoplasty: hybrid technique combining DSAEK stability with DMEK visual results. J Cataract Refract Surg. 2009;35(10):1659-1664. Yoeruek E, Bayyoud T, Hofmann J, Szurman P, Bartz-Schmidt KU. Comparison of pneumatic dissection and forceps dissection in Descemet membrane endothelial keratoplasty: histological and ultrastructural findings. Cornea. 2012;31(8):920-925. Schlötzer-Schrehardt U, Bachmann BO, Tourtas T, et al. Reproducibility of graft preparations in Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2013;120(9):1769-1777. Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology. 2009;116(12):2361-2368. Ham L, van der Wees J, Melles GR. Causes of primary donor failure in Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145(4):639-644. Busin M, Madi S, Santorum P, Scorcia V, Beltz J. Ultrathin Descemet’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique: two-year outcomes. Ophthalmology. 2013;120(6):1186-1194. Tan GS, He M, Tan DT, Mehta JS. Correlation of anterior segment optical coherence tomography measurements with graft trephine diameter following descemet stripping automated endothelial keratoplasty. BMC Med Imaging. 2012;12:19. Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEK—the thinner the better? Curr Opin Ophthamol. 2009;20(4):299-307. Agarwal A, Dua, HS, Narang P et al. Pre-Descemet’s endothelial keratoplasty (PDEK) [published online ahead of print March 27, 2014]. Br J Opthalmol. doi: 10.1136/bjophthalmol-2013-304639. Engelmann K, Bednarz J, Böhnke M. Endothelial cell transplantation and growth behavior of the human corneal endothelium [in German]. Ophthalmologe. 1999;96(9):555-562. Anwar M, Teichmann KD. Big-bubble technique to bare Descemet’s membrane in anterior lamellar keratoplasty. J Cataract Refract Surg. 2002;28(3):398-403. McKee HD, Irion LC, Carley FM, Jhanji V, Brahma AK. Donor preparation using pneumatic dissection in endothelial keratoplasty: DMEK or DSEK? Cornea. 2012;31(7):798-800. Busin M, Scorcia V, Patel AK, Salvalaio G, Ponzin D. Pneumatic dissection and storage of donor endothelial tissue for Descemet’s membrane endothelial keratoplasty: a novel technique. Ophthalmology. 2010;117(8):1517-1520.

Please see video on the accompanying website at

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11 Corneal Graft Rejection Saima M. Qureshi, MD and Robert A. Copeland Jr, MD Corneal transplantation has become the most commonly performed transplant procedure. In recent years, there has been an increasing trend toward endothelial and anterior lamellar keratoplasties with improved techniques. However, successful transplantation has always been threatened by numerous factors, including poor surgical technique, ocular inflammation, and host graft vascularization, but most commonly by the immune-mediated response to the donor cornea. Graft failure is typically preceded by graft rejection. Rejection can be thought of as the immunologic response of the host toward the donor. Furthermore, it is defined as corneal graft edema with associated inflammation of a graft that had been clear for at least 2 weeks for firsttime grafts.1,2 A graft is considered failed if rejection persists with associated compromise of vision for at least 3 consecutive months.3 This differs from primary graft failure, in which the corneal graft never clears after transplantation.4 Corneal graft survival rates have been reported to average 64.5% to 91% at 5 years, 64% at 10 years, and 37% at 20 years.5,6 However, given several recipient risk factors reported in the literature, there is great variation of the incidence of graft rejection. In a 12-year retrospective study, the incidence was reported to be 9% to 12%,7 and in a more recent study, the overall incidence of graft rejection was reported to be 11.6% over 15 months of follow-up.8 Identification of risk factors is important when predicting outcomes and prognosis preoperatively.

Pathophysiology To adequately identify and manage corneal graft rejection, it is imperative to understand the immunology as it relates to the eye and, more specifically, the cornea. The eyes are known to have immune privilege, meaning that antigens may be presented to the eye without the elicitation of an inflammatory immune response.9 This evolutionary feature enables the eye to tolerate tissue grafts by allowing extended survival in corneal transplantation. The physical absence of lymphatics and vasculature and the paucity of mature antigen-presenting cells in the central cornea limit access of the immune system components. Furthermore, the low expression of major histocompatability (MHC) class Ia molecules and low polymorphic MHC class Ib molecules contribute to the immunological privilege of the eye. Surface molecule expression inhibiting complement activation, production of immunosuppressive cytokines, and expression of Fas ligand controlling the entry of Fas-expressing lymphoid cells are also important factors in the maintenance of immune privilege.10-12 In addition to these mechanisms, the eye also has the anterior chamber–associated immune deviation (ACAID) response, in which the eye’s active immune cells act on foreign - 109 -

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antigens and induce suppression of the systemic immune system response to the antigen.13,14 Inflammation, trauma, and the development of neovascularization and lymphatics can cause this corneal privilege to be lost. Corneal graft rejection is primarily a cell-mediated immune reaction, or a type IV hypersensitivity. For a graft to experience immunological rejection, certain events must occur. In response to trauma or inflammation, MHC antigen expression is upregulated on corneal cells. These foreign donor antigens get transported via afferent lymph vessels to regional lymph nodes, where the host immune system responds by initiating an immune cascade. This is known as the afferent phase. The host immune system presents these antigens to alloreactive T cells, leading to their proliferation and differentiation into immune effector elements that travel back to the donor graft and lead to decompensation of the graft tissue. This is known as the efferent phase.15 The corneal epithelium, stroma, and endothelium contain class I antigens and include HLA-A, -B, and -C. Limbal Langerhans cells, B cells, macrophages, and interstitial dendritic cells that migrate to the corneal graft bed primarily express class II antigens, which include HLA-DR, -DQ and -DP. Foreign MHC class II antigens can stimulate the host CD4 + T cells to release interleukin 2 (IL-2) and other lymphokines that stimulate further activation and proliferation of CD4 + T cells, cytotoxic T cells, and B lymphocytes. Furthermore, CD4 + T cells produce interferon gamma and tumor necrosis factor alpha (TNF-α), which directly induce apoptosis of corneal cells. CD8 + T cells are stimulated not only by CD4 + T cells but also by foreign class I cell-surface antigens on donor cells, resulting in lysis of donor cells and further release of interferon gamma. With the production of interferon gamma, macrophages are activated, leading to further proliferation of TNF-α, nitric oxide, hydrogen peroxide, and oxygen radicals, inducing apoptosis. CD4 + T cell–activated B cells produce antibodies, leading to corneal cell death by antibody-dependent cytotoxicity by natural killer cells and by complement-mediated cytolysis (Figure 11-1). Class II antigen expression on donor cells is induced, creating a positive feedback loop on the cell-mediated allograft rejection.16,17 Understanding the mechanism leading to corneal graft rejection is important in recognizing its clinical presentation.

Clinical Presentation Clinical recognition of corneal graft rejections can sometimes be a challenge, given that symptoms can be somewhat nonspecific. Redness, photophobia, and excessive lacrimation along with decreased vision are common symptoms. It is also important to recognize the severity and location of rejection because this will assist in management selection and urgency. Mild and severe graft rejections are differentiated based on the number of keratic precipitates, the central corneal thickness, and the degree of associated anterior chamber inflammation, as well as subepithelial, stromal, or endothelial involvement as characterized by the Collaborative Corneal Transplant Study (CCTS) (Table 11-1).18 Graft rejection involving the epithelium presents an average of 3 months post-transplantation. On examination, an epithelial rejection line may be visualized and appears as a superficial epithelial infiltrate, referred to as Kaye’s dots (Figure 11-2). Epithelial rejection alone is often selflimited; however, careful examination of the involvement of subepithelial structures should be ruled out. Stromal corneal rejection may occur up to approximately 2 years after transplantation and presents as subepithelial infiltrates. Hyperacute stromal rejection is typically the sudden onset of fullthickness edema confined to the limits of the graft. Endothelial rejection requires more aggressive and urgent treatment. On average, patients present within the first year with the symptoms of pain and decreased vision. Oftentimes, keratic precipitates and diffuse graft edema are seen along with anterior chamber inflammation and a Khodadoust line. The Khodadoust line is a focal inflammatory reaction composed of mononuclear white blood cells that appear at the vascularized edge of the graft. This line can progress rapidly in a matter of days, damaging the endothelial cells of the graft if left untreated (Figure 11-3).19

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Figure 11-1. Immune model of the host response within host lymph nodes. The development of neovascularization and lymphatics triggered by inflammation or trauma cause upregulation of host CD4 + T cells, resulting in a release of interferon gamma as well as the upregulation of host CD8 + T cells and B cells. CD8 + T cells also release interferon gamma, which triggers macrophages to produce TNF-α, nitric oxide, and hydrogen peroxide, inducing cytolysis. CD8 + T cells can themselves illicit cytolysis. CD4 + T cell‒activated host B cells produce antibodies to foreign antigens, also resulting in cytolysis.

TABLE 11-1

Characteristics of Graft Rejection Categorized by the Collaborative Corneal Transplantation Studies MILD GRAFT REJECTION

SEVERE GRAFT REJECTION

1 to 5 keratic precipitates

More than 5 keratic precipitates

Subepithelial infiltration

Noninfectious stromal inflammatory cells

Increased central corneal thickness without increased aqueous cells

Endothelial rejection line

Increased aqueous cells without an increase in central corneal thickness

Increased corneal thickness and increased aqueous cells

Reprinted with permission from Khalid F. Tabbara, MD, The Eye Center, Riyadh, Saudi Arabia.

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Figure 11-2. Kaye s dots in epithelial rejection. (Reprinted with permission from Terry Kim, Duke University Eye Center, Durham, NC.)

Figure 11-3. Khodadoust line in endothelial graft rejection.

Clinical Risk Factors Identification of risk factors may assist in determining prognosis of the graft after corneal transplantation. The CCTS attempted to do so by looking at factors such as ABO compatibility, HLA type, tissue storage, and the presence and amount of corneal host vascularity. HLA matching showed no reduced likelihood of rejection; however, it found that ABO incompatibility was a strong risk factor for graft failure.20 In more recent literature, ABO incompatibility was not shown to increase the overall risk of graft failure secondary to graft rejection, and HLA typing may have a role in reducing allograft rejection in all patients, both low and high risk.21-24 Tissue storage also did not seem to influence graft outcome in the CCTS, and in a more recent study by Xu et al, 25 similarly fresh and cryopreserved tissue yielded no difference in graft rejection rates. However, storage of corneal tissue at + 4°C has been reported to reduce the frequency of rejection in high-risk patients.26-28 More importantly, prior to consideration of transplantation, identifying host factors that may influence the likelihood of graft rejection can assist the clinician in determining candidacy for long-term prognosis and reduced rates of rejection. The CCTS identified corneal host vascularity as a key risk factor associated with graft rejection. The presence of 2 or more quadrants of vascularization extending 2 mm or more into the stroma was defined as high risk for graft rejection, and as the number of corneal quadrants involved increased, so did the graft rejection risk (Figure 11-4).20,29 Also considered to be at high risk for graft rejection are regrafts secondary to a previously failed graft. This is likely due to host sensitization from the initial graft and can further be increased if there is vascularization of the host bed.20,28 Individuals receiving corneal transplantation for herpetic keratitis are also considered at high risk for graft rejection because even clinically quiescent cases were found to have histopathological evidence of inflammation (Figure 11-5).30,31

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Figure 11-4. Graft failure in a host with pretransplantation corneal vascularity.

A

B

Figure 11-5. (A) Recurrent herpetic keratitis in a corneal graft. (B) Recurrent herpetic keratitis with associated graft rejection. (Reprinted with permission from Khalid F. Tabbara, MD, The Eye Center, Riyadh, Saudi Arabia.)

Similarly, a study looking at factors associated with poor graft outcome in a population of contact lens–associated Fusarium keratitis showed that the rejection rate was 57.1% and the recurrence rate was 28.6%.32 Possible factors were larger ulcer size, larger graft size, and greater number and longer duration of medical agents used before and after corneal transplantation. Other associated host factors, including young patient age, presence of atopic conditions, previous anterior segment surgery, active inflammation or infection at the time of procedure, female recipient, history of glaucoma, and corneal edema, have also been identified as high risk for graft rejection.20,33-36 Donor age was not associated with graft rejection.35 Given that clinically certain histopathologic and immunologic factors may not be easily identified, attention has also been given to the association of surgical techniques, including graft size, loose sutures, and longer operative times, to graft rejection rates.37-39 Studies have shown that larger grafts improve visual and refractive outcomes, likely because of more endothelial cell availability, more peripheral placement of the graft-host interface, and reduction of astigmatism. Furthermore, larger grafts (0.5-mm graft-host disparity) also yielded improved biomechanical properties.40 However, the drawback of donor grafts larger than 8.5 mm is the correlation with a higher rate of graft rejection.41 With the increasing number of lamellar keratoplasties being performed, it is also imperative to investigate rejection rates and factors associated with rejection. Overall, lower rates of rejection have been reported following endothelial keratoplasty versus those reported for full-thickness or penetrating keratoplasty (PK). In cases of deep lamellar endothelial keratoplasty (DLEK) and Descemet’s stripping endothelial keratoplasty (DSEK), the rate of rejection over a 2-year period was found to be 7.5%.42 After Descemet’s stripping automated endothelial keratoplasty (DSAEK), the rate of rejection was reported to be 5% versus 16% after PK for Fuchs’ endothelial dystrophy,

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despite the use of oral prednisone in the PK group.43 When examining graft rejection of deep B 0% to 8% and were typically isolated epithelial or anterior lamellar keratoplasty, rates ranged from 44-47 stromal rejection or a combination of both. When investigating risk factors associated with graft rejection after DSEK, Black patients were found to have a relative risk of rejection 5 times higher than that of White patients, and patients with preexisting glaucoma or steroid responsive ocular hypertension had twice the relative risk of rejection.48 Although the presence of glaucoma is associated with higher relative risk of rejection, patients with medically managed glaucoma were found to have significantly better 5-year graft survival than those with surgically managed glaucoma, and prior glaucoma shunt or trabeculectomy significantly increased the risk of endothelial failure in DSEK.49 Although careful identification of risk factors pre- and intraoperatively is important in predicting prognosis, understanding how to adequately and efficiently manage graft rejection is imperative in the prevention of graft failure.

Treatment Traditionally, steroids have long been the treatment of choice when managing graft rejection. Epithelial and stromal rejection usually respond well to topical steroid therapy, whereas more severe rejection involving the endothelium requires systemic steroids.50 Pulsed steroids have been shown to be more effective than oral steroids, and graft survival rates have been shown to be significantly better. There is no difference in survivability between single-pulse and double-pulse therapy.51-53 When choosing between intravenous steroids, dexamethasone was equally effective as methylprednisolone in treating graft rejection.54 However, intravenous administration may require hospital admission, so more cost-effective measures have been studied to be as effective in the reversal of rejection. Routes such as subconjunctival-, intracameral-, and intracornealinjected steroids have been used with great success.55-57 Biological and immunomodulating agents have also shown promising results in patients in whom systemic steroid therapy is ineffective or contraindicated. Agents such as cyclosporine A, mycophenolate, tacrolimus, and bevacizumab have been studied for the management of graft rejection. Cyclosporine A acts by inactivating calcineurin, which in turn inhibits IL-2 and lymphokine production, limiting the activity of CD4 + and CD8 + lymphocytes. In initial studies,58,59 topical cyclosporine A was shown to be effective in reducing the risk of allograft rejection; however, these results have been refuted in more current literature, in which neither 0.05% or 2% concentration reduced the risk of rejection.60-62 Oral cyclosporine A has also been investigated, and its efficacy and safety were assessed in a study for high-risk corneal transplantation in a prospective, randomized clinical trial. Oral administration of cyclosporine A for at least 6 months with a blood concentration of 800 ng/mL showed no positive effect in reducing rejection in high-risk corneal transplantation and was found to have a relatively high incidence of systemic side effects.63 Mycophenolate inhibits inosine monophosphate dehydrogenase required for T and B cell proliferation. In a side-by-side comparison of cyclosporine A and mycophenolate, high-risk keratoplasty patients were treated with mycophenolate (2 doses of 1 g daily) and a second group received oral cyclosporine A at a blood concentration of 120 to 150 ng/mL for 6 months, and no statistical significance was found between systemic mycophenolate and systemic cyclosporine A. Mycophenolate was shown to be at least as safe as cyclosporine A.64 Combination therapy of cyclosporine A and mycophenolate in a murine model was shown to be superior to monotherapy without an increase in adverse events.65 Tacrolimus has also been used topically and systemically. Its mechanism of action is similar to that of cyclosporine A in that it also inhibits calcineurin. Topical application has been shown to be an effective prophylactic agent for graft rejection.67,68 The safety and efficacy of systemic administration has also shown promising results in reduced rejection and improved survivability in high-risk keratoplasty.66-68 With its increasing uses, antivascular endothelial growth factor, such as bevacizumab, has been shown to be beneficial and effective in inducing the regression of neovascularization. Bevacizumab has been used as an adjunctive treatment in high-risk vascularized corneas at the time of keratoplasty to reduce the risk of graft failure. In several case reports, bevacizumab was injected subconjunctivally twice along with cauterization of feeder vessels at the limbus, and the graft remained clear of vessels for 6 months in one case and up to 2 years in another.69,70 However, this yields good short-term results but long-term vessel regrowth is often seen. Bevacizumab may

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be most useful when offered as an adjunctive measure to conventional therapies in the prevention of graft rejection in high-risk transplants.

Conclusion Corneal graft rejection remains a challenge in the long-term success of corneal transplantation. Early recognition and initiation of therapy remain the most important factors in the reversibility of graft rejection. Identification of preoperative risk factors may assist in the selection of patients with better long-term prognoses and outcomes after keratoplasty. Although steroid therapy has remained the mainstay treatment of choice, topical and systemic immunosuppressive treatments show promising results in the prophylaxis and treatment of graft rejections.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol. 2003;121(8):1087-1092. Thompson RW Jr, Price MO, Bowers PJ, Price FW Jr. Long-term graft survival after penetrating keratoplasty. Ophthalmology. 2003;110(7):1396-1402. Cornea Donor Study Investigator Group, Gal RL, Dontchev M, et al. The effect of donor age on corneal transplantation outcome: results of the Cornea Donor Study. Ophthalmology. 2008;115(4):620626.e6. Wilhelmus KR, Stulting RD, Sugar J, Khan MM. Primary corneal graft failure. A national reporting system. Medical Advisory Board of the Eye Bank Association of America. Arch Ophthalmol. 1995;113(12):1497-1502. Garg P, Krishna PV, Stratis AK, Gopinathan U. The value of corneal transplantation in reducing blindness. Eye (Lond). 2005;19(10):1106-1114. Borderie VM, Boëlle PY, Touzeau O, Allouch C, Boutboul S, Laroche L. Predicted long-term outcome of corneal transplantation.Ophthalmology. 2009;116(12):2354-2360. Polack FM. Clinical and pathological aspects of the corneal graft reaction. Trans Am Acad Ophthalmol Otolaryngol. 1973;77(4):OP418-OP432. Sangwan VS, Ramamurthy B, Shah U, Garg P, Sridhar MS, Rao GN. Outcome of corneal transplant rejection: a 10-year study. Clin Experiment Ophthalmol. 2005;33(6):623-627. Hong S, Van Kaer L. Immune privilege: keeping an eye on natural killer T cells. J Exp Med. 1999;190(9):1197-1200. Ziv Y, Ron N, Butovsky O, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268-275. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2006. Green DR, Ware CF. Fas-ligand: privilege and peril. Proc Natl Acad Sci USA. 1997;94(12):5986-5990. Keino H, Takeuchi M, Kezuka T, et al. Induction of eye-derived tolerance does not depend on naturally occurring CD4 + CD25 + T regulatory cells. Invest Ophthalmol Vis Sci. 2006;47(3):1047-1055. Stein-Streilein J, Streilein JW. Anterior chamber associated immune deviation (ACAID): regulation, biological relevance, and implications for therapy. Int Rev Immunol. 2002;21(2-3):123-152. Yamada J, Streilein JW. New insights into prevention of donor corneal graft rejection. Cornea. 2000;19(3):S177-S182. Niederkorn JY. Mechanisms of corneal graft rejection: the sixth annual Thygeson Lecture, presented at the Ocular Microbiology and Immunology Group meeting, October 21, 2000. Cornea. 2001;20(7):675-679. Milani, BY, Majdi M, Moarefi MA, Djalilian AR. Basic immunology. In: Copeland RA Jr, Afshari N, eds. Copeland and Afshari’s Principles and Practice of Cornea. New Delhi, India: JayPee Brothers Medical Publishers Ltd; 2003:43-55. Design and methods of The Collaborative Corneal Transplantation Studies. The Collaborative Corneal Transplantation Studies Research Group. Cornea. 1993;12(2):93-103. Khodadoust AA, Silverstein AM. Induction of corneal graft rejection by passive cell transfer. Invest Ophthalmol. 1976;15(2):89-95. Maguire MG, Stark WJ, Gottsch JD, et al. Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology. 1994;101(9):1536-1547. Dunn SP, Stark WJ, Stulting RD, et al. The effect of ABO blood incompatibility on corneal transplant failure in conditions with low risk of graft rejection. Am J Ophthalmol. 2009;147(3):432-438.e3.

116 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

Chapter 11 Khaireddin R, Wachtlin J, Hopfenmüller W, Hoffmann F. HLA-A, HLA-B and HLA-DR matching reduces the rate of corneal allograft rejection. Graefes Arch Clin Exp Ophthalmol. 2003;241(12):1020-1028. Bartels MC, Otten HG, van Gelderen BE, Van der Lelij A. Influence of HLA-A, HLA-B, and HLA-DR matching on rejection of random corneal grafts using corneal tissue for retrospective DNA HLA typing. Br J Ophthalmol. 2001;85(11):1341-1346. Bartels MC, Doxiadis II, Colen TP, Beekhuis WH. Long-term outcome in high-risk corneal transplantation and the influence of HLA-A and HLA-B matching. Cornea. 2003;22(6):552-556. Xu L, Chen J, Hung T. Comparing cryopreserved with fresh corneas on clinical application in penetrating keratoplasty [in Chinese]. Yan Ke Xue Bao. 2001;17(2):68-71. Borderie V, Laroche L, Vedie F, Lopez M. Penetrating keratoplasty after graft preservation in organ culture at + 37 degrees centigrade. 1-year results [in French]. J Fr Ophtalmol. 1995;18(10):570-577. Simon M, Fellner P, El-Shabrawi Y, Ardjomand N. Influence of donor storage time on corneal allograft survival. Ophthalmology. 2004;111(8):1534-1538. Trigui A, Smaoui M, Masmoudi J, Mhiri W, Maatoug S, Feki J. Corneal graft rejection: donor and receiver implication [in French]. J Fr Ophtalmol. 2005;28(6):631-634. Bachmann B, Taylor RS, Cursiefen C. Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology. 2010;117(7):13001305.e7. Shtein RM, Garcia DD, Musch DC, Elner VM. Herpes simplex virus keratitis: histopathologic inflammation and corneal allograft rejection. Ophthalmology. 2009;116(7):1301-1305. Shtein RM, Elner VM. Herpes simplex virus keratitis: histopathology and corneal allograft outcomes. Expert Rev Ophthalmol. 2010;5(2):129-134. Belliappa S, Hade J, Kim S, Ayres BD, Chu DS. Surgical outcomes in cases of contact lens-related Fusarium keratitis. Eye Contact Lens. 2010;36(4):190-194. Williams KA, Roder D, Esterman A, Muehlberg SM, Coster DJ. Factors predictive of corneal graft survival. Report from the Australian Corneal Graft Registry. Ophthalmology. 1992;99(3):403-414. Küchle M, Cursiefen C, Nguyen NX, et al. Risk factors for corneal allograft rejection: intermediate results of a prospective normal-risk keratoplasty study. Graefes Arch Clin Exp Ophthalmol. 2002;240(7):580-584. Stulting RD, Sugar A, Beck R, et al. Effect of donor and recipient factors on corneal graft rejection. Cornea. 2012;31(10):1141-1147. Koay PY, Lee WH, Figueiredo FC. Opinions of risk factors and management of corneal graft rejection in the United Kingdom. Cornea. 2005;24(3):292-296. Jonas JB, Rank RM, Budde WM. Immunologic graft rejections after allogeneic penetrating keratoplasty. Am J Ophthalmol. 2002;133(4):437-443. Inoue K, Amano S, Oshika T, Tsuru T. Risk factors for corneal graft failure and rejection in penetrating keratoplasty. Acta Ophthalmol Scand. 2001;79(3):251-255. Sharif KW, Casey TA. Penetrating keratoplasty for keratoconus: complications and long-term success. Br J Ophthalmol. 1991;75(3):142-146. Feizi S, Einollahi B, Yazdani S, Hashemloo A. Graft biomechanical properties after penetrating keratoplasty in keratoconus. Cornea. 2012;31(8):855-858. Perera C, Jhanji V, Vajpayee RB. Factors influencing outcomes of the treatment of allograft corneal rejection. Am J Ophthalmol. 2011;152(3):358-363.e2. Allan BD, Terry MA, Price FW Jr, Price MO, Griffin NB, Claesson M. Corneal transplant rejection rate and severity after endothelial keratoplasty. Cornea. 2007;26(9):1039-1042. Hjortdal J, Pedersen IB, Bak-Nielsen S, Ivarsen A. Graft rejection and graft failure after penetrating keratoplasty or posterior lamellar keratoplasty for Fuchs’ endothelial dystrophy. Cornea. 2013;32(5):e60-e63. Han DC, Mehta JS, Por YM, Htoon HM, Tan DT. Comparison of outcomes of lamellar keratoplasty and penetrating keratoplasty in keratoconus. Am J Ophthalmol. 2009;148(5):744-51.e1. Watson SL, Ramsay A, Dart JK, Bunce C, Craig E. Comparison of deep lamellar keratoplasty and penetrating keratoplasty in patients with keratoconus. Ophthalmology. 2004;111(9):1676-1682. Al-Torbak AA, Al-Motowa S, Al-Assiri A, et al. Deep anterior lamellar keratoplasty for keratoconus. Cornea. 2006;25(4):408-412. Watson SL, Tuft SJ, Dart JK. Patterns of rejection after deep lamellar keratoplasty. Ophthalmology. 2006;113(4):556-560. Price MO, Jordan CS, Moore G, Price FW Jr. Graft rejection episodes after Descemet stripping with endothelial keratoplasty: part two: the statistical analysis of probability and risk factors. Br J Ophthalmol. 2009;93(3):391-395. Anshu A, Price MO, Price FW. Descemet’s stripping endothelial keratoplasty: long-term graft survival and risk factors for failure in eyes with preexisting glaucoma. Ophthalmology. 2012;119(10):1982-1987.

Corneal Graft Rejection 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

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Panda A, Vanathi M, Kumar A, Dash Y, Priya S. Corneal graft rejection. Surv Ophthalmol. 2007;52(4):375-396. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral versus single pulse therapy. Ophthalmology. 1991;98(3):329-333. Costa DC, Castro RS, Camargo MS, Kara-José N. Corneal allograft rejection: topical treatment vs. pulsed intravenous methylprednisolone—ten years’ result [in Portuguese]. Arq Bras Oftalmol. 2008;71(1):57-61. Hill JC, Ivey A. Corticosteroids in corneal graft rejection: double versus single pulse therapy. Cornea. 1994;13(5):383-388. Tandon R, Verma K, Chawla B, et al. Intravenous dexamethasone vs methylprednisolone pulse therapy in the treatment of acute endothelial graft rejection. Eye (Lond). 2009;23(3):635-639. Costa DC, de Castro RS, Kara-José N. Case-control study of subconjunctival triamcinolone acetonide injection vs intravenous methylprednisolone pulse in the treatment of endothelial corneal allograft rejection. Eye (Lond). 2009;23(3):708-714. Birnbaum F, Maier P, Reinhard T. Intracameral application of corticosteroids for treating severe endothelial rejection after penetrating keratoplasty [in German]. Ophthalmologe. 2007;104(9):813-816. Arenas E, Navarro M, Mieth MA. Intracorneal depot steroids for the treatment of corneal rejection after keratoplasty [in Spanish]. Arch Soc Esp Oftalmol. 2004;79(2):75-79. Hoffmann E, Wiederholt M. Topical cyclosporin A in the treatment of corneal graft rejection. Cornea. 1986;5(3):129. Inoue K, Amano S, Kimura C, et al. Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol. 2000;44(3):302-305. Unal M, Yücel I. Evaluation of topical ciclosporin 0.05% for prevention of rejection in high-risk corneal grafts. Br J Ophthalmol. 2008;92(10):1411-1414. Price MO, Price FW Jr. Efficacy of topical cyclosporine 0.05% for prevention of cornea transplant rejection episodes. Ophthalmology. 2006;113(10):1785-1790. Sinha R, Jhanji V, Verma K, Sharma N, Biswas NR, Vajpayee RB. Efficacy of topical cyclosporine A 2% in prevention of graft rejection in high-risk keratoplasty: a randomized controlled trial. Graefes Arch Clin Exp Ophthalmol. 2010;248(8):1167-1172. Shimazaki J, Den S, Omoto M, Satake Y, Shimmura S, Tsubota K. Prospective, randomized study of the efficacy of systemic cyclosporine in high-risk corneal transplantation. Am J Ophthalmol. 2011l;152(1):33-39.e1. Reinhard T, Reis A, Böhringer D, et al. Systemic mycophenolate mofetil in comparison with systemic cyclosporin A in high-risk keratoplasty patients: 3 years’ results of a randomized prospective clinical trial. Graefes Arch Clin Exp Ophthalmol. 2001;239(5):367-372. Reis A, Reinhard T, Sundmacher R, Braunstein C, Godehardt E. Effect of mycophenolate mofetil, cyclosporin A, and both in combination in a murine corneal graft rejection model. Br J Ophthalmol. 1998;82(6):700-703. Dhaliwal JS, Mason BF, Kaufman SC. Long-term use of topical tacrolimus (FK506) in high-risk penetrating keratoplasty. Cornea. 2008;27(4):488-493. Reis A, Mayweg S, Birnbaum F, Reinhard T. Long-term results of FK 506 eye drops following corneal transplantation. Klin Monbl Augenheilkd. 2008;225(1):57-61. Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosuppression in highrisk corneal grafts. Br J Ophthalmol. 2007;91(1):51-55. Symes RJ, Poole TR. Corneal graft surgery combined with subconjunctival bevacizumab (Avastin). Cornea. 2010;29(6):691-693. Pinsard L, Malet F, Colin J, Touboul D. Neovascular invasion of the endothelio-descemetic interface occurring after deep anterior lamellar keratoplasty [in French]. J Fr Ophtalmol. 2013;36(5):e77-e81.

12 Femtosecond Laser–Assisted Corneal Graft Surgery Jorge L. Alió, MD, PhD; Felipe Soria, MD; Alfredo Vega-Estrada, MD; and Ahmed Abdou, MD, PhD Femtosecond laser technology for cataract surgery has undergone a paradigm shift, with promising results. In 1905, Zimmer performed the first full-thickness penetrating keratoplasty (PK).1 In 1950, Barraquer described the top-hat pattern, and in the early 1970s, there was an increased interest in lamellar corneal transplantation.2 Despite this, PK is still one of the most common procedures for corneal transplant. The main advantages of PK are its universal application for the treatment of corneal conditions that involve the endothelium, penetrating corneal traumas, and scars comprising Descemet’s membrane; and the operative procedure familiar to most surgeons. A significant decision to be made applicable to this technique is determining the incisional configuration, and it is here that the femtosecond laser technology is outstanding. Various studies have demonstrated that zig-zag and top-hat configurations are optimal for treatment.3-5 Our experience has been with the 60 kHz IntraLase (IntraLase Corp), which allows the selection of 3 different types of cutting patterns with precise coupling between donor and recipient (Figure 12-1). A tightly sealed incision in conjunction with sutures and the photodisruption occurring with a femtosecond laser may stimulate more rapid and stronger healing of the incision.6

General Considerations Adequate and appropriate assessment, including a detailed history evaluation of specific bleeding disorders and related medication use, must be addressed preoperatively. Patients receiving anticoagulants are advised to withhold their use at least a few days preoperatively to avoid the increased risk of expulsive hemorrhage.7 Patients undergoing anterior corneal lamellar procedures are advised to follow the same indication because, in the event of an inadvertent complication, a lamellar procedure can be converted to a PK.

Indications for Femtosecond Laser–Assisted Keratoplasty Penetrating Keratoplasty The indications for femtosecond laser–assisted PK follow 8: • Corneal edema associated with corneal scarring or chronic evolution

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Figure 12-1. (A) Mushroom, (B) zig-zag, and (C) top-hat patterns.

• Deep stromal scars caused by trauma, severe infectious process of any etiology, and hydrops in keratoconus. In the case of hydrops, the rupture of Descemet’s membrane makes it almost impossible to find the plane of cleavage to perform a lamellar technique. • Immunological disorders associated with corneal perforation (rheumatoid arthritis and Mooren’s ulcer) • Active infective process (any etiology). The only limitation is the possibility of the femtosecond laser to overstep dense opacities and blood vessels. • Recurrent transplant rejection In case of corneal perforation less than 3 mm and in cases where the corneal thickness is acceptable, the procedure can be performed with perpendicular docking which closes the perforation during the femtosecond dissection. A cohesive ophthalmic viscosurgical device is injected into the anterior chamber prior to the procedure.

Deep Anterior Lamellar Keratoplasty The indications for femtosecond laser–assisted deep anterior lamellar keratoplasty (DALK) are as follows: • Corneal ectasia. Keratoconus is the most common indication for DALK, followed by other pathologies like pellucid marginal degeneration and post-LASIK ectasia. • Corneal dystrophies • Corneal scars due to trauma or infectious keratitis

Relevant Opthalmological Diagnostic Tests Visual Acuity and Refraction We usually indicate PK and DALK procedures in patients with best corrected visual acuity (BCVA) worse than 0.2 decimal notation, intolerance to contact lenses and when other treatment such as intracorneal ring segments have failed or are contraindicated.

Pachymetry Assessment Anterior Optical Coherence Tomography Anterior optical coherence tomography (OCT) is a mandatory preoperative test that measures the central and peripheral corneal thickness and helps determine the parameters of the incision for the surgical approach. It is also important to verify and obtain the dimensions (depth and longitude) of the opacities and evaluate the possibility of the femtosecond laser to break through them. It also gives us valuable information on the anatomical condition of the entire anterior segment.

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Ultrasonic Pachymetry Before the femtosecond laser procedure begins, measurements are repeated because some thickness changes may be encountered. Ultrasonic pachymetry provides a double check of all measurements.

Surgical Procedure for the Corneal Receptor The limitations of a standard corneal trephine in achieving a perfect coupling are evident when compared with femtosecond laser technology, which allows different patterns. These patterns result in excellent tissue apposition, which leads to rapid wound healing, earlier suture removal, and faster patient recovery (see Figure 12-1).

Pattern Shape Selection Zig-Zag This pattern is indicated for any case. Having experience with corneal 3-plane incisions during cataract surgery, our preference for PK is the zig-zag pattern, which simulates 2 grooves that, in the correct angle, allow the maximum apposition to prevent leakage. As an added value, the maximum apposition established allows a perfect suture pattern with the refractive benefits. However, it is not possible to use this configuration in cases of peripheral thickening.

Top Hat This pattern is indicated in cases with central scars, posterior peripheral scars, corneal edema, and peripheral superior corneal thickening more than 350 μm. Larger amounts of corneal stroma and endothelium graft are transplanted with this pattern. However, the straight-edge-to-straightedge configuration is associated with delayed, weak, and incomplete healing of the donor-host junction.

Mushroom This pattern is indicated in cases with central scars, superficial peripheral scars, keratoconus, and peripheral inferior corneal thickening more than 350 μm. Larger amounts of corneal tissue are added to the thin periphery, minimizing the extraction of healthy endothelium. However, the straight-edge-to-straight-edge configuration is associated with delayed, weak, and incomplete healing of the donor-host junction.

Surgical Technique All settings must be established by the surgeon and double checked by the technician. Set the optical wheel of the IntraLase to position D (Figure 12-2) and focus on the receptor cornea. Verify the white-to-white measurement with a calliper. This allows assessment of the parameters that were programmed in the femtosecond laser and checks whether they are in accordance with the diameter of the cornea.

Ultrasonic Pachymetry Measurements Starting in the center and placing the probe in the intended zone of the incisions, approximately in the midperiphery of the cardinal points, follow the midperiphery obliquely to the cardinal points (between 7 and 9 mm); we suggest at least 9 measurements. These data should be compared with the OCT pachymetry data. In cases of corneal edema, it is mandatory to calculate the posterior depth of the posterior side cut to 50% as mentioned earlier. With a marker, check the center of the cornea for an accurate centration of the dissection with the femtosecond laser.

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Figure 12-2. Optical wheel of the IntraLase in position D.

Figure 12-3. Docking procedure.

Figure 12-4. Optical wheel of the IntraLase in position 2.

Eye Fixation With a Corneal Suction Ring The easiest way to achieve a good suction of the eye ball is to have an assistant hold the inferior eyelid while the surgeon holds the upper lid. When the inferior border of the ring is gently but firmly placed over the inferior globe, the ring is placed over the sclera, making sure to achieve the best symmetrical position. As soon as the best position is achieved, the vacuum is raised (Figure 12-3).

Cone Positioning and Perpendicular Docking One of the most important steps in this procedure is achieving a perfect perpendicular docking. When lowering the cone, the optical wheel is changed to position 2 (Figure 12-4), and the key orientation will be the circular light pattern of the illumination mechanism projected over the cornea. We suggest calling these steps perpendicular docking, because we emphasize the correct positioning of the cone over the cornea. When contact is made with the cornea, a meniscus is seen starting from the center and moving to the periphery. If the meniscus is not even, corrections can

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Figure 12-5. Donor cornea.

be made by moving the suction ring where the meniscus is greater, but never move the joystick in the X/Y direction.

Centration of the Dissection After the suction ring is fixated onto the globe, the assistant centers the dissection circle from the screen of the IntraLase on the mark on the cornea that was previously made by the surgeon.

Pressing the Foot Pedal During this step, it is essential that all personnel in the operating room stand still, making sure that no one touches the operating table or the IntraLase. The eye is patched and the patient is transferred on a stretcher and taken to the operating room, where the procedure is completed. Ideally, the surgical extraction of the cornea receptor begins while the donor cornea procedure is performed. Experience allows us to do both procedures simultaneously, and the donor cornea is ready when the surgeon requires it.

Surgical Procedure for the Donor Cornea in an Artificial Anterior Chamber The use of an artificial anterior chamber is mandatory to obtain the donor tissue during femtosecond laser–assisted keratoplasty.9 When donor tissue is to be used in an artificial anterior chamber, the diameter of the corneoscleral button should be larger to be properly held in the device. The diameter of tissue prepared in eye banks has changed in recent years, from 14 mm to 16 to 17 mm. During this procedure, the patient is kept in the general operating room where the recipient tissue is being removed. Under aseptic precautions, the following instruments are kept ready in the surgical tray: • Donor corneal tissue (Figure 12-5) • Medicine cup with 10 mL of chlorhexidine • Medical cup with 50 mL of balanced salt solution • Artificial anterior chamber • Forceps • Calliper • Surgical sponge • Barraquer tonometer • 10-mL syringe

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A

B

Figure 12-6. (A) Donor cornea fitted in the artificial anterior chamber. (B) Well-centered donor cornea and placement of the cover. Figure 12-7. Barraquer tonometer.

Begin the procedure with a 5-minute surgical scrub technique, followed by the placement of sterile gown and gloves. Connect the infusion intravenous (IV) line to the 3-way stopcock artificial anterior chamber. Fill the syringe with 10 mL of balanced salt solution and connect it to infusion IV line, injecting the balanced salt solution until the concave superior part of the piston is filled. Using the forceps, place the sclerocorneal donor graft on the piston with the endothelium facing down. Achieve a good centration and ensure that no sclera is over the concave part of the piston. Hold the graft with the forceps and, with the other hand, inject balanced salt solution to eliminate any air bubbles. Gentle movement of the graft can be done to achieve this. When finished, place the 3-way stopcock in the closed position. Fit the anterior chamber cover over the graft and lock it in place with a clockwise turn (Figure 12-6). Elevate the piston to tighten the chamber to the base and fixate the sclerocorneal rim. Measure the intraocular pressure (IOP) with the Barraquer tonometer to make sure that adequate pressure is present in the sclerocorneal rim (Figure 12-7). Place the table below the femtosecond laser and use the same cone that was used in the patient’s cornea; the incisions must match precisely (Figure 12-8). Connect the infusion IV line to the 3-way stopcock artificial anterior chamber. Double check with the assistant that the correct pattern was selected (preview the pattern in the IntraLase). Press the foot pedal. In a normal view, depending on the pattern, the laser cuts from posterior to anterior, so you must see the formation of air bubbles inside the artificial anterior chamber. In an abnormal view, with an uneven dissection pattern, the procedure should not be stopped, but you must consider that the part of the cornea that was not properly dissected will not be easily removed from the sclera. During undocking, elevation of the cone should be performed slowly to observe the behavior of the donor cornea. If it is observed that the cornea is collapsing, balanced salt solution must be injected. Releasing the anterior chamber cover requires slow movements, as does lowering the

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B

Figure 12-8. (A) Cone used for donor cornea. (B) Docking in the donor cornea.

piston. Performing both of these steps requires concomitant injection of balanced salt solution so the cornea does not collapse. This avoids the creation of striae and the loss of endothelial cells. The corneal graft is placed in the medical cap with chlorhexidine and taken to the operating room for implantation. Once in the operating room, the donor cornea can be dissected from the scleral rim using an inverted Sinskey hook. If an even dissection pattern was achieved with the femtosecond laser, grasping the scleral rim with forceps and using the inverted Sinskey hook to dissect 360 degrees around the incision with the sclerocorneal rim over the donor cap should be enough to get the corneal lenticule away from the scleral rim. Afterward, continue with the standard PK or DALK procedure.

Outcomes of Femtosecond Laser–Assisted Keratoplasty Femtosecond laser–assisted PK is safe and enables faster suture removal with better refractive and visual outcomes than Conventional PK.10,11 Farid et al12 reported comparable refractive and visual outcomes between femtosecond laser–assisted PK (zig-zag pattern) and conventional PK. At 3 months, average astigmatism was 3 diopters in the femtosecond laser–assisted group and 4.46 diopters in the conventional group. Significant differences in BCVA were achieved after the first (P = .0003) and third (P = .006) months. Eighty-one percent of the femtosecond laser–assisted group versus 45% of the conventional group achieved a BCVA of 20/40 or better by the third month (P = .03). These results are similar to those reported by Chamberlain et al13 and Gaster et al.14 Regarding femtosecond laser–assisted DALK, 1-year postoperative BCVA ranging from 20/40 to 20/20 has been reported.15-22 Although there is not total agreement in the published results, most investigations found an induction of astigmatism from 2 to 5 diopters after femtosecond laser–assisted DALK.16,17,23,24 In terms of which incision pattern to choose, each has its pros and cons. Particularly, the tophat pattern has shown higher stability with higher wound leakage pressure.14,25-29 With this pattern configuration, where a larger posterior corneal tissue is transplanted, the possibility of endothelial rejection is higher. Using high-resolution anterior-segment OCT, we analyzed 11 eyes operated by femtosecond laser–assisted PK with different patterns to evaluate the posterior donorhost interface elevation (nasal and temporal sides). Wound analysis of the zig-zag pattern revealed a highly coapted donor-host interface compared with the mushroom and top-hat patterns.30

Conclusion Limitations of femtosecond laser–assisted keratoplasty include difficulty cutting the peripheral corneal opacity and achieving the desired planar cuts in eyes with significant anterior and posterior surface irregularities like descemetocele, which can be overcome by optimization and innovation

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of femtosecond laser technology. Currently, outcomes are optimized by application of femtosecond laser technology toward achieving the following goals: • Excellent wound apposition • Biomechanical stable incision • Minimal suturing with nominal voltage-induced astigmatism • Rapid recovery of the wound and vision • Good selection of incision type More than 100 years have passed since the first corneal transplant was performed, and in the past 10 years, femtosecond laser technology has completely changed the landscape of corneal procedures. Despite the benefits of the femtosecond laser in keratoplasty, there is still a need to innovate and improve to achieve perfection of the technique.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty: a report by the American Academy of Ophthalmology. Ophthalmology. 2011;118(1):209-218. Richard JM, Paton D, Gasset AR. A comparison of penetrating keratoplasty and lamellar keratoplasty in the surgical management of keratoconus. Am J Ophthalmol. 1978;86(6):807-811. Maier P, Böhringer D, Birnbaum F, Reinhard T. Improved wound stability of top-hat profiled femtosecond laser-assisted penetrating keratoplasty in vitro. Cornea. 2012;31(8):963-966. Farid M, Kim M, Steinert RF. Results of penetrating keratoplasty performed with a femtosecond laser zigzag incision: initial report. Ophthalmology. 2007;114(12):2208-2212. Gaster RN, Dumitrascu O, Rabinowitz YS. Penetrating keratoplasty using femtosecond laser-enabled keratoplasty with zig-zag incisions versus a mechanical trephine in patients with keratoconus. Br J Ophthalmol. 2012;96(9):1195-1199. Busin M. A new lamellar wound configuration for penetrating keratoplasty surgery. Arch Ophthalmol. 2003;121(2):260-265. van Dooren BT, Mulder PG, Nieuwendaal CP, Beekhuis WH, Melles GR. Endothelial cell density after deep anterior lamellar keratoplasty (Melles technique). Am J Ophthalmol. 2004;137(3):397-400. Lahners WJ, Culbertson W, Rabinowitz Y, Azar D, Stahl J, eds. Femtosecond laser in corneal and refractive surgery. Online Interactive Ophthalmology Textbook. San Francisco, CA: American Academy of Ophthalmology; 2007. Meltendorf C, Schroeter J, Bug R, Kohnen T, Deller T. Corneal trephination with the femtosecond laser. Cornea. 2006;25(9):1090-1092. Chamberlain WD, Rush SW, Mathers WD, Cabezas M, Fraunfelder FW. Comparison of femtosecond laser-assisted keratoplasty versus conventional penetrating keratoplasty. Ophthalmology. 2011;118(3):486-491. Bahar I, Kaiserman I, McAllum P, Rootman D. Femtosecond laser-assisted penetrating keratoplasty: stability evaluation of different wound configurations. Cornea. 2008;27(2):209-211. Farid M, Steinert RF, Gaster RN, Chamberlain W, Lin A. Comparison of penetrating keratoplasty performed with a femtosecond laser zig-zag incision versus conventional blade trephination. Ophthalmology. 2009;116(9):1638-1643. Chamberlain WD, Rush SW, Mathers WD, Cabezas M, Fraunfelder FW. Comparison of femtosecond laser-assisted keratoplasty versus conventional penetrating keratoplasty. Ophthalmology. 2011;118(3):486-491. Gaster RN, Dumitrascu O, Rabinowitz YS. Penetrating keratoplasty using femtosecond laser-enabled keratoplasty with zig-zag incisions versus a mechanical trephine in patients with keratoconus. Br J Ophthalmol. 2012;96(9):1195-1199. Panda A, Bageshwar LM, Ray M, Singh JP, Kumar A. Deep lamellar keratoplasty versus penetrating keratoplasty for corneal lesions. Cornea. 1999;18(2):172-175. Fogla R, Padmanabhan P. Results of deep lamellar keratoplasty using the big-bubble technique in patients with keratoconus. Am J Ophthalmol. 2006;141(2):254-259. Al-Torbak AA, Al-Motowa S, Al-Assiri A, et al. Deep anterior lamellar keratoplasty for keratoconus. Cornea. 2006;25(4):408-412. Shimmura S, Shimazaki J, Omoto M, Teruya A, Ishioka M, Tsubota K. Deep lamellar keratoplasty (DLKP) in keratoconus patients using viscoadaptive viscoelastics. Cornea. 2005;24(2):178-181. Ardjomand N, Hau S, McAlister JC, et al. Quality of vision and graft thickness in deep anterior lamellar and penetrating corneal allografts. Am J Ophthalmol. 2007;143(2):228-235.

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20. Bahar I, Kaiserman I, Srinivasan S, Ya-Ping J, Slomovic AR, Rootman DS. Comparison of three different techniques of corneal transplantation for keratoconus. Am J Ophthalmol. 2008;146(6):905912.e1. 21. Alió JL. Visual improvement after late debridement of residual stroma after anterior lamellar keratoplasty. Cornea. 2008;27(8):871-873. 22. Ing JJ, Ing HH, Nelson LR, Hodge DO, Bourne WM. Ten-year postoperative results of penetrating keratoplasty. Ophthalmology. 1998;105(10):1855-1865. 23. Trimarchi F, Poppi E, Klersy C, Piacentini C. Deep lamellar keratoplasty. Ophthalmologica. 2001;215(6):389-393. 24. Krumeich JH, Knü lle A, Krumeich BM. Deep anterior lamellar (DALK) vs. penetrating keratoplasty (PKP): a clinical and statistical analysis [in German]. Klin Monbl Augenheilkd. 2008;225(7):637-648. 25. Steinert RF, Ignacio TS, Sarayba MA. “Top-hat”-shaped penetrating keratoplasty using the femtosecond laser. Am J Ophthalmology. 2007;143(4):689-691. 26. Bahar I, Kaiserman I, McAllum P, Rootman D. Femtosecond laser-assisted penetrating keratoplasty: stability evaluation of different wound configurations. Cornea. 2008;27(2):209-211. 27. Ignacio TS, Nguyen TB, Chuck RS, Kurtz RM, Sarayba MA. Top hat wound configuration for penetrating keratoplasty using the femtosecond laser: a laboratory model. Cornea. 2006;25(3):336-340. 28. Maier P, Böhringer D, Birnbaum F, Reinhard T. Improved wound stability of top-hat profiled femtosecond laser-assisted penetrating keratoplasty in vitro. Cornea. 2012;31(8):963-966. 29. Birnbaum F, Wiggermann A, Maier PC, Böhringer D, Reinhard T. Clinical results of 123 femtosecond laser-assisted penetrating keratoplasties. Graefes Arch Clin Exp Ophthalmol. 2013;251(1):95-103. 30. Alio JL, Abdou A, Vega-Estrada A, Pena P. Posterior donor-host interface elevation measurement of femtosecond laser-assisted penetrating keratoplasty using high-resolution AS-OCT. Paper presented at: 30th Congress of the European Society of Cataract and Refractive Surgeons; October 2012; Milan, Italy.

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Section II Keratoprosthesis and Ocular Surface Disorders

13 Boston Keratoprosthesis Bishoy Said, MD and Natalie A. Afshari, MD, FACS Corneal transplantation has become a successful option for the treatment of reversible corneal blindness worldwide. With the advent of multiple partial transplant techniques, the indications for surgical intervention have expanded along with improved outcomes. However, despite surgical advancements in these modalities, there are still patients who fail standard corneal transplants. The keratoprosthesis is an alternative procedure for patients who have previously failed grafts, and it has recently been suggested as a primary surgical option for select patients. The concept of an artificial lens was first described more than 2 centuries ago. Initial attempts were challenging, with complications from extrusion and subsequent infections. Interest in artificial transplantation rekindled in the past few decades with marked advancement in the development of implants. The idea of the keratoprosthesis was to provide a clear visual axis that would not be compromised by the diseased adjacent ocular tissue.1 Although multiple models are used worldwide, 2 primary prosthetics are used in the United States today: the Boston Keratoprosthesis (KPro; Massachusetts Eye and Ear Infirmary) and the osteo-odonto-keratoprosthesis. The Boston KPro was developed by Dr. Claes H. Dohlman at the Massachusetts Eye and Ear Infirmary, with multiple subsequent modifications since it was originally described. There are 2 types of Boston KPros. The type I Boston KPro is composed of a front plate of polymethylmethacrylate (PMMA) that is 5.0 mm in diameter attached to a central stem that is 3.4 mm deep. Posterior to this is the back plate, which is 7.0 to 8.5 mm in diameter. These are then secured into place using a titanium locking ring (Figure 13-1). The refractive power comes from the central stem. The PMMA back plate has 16 holes that are 1 mm in diameter, each of which allows for nutrition and hydration of the corneal endothelium from the aqueous. It is believed that possibly converting the posterior plate to titanium may help in this regard. The type II Boston KPro, which is less commonly used, has a similar design. It has the same 5.0-mm anterior plate attached to the 3.4-mm stem with a posterior 8.5-mm plate secured in place with a titanium locking ring. The modification in the type II is a second 3.0-mm central optical cylinder that is 2 mm in depth, which is attached to the anterior aspect of the front plate (Figure 13-2). This additional item is what protrudes through the closed eyelid. The advantage of both designs is that they allow for a clear optical axis that will not be compromised by underlying corneal disease without significantly changing the quality or magnification of the visualized object. Given the size of the central optic, the visual fields are restricted to approximately the central 90 degrees. - 131 -

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Figure 13-1. Schematic drawing illustrating the assembly of the original type I Boston KPro and its various components. (Reprinted with permission from Khan B, Harissi-Dagher M, Khan D, et al. Advances in Keratoprostheses: Enhancing Retention and Prevention of Infection and Inflammation. San Diego, CA: Wolters Kluwer Health; 2014.) Figure 13-2. Boston type II KPro. (Reprinted with permission from Claes H. Dohlman, MD, PhD.)

Patient Selection and Indications The Boston KPro has classically been considered a surgical option only when a patient has failed one or more conventional penetrating keratoplasties (PKs). Those with the most favorable prognosis are patients with no ocular surface disease, no autoimmune disorders, and satisfactory blink rate and tear secretion. Although a challenging cohort, the Boston KPro can also be implanted in certain pediatric patients. The more rapid visual recovery compared with conventional PK may help in amblyopia management in children.2

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Figure 13-3. Algorithm for the selection of the most appropriate style of keratoprosthesis. (Reprinted with permission from Focal Points: An Overview of Keratoprostheses, American Academy of Opthalmology.)

It is important to consider the ocular surface because the Boston KPro can fail secondary to a dry or insufficient tear surface. Although more challenging, the Boston KPro can be successful in patients with cicatricial diseases like Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and chemical and thermal burns, especially with a good blink and tear film. This particular cohort of patients poses a specific challenge because they commonly have limbal stem cell deficiency and ocular surface inflammation. Multiple studies have demonstrated that these patients have the poorest prognosis when receiving a Boston KPro.3,4 It is thought that ongoing inflammation combined with deficient stem cells and limited tear film contribute to corneal melt and ultimate graft failure. However, recent reports suggest some promise in combating these challenges.3-5 Although the Boston KPro has historically been used in the setting of previously failed conventional PKs, recent literature suggests a potential for the Boston KPro as a primary modality for select patients. Primary indications for surgery include chemical or thermal injury, herpetic keratitis, aniridia, and Stevens-Johnson syndrome (Figure 13-3).6,7

Surgical Procedure Implantation of a Boston KPro is similar to the PK procedure.8-11 Because healthy corneal endothelial tissue is not needed for clear vision, a poor-quality donor cornea is sufficient. Standard retrobulbar anesthesia, as with regular PK, is generally performed.

Donor Corneal Tissue Preparation An 8.5-mm trephine is used in the standard manner on the donor cornea tissue. In addition to this, a 3.0-mm central button is punched in the middle of the prepared 8.5-mm donor tissue; this allows for the stem to go through the donor tissue. The 3.0-mm punch instrumentation is generally provided with Boston KPro packaging. Attention should be paid to drying both surfaces of the donor tissue to minimize edema and reduce the risk of future necrosis or melt. Because the endothelial cells are not needed, no specific care needs to be taken regarding cell protection.

Prosthetic Assembly It is recommended that the prosthetic is prepared under the microscope. The anterior 5.0-mm plate is placed on a secure field, and the prepared donor tissue is slid through the stem. Then the posterior 8.0-mm plate with the holes is placed through the stem. Finally, the titanium locking ring is placed and secured using the wrench provided with the prosthesis. This effectively creates

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Figure 13-4. Postoperative appearance of a type I Boston KPro in situ with an overlying bandage contact lens.

a sandwich composed of the prosthetic front plate, donor cornea tissue, and prosthetic back plate, all secured into place with the locking ring. The entire device is then generally soaked in antibiotic solution until ready for surgical placement.

Prosthetic Options There are 2 types of central optics: pseudophakic and aphakic. If pseudophakic, there is no need for axial length measurements. If aphakic, axial length is necessary for selection of the appropriate-power optical stem. If the patient is phakic, cataract extraction should be performed. If there is decent visualization, a standard phacoemulsification technique can be performed. Alternatively, extracapsular cataract extraction or open sky lens extraction can be performed, leaving the posterior capsule intact if possible. We prefer leaving patients aphakic if possible. Anterior vitrectomy is performed as needed.

Surgical Technique Once the prosthetic is assembled and the cataract is no longer present, surgery is similar to a standard PK with a few minor modifications. Sixteen interrupted sutures are placed in a radial fashion using 9-0 nylon. Because the prosthetic is made of a rigid PMMA material, there is no concern about suture-induced astigmatism. There should be no leak in the interface where all sutures are placed. Subconjunctival injections of corticosteroids and antibiotics are given at the end of the procedure, as in standard PK. At the completion of the procedure, attention should be paid to ensuring that the pressure in the eye is not elevated, to reduce the risk of glaucoma (Figure 13-4).

Management The placement of a soft contact lens postoperatively and the long-term use of topical vancomycin and a fourth-generation fluoroquinolone after implantation have dramatically reduced the incidence of corneal necrosis and bacterial endophthalmitis, respectively.12 Given the elevation from the front plate of the prosthetic, evaporative forces can often result in uneven wetting of the surface. This can result in focal areas of dryness, which can interfere with epithelial healing, eventually leading to leaks or melts. Accordingly, a long-term bandage contact lens has been shown to distribute the tear film uniformly. This allows for fine-tuning refractive corrections and reversing desiccation of the corneal surface. Additionally, it provides increased patient comfort.12-14 We recommend a Kontur Kontact Lens (Kontur Kontact Lens, Co, Inc) for this purpose. These lenses are typically thicker with a wider diameter (16.0 and 18.0 mm), allowing for better retention and tolerance. We recommend that they be removed and cleaned each visit and exchanged every 3 months. Consider performing a lateral tarsorrhaphy in patients who recurrently lose the lens.

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The use of topical vancomycin in combination with a quinolone has been shown to be effective in preventing bacterial endophthalmitis in patients with the Boston KPro.15-18 It is now generally recommended to continue patients indefinitely with topical vancomycin (14 mg/mL) twice daily in combination with a fourth-generation fluoroquinolone once or twice daily. Special attention should be paid to patients with a history of autoimmune disease. In other patients, Polytrim (polytrim B sulfate/trimethoprim sulfate) once daily is usually sufficient. The rate of bacterial infection has declined considerably with the long-term use of antibiotics; however, there seems to be an increased risk of fungal colonization and infection. Accordingly, the use of amphotericin drops has been advocated in addition to monthly topical povidone-iodine in the postoperative care routine to decrease the risk of infection.15 Topical prednisolone acetate is used in the perioperative period. This regimen is the same for a standard cataract procedure: start with 4 times daily and taper to 1 drop/week. Systemic steroids can be considered in patients with preexisting autoimmune disorders or ocular inflammation.

Outcomes The Multicenter Boston Type I Keratoprosthesis Study was the first multicenter study of this device.17 Preoperative best corrected visual acuity (BCVA) ranged from 20/100 to light perception, and 96% of eyes had vision worse than 20/200. At an average follow-up of 8.5 months, BCVA was 20/200 or better in 56% of eyes and 20/40 or better in 23% of eyes, with graft retention at 95%.17 Aldave et al18 showed 90% of eyes (N = 50) with vision worse than 20/200 prior to surgery and 82% had vision better than 20/200 with 17 months of follow-up; retention rate in this series was 84%. The University of California, Davis reported similar results with a much longer follow up of nearly three years.19 As previously discussed, many studies have shown that eyes with prior transplant failure from noncicatricial causes have the best prognosis, whereas patients with Stevens-Johnson syndrome have the worst prognosis.3,4,9,17,18,20,21 Limitations to success are often secondary to postoperative complications, which will be discussed later. Recently, interest has centered on the Boston KPro as a primary modality for select patients with a poor prognosis for PK. Kang et al 21 reported a BCVA of 20/200 or higher in 71.4% (n = 15) of eyes and 20/50 or higher in 19% (n = 4) of eyes. Average follow-up in this group was 14.6 months. Postoperative complications were comparable with those of the Multicenter Boston Type I Keratoprosthesis Study.17 Patients included those with limbal stem cell deficiency secondary to chemical/thermal injury, aniridia, and Stevens-Johnson syndrome. Other preoperative diagnoses included gelatinous drop-like dystrophy, herpetic keratitis, corneal scarring from infectious keratitis, ocular cicatricial pemphigoid, and trachoma. Poorest outcomes occurred in those with chemical burns and cicatricial disease, as was found in previous studies.3,4,9,17,18,20,21

Complications Each follow-up examination should include specific routine steps. Slit-lamp examination should include particular attention to the ocular surface, the posterior plate of the PMMA cylindrical stem for retroprosthetic membrane, and the anterior chamber for vitreous cells. A Seidel test should be performed to look for corneal melt or wound leak. Tactile pressure should be routinely checked.

Retroprosthetic Membrane Retroprosthetic membrane is one of the most common postoperative findings in patients with the Boston KPro. Although the incidence of membranes has decreased since the development of the titanium back plates, they are still common and should be checked for routinely. The membranes have been shown to originate from the host’s corneal stroma, suggesting stromal downgrowth as a possible etiology.22 Rates of formation have been reported to range from 25% to 65%.17,18,22 When diagnosed early, it is easy to treat the membrane with Nd:YAG laser. It is recommended not to use more than 1.2 mJ of laser energy to prevent damage to the stem. It is common for these membranes to recur, and early detection and treatment facilitates management. After the laser procedure, topical corticosteroids 4 times daily with a weekly taper is usually used

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to minimize inflammation and reduce the recurrence rate. If the membrane is too thick, surgical removal with vitrectomy and membranectomy can be considered.

Persistent Epithelial Defects Aldave et al18 reported an incidence of persistent epithelial defects in 19 (38%) of 50 eyes, more than half of which were in patients with limbal stem cell deficiency. Most of these eyes had a donor corneal epithelial defect present on postoperative day 1 and failed to resolve within 3 weeks. The source of defects included a dellen effect from elevation of the edge of the anterior plate and an infectious etiology, both bacterial and fungal. Additionally, antimicrobial coverage for positive cultures, bandage contact lens use, or lateral tarsorrhaphy was found to be helpful.18

Glaucoma Both the development of de novo glaucoma and the progression of underlying glaucoma are serious issues in this patient population. Glaucoma is a common long-term complication of patients receiving the Boston KPro, with incidences ranging from 14% to 28%.23-25 Similar studies have reported the prevalence of glaucoma in patients receiving a prosthetic to be as high as 76%.23-25 It has been suggested that angle closure is the mechanism responsible for elevated pressure; topical medications may also play a role in steroid responders in addition to chronic low-grade inflammation.23-25 Accurate assessment of intraocular pressure is compromised by the presence of the PMMA plates of the prosthetic. However, studies have shown that palpation by an experienced surgeon can be reliable in detecting pressures above 30 mm Hg and within 5 mm Hg.26-28 Management of glaucoma in patients with the Boston KPro is challenging. Given the presence of the PMMA plates, there is less corneal surface area for penetration of topical drops, and they tend to be less effective. Additionally, the marked progression of angle closure makes topical management limitedly effective. The threshold for surgical intervention is lowered in this population. Appropriate management begins preoperatively in the assessment of existing glaucoma. Surgeons should consider a glaucoma drainage device or cyclophotocoagulation intraoperatively for any patient with underlying glaucoma. In the setting of advanced glaucoma, some advocate staged surgical procedures for glaucoma prior to placing the Boston KPro.23 In all patients with a Boston KPro, close attention should be paid to checking the pressure and monitoring the optic nerve because glaucoma is the most common, permanent, and preventable blinding sequelae of Boston KPro placement.

Infectious Keratitis and Endophthalmitis Although historically higher, the incidence of bacterial endophthalmitis has been nearly eliminated with the chronic use of topical antibiotic drops. However, with the advent of chronic antibiotic use and soft contact lens use in the postoperative management of patients with the Boston KPro, the presence of fungal colonization has been shown to be increased.16,29 Barnes et al 29 and Aldave et al18 demonstrated growth of Candida parapsilosis, which has been shown to have a propensity to adhere to prosthetic materials.30 As previously discussed, the use of amphotericin drops in patients with positive fungal cultures or routine monthly povidone-iodine drops in the clinic may help to reduce infection rates.15,31

Retinal Detachment The incidence of retinal detachment has been reported to be 12% in 2002 and 3.5% in 2006 in the Multicenter Boston Type I Keratoprosthesis Study.17 This may be due to a shorter follow-up in the study or to changes in the procedure or prosthetic design.32

Conclusion The Boston KPro seems to be a viable option in patients with multiple failed corneal grafts and in certain patients as a primary surgical modality. Marked modifications have reduced the historically acute complications related to keratoprosthesis implantation. A focus on the management of chronic comorbidities like glaucoma will help improve long-term visual outcomes with this device.

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A proper understanding of appropriate patient selection and postoperative management will help optimize outcomes and rehabilitate vision in many patients blinded by advanced corneal disease.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

Ament JD, Stryjewski TP, Ciolino JB, Todani A, Chodosh J, Dohlman CH. Cost-effectiveness of the Boston keratoprosthesis. Am J Ophthalmol. 2010;149(2):221-228.e2. Aquavella JV, Gearinger MD, Akpek EK, McCormick GJ. Pediatric keratoprosthesis. Ophthalmology. 2007;114(5):989-994. Yaghouti F, Nouri M, Abad JC, Power WJ, Doane MG, Dohlman CH. Keratoprosthesis: preoperative prognostic categories. Cornea. 2001;20(1):19-23. Ciralsky J, Papaliodis GN, Foster CS, Dohlman CH, Chodosh J. Keratoprosthesis in autoimmune disease. Ocul Immunol Inflamm. 2010;18(4):275-280. Yildiz EH, Saad CG, Eagle R, Ayres BD, Cohen EJ. The Boston keratoprosthesis in 2 patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Cornea. 2010;29(3):354-356. Colby KA, Koo EB. Expanding indications for the Boston keratoprosthesis. Curr Opin Ophthalmol. 2011;22(4):267-273. Traish AS, Chodosh J. Expanding application of the Boston type I keratoprosthesis due to advances in design and improved post-operative therapeutic strategies. Semin Ophthalmol. 2010;25(5-6):239-243. Dohlman CH, Harissi-Dagher M, Khan BF, Sippel KC, Aquavella J, Graney JM. Introduction to the use of the Boston Keratoprosthesis. Expert Rev Ophthalmol. 2006;1:41-48. Magalhães FP, Sousa LB, Oliveira LA. Boston type I keratoprosthesis: review. Arg Bras Oftalmol. 2012;75(3):218-222. Dohlman CH, Abad JC, Dudenhoefer EJ, Graney JM. Keratoprosthesis: beyond corneal graft failure. In: Spaeth GL, ed. Ophthalmic Surgery: Principles and Practice. 3rd ed. Philadelphia, PA: WB Saunders; 2002:199-207. Gomaa A, Comyn O, Liu C. Keratoprostheses in clinical practice—a review. Clin Experiment Ophthalmol. 2010;38(2):211-224. Khan BF, Harissi-Dagher M, Khan DM, Dohlman CH. Advances in Boston keratoprosthesis: enhancing retention and prevention of infection and inflammation. Int Ophthalmol Clin. 2007;47(2):61-71. Dohlman CH, Dudenhoefer EJ, Khan BF, Morneault S. Protection of the ocular surface after keratoprosthesis surgery: the role of soft contact lenses. CLAO J. 2002;28(2):72-74. Harissi-Dagher M, Beyer J, Dohlman CH. The role of soft contact lenses as an adjunct to the Boston keratoprosthesis. Int Ophthalmol Clin. 2008;48(2):43-51. Magalhães FP, do Nascimento HM, Ecker DJ, et al. Microbiota evaluation of patients with a Boston type I keratoprosthesis treated with topical 0.5% moxifloxacin and 5% povidone-iodine. Cornea. 2013;32(4):407-411. Durand ML, Dohlman CH. Successful prevention of bacterial endophthalmitis in eyes with the Boston keratoprosthesis. Cornea. 2009;28(8):896-901. Zerbe BL, Belin MW, Ciolino JB; Boston Type 1 Keratoprosthesis Study Group. Results from the multicenter Boston Type 1 Keratoprosthesis Study. Ophthalmology. 2006;113(10):1779.e1-7. Aldave AJ, Kamal KM, Vo RC, Yu F. The Boston type I keratoprosthesis: improving outcomes and expanding indications. Ophthalmology. 2009;116(4):640-651. Greiner MA, Li JY, Mannis MJ. Longer-term vision outcomes and complications with the Boston Type 1 keratoprosthesis at the University of California, Davis. Ophthalmology. 2011;118(8):1543-1550. Bradley JC, Hernandez EG, Schwab IR, Mannis MJ. Boston type 1 keratoprosthesis: the University of California Davis experience. Cornea. 2009;28(3):321-327. Kang JJ, de la Cruz J, Cortina MS. Visual outcomes of Boston keratoprosthesis implantation as the primary penetrating corneal procedure. Cornea. 2012;31(12):1436-1440. Stacy RC, Jakobiec FA, Michaud NA, Dohlman CH, Colby KA. Characterization of retrokeratoprosthetic membranes in the Boston type 1 keratoprosthesis. Arch Ophthalmol. 2011;129(3):310-316. Banitt M. Evaluation and management of glaucoma after keratoprosthesis. Curr Opin Ophthalmol. 2011;22(2):133-136. Netland PA, Terada H, Dohlman CH. Glaucoma associated with keratoprosthesis. Ophthalmology. 1998;105(4):751-757. Rivier D, Paula JS, Kim E, Dohlman CH, Grosskreutz CL. Glaucoma and keratoprosthesis surgery: role of adjunctive cyclophotocoagulation. J Glaucoma. 2009;18(4):321-324. Baum J, Chaturvedi N, Netland PA, Dreyer EB. Assessment of intraocular pressure by palpation. Am J Ophthalmol. 1995;119(5):650-651.

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27. Birnbach CD, Leen MM. Digital palpation of intraocular pressure. Ophthalmic Surg Lasers. 1998;29(9):754-757. 28. Rubinfeld RS, Cohen EJ, Laibson PR, Arentsen JJ, Lugo M, Genvert GI. The accuracy of finger tension for estimating intraocular pressure after penetrating keratoplasty. Ophthalmic Surg Lasers. 1998;29(3):213-215. 29. Barnes SD, Dohlman CH, Durand ML. Fungal colonization and infection in Boston keratoprosthesis. Cornea. 2007;26(1):9-15. 30. Panagoda GJ, Ellepola AN, Samaranayake LP. Adhesion of Candida parapsilosis to epithelial and acrylic surfaces correlates with cell surface hydrophobicity. Mycoses. 2001;44(1-2):29-35. 31. Chew HF, Ayres BD, Hammersmith KM, et al. Boston keratoprosthesis outcomes and complications. Cornea. 2009;28(9):989-996. 32. Ray S, Khan BF, Dohlman CH, D’Amico DJ. Management of vitreoretinal complications in eyes with permanent keratoprosthesis. Arch Ophthalmol. 2002;120(5):559-566.

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14 Modified Osteo-Odonto-Keratoprosthesis Giancarlo Falcinelli, MD; Paolo Colliardo, MD; Giovanni Falcinelli, MD; Andrea Gabrielli, MD; and Maurizio Taloni, MD Keratoprosthesis is a surgical technique that can restore vision in eyes with opaque vascularized corneas (Figures 14-1 and 14-2) and eyes with major ocular surface alterations. Ocular surface changes may partially or totally affect the conjunctiva, stem cells, and eyelids with symblepharon, ankyloblepharon, dry eye, and sometimes loss of periocular tissues. In 1964, Strampelli introduced osteo-odonto-keratoprosthesis.1,2 Later, Falcinelli3,4 changed the original technique into modified osteo-odonto-keratoprosthesis (MOOKP), and this has been performed successfully in eyes with ocular surface problems.

Keratoprosthesis Types Keratoprostheses differ from each other in the different haptics that are used to join the optical part to the eye’s anterior segment. They are classified as biocompatible, biointegrated, or biological.

Biocompatible The haptic is made of synthetic material, with polymethylmethacrylate (PMMA) being the most commonly used and well tolerated by the human body in deep implants. Types I and II Boston or Dohlman-Doane keratoprostheses5,6 are commonly used.

Biointegrated The haptic, always synthetic, is put in contact with ocular or periocular tissues to be biointegrated.

Biological Since 1973, we have been using the biological keratoprosthesis prepared with Strampelli’s osteodental lamina, with its haptic made of biological, living human material, removed from the blind patient and therefore perfectly tolerated, or from highly biocompatible blood relations.

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Figure 14-1. Pemphigoid.

Figure 14-2. Chemical burn.

Figure 14-3. Osteodental lamina.

Modified Osteo-Odonto-Keratoprosthesis Surgical Technique The MOOKP is made of a 2.5- to 3-mm-thick, 14- to 16-mm-long, and 9- to 10-mm-high lamina removed from the blind patient by a monoradicular tooth (Figure 14-3). One of the 2 surfaces of the lamina (Figures 14-3 and 14-4) is made of alveolar bone only, whereas the other

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Figure 14-4. Applied anatomy of the tooth in MOOKP.

Figure 14-5. MOOKP OOAL.

is mainly made of dentin surrounded by bone. The hole for the optic cylinder is perpendicular to the pulp channel in the osteo-ondonto-acrylic lamina (OOAL) (Figure 14-5). MOOKP surgery is performed in 2 fundamental stages in 3-month intervals, with a smaller additional intermediate intervention performed 1 month after the first stage. The 2 stages, plus the short intermediate stage, represent our latest modification to Strampelli’s original technique to make the last stage safer. The stages are as follows: • First stage ° Preparing the anterior surface of the eye ° Preparing the anterior segment of the eye ° Removing the monoradicular tooth root ° Preparing the OOAL • Intermediate stage ° Covering the blind eye with buccal mucosa • Second stage ° Implanting the OOAL in the eye (implanting the prosthesis)

First Stage Preparing the Anterior Surface of the Eye At a conjunctival level, even in the presence of light alterations (hyperemia or poor fibrotic and/ or degenerative phenomena), a complete and irreversible involvement of the stem cells is always

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observed. In the majority of cases, fibrotic-degenerative phenomena are evident and complicated by serious ocular dryness. The conjunctiva may look thickened, and a partial or complete symblepharon, and sometimes an ankyloblepharon, may be present. If the cornea is free from conjunctiva and fibrotic tissues, it is advisable to perform a peritomy horizontally, extending to the medial and lateral canthi. On the contrary, if the cornea is covered by conjunctiva, cicatricial, and/ or fibrotic tissue, the conjunctiva must be incised at the intermediate point between the 2 eyelids, following the palpebral edges. The incision between the 2 eyelids is performed even in the presence of a total symblepharon. After the peritomy or the horizontal incision has been performed, both the cornea and the sclera are laid bare by delicately detaching—toward the upper and lower fornices—the possible conjunctival or palpebral fibrotic and/or degenerated tissue covering the ocular surface and by removing those parts that may be more thickened and/or degenerated, requiring repair with sutures. Then, a Flieringa ring is applied over the sclera.

Preparing the Anterior Segment of the Eye Once the Flieringa ring is positioned, the anterior chamber is opened at the upper limbus, and after the iris has been cleared of possible anterior and/or posterior synechiae and the retro corneal or retro iridal inflammatory membranes removed, the iris can be taken off. The iris is peripherally grabbed at 12 o’clock with a toothless forceps. To avoid excessive traction, after the first dialysis with traction from above, the iris is grabbed at 9 and/or 3 o’clock and carefully pulled to the bottom first and then to the top while totally detaching the iris from the ciliary body. At this stage, bleeding generally occurs; however, prolonged (5 to 10 minutes) washing with low-temperature balanced salt solution is generally sufficient, and there is no need to use diathermy forceps or thermocautery. The anterior chamber’s opening must be slightly larger than 180 degrees to allow for opaque or transparent lens cryoextraction. It is better to avoid extracapsular cataract extraction or phacoemulsification because, in the presence of an opaque cornea, visibility is often incomplete. We use an anterior vitrectomy with a high-cut frequency, moderate aspiration, and no balanced salt solution infusion. Once the anterior vitrectomy up to the ora serrata is completed, the cornea—whose sutures with separate stitches (7-0 Vicryl; Ethicon, Inc) have already been prepared and moved to the sclera—is quickly closed, and some air or liquid is immediately introduced, normalizing the intraocular pressure (IOP). The Flieringa ring is removed, and the cornea and sclera are covered with the previously detached conjunctival or pseudoconjunctival tissue. If the conjunctival and/or pseudoconjunctival tissue is not sufficient, then the eyelids are sutured either partially or completely until the eye is covered, even by a tarsorraphy, leaving some space at the temporal canthus for medications.

Removing the Monoradicular Tooth Root A monoradicular tooth root is used because to help the prosthesis survive for as long as possible, it is necessary to use a lamina with the largest surface of dentin and the greatest quantity of bone surrounding it. The upper canine is considered the most eligible tooth. If this tooth is not available, the next most eligible, in descending order, are the lower canines, the upper second premolars, any of the 2 upper incisive teeth, the first and second lower premolars, the first upper premolars, and the lower incisive teeth. Preliminary radiography is necessary, including an orthopantomogram of both the upper and lower dental arches and an endo-oral radiograph of the single tooth to be removed. Performing a dental scan with spiral computed tomography provides all information necessary (ie, length, thickness, sizes of the various structures and possible root, and surrounding bone pathologies) to find the most eligible tooth.7 Before the chosen tooth is removed, 2 lines are traced over the gingival vestibular mucosa with diathermy all along the tooth’s axis to mark the boundary of the alveolar interdental bone portion to be removed with the tooth. All the soft tissues are incised along these 2 lines up to the alveolar bone. The canine tooth gum’s vestibular portion, already delimited by the parallel lines and covering the half of the tooth closest to the apex, is detached by scissors millimeters beyond the tooth apex. A small quantity of connective tissue adhering to the alveolar bone just next to the canine tooth is left in place as a protection to its periosteum, and the detached edge of the gum is hooked through a retractor and moved upward. With a high-frequency-cut oscillating saw, a cut is

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made with an appropriately angled blade perpendicular to the tooth axis and localized beyond the dental apex. Afterward, with the same oscillating saw equipped with a fan-shaped straight blade, 2 cuts are made longitudinally and parallel to each other and to the pulp’s canal corresponding to the former diathermies and soft tissues incisions to facilitate removal of the osteodental block, including the whole dental root and as much of the surrounding bone as possible. It is important that a low-temperature balanced salt solution jet continuously washes the removal area because the high temperature generated by the high-frequency cut may damage the alveolar bone components, especially the alveolar-dental ligament. Once the osteodental unit is dissected, the soft tissues’ residuals must be cut off, avoiding traction and lever movements. No repair surgery is needed, except for putting in one stitch on the detached mucosal edge by the tooth’s gum and fixing it to the palatal mucosa from which the tooth was detached.

Preparing the Osteo-Odonto Acrylic Lamina The dental crown is disinfected with 10% povidone solution as it is cleared from the mucous tissue covering it and from most of the soft tissues. The 2 cut surfaces of the osteodental block are examined, and the one with the largest amount of alveolar bone will be saved during the first stage of osteodental block creation. The surface of the osteodental block with the smallest bone is manufactured by a sharp-edge, diamond-surface circular milling cutter installed on a dentist drill until the pulp’s channel is reached, while continuously irrigating with low-temperature balanced salt solution to avoid the harmful rise in temperature generated by the milling cutter. The pulp’s channel is cleared of the neurovascular bundle, and the dentin’s surface is smoothed by the milling cutter. Any extra alveolar bone causing a greater laminar thickness than intended will be removed from the lamina’s surface that was saved at the beginning of the procedure until an approximately rectangular lamina with the size previously indicated is obtained. Before the extra bone is removed from the apical end, the periosteum is detached and brought toward the tooth’s crown and, after the bone cut, will be moved back to its initial location and used to cover the part of alveolar bone that is lacking it. The periosteum will be reattached with biological glue,8 a device that was not used in Strampelli’s original technique.2 The biological glue is also used to reattach the periosteum that might have been accidentally removed from the alveolar bone during the lamina’s preparation. We now have an osteodental lamina with one of its surfaces completely made of bone and the other almost totally made of dentin (see Figure 14-5). In the contact area between the bone and the dentin stands the alveolar-dental ligament (see Figure 14-5) which, as we will see later, will give adhesion to the buccal mucosa’s epithelium covering the prosthesis. In rare cases where, due to edentulia or advanced periodontosis, it is not possible to remove an osteodental lamina and we take advantage of the union of 2 laminae obtained by 2 teeth removed from the same patient. However, in cases where the union of 2 laminae cannot be used, we use a tooth removed from a histocompatible blood relation. We use cyclosporine per os, beginning before the tooth removal and continuing during the first few months after the prosthesis is implanted. These are 2 additional innovations to Strampelli’s technique that we have used in just a few cases, but we know that in these particular conditions, the survival of the prostheses is shorter. Prepared in this way, the lamina still needs to be perforated to allow the optic cylinder to be inserted and fastened to it. To that end, the lamina must be positioned perfectly horizontal with its dentin surface facing up and held up by the dentist forceps while the drill’s handpiece is kept perfectly perpendicular to the lamina to avoid tilting the optic cylinder and possibly decentering the visual field. To avoid this event, our colleagues at Bascom Palmer Eye Institute (Miami) are studying a specific device. The hole in the lamina is made by using a spherical, rotating milling cutter whose diameter is reduced, and it is completed through the use of a conic diamond milling cutter until the desired diameter is reached. The hole is not located at the geometrical center of the lamina and can be moved even 1 to 2 mm toward the dental crown, where the dentin’s surface is larger. In between the hole made on the dentin for the optic cylinder and the alveolar bone surrounding it, a dentin surface of at least 1.5 mm must remain, and, if at all possible, the hole should be decentered to the

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side where the bone’s surface is larger (palatal side) so the smaller dentin side may coincide with the side with more bone in an attempt to prevent possible laminar reabsorption.

Features of the Optic Cylinder The features of the PMMA optic cylinder inserted into the osteodental lamina’s hole and sealed to it through biocompatible resin are as follows: • The total average length of the optic cylinder used for MOOKP is 8 to 8.2 mm. The anterior part is longer (6 to 6.2 mm), whereas the posterior part is shorter (1.90 to 2 mm). • The average extraocular diameter (diameter of the cylinder’s anterior part located inside the lamina’s hole and outside the eye) is approximately 3.65 mm (range, 3.50 to 3.85 mm). • The average intraocular diameter (diameter of the cylinder’s internal part located beyond the lamina’s hole and inside the eye) is approximately 3.90 mm (range, 3.70 to 4 mm). The difference between the 2 diameters produces a step allowing the cylinder’s intraocular part to adhere to the lamina’s posterior side, which is chiefly made of dentin. • In Strampelli’s OOKP procedure, 2 the average bending radius of the convex extraocular surface was 16 mm, and the average bending radius of the convex intraocular surface was 6.5 mm. The PMMA refraction rate was 1.49 (unit of measurement nD 20). The optic cylinder’s equivalent power was 50 to 51 diopters. To perform the MOOKP procedure, we use personalized optic cylinders, representing a further modification to Strampelli’s technique. The bending radii are set up on the basis of the eye’s axial length to obtain refraction close to emmetropy.

Fastening the Optic Cylinder The osteodental lamina and the optic cylinder are carefully dried. The biocompatible acrylic resin, which is used to join the optic cylinder to the lamina, is prepared. A small quantity of acrylic resin powder is blended with some drops of solvent until a semiliquid preparation is obtained, which is kept stable by adding 1 drop of solvent every 1 or 2 minutes. The optic cylinder is held up with its posterior edge mounted over a small rubber tube, which blocks it and allows it to be operated when necessary. The resin is spread with a small spatula approximately 2 to 3 mm on the posterior edge of the optic cylinder’s anterior segment. The cylinder previously treated with semiliquid resin is immediately inserted into the lamina’s hole on the dentin side and pushed against the dentin surface on which the posterior edge’s step will stop, and the rubber support is taken off. The resin, which will grow hard in a few minutes, is pressed with a spatula around the optic cylinder’s hole while the exceeding resin is removed from the lamina’s alveolar-dental ligament and bone with a suitable blade; it is toxic to the tissues at the moment of solidification. The OOAL obtained in this way is ready to be inserted into a subcutaneous pocket located in the orbital-zygomatic area, just beneath the nonoperated eye, for an average of 3 months (range, 2.5 to 3.5 months). The subcutaneous pocket is prepared by horizontally incising the skin, subcutaneous, and muscle layers of the nonoperated eye’s lower orbital profile and detaching tissue right below the muscle layer to obtain an approximately 3.0-cm-wide pocket. Once hemostasis has been verified, the OOAL is inserted with its dentin surface facing the pocket’s floor to facilitate the vascularization of the bone side that is facing upward. As soon as a small quantity of antibiotic powder is placed, the deep muscle and superficial cutaneous layers are sutured. A small drain tube is used only if the preparation of the lamina proved difficult and/or the pocket has been bleeding for a long time. Postoperatively, broad-spectrum antibiotics are administered for 7 days. After 4 or 5 days, the drainage, if used, is removed, and the sutures are removed after 8 or 10 days.

Intermediate Stage During this short surgery, the buccal mucosa is put on the anterior surface of the blind eye. The often fibrotic or degenerated conjunctiva is opened by a horizontal cut equidistant from both eyelids and detached from the cornea and sclera, removing the underlying cicatricial, fibrous, or degenerative tissue, if any, up to the recti muscles’ insertions. In the presence of a symblepharon

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and/or ankyloblepharon, the tarsal surface must be carefully detached from the cornea, starting with a horizontal incision at the point where the 2 palpebral edges join together. Separation of the tarsal surface from both the cornea and sclera up to the recti muscles’ insertions is performed. The recti muscles are secured with 5-0 silk stitches to pull the eye when the mucosa is sutured or for any other surgical maneuvers. Hemostasis should be maintained as much as possible by avoiding damage to the episcleral vessels. Intraoperatively, the operating field should be washed often with a broad-spectrum antibiotic solution. Later, a keratectomy is performed, including Bowman’s layer. This maneuver represents a further modification of Strampelli’s technique, which used decortication to remove only the corneal epithelium with a scarifier. The removal of Bowman’s layer helps the corneal vascularization, which is beneficial to the vitality and trophism of both the cornea and the buccal mucosa that is going to cover it. During keratectomy, the conditions of the cornea are evaluated; in the event of a previous corneal perforation or the development of one at the start of surgery, and/or in the presence of a descemetocele, we perform a lamellar or penetrating keratoplasty. In the presence of major corneal thinning and a scarcely vascularized cornea, we take advantage of Tenon’s edges, moved forward to thicken the thinned corneal surface. Removal of the necessary buccal mucosa takes place after disinfection of the oral cavity and all of its recesses with 10% iodopovidone. The cheek mucosa will be removed because it is thicker and more abundant than the labial mucosa used by Strampelli. Removal is performed with a round hemostatic plaque we designed with the lower edge just slightly flattened, with an average 4-cm inner diameter. The plaque is positioned as close as possible to the mouth’s floor and not too close to the labial commissure to prevent any possible intraoperative involvement of Stensen’s duct or the commissure itself. Removal must be performed by cutting the buccal mucosa up to the muscular layer, which must be respected. The thickness must be approximately 1.50 to 2 mm. Hemostasis may have to be performed with diathermy, but the application of single sutures is seldom necessary. After its removal, the mucosa is plunged into a broad-spectrum antibiotic solution, and the bloody surface is regularized by removing any extra adipose or muscular tissues. The mucosa is laid on the ocular surface, and the edge is sutured with 6-0 Vicryl by the upper rectum muscle’s tendon. The other stitches are put in the intermediate spaces between one muscle’s tendon and the next, at the same distance from the cornea, starting by the upper sector. The sutured mucosa must not be crinkled or stretched. The anterior surface of the eye is usually covered up to the muscular insertions. The lower temporal sector of the buccal mucosa is sutured last because if the mucosa is too large, as often happens, it is necessary to remove a small triangle, the external base, of the mucosa itself. The edges of incised mucosa are sutured between them. The free edge of the conjunctiva or pseudobulbar conjunctiva that had been initially detached from the eye up to the muscular insertions is now sutured with separate stitches along the mucosa’s edge that was sutured to the sclera.

Second Stage The second stage occurs 3 months after the first stage. Once the operating field has been disinfected with 10% iodopovidone, the surgeon removes the OOAL surrounded by a soft tissues layer from the subcutaneous orbital-zygomatic pocket and gives it to another surgeon to prepare the implant while the first surgeon prepares the eye to receive the osteodental lamina. Four traction stitches are put in, 2 on each eyelid edge. A large lateral cantotomy is performed. Once the eye has been turned downward, the buccal mucosa is along a horizontal line located 2 mm in front of the junction between the conjunctiva and mucosa. The buccal mucosa is detached, keeping in mind that the mucosa itself must cover not only the OOAL but also the fibrous tissues surrounding it. The mucosa is then detached from top to bottom to at least 3 to 4 mm beyond the lower limbus, where the lamina will have to be accurately sutured. A Flieringa ring able to contain the OOAL is inserted. Four scleral stitches are put in place (6-0 Vicryl at 3, 6, 9, and 12 o’clock) using a paper template of the lamina. Three more stitches are placed 5 to 6 mm from the center on the cornea (7-0 silk at 5, 7, and 12 o’clock) to keep the corneal hole open when the posterior end of the lamina’s optic cylinder is introduced. Meanwhile, the OOAL is prepared by removing all the fibrous tissues present on the

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Figure 14-6. MOOKP 15 days after implantation.

side, mainly made of dentin, except for 1 mm of tissue along its edges. It is necessary to leave a thin fibrous tissue layer (approximately 1.50 mm) over the bone’s surface opposite the dentin side. It will be used to hook the sutures that will join the OOAL to the eye’s anterior surface while maintaining the acrylic cylinder well centered over the macula, the optic disc, and the temporal vascular arcades. The center of the cornea is marked using transillumination, and corneal trephination is performed with a drill the same size as the optic cylinder’s posterior edge, with the cut completed with a curved microscissors if necessary. Assistants hold the Flieringa ring and the corneal stitches are put in at 5 and 7 o’clock; the surgeon takes the 12 o’clock stitch with one hand while holding the OOAL mounted on forceps with the other hand. Once the optic cylinder’s posterior portion is introduced into the corneal hole and the lamina has been leaned on the eye, the surgeon passes the previously placed sutures on the OOAL’s bone surface. As the first 4 predisposed stitches are fixed, some air or balanced salt solution is introduced into the anterior chamber to reestablish the IOP. More sutures are added (2 along the long sides, 1 along the short sides) while constantly controlling the optic cylinder’s centering through a binocular ophthalmoscope. Once the OOAL is definitely fastened, the eye is covered with the buccal mucosa that was previously detached and turned downward (separate 6-0 Vicryl stitches) and, before the last sutures from 10 to 2 o’clock are put in, trephination of the mucosa is performed to let the optic cylinder out. The last few sutures are put on the buccal mucosa. At the conclusion of the procedure, a broad-spectrum antibiotic ointment is abundantly applied to the buccal mucosa. The patient is kept in bed, without or with just one pillow, until any air that was introduced is completely reabsorbed (approximately 4 to 6 days). In addition to local and systemic antibiotic therapy, ocular hypotoning therapy is administered systemically (eg, acetazolamide or osmotics) to prevent a possible postoperative IOP increase. The patient undergoes these therapies from postoperative day 1, and his or her visual recovery, which is generally immediate, is checked after the ointment residuals have been removed from the optic cylinder’s surface and the patient has been positioned in the best way to let air out of his or her optical axis. As soon as the air has reabsorbed, the patient may leave the hospital while continuing to take antibiotics and hypotonizing drugs until the mucosal stitches are removed (15 days postoperatively) (Figure 14-6). After 30 days, a cosmetic shield can be used. (Figure 14-7)

Falcinelli’s Modifications to Strampelli’s Technique The following 13 modifications have been made to improve functional results and keratoprosthesis survival: 1. Increase in the cylinder’s diameter and biometrical calculation of the optical power 2. Total removal of the iris 3. Cryoextraction of the opaque or transparent lens 4. Anterior vitrectomy 5. Use of biological glue to reattach the periosteum if it is damaged 6. Lamellar keratectomy, including Bowman’s layer

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Figure 14-7. MOOKP with cosmetic shield 45 days after implantation.

7. 8. 9. 10. 11. 12. 13.

Use of cheek mucosa that is thicker and larger than the labial mucosa Conjunction of 2 osteodental laminae if one of them has too small of a surface Use of impacted teeth Use of blood relations’ teeth Use of the Eckardt temporary prosthesis (DORC) in retinal detachment Double-thread cyclodiastasis with single sclerotomy (refractory glaucoma) Posterior drainage tube (refractory glaucoma) substituted by the Ahmed Glaucoma Valve (New World Medical, Inc) The first 4 modifications are fundamental. 1. An increase in the optical cylinder’s diameter to enlarge the visual field (not larger than 4 mm) avoids retroprosthetic membranes or infections. The biometrical calculation of the optical power is necessary to obtain a refraction that may be emmetropic. 2. Total removal of the iris avoids all iris pathologies. 3. Cryoextraction of the opaque or transparent lens is performed because in Strampelli’s original technique, lens extraction required a further surgery, and the presence of the lens may cause uveitis or phacoanaphylaxis from the risk of contact of the optic cylinder with the lens. 4. An open-sky vitrectomy of approximately 1.5 cc is performed to prevent vitreal adherences and consequent vitreoretinal tractions.

Visual Field in the Modified Osteo-Odonto-Keratoprosthesis MOOKP surgery allows patients to live an autonomous life, to work, and, in some cases of formerly blind patients operated in both eyes, to obtain a driver’s license. The largest visual field in our cases are obtained via the following: • Enlarging the diameter of the optic cylinder’s anterior segment, which is usually 3.5 to 3.8 mm • Reducing the cylinder’s total length, which is usually 8.2 to 8 mm • Increasing the bending radius of the same cylinder’s posterior surface, from 3.21 mm for an axial length of 20 mm to 4.98 mm for an axial length of 25 mm. The anterior surface’s bending radius remains the same (20 mm) We put all the elements that provided the largest visual field together in the same cylinder and obtained a visual field that was the same in all quadrants (ie, 40 degrees concentric). In another cylinder, we put all the elements providing the narrowest visual field and obtained a visual field

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Figure 14-8. Visual field in MOOKP.

Figure 14-9. Histology shows adhesion between buccal mucosa epithelium and alveolar ligament.

4 degrees narrower than the previous one. We concluded that with the MOOKP, if no special pathology is present, the visual field is between 40 and 36 degrees concentric (Figure 14-8).

Biological Properties of Strampelli’s Osteodontal Lamina In Strampelli’s OOKP,9 the most important biological property is the ability of the anterior chamber’s epithelial seal to prevent infection. The seal is obtained from the epithelium of the buccal mucosa covering the prosthesis and joining the alveolar dental ligament, dentin, and alveolar bone. This is similar to what happens inside the mouth, where the epithelium of the gingival mucosa joins the alveolar dental ligament of the tooth neck, creating an epithelial seal capable of defending the tooth against infection.9-11 The epithelial seal can be seen in the image by Strampelli (Figure 14-9) that shows the result of histological research: the mucosal epithelium covering the prosthesis does not stand around the cylinder to which it cannot adhere, but it joins the alveolar dental ligament at the same point at which the cylinder and lamina are united.

Complications During and After Treatment With the Modified Osteo-Odonto-Keratoprosthesis Blind patients previously operated on by surgeons at various hospitals that present to us to undergo our surgical procedure often need further surgeries for reconstructive techniques of the eye or of the adnexe and pathologies like glaucoma or retinal detachment. Complications should not be surprising in eyes that have undergone all operations in a short period of time. Twenty-one intraoperative complications have occurred, including fractures of the dental arches, damaged teeth, corneal perforations, and hemovitreous; they were all cured. Eleven

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postoperative complications have occurred after the first surgical stage, including lamina infections, lamina reabsorption, and retinal and choroidal detachments; they were all cured. Six postoperative complications have occurred after the intermediate surgical stage, all alterations of the buccal mucosa; they were all cured. After the last stage, there were 28 prosthesis complications; 26 were cured, including 20 alterations of the buccal mucosa, and 2 were not cured, including one optic cylinder expulsion and one prosthesis expulsion. Forty-three complications also occurred in the eye after the last stage, the most important of which were not cured (n = 17), including endophthalmitis and retinal detachment. One hundred eight of our patients already suffered from glaucoma when they presented. Some had already been healed by surgical treatment, and others were undergoing pharmacological treatment. However, before we started treatment, all patients’ endo-ocular pressures were set, either surgically or by means of pharmacological treatment. Glaucoma reappeared in 54 eyes after our procedure, in 17 as an ex novo glaucoma post-MOOKP. These complications had little influence over the results of the MOOKP procedure. Three eyes were lost due to glaucoma, and 28 of the eyes took a turn for the worse due to glaucoma but did not lose their vision. There were 15 retinal detachments among our patients: 10 were treated by pars plana vitrectomy, Eckardt keratoprosthesis, and/or encircling band and criopexy (9 were cured and one was not); one was cured by an endoscopy and pars plana vitrectomy; and 4 did not recover because they presented to us too late, and in Italy vitrectomy was not in use before 1980.

Results We operated on 292 eyes (258 patients; 29 operated in both eyes, and 5 operated twice in the same eye) between 1973 and 2011. Follow-up ranged from 6 months to 33 years (mean, 11.15 ± 7.03 years). Pathologies included dry eye (n = 124), comprising pemphigoid (n = 67), Stevens-Johnson syndrome (n = 12), Sjögren’s syndrome (n = 12), trachoma (n = 11), Lyell’s syndrome (n = 12), graftversus-host disease (n = 5), xeroderma pigmentosum (n = 3), and congenital alterations of the lids (n = 2); eyes damaged by chemical or physical burns (n = 108), including alcali, acid, fire, and boiling water; keratitis (n = 21); bullous keratopathy (n = 19); and outcomes of anterior segment surgeries (n = 20). A visual acuity ranging between 10/10 and 2/10—good enough for those patients to live an autonomous life—was obtained in 88.70% of operated eyes.12,13

Conclusion The biological properties of Strampelli’s OOKP and the surgical modifications made by Falcinelli et al12 created the MOOKP, a keratoprosthesis that can restore complete visual acuity without time limitations and with a visual field which can reach 40 degrees concentric (see Figure 14-8). The MOOKP is suitable in all cases of corneal blindness caused by any type of severe corneal injury, including opaque and vascularized corneas; seriously damaged anterior eye surfaces, including the conjunctiva, stem cells, adnexae, and eyelids; symblepharon and ankyloblepharon; and dry eye up to the last stage.

References 1. 2. 3. 4. 5. 6.

Strampelli B. Nouvelle orientation biologique dans la kératoplastie. Bull Mem Soc Fr Ophthalmol. 1964;77:145-161. Strampelli B. Osteo-odonto-cheratoprotesi. An Inst Barraquer (Barc). 1974;75:12-21. Falcinelli GC, Missiroli A, Petitti V, Pinna C. Osteo-odonto-keratoprosthesis up-to-date. Acta XXV Concilium Ophthalom. 1987;2:2772-2776. Falcinelli GC, Barogi G, Taloni M, Falcinelli G. Osteoodontokeratoprosthesis: present experience and future prospects. Refract Corneal Surg. 1993;9:193. Aldave AJ, Kamal KM, Vo RC, Yu F. The Boston type I keratoprosthesis: improving outcomes and expanding indications. Ophthalmology. 2009;116(4):640-651. Dohlman C, Harissi-Dagher M. The Boston keratoprosthesis: a new threadless design. Digital Journal of Ophthalmology. 2007;13(3). http://www.djo.harvard.edu/site.php?url=/physicians/oa/1055.

150 7. 8. 9. 10. 11. 12. 13.

Chapter 14 Monaco B, Colliardo P, D’Ambrosio F, Serra G. La scelta dell’elemento dentale per l’osteoodontocheratoprotesi. La TC dei mascellari con programma Dentascan. Atti LXXIV Congresso SOI. 1994:109-116. Falcinelli G, Colliardo P, Petitti V, Pinna C. Tissucol in surgery of the ocular anterior segment. Ophthalmology Neurosurgery. Springer-Verlag. 1986;2:98-103. Falcinelli GC, Colliardo MP, Falcinelli G, Taloni M. Biological properties of Strampelli’s OOKP and surgical improvement of Falcinelli’s modified OOKP: prevention against inflammation. Anales Instituto Barraquer. 2003;32:201-205. Ricci R, Pecorella I, Ciardi A, Della Rocca C, Di Tondo U, Marchi V. Strampelli’s osteo-odontokeratoprosthesis. Clinical and histological long-term features of three prostheses. Br J Ophthalmol. 1992;76(4):232-234. Pecorella I, Taloni M, Caselli M, et al. Histological findings in OOKPs. Anales Inst Barraquer. 1999;(28 suppl):167. Falcinelli GC, Falsini B, Taloni M, Colliardo P, Falcinelli G. Modified osteo-odonto-keratoprosthesis for treatment of corneal blindness: long-term anatomical and functional outcomes in 181 cases. Arch Ophthalmol. 2005;123(10):1319-1329. Hille K, Grabner G, Liu C, et al. Standards for modified osteoodontokeratoprosthesis (OOKP) surgery according to Strampelli and Falcinelli: the Rome-Vienna Protocol. Cornea. 2005;24(8):895-908.

15 Foldable Nonpenetrating Artificial Cornea Yichieh Shiuey, MD and Jose M. Vargas, MD The KeraKlear artificial cornea (KeraMed, Inc) is the first foldable nonpenetrating artificial cornea. Its development was funded in part by the US National Institutes of Health and National Eye Institute. The device may be implanted through a 3.5-mm incision into a partial-thickness corneal pocket. This method of implantation is significantly less invasive than other methods of artificial cornea placement, which require full-thickness incisions and possibly simultaneous corneal transplantation and glaucoma valve placement. The less invasive implantation method of the KeraKlear allows a more accelerated recovery compared with the currently available artificial corneas and penetrating keratoplasty (PK). The ability to implant the KeraKlear without penetration into the anterior chamber avoids 2 of the most serious complications of artificial cornea implantation: endophthalmitis1 and expulsive hemorrhage.2 The use of the KeraKlear artificial cornea also avoids the common complications of corneal transplantation, including high astigmatism, corneal graft failure, and corneal graft rejection. Finally, the KeraKlear enables the treatment of cornea blindness in a much larger number of patients. Currently, corneal transplantation is limited to approximately 100,000 per year worldwide because of a lack of suitable donor corneas. This represents only 1% of the estimated 10 million people worldwide who have cornea blindness in both eyes. The availability of the KeraKlear artificial cornea means that a significantly larger percentage of cornea blind patients around the world can now be treated.

KeraKlear Characteristics The KeraKlear artificial cornea is made of a proprietary biocompatible material flexible enough to be inserted through a small incision but rigid enough to provide a smooth and stable optical surface after implantation into the cornea. The device is 7 mm in total diameter and has a 4-mm-diameter central optic (Figure 15-1). The 4-mm central optic provides a full visual field for the patient and allows adequate visualization of the fundus after pupil dilation. Cataract surgery has been performed successfully after implantation of the KeraKlear.

Mechanisms of Action The KeraKlear is able to improve vision in cornea blind patients by 2 mechanisms. The first is that the KeraKlear provides a smooth optical surface at the corneal plane. In this way, the KeraKlear is similar to a rigid contact lens in that it restores the optical smoothness and regularity - 151 -

Agarwal A, John T, eds. Mastering Corneal Surgery: Recent Advances and Current Techniques (pp 151-157). © 2015 SLACK Incorporated.

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Figure 15-1. KeraKlear artificial cornea (KeraMed, Inc).

necessary for clear image formation by the cornea. This is important for the treatment of patients with limbal stem cell deficiency (LSCD), such as in cases of chemical injury. Patients with LSCD have decreased vision largely because of an irregular surface. Another example where surface irregularity causes much of the decreased vision is corneal edema. Typically, visual loss in corneal edema is profound only after epithelial edema has caused epithelial irregularity. Therefore, the KeraKlear is able to improve vision in patients with corneal edema by restoring a smooth and regular optical surface. However, corneal edema behind the KeraKlear may still limit the vision. The second mechanism by which the KeraKlear improves vision is that it replaces opaque central corneal tissue with an optically clear material. With the exception of corneal edema, most visually significant cornea opacities (eg, due to trauma or infection) reside in the anterior cornea. Therefore, implantation of the KeraKlear in the anterior half of the cornea is able to improve vision by removing most of the visually significant corneal opacities.

Method of Implantation The KeraKlear is implanted into a cornea pocket made at a constant depth of 300 μm. Because reproducibly good results with the KeraKlear depend on the precise creation of this constant depth pocket, manual corneal pocket creation is strongly discouraged for the purpose of KeraKlear implantation. It is recommended that a femtosecond laser with the capability of producing a corneal pocket as well as trephination incisions be used for the implantation of the KeraKlear. Ziemer Ophthalmic Systems AG has developed a customized femtosecond laser program that allows onestep bladeless implantation of the KeraKlear. Successful KeraKlear implantation has also been reported with the use of a cornea pocket–making microkeratome.3 The steps in KeraKlear implantation are as follows (Figure 15-2): 1. Application of antibiotic and anesthetic eye drops 2. Creation of an 8-mm-diameter corneal dissection at a depth of 300 μm using a femtosecond laser 3. Creation of a 3.5-mm-diameter circular trephination incision to a depth of 300 μm using a femtosecond laser 4. Removal of the central 3.5-mm disc of anterior corneal tissue, which represents only approximately 5% of the corneal volume 5. Insertion of the KeraKlear artificial cornea inside the corneal pocket and placement of the KeraKlear central optic inside the trephination opening 6. Optional placement of 10-0 nylon sutures through the peripheral holes and burial of the knots. We recommend 1 suture placed in each quadrant when suturing. Patients who

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Figure 15-2. KeraKlear artificial cornea implantation (upper row, cross-sectional view of the cornea; lower row, overhead view). (A) The pocket (dashed lines) is created within the layers of the diseased cornea using a femtosecond laser. The pocket divides the cornea into an anterior layer and posterior layer. The spots in the anterior layer represent abnormalities such as epithelial edema or corneal scarring. A 3.5-mm trephination incision made with the femtosecond laser is shown in dashed lines in the center of the cornea. (B) The central 3.5 mm of diseased anterior cornea is excised. The edge of the 3.5-mm-diameter excision is shown as a circle in dashed lines. (C) The KeraKlear artificial cornea is held by smooth (nontoothed) insertion forceps. (D) The KeraKlear is inserted into the corneal pocket through the 3.5-mm-diameter incision. During the insertion, the thin and flexible rim of the KeraKlear will fold upon itself. (E) The KeraKlear optic fills the space left by the removal of the diseased central 3.5 mm of the cornea. Optionally, the KeraKlear can be sutured in place by passing sutures through the holes of the KeraKlear and through the anterior and posterior layers of the cornea. Importantly, the posterior cornea remains intact, which mitigates the risk of endophthalmitis, expulsive hemorrhage, and retroprosthetic membrane formation.

frequently rub their eyes (eg, keratoconus patients) should have the KeraKlear sutured in place. 7. Placement of a high-oxygen-permeability extended-wear contact lens over the cornea

Postoperative Care and Results Like other artificial corneas, the KeraKlear requires the daily use of antibiotic drops for the prevention of infection.1,4 However, daily steroids for the prevention of rejection are not necessary, as is usually the case with PK or the Boston keratoprosthesis (KPro). The lack of chronic steroid use helps to avoid the complications of glaucoma and cataract formation. A suggested antibiotic regimen is ofloxacin 0.3% and polymyxin B/trimethoprim ophthalmic solutions, each given twice daily. A high-oxygen-permeability extended-wear bandage contact lens such as the Oasys (AcuFocus, Inc) is also suggested to help protect the interface between the KeraKlear and the recipient cornea. Contact lenses need to be replaced on a regular basis to prevent contact lens–related complications. Contact lens rewetting drops containing ethylenediaminetetraacetic acid (EDTA; eg, Opti-Free Replenish [Alcon]) used 3 to 4 times daily may help improve comfort and retard the formation of biofilm. Regular follow-up visits are important to check for possible complications such as infection or corneal melting. A suggested postoperative visit schedule is 1 day, 1 week, 1 month, and every 2 to 3 months thereafter. Because most of these visits will be routine, optometric follow-up after the 1-month visit in conjunction with annual visits with the corneal surgeon are reasonable. Intraocular pressure may be easily checked in KeraKlear patients with the use of a Tono-Pen (Reichert Technologies) at the peripheral cornea.

Results in Patients With a High Risk of Graft Failure Traditionally, artificial corneas have been reserved only for patients who have already failed transplantation or who are known to have a poor prognosis with transplantation. Here we report the 1-year results of 6 patients in this category. These 6 patients included 5 patients with failed PK (Figure 15-3) and 1 patient with severe limbal stem cell deficiency secondary to a chemical burn (Figure 15-4 and Table 15-1). One hundred percent of the patients improved by greater

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Figure 15-3. (A) An edematous and opaque failed graft, which limited vision to hand motions preoperatively, in a patient with a history of multiple failed PKs. (B) One year after KeraKlear implantation, the central cornea is clear, with improvement of vision to 20/60.

Figure 15-4. (A) Extensive haze and neovascularization due to limbal stem cell deficiency in a patient who received a KeraKlear artificial cornea after a chemical burn. (B) One year after removal of the superficial neovascular tissue and implantation of the KeraKlear, the central cornea is clear, with easy visibility of the iris details, and the patient s vision was 20/20.

than 2 lines of vision. The average improvement in vision was 6.8 lines. One hundred percent of the patients improved from being legally blind (20/200 or worse) to being at least able to read typical large print (20/100 or better). Sixty-six percent of patients had vision that would legally allow daytime driving (20/70 or better). During the follow-up period, no significant complications occurred. One of the patients with a failed graft experienced trauma to the implanted eye, which caused decentration of the optic of the KeraKlear. This was easily corrected by repositioning the implant in the laser suite and did not affect visual acuity. Intraocular pressures as measured by the Tono-Pen (Reichert Technologies) were within normal limits during the follow-up period.

Results in Patients With a Lower Risk of Graft Failure In addition to data collected from patients with a poor prognosis for PK, data have also been collected from patients with corneal blindness who were reasonable candidates for PK (Figure 15-5). These patients received the KeraKlear because corneal graft tissue was not available. The data for these patients are presented in Table 15-2.

Conclusion The KeraKlear artificial cornea is an important addition to the armamentarium of the corneal surgeon. This device is able to improve vision in cornea blind patients using a minimally invasive procedure that uses small incisions and does not penetrate into the anterior chamber. Importantly, the device does not require donor corneal tissue to implant and therefore may be used in places where corneal transplant tissue is unavailable. Because the deeper stroma and Descemet’s membrane remains intact during the KeraKlear procedure, deep anterior lamellar keratoplasty, PK, and the Boston KPro remain viable options if the need arises. The KeraKlear artificial cornea has received European CE mark approval, but at the time of the writing of this chapter, it does not have US Food and Drug Administration clearance.

References 1.

Nouri M, Terada H, Alfonso EC, Foster CS, Durand ML, Dohlman CH. Endophthalmitis after keratoprosthesis: incidence, bacterial causes, and risk factors. Arch Ophthalmol. 2001; 119(4):484-489. 2. Tan DT, Tay AB, Theng JT, et al. Keratoprosthesis surgery for end-stage corneal blindness in Asian eyes. Ophthalmology. 2008;115(3):503-510.e3.

Count fingers

20/200

20/400

Count fingers

Count fingers

Failed graft

Failed graft

Failed graft

Failed graft

Chemical burn

Limbal stem cell deficiency

Leucoma post-trauma

Fuchs dystrophy

Fuchs dystrophy

Cystoid macular edema

Multiple graft failure, unknown

20/50

20/70

20/80

20/200

20/100

20/100

20/30

20/70

20/80

20/70

20/100

20/60

VISUAL ACUITY AT VISUAL POSTOPERATIVE ACUITY AT DAYS 5 TO 9 2 MOS

20/50

20/70

20/80

20/70

20/100

20/60

VISUAL ACUITY AT 6 MOS

20/20

20/70

20/100

20/70

20/100

20/60

VISUAL ACUITY AT 12 MOS

13

7

4

4

5

8

LINES OF IMPROVEMENT

Snellen visual acuity was used for testing at an effective distance of 20 feet. In cases where vision was worse than 20/400, an improvement from hand motions to counting fingers or from counting fingers to 20/400 was counted as 1 line of improvement.

Hand motions

Failed graft

ORIGINAL PREOPERATIVE PREEXISTING PATHOLOGY VISUAL ACUITY OCULAR CONDITIONS

Postoperative Outcomes With the KeraKlear Artificial Cornea

TABLE 15-1

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Figure 15-5. (A) A patient with corneal dystrophy and a past history of radial keratotomy. (B) After the same patient received a KeraKlear artificial cornea.

3.

Studeny P. New technique of non-penetrating keratoprosthesis implantation. Paper presented at: American Society of Cataract and Refractive Surgery Annual Meeting; April 19-23, 2013; San Francisco, CA. 4. Hicks CR, Crawford GJ, Lou X et al. Corneal replacement using a synthetic hydrogel cornea, AlphaCor: device, preliminary outcomes and complications. Eye (Lond). 2003;17(3):385-392.

Please see video on the accompanying website at

www.healio.com/books/cornealvideos

Hand motions

Count fingers

20/400

Count fingers

Count fingers

Count fingers

20/100

Count fingers

Corneal scar

Keratoconus

Keratoconus

Corneal scar

Corneal dystrophy

Corneal scar

Corneal dystophy

Bullous keratopathy

20/200

20/40

20/100

20/400

20/200

20/30

20/80

20/200

20/100

20/40

20/50

20/100

20/80

20/30

20/80

20/80

20/70

20/100

20/40

20/50

20/100

20/80

20/30

20/80

20/80

20/70

20/40

VISUAL ACUITY AT 6 MOS

20/100

20/40

20/50

20/100

20/80

20/30

20/80

20/80

20/70

20/30

VISUAL ACUITY AT 12 MOS

5

5

9

5

10

6

7

6

10

LINES OF IMPROVEMENT

Snellen visual acuity was used for testing at an effective distance of 20 feet. In cases where vision was worse than 20/400, an improvement from hand motions to counting fingers or from counting fingers to 20/400 was counted as 1 line of improvement.

Abbreviation: CME, cystoid macular edema.

Fuchs dystrophy, CME

Corneal dystrophy

Ocular trauma

Radial keratotomy, myopic degeneration

Trauma

Keratoconus

Keratoconus

Trauma

Fuchs dystrophy

20/70

20/400

Bullous keratopathy

20/100

20/70

20/400

Corneal scar

Leucoma

VISUAL ACUITY AT VISUAL POSTOPERATIVE ACUITY AT DAYS 5 TO 9 2 MOS

ORIGINAL PREOPERATIVE PREEXISTING PATHOLOGY VISUAL ACUITY OCULAR CONDITIONS

Postoperative Outcomes After KeraKlear Artificial Cornea Implantation in Eyes With a Low Risk of Graft Failure

TABLE 15-2

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16 Limbal Stem Cell Deficiency Charles L. Thompson, MD and W. Barry Lee, MD A healthy ocular surface is dependent on a symbiotic relationship between a multitude of factors. The form and function of the eyelids, a healthy precorneal tear film, and an intact neuronal reflex arc are vital in protecting the cornea and maintaining its optical clarity. The role of stem cells in the health of the ocular surface has evolved over the past century and has played a critical role in the evolution of management in a multitude of potentially blinding conditions. Stem cells are present in all self-renewable tissues in the body. They represent a small subset of epithelial cells, ranging from 0.5% to 10% of all epithelial cells. Certain characteristics are unique to stem cells, including a longer life span, longer cell cycle time, increased potential for error-free proliferation, the ability to divide asymmetrically, a pluripotential nature, and a high proliferative capacity. Amid a steady state environment, present in the setting of a healthy ocular surface, stem cells remain relatively dormant, which minimizes replication errors during cell division. Conjunctival stem cells are thought to be present in the conjunctival fornix, and corneal epithelial stem cells reside in the limbal palisades of Vogt at the corneoscleral limbus. The role of limbal epithelial cells in the regeneration of the corneal epithelium, first proposed by Davanger and Evensen1 in 1971, was realized when striate melanokeratosis was observed in heavily pigmented eyes during healing of corneal epithelial defects. Labeling studies demonstrating incorporation of titrated thymidine for extended time intervals into the limbal basal cells further supported the location of corneal stem cells.2 Cytokeratin markers have subsequently been used to identify the location of the corneal stem cells. Schermer et al3 found a 64 kDa keratin, K3, to be uniformly present in differentiated corneal epithelial cells of the suprabasal limbal region and other more superficial epithelial cells but absent in the basal layer. Kurpakus et al4,5 demonstrated K12 to be similarly represented. Clinical evidence to support the location of corneal epithelial stem cells is provided by clinical and experimental observations of abnormal corneal epithelial wound healing following the partial or complete removal of the limbal epithelium.6-9 In these instances, conjunctivalization of the corneal surface, vascularization, and chronic inflammation were all noted, and impression cytology and immunofluorescent staining with monoclonal antibodies were used to demonstrate corneal overgrowth, with epithelial cells demonstrating a conjunctival phenotype.6-11 Despite substantial evidence to suggest that corneal epithelial stem cells reside at the corneoscleral limbus, one concept that remains elusive to investigators is the interplay between intrinsic and extrinsic factors critical to maintaining the stem cell niche. Several clinical hypotheses have been investigated in an attempt to advance our current understanding of limbal stem cell physiology. The role of cytokines elaborated by corneal and limbal epithelial cells and fibroblasts, the - 159 -

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difference between basement membrane morphology at the limbus and central cornea, the differing concentrations of various enzymes (sodium potassium–activated adenosine triphosphotase, cytochrome oxidase, and carbonic anhydrase) at these respective sites in response to corneal injury, and the proximity of the limbus to blood vessels all seem to play an unspecified role in maintaining the stem cell niche.12-18 Although our understanding of stem cell function is incomplete, there is no debate regarding the regenerative capacity of corneal epithelial stem cells and the role these stem cells play as a mechanical barrier to conjunctivalization of the corneal epithelium. In response to the demand for corneal epithelial cell regeneration, limbal stem cells give rise to transient amplifying cells (TACs), which increase rapidly in number to replace diseased or dead cells. After the amplification process, cells are referred to as postmitotic cells (PMCs). PMCs have no replicative capacity and will further differentiate into terminally differentiated cells (TDCs), which display the final phenotypic characteristics of mature corneal epithelial cells. Additional studies postulated the migratory pattern of epithelial cells following corneal injury.19,20 Thoft and Friend 20 elucidated the X,Y,Z hypothesis of corneal epithelial maintenance, in which basal epithelial cells (X) and epithelial cells from the periphery (Y) divide and replace desquamated epithelial cells (Z is cell loss from the corneal surface.). This process is critical in the maintenance of the corneal epithelium and its ability to regenerate following injury. Limbal stem cell deficiency (LSCD) and ocular surface disease present with various clinical signs and symptoms. Initial symptoms may include persistent foreign body sensation, decreased vision, redness, pain, photophobia, excessive tearing, dryness, and blepharospasm. Patients may report a history of recurrent corneal erosion resulting from abnormal epithelial morphology/phenotype, dryness, and persistent inflammation. External examination and slit lamp biomicroscopy provide clinical information that facilitates establishment of the underlying diagnosis responsible for the ocular surface disease and allows the clinician to identify associated pathology, which often requires treatment prior to addressing the stem cell deficiency. The eyelids may demonstrate entropion or ectropion, trichiasis, keratinization of the eyelid margin with meibomian gland dysfunction, symblepharon, or ankyloblepharon. The conjunctiva is examined for subepithelial fibrosis, forniceal shortening, ankyloblepharon, symblepharon, and chronic inflammation evidenced by persistent injection. Corneal findings increase proportionally with the degree of LSCD. Early LSCD results in the loss of the limbal palisades of Vogt. Conjunctivalization of the corneal epithelium ensues once the mechanical barrier of the limbal stem cells is lost. Conjunctival epithelial cells have less robust intercellular tight junctions compared with corneal epithelial cells, which results in a characteristic late staining pattern of the ocular surface (may assume a whorl-like keratopathy in later stages), increased white blood cell penetration into the subepithelial space, and anterior stroma facilitating corneal haze and scarring. The ratio of proangiogenic factors to antiangiogenic factors becomes skewed in favor of angiogenesis, and various degrees of superficial corneal pannus and deep stromal neovascularization can be seen. Persistent epithelial defects often arise, which increase the incidence of corneal ulcers, melting, infection, and corneal perforation. Impression cytology or excisional corneal biopsy may demonstrate the presence of conjunctival goblet cells on the corneal surface, the characteristic histopathologic finding in LSCD.

Causes of Limbal Stem Cell Deficiency The causes of LSCD can be grouped into primary or secondary disorders (Table 16-1). Secondary causes are seen more commonly. Primary LSCD results from congenital disorders. Aniridia is the prototypical form of primary LSCD (Figure 16-1). Other conditions include autosomal dominant keratitis, sclerocornea, ectodermal dysgenesis syndromes, multiple endocrine neoplasia, and keratitis-ichthyosis-deafness syndrome. Primary LSCD may present at birth or may progress over several decades early in life. Secondary LSCD is more commonly encountered clinically. The causes are numerous but can be grouped into several categories. Direct stem cell loss occurs in the setting of chemical or thermal burns and radiation therapy. Inflammation in the setting of autoimmune disorders such as Stevens-Johnson syndrome/toxic epidermal necrolysis and ocular cicatricial pemphigoid often leads to profound LSCD (Figures 16-2 and 16-3). Nonautoimmune causes of inflammation, such as staphylococcal marginal keratitis, rosacea, chronic infections (bacterial, viral, fungal, parasitic),

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TABLE 16-1

Causes of Limbal Stem Cell Deficiency PRIMARY STEM CELL DISEASE Aniridia

Multiple endocrine neoplasia

Sclerocornea

Ectodermal dysplasia syndromes

Autosomal dominant keratitis

Keratitis-ichthyosis-deafness syndrome

SECONDARY STEM CELL DISEASE Direct stem cell loss

Contact lens wear

Alkali or acid injury Thermal injury

Bacterial, viral, fungal keratitis-related stem cell loss

Radiation injury

Staphylococcal marginal disease

Autoimmune disease

Pterygia/pseudopterygia

Stevens-Johnson syndrome

Xerophthalmia

Toxic epidermal necrolysis

Limbal neoplasm

Mucous membrane pemphigoid

Iatrogenic stem cell deficiency

Collagen vascular diseases

• Multiple ocular surgeries

Chronic nonautoimmune inflammatory disorders

• Excision of pterygia

Atopy Ocular rosacea

• Excision of limbal neoplasm • Cryotherapy/cyclophotocoagulation of limbus • Medication toxicity

Figure 16-1. Aniridic keratopathy manifested by corneal neovascularization, irregular corneal epithelium, and corneal scarring.

chronic contact lens wear, limbal neoplasia, and pterygia, produce varying degrees of LSCD. Finally, iatrogenic causes of LSCD include chronic use of topical medications, multiple surgeries involving the corneoscleral limbus, and cryotherapy or cyclophotocoagulation of the limbus. One important clinical caveat related to secondary causes of LSCD is the associated degree of

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Figure 16-2. Severe LSCD with dense corneal scarring and neovascularization from StevensJohnson syndrome.

Figure 16-3. Ocular cicatricial pemphigoid manifested by conjunctival inflammation, LSCD, and diffuse corneal scarring and neovascularization.

conjunctival deficiency, in terms of both chronic inflammation and tissue loss. The presence of associated conjunctival deficiency will influence surgical options for these patients.

Preoperative Considerations A multidisciplinary surgical approach is needed for patients with ocular surface disease and LSCD. A comprehensive preoperative examination should identify associated pathology that represents poor prognostic factors for surgical success with limbal stem cell transplantation.21-27 The presence of eyelid entropion or ectropion requires oculoplastic repair to ensure adequate closure of the eyelid and protection of the ocular surface, as well as to aid in a functional blink reflex that supplies a healthy precorneal tear film. Trichiasis and distichiasis should be managed with a combination of cryotherapy, electrolysis, and eyelid wedge resections (if there is a single section of aberrant lashes). Evaluation of the triphasic tear film involves the appropriate use of Schirmer testing, tear breakup time (TBUT) testing, assessment of meibomian gland morphology and function, and a combination of Lissamine green (PerkinElmer Inc), rose Bengal, and fluorescein staining patterns. Severe dry eye and a keratinized ocular surface are associated with poor prognosis of limbal stem cell transplantation.22-26 Permanent punctual occlusion and initiation of frequent preservative-free artificial tear supplementation is warranted.21 The use of autologous serum drops postoperatively to replace numerous growth factors, as well as vitamin A, plays an important role in the postoperative management of patients with a poor tear film.22-25 Slit lamp evaluation of the palpebral and bulbar conjunctiva for subepithelial fibrosis, symblepharon, and ankyloblepharon aids in surgical planning. Keratolimbal allograft (KLAL) success is inversely proportional to the

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degree of conjunctival inflammation and scarring.28 In those with mild to moderate conjunctival involvement, KLAL may be beneficial if preoperative control of the inflammation can be achieved. If significant conjunctival involvement is present or inflammation cannot be controlled, then a combined conjunctival and keratolimbal allograft (C-KLAL) is indicated.27,28 The degree of LSCD (partial versus complete) and whether the disease is unilateral or bilateral is also important in surgical planning. Lastly, evaluation for the presence and degree of glaucoma is imperative. Patients with glaucoma should be considered for glaucoma drainage devices because the chronic toxicity from the preserved glaucoma medications can be damaging to the limbal stem cells. Chronic glaucoma is a major risk factor for diminished long-term success in patients undergoing limbal stem cell surgery. Once associated pathology has been properly addressed, consideration for the appropriate surgical procedure to rehabilitate the LSCD may ensue.

Historical Perspective of Ocular Surface Transplantation Early literature regarding ocular surface transplantation introduces some confusion regarding interpretation of the clinical success of various surgical procedures due to a lack of uniform nomenclature (Table 16-2). In 1996, Holland and Schwartz29 proposed a classification system for stem cell transplantation that has facilitated a better understanding of the surgical techniques, promoted better communication among surgeons, and allowed for more accurate assessment of clinical success with various procedures. The classification system is based on the anatomical location of the donor and the source of the tissue as either an autograft or allograft, with allograft donors being further divided into living related versus cadaveric donors. The classification system was expounded on by the Cornea Society’s International Committee for the Classification of Ocular Surface Rehabilitation Procedures in 2008.30 In 1984, Thoft31 performed keratoepithelioplasty on a limited number of patients using 4 partial-thickness midperipheral corneal lenticules harvested from a whole-globe cadaveric donor. Interestingly, these lenticules did not include limbal tissue. The donor segments were placed evenly around the corneoscleral limbus and secured to the sclera with sutures. Three of the 4 patients operated on using Thoft’s original technique were reported to have developed a stable ocular surface and improved vision (all 3 successful cases were bilateral chemical burns).31 In 1990, Turgeon et al 32 modified the original keratoepithelioplasty technique. Credited as being the first true keratolimbal transplantation, the lenticules harvested from the whole-globe cadaveric donor included tissue from the corneoscleral limbus. Moderate success was reported as it relates to ocular surface stability and improved visual function, but many of the patients suffered from pathology that involved both LSCD and conjunctival deficiency, the latter of which is now known to be a poor prognostic indicator for postoperative success of limbal stem cell transplantation alone.32 In 1994, Tsai and Tseng33 evolved limbal allograft transplantation still further. Using a wholeglobe cadaveric donor, a suction trephine was used to make a partial thickness (50% to 66% depth) incision in the midperipheral cornea. A rounded blade was then used to fashion an incision of similar depth 1 mm outside the corneoscleral limbus. Lamellar dissection was then completed with the rounded steel blade. The result was a keratolimbal ring that was subsequently divided into 3 equal parts that were transferred to the recipient eye. Much information is lacking as to the stability of the ocular surface following this procedure in patients who are described as truly having LSCD.33 The first use of the term limbal allograft transplantation to describe a surgical technique for corneal epithelial reconstruction in the setting of ocular surface disease was in 1995 by Tsubota et al.34 This was the first technique to use a cadaveric corneoscleral rim preserved in tissue storage medium. Nine patients with severe ocular surface disease (3 chemical injuries, 3 LSCDs of unknown etiology, 2 ocular cicatricial pemphigoids, 1 traumatic LSCD) were treated with this technique. The central donor cornea was removed with sizing appropriate for penetrating keratoplasty (PK). The remaining corneoscleral ring was sectioned into 2 equal segments, excess stroma was removed using microscissors with care taken to preserve the conjunctiva, and lamellar dissection was performed to complete the donor preparation. The donor was secured to the recipient and centered on the 12 and 6 o’clock meridians using interrupted 10-0 nylon sutures. Seven of the 9 patients

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Classification of Epithelial Transplantation Procedures for Severe Ocular Surface Disease PROCEDURE

ABBREVIATION

TRANSPLANTED TISSUE

Conjunctival autograft

CAU

Conjunctiva

Cadaveric conjunctival allograft

c-CAL

Conjunctiva

Living related conjunctival allograft

lr-CLAL

Conjunctiva

Living nonrelated conjunctival allograft

lnr-CLAL

Conjunctiva

Transplantation Procedures Conjunctival Transplantation

Limbal Transplantation Conjunctival limbal autograft

CLAU

Limbus/conjunctiva

Cadaveric conjunctival limbal allograft

c-CLAL

Limbus/conjunctiva

Living related conjunctival limbal allograft

lr-CLAL

Limbus/conjunctiva

Living nonrelated conjunctival limbal allograft

lnr-CLAL

Limbus/cornea

Keratolimbal autograft

KLAU

Limbus/cornea

Other Mucosal Transplantation Oral mucosa autograft

OMAU

Oral mucosa

Nasal mucosa autograft

NMAU

Nasal mucosa

Intestine mucosa autograft

IMAU

Intestinal mucosa

Peritoneal mucosa autograft

PMAU

Peritoneum

Ex Vivo Tissue-Engineered Procedures Ex Vivo-Cultivated Conjunctival Transplantation Ex vivo-cultivated conjunctival autograft

EVCAU

Conjunctiva

Ex vivo-cultivated cadaveric conjunctival allograft

EVc-CAL

Conjunctiva

Ex vivo-cultivated living related conjunctival allograft

EVlr-CAL

Conjunctiva

Ex vivo-cultivated living non-related conjunctival allograft

EVlnr-CAL

Conjunctiva

Ex Vivo-Cultivated Limbal Transplantation Ex vivo-cultivated cadaveric limbal autograft

EVLAU

Limbus/cornea (continued)

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TABLE 16-2 (CONTINUED)

Classification of Epithelial Transplantation Procedures for Severe Ocular Surface Disease PROCEDURE

ABBREVIATION

TRANSPLANTED TISSUE

Ex vivo-cultivated cadaveric limbal allograft

EVc-LAL

Limbus/cornea

Ex vivo-cultivated living related limbal allograft

EVlr-LAL

Limbus/cornea

Ex vivo-cultivated living nonrelated limbal allograft

EVlnr-LAL

Limbus/cornea

Other Ex Vivo-Cultivated Mucosal Transplantation Ex vivo-cultivated oral mucosa autograft

EVOMAU

Oral mucosa

Adapted from the Cornea Society s International Committee for the Classification of Ocular Surface Rehabiliation Procedures, 2008.

achieved a stable ocular surface with epithelial cells of the appropriate corneal phenotype (2 of these patients required a second limbal transplantation to achieve ocular surface stability), and 2 of the 9 demonstrated partial conjunctivalization of the corneal surface.34 The advent of surgical techniques using noncadaveric material (conjunctival autografts, conjunctival-limbal autografts, and living related conjunctival limbal allografts) has also helped shape our current surgical procedures. In 1989, Kenyon and Tseng35 described conjunctival limbal autograft (CLAU) transplantation in the management of diffuse unilateral LSCD and bilateral partial LSCD. Twenty-six patients were treated with CLAU (20 chemical burns, 2 thermal burns, 3 contact lens–induced keratopathy, 1 LSCD secondary to multiple surgical procedures). Twenty-one of the patients had 6 months or more of follow-up, with the majority demonstrating increased visual acuity (17/21), rapid surface healing (19/21), stable epithelium without recurrent corneal erosion or persistent epithelial defect (20/21), arrest or regression in corneal neovascularization (15/21), and improved success in those requiring subsequent PK (8/21). CLAU remains the procedure of choice for unilateral partial and complete LSCD in the setting of a normal contralateral donor eye.35 In 1995, the first techniques using living related donor tissue were reported. In a technique they termed allograft conjunctival transplantation, Kwitko et al 36 harvested 1 to 2 living related conjunctival grafts to be transferred to the recipient following a complete, 360-degree conjunctival peritomy and superficial keratectomy. Twelve eyes (8 Stevens-Johnson syndrome/toxic epidermal necrolysis, 3 alkali burns, 1 thermal burn) in 10 patients were treated. Interestingly, in patients with 6 months or more of follow-up, 10 of 11 experienced an improved ocular surface with increased corneal transparency, decreased corneal neovascularization, and a lack of epithelial defects. Three patients experienced epithelial rejection episodes. Of those with epithelial rejection, 100% incompatible human leukocyte antigen (HLA) donor-recipient pairs were present in 2 cases, whereas no HLA information was available for the third case. Despite the lack of corneal epithelial cells in the conjunctival allograft technique, reasonable postoperative success was achieved.36 On the heels of Kwitko et al,36 Kenyon and Rapoza 37 developed a technique termed limbal allograft transplantation. This represents the first use of living related limbal tissue with a conjunctival carrier in combination with systemic immunosuppression. Harvested conjunctival limbal specimens were 2 mm wide and 10 mm in circumferential length, taken from the superior and inferior limbal locations of the living related donor. The donor specimens were maintained in a moisture chamber while the recipient was prepared with a conjunctival peritomy and superficial keratectomy as previously described. The grafts were then sutured to the recipient limbus at the

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A

B

C

D

Figure 16-4. Schematic of the major steps of CLAU. (A) Two conjunctival-limbal grafts are harvested from the healthy contralateral eye. (B) A 360-degree conjunctival peritomy is performed with limited resection of diseased conjunctiva superiorly and inferiorly for placement of the future donor tissue. (C) A lamellar keratectomy is performed to remove all diseased epithelium, including all corneal pannus and scarring. (D) The donor conjunctiva-limbal grafts are secured to the recipient at the superior and inferior 3- to 4-o clock hours with interrupted sutures and/or fibrin glue.

superior and inferior locations. Eight eyes (4 chemical burns, 2 erythema multiforme, 1 LSCD secondary to multiple limbal-based surgeries, 1 atopic keratoconjunctivitis) with a follow-up of 6 months or more were evaluated. Postoperative visual acuity was improved (6/8) or remained the same (2/8), and a stable ocular surface was achieved in 6 of 8 patients.37

Current Surgical Techniques Current surgical techniques for limbal stem cell transplantation include CLAU; living related conjunctival limbal allograft (lr-CLAL); KLAL; C-KLAL, which can include conjunctival limbal autograft or living related conjunctival limbal allograft with keratolimbal autograft (modified Cincinnati and Cincinnati procedure, respectively); and ex vivo tissue-engineered procedures.

Conjunctival Limbal Autograft CLAU involves transplanting limbal tissue with a conjunctival carrier from a healthy contralateral eye to the stem cell–deficient eye. CLAU is the procedure of choice for unilateral LSCD and is probably best suited for patients with partial LSCD (Figure 16-4). The advantage lies in the fact that systemic immunosuppression is not required. Disadvantages include the risk of iatrogenic LSCD in the donor eye. Strict preoperative evaluation should include a detailed history regarding chronic contant lens wear, chronic use of topical medications, and any history of previous limbalbased surgery to identify and exclude poor CLAU candidates.6,7

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Figure 16-5. (A) Sectoral inferior stem cell deficiency created from a previous alkaline chemical burn. (B) Postoperative photograph 3 months after CLAU.

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Preparation of the recipient eye in CLAU involves making a circumferential, 360-degree conjunctival peritomy with excision of any abnormal conjunctival epithelium at the 12- and 6-o’clock meridians. The conjunctiva is undermined to allow the tissue to recess posteriorly. A superficial lamellar keratectomy is then performed to remove abnormal epithelium and any fibrovascular pannus. Special care should be taken to avoid dissection into the anterior stroma. Attention is then turned to the donor eye, where 2 trapezoidal limbal grafts are outlined using calipers marked with a gentian violet surgical marking pen at the 12- and 6-o’clock meridians. The grafts should measure approximately 6 mm along the limbus and 5 to 8 mm posteriorly. The conjunctiva is then separated from underlying Tenon’s layer by injected balanced salt solution or lidocaine on a 30-gauge needle fastened to a tuberculin syringe. Blunt-tip Wescott scissors (Bausch + Lomb Inc) and nontoothed forceps are used to excise the posterior and lateral margins of the graft, and the tissue is reflected anteriorly onto the corneal surface. Careful anterior dissection is extended through the limbal palisades of Vogt and into the clear cornea for 0.5 to 1 mm using a crescent blade. This ensures isolation of the limbal stem cells with the conjunctival carrier tissue. The proximal portion of the graft (in the clear cornea) is then transected, and the graft is freed from the donor surface. This process is repeated in a similar fashion inferiorly. The grafts are then transferred to the recipient eye and secured using interrupted 10-0 nylon sutures. Suture bites should incorporate the donor tissue and the recipient episcleral tissue along the lateral and posterior margins of the graft. No sutures should be passed through the limbal margin of the graft to prevent iatrogenic stem cell damage. Postoperatively, patients are maintained on topical antibiotics until all epithelial defects have healed. Topical immunosuppression can be achieved with topical steroids alone (in a tapering fashion in accordance with ocular surface inflammation). No systemic immunosuppression is required with this surgical technique given the nature of the donor (Figure 16-5).

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Living Related Conjunctival Limbal Allograft Lr-CLAL requires 2 surgical procedures on 2 different patients. Indications for lr-CLAL are unilateral LSCD in patients whose contralateral eye is not suitable for CLAU and bilateral LSCD with an associated cicatricial conjunctival disease process. This procedure is probably best for patients with limited or partial stem cell dysfunction compared with those demonstrating complete loss of stem cells. One advantage of lr-CLAL is the presence of its conjunctival tissue carrier. As such, indications for lr-CLAL have been Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and atopic keratoconjunctivitis. The disadvantages include a risk of rejection, the need for topical and systemic immunosuppression, the presence of fewer transplanted corneal stem cells compared with KLAL, and the possibility of iatrogenic LSCD in the related donor. As with all allograft procedures, immunosuppression is critical to maintaining graft survival. Patients should be screened for systemic diseases that may limit their use of these medications. Uncontrolled diabetes mellitus, blood dyscrasias, liver dysfunction, renal insufficiency, and advanced age are all potential contraindications to immunosuppression and, as a result, allograft surgery. Assuming the presence of an appropriate donor and recipient, the surgical technique involves 2 separate operations. The donor allograft is harvested from the living related donor in a manner similar to CLAU. Special care is taken to place adequate surgical marks on the donor graft prior to placing the tissue onto glove paper and immersing it in colloidal storage solution. This ensures proper orientation of the donor tissue. The recipient is prepared and the graft is sutured as previously described in CLAU.

Keratolimbal Allograft KLAL always uses a cadaveric donor. KLAL is ideally suited for total bilateral LSCD, unilateral complete LSCD (in which CLAU or lr-CLAL may not provide a sufficient amount of limbal stem cells or is otherwise contraindicated or not feasible), or unilateral partial LSCD in those who fear iatrogenic damage to the contralateral eye (in CLAU) or the living related donor (in lr-CLAL). Poor prognostic factors in individuals being considered for KLAL include severe dry eye, a keratinized ocular surface, and uncontrolled conjunctival inflammation and scarring.22-27 Assessment of the precorneal tear film is essential preoperatively. If the tear film is decreased, intervention with permanent punctual occlusion, tear supplementation with preservative-free artificial tears, and/or treatment of associated meibomian gland dysfunction is warranted. The advent of autologous serum tears postoperatively to replace numerous growth factors and vitamin A is a useful adjunctive treatment option for patients with a poor tear film.22-25 Patients with significant conjunctival inflammation, conjunctival subepithelial fibrosis, or symblepharon/anklyoblepharon may be more appropriate candidates for C-KLAL (Cincinnati or modified Cincinnati procedure). Aniridia and cases of iatrogenic LSCD exemplify the optimal disease processes suited for KLAL because these patients typically have reasonably normal conjunctiva.28,38 KLAL has been modified from the original description of keratoepithelioplasty by Thoft.31 Turgeon et al 32 is credited with describing the first true KLAL procedure in 1990. Early KLAL techniques by Turgeon et al 32 and Tsai and Tseng33 used whole-globe cadaveric donor tissue to harvest limbal stem cells for transplantation. In 1995, Tsubota et al 34 was the first to describe the use of a corneoscleral donor stored in Optisol GS (Bausch + Lomb Inc) media for limbal transplantation. They are credited with describing the initial corneoscleral crescent technique for limbal transplantation. In this procedure, a central 8- to 9-mm corneal button appropriate for PK was trephined. The remaining corneoscleral rim was bisected into 2 equal segments for transplantation.34 The recipient was prepared similar to previously described techniques, including circumferential conjunctival peritomy, appropriate resection of conjunctival tissue to provide an adequate bed for the graft, and superficial lamellar keratectomy to remove abnormal epithelium and any corneal pannus. Adjunctive amniotic membrane was placed epithelial side up to provide a substrate for epithelial attachment and migration and to reduce postoperative inflammation, vascularization, and scarring. The keratolimbal crescents were then sutured atop the amniotic membrane using interrupted 10-0 nylon sutures. One problem with this technique was the presence of a clinically significant tissue gap in the horizontal meridians and resulting conjunctivalization in these areas. In 1996, Holland and Schwartz28 rectified this procedural shortcoming by using the central corneal button trephined from the donor specimen. The corneal button was bisected and

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Figure 16-6. Intraoperative photograph depicting the corneoscleral ring technique for KLAL.

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Figure 16-7. Schematic of the major steps of the corneoscleral crescent technique of KLAL surgery. (A) Donor KLAL lenticules are fashioned from 2 cadaveric corneoscleral rims with the central 7.5 mm of cornea removed by trephination. (B) Conjunctival peritomy for 360 degrees with tenectomy. The conjunctiva will contract. (C) Abnormal corneal epithelium and fibrovascular pannus are removed with a lamellar keratectomy using a beaver blade. (D) KLAL lenticules are secured to the recipient limbus using 10-0 nylon sutures and/or fibrin glue.

sutured at the sites of tissue gap in the horizontal meridians. This did not supply additional stem cells to the recipient, but it served as a mechanical barrier to conjunctivalization in these areas.

Corneoscleral Ring Technique Croasdale et al 39 and Tsubota et al40 modified their initial stem cell transplantation techniques, describing what is currently accepted as the corneoscleral crescent technique and the corneoscleral ring technique, respectively. The corneoscleral ring technique simply removes the central 8- to 9-mm corneal button from the cadaveric corneoscleral donor as a means of fashioning a doughnut-shaped limbal graft. Excess sclera is removed, leaving a uniform peripheral scleral skirt. The posterior lamellae of the ring is dissected away and discarded to thin the graft prior to transplantation. The recipient is prepared as previously described. The graft is then secured with interrupted 10-0 nylon sutures along the posterior border of the graft, with care being taken to align the donor and recipient limbus (Figure 16-6).

Corneoscleral Crescent Technique Perhaps the more accepted technique for KLAL is the corneoscleral crescent technique (Figure 16-7). This procedure uses 2 stored corneoscleral rims from both donor eyes (which

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Figure 16-8. Postoperative photograph 1 year after the corneoscleral crescent KLAL technique for severe LSCD.

increases the demand on available tissue for transplant) to fashion multiple segments (4) available for transplantation. Each donor has a central 7.5-mm corneal button excised before sectioning the rim into equal halves. Excess sclera is then removed, leaving a 1-mm scleral skirt peripheral to the limbus. Dissection of the posterior lamellae is performed on each hemisection to thin the graft. The 3 most suitable donor crescents are selected for transplant. The recipient eye is prepared as previously described. The anterior and posterior corners of each donor crescent are secured with interrupted 10-0 nylon sutures. Additional interrupted 10-0 nylon sutures or fibrin glue is used to secure the posterior conjunctival margin of the graft. The crescents are aligned end to end to cover the entire circumference of the recipient limbus. Meticulous irrigation with balanced salt solution and viscoelastic should be placed over the donor epithelium during suturing to protect against desiccation and mechanical trauma. The use of 3 donor crescents provides 1.5 times the number of limbal epithelial cells compared with other techniques and ensures appropriate barrier function postoperatively (Figure 16-8).

Tissue Selection and Preparation In 1999, Croasdale et al 39 described the Minnesota Lions Eye Bank (MLEB) Protocol for KLAL recovery, processing, and preservation. The MLEB protocol specified specific donor tissue requirements and ensured standardized processing of KLAL tissue. Optimal KLAL donor tissue is less than 50 years old with intact corneal epithelium (the presence of epithelial cells on the donor surface represent a surface marker suggesting appropriate care and precaution was taken during donor preparation so as to minimize stem cell damage) and has a preferential 72-hour death-totransplantation time. Both the corneoscleral ring technique and the corneoscleral crescent technique require appropriate posterior lamellar dissection of the donor tissue. A thin donor tissue decreases the antigenic burden being placed at the vascularized limbus, reduces any significant stepoff that may pose a migratory challenge to new epithelial cells, and decreases eyelid friction over the new graft, which may be a source of chronic inflammation. There is no standardized technique for posterior lamellar dissection. If a surgical assistant is available to provide stabilization of the donor tissue, then no additional instrumentation is needed. Meticulous dissection can proceed with the surgical assistant maintaining countertraction with a pair of toothed forceps while the surgeon performs dissection. If no surgical assistant is available, one can use other proposed methods. Mannis et al41 used a 22-mm silicone orbital sizing sphere and 3 25-gauge needles for fixation of the corneoscleral rims. The posterior two-thirds of each circular rim are dissected from the anterior one-third using a rounded crescent blade. The authors of this chapter have experimented using a novel preparation method involving the use of cyanoacrylate glue to secure each hemisection to

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a disposable plastic needle counter box while dissection is performed with toothed forceps and a rounded crescent blade.

Advantages and Disadvantages of Keratolimbal Allograft KLAL offers several advantages over other forms of limbal stem cell transplantation. The corneoscleral crescent technique supplies 1.5 times the number of stem cells to the recipient. Use of a cadaveric donor eliminates possible iatrogenic damage to the contralateral eye of the recipient (CLAU) or to the living related donor (lr-CLAL). KLAL can be used in cases of partial or complete LSCD. A disadvantage of KLAL is the need for increased donor tissue when implementing the corneoscleral technique. Patients require topical and systemic immunosuppression postoperatively to reduce graft rejection. Limbal tissue has a significant population of Langerhans cells and other highly antigenic material. KLAL segments are transplanted directly into the highly vascular recipient limbus as compared with avascular PK corneal tissue that has a lower antigenic burden and is transplanted into an avascular recipient bed. Successful immunosuppression has been noted with topical cyclosporine 0.05% twice daily (for the duration of the patient’s follow-up), brand name steroid prednisolone acetate 4 times daily (for the first 3 months, then tapered by 1 drop/month in accordance with the degree of ocular surface inflammation), and a fourth-generation fluoroquinolone 4 times daily (until the corneal epithelium is healed). A systemic immunosuppression regimen consisting of systemic steroids, tacrolimus, and mycophenolate mofetil has been used with good success to increase graft survival.42-44 Patients with uncontrolled diabetes mellitus, blood dyscrasias, hepatic or renal insufficiency, and advancing age may be poor candidates for KLAL because of postoperative issues with systemic immunosuppression. Additionally, the success of KLAL is known to be inversely proportional to the degree of dry eye, conjunctival inflammation, corneal sensation (neurotrophic cornea), and keratinization of the ocular surface. In the presence of these relative contraindications, every attempt should be made preoperatively to control these variables. Consideration should also be given to C-KLAL in this subset of patients.

Combined Conjunctival and Limbal Transplantation Disorders of the ocular surface may represent LSCD alone or combined LSCD and conjunctival deficiency. Conjunctival deficiency is observed with pathology that leads to significant conjunctival inflammation, resulting in goblet cell loss with mucin deficiency and symblepharon formation. Most often, this occurs in the setting of Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chemical and thermal burns, and chronic atopic keratoconjunctivitis. The use of proposed classification systems for ocular surface disease can aid in surgical decision making regarding these patients.41 KLAL surgery alone is typically insufficient to correct ocular surface disease with combined LSCD and conjunctival deficiency. Combined C-KLAL (combined conjunctival limbal graft + keratolimbal allograft) is indicated in unilateral or bilateral LSCD with associated conjunctival deficiency. Combined C-KLAL can be performed with a conjunctival limbal autograft (modified Cincinnati procedure, CLAU + KLAL) or a conjunctival limbal allograft (Cincinnati procedure, lr-CLAL + KLAL) (Figure 16-9). The techniques for each of these procedures have been discussed previously in this chapter.

Cincinnati Procedure In the Cincinnati procedure (lr-CLAL + KLAL), surgery begins with harvesting the lrCLAL. The best HLA matched living related donor is accepted for surgery. A gentian violet surgical marking pen is used to outline the graft margins. Three clock hours are marked along the limbus at the 12- and 6-o’clock meridians. The graft area is then extended toward the superior and inferior fornix, respectively, and should assume a trapezoidal shape. The superior graft extends 8 mm from the limbus in the vertical meridian, and the inferior graft extends 5 mm from the limbus (because the superior bulbar conjunctiva has increased surface area). The conjunctiva is then elevated with balanced salt solution or lidocaine on a tuberculin syringe using a 30-gauge needle. Dissection is then performed with blunt Wescott scissors along the posterior and lateral margins,

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Figure 16-9. Schematic of KLAL combined with lr-CLAL or CLAU. (A) Donor conjunctival limbal tissue is harvested. (B) Donor KLAL lenticules are fashioned from 1 cadaver corneoscleral rim with the central 7.5 mm of cornea removed by trephination. (C) Conjunctival peritomy for 360 degrees and tenectomy to allow conjunctiva to retract followed by lamellar keratectomy to remove abnormal corneal epithelium and fibrovascular pannus. (D) CLAU or lr-CLAL donor tissue is secured to the recipient limbus with 10-0 nylon sutures and/or fibrin tissue glue. (E) KLAL lenticules are secured to the recipient limbus using 10-0 nylon sutures and/or fibrin tissue glue.

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reflecting the tissue anteriorly onto the corneal surface. Dissection for 1 mm into clear cornea ensures that limbal stem cells are harvested on the conjunctival carrier. This sequence is performed identically at both the 12- and 6-o’clock positions. The grafts can be placed in balanced salt solution and the conjunctival defect is closed with dissolvable suture. Next, KLAL corneoscleral crescents are prepared from a single donor (as opposed to 2 corneoscleral donors as in traditional KLAL). The central cornea of the corneoscleral rim is excised with a 7.5-mm trephine. Two equal crescentic donor segments are then fashioned, and posterior lamellar dissection is performed to yield thin KLAL segments. KLAL segments are returned to corneal storage media, and attention is turned to the recipient. Care should be taken in eyes with significant symblepharon formation to avoid excision of conjunctiva. Instead, following the 360-degree peritomy, the conjunctiva should be undermined using Wescott or tenotomy scissors, allowing the tissue to recess as much as possible. Excessive Tenon’s fascia should be excised. Allowing the conjunctiva to recess will provide increased palpebral conjunctival tissue that may help in decreasing the postoperative recurrence of symblepharon. Any abnormal corneal epithelium and fibrovascular pannus is then removed with lamellar keratectomy. The harvested lr-CLAL is sutured into position first at the 12-o’clock position and then at the 6-o’clock position on the recipient, with care taken to maintain proper orientation. The anterior and posterior lateral borders are secured first with interrupted 10-0 nylon sutures with episcleral bites. Additional interrupted 10-0 nylon sutures are placed along the lateral and posterior graft borders. KLAL segments are then placed at the 3- and 9-o’clock meridians, again with care taken to maintain proper orientation. Interrupted 10-0 nylon sutures are used to secure KLAL segments at the limbus. Fibrin glue (or additional 10-0 nylon sutures) is used to secure the posterior edge of the KLAL segment and reapproximate the conjunctiva adjacent to the graft’s posterior edge.

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Modified Cincinnati Procedure The modified Cincinnati procedure (CLAU + KLAL) is performed in a similar fashion, with the exception that the conjunctival limbal graft is harvested from the unaffected eye of a patient with unilateral LSCD and conjunctival deficiency. This is typically reserved for patients with unilateral chemical or thermal burns because the other usual culprits of combined LSCD and conjunctival deficiency (Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe atopic keratoconjunctivitis) are bilateral disease processes.

Advantages and Disadvantages of Combined Conjunctival and Limbal Transplantation Combined C-KLAL is advantageous in those with combined LSCD and conjunctival deficiency. Patients classified in stage IIb and IIc represent the group with both the worst natural disease course and the poorest prognosis related to surgical success. Postoperative immunosuppression with topical and systemic medications is required for C-KLAL. The postoperative regiment helps to control significant postoperative inflammation and prevent rejection of both lr-CLAL (Cincinnati procedure) and KLAL (both Cincinnati and modified Cincinnati procedures) grafts. Successful postoperative topical and systemic immunosuppression has been discussed previously.42-44 Transplanting surgeons should have an adequate working understanding of various immunosuppressive agents available and should work closely with colleagues adept with organ transplantation.

Visual Rehabilitation Following Ocular Surface Reconstruction Many patients with significant ocular surface disease and LSCD have visually significant corneal scarring that may limit visual acuity, even after stability is restored to the ocular surface following transplantation. Studies have shown that staged keratoplasty (PK vs deep anterior lamellar keratoplasty [DALK]) or keratoprosthesis offers better visual outcomes then combined procedures. Current recommendations involve assessment of ocular surface stability 3 months after limbal stem cell transplantation. In those with a stable or improved ocular surface, keratoplasty may be considered. The decision to proceed with PK vs DALK depends largely on the health of the corneal endothelium. Alterations to the usual surgical techniques for PK have been advocated and deserve mention.45 Briefly, large-diameter grafts (9.5 to 11 mm) may allow for optimal wound healing, with same-size donor and recipient trephination; the exception is chemical burn patients whose recipient beds tend to contract following trephination, prompting the recommendation for oversizing the donor graft by 0.5 to 0.75 mm. Single interrupted 10-0 nylon sutures are advisable in this setting. Vascularization of the graft-host junction and the sutures may require early selective suture removal. Additionally, the presence of ocular surface disease can result in asymmetric wound healing, and the presence of interrupted sutures allows the surgeon to better manage postoperative astigmatism. Care should be taken to pass each suture in a manner that approximates donor and recipient but avoids the KLAL segments and the CLAU or lr-CLAL segments.

Ex Vivo Tissue-Engineered Procedures The latest approach to ocular surface transplantation involves the use of bioengineered tissues equivalents. The clinical use of ex vivo–cultivated limbal stem cells was first published by Pellegrini et al46 in 1997. This technique is known as cultivated limbal epithelial transplantation (CLET). Since that time, numerous ex vivo procedures have been described, providing conjunctiva, limbal stem cells, or mucosal epithelial cells. The basic premise for ex vivo procedures involves harvesting a small amount of stem cells (as autografts or allografts) and allowing them to be cultivated in a suitable environment, on proper tissue substrate submerged in culture medium, to foster growth of an epithelial sheet that can ultimately be transplanted to the recipient.

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Donor Preparation First, limbal epithelial cells must be harvested. The size of the biopsy ranges from 2 to 6 square millimeters. Tsai et al47 described the surgical technique for limbal biopsy. Regardless of the overall size of the biopsy, dissection typically extends for approximately 1 mm on either side of the corneoscleral limbus. The major methods for producing ex vivo–cultivated limbal epithelial cells are the explant culture system48-57 and the suspension culture system.45,58-62 Both ex vivo cultivation techniques carry a risk of transfer of viruses, bacteria, and prions to patients and laboratory personnel involved in tissue preparation. Screening of donors and donor tissue for human immunodeficiency virus, hepatitis B and C, syphilis, human T-lymphotropic virus 1, and prion disease is required. Briefly, the explant culture system typically involves the use of amniotic membrane as a substrate and carrier for the cultivated cells. Various media have been studied in an attempt to find the most effective substrate and carrier vehicle, but intact human amniotic membrane appears to be the most suitable medium.46 Limbal biopsy is placed on the basement membrane surface of the amniotic membrane and allowed to adhere. It is then submerged into culture medium that nourishes the limbal epithelial cells and stimulate proliferation and migration of the cells over the amniotic membrane surface. This process takes between 14 and 21 days. Several studies cite the addition of growth-arrested 3T3 fibroblasts in the bottom of the cell culture well. The use of 3T3 explant coculture system is thought to inhibit differentiation of corneal epithelial cells in vitro and allow for increased expansion of the population of limbal stem cells.63-65 The suspension culture system involves the use of enzymes, dispase (to digest basement membrane collagen and separate epithelial cells from stroma), and trypsin (to separate clumps of epithelial cells into a suspension of single cells) to produce a suspension of single cells. The suspension is then transferred to an amniotic membrane or plastic tissue culture dish that contains a feeder layer of growth-arrested 3T3 fibroblasts. The cells are incubated in culture medium for 14 to 21 days until a confluent sheet of epithelial cells forms and can be transferred to the recipient ocular surface.

Tissue Analysis Immunohistochemical analyses of cultivated ex vivo epithelial transplants have examined the presence of cytologic markers CK3, CK12, CK19, beta 1 integrin, p63, and ABCG2, among others.45,50,59-60,66 Numerous studies have shown phenotypic characteristics consistent with limbal epithelial cells in 2% to 9% of the cultivated epithelial cells, which is thought to represent the same percentage of limbal epithelial cells in vivo.67-69 Simply stated, the cultivated ex vivo tissue equivalents contain a small percentage of cells whose phenotype appears consistent with limbal stem cells and a larger percentage of cells whose phenotype is consistent with suprabasilar epithelial cells (transient amplifying cells, post-mitotic cells, and terminally differentiated cells).

Surgical Technique Despite some variation in methods used to cultivate limbal epithelial cells, the surgical technique for transplanting ex vivo limbal epithelial cells is similar. A 360-degree conjunctival peritomy and superficial lamellar keratectomy are performed to remove abnormal epithelium and fibrovascular pannus. Hemostasis is achieved with cautery and the use of 10% topical phenylephrine. The cultivated limbal epithelial cells are then placed onto the prepared corneal surface and limbus. Desiccation of the ex vivo graft is prevented with the use of viscoelastic material and balanced salt solution. If the cells are cultivated on amniotic membrane, then the graft is placed on the corneal stoma with cultivated cells facing outward toward the tear film. The graft is sutured into place using 10-0 nylon or dissolvable sutures. If the cells are transplanted without a carrier (eg, on a plastic dish), then the basal aspect of the epithelial sheet is placed directly onto the corneal stroma and no sutures are required. Mechanical protection of the graft is achieved by placement of a therapeutic/bandage contact lens or an amniotic membrane onlay graft. The contact lens is left in place for 1 week to 3 months postoperatively. The use of a sutured amniotic membrane onlay graft will typically slough or dissolve over a 10- to 21-day period.

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Postoperative Management Postoperative management for ex vivo stem cell transplantation is still evolving. All patients receive topical steroid (of varying frequency and taper schedule in response to the degree of inflammation present) and topical antibiotic 4 times daily for 1 to 3 months (the length typically adjusted depending on the type of mechanical barrier placed over the ex vivo graft). Systemic immunosuppression is required for all patients receiving allograft transplantation, but the preferred agents and duration are variable.

Advantages and Disadvantages of Ex Vivo–Cultivated Stem Cell Transplantation CLET and variations of ex vivo–cultivated limbal stem cell transplantation offer some advantages over traditional limbal stem cell transplantation. Ex vivo–cultivated limbal stem cell transplantation requires less donor tissue. In cases of autologous or living related donors, less risk of iatrogenic LSCD exists. A theoretically decreased risk of allograft rejection exists due to the relative paucity of antigen-presenting Langerhans cells in the ex vivo–cultivated limbal epithelial cells. Finally, ex vivo transplantation procedures are repeatable.52 The disadvantages are the cost, the availability of laboratories capable of generating cultivated limbal epithelial cells, and the fact that topical and systemic immunosuppression is still required (except in cases of autografts).

Results of Ex Vivo–Cultivated Limbal Stem Cell Transplantation The success of ex vivo–cultivated limbal transplantation varies with respect to the pathology being treated. An overall success rate of 77% improvement in clinical signs of LSCD has been reported in some studies,70 with other reports ranging from 33% to 100%.45,48-62 Cases of combined LSCD and conjunctival deficiency, class IIb and IIc (Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe atopic keratoconjunctivitis), appear to have lower success rates with ex vivo–cultivated limbal stem cell transplantation. The same is true for traditional limbal stem cell transplantation. This concept underscores the importance of preoperative assessment of the pathologic cause of ocular surface disease and the idea that addressing all ocular surface deficiencies with surgical intervention maximizes the long-term success. Studies evaluating the evidence of donor cell survival exist but are limited. Pellegrini et al46 and Rama et al71 performed impression cytology on the recipient at varying time intervals postoperatively that confirmed the presence of a normal corneal phenotype with an absence of goblet cells but failed to determine whether these cells were of donor or recipient origin. Daya et al 59 used polymerase chain reaction genotyping in a small study group to determine the origin of epithelial cells populating the corneal surface postoperatively. The results demonstrated only a transient presence of allogeneic epithelial cells on the corneal surface.59 Such results question the reported mechanism for clinical and histological success. Advocates for the procedure propose that success relies on the integration of ex vivo limbal stem cells into the recipient ocular surface and function to continuously replenish the corneal epithelium.72-75 However, consideration must be given to proposals that the ex vivo limbal stem cells coupled with the amniotic membrane graft serve as a biological bandage that provides sufficient time, nourishment, and stimulation for the recipient’s own endogenous limbal stem cells to regenerate or for the recruitment of precursor cells from the bone marrow that may be present in the scleral stroma.76-78 Despite the success rates seen with ex vivo–cultivated stem cell transplantation in its various forms, much is still needed in field of clinical research.

Ex Vivo–Cultivated Mucosal Transplantation Kinoshita and Nakamura79 first proposed the use of ex vivo–cultivated autologous oral mucosal epithelium for ocular surface transplantation, and subsequent studies seemed to validate this technique.46,79,80 Current research seeks to identify sufficient immunohistochemical markers for stem cells present in the oral mucosa. Techniques for tissue harvesting and cultivation are similar

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to those in ex vivo–cultivated limbal/conjunctival transplantation and, with further study, may provide a reasonable surgical alternative to patients with unilateral or bilateral partial or complete LSCD.

Additional Transplantation Techniques Future studies in ocular surface transplantation will continue to search for available stem cell sources (eg, hair follicles or bone marrow stem cells) that may increase the availability of suitable tissue for transplant and offer a reasonable chance for success in rehabilitation of the ocular surface. A new and novel approach to unilateral partial or total LSCD was recently proposed by Sangwan et al72 Simple limbal epithelial transplantation involves a single-stage procedure requiring little donor tissue (2 mm) transplanted onto the ocular surface of someone with unilateral partial or total LSCD atop human amniotic membrane. This procedure is cost-effective, does not introduce iatrogenic LSCD in the donor eye, is repeatable, and does not require specialized laboratories for tissue cultivation. Long-term success rates and large studies using this procedure are not available to date.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature. 1971;229(5286):560-561. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989;57(2):201-209. Schermer A, Galvin S, Sun TT. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J Cell Biol. 1986;103(1):49-62. Kurpakus MA, Stock EL, Jones JC. Expression of the 55-kD/64-kD corneal keratins in ocular surface epithelium. Invest Ophthalmol Vis Sci. 1990;31(3):448-456. Kurpakus MA, Maniaci MT, Esco M. Expression of keratins K12, K4 and K14 during development of ocular surface epithelium. Curr Eye Res. 1994;13(11):805-814. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci. 1990;31(7):1301-1314. Chen JJ, Tseng SC. Abnormal corneal epithelial wound healing in partial-thickness removal of limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32(8):2219-2233. Kruse FE, Chen JJ, Tsai RJ, Tseng SC. Conjunctival transdifferentiation is due to incomplete removal of limbal basal epithelium. Invest Ophthalmol Vis Sci. 1990;31(9):1903-1913. Huang AJ, Tseng SC. Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci. 1991;32(1):96-105. Puangsricharern V, Tseng SC. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology. 1995;102(10):1476-1485. Tseng SCG. Conjunctival grafting for corneal diseases. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology. Vol. 6. Philadelphia, PA: JB Lippincott; 1994:1-11. Tseng SC. Regulation and clinical implications of corneal epithelial stem cells. Mol Biol Rep. 1996;23(1):47-58. Gipson IK. The epithelial basement membrane zone of the limbus. Eye (Lond). 1989;3(Pt 2):132-140. Hayashi K, Kenyon KR. Increased cytochrome oxidase activity in alkali-burned corneas. Curr Eye Res. 1988;7(2):131-138. Steuhl KP, Thiel HJ. Histochemical and morphological study of the regenerating corneal epithelium after limbus-to-limbus denudation. Graefes Arch Clin Exp Ophthalmol. 1987;225(1):53-58. Kasper M, Moll R, Stosiek P, Karsten U. Patterns of cytokeratin and vimentin expression in the human eye. Histochemistry. 1988;89(4):369-377. Kolega J, Manabe M, Sun TT. Basement membrane heterogeneity and variation in corneal epithelial differentiation. Differentiation. 1989;42(1):54-63. Dong Y, Roos M, Gruijters T, et al. Differential expression of two gap junction proteins in corneal epithelium. Eur J Cell Biol. 1994;64(1):95-100. Lehrer MS, Sun TT, Lavker RM. Strategies of epithelial repair: modulation of stem cell and transient amplifying cell proliferation. J Cell Sci. 1998;111(Pt 19):2867-2875. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance (letter). Invest Ophthalmol Vis Sci. 1977;16:14-20.

Limbal Stem Cell Deficiency 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

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Jenkins C, Tuft S, Liu C, Buckley R. Limbal transplantation in the management of chronic contactlens-associated epitheliopathy. Eye (Lond). 1993;7(Pt 5):629-663. Shimazaki J, Shimmura S, Fujishima H, Tsubota K. Association of preoperative tear function with surgical outcome in severe Stevens-Johnson syndrome. Ophthalmology. 2000;107(8):1518-1523. Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology. 1999;106(10):1984-1989. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol. 1999;83(4):390-395. Tsubota K. Tear dynamics and dry eye. Prog Retin Eye Res. 1998;17(4):565-596. Tsubota K, Higuchi A. Serum application for the treatment of ocular surface disorders. Int Ophthalmol Clin. 2000;40(4):113-122. Tsubota K, Shimazaki J. Surgical treatment of children blinded by Stevens-Johnson syndrome. Am J Ophthalmol. 1999;128(5):573-581. Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc. 1996;94:677-743. Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea. 1996;15(6):549-556. Daya SM, Chan CC, Holland EJ; Members of the Cornea Society Ocular Surface Procedures Nomenclature Committee. Cornea Society nomenclature for ocular surface rehabilitative procedures. Cornea. 2011;30(10)1115-1119. Thoft RA. Keratoepithelioplasty. Am J Ophthalmol. 1984;97(1):1-6. Turgeon PW, Nauheim RC, Roat MI, Stopak SS, Thoft RA. Indications for keratoepithelioplasty. Arch Ophthalmol. 1990;108(2):233-236. Tsai RJ, Tseng SC. Human allograft limbal transplantation for corneal surface reconstruction. Cornea. 1994;13(5):389-400. Tsubota K, Toda I, Saito H, Shinozaki N, Shimazaki J. Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology. 1995;102(10):1486-1496. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Ophthalmology. 1989;96(5):709-722. Kwitko S, Marinho D, Barcaro S, et al. Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology. 1995;102(7):1020-1025. Kenyon KR, Rapoza PA. Limbal allograft transplantation for ocular surface disorders. Ophthalmology. 1995;102(suppl):101-102. Schwartz GS, Holland EJ. Iatrogenic limbal stem cell deficiency. Cornea. 1998;17(1):31-37. Croasdale CR, Schwartz GS, Malling JV, Holland EJ. Keratolimbal allograft: recommendation for tissue procurement and preparation by eye banks, and standard surgical technique. Cornea. 1999;18(1):52-58. Tsubota K, Satake Y, Kaido M, et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. 1999;340(22):1697-1703. Mannis MJ, McCarthy M, Izquierdo L Jr. Technique for harvesting keratolimbal allografts from corneoscleral buttons. Am J Ophthalmol. 1999;128(2):237-238. Schwartz GS, Gomes JAP, Holland EJ. Preoperative staging of disease severity. In: Holland EJ, Mannis MJ, eds. Ocular Surface Disease. New York, NY: Springer; 2002:158-168. Holland EJ, Mogilishetty G, Skeens HM, et al. Systemic immunosuppresion in ocular surface stem cell transplantation: results of a 10-year experience. Cornea. 2012;31(6):655-661. Mogilishetty, G, Haird D, Alloway RR, et al. Comparision of immunosuppresion related toxicities and complications in ocular surface transplant and renal transplant recipients: implications for composite tissue transplantation [abstract]. Transplantation. 2008;86:11. Liang L, Sheha H, Tseng SC. Long-term outcomes of keratolimbal allograft for total limbal stem cell deficiency using combined immu¬nosuppressive agents and correction of ocular surface deficits. Arch Ophthalmol. 2009;127(11):1428-1434. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349(9057):990-993. Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med. 2000;343(2):86-93. Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K, Adachi E et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351(12):1187-1196.

178 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.

Chapter 16 Grueterich M, Espana EM, Touhami A, Ti SE, Tseng SC. Phenotypic study of a case with successful transplantation of ex vivo expanded human limbal epithelium for unilateral total limbal stem cell deficiency. Ophthalmology. 2002;109(8):1547-1552. Koizumi N, Inatomi T, Suzuki T, Sotozono C, Kinoshita S. Cultivated corneal epithelial stem cell transplantation in ocular surface disorders. Ophthalmology. 2001;108(9):1569-1574. Koizumi N, Inatomi T, Suzuki T, Sotozono C, Kinoshita S. Cultivated corneal epithelial transplantation for ocular surface reconstruction in acute phase of Stevens-Johnson syndrome. Arch Ophthalmol. 2001;119(2):298-300. Nakamura T, Inatomi T, Sotozono C, Koizumi N, Kinoshita S. Successful primary culture and autologous transplantation of corneal limbal epithelial cells from minimal biopsy for unilateral severe ocular surface disease. Acta Ophthalmol Scand. 2004;82(4):468-471. Nakamura T, Koizumi N, Tsuzuki M, et al. Successful regrafting of cultivated corneal epithelium using amniotic membrane as a carrier in severe ocular surface disease. Cornea. 2003;22(1):70-71. Sangwan VS, Matalia HP, Vemuganti GK, et al. Clinical outcome of autologous cultivated limbal epithelium transplantation. Indian J Ophthalmol. 2006;54(1):29-34. Sangwan VS, Murthy SI, Vemuganti GK, Bansal AK, Gangopadhyay N, Rao GN. Cultivated corneal epithelial transplantation for severe ocular surface disease in vernal keratoconjunctivitis. Cornea. 2005;24(4):426-430. Sangwan VS, Vemuganti GK, Iftekhar G, Bansal AK, Rao GN. Use of autologous cultured limbal and conjunctival epithelium in a patient with severe bilateral ocular surface disease induced by acid injury: a case report of unique application. Cornea. 2003;22(5):478-481. Sangwan VS, Vemuganti GK, Singh S, Balasubramanian D. Successful reconstruction of damaged ocular outer surface in humans using limbal and conjunctival stem cell culture methods. Biosci Rep. 2003;23(4):169-174. Shimazaki J, Aiba M, Goto E, Kato N, Shimmura S, Tsubota K. Transplantation of human limbal epithelium cultivated on amniotic membrane for the treatment of severe ocular surface disorders. Ophthalmology. 2002;109(7):1285-1290. Daya SM, Watson A, Sharpe JR, et al. Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction. Ophthalmology. 2005;112(3):470-477. Nakamura T, Inatomi T, Sotozono C, et al. Transplantation of autologous serum-derived cultivated corneal epithelial equivalents for the treatment of severe ocular surface disease. Ophthalmology. 2006;113(10):1765-1772. Rama P, Bonini S, Lambiase A, et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation. 2001;72(9):1478-1485. Schwab IR. Cultured corneal epithelia for ocular surface disease. Trans Am Ophthalmol Soc. 1999;97:891-986. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea. 2000;19(4):421-426. Freshney RI. Culture of Animal Cells: A Manual of Basic Techniques. New York, NY: John Wiley & Sons Inc; 2000. Grueterich M, Espana EM, Tseng SC. Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv Ophthalmol. 2003;48(6):631-646. Pellegrini G, Golisano O, Paterna P, et al. Location and cloncal analysis of stem cells and their differentiated progency in the human ocular surface. J Cell Biol. 1999;145(4):769-782. Kim HS, Jun Song X, de Paiva CS, Chen Z, Pflugfelder SC, Li DQ. Phenotypic characterization of human corneal epithelial cells expanded ex vivo from limbal explant and single cell cultures. Exp Eye Res. 2004;79(1):41-49. Budak MT, Alpdogan OS, Zhou M, Lavker RM, Akinci MA, Wolosin JM. Ocular surface epithelia contain ABCG2-dependent side population cells exhibiting features associated with stem cells. J Cell Sci. 2005;118(Pt 8):1715-1724. de Paiva CS, Chen Z, Corrales RM, Pflugfelder SC, Li DQ. ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells. Stem Cells. 2005;23(1):63-73. Watanabe K, Nishida K, Yamato M, et al: Human limbal epithelium contains side population cells expressing the ATP-binding cassette transporter ABCG2. FEBS Lett. 2004;565(1-3):6-10. Rama P, Bonini S, Lambiase A, et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation. 2001;72(9):1478-1485. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol. 2012;96(7):931-934.

Limbal Stem Cell Deficiency 73. 74. 75. 76. 77. 78. 79. 80.

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Daniels JT, Dart JK, Tuft SJ, Khaw PT. Corneal stem cells in review. Wound Repair Regen. 2001;9(6):483-494. Tseng SC. Concept and application of limbal stem cells. Eye (Lond). 1989;3(Pt 2):141-157. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000;44(5):415-425. Dua HS, Saini JS, Azuara-Blanco A, Gupta P. Limbal stem cell deficiency: concept, aetiology, clinical presentation, diagnosis and management. Indian J Ophthalmol. 2000;48(2):83-92. Ma Y, Xu Y, Xiao Z, et al. Reconstruction of chemically burned rat corneal surface by bone marrowderived human mesenchymal stem cells. Stem Cells. 2006;24(2):315-321. Nakamura T, Ishikawa F, Sonoda KH, et al. Characterization and distribution of bone marrowderived cells in mouse cornea. Invest Ophthalmol Vis Sci. 2005;46(2):497-503. Kinoshita S, Nakamura T. Development of cultivated mucosal epithelial sheet transplantation for ocular surface reconstruction. Artif Organs. 2004;28(1):22-27. Chakraborty A, Dutta J, Das S, Datta H. Comparison of ex vivo cultivated human limbal epithelial stem cell viability and proliferation on different substrates. Int Ophthalmol. 2013;33(6):665-670.

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17 Amniotic Membrane Transplantation Athiya Agarwal, MD, DO; Soosan Jacob, MS, FRCS, DNB, MNAMS; and Amar Agarwal, MS, FRCS, FRCOphth

Embryology The amniotic membrane is part of the amniotic sac, inside which the human embryo develops. It is formed by the mesoderm on the outer side and the ectoderm on the inner side. The amniotic cavity appears at approximately the second week of gestation. As the blastocyst burrows into the endometrium, lacunae are formed between the inner cell mass and the cytotrophoblast, which join to form the amniotic cavity. The amniotic sac continues to enlarge by cell division until approximately 28 weeks of gestation, after which it enlarges mainly by stretching.1 As the amniotic cavity enlarges, the extraembryonic coelom gets smaller until it is finally obliterated. At this stage, the amniotic membrane lies against the chorion to form the chorioamniotic membrane. Thus, the amniotic membrane arises from the cytotrophoblast. The amniotic sac contains the amniotic fluid, which is formed from both the maternal and fetal circulation. The main functions of the amniotic fluid are to form a protective cushion around the fetus and regulate its body temperature.

Anatomy of the Amniotic Membrane The placenta consists of the maternal desidua and the fetal amniochorion. The amnion and the chorion are loosely fused together. The amniotic membrane has a smooth and shiny appearance and consists of a single layer of cells on a thick basement membrane. This rests on an avascular stroma composed of a compact layer, a fibroblastic layer, and a spongy layer. It is 0.02 to 0.5 mm thick.2 The amniotic membrane has multipotent stem cells that are of low immunogenicity.

Physiology of the Amniotic Membrane The basement membrane of the amniotic membrane consists of types I, III, IV, V, and VII collagen; fibronectin; and types 1 and 5 laminin. It is abundant in various extracellular matrix materials.3,4 The basement membrane side of the amniotic membrane promotes epithelial cell adhesion, migration, and differentiation and prevents cellular apoptosis. It downregulates the transforming growth factor (TGF)-ß system and therefore allows normal differentiation and maintenance of cellular characteristics by corneal cells.5 The amniotic membrane also has anti-inflammatory and antiangiogenic properties. It expresses various growth factors and antiproteinases6,7 and myofibroblast differentiation.8,9 Because of

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the amniotic membrane’s dual role, that is, and anti-inflammatory and antifibrotic properties, it is likely to have an antiscarring effect, which can be put to good use in the cornea. The amniotic membrane has no human leukocyte antigen A, B, C, or DR antigens on its surface, which is why it does not incite an effective immune response following amniotic membrane allograft transplantation.10

Amniotic Membrane Preparation The amniotic membrane has the great advantage of being easily obtainable. When used for ophthalmological purposes, it is taken from placentas obtained via elective Caesarean section and is handled in sterile conditions. The amniotic membrane is easily separated from the chorion at the level of the spongy layer of stroma by stripping it off. Once stripped, it is cleaned of blood and blood clots under a laminar flow hood and is prepared as described by Tseng et al.11 It is immersed in phosphate-buffered saline (PBS) containing 50 μg/mL of penicillin, 50 μg/mL of streptomycin, 100 μg/mL of neomycin, and 2.5 μg/mL of amphotericin B. The membrane is then laid onto nitrocellulose filter paper stromal side down and is cut into pieces, each of which is stored in Dulbecco’s modified Eagle medium and glycerol in a 1:1 ratio. The membranes are then cryopreserved until use at – 80°C.12 The placental donor is always screened for infectious diseases such as human immunodeficiency virus 1 and 2, hepatitis B surface antigen, hepatitis C virus, and syphilis at the time of obtaining the placenta and then again 3 months after Caesarean section. A small section of the membrane is also sent for microbiological evaluation and culture and sensitivity for bacteria and fungi. Once all tests come back negative, the membranes are released for use. Freshly prepared amniotic membrane may also be used from the placenta obtained through elective Caesarean section of serologically screened individuals. These are cleaned and prepared as described earlier and are used immediately in the patient.

Role of the Amniotic Membrane in Ophthalmology The amniotic membrane was first used by De Rotth13 in 1940, but it was not until 1995 that Kim and Tseng14 made its use widespread and popular. The amniotic membrane is used for its anti-inflammatory and antiangiogenic properties and for its ability to promote epithelial differentiation, adhesion, and migration. It also has antibacterial, wound-protecting, pain-reducing, and fibrosis-suppressing effects. It can be used as a graft, where it fills defects and promotes epithelialization, or it can be used as a patch, where its anti-inflammatory and antiangiogenic properties are important.15-17 It may also be used simultaneously as a patch graft, according to the underlying condition being treated. The stromal side of the amniotic membrane is differentiated from the basement membrane by touching with a sponge. The stromal side is sticky, whereas the basement membrane side is not.

Corneal Uses Persistent Epithelial Defects The amniotic membrane has been used in the treatment of persistent epithelial defects secondary to neurotrophic corneas, autoimmune disorders, or limbal stem cell deficiency (Figure 17-1). In these cases, the amniotic membrane may act by inhibition of collagenases while simultaneously providing collagen and a basement membrane on which to grow epithelial cells. The amniotic membrane also provides growth factors, which provide a conducive atmosphere in which to grow epithelial cells.15,18

Corneal/Scleral Melts The amniotic membrane can be used as a patch graft or an inlay-onlay graft. It is used to fill the defect and replace stromal matrix loss caused by the melt. This is done by using a multilayered

Amniotic Membrane Transplantation

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Figure 17.1. (A) Slit and (B) oblique views of a persistent epithelial defect in a corneal graft.

Figure 17-2. (A) Amniotic membrane with fibrinogen applied on one half and thrombin on the other half. On folding together, these 2 constituents of fibrin glue stick layers of the folded amniotic membrane together. (B) The process is repeated to produce a 4-layered amniotic membrane. (C) The area of scleral melt is filled with this multilayered amniotic membrane graft cut to size and glued into place as an inlay. Any excess outside the area of melt is trimmed. (D) The entire inlay graft is covered with an onlay patch graft of amniotic membrane.

amniotic membrane. The amniotic membrane is repeatedly folded on itself, and fibrin glue is used to stick the multiple layers to each other. Once this inlay is prepared, the base and edges of the defect are scraped, and all necrotic tissue and loose epithelium are removed. The inlay is then used to fill the defect and is stuck into place using glue and anchoring sutures. An amniotic membrane patch or an onlay graft is then used to cover the inlay graft in such a manner as to extend beyond the denuded epithelium. This onlay provides anti-inflammatory effects and promotes wound healing (Figure 17-2). Confocal microscopy of the transplanted amniotic membrane filler shows its contraction, remodeling with new collagen formation, and population by corneal stroma–derived cells by approximately 3 months, implying the integration of the filler inlay graft into the corneal matrix.19 Reepithelialization of the amniotic membrane is essential for integration of the graft into the stroma. In the sclera, integration into the scleral stroma usually halts the disease process; however, in the cornea, the graft persists as a scar in the stroma. Nevertheless, it makes the cornea amenable to a future transplant in a quiet eye. Some studies have also used this technique in deep ulcers and descemetoceles.15,20 Amniotic membrane use alone is insufficient in cases of corneal ulcer with active infection and should be avoided. It may also not be enough by itself to provide tectonic support in cases of large areas of scleral melt with staphyloma formation or in large corneal ulcers where tissue with greater tectonic support, such as a corneal or scleral tectonic graft, should be used. In cases with ongoing scleral melt and necrosis, additional medical management directed at the disease pathology is required.

Bullous Keratopathy Bullous keratopathy secondary to surgery or Fuchs’ dystrophy in an eye with no potential for vision can be treated with amniotic membrane grafting.21 The amniotic membrane may be used as isolated treatment after removing the unhealthy epithelium or in conjunction with anterior stromal puncture or phototherapeutic keratectomy. The membrane is spread out under tension and sutured

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Figure 17-3. The use of freshly prepared amniotic membrane for partial limbal stem cell deficiency.

onto the cornea stromal side down. It acts as a good alternative to conjunctival hooding in these cases and provides better cosmetic results to the patient than the conjunctival flap. It also does not decrease the chances of survival of a future keratoplasty if required, unlike conjunctival flaps.

Limbal Stem Cell Deficiency The limbal stem cells are responsible for continuous replenishment of the corneal epithelial cells, which Thoft and Friend 22 proposed to occur via the X,Y,Z hypothesis.22

Partial Limbal Stem Cell Deficiency The amniotic membrane can be used in partial limbal stem cell deficiency as an isolated treatment modality. It is spread over the corneal and conjunctival surface and anchored in place using sutures with or without fibrin glue (Figure 17-3). This may be attributed to its unique properties of prolonging the lifespan of corneal and conjunctival progenitor cells and maintaining slow-cycling label-retaining cells.23-25 It can thus be used to expand the surviving limbal stem cells and the transient amplifying cells of the cornea.25

Total Limbal Stem Cell Deficiency In a patient with total limbal stem cell deficiency, stem cell transplantation restores the normal phenotypic corneal epithelium. It also acts as a barrier to conjunctivalization. Amniotic membrane is used in conjunction with limbal stem cell autograft (Figure 17-4) or allograft. In all cases, it has multiple beneficiary effects. It provides a protective cover over the transplanted stem cells and protects it from external trauma and lid movements until the stem cell graft is incorporated into the recipient eye. Its anti-inflammatory properties and its inhibition of angiogenesis help in suppressing graft rejection to an extent. It decreases corneal scar formation after pannus excision. It also promotes epithelial differentiation, adhesion, and migration from the newly transplanted limbal stem cells. The limbal stem cells are harvested as an autograft from the other eye of the same patient (Figure 17-5) or are taken as an allograft. An allograft can be from either a living related donor or a cadaveric eye (Figures 17-6 and 17-7). An advantage of cadaveric eyes is the ability to transplant a much greater number of limbal stem cells, which is not possible in either autograft or a living related donor because of the risk of inducing iatrogenic limbal stem cell deficiency (Figure 17-8). It is also used in cases where the patient or the relative is not willing to be a donor. Once the host cornea is cleared of scar tissue and pannus, the limbal stem cell donor tissue is sutured onto the host limbus. The entire graft and sometimes the entire donor cornea (depending on the amount of corneal dissection) are covered with the amniotic membrane. A small central hole may be cut with scissors over the pupillary area to enable the patient to see (in the case of a one-eyed patient).

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Figure 17-4. (A) A conjunctival limbal autograft (CLAU) is taken from the contralateral eye. (B) The CLAU after harvesting. Two such grafts were harvested. (C) Unhealthy epithelium and pannus are resected off the affected eye in preparation for limbal stem cell transplantation. (D) The inferior CLAU is sutured in place. (E) Recipient eye after both grafts have been sutured in place. (F) Amniotic membrane is used to cover the entire ocular surface.

Figure 17-5. Patient shown in Figure 17-4 at 1 year postoperatively. (A) Healthy contralateral donor eye. (B) Healthy stem cell graft in recipient eye with an improved ocular surface.

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Figure 17-6. (A) Cadaveric keratolimbal allograft (KLAL) performed in a patient unwilling to receive an autograft and with no other willing donor. (B) The KLAL is covered with an amniotic membrane graft at the conclusion of surgery. The amniotic membrane is firmly fixed at the limbus with sutures in addition to being sutured at the edges.

A

B

Figure 17-7. (A) Preoperative appearance of the patient in Figure 17-6. (B) Six-month postoperative appearance of the same patient, maintained on systemic and topical immunosuppressives.

The amniotic membrane helps make the perilimbal microenvironment conducive to the limbal stem cell transplantation.27

Amniotic Membrane Transplantation

A

187

B

Figure 17-8. (A) Illustration of a cadaveric stem cell graft, which gives the ability to harvest and transplant up to 1.5 times more stem cells than an autograft or a living related allograft. (B) Cadaveric KLAL performed on a patient with severe limbal stem cell deficiency.

Conjunctival Uses Pterygium Excision Pterygia are known to be associated with a high recurrence rate. Various modalities including the use of mitomycin C and conjunctival autografts have been reported to decrease the incidence of recurrence. Amniotic membranes have also been used in pterygium surgery, especially in surgery for large, double-headed pterygia and in patients with inadequate conjunctiva to perform a conjunctival autograft. Nevertheless, conjunctival autograft has been shown to have a lower incidence of postoperative inflammation and recurrence than amniotic membrane transplantation.28,29 The amniotic membrane graft provides anti-inflammatory and antifibrotic effects via downregulation of TGF-ß and is thus beneficial in preventing recurrence (Figure 17-9).

Fornix Reconstruction Many cases of symblephara, fornix foreshortening, and forniceal obliteration require correction of lid deformity and reformation of fornices. Simple dissection alone, even if combined with symblepharon rings, may not always succeed because the raw surfaces obtained after dissection easily adhere and fuse again if allowed to be in contact with each other. The amniotic membrane may be used to cover these raw surfaces.30,31 Once the fornix is dissected out, the affected part of the bulbar, forniceal, and palpebral conjunctiva is covered with amniotic membrane, which is held in place using a combination of glue and sutures. Glue alone is generally not sufficient. Fornixforming sutures are then placed: double-armed sutures are passed through the fornix, through the orbital rim periosteum, and tied down on the surface of the lids using bolsters (Figure 17-10).

Surface Reconstruction The amniotic membrane can be used for ocular surface reconstruction after removal of large lesions, such as ocular surface squamous neoplasias or large pterygia, or for other surgeries that result in the loss of a large area of the conjunctival surface with inadequate conjunctiva available for autograft (Figure 17-11). It is also used for closing conjunctival defects in patients with preexisting blebs or those who might require a trabeculectomy or valve surgery in the future. Placing an amniotic membrane graft in such patients leaves the superior conjunctiva untouched for possible future use.

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Figure 17-9. (A) A large pterygium extending onto the cornea. The conjunctival component is cut. (B) The pterygium head is stripped off the underlying stroma. (C) An amniotic membrane graft is used to cover the conjunctival defect and is placed over the raw surface on the cornea. (D) The amniotic membrane is glued into place.

Acute Corneal and Conjunctival Insults Stevens-Johnson syndrome, toxic epidermal necrolysis, mucous membrane pemphigoid, and chemical and thermal burns can all cause extensive damage to the limbal stem cells and the conjunctiva, resulting in a multitude of problems, including persistent epithelial defects, corneal ulceration, stem cell deficiency, conjunctival cicatrization, symblepharon formation, and fornix foreshortening (Figure 17-12). In the early stages of these conditions, covering the ocular surface with an amniotic membrane graft decreases the chances of complications by means of its antiinflammatory, antiangiogenic, antiscarring, and proepithelial effects. The amniotic membrane graft prevents symblepharon formation by acting as a physical barrier, and it also likely provides a scaffold for early reepithelialization.32-34 During the acute phase of Stevens-Johnson syndrome or toxic epidermal necrolysis, amniotic membrane is used as a patch graft covering the entire ocular surface and dipping into the fornix and out onto the eyelid margin. Delayed or inadequate coverage may result in substandard results. It is used in combination with intensive steroid therapy and a large-diameter Kontur lens (Kontur Kontact Lens Co, Inc) to maintain the fornices. They can also be used similarly for acute chemical and thermal burns.35

Bleb Leaks and Overfiltering Blebs Late bleb leaks and overfiltering blebs are generally seen after the application of wound-modulating agents. The conjunctiva covering the bleb is often thin and avascular. Excision of the bleb and direct resuturing, conjunctival advancement, or conjunctival autografts may be used, but these depend on the availability of adequate mobile conjunctiva to cover the defect without shortening the fornix. As described by Budenz et al,36 these blebs can be closed with amniotic membrane

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Figure 17-10. (A) The amniotic membrane is placed into the raw area created after separation of the symblepharon. (B) Fornix-forming sutures are placed: doublearmed sutures are passed through the fornix, the inferior orbital rim periosteum, and out through the skin. (C) The sutures are tied over bolsters on the eyelid skin.

graft, although they reported superior results with conjunctival advancement. The amniotic membrane is used to cover the defect after excising the area of thin, avascular conjunctiva. In our personal experience, we prefer performing a conjunctival advancement in conjunction with an amniotic membrane graft applied under the conjunctiva. The amniotic membrane decreases subconjunctival fibrosis and the possible failure of bleb functioning (Figures 17-13 and 17-14). This is because the amniotic membrane is thin and avascular, similar to a bleb with antimetabolite; therefore, it is possible that there may be bleb leak and an increased risk of endophthalmitis in cases of blebs reconstructed with amniotic membrane alone (as noted by Budenz et al36). The use of amniotic membrane under the scleral flap instead of antifibrotic agents has also been described by Fujishima et al.37

Tissue-Cultured Human Amniotic Epithelial Cells Corneal collagen sheets seeded with amniotic epithelial cells obtained from human donor placentas are cultured ex vivo and have been used for the treatment of various conditions, such as

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Figure 17-11. (A) Ocular surface squamous neoplasia for which an epitheliectomy with conjunctivo-tenonectomy and superficial lamellar sclerectomy is performed. (B) The eye after resection of the tumor. (C) The conjunctival defect and corneal deepithelialized area of the cornea is covered with an amniotic membrane graft.

Figure 17-12. The loss of limbal stem cells secondary to chemical burns as opposed to the normal appearance of the palisades of Vogt (inset).

persistent epithelial defects.38 The advantage of this technique is that it is repeatable, fast, and easy to perform and does not involve surgery.

Amniotic Membrane Substrate for Ex Vivo Expansion of Limbal Stem Cells The amniotic membrane is nonimmunogenic and contains no actively replicating cells. It also promotes epithelial adhesion and migration. Hence, it is an ideal substrate for ex vivo expansion of limbal stem cells obtained via a small biopsy from the patient’s eye.39 Once expanded on the amniotic membrane sheet, this can be used to transfer the limbal stem cells to the patient’s eye. It

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Figure 17-13. (A) A thin-walled mitomycin C bleb is excised. (B) A scleral autopatch graft is applied. (C) The amniotic membrane is applied. (D) A conjunctival advancement flap is created at the end of the procedure.

has the advantage of not leading to iatrogenic limbal stem cell deficiency in the donor eye because only a small biopsy is required.

Conclusion Although various theories have been proposed regarding how the amniotic membrane works under various conditions, the exact mechanism and composition of this invaluable membrane are not fully understood. It is easily obtainable, relatively inexpensive, and easy to manipulate. Despite being an allograft, it has low immunogenicity and therefore does not cause rejection.

References 1. 2. 3. 4. 5. 6.

Blackburn ST. Prenatal period and placental physiology. In: Maternal, Fetal, and Neonatal Physiology: A Clinical Perspective. 4th ed. St Louis, MO: Saunders; 2007:70-120. Bourne GL. The microscopic anatomy of the human amnion and chorion. Am J Obstet Gynecol. 1960;79:1070-1073. Fukuda K, Chikama T, Nakamura M, Nishida T. Differential distribution of subchains of the basement membrane components type IV collagen and laminin among the amniotic membrane, cornea, and conjunctiva. Cornea. 1999;18(1):73-79. Dua HS, Gomes JA, King AJ, Maharajan VS. The amniotic membrane in ophthalmology. Surv Ophthalmol. 2004;49(1):51-77. Boudreau N, Sympson CJ, Werb Z, Bissell MJ. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science. 1995;267(5199):891-893. Koizumi N, Inatomi T, Sotozono C, Fullwood NJ, Quantock AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res. 2000;20(3):173-177.

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Figure 17-14. (A) The same patient 6 months postoperatively, after undergoing a cataract extraction with intraocular lens implantation. The superior area of the bleb is seen. The intraocular pressure remained under control. (B) Slit lamp view of the cornea and anterior chamber.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Na BK, Hwang JH, Kim JC, et al. Analysis of human amniotic membrane components as proteinase inhibitors for development of therapeutic agent of recalcitrant keratitis. Trophoblast Res. 1999;13:459-466. Tseng SC, Li DQ , Ma X. Suppression of transforming growth factor-beta isoforms, TGF-beta receptor type II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. J Cell Physiol. 1999;179(3):325-335. Lee SB, Li DQ , Tan DT, Meller DC, Tseng SC. Suppression of TGF-beta signaling in both normal conjunctival fibroblasts and pterygial body fibroblasts by amniotic membrane. Curr Eye Res. 2000;20(4):325-334. Adinolfi M, Akle CA, McColl I, et al. Expression of HLA antigens, beta 2-microglobulin and enzymes by human amniotic epithelial cells. Nature. 1982; 295(5847):325-327. Tseng SCG, Prabhasawat P, Lee S-H. Amniotic membrane transplantation for conjunctival surface reconstruction. Am J Ophthalmol. 1997:124:765-774. Wang MX, Gray TB, Park WC, et al. Reduction in corneal haze and apoptosis by amniotic membrane matrix in excimer laser photoablation in rabbits. J Cataract Refract Surg. 2001;27(2):310-319. De Rotth A. Plastic repair of conjunctival defects with fetal membrane. Arch Ophthalmol. 1940;23:522-525. Kim JC, Tseng SC. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas. Cornea. 1995;14(5):473-484. Hanada K, Shimazaki J, Shimmura S, Tsubota K. Multilayered amniotic membrane transplantation for severe ulceration of the cornea and sclera. Am J Ophthalmol. 2001;131(3):324-331. Colocho G, Graham WP III, Greene AE, Matheson DW, Lynch D. Human amniotic membrane as a physiologic wound dressing. Arch Surg. 1974;109(3):370-373. Talmi YP, Finkelstein Y, Zohar Y. Use of human amniotic membrane as a biologic dressing. Eur J Plast Surg. 1990;13:160-162. Meller D, Tseng SC. Conjunctival epithelial cell differentiation on amniotic membrane. Invest Ophthalmol Vis Sci. 1999;40(5):878-886.

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19. Nubile M, Dua HS, Lanzini M, et al. In vivo analysis of stromal integration of multilayer amniotic membrane transplantation in corneal ulcers. Am J Ophthalmol. 2011;151(5):809-822.e1. 20. Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology. 2002;109(4):694-703. 21. Pires RT, Tseng SC, Prabhasawat P, et al. Amniotic membrane transplantation for symptomatic bullous keratopathy. Arch Ophthalmol. 1999;117(10):1291-1297. 22. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci. 1983;24(10):1442-1443. 23. Meller D, Tseng SC. In vitro conjunctival epithelial differentiation on preserved human amniotic membrane. Invest Ophthalmol Vis Sci. 1998;39(suppl):S428. 24. Meller D, Pires RT, Tseng SC. Ex vivo preservation and expansion of human limbal epithelial progenitor cells by amniotic membrane. Invest Ophthalmol Vis Sci. 1999;40(suppl):S329. 25. Anderson DF, Ellies P, Pires RT, Tseng SC. Amniotic membrane transplantation for partial limbal stem cell deficiency. Br J Ophthalmol. 2001;85(5):567-575. 26. Tseng SC, Prabhasawat P, Barton K, Gray T, Meller D. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency. Arch Ophthalmol. 1998;116(4):431-441. 27. Gomes JA, dos Santos MS, Cunha MC, Mascaro VL, Barros JN, de Sousa LB. Amniotic membrane transplantation for partial and total limbal stem cell deficiency secondary to chemical burn. Ophthalmology. 2003;110(3):466-473. 28. Kheirkhah A, Nazari R, Nikdel M, Ghassemi H, Hashemi H, Behrouz MJ. Postoperative conjunctival inflammation after pterygium surgery with amniotic membrane transplantation versus conjunctival autograft. Am J Ophthalmol. 2011;152(5):733-738. 29. Miyai T, Hara R, Nejima R, Miyata K, Yonemura T, Amano S. Limbal allograft, amniotic membrane transplantation, and intraoperative mitomycin C for recurrent pterygium. Ophthalmology. 2005; 112(7):1263-1267. 30. Kheirkhah A, Blanco G, Casas V, Hayashida Y, Raju VK, Tseng SC. Surgical strategies for fornix reconstruction based on symblepharon severity. Am J Ophthalmol. 2008;146(2):266-275. 31. Solomon A, Espana EM, Tseng SC. Amniotic membrane transplantation for reconstruction of the conjunctival fornices. Ophthalmology. 2003;110(1):93-100. 32. Shammas MC, Lai EC, Sarkar JS, Yang J, Starr CE, Sippel KC. Management of acute StevensJohnson syndrome and toxic epidermal necrolysis utilizing amniotic membrane and topical corticosteroids. Am J Ophthalmol. 2010;149(2):203-213.e2. 33. Barabino S, Rolando M, Bentivoglio G, et al. Role of amniotic membrane transplantation for conjunctival reconstruction in ocular-cicatricial pemphigoid. Ophthalmology. 2003;110(3):474-480. 34. John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology. 2002;109(2):351-360. 35. Sridhar MS, Bansal AK, Sangwan VS, Rao GN. Amniotic membrane transplantation in acute chemical and thermal injury. Am J Ophthalmol. 2000;130(1):134-137. 36. Budenz DL, Barton K, Tseng SC. Amniotic membrane transplantation for repair of leaking glaucoma filtering blebs. Am J Ophthalmol. 2000;130(5):580-588. 37. Fujishima H, Shimazaki J, Shinozaki N, Tsubota K. Trabeculectomy with the use of amniotic membrane for uncontrolled glaucoma. Ophthalmic Surg Lasers. 1998;29(5):428-431. 38. Parmar DN, Alizadeh H, Awwad ST, et al. Ocular surface restoration using non-surgical transplantation of tissue-cultured human amniotic epithelial cells. Am J Ophthalmol. 2006;141(2):299-307. 39. Grueterich M, Espana EM, Tseng SC. Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Surv Ophthalmol. 2003;48(6):631-646.

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Section III Corneal Surgery Related to Cataract Surgery

18 Limbal Relaxing Incisions Rachel Kwok, MBBS; Sunil Ganekal, FRCS; and Vishal Jhanji, MD A limbal relaxing incision (LRI) involves the placement of an incision near the limbus to flatten the central cornea and correct astigmatism. The first description of a nonpenetrating incision placed near the limbus for correction of astigmatism dates back to 1898, when it was first performed by Dutch ophthalmologist L.J. Lans.1 The demand for good unaided visual acuity at the time of cataract surgery has increased with advances in technology, especially with the use of the presbyopic intraocular lens (IOL) and keratorefractive surgery.2 Astigmatism has a significant influence on postoperative unaided visual acuity after cataract surgery. Past experience shows that astigmatism as low as 0.75 diopters may cause patients to have visual blurring and halos after a successful cataract operation.3,4 Studies suggest that approximately a quarter of patients who undergo cataract surgery have preexisting astigmatism of more than 0.75 diopters. After the addition of 0.5 diopters of surgically induced astigmatism caused by a clear corneal wound during phacoemulsification, more than a quarter of the patients may suffer from postoperative visually disturbing astigmatism. Corneal astigmatism can be reduced by manipulating corneal surfaces by corneal incisions, mainly limbal relaxing incisions and astigmatic keratotomies. It can also be achieved with the help of laser refractive surgery such as photorefractive keratectomy and LASIK. More commonly used toric IOLs have the potential to avoid induced irregular astigmatism from corneal manipulation while providing the option of reversibility.5 The main advantages of LRIs over astigmatic incisions include a lesser chance of causing a shift in the resultant cylinder axis, a low incidence of overcorrection, and a reduced incidence of dry eye syndrome due to resultant corneal denervation. Moreover, LRIs are easier to perform and are stable over the long term. LRI is usually effective in patients with preexisting astigmatism of 1 to 1.5 diopters. Astigmatism less than this would be easily corrected by placing a clear corneal incision on the steep axis during cataract surgery.6 Once the preexisting astigmatism is more than 1.5 diopters, the risk of LRI may not be outweighed by its benefit, and some surgeons may choose a toric IOL for correction of astigmatism in this range.2 During LRI creation, paired incisions are fashioned on the steep axis, at the most peripheral extent of the clear corneal tissue, just inside the true surgical limbus. By adjusting length, depth, and location one can induce change in corneal astigmatism.6,7 The incised steep meridian flattens with simultaneous steepening of the flat meridian. The amount of flattening that occurs in the incised meridian relative to the amount of steepening that occurs 90 degrees away is called the coupling ratio. Typically, paired LRIs exhibit a coupling ratio of 1:1. - 197 -

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When a toric IOL is not available, LRI is capable of correcting astigmatism up to 3.5 diopters.5

Timing of Surgery LRI can be performed in the same setting as phacoemulsification,6,8,9,10 or it can be performed for any significant astigmatism after cataract surgery.8 When LRIs are done in the same setting as phacoemulsification, there is the advantage of avoiding two visits to the operating room and thus enhancing the efficiency of the surgery. LRIs performed in another setting after the primary cataract operation are usually performed 6 weeks after cataract surgery to allow for refraction stability and complete healing before the second procedure. It has the advantage of a more accurate measurement of corneal astigmatism to be corrected.

Preoperative Assessment Preoperative evaluation is important for patients receiving an LRI, including a thorough medical and ocular history to look for any disease or condition that may potentially affect the results of LRI. It is generally taught that the most challenging part of astigmatism surgery involves determination of the quantity and exact location of the cylinder to be treated.4 It is particularly so when preoperative assessments, including manifest refraction, keratometry, and corneal topography, do not agree with each other. Although manifest refraction is an important assessment before cataract surgery, one should be careful in planning LRI with manifest astigmatism because a lenticular component is also reflected. Corneal tomography measured either by scanning slit or Scheimpflug imaging is now standard protocol before planning for LRI. Topographic measurement of corneal astigmatism is also helpful in detecting early ectasia. In cases with a small discrepancy between the above results, one can consider taking an average of the measurements. However, for patients with very different results from the above measurements, a sequential LRI procedure should be performed to obtain more accurate measurements.4

Nomograms After obtaining the quantity and location of astigmatism to be treated, a nomogram can be referred to for incision length in millimeters, degrees, or clock hours. In principle, the younger the patient, the more aggressive the incision. Several nomograms are available for determination of the degree of arc to be incised. Surgeons could also develop their own nomograms. The degree of arc to be incised is decided after considering the patient’s age and preoperative cylinder to be corrected. The Nichamin nomogram takes into account the patient’s age, and astigmatism is considered to be with-the-rule if the steep axis is between 45 and 135 degrees. Against-the-rule astigmatism is considered to fall between 0 and 44 degrees and 136 and 180 degrees. Most nomograms for LRIs call for nonpenetrating incisions placed perpendicular to the corneal tissue. Many nomograms are currently available, including Gills,3,10,11 Koch,8 the Nichamin Age and Pachymetry Adjusted,4 and Thorton.4 In the Gills nomogram, paired incisions of 6 mm are required for each diopter of astigmatism up to 2 diopters. To correct between 2 and 3 diopters, LRIs of 8 mm in length are used. The Nichamin nomogram, which was designed specifically for the cataract patient, is based on the use of an empiric blade depth setting of 600 μm. The Nichamin Age and Pachymetry Adjusted nomogram is used in relatively younger patients, particularly in the setting of refractive lens exchange surgery and when presbyopia-correcting IOLs are used, or in conjunction with LASIK for the correction of higher levels of astigmatism. Online nomograms are also available, including one at www.lricalculator.com.

Surgical Procedure It is thought that LRI may be a misnomer because the incisions are not exactly placed at the surgical limbus (otherwise it would not have a flattening effect on the central cornea). The incisions are usually placed 1 to 1.5 mm anterior to the surgical limbus.4 When LRI is performed together with cataract surgery, it is usually performed at the beginning of the procedure so that a

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Figure 18-1. LRI technique. The eye is stabilized firmly, and the diamond blade is held perpendicular to the corneal surface.

consistent depth can be produced with an intact globe.4,6,8,10,12 However, some surgeons prefer to perform LRI at the conclusion of surgery in the event that a complication occurs, necessitating a modification to the phacoemulsification incision. Most surgeons prefer to place the reference marking on the cornea in a sitting position under a slit lamp13 preoperatively to avoid unpredictable cyclotorsion of the eyeball, especially when an injection anesthesia is used. This is particularly important in cases with high astigmatism. Increasing evidence supports the notion that significant cyclotorsion may occur when the patient is supine. An axis deviation of only 15 degrees may result in up to a 50% reduction of surgical effect. A special fixation ring with markings is used to mark the location of the meridian to be treated. Pachymetry is performed over the entire arc length of the intended incision site, and a diamond blade with an adjustable micrometer is set to 90% of the thinnest reading obtained.2 Various instruments have been designed for LRI, ranging from disposable steel blades to diamond blades. Special astigmatic keratotomy blades come with an adjustable micrometer handle or a preset depth of 600 μm. The incision should be made in the limbal area just inside the conjunctiva. The incision can be single or paired in the 180-degree opposite meridian (Figure 18-1). Paired incisions can be performed in patients with a higher degree of astigmatism to prevent postoperative irregular astigmatism. The incision depth should be approximately 90% of the thinnest corneal depth in the periphery (approximately 450 to 600 μm). More accuracy can be achieved by performing pachymetry of the peripheral cornea prior to the procedure. The blade should be held in a perpendicular direction and the incision performed following the limbal curvature. An intraoperative keratoscope, such as the Maloney (Storz, Katena) or Nichamin (Mastel Precision) keratoscope, or a microscope-mounted instrument such as the Mastel Ring Light (Mastel Precision) can be used to identify the steep axis. When an LRI is superimposed on the phacoemulsification tunnel, keratome entry is first accomplished by pressing the bottom surface of the keratome blade downward on the outer or posterior edge of the LRI. The keratome is then advanced into the LRI at an iris-parallel plane. This angulation will promote a dissection that occurs at midstromal depth, which will help assure adequate tunnel length and a self-sealing closure. Proper centration of the incisions over the steep corneal meridian is of utmost importance (Figure 18-2). Basic concepts in the creation of corneal incisions include the following:2,4,14,15 • Larger incisions cause greater flattening. • Larger corneal incision arc length produces greater flattening of the cornea at that meridian. Due to the coupling effect, arc lengths of more than 90 degrees are ineffective.

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Figure 18-2. LRI barely visible 4 weeks after cataract surgery (arrow).

• Central incisions cause greater flattening as compared with more peripheral incisions. • For penetrating incisions, the shorter the tunnel length, the greater the flattening; and for nonpenetrating incisions, the deeper the incision, the greater the flattening effect.

Complications LRIs are a safer and more forgiving approach to managing astigmatism compared with more central corneal incisions.4 Nonetheless, as with any surgical technique, potential complications exist. Of these, the most likely to be encountered is the placement of incisions on the wrong axis. When this occurs, it typically takes the form of a 90-degree error with positioning on the opposite, flat meridian. The surgeon should consider using safety checks to prevent this complication from occurring, such as having a written plan and keeping the location and length of the corneal incision properly oriented during the surgery. When using a blade depth setting of 600 μm, corneal perforation, although rare, is possible. This may be due to an improper setting of the blade depth or as a result of a defect in the micrometer mechanism. The latter problem may arise after repeated autoclaving and many sterilization runs. Periodic inspection and calibration are therefore warranted. When encountered, unlike radial microperforations, these circumferential perforations will likely require placement of temporary sutures. Other potential complications associated with LRI include the following:4,14 • Induction of irregular astigmatism • Decreased corneal sensation • Dry eye symptoms • Keratitis • Endophthalmitis16

Comparison of Limbal Relaxing Incision With Other Modalities In the past, when LRI was less popular, more centrally located corneal relaxing incisions and arcuate keratotomy were performed for astigmatism correction. When compared with corneal relaxing incisions and arcuate keratotomy, LRIs are more forgiving in terms of incision depth and length. LRIs also produce less distortion to the central cornea; thus, there is less chance of causing irregular astigmatism. Due to the closer distance to well-vascularized limbal tissue, LRIs are less

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likely to cause dry eye problems due to denervation. The recovery period is also reduced, with less postoperative pain. When compared with a toric IOL, LRI has the advantage of refractive stability after the procedure and can be performed with many IOLs.2 It treats astigmatism at the corneal plane and also has a lower cost than a toric IOL.9 LRI can also be used as an augmentation in an outpatient setting after the procedure. However, a toric IOL can treat a higher degree of astigmatism and causes less pain and fewer potential corneal complications postoperatively.

Contraindications Similar to other keratorefractive procedures, LRI should not be performed on corneas with ectasia such as keratoconus.2 LRI is also contraindicated in patients with a history of peripheral ulcerative keratitis, such as in cases of autoimmune disease. Other inflammatory or degenerative diseases affecting the peripheral cornea can be easily detected during preoperative assessment.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Abrams D. Ophthalmic optics and refraction. In: Duke-Elder SS, ed. System of Ophthalmology. St. Louis, MO: Mosby; 1970:671-674. Amesbury EC, Miller KM. Correction of astigmatism at the time of cataract surgery. Curr Opin Ophthalmol. 2009;20(1):19-24. Kim DH, Wee WR, Lee JH, Kim MK. The short term effects of a single limbal relaxing incision combined with clear corneal incision. Korean J Ophthalmol. 2010:24(2):78-82. Nichamin LD. Astigmatism control. Ophthalmol Clin North Am. 2006;19(4):485-493. Talley-Rostov A. Patient-centered care and refractive cataract surgery. Curr Opin Ophthalmol. 2008;19(1):5-9. Kaufmann C, Peter J, Ooi K, et al. Limbal relaxing incisions versus on-axis incisions to reduce corneal astigmatism at the time of cataract surgery. J Cataract Refract Surg. 2005;31(12):2261-2265. Arraes JC, Cunha F, Arraes TA, Cavalvanti R, Ventura M. Limbal relaxing incisions during cataract surgery: one-year follow-up [in Portuguese]. Arq Bras Oftalmol. 2006;69(3):361-364. Budak K, Friedman NJ, Koch DD. Limbal relaxing incisions with cataract surgery. J Cataract Refract Surg. 1998;24(4):503-508. Poll JT, Wang L, Koch DD, Weikert MP. Correction of astigmatism during cataract surgery: toric intraocular lens compared to peripheral corneal relaxing incisions. J Refract Surg. 2011;27(3):165-171. Müller-Jensen K, Fischer P, Siepe U. Limbal relaxing incisions to correct astigmatism in clear corneal cataract surgery. J Refract Surg. 1999;15(5):586-589. Bayramlar H Hü, Dağlioğlu MC, Borazan M. Limbal relaxing incisions for primary mixed astigmatism and mixed astigmatism after cataract surgery. J Cataract Refract Surg. 2003;29(4):723-728. Ganekal S, Dorairaj S, Jhanji V. Limbal relaxing incisions during phacoemulsification: 6-month results. J Cataract Refract Surg. 2011;37(11):2081-2082. Miyata K, Miyai T, Minami K, Bissen-Miyajima H, Maeda N, Amano S. Limbal relaxing incisions using a reference point and corneal topography for intraoperative identification of the steepest meridian. J Refract Surg. 2011;27(5):339-344. Ouchi M, Kinoshita S. Prospective randomized trial of limbal relaxing incisions combined with microincision cataract surgery. J Refract Surg. 2010;26(8):594-599. Carvalho MJ, Suzuki SH, Freitas LL, Branco BC, Schor P, Lima AL. Limbal relaxing incisions to correct corneal astigmatism during phacoemulsification. J Refract Surg. 2007;23(5):499-504. Haripriya A, Syeda TS. A case of endophthalmitis associated with limbal relaxing incision. Indian J Ophthalmol. 2012;60(3):223-225.

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19 Femtosecond Laser Corneal Incisions H. Burkhard Dick, MD, PhD; Tim Schultz, MD; and Ronald D. Gerste, MD, PhD The femtosecond laser is a relatively new feature of cataract surgery. It is too early to predict whether the technology will become standard and one day replace manual phacoemulsification. It is currently the method of choice for patients with the highest expectations for their postoperative visual quality and with the willingness to pay for it; in this group, the femtosecond laser seems to be the perfect instrument for preparing the capsular bag for the implantation of a premium intraocular lens (IOL).

Case Study A slight cataract in the left eye of a 53-year-old man was not the prime motivation for him to undergo phacoemulsification followed by IOL implantation. As in many patients younger than the typical age for cataracts, exchanging the natural lens with an IOL was done mainly for refractive reasons. The refractive power of his left glass was sph + 6.0 cyl – 4.50 A 93 degrees, his uncorrected visual acuity (UVCA) was 20/320, and his best distance corrected visual acuity (BDCVA) was 20/63. Examination using Scheimpflug topography (Pentacam HR; Oculus) revealed an astigmatism of – 2.3 diopters A 88.9 degrees (Figure 19-1A). His endothelial cell count was 2.580 cells/mm 2 , and his central corneal thickness was measured as 536 μm by optical coherence tomography (OCT). The patient underwent femtosecond laser–assisted cataract surgery in the left eye. The surgeon performed capsulotomy with a diameter of 5.0 mm and lens fragmentation in a 350-μm grid. The triplanar primary cataract incision was placed with the laser at 100 degrees. The width of the cut was 2.8 mm, and the length of the cut was 1.8 mm. At the end of the laser treatment, 2 anterior penetrating arcuate incisions were performed with the laser at the 175- and 355-degree positions. Following these steps, the patient was placed on the operating table and under the microscope. As is frequently the case after femtosecond laser pretreatment, no ultrasound energy was necessary for the removal of the lens fragments; this was achieved solely with irrigation/aspiration. An IOL was implanted; according to the patient’s requirements, it was a + 28.0-diopter KS-Xs (Staar). One week postoperatively, the astigmatism on the patient’s left eye was reduced to – 0.9 diopters A 91.6 degrees (Figure 19-1B), and both his UCVA and BDCVA were 20/50. After 1 month, his UCVA and BDCVA were 20/25.

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Figure 19-1. (A) Pre- and (B) postoperative Scheimpflug corneal topography (Pentacam HR) after femtosecond laser‒assisted cataract surgery with penetrating arcuate incisions.

A

B

Figure 19-2. Screenshot of high-resolution 3-dimensional spectral-domain OCT. Due to the nonapplanating fluid-filled interface, no corneal folds are visible.

Femtosecond Laser As this case illustrates, eliminating astigmatism is a rather small step within a procedure that has become safe and precise to a degree unimaginable just a few years ago: refractive cataract surgery. Admittedly, using the term refractive comes close to tautology: these days, almost every cataract operation is also a refractive procedure. Cataract surgery has recently undergone a remarkable evolution with the introduction of the femtosecond laser, which has been in use for LASIK since approximately the year 2000 and was first used for cataract surgery in 2009 by Nagy. The IntraLase FS laser (Abbott Medical Optics Inc) was the first commercially available femtosecond laser and is currently the most widely used platform. The Catalys Precision Laser System (Abbott Medical Optics Inc) used in our clinical center was specifically developed for cataract surgery and comes with a fluid-filled nonapplanating interface that produces fewer corneal folds1 than some other devices and leads to only minor increases in intraocular pressure (IOP) during the docking process (Figure 19-2).2 Such IOP increases have been a cause for concern, particularly in patients with ocular comorbidities like glaucoma or reduced ocular perfusion. Cataract surgeons in ever-increasing numbers are using the femtosecond laser for capsulotomy and lens fragmentation before they perform the somewhat shorter part of manual surgery: removal of the lens fragments and IOL implantation. Both steps can be performed with a higher

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Figure 19-3. Planning screen of the Catalys Precision Laser System with main cataract incision, sideport incisions, and arcuate incisions.

Figure 19-4. Screenshot of the planning screen showing the main cataract incision with an uncut area of 100 µm.

precision than ever before, leading to well-centered and geometrically perfect capsulotomies.3 Fragmentation by the laser has led to a remarkable development from which the cornea probably profits more than any other intraocular structure: the laser-guided lens fragmentation is safe and so effective that the use of phaco power has been greatly reduced. The higher a surgeon is on the learning curve, the better optimized the aspiration equipment is, the better the laser settings are, and the less need seems to exist for the application of ultrasound energy. Although the group comprising our 200th through 400th femtosecond laser procedures needed phacoemulsification in 51% of eyes, in patients number 1200 through 1400, only 9% of eyes required any ultrasound application—a major step to a safe kind of surgery.

Femto Corneal Incisions Besides capsulotomy and lens fragmentation, there is another step that the femtosecond laser can perform, which, when properly done, can contribute to a superb refractive and functional result and high patient satisfaction. The cataract laser systems currently on the market can perform free-positioned main cataract incisions, sideport incisions, perforating and intrastromal arcuate incisions, or limbal relaxing incisions in any angle (Figure 19-3). With the Catalys Precision Laser System, the main cataract incision or sideport incisions can be planed as a triplanar incision or a central uncut region (Figure 19-4).

Technique Figure 19-5 shows the laser system’s touchscreen that allows the surgeon to enter all of the patient’s individual data to plan the surgery. Alternatively, templates with preconfigured settings

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Figure 19-5. Touchscreen of the Catalys Precision Laser System with preset templates.

Figure 19-6. Screenshot of the actual incision cut plan overlay on the real-time spectral-domain OCT (automatically positioned main cataract incision).

can be used. After the suction process and docking the eye to the system, an examination by the system’s high-definition 3-dimensional spectral-domain OCT, which automatically identifies the anterior eye’s different structures, is performed. Based on this imaging, the intended cut through the cornea is positioned and displayed on the screen (Figure 19-6). This is the moment to make adjustments, if necessary. The triplanar cataract main incision is 2.8 mm wide and 1.5 mm long. The anterior side cut angle is 120 degrees, and the posterior side cut angle is 30 degrees. The setting for the energy pulse is 5 μJ. The middle section of the cut is supposed to be 65% to 60% of the cornea’s depth. The laser commences the incision from the side of the cut facing toward the endothelium. Small cavitation bubbles may be seen in the anterior chamber (Figure 19-7A). While the laser performs the incision, the surgeon might identify an increasing whitening of the tissue through the transparent overlay (Figure 19-7B). At the end of the cutting procedure, small bubbles above the epithelium indicate that the intended plane of the cut has been achieved (Figure 19-7C). Working under operating microscope, the incision can be opened with a blunt instrument (Figure 19-8). Figure 19-9 shows the histologic features of a main incision performed with the femtosecond laser. This patient was suffering from a malignant retinal tumor, and enucleation was scheduled. Before commencing the enucleation, diverse corneal incisions were performed; after removal, the eye was fixated in paraformaldehyde. Hematoxylin-eosin staining showed that both the epithelium and Bowman’s layer were completely cut through. The same applied to Descemet’s membrane.

Discussion Laser incisions to treat a patient’s pre-existing astigmatism are usually performed after lens fragmentation. Femtosecond laser astigmatism correction or femtosecond arcuate keratotomy is especially important in patients in which a nontoric multifocal premium IOL is implanted. The femtosecond laser enables the surgeon to create an incision that is entirely intrastromal, leaving both the epithelium and Bowman’s layer intact. It is widely believed that this approach does not only yield higher precision and a greater postoperative comfort but also reduces the threat of postoperative infection. Intrastromal astigmatic keratotomy (guided by the laser system’s pachymetric OCT) can be performed on naturally occurring astigmatism, astigmatism after cataract surgery,

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Figure 19-7. Screenshot of the laser live camera demonstrating the course of a main cataract incision. (A) Beginning of the cut. Bubbles are visible in the anterior chamber. (B) Middle of the cut. Whitening of the cornea is seen. (C) Cut of the epithelium. A small bubble is visible within the balanced salt solution‒filled liquid optics interface.

Figure 19-8. Opening of the main cataract incision using a blunt spatula.

Figure 19-9. High-magnification light microscopy of a spectral-domain OCT-guided femtosecond laser‒assisted main cataract incision (histological preparation).

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A

B

Figure 19-10. (A) Planning screen of a penetrating arcuate incision with an angle of 90 degrees. (B) Planning screen of an intrastromal arcuate incision with an angle of 30 degrees.

Figure 19-11. Screenshot of the laser live camera (Catalys Precision Laser System) demonstrating (A) a penetrating and (B) an intrastromal corneal incision without bubbles in the anterior chamber.

A

B

and astigmatism after keratoplasty. Contraindications for astigmatic keratotomy with the femtosecond laser, whether in conjunction with cataract surgery or independently, are: • Ectatic disorders of the cornea • Highly irregular astigmatism • Limbal peripheral corneal pathology • Extreme dry eye syndrome • Ocular surface disease4 The Catalys Precision Laser System provides the option of performing both perforating and intrastromal arcuate incision to correct astigmatism of up to 3.5 diopters, flattening the steepest meridian of the cornea, and thus eliminating a source of refractive error (Figure 19-10). After docking, the data provided by the OCT are deployed to position the corneal incisions as effectively as possible. A safety zone, measured in percent or micrometer, can be selected to achieve the same effect with numerous incisions. An angle of 90 degrees has been proven to be safe and efficient for a penetrating incision. When performing this procedure, the laser starts from a position closest to the endothelium and works its way in an anterior direction to prevent the formation of gas bubbles, which might obscure the pulse direction. The surgeon will carefully avoid any development of these bubbles in the anterior chamber (Figure 19-11). If that happens, the procedure must be aborted immediately because it indicates the threat of corneal perforation. This may happen in fidgety patients. Higher astigmatism may require a penetrating incision under the operating microscope. Intraoperative aberrometry (Optiwave Refractive Analysis System; WaveTec) allows the surgeon to immediately assess the corneal incision’s effect on the patient’s refraction. If it is not deemed sufficient, the incision can be opened manually (Figure 19-12). If that still does not

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Figure 19-12. Manual opening of a penetrating femtosecond laser‒assisted arcuate incision within the corneal graft in high astigmatism after penetrating keratoplasty.

lead to a satisfying result, the patient can be docked to the laser unit again, and a second pair of incisions can be performed.

Results Given the fact that the femtosecond laser has been used much longer in refractive surgery and corneal procedures than in cataract surgery, there are currently more data on its success rates in the former field than in the latter. In a group of 112 eyes with mixed astigmatism after previous refractive surgery, intrastromal femto¬second laser keratotomy led to an average decrease of the absolute subjective cylinder, from 1.20 ± 0.47 diopters preoperatively to 0.55 ± 0.40 diopters (P < .01) postoperatively, as well as to a statistically significant decrease of the subjective sphere from + 0.61 ± 0.33 diopters to + 0.17 ± 0.36 diopters (P < .01).5 Mean corrected distance visual acuity was – 0.03 ± 0.08 logMAR (≈ 6/6 Snellen) preoperatively and – 0.05 ± 0.09 logMAR (≈ /5 Snellen) postoperatively (P = .06). There were no complications following femtosecond laser intrastromal astigmatic keratotomy in this population. A small change in spherical refraction is usually the result of the flattening produced by incisions in the steep axis, which is countered by steepening of the unincised meridian, known as the coupling effect.6 A Canadian study group reported a reduction of absolute astigmatism in 37 eyes with relatively high astigmatism following keratoplasty, from 7.46 ± .70 diopters preoperatively to 4.77 ± 3.29 diopters postoperatively (P = .0001).7 In this population, there were no cases of perforation, wound dehiscence, or infectious keratitis after femtosecond laser application. Rückl et al8 reported 16 eyes with naturally occurring astigmatism or astigmatism following cataract surgery that were treated with paired femtosecond laser arcuate cuts on the steep axis completely placed within the corneal stroma. In this group, the mean refractive cylinder was reduced significantly from 1.41 ± 0.66 diopters to 0.33 ± 0.42 diopters (P < .001). Mean topographic astigmatism was reduced significantly, from 1.50 ± 0.47 diopters preoperatively to 0.63 ± 0.34 diopters at 6 months (P = .002). With the endothelial cell density virtually unchanged after 6-month follow-up, the authors emphasize the safety profile, rapid recovery, and stability of vision without the known risks associated with incisions that penetrate Bowman’s layer.8 The architectural stability of femtosecond laser corneal incisions has been demonstrated so far only in cadaver eyes, which is not ideal because corneal thickness increases postmortem and may have influenced the results.9 It will also be a matter of future exploration to determine the potential of the femtosecond laser in treating astigmatism associated with congenital cataract. Our first results with femtosecond laser–assisted cataract surgery in a group of young infants have been encouraging, but the focus in this early stage of new development has been on achieving a centered central posterior capsulotomy that allows a safe mechanical anterior vitrectomy and to be able to remove anterior and posterior capsule discs without capsule tears rather than influencing refraction with corneal incisions.10

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Conclusion Femtosecond laser corneal incisions, like astigmatic keratotomy, hold great promise for clinical practice. The precision, accuracy, and safety displayed by the femtosecond laser in cataract surgery will no doubt offer the surgeon a distinct advantage over manual intrastromal incisions to correct either preoperative astigmatism or the remnants of astigmatism at the end of an intervention on the lens, whether as a regular cataract operation in a mature patient or a lens exchange (or some other lens procedure) for refractive purposes, usually performed on younger patients. Clinical data and experience with this still new and expanding technology point convincingly to minimal or no epithelial injury, less foreign body sensation than following manual keratotomy, and a faster visual recovery in our patients.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Talamo JH, Gooding P, Angeley D, et al. Optical patient interface in femtosecond laser-assisted cataract surgery: contact corneal applanation versus liquid immersion. J Cataract Refract Surg. 2013;39(4):501-510. Schultz T, Conrad-Hengerer I, Hengerer FH, Dick HB. Intraocular pressure variation during femtosecond laser-assisted cataract surgery using a fluid-filled interface. J Cataract Refract Surg. 2013;39(1):22-27. Friedman NJ, Palanker DV, Schuele G, et al. Femtosecond laser capsulotomy. J Cataract Refract Surg. 2011;37(7):1189-1198. Canto AP, Yoo SH, Zaldivar R, Zaldivar R. Relaxing incisions for astigmatism correction in ReLACS. In: Krueger RR, Talamo JH, Lindstrom RL, eds. Textbook of Refractive Laser Assisted Cataract Surgery (ReLACS). New York, NY: Springer; 2013:125-147. Venter J, Blumenfeld R, Schallhorn S, Pelouskova M. Non-penetrating femtosecond laser intrastromal astigmatic keratotomy in patients with mixed astigmatism after previous refractive surgery. J Refract Surg. 2013;29(3):180-186. Kim P, Sutton GL, Rootman DS. Applications of the femtosecond laser in corneal refractive surgery. Curr Opin Ophthalmol. 2011;22(4):238-244. Kumar NL, Kaiserman I, Shehadeh-Mashor R, Sansanayudh W, Ritenour R, Rootman DS. IntraLase-enabled astigmatic keratotomy for post-keratoplasty astigmatism: on-axis vector analysis. Ophthalmology. 2010;117(6):1228-1235.e1. Rückl T, Dexl AK, Bachernegg A, et al. Femtosecond laser-assisted intrastromal arcuate keratotomy to reduce corneal astigmatism. J Cataract Refract Surg. 2013;39(4):528-538. Masket S, Sarayba M, Ignacio T, Fram N. Femtosecond laser-assisted cataract incisions: architectural stability and reproducibility. J Cataract Refract Surg. 2010;36(6):1048-1049. Dick HB, Schultz T. Femtosecond laser-assisted cataract surgery in infants. J Cataract Refract Surg. 2013;39(5):665-668.

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20 Intrastromal Arcuate Keratotomy to Reduce Corneal Astigmatism With a Femtosecond Laser Theresa R ckl, MD; Alexander Bachernegg, MD; Perry S. Binder, MS, MD; and G nther Grabner, MD Corneal astigmatism is a very common refractive error. In cataract surgery candidates, naturally occurring corneal astigmatism between 0.25 and 1.25 diopters (D) is observed in 64.4% of all patients; in an additional 22.2%, it is 1.50 D or higher.1 In a recent trial, Hoffmann and Hütz2 evaluated a total of 23,239 eyes and reported that corneal astigmatism of 0.75 or more diopters occurred in 36.05% of them, with a mean astigmatism of 0.98 diopters. Naturally occurring and residual corneal astigmatism after cataract surgery in otherwise healthy eyes is significantly associated with decreased uncorrected distance visual acuity and, therefore, patient dissatisfaction. Different corneal procedures are available to reduce either naturally occurring astigmatism or corneal astigmatism following cataract surgery or penetrating keratoplasty (PK). Limbal relaxing incisions (LRIs),3-8 wedge resections,3-10 or manually created arcuate keratotomy 3-8,10-13 are technically challenging procedures often leading to somewhat unpredictable refractive results, complications such as wound gape associated with epithelial ingrowth into the incisions, and occasionally a full-thickness corneal perforation.5-7 In addition to these procedures, photorefractive keratectomy (PRK) and LASIK have been investigated in the management of mainly postkeratoplasty corneal astigmatism but are limited in the predictability of outcomes and are fraught with some well-described complications.3-7 Of all of these corneal approaches, arcuate LRIs (versus straight intermediate cuts) are probably the most commonly performed procedures for the reduction of astigmatism. They offer fast visual recovery, the potential to reduce high corneal astigmatism,10 and a limited but still superior predictability when compared with other manual techniques.7 Relaxing incisions are traditionally performed manually or with the use of a mechanized keratome.4,7,14 However, the lack of reproducibility of incision length and incision depth, as well as the potential for axis misalignment, may lead to complications and unpredictable outcomes.7,14 Femtosecond laser–enabled keratotomy has become a popular alternative to these mechanical techniques because of the higher precision of the incisions, improved accuracy and safety, and enhanced reproducibility.3-8,13 Most published articles using femtosecond laser–enabled

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keratotomy reported incisions that penetrate Bowman’s layer and epithelium anteriorly and were performed in small series, mainly after PK (Table 20-1).3-5,9-14 A prospective, nonrandomized, single-center study of nonpenetrating intrastromal arcuate keratotomy (ISAK) was performed in 21 patients with corneal astigmatism of 0.75 to 3.5 diopters at the eye clinic of the Paracelsus Medical University. The goal of this investigation was to evaluate the effect, feasibility, and safety of intrastromal arcuate keratotomy procedures performed with a femtosecond laser.15

Materials and Methods Study Description In this prospective, interventional case series, the safety and efficacy of the same femtosecond laser incision pattern was reported for a total of 16 patients. Key requirements for participation in this study included the following: • Refractive astigmatism between 0.75 and 7.0 diopters (as determined by manifest refraction [MR]) • Uncorrected distance visual acuity (UDVA) of 0.10 logMAR or less (approximately 20/25) • Consistency between corneal astigmatism measurements (as determined by manual keratometry) and refractive astigmatism (as determined by MR) within 0.75 diopters of magnitude and within a 15-degree axis of each other when the cylinder was 1.5 diopters or less or within a 10-degree axis when the astigmatism exceeded 1.5 diopters • Minimum central corneal thickness of 480 μm (as determined by Scheimpflug tomography [Pentacam HR; Oculus]) • Minimum age of 21 years Patients with diabetes mellitus, autoimmune disease, keratoconus, irregular astigmatism, retinal disease, or glaucoma and patients who were pregnant or on systemic or ocular steroids were not included. ISAK was performed in one eye only. Three types of patients were included in the study. The majority (13/16; 81.3%) were patients with lenticular changes who were expected to undergo cataract surgery within the next 6 months. The goal for these patients was to reduce astigmatism prior to cataract surgery. A second group included 2 (12.5%) phakic patients with healthy crystalline lenses who needed astigmatic correction to achieve emmetropia. In a third group, one (6.3%) patient had residual astigmatism following cataract/intraocular lens (IOL) surgery. For the latter 2 groups, good corrected distance visual acuity (CDVA) was the goal. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the County of Salzburg. Written informed consent was obtained from all patients prior to study enrollment.

Preoperative and Postoperative Examinations Preoperatively, all patients underwent an extensive ophthalmic evaluation that included MR and corneal topography (Keratron Scout Opticon 2000; Optikon). Corneal pachymetry (central and in 4 quadrants at a diameter of 6 mm, using the Pentacam HR) and mesopic pupil size (Procyon P3000; Procyon Instruments) were also determined. Noncontact specular microscopy (NonconRobo CA; Konan Medical) was performed in both eyes centrally and in 2 quadrants in the area of the planned steep axis. Measurement of intraocular pressure (IOP) by Goldmann applanation tonometry as well as a detailed examination of the anterior and posterior segment was conducted in all patients prior to treatment. In a subgroup of 11 (68.8%) patients, anterior-segment optical coherence tomography (OCT) (Visante, Carl Zeiss Meditec AG) was also performed preoperatively and during follow-up examinations to evaluate the placement, precision, and shape of the intrastromal incisions. Follow-up examinations were scheduled at 1 day, 1 week, and 1, 3, and 6 months after ISAK. All preoperative examinations were repeated during postoperative visits. In addition, a subjective

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TABLE 20-1

Peer-Reviewed Publications on Astigmatic Keratotomy With the Femtosecond Laser STUDY

INDICATION TECHNIQUE

NO. OF EYES

PREOP/POSTOP KERATOMETRY RESULTS, DIOPTERS

Nubile et al4

Post-PK

12

7.16 ± 3.07/

• 1.0 mm smaller than graft

2.23 ± 1.55

• 40- to 80-degree arc length

(subjective refraction)

• 90% depth Kiraly et al9

Post-PK

• 5 to 6 mm

10

4.75 ± 2.86

• 75% to 85% depth HarissiDagher & Azar13

Post-PK

• 6 ± 7 mm

7.70 ± 3.10/

2

8.50/4.90 & 7.00/4.30

20

7.84 ± 2.35/

• 60- to 75-degree arc length • 400 µm

Bahar et al6

Post-PK

• 0.5 mm smaller

3.58 ± 2.21

• 60- to 90-degree arc length • 90% depth Kook et al3

Post-PK

• 6 to 7.2 mm

10

9.30 ± 4.10/ 6.50 ± 4.20

• 20- to 50-degree arc length • 90% depth • 90-degree side cut angle Kymionis et al10

Post-PK

• 6.5 mm

1

4.40/0.67

9

9.80 ± 1.90/

• 60-degree arc length • 75% depth

Buzzonetti11

Post-PK

• 4.8 to 6.8 mm • 70-degree arc length

5.20 ± 1.50

• 90-degree side cut angle (continued)

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Peer-Reviewed Publications on Astigmatic Keratotomy With the Femtosecond Laser STUDY

INDICATION TECHNIQUE

NO. OF PREOP/POSTOP EYES KERATOMETRY RESULTS, DIOPTERS

Kumar et al5

Post-PK

37

• 0.5 mm smaller than graft

7.46 ± 2.70/ 4.77 ± 3.29

• 40- to 90-degree arc of length • 90% depth Abbey et al12

Naturally occurring high astigmatism

• 6.5 mm

2

5.92/3.60 & 5.80/2.42

1

Refr: 5.75/2.75

• 80-degree arc length • 400 µm

Levinger et al14

Post-DSAEK

• 8 mm

Ker: 4.66/0.81

• 60-degree arc length • 90% depth

R ckl et al15

Naturally occurring astigmatism

• 7.5 mm

16

Refr: 1.41 ± 0.66/0.33 ± 0.42 Ker: 1.50 ± 0.47/0.63 ± 0.34

• 90-degree arc length • 30-degree side cut angle

Wetterstrand Post-PK et al18

• 6 to 7 mm

16

Refr: 6.78 ± 2.20/3.67 ± 1.66 Ker: 9.49 ± 4.78/4.41 ± 2.14

• 90- or 120-degree side cut angle • 90-degree arc length • 90% depth

Venter et al19 Previous refractive surgery

• 7 mm

112

Refr: 1.20 ± 0.47/0.55 ± 0.40

• 40- to 60-degree arc of length • 80% depth

Abbreviations: AK, arcuate keratotomy; DSAEK, Descemet s stripping automated endothelial keratoplasty; Ker, keratometric; PK, penetrating keratoplasty; Refr, refractive.

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TABLE 20-2

IntraLase iFS System Settings PARAMETER

VALUE

Arc diameter

7.5 mm

Anterior depth (depth in glass)

‒ 100 µm

Posterior depth

Thinnest peripheral US pachymetry measurement minus 100 µm

Energy

1.8 µJ

Cut position 1

Steep meridian

Cut position 2

Steep meridian + 180

Cut angle

90 degrees

Side cut angle

30 degrees

Spot separation

3

Line separation

3

questionnaire was designed specifically for the assessment of outcomes and patient satisfaction after ISAK.

Surgical Procedure ISAK was performed in all patients by a single experienced surgeon (G.G.) between July 2010 and April 2011. All procedures were conducted under topical anesthesia using the 150-kHz IntraLase iFS System (Abbott Medical Optics) (Table 20-2). The axis of astigmatism was marked preoperatively and verified intraoperatively with high-precision topography. The IntraLase iFS System can be programmed to make cuts of virtually any configuration by customizing the depth, length, and angle of inclination. In all cases in this study, the angular arc length of the incisions was 90 degrees and the side cut angle was set at 30 degrees. We selected these parameters to maximize the area of each incision expecting to achieve a maximal effect. The optical zone diameter was set at 7.5 mm to minimize potential glare because a 7.5-mm anterior incision would leave a larger optical zone close to Descemet’s membrane using a 30-degree side cut angle. Much like a traditional astigmatic keratotomy (AK), these incisions cut the lamellae, achieving a relaxing effect along the steep axis. However, unlike a traditional AK, the cuts were completely intrastromal; there was no penetration of the anterior corneal surface, so there was no wound gape, epithelial ingrowth, or risk of infection. The surgical goal was to make the arcuate incisions at least 100 μm away from Bowman’s layer and Descemet’s membrane. Pachymetry often changes rapidly due to variations in stromal hydration or deswelling following the use of topical anesthetics, the heat of the operating microscope light, and/or reduction in the blink rate.16 To confirm the intended incision depth, ultrasound pachymetry measurements were recorded in the center and all 4 quadrants of the cornea immediately before performing ISAK. After modification of the treatment parameters in the anterior side cut incision-planning window of the IntraLase-enabled keratoplasty (IEK) mode of the IntraLase iFS System, the IntraLase limbal suction ring was applied and the cone was positioned. All intrastromal cuts were created with the IntraLase iFS System (150 kHz) using an energy setting of 1.8 μJ and a spot/line separation of 3 x 3 μm. All treatments were performed in a surgical environment where the noncondensing humidity was between 35% and 65% and the temperature was between 67°F and 73°F (19°C to 23°C). After ISAK completion, suction was released, the ring was removed, and the position of the cuts was checked under the microscope.

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Postoperatively, all patients were treated with a combination of topical antibiotic and steroid eyedrops 4 times daily for 1 week and lubricating eye drops 4 times daily for at least 1 month and continued if necessary.

Statistical Analysis Statistical analysis was performed using SPSS version 19.0 statistical software for Windows (SPSS, Inc). Mean values and standard deviations were calculated for every parameter. To analyze the data from pre- and postoperative examinations and between consecutive postoperative visits, one-way analysis of variance for repeated measures was used. If sphericity could not be assumed, the Greenhouse-Geisser estimates were used as a correction factor. Post-hoc comparisons were performed by the Bonferroni procedure. In all instances, the level of statistical significance required was the same (P < .05).

Vector Analysis Vector analysis and graphical displays were performed using the Alpins method, facilitated by the ASSORT program (ASSORT Pty, Ltd). Preoperative and 6-month postoperative values for topographic astigmatism were analyzed.17 The Alpins method allows the evaluation of the effective change in astigmatism with consideration of change in the astigmatic axis. Therefore, 3 fundamental vectors and the relationship among them were examined: 1. The target-induced astigmatism (TIA) vector, defined as the astigmatic change in magnitude and axis the surgery was intended to induce 2. The surgically induced astigmatism (SIA) vector, defined as the amount and axis of the astigmatism the surgery actually induced 3. The difference vector (DV), defined as the induced astigmatic change by magnitude and axis that would enable the initial surgery to achieve its intended target. Related to the SIA is the correction index (CI), which is calculated by determining the ratio between the SIA and the TIA by dividing SIA by TIA; the ratio is preferably 1.0. A CI greater than 1.0 indicates an overcorrection, and a CI less than 1.0 indicates an undercorrection.11,17 From our previous experience and the pattern that was chosen, and assuming a significantly reduced effect due to the nonperforating nature of the incision, we chose to take the mean SIA as our intended TIA in the preliminary assessment of this new technique. We chose to only show the topographic vector analysis because the refractive data would have been significantly influenced by the cataract surgery (lenticular astigmatism) itself that was planned after ISAK.

Results Postoperatively, topographic and refractive cylinders were reduced in all eyes. Mean preoperative refractive cylinder was 1.41 ± 0.66 diopters, with 7 (43.8%) eyes having a refractive cylinder between 0.75 and 1.00 diopters, 8 (50%) eyes having a refractive cylinder between 1.00 and 2.00 diopters, and one (6.3%) eye having a refractive cylinder of 3.5 diopters (Figure 20-1). Mean preoperative topographic cylinder, as measured by corneal topography, was 1.50 ± 0.47 diopters, with 2 (12.5%) eyes having a topographic cylinder between 0.75 and 1.00 diopters, 12 (75%) eyes having a topographic cylinder between 1.00 and 2.00 diopters, and 2 (12.5%) eyes having a topographic cylinder between 2.00 and 3.00 diopters (see Figure 20-1). Mean preoperative UDVA was 0.45 logMAR (approximately 20/50), and mean preoperative CDVA was 0.09 logMAR (approximately 20/25).

Efficacy One day postoperatively, mean subjective cylinder was reduced significantly, from 1.41 ± 0.66 diopters preoperatively to 0.45 ± 0.49 diopters (P < .001) (Figure 20-2), with a stable course during the follow-up period (mean, 0.33 ± 0.42 diopters at 6 months postoperatively). Mean topographic astigmatism improved significantly, from 1.50 ± 0.47 diopters preoperatively to 0.61 ± 0.43 one day postoperatively (P < .001), with a stable course during the follow-up period (mean, 0.63 ± 0.34 diopters at 6 months postoperatively) (see Figure 20-2). Figure 20-3 shows a difference map of

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Figure 20-1. Preoperative frequency distribution of refractive and topographic astigmatism in 16 eyes.

A

B

Figure 20-2. Box-and-whisker plots showing (A) refractive and (B) topographic astigmatism in 16 eyes within 6 months after ISAK. One patient missed a corneal topography examination at the 6-month evaluation.

a preoperative versus 6-month postoperative corneal topography of 1 patient. In this patient, a reduction of corneal astigmatism was achieved, from 2.68 diopters preoperatively to 0.58 diopters 6 months postoperatively. Mean UDVA improved significantly (P = .009), from 0.45 ± 0.27 logMAR (approximately 20/50) preoperatively to 0.26 ± 0.33 logMAR (approximately 20/32) 6 months postoperatively, with 5 (31.3%) eyes having an unchanged UDVA and 11 (68.8%) eyes showing a mean gain of 2.8 ± 1.47 lines (Figure 20-4). No patient lost a single line of UDVA. One of the 5 remaining patients with a stable UDVA was highly myopic, so no change of UDVA was expected. Four patients showed an expected increase of the preexisting nuclear sclerosis as detected by slit lamp examination, which also affected UDVA negatively without being related to the ISAK procedure. Mean CDVA remained fairly stable, from 0.09 ± 0.15 logMAR (approximately 20/25) preoperatively to 0.12 ± 0.18 logMAR (approximately 20/25) 6 months postoperatively, with 6 (37.5%) eyes showing an improvement of 1 to 2 lines, 4 (25.0%) eyes showing stable acuity, and 6 (37.5%) eyes showing a loss of CDVA (1/16 = 3 lines; 3/16 = 2 lines; 2/16 = 1 line) (see Figure 20-4). We consider this loss of CDVA to be associated with an increase of their lens opacities as observed when evaluated at the slit lamp. There was a slight change in the mean refractive spherical equivalent (MRSE), from 0.13 ± 1.68 diopters preoperatively to – 0.41 ± .71 diopters 6 months postoperatively, but these results were not significant and were possibly caused by an increase in nuclear sclerosis (Table 20-3).

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Figure 20-3. Difference map of (A) preoperative and (B) 6-month postoperative corneal topography (Keratron Scout Opticon 2000; Optikon) in a 47-year-old woman. Astigmatism was 2.68 diopters preoperatively and 0.58 diopters 6 months postoperatively.

A

B

Figure 20-4. Box-and-whisker plots of (A) uncorrected and (B) corrected distance visual acuity in 16 eyes within 6 months after ISAK.

The topographic vectors were calculated for each eye and are shown in Table 20-4. Mean SIA was 1.59 ± 0.70 diopters (Figure 20-5). As previously explained, we chose to take the mean topographic SIA for our TIA, which was 1.59 diopters in all cases. Mean DV was 0.63 ± 0.34 diopters for topographic data (Figure 20-6), and mean CI was 1.07 ± 0.43 diopters (Figure 20-7). Mean error of the angle of the surgically induced astigmatism was 6.60 ± 6.10 degrees. Astigmatism-correcting corneal incisions flatten the steep meridian and are associated with an equal steepening of the orthogonal flat meridian so that the overall corneal power, and therefore the spherical equivalent refraction, remains the same. If these changes are equal (ie, the steep meridian changes the same amount as the flat meridian), the association or coupling of the meridian is said to be 1 to 1, or a coupling ratio of 1.0. In our study, the coupling ratio for eyes with the same optical zone and arc length was 1.02 ± 0.01. The MRSE decreased in 12 eyes, increased in

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TABLE 20-3

Preoperative and 6-month Postoperative Clinical Measurements (N = 16) PARAMETER

PREOPERATIVE

6-MONTH POSTOPERATIVE

P

Refractive astigmatism

1.41 ± 0.66 (0.75 to 3.5)

0.33 ± 0.42 (0 to 1.25)

< .001

Topographic astigmatism (n = 15)

1.50 ± 0.47 (0.84 to 2.68)

0.63 ± 0.34 (0.24 to 1.57)

.002

MRSE, diopters

0.125 ± 1.68 (‒ 4.75 to 2.50)

‒ 0.41 ± 1.71 (‒ 6.0 to 2.0)

NS

UDVA, logMAR

0.45 ± 0.27 (1.30 to 0.20)

0.26 ± 0.33 (1.30 to ‒ 0.08)

.009

CDVA, logMAR

0.09 ± 0.15 (0.40 to ‒ 0.18) 0.12 ± 0.18 (0.40 to ‒ 0.18)

NS

Abbreviations: CDVA, corrected distance visual acuity; MRSE, mean refracted spherical equivalent; NS, not significant; UDVA, uncorrected distance visual acuity.

TABLE 20-4

Alpins Method Topographic Analysis of Surgically Induced Astigmatism Target-Induced Astigmatism, Difference Vector and Correction Index for Each Eye PATIENT NO.

SIA

TIA

DV

CI

1

1.50

1.59

0.80

0.94

2

3.07

1.59

1.52

1.93

3

1.78

1.59

0.22

1.12

4

1.61

1.59

0.02

1.01

5

1.75

1.59

1.11

1.10

6

0.76

1.59

1.07

0.48

7

1.42

1.59

0.42

0.89

8

1.85

1.59

0.26

1.16

9

1.87

1.59

0.55

1.17

10

1.36

1.59

0.30

0.86

11

1.46

1.59

0.31

0.92

12

0.88

1.59

0.76

0.55

13

0.65

1.59

0.95

0.41

14

0.98

1.59

0.65

0.62

15

2.96

1.59

1.37

1.86

16

‒

‒

‒

‒

Abbreviations: CI, correction index; DV, difference vector; SIA; surgically induced astigmatism; TIA, target-induced astigmatism.

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Figure 20-5. Alpins vectorial display of the achieved treatments (SIA) measured by topographic parameters. The summated vector mean of the group is highlighted in green.

Figure 20-6. Alpins vectorial display of the treatment errors (DV) calculated by topographic values at their own axis to achieve the targeted result. The summated vector mean of the group is highlighted in green.

Figure 20-7. Astigmatic CI (Alpins SIA/TIA) calculated by topographic values displayed at the meridian of their respective treatments (TIA). The semicircular line indicates the line of the desired astigmatic correction. A CI greater than 1 indicates an overcorrection, and a CI less than 1 indicates an undercorrection.

2 eyes, and was unchanged in 2 eyes. The coupling ratio for these eyes was 1.03 ± 0.02, 1.02 ± 0.01, and 1.02 ± 0.01, respectively.

Safety and Complications All incisions were placed as intended and totally confined within the corneal stroma. No penetration of Bowman’s layer or Descemet’s membrane occurred. Slit lamp examination during follow-up showed no sign of ocular surface irritation or anterior chamber inflammatory reaction. In one case, there was an intraoperative loss of suction when the patient fell asleep and inadvertently moved his head. The laser stopped automatically, suction was reapplied, and the procedure was completed as planned. Images generated with OCT showed an appropriate incision with no damage due to the suction loss (Figure 20-8). There was no statistically significant loss of endothelial cells in the treated eyes compared with the fellow eyes. One day postoperatively, the intrastromal incisions were barely visible by slit lamp examination. In some patients, we could see a narrow band of increased reflectivity, comparable with the reflectivity of the epithelial basement membrane. In accordance with those minimal changes, patients did not recognize a disturbing glare or halos after ISAK. All intrastromal incisions could

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Figure 20-8. OCT images within 1 week after an intraoperative complication of suction loss during laser application due to patient movement showing an incomplete but still intrastromal cut without penetration of the endothelium or epithelium.

be detected by OCT throughout the 6 months of study. No adverse events occurred during the follow-up period.

Patient Satisfaction After ISAK treatment, patients were asked to score their quality of vision, overall satisfaction with the procedure (from 0 [vision is much improved or very satisfied] to 10 [vision is much worse or very unsatisfied]), and whether they would undergo this treatment again if given a choice. Six months postoperatively, a score of 0 to 2 was given by 10 (62.5%) patients concerning their quality of vision and by 13 (81.25%) patients concerning their satisfaction with the result of the procedure. No patient reported a worsening of either quality of vision or satisfaction after treatment. When asked if they would undergo the surgical treatment again, all (100%) patients answered yes.

Discussion The main objective of this prospective, nonrandomized interventional case series was to evaluate the safety and efficacy of ISAK. Several publications have previously reported using a femtosecond laser for the creation of arcuate keratotomies (see Table 20-1).3-5,7-14 The current study reports on a new application of the IntraLase (150 kHz) laser for the treatment of corneal astigmatism: the creation of arcuate cuts totally confined within the corneal stroma at the desired position and a precise depth in the corneal stroma.15,18,19 With manual blades, some of these parameters are impossible to achieve, and others are difficult to control.6,14 Natural or postoperative astigmatism are common findings, and the demand for their surgical correction is growing as cataract surgery more and more becomes a refractive procedure. AK is a simple, minimally invasive technique, usually performed freehand or with a mechanical keratome.4,7,14 Technical difficulties such as incision predictability and complications such as perforation, wound gape, and the potential for infection and inflammation are limiting variables of this technique.5-7 To make AK even more safe, predictable, and effective, there have been several attempts to improve the manual technique; the Hanna arcuate keratome offers the possibility to create significantly more regular mechanical arcuate incisions.20 More recently, femtosecond laser technology has been used to perform AK for the correction of astigmatism. First results have been promising because the femtosecond laser has the ability to create precise corneal dissections at various depths and orientations7,10 which was previously unattainable using manual techniques.5 Most published reports deal with correction of high residual astigmatism after PK,3-6,8-11,13-14 and most use incisions penetrating the corneal epithelium anteriorly (see Table 20-1).3-6,8-14 Only a few recent papers are concerned only with intrastromal arcuate keratotomy, and the results are promising (see Table 20-1).18,19 In a retrospective analysis, Bahar et al6 compared the results of 20 eyes that underwent manual AK using a diamond blade and 20 eyes that underwent femtosecond laser–enabled AK. Better

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results concerning UDVA and CDVA improvement, absolute postoperative cylinder, and complications were seen in the femtosecond laser group. In the only randomized study to date, Hoffart et al8 compared a mechanical diamond blade AK (Hanna Arcutome; Moria) with femtosecond laser–enabled AK (Femtec laser; 20/10 Perfect Vision). Twenty eyes were randomized to either mechanized or femtosecond laser treatment. The femtosecond laser showed a higher reduction of cylinder power. Furthermore, there was a tendency toward greater axis misalignment with the Hanna Arcutome. Other than after mechanized AK, no complications were reported for the femtosecond laser group. Experience in reducing naturally occurring astigmatism with the femtosecond laser is limited. Only Abbey et al12 reported the results of one patient with high naturally occurring astigmatism. Significant UDVA improvement and reduction of the manifest cylinder were measured 1 year after treatment. Complications in femtosecond laser–enabled AK are minimal compared with mechanized AK.6-8 Still, all incisions that penetrate the corneal surface anteriorly and thereby incise Bowman’s layer come with a higher risk for wound gape, postoperative inflammation and infection, overcorrection, scarring, and/or haze. To maintain transparency and a stable refractive outcome, a minimal repair and replacement of stromal tissue in wound healing after corneal surgery is desirable.21 The idea that intense light scattering from fibroblasts repairing corneal wounds can cause loss of transparency and reduction of vision was mentioned in various articles during the past decade.21,22 Meltendorf et al 23,24 examined the corneal repair response after intrastromal femtosecond laser keratotomy and after treatment with photorefractive keratectomy (PRK) in rabbit corneas. In contrast to corneas after PRK, no differentiation of keratocytes into fibroblasts and no fibrotic stromal scars, commonly referred to as haze, could be detected after isolated intrastromal injury. No histological signs of infection or inflammation were observed after intrastromal keratotomy. All of these findings indicate a minimal wound-healing response that makes the intrastromal femtosecond laser technique attractive for clinical use.24 In contrast to other trials using a femtosecond laser to create AKs with penetration of the corneal epithelium, the current pilot study used the IntraLase iFS System for placing incisions totally confined within the corneal stroma and did not involve an incision through Bowman’s layer, as has been the previous standard of care used for the development of nomograms. Therefore, because no nomogram was available, the particular incision pattern was designed to maximize the effect of the incision using a 90-degrees arc length and a 30-degree cut angle to obtain a stable final effect by creating a large healing area while minimizing glare with a comparatively large optic zone diameter. We detected a significant, and so far stable, reduction of absolute refractive astigmatism, from 1.41 ± 0.66 diopters preoperatively to 0.33 ± 0.42 diopters 6 months postoperatively (mean reduction, 76.6%). These are satisfying results when compared with outcomes achieved with anteriorly penetrating femtosecond laser–enabled AK.4,5,9 In addition to manifest astigmatism, we also measured a significant reduction of the absolute topographic cylinder, from 1.50 ± 0.47 diopters preoperatively to 0.63 ± 0.34 diopters 6 months postoperatively, which represents a reduction of 58.0%. Again, these data compare favorably with the reduction after treatment with the anteriorly penetrating technique.9,13 In a recent trial, Venter et al19 presented results after nonpenetrating intrastromal keratotomy with the IntraLase iFS System in 112 patients with mixed astigmatism after previous refractive surgery. Similarly to our study, the astigmatism before ISAK was low (mean, 1.20 ± 0.47 diopters) in this large group of patients. The results are also comparable with ours, with a gain of UCVA in all patients and a significant reduction of subjective cylinder, from 1.20 ± 0.47 diopters to 0.55 ± 0.40 diopters. No intra- or postoperative complications were described.19 Wetterstrand et al18 used the IntraLase iFS System to examine the effect after purely intrastromal relaxing incisions in 16 patients with regular astigmatism after PK. Significant improvements were found in CDVA and the refractive and topographic cylinders, and a significant correlation was found between the magnitude of preoperative values and the amount of improvement of refractive and topographic cylinders. When comparing the effect of intrastromal to epithelium-breaking methods, Wetterstrand et al18 observed a similar decrease in the refractive cylinder.

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These studies underline the theoretical advantage of intrastromal arcuate keratotomy: a similar effect but less risk of intra- or postoperative complications as well as reduced discomfort to the patient. In view of the dearth of experience and literature when our study was performed, and expecting a lower amount of correction after ISAK due to the fact that Bowman’s layer as an important stabilizing layer of the cornea was not severed, only patients requiring minor to medium astigmatism correction (mean astigmatism at study entry, 1.41 ± 0.66 diopters [range, 0.75 to 3.5 diopters]) were selected for our case series. The first patients selected were those prior to cataract surgery so that, in case of unexpected results, the option to implant a toric IOL would be available. In addition, the incision that the surgeon routinely uses for cataract surgery (a sclerocorneal tunnel at 12 o’clock) is astigmatism neutral in basically all cases. After the first successful cases, patients with clear lenses or postcataract surgery were included. With the majority of our patients (13/16; 81.3%) showing signs of nuclear sclerosis at study entry and expecting to undergo cataract surgery within the next 6 months, our goal was to eliminate the need for a toric IOL or LRI. Mean reduction of refractive astigmatism in those 13 patients was 0.94 diopters (1.25 ± 0.40 diopters preoperatively to 0.31 ± 0.36 diopters 6 months postoperatively; range of reduction, 0.25 to 1.5 diopters). One (6.3%) patient showed residual astigmatism after cataract surgery. The goal in that patient was to reduce the astigmatism and to improve UDVA, which was successfully achieved, with 100% reduction of refractive astigmatism and a gain of 4 lines in UDVA. The remaining 2 (12.5%) patients presented with clear crystalline lenses and needed only correction of their natural astigmatism. Our aim was to achieve or approach emmetropia and improve UDVA. UDVA was improved by 5 lines in one patient and by 3 lines in the other, and refractive astigmatism was eliminated in one patient and reduced by 64.3% (3.5 diopters preoperatively to 1.25 diopters 6 months postoperatively) in the other. Using the method of vector analysis (according to Alpins), we also evaluated the predictability of the astigmatic correction. Topographic data were analyzed. To the best of our knowledge, this was the first time ISAK was performed in human eyes, so the achievable effect has been unknown until now. Calculated with a mean TIA of 1.59 diopters (= mean SIA), the mean CI, which is preferably 1.0, was 1.00 ± 0.44 for topographic data and 0.92 ± 0.37 for refractive data. Individual analysis of topographic values showed an overcorrection in 7 eyes (CI > 1; mean, 1.34 ± 0.39) and an undercorrection in 8 eyes (CI < 1; mean, 0.71 ± 0.22). We observed no postoperative inflammation around the treatment area in any of the 16 eyes. Furthermore, due to the purely intrastromal location of incisions, there is no risk (compared with traditional AK) of wound gape or epithelial ingrowth. These findings indicate an excellent safety profile of ISAK. Our results showed a significant improvement in manifest and topographic cylinders and UDVA and indicate high patient satisfaction. Overcorrection, which sometimes happens with penetrating incisions5,6 and may require suturing, was not seen in any case. We believe the astigmatic effect can be increased as the nomogram is further refined; a larger series is needed to refine the outcome and predictability of this new procedure. This is currently underway at our clinic with use of the Catalys Precision Laser System (Abbott Medical Optics Inc). More parameters, especially the measurement of corneal biomechanical properties, which is now enabled by new technology, must be included in refining and establishing nomograms. The ISAK procedure is potentially useful for the correction of astigmatism in numerous settings. Its use may reduce the need for toric IOL implantation in low corneal astigmatism cases, improve the precision of LRIs, and enhance postoperative refractive outcomes. From a practical standpoint, it is convenient and cost-effective to identify additional applications for a well-established laser platform that is already used for refractive surgery. In the era of therapeutic laser-assisted cataract surgery, it is possible to take advantage of the precision of a femtosecond laser to create accurate, purely intrastromal arcuate incisions for the correction of astigmatism. The aim after cataract surgery is to reach independence from glasses to improve quality of life. In patients with astigmatism of a medium or higher level, this aim is difficult or impossible to achieve with no additional refractive intervention.

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This case series demonstrates that a predictable, stable effect can be achieved with femtosecond-laser intrastromal arcuate incisions. It will be interesting to compare ISAK with alternative procedures such as low-power toric IOLs. Large randomized studies on ISAK are forthcoming to refine the nomogram and adapt it for higher levels of astigmatic correction.

References 1. Ferrer-Blasco T, Montés-Micó R, Peixoto-de-Matos SC, González-Méijome JM, Cerviño A. Prevalence of corneal astigmatism before cataract surgery. J Cataract Refract Surg. 2009;35(1):70-75. 2. Hoffmann PC, Hütz WW. Analysis of biometry and prevalence data for corneal astigmatism in 23,239 eyes. J Cataract Refract Surg. 2010;36(9):1479-1485. 3. Kook D, Bühren J, Klaproth OK, Bauch AS, Derhartunian V, Kohnen T. Astigmatic keratotomy with the femtosecond laser: correction of high astigmatisms after keratoplasty [in German]. Ophthalmologe. 2011;108(2):143-150. 4. Nubile M, Carpineto P, Lanzini M, et al. Femtosecond laser arcuate keratotomy for the correction of high astigmatism after keratoplasty. Ophthalmology. 2009;116(6):1083-1092. 5. Kumar NL, Kaiserman I, Shehadeh-Mashor R, Sansanayudh W, Ritenour R, Rootman DS. IntraLase-enabled astigmatic keratotomy for post-keratoplasty astigmatism: on-axis vector analysis. Ophthalmology. 2010;117(6):1228-1235.e1. 6. Bahar I, Levinger E, Kaiserman I, Sansanayudh W, Rootman DS. IntraLase-enabled astigmatic keratotomy for postkeratoplasty astigmatism. Am J Ophthalmol. 2008;146(6):897-904.e1. 7. Wu E. Femtosecond-assisted astigmatic keratotomy. Int Ophthalmol Clin. 2011;51(2):77-85. 8. Hoffart L, Proust H, Matonti F, Conrath J, Ridings B. Correction of postkeratoplasty astigmatism by femtosecond laser compared with mechanized astigmatic keratotomy. Am J Ophthalmol. 2009;147(5):779-787,787.e1. 9. Kiraly L, Herrmann C, Amm M, Duncker G. Reduction of astigmatism by arcuate incisions using the femtosecond laser after corneal transplantation [in German]. Klin Monbl Augenheilkd. 2008;225(1):70-74. 10. Kymionis GD, Yoo SH, Ide T, Culbertson WW. Femtosecond-assisted astigmatic keratotomy for post-keratoplasty irregular astigmatism. J Cataract Refract Surg. 2009;35(1):11-13. 11. Buzzonetti L, Petrocelli G, Laborante A, Mazzilli E, Gaspari M, Valente P. Arcuate keratotomy for high postoperative astigmatism performed with the IntraLase femtosecond laser. J Refract Surg. 2009;25(8):709-714. 12. Abbey A, Ide T, Kymionis GD, Yoo SH. Femtosecond laser-assisted astigmatic keratotomy in naturally occuring high astigmatism. Br J Ophthalmol. 2009;93(12):1566-1569. 13. Harissi-Dagher M, Azar DT. Femtosecond laser astigmatic keratotomy for postkeratoplasty astigmatism. Can J Ophthalmol. 2008;43(3):367-369. 14. Levinger E, Bahar I, Rootman DS. IntraLase-enabled astigmatic keratotomy for correction of astigmatism after Descemet stripping automated endothelial keratoplasty: a case report. Cornea. 2009;28(9):1074-1076. 15. Rückl T, Dexl AK, Bachernegg A, et al. Femtosecond laser-assisted intrastromal arcuate keratotomy to reduce corneal astigmatism. J Cataract Refract Surg. 2013;39(4):528-538. 16. Villasenor RA, Salz J, Steel D, Krasnow MA. Changes in corneal thickness during radial keratotomy. Ophthalmic Surg. 1981;12(5):341-342. 17. Alpins N. Astigmatism analysis by the Alpins method. J Cataract Refract Surg. 2001;27(1):31-49. 18. Wetterstrand O, Holopainen JM, Krootila K. Treatment of postoperative keratoplasty astigmatism using femtosecond laser-assisted intrastromal relaxing incisions. J Refract Surg. 2013;29(6):378-382. 19. Venter J, Blumenfeld R, Schallhorn S, Pelouskova M. Non-penetrating femtosecond laser intrastromal astigmatic keratotomy in patients with mixed astigmatism after previous refractive surgery. J Refract Surg. 2013;29(3):180-186. 20. Hoffart L, Touzeau O, Borderie V, Laroche L. Mechanized astigmatic arcuate keratotomy with the Hanna arcitome for astigmatism after keratoplasty. J Cataract Refract Surg. 2007;33(5):862-868. 21. Baldwin HC, Marshall J. Growth factors in corneal wound healing following refractive surgery: a review. Acta Ophthalmol Scand. 2002;80(3):238-247. 22. Wilkins MR, Mehta JS, Larkin DF. Standardized arcuate keratotomy for postkeratoplasty astigmatism. J Cataract Refract Surg. 2005;31(2):297-301. 23. Meltendorf C, Burbach GJ, Bühren J, Bug R, Ohrloff C, Deller T. Corneal femtosecond laser keratotomy results in isolated stromal injury and favorable wound-healing response. Invest Ophthalmol Vis Sci. 2007;48(5):2068-2075.

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Meltendorf C, Burbach GJ, Ohrloff C, Ghebremedhin E, Deller T. Intrastromal keratotomy with femtosecond laser avoids profibrotic TGF-beta1 induction. Invest Ophthalmol Vis Sci. 2009;50(8):3688-3695.

Please see video on the accompanying website at

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21 Descemet’s Membrane Detachment Classification and Management Soosan Jacob, MS, FRCS, DNB, MNAMS and Amar Agarwal, MS, FRCS, FRCOphth Descemet’s membrane detachment can cause corneal damage.1-32 It is important for the surgeon to understand the different types of detachment that can occur and how to manage them.

Descemet’s Membrane Detachment Descemet’s membrane detachment is a complication occasionally faced postoperatively.7,8 Various techniques have been proposed as treatment for Descemet’s membrane detachment, including observation,9 viscoelastic injection,10 air injection, the use of long-acting intracameral gas,11,12 and insertion of transcorneal mattress sutures.13 A detached Descemet’s membrane can be diagnosed on slit lamp examination as a clear optical space between the stroma and Descemet’s membrane. During surgery, trypan blue dye may be injected into the anterior chamber to stain Descemet’s membrane and aid in visualization. The anterior chamber is then irrigated with balanced salt solution to wash away excess trypan blue and to study the dynamics of the detached Descemet’s membrane (Figure 21-1). Though it is generally sufficient to inject an air bubble to appose Descemet’s membrane to the corneal stroma, sometimes other maneuvers may be required.

New Classification of Descemet’s Membrane Detachment Based on pathological features, Descemet’s membrane detachment was classified by Samuels6 as active (pushed back) or passive (pulled back and torn away) due to the difference in elasticity between the parenchyma and the glass membrane. Samuels6 also stated that this classification was more relevant pathologically and that no great importance could be ascribed to these forms of detachment from the surgical standpoint. Descemet’s membrane detachment has also been previously classified as planar (less than a 1-mm gap between Descemet’s membrane and the stroma) or nonplanar (more than a 1-mm gap between Descemet’s membrane and the stroma) based on morphology.7 - 227 -

Agarwal A, John T, eds. Mastering Corneal Surgery: Recent Advances and Current Techniques (pp 227-240). © 2015 SLACK Incorporated.

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Figure 21-1. A stripped Descemet s membrane. It is typically seen near incisions, and it lies loose, floating in the anterior chamber. It may have a crumpled or rolled-up edge with an undulating appearance on anterior-segment OCT, and it flutters on irrigating the anterior chamber with balanced salt solution.

Dr. Soosan Jacob proposed a new classification of Descemet’s membrane detachment based on the clinicomorphological, etiological, tomographic, and intraoperative features, and she proposed a new treatment algorithm for Descemet’s membrane detachment based on its classification. This classification of Descemet’s membrane detachment is analogous to the classification of retinal detachment. Descemet’s membrane is a vital layer of the cornea and is necessary for maintaining the clarity of the cornea, just as the neurosensory retina is required for visual perception. Just as a retinal detachment can be rhegmatogenous retinal detachment [secondary to hole, tear, or dialysis]), tractional retinal detachment, or bullous/exudative retinal detachment, Descemet’s membrane detachment may be classified into rhegmatogenous Descemet’s detachment, tractional Descemet’s detachment, bullous Descemet’s detachment, or complex Descemet’s detachment (CDD) (Table 21-1). A rhegmatogenous Descemet’s detachment generally occurs as an intraoperative event when there is a break in Descemet’s membrane, with fluid accumulation between Descemet’s membrane and the overlying stroma. Analogous to a rhegmatogenous retinal detachment, a rhegmatogenous Descemet’s detachment can be secondary to a hole (eg, a double anterior chamber following perforation during deep anterior lamellar keratoplasty [DALK]) or a tear (eg, Descemet’s membrane detachment occurring during insertion of blunt instruments or IOL implantation during phacoemulsification). Rhegmatogenous Descemet’s detachment can also occur secondary to a dialysis of Descemet’s membrane from its attachment at Schwalbe’s line, sometimes seen during trabeculotomy, punch insertion in trabeculectomy, or anterior chamber maintainer insertion, or if stripping of Descemet’s membrane accidentally extends toward the periphery during Descemet’s membrane endothelial keratoplasty (DMEK). Descemet’s membrane may also become detached secondary to an inflammatory/fibrotic process, resulting in tractional Descemet’s detachment, which is analogous to a tractional retinal detachment. This could be secondary to incarceration of Descemet’s membrane in an inflammatory process (eg, in peripheral anterior synechiae or within the graft host junction in large-diameter grafts) or secondary to incarceration in a wound or suture with subsequent contraction, resulting in a tractional Descemet’s detachment. A long-standing rhegmatogenous Descemet’s detachment can also sometimes adhere to intraocular contents with secondary fibrosis, thus turning into a tractional Descemet’s detachment. A bullous Descemet’s detachment can occur secondary to a disease process, such as posterior corneal abscess, tumor, infection, or inflammation (analogous to bullous retinal detachment). In this type of Descemet’s membrane detachment, a separation and convex bulging of Descemet’s membrane into the anterior chamber occurs in the absence of a break in Descemet’s membrane. The space between the stroma and Descemet’s membrane is filled with pus, exudates, fluid, viscoelastic, blood, or air, depending on the cause of bullous Descemet’s detachment. This configuration of Descemet’s membrane can also be seen as part of Anwar’s bigbubble technique in DALK, which detaches Descemet’s membrane from the stroma and sometimes occurs from accidental injection of viscoelastic into the predescemetic space.33 Clinically, a

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rhegmatogenous Descemet’s detachment is usually seen as an undulating membrane lying loose in the anterior chamber. It may also be scrolled or crumpled, depending on the extent of detachment. It has folds and is mobile, similar to a rhegmatogenous retinal detachment. However, a tractional Descemet’s detachment is stretched tight, like a trampoline, between the points of attachment. It has no folds and is not mobile. A bullous Descemet’s detachment is seen as a convex membrane bulging into the anterior chamber, similar to a bullous retinal detachment. A complex Descemet’s detachment shows complex folds, scrolls, or a combination of other features and can sometimes be seen in a poorly attached DMEK graft.

Anterior-Segment Optical Coherence Tomography Features In all cases of Descemet’s membrane detachment, there is generally overlying corneal epithelial and stromal edema, which may make visualization difficult. In this case, anterior-segment optical coherence tomography (OCT) is useful for diagnosing this condition, as well as differentiating between various types of Descemet’s membrane detachment. A rhegmatogenous Descemet’s detachment is seen as an undulating linear hyper-reflective signal in the anterior chamber, whereas a tractional Descemet’s detachment is seen as a straight, taut linear signal between 2 points of attachment (Figures 21-2 and 21-3). In tractional Descemet’s detachment, the arc length of the cornea, if measured, is found to be more than the length of the detached Descemet’s membrane, unlike in rhegmatogenous Descemet’s detachment, where the arc length of the overlying corneal stroma is similar to the length of the detached Descemet’s membrane. A bullous Descemet’s detachment is seen as a convex, hyper-reflective signal bulging into the anterior chamber from the overlying stroma, with the space between filled with exudate, pus, fluid, or air, depending on the cause of Descemet’s membrane detachment. A CDD shows complex configurations on anteriorsegment OCT. Intraoperatively, tractional Descemet’s detachment can be verified by its more immobile nature and the absence of the typical undulating movement that is associated with a rhegmatogenous Descemet’s detachment on irrigating the anterior chamber with balanced salt solution. A taut Descemet’s membrane does not move with the undulations seen in a rhegmatogenous Descemet’s detachment, although it might show some sharp, small, fluttery movements on forcible irrigation with balanced salt solution.

Relaxing Descemetotomy Relaxing retinotomy is an established surgical technique in vitreoretinal surgery for periretinal traction and retinal foreshortening that does not allow the retina to settle down. Similar traction on Descemet’s membrane secondary to inflammation or fibrosis or Descemet’s membrane becoming incarcerated in a wound or suture leading to a tractional Descemet’s detachment may not respond to the classic management strategies for Descemet’s membrane detachment. Injecting air or long-acting gas into the anterior chamber in an eye with tractional Descemet’s detachment will not appose it to the corneal stroma because of foreshortening. Dr. Soosan Jacob developed a technique called relaxing descemetotomy, which is based on a principle similar to relaxing retinotomy, as a solution for this scenario.

Treatment for Descemet’s Membrane Detachment Based on Classification Treatment of the aforementioned conditions differs. Although both rhegmatogenous Descemet’s detachment and tractional Descemet’s detachment require internal gas tamponade or pneumodescemetopexy and sub-Descemet’s fluid drainage—which is analogous to internal tamponade and subretinal fluid drainage in retinal detachments—tractional Descemet’s detachment also requires relief or removal of the element of traction for Descemet’s membrane to settle onto the stroma. This can be done by relaxing descemetotomy incisions. Sub-Descemet’s fluid drainage is

Mostly intraoperative

History of surgery

Tear, hole, or dialysis

Time of onset

History

Cause

Long-standing RDD becoming adherent to intraocular contents with secondary TDD

Incarceration of Descemet s membrane in inflammation/fibrosis/peripheral anterior synechiae/within the graft host junction/ in wound/suture with subsequent contraction

History of inflammation/ trauma/surgery

Mostly postoperative

TDD

Generally history of surgery Poorly positioned DMEK graft Combination of other Descemet s detachments

Disease process, infection or inflammation Intraoperative complication (eg, blood or accidental injection of viscoelastic)

Intra- or postoperative

CDD

History specific to underlying etiology/ surgery

Secondary to disease process/intraoperative

BDD

(continued)

Abbreviations: BDD, bullous Descemet s detachment; CDD, complex Descemet s detachment; DMEK, Descemet s membrane endothelial keratoplasty; OCT, optical coherence tomography; RDD, rhegmatogenous Descemet s detachment; TDD, tractional Descemet s detachment.

RDD

PARAMETER

Differentiating Features of Descemet s Membrane Detachment Types

TABLE 21-1

230 Chapter 21

Undulating linear hyperreflective signal in the anterior chamber

Anterior segment OCT

Complex configurations or combination of other features

Convex hyperreflective signal bulging into anterior chamber from overlying stroma

Straight, taut, linear hyperreflective signal between 2 points of attachment

Good if residual endothelial function adequate

Depends on cause

Depends on cause

Abbreviations: BDD, bullous Descemet s detachment; CDD, complex Descemet s detachment; DMEK, Descemet s membrane endothelial keratoplasty; OCT, optical coherence tomography; RDD, rhegmatogenous Descemet s detachment; TDD, tractional Descemet s detachment.

Good if residual endothelial function adequate

Complex configurations or combination of other features

Convex membrane bulging into the anterior chamber with no break

Stretched tight like a trampoline between points of attachment. No folds. Immobile or sharp, fluttering movements seen on forcible irrigation with balanced salt solution.

Space filled with exudate, pus, blood, visArc length of corcoelastic, air, etc. nea is more than length of detached Descemet s membrane

CDD

BDD

TDD

.

Prognosis

Undulating membrane lying loose in the anterior chamber. Folds present. Undulating movements seen on irrigating anterior chamber with balanced salt solution.

Clinical findings

Arc length of overlying stroma is similar to length of detached Descemet s membrane

RDD

PARAMETER

Differentiating Features of Descemet s Membrane Detachment Types

TABLE 21-1 (CONTINUED)

Descemet's Membrane Detachment: Classification and Management 231

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Figure 21-2. (A) Anterior segment optical coherence tomograph of Rhegmatogenous Descemet s detachment. (B) Anterior segment optical coherence tomograph of tractional Descemet s detachment. (continued)

performed by injecting gas from the side opposite the tear (internal drainage) or, in some cases, by making a small stab incision in the cornea overlying the Descemet’s membrane detachment to drain the fluid externally. Relaxing descemetotomy may be performed with the anterior chamber filled with viscoelastic or air. The tip of a 26-gauge needle is bent in the reverse direction, of a capsulotomy needle, and is introduced into the anterior chamber to make the relaxing descemetotomy incisions (Figure 21-4). The extent of the incision is determined intraoperatively by assessing the degree of foreshortening that remains. If foreshortening is not completely relieved, the incisions are further extended until Descemet’s membrane is able to lie fully apposed against the stroma. These incisions are made in the peripheral cornea, avoiding the pupillary plane and the visual axis. Postoperative tamponade with nonexpansile concentration of perfluoropropane (14%) or sulphur hexafluoride (12%) is administered with face-up positioning of the patient for 1 hour (Figure 21-5). Relaxing descemetotomy may not be suitable for those patients with tractional Descemet’s detachment who have unhealthy endothelium and for those with long standing disease where, again, the endothelial may be irreversibly damaged. The term descemetotomy was first used by Lowenstein.21-24 It was used to reference a procedure where the Nd:YAG laser was used in the postoperative period to perform descemetotomy to create communication between the anterior chamber and the supernumerary chamber after intentionally retaining Descemet’s membrane during keratoplasty for bullous keratopathy. The authors found that the membrane was resistant to the Nd:YAG laser and required the use of high-energy levels and multiple pulses. Steinemann et al 25 and Masket and Tennen 26 also used the Nd:YAG laser to create a central opening in inadvertently retained opacified host Descemet’s membrane after penetrating keratoplasty (PK). Chen et al 27 surgically removed a similarly retained host Descemet’s membrane after keratoplasty. We have previously used the term iatrogenic descemetorhexis for a case where accidental descemetorrhexis occurred in a patient during phacoemulsification.14 A similar case was also reported by Pan and Au Eong.15 Descemetorrhexis has been described as part of endothelial keratoplasty procedures, where the central Descemet’s membrane is intentionally removed from the host cornea.28-32 The term relaxing descemetotomy differs from the aforementioned terms in that it describes a therapeutic procedure that relieves the traction forces and decreases foreshortening of Descemet’s membrane in a procedure similar to that of relaxing retinotomy. The relaxing descemetotomy incisions break the stress forces acting on Descemet’s membrane. The tautness of

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Figure 21-2 (continued). (C) Classifications of Descemet s detachment.

Descemet’s membrane is relieved, and an air or gas bubble is able to appose the now lax Descemet’s membrane against the overlying corneal stroma. A long-acting gas, such as perfluoropropane or sulphur hexafluoride, may be preferable over an air bubble to provide a longer period of tamponade, such as is sometimes preferred in rhegmatogenous Descemet’s detachment.11,12

Intraocular Lens Implantation in the Presence of Corneal Damage The authors prefer to use the glued IOL technique with Descemet’s stripping automated endothelial keratoplasty (DSAEK) in cases with aphakic corneal decompensation. We have also used the glued IOL in cases requiring full-thickness keratoplasty, as well as in DMEK. It is important to make the anterior segment stable if combining posterior lamellar keratoplasty techniques with glued IOL implantation. A pupilloplasty may be required for widely dilated, nonconstricting

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Figure 21-3. (A) Rhegmatogenous retinal detachment with hole. (B) Rhegmatogenous Descemet s detachment with hole (in DALK with perforation and double anterior chamber seen postoperatively). (C) Rhegmatogenous retinal detachment with tear. (D) Rhegmatogenous Descemet s detachment with tear (post phacoemulsification). (E) Rhegmatogenous Descemet s detachment with dialysis during Descemet s stripping in Descemet s membrane endothelial keratoplasty (DMEK). (F) Rhegmatogenous retinal detachment with dialysis.

pupils to attain a good air fill in the anterior chamber at the end of surgery, as well as to avoid donor graft dislocation. This allows a good compartmentalization of the eye into a bicameral structure, allowing a greater support for the donor tissue. In our experience of DSAEK combined with glued IOL implantation, there has been no incidence of donor dislocation into the posterior segment. We feel the difference from sutured secondary posterior-chamber IOLs lies in the rigid, nonelastic attachment of the IOL to the sclera with the glued IOL technique. The crystalline lensbag-zonule complex—due to its 360-degree attachment to the ciliary area—is a trampoline-like structure (Figure 21-6). However, the Prolene sutures (2 or 4, depending on the technique) used

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Figure 21-4. Relaxing descemetotomy is performed to relieve the tension and stress forces acting on the tractional Descemet s detachment. Once the relaxing descemetotomy cuts are made (arrows), Descemet s membrane becomes lax and can now be apposed to the overlying corneal stroma by injecting an air bubble.

A

B

Figure 21-5. (A) Preoperative OCT showing a TDD. (B) Postoperative OCT showing Descemet s membrane attached after relaxing descematotomy. (Reprinted with permission from Agarwal A, Jacob S. Relaxing descemetotomy relieves stress forces in taut Descemet s membrane detachment. Ocular Surgery News [US Edition]. http://www.healio.com/ophthalmology/cornea-external-disease/news/print/ocular-surgerynews/%7Bae1cce40-93c8-483f-bb44-d84016e72ec1%7D/relaxing-descemetotomy-relieves-stress-forces-intaut-descemets-membrane-detachment. Published October 10, 2010. Accessed July 8, 2014.)

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A

B

C

D

Figure 21-6. IOL implantation and posterior capsular rupture. (A) Schematic diagram showing normal trampoline line arrangement of the ciliary body, zonules, and crystalline lens in a normal eye. (B) Schematic diagram showing the change in the case of a pseduophakic eye with an in-the-bag posterior-chamber IOL. (C) Schematic diagram showing a pseudophakic eye with a sutured scleral-fixated IOL with increased torsional instability and increased pseudophacodonesis due to sclera-suture-haptic-optic attachment. (D) Schematic diagram showing a pseduophakic eye with a glued IOL and reduced torsional instability and lesser pseudophacodonesis due to rigid sclera-haptic-optic attachment.

for suture fixating an IOL to the sclera act as a hammock, which provides less torsional stability than the natural state. The glued IOL reduces the torsional and oscillatory freedom of the implant because the resultant IOL-haptic-sclera complex is more stable than the IOL-haptic-suture-sclera complex of the suture-fixated IOLs. This same biomechanical model is the reason for lesser pseudophacodonesis seen after glued IOL compared with suture-fixated IOL. The learning curve for the glued IOL procedure is fairly simple for most anterior segment surgeons, and the detailed steps for the combination surgery are provided in the literature, as well as in this book. Other authors have also noted the disastrous complications of the donor lenticule falling into the vitreous in aphakic eyes.34 The placement of a glued IOL in situ before placement of the lenticule compartmentalizes the aphakic eye from a unicameral to partly bicameral environment. This will produce less instability in the anterior segment and act as a rigid barrier to decrease chances of the donor lenticule from falling into the vitreous.

Descemet’s Membrane Endothelial Keratoplasty With Glued Intraocular Lenses DMEK was described by Melles et al 35 for pseudophakic bullous keratopathy (Figure 21-7A). The basic technique consists of preparing the donor graft by partially trephining it and using a Sinskey hook to lift up the edge of the cut Descemet’s membrane. After an adequate edge is lifted, a nontoothed forceps is used to gently grab Descemet’s membrane at its edge, and the graft is separated from the underlying stroma in a capsulorrhexis-like circumferential manner (Figure 21-7B). These steps are performed using the submerged cornea using backgrounds away technique described by Giebel.36 The DMEK graft is then stained with trypan blue and replaced in the sterile corneal storage medium while the recipient eye is prepared.

Descemet's Membrane Detachment: Classification and Management

A

237

Figure 21-7. (A) Preoperative pseudophakic bullous keratopathy. Note the posterior-chamber IOL implanted in the anterior chamber. (B) Preparation of a DMEK graft.

B

An anterior-chamber maintainer is inserted, and 2 points are marked on the sclera exactly 180 degrees apart. Two 2.5 × 2.5-mm lamellar scleral flaps are created on either side, centered on the marks. Trypan blue is used to stain the patient’s Descemet’s membrane before scoring and stripping it from approximately 8.5-mm diameter (as marked from above the corneal surface) using a reverse Sinskey hook. A 20-gauge needle is used to create a sclerotomy approximately 1 to 1.5 mm from the limbus under each scleral flap, and a 23-gauge vitrector introduced through the sclerotomy performs anterior vitrectomy. If a posterior-chamber IOL is in the anterior chamber, it is repositioned in a closed-globe manner by exteriorizing its haptics through the sclerotomies (Figure 21-8A and 21-8B). If there is an anterior-chamber IOL, it is explanted, and a new IOL is implanted by performing the conventional glued IOL technique. In aphakic eyes, a foldable IOL is injected into the anterior chamber and its haptics are exteriorized through the sclerotomy. In all situations, once both haptics are exteriorized, the Scharioth tuck is used to tuck them into scleral tunnels made at the edge of the scleral flaps using a 26-gauge needle. Intracameral pilocarpine is then used to constrict the pupil, and, if necessary, a pupilloplasty is performed. The graft is then carefully loaded into a 1.8 mm Viscoglide cartridge (Medicel, Switzerland). The cartridge is then loaded onto the Viscoject injector (Medicel, Switzerland) after removing the spring coil. This technique is as described by Professor Francis Price.37 The cartridge tip is held occluded with a finger. It is then injected gently into the anterior chamber by plunging the soft-tipped injector, taking care not to fold the graft (Figure 21-8C). Wound-assisted implantation is avoided, and the anterior-chamber maintainer flow is titrated carefully to prevent backflow and extrusion of the graft through the incision. The graft orientation is then checked, and it is unfolded gently (Figure 21-8D). Once unfolded, an adequately tight air bubble is injected under the graft to float it up against the stroma (Figure 21-8D). Finally, fibrin glue is used to seal the lamellar scleral flaps, conjunctiva, and clear corneal incisions. In patients with aphakia, loss of bicamerality of the eye because of absence of an iris-lens diaphragm is seen. This leads to a poor tamponade effect and posterior migration of the injected air. This technique combines the advantages of stable fixation of the IOL and the advantages of

238

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Figure 21-8. DMEK with glued IOL. (A) PCIOL implanted in anterior chamber leading to corneal decompensation. The same PCIOL is being relocated into the posterior chamber using a closed-globe, glued IOL technique. The haptic is grabbed from over the iris using an end-gripping forceps and, using a handshake technique, is transferred between the 2 hands until the tip of the haptic is held. (B) The haptic is exteriorized through the sclerotomy made under the scleral flap. The same procedure is followed for the second haptic, which is exteriorized through a sclerotomy under a second scleral flap created 180 degrees away from the first. Each haptic is then tucked into a scleral tunnel created at the edge of the scleral flap. (C) The DMEK graft is loaded into a Visian implantable contact lens injector and is injected into the anterior chamber. (continued)

A

B

C

lamellar keratoplasty. In contrast, an anterior chamber IOL has the disadvantage of decreased IOL-endothelial distance, which can cause long-term graft failure when combined with PK. It becomes especially disadvantageous when combined with DSAEK, where the endothelium with donor stroma also occupies space within the anterior chamber, thereby bringing the anterior surface of the anterior chamber IOL close to the DSAEK lenticule. Hence, these patients require explantation of the anterior-chamber IOL, with secondary IOL fixation and corneal transplantation. A sutured scleral-fixated IOL can be combined with endothelial keratoplasty, but it has the disadvantage of a longer open-sky period, making the patient more vulnerable to potential complications such as expulsive hemorrhage. Also, more pseudophakodonesis is associated with sutured

Descemet's Membrane Detachment: Classification and Management

D

239

E

Figure 21-8 (continued). (D) The DMEK graft is unrolled. (E) An air bubble is used to appose it against the overlying stroma. (Reprinted with permission from Agarwal A, Jacob S. Corneal damage and posterior capsular rupture. In: Agarwal A, Jacob S, eds. Posterior Capsular Rupture: A Practical Guide to Prevention and Management. Thorofare, NJ: SLACK Incorporated; 2014:194-195.

IOLs because the fixation to the sclera is via sutures at 2 points. In the glued IOL technique, the haptic of the IOL itself is anchored to the sclera along a significant portion of its length. In our opinion, this stability of the glued IOL can lead to a decreased rate of graft dislocation compared with a sutured scleral-fixated IOL, which has more intraocular mobility. The glued IOL also offers the ability to adjust the centration of the IOL at any time intraoperatively by simply adjusting the degree of tuck of the haptics into the scleral tunnel, unlike the longer and more tedious procedure that would be required to recenter a decentered sutured scleral-fixated IOL. All suturerelated complications, such as erosion, degradation, and exposure, are also eliminated. The fibrin glue seals the flaps hermetically over the haptics and makes the procedure safe.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Machemer R. Cutting of the retina: a means of therapy for retinal reattachment [in German]. Klin Monbl Augenheilkd. 1979;175(5):597-601. Machemer R. Retinotomy. Am J Ophthalmol. 1981;92(6):768-774. Machemer R, McCuen BW II, de Juan E Jr. Relaxing retinotomies and retinectomies. Am J Ophthalmol. 1986;102(1):7-12. Alturki WA, Peyman GA, Paris CL, Blinder KJ, Desai UR, Nelson NC Jr. Posterior relaxing retinotomies: analysis of anatomic and visual results. Ophthalmic Surg. 1992;23(10):685-688. Bovey EH, De Ancos E, Gonvers M. Retinotomies of 180 degrees or more. Retina. 1995;15(5):394-398. Samuels B. Detachment of Descemet’s membrane. Trans Am Ophthalmol Soc. 1928;26:427-437. Mackool RJ, Holtz SJ. Descemet membrane detachment. Arch Ophthalmol. 1977;95(3):459-463. Kim T, Sorenson A. Bilateral Descemet membrane detachments. Arch Ophthalmol. 2000;118(9):1302-1303. Minkovitz JB, Schrenk LC, Pepose JS. Spontaneous resolution of an extensive detachment of Descemet’s membrane following phacoemulsification. Arch Ophthalmol. 1994;112(4):551-552. Hoover DL, Giangiacomo J, Benson RL. Descemet membrane detachment by sodium hyaluronate. Arch Ophthalmol. 1985;103(6):805-808. Zusman NB, Waring GO III, Najarian LV, Wilson LA. Sulfur hexafluoride gas in the repair of intractable Descemet’s membrane detachment. Am J Ophthalmol. 1987;104(6):660-662. Kim T, Hasan SA. A new technique for repairing Descemet membrane detachments using intracameral gas injection. Arch Ophthalmol. 2002;120(2):181-183. Amaral CE, Palay DA. Technique for repair of Descemet membrane detachment. Am J Ophthalmol. 1999;127(1):88-90. Agarwal A, Jacob S, Agarwal A, Agarwal S, Kumar MA. Iatrogenic descemetorrhexis as a complication of phacoemulsification. J Cataract Refract Surg. 2006;32(5):895-897. Pan JC, Au Eong KG. Spontaneous resolution of corneal oedema after inadvertent ‘descemetorhexis’ during cataract surgery. Clin Experiment Ophthalmol. 2006;34(9):896-897.

240 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

Chapter 21 Dirisamer M, Dapena I, Ham L, et al. Patterns of corneal endothelialization and corneal clearance after Descemet membrane endothelial keratoplasty for Fuchs’ endothelial dystrophy. Am J Ophthalmol. 2011;152(4):543-555.e1. Jacobi C, Zhivov A, Korbmacher J, et al. Evidence of endothelial cell migration after Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2011;152(4):537-542.e2. Balachandran C, Ham L, Verschoor CA, Ong TS, van der Wees J, Melles GR. Spontaneous corneal clearance despite graft detachment in Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2009;148(2):227-234.e1. Stewart RM, Hiscott PS, Kaye SB. Endothelial migration and new Descemet membrane after endothelial keratoplasty. Am J Ophthalmol. 2010;149(4):683-684. Cursiefen C, Kruse FE. DMEK: Descemet membrane endothelial keratoplasty [in German]. Ophthalmologe. 2010;107(4):370-376. Lazar M, Loewenstein A, Geyer O. Intentional retention of Descemet’s membrane during keratoplasty. Acta Ophthalmol (Copenh). 1991;69(1):111-112. Loewenstein A, Geyer O, Lazar M. Intentional retention of Descemet’s membrane in keratoplasty for the surgical treatment of bullous keratopathy. Acta Ophthalmol (Copenh). 1993;71(2):280-282. Loewenstein A, Lazar M. Deep lamellar keratoplasty in the treatment of bullous keratopathy. Br J Ophthalmol. 1993;77(8):538. Loewenstein A, Geyer O, Lazar M. Descemetotomy. J Cataract Refract Surg. 1996;22(6):652. Steinemann TL, Henry K, Brown MF. Nd:YAG laser treatment of retained Descemet’s membrane after penetrating keratoplasty. Ophthalmic Surg. 1995;26(1):80-81. Masket S, Tennen DG. Neodymium:YAG laser optical opening for retained Descemet’s membrane after penetrating keratoplasty. J Cataract Refract Surg. 1996;22(1):139-141. Chen YP, Lai PC, Chen PY, Lin KK, Hsiao CH. Retained Descemet’s membrane after penetrating keratoplasty. J Cataract Refract Surg. 2003;29(9):1842-1844. Dapena I, Ham L, Moutsouris K, Melles GR. Incidence of recipient Descemet membrane remnants at the donor-to-stromal interface after descemetorhexis in endothelial keratoplasty. Br J Ophthalmol. 2010;94(12):1689-1690. Mehta JS, Hantera MM, Tan DT. Modified air-assisted descemetorhexis for Descemet-stripping automated endothelial keratoplasty. J Cataract Refract Surg. 2008;34(6):889-891. Wylegała E, Tarnawska D, Dobrowolski D, Janiszewska D. Outcomes of endothelial keratoplasty with descemetorhexis (DSEK) [in Polish]. Klin Oczna. 2007;109(7-9):287-291. Bradley JC, McCartney DL, Busin M. Donor corneal disk insertion techniques in descemetorhexis with endokeratoplasty. Ann Ophthalmol (Skokie). 2007;39(4):277-283. Nieuwendaal CP, Lapid-Gortzak R, van der Meulen IJ, Melles GJ. Posterior lamellar keratoplasty using descemetorhexis and organ-cultured donor corneal tissue (Melles technique). Cornea. 2006;25(8):933-936. Javadi MA, Feizi S. Deep anterior lamellar keratoplasty using the big-bubble technique for keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2010;36(7):1156-1160. Singh A, Gupta A, Stewart JM. Posterior dislocation of Descemet stripping automated endothelial keratoplasty graft can lead to retinal detachment. Cornea. 2010;29(11):1284-1286. Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. 2006;25(8):987-990. SCUBA technique for DMEK donor preparation. www.youtube.com/watch?v=vpToO8PFsvI. Accessed November 6, 2014. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: early challenges and technique to enhance donor adherence. J Cataract Refract Surg. 2006;32:411-18.

Please see video on the accompanying website at

www.healio.com/books/cornealvideos

22 Corneoscleral Pocket Technique Richard S. Hoffman, MD; Alejandro Cerda, MD; I. Howard Fine, MD; and Annette Chang Sims, MD Stabilization of the decentered or subluxed intraocular lens (IOL)-capsular bag complex or implantation of a secondary posterior-chamber IOL lacking capsular support can be accomplished by means of iris fixation1-3 and trans-scleral fixation through the ciliary sulcus or pars plana.4-6 Although iris fixation of decentered IOLs is a popular technique for lens stabilization, late-onset IOL-capsular bag complex subluxation resulting from zonular weakness or dialysis may be more easily repaired with scleral fixation.7-9 Techniques for trans-scleral fixation include ab interno methods,10-14 wherein the suture is passed from the inside of the eye to the external surface, and ab externo methods,15-19 in which the suture is initially passed from the external surface. Common to all of the techniques for trans-scleral fixation is the need to bury, cover, or rotate the knot created for fixation so that conjunctival erosion and subsequent endophthalmitis is less likely to develop.19,20 Scleral fixation of IOLs and adjunctive capsular devices can be performed under the protection of a scleral flap. In 2006, we described a technique that allowed for suture knot coverage that avoided the need for conjunctival dissection, scleral cauterization, or sutured wound closure.21 With this technique, a scleral pocket is initiated through a peripheral clear corneal incision. This is followed by full-thickness passage of a double-armed suture through the scleral pocket and conjunctiva with subsequent retrieval of the suture ends through the external corneal incision for tying. The corneoscleral pocket technique offers a refined method for fixation of IOLs and other intraocular adjunctive devices.21 Herein, we describe the technique for a late subluxed IOLcapsular complex, secondary implantation of a foldable IOL without capsular support, and an iridodialysis repair, but it can be used for any IOL or intraocular device that requires trans-scleral fixation. Numerous methods are currently used for trans-scleral fixation of IOLs and adjunctive surgical devices.22 Common to these techniques is the requirement for conjunctival dissection and the need to prevent suture knot erosion of the overlying conjunctiva with the ensuing risk of endophthalmitis.23 Existing methods for knot concealment include covering the knot with a patch graft, 24 fascia lata,25 or triangular scleral flap,11,15,24-29 in addition to suturing within a scleral groove30-32 and suture knot rotation into the eye.33-35 All of these techniques have limitations. Scleral patch grafts and fascia lata coverings require additional procurement of tissue from eye banks or the patient’s body and add unnecessary time - 241 -

Agarwal A, John T, eds. Mastering Corneal Surgery: Recent Advances and Current Techniques (pp 241-250). © 2015 SLACK Incorporated.

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to the procedure. Use of a triangular scleral flap necessitates extremely accurate suture placement when using an ab interno technique to insure that the suture passes through the floor of the dissection. Similarly, the scleral groove technique can be used for ab externo suture passes, but, by nature of the limited groove area, it can not be used effectively with an ab interno method. Rotation of full-thickness scleral suture knots can be impeded by short suture passes and may be more difficult with the larger knots that result from currently recommended thicker 9-0 Prolene (Ethicon, Inc) and 8-0 Gore-Tex (W.L. Gore & Associates, Inc) suture gauges.36,37

Advantages The scleral pocket technique for scleral fixation has several advantages. First, a larger surface area can be created for suture passes than with triangular scleral flaps or scleral grooves. This allows the suture needles to exit anywhere inside the large dissected pocket as long as they are at the appropriate distance from the surgical limbus (0.5 to 1 mm for ciliary sulcus fixation38). This is especially useful when using an ab interno approach. Second, dissection of the scleral pocket initiated from a clear corneal incision avoids the need for conjunctival dissection or scleral cautery. This should induce less discomfort in patients undergoing procedures with topical anesthesia in which unforeseen complications may necessitate use of scleral fixated lenses or fixated capsular bag prostheses. The dissection of the distal scleral pocket is also easier to perform than a triangular flap in the distal location because the dissection can proceed directed away from the surgeon in a slightly downhill direction. In addition, the procedure may be expedited relative to a triangular flap technique because conjunctival dissection is avoided and sutured wound closure is unnecessary. Finally, less astigmatism may be induced than would occur with the placement of 2 radial sutures through each of 2 opposing triangular flaps in the same meridian. Although 2 opposed 30-degree vertical clear corneal incisions have a small flattening effect in the meridian of placement, the small arc length and relatively superficial depth compared with traditional limbal relaxing incisions induces little astigmatic effect, and this can be modified by using more superficial 300-μm incisions depending on the desired astigmatic result. Use of a scleral pocket with hook retrieval of the suture ends can be performed for any procedure requiring trans-scleral fixation. This includes implantation of secondary IOLs, repair of dislocated IOLs,7-9,39,40 use of adjunctive surgical devices such as Ahmed capsular tension segments (Morcher GmbH) and Cionni capsular tension rings (Morcher GmbH),41 and repair of iridodialyses.42-45 This modification of the traditional scleral flap allows simpler creation of a scleral covering, negating the need to rotate suture knots while facilitating needle placement for either an ab interno or ab externo technique.

Corneoscleral Pocket Technique for Late Subluxed Intraocular Lens-Capsular Complex Calipers dipped in gentian violet are used to mark the locations for the peripheral clear corneal incisions. These incisions are made 180 degrees from each other in a meridian that will facilitate proper final positioning of the IOL optic. The haptics should be incorporated into the suture passes unless a capsular tension ring (CTR) was previously placed, in which case the CTR can be secured within the suture passes.8 The 3- and 9-o’clock meridians should be avoided to prevent damage to the long posterior ciliary arteries. A guarded diamond step knife (#05-5027; Rhein Medical) or #64 Beaver blade (#376400; Becton, Dickinson and Company) is used to make the 30-degree-long (1 clock hour) and 300- to 400-μm-deep incisions just anterior to the conjunctival insertion at the limbus (Figure 22-1). The depth of these incisions can be modified depending on whether more or less flattening is desired in that meridian. Two scleral pockets are then dissected posteriorly from the 2 opposing incisions using a diamond crescent knife (#60505; Mastel Precision) or a metal crescent blade (990002 A-OK; Alcon Laboratories) (Figure 22-2). The pockets are extended approximately 3 mm posteriorly from the clear corneal incisions. A 1-mm paracentesis is then created just anterior to each of the clear corneal incisions into the anterior chamber to aid in suture placement. Initiating the paracentesis just anterior to the clear corneal incision instead of within the incision will facilitate the passing of Prolene sutures because the external

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Figure 22-1. Subluxed IOL-capsular bag complex containing Soemmering s ring. Two 30-degreelong (1 clock hour) and 300- to 400-µm-deep clear corneal incisions are made with a diamond step knife 180 degrees apart. These incisions are placed in a meridian that will allow fixation of the lens haptics to the sclera.

Figure 22-2. Posterior dissection of scleral pockets using a diamond crescent blade. Note the paracentesis originating anterior to the clear corneal incision.

opening of the paracentesis can be more easily identified. The paracentesis can also be placed immediately adjacent to the clear corneal incision. These 1-mm paracenteses can be used to place single iris hooks to expose the peripheral capsular bag or concealed IOL haptics. A small quantity of viscoelastic is placed into the anterior chamber through one paracentesis to stabilize the anterior chamber. Viscoelastic may also be placed in the ciliary sulcus underlying the scleral pocket to aid the suture passes. Suture placement is initially directed toward the haptic that has been exposed through the pupil secondary to the IOL decentration. A 25- or 27-gauge needle is passed through the conjunctiva and the full thickness of the scleral pocket 1 mm posterior to the surgical limbus. This needle is inserted into the eye, behind the iris and in front of the capsular bag far enough to allow visualization of the beveled tip. A double-armed 9-0 Prolene suture on a long curved needle (D-8229 CTC-6L; Ethicon, Inc) is inserted through the opposite paracentesis and docked into the 27-gauge needle (Figure 22-3), and both are removed externally through the scleral pocket and the conjunctiva. The 27-gauge needle is then passed again through the conjunctiva and the full

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Figure 22-3. Docking of a Prolene suture needle into a 27-gauge hollow needle above the capsular bag. The suture needle is passed through the 1-mm paracentesis. The 27-gauge needle is passed into the eye through the conjunctiva and the scleral pocket, 1 mm posterior to the surgical limbus.

Figure 22-4. The second arm of the doublearmed Prolene suture is inserted through the paracentesis and docked with a second 27-gauge needle that has perforated the capsular bag central to the exposed haptic.

thickness of the scleral pocket 1 mm posterior to the surgical limbus and 1 to 2 mm adjacent to the first pass of the needle. This 27-gauge needle is inserted into the eye behind the capsular bag equator. The needle perforates the capsular bag central to the IOL haptic and passes completely through the posterior and anterior capsule. The second arm of the double-armed Prolene suture is passed through the opposite paracentesis and docked with the 27-gauge needle, and both are again removed through the full thickness of the eye (Figure 22-4). At this point, all suture passes are through the full thickness of the sclera at the ciliary sulcus. By removing the needles from all suture passes, each suture end can then be retrieved through the scleral pocket opening by passing a Sinskey hook into the pocket and pulling the trailing suture end through the corneal incision so that the sutures are now passing through the corneal incision, through the floor of the scleral pocket (1 mm posterior to the surgical limbus), and into the eye through the ciliary sulcus. When retrieving the sutures through the corneal incision, holding the other suture of the double-armed pass with a forceps will prevent inadvertently pulling that suture end out of the eye (Figure 22-5).

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Figure 22-5. Following the second pass of the double-armed suture, the needles are removed and the suture ends are retrieved through the scleral pocket incision using a Sinskey hook. The left suture has already been retrieved and is being held with forceps to avoid inadvertent suture loss during retrieval of the right suture.

Figure 22-6. Prolene sutures for each haptic are tied, allowing the knot to slide under the roof of the scleral pocket.

Tying of the suture ends recenters the IOL and allows the knot to be concealed as it slides under the protective roof of the scleral pocket. The same technique can now be performed on the opposite haptic using the second scleral pocket and the opposing paracentesis (Figure 22-6). An iris hook can be placed in the first paracentesis to aid in visualization of the capsular bag equator and lens haptic for the second fixation site. Suturing of the scleral pockets is not necessary. Viscoelastic can be removed by injecting Miochol-E (acetylcholine chloride intraocular solution) into the anterior chamber while depressing the posterior lip of one of the paracenteses or with bimanual irrigation and aspiration cannulas inserted into each of the 2 paracenteses.

Secondary Implantation of a Foldable Posterior-Chamber Intraocular Lens Without Capsular Support Using Scleral Pockets When confronting the clinical scenario of a compromised capsular bag that precludes the use of a sulcus IOL or a lens placed in the bag, the surgeon has several options. The easiest approach is to place an anterior-chamber IOL. When properly sized, anterior-chamber lenses are well tolerated and represent the simplest and least time-consuming method for dealing with aphakia.

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Unfortunately, instances of chronic discomfort, cystoid macular edema, and cornel endothelial compromise from poorly sized lenses has led to a tendency to avoid their use whenever possible. Another popular method for treating aphakia is to insert a posterior-chamber IOL and fixate it to the iris. Iris fixation involves much less dissection than scleral fixation but has the potential complications of pupil distortion, late hyphema from iris chaffing, and late decentration and dislocation.46 In addition, when performed in a fully vitrectomized eye, iris fixation can be more challenging in the presence of an anterior-chamber infusion port (thus usually necessitating pars plana infusion) and runs the risk of complete IOL dislocation onto the retina during the procedure if the iris-captured optic is pulled off of the pupil. Although there are many methods for performing scleral fixation, the following technique allows for placement and fixation of a foldable posterior-chamber IOL. After placement of a dispersive viscoelastic or an anterior-chamber infusion port, 2 grooved incisions of 1 to 2 clock hours’ length are placed at the 12- and 6-o’clock meridians. The incisions are created with a diamond or metal step knife at a depth of 350 μm. Each of these grooved incisions is then dissected posterior for approximately 3 mm with a metal crescent blade to create 2 corneoscleral pockets 180 degrees apart. Lifting up of the posterior lip of the grooved incision while creating the pockets will facilitate the dissection.21 The dissection is within the plane of the sclera. Marking the lateral extents of the scleral pockets with a gentian violet mark on the conjunctival surface will help avoid passing sutures through nondissected sclera. If the procedure is performed at the same time as the complicated cataract surgery, the temporal clear corneal incision is widened to 3.0 mm for insertion of a foldable IOL and for placement of the 9-0 Prolene fixation sutures. If present, vitreous should be removed from the anterior chamber with bimanual vitrectomy instrumentation. A 27-gauge needle is then passed through the full thickness of the globe, corresponding to the right-sided scleral pocket, 2 mm posterior to the surgical limbus (not the conjunctival insertion). The needle passes through the conjunctiva, the roof of the pocket, the floor of the pocket, and the ciliary sulcus, taking care to angle the needle obliquely to avoid the ciliary processes. One long-curved needle of a double-armed 9-0 Prolene suture is then passed through the temporal clear corneal incision and docked into the 27-gauge needle. The curved suture needle will usually lock itself into the straight 27-gauge needle bore so that both can be removed from the globe without internal assistance. The Prolene suture should be 9-0 rather than 10-0 to reduce the risk of late suture breakage and IOL dislocation.36 The maneuver is then repeated with the needle of the second arm of the double-armed suture, using a new 27-gauge needle passed 1 to 2 mm adjacent to the first pass, 2 mm posterior to the surgical limbus. As the second set of needles are removed from the globe, a loop of Prolene is left outside the temporal corneal incision to create a cow-hitch knot that will be attached to the leading haptic of the IOL.47 A small dollop of viscoelastic is placed on the corneal surface to assist in creating the cow-hitch knot. The loop of Prolene suture is then flipped back onto the viscoelastic on the cornea to create the cow-hitch knot. The IOL design for implantation is at the discretion of the surgeon. Unfortunately, there is currently a lack of foldable posterior chamber IOLs with fixation eyelets. For many surgeons, an all polymethylmethacrylate IOL with fixation eyelets is the first choice for scleral fixation. This design has the benefit of allowing the suture to pass through the eyelet and avoiding the need for creating knots that fixate the suture to the IOL haptic. Unfortunately, these lenses require larger incisions with greater induced astigmatism, although placing the incision at the temporal location will help reduce the amount of induced astigmatism. In addition, these eyelet lenses usually need to be special ordered, which may not be feasible in a primary case with a completely compromised capsule. Using a cow-hitch knot allows for the use of foldable IOLs, which can be injected through relatively small incisions with a cartridge system. Treating each end of the foldable IOL’s haptics with low-temperature cautery will produce a small enlargement or a frank burr at the end of the haptic that should help prevent suture slippage off the haptic. Low-temperature handheld cautery (not high-temperature) placed close to the tip of the haptic for a brief second will create the burr. High-temperature cautery or prolonged contact will melt or shrink the haptic, making the IOL unusable. The design of the cow-hitch knot is such that slippage should be avoided if constant traction is placed on the knot and suture as the IOL is inserted. After preparing the lens, it is inserted in its cartridge injector and extruded enough to allow the leading haptic of the lens to be exposed outside of the cartridge. The leading haptic

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is then placed through each loop of the cow-hitch knot that was created outside of the temporal incision, and the suture is tightened by pulling on both ends of the Prolene exiting from the scleral pocket. The haptic is then inserted through the incision, followed by the cartridge, and the IOL is injected into the anterior chamber, leaving the trailing haptic outside of the globe. Gentle traction is placed on the Prolene sutures to help direct the leading haptic toward the ciliary sulcus, taking care to leave the trailing haptic outside of the temporal corneal incision. The same technique is then repeated for the opposite scleral pocket. A second double-armed Prolene suture is used for the left-sided pocket, and another cow-hitch knot is created and attached to the trailing haptic of the IOL. The trailing haptic is then pulled into the eye by means of traction on the connected Prolene sutures emanating from the corresponding scleral pocket. Starting the fixation process with the right-handed pocket (superior pocket for the left eye, inferior pocket for the right eye) will help prevent slippage of the suture off the haptic during IOL insertion. Once the IOL has been inserted, both sets of Prolene sutures are tightened to center the IOL. The needles of the sutures are then removed, and the ends of each set of sutures are retrieved though the opening of the scleral pocket by placing a Sinskey hook into the dissected pocket and pulling the ends out though the corneal opening.21 Each set of externalized sutures are then tightened and tied, allowing the knot to slide under the protective roof of the scleral pocket and avoiding the risk of knot erosion through the overlying conjunctiva with the associated risks of endophthalmitis. No suture closure is necessary for the scleral pockets, and suture closure of the clear corneal incision is at the discretion of the surgeon once all viscoelastic has been removed from the anterior chamber or the anterior chamber infusion is removed from the eye. Although there are many different approaches for placement of a primary or secondary IOL in the absence of a functional capsular bag, scleral fixation using this technique offers some inherent benefits. With the use of scleral pockets, suture knots can be created and covered without the need to rotate knots and the need to perform conjunctival dissection. The use of a cow-hitch knot with this method also allows for the use of a foldable IOL, which should be readily available in most ambulatory surgery centers on the day of the complicated surgery. The insertion of a foldable IOL though a 3.0-mm incision using a cartridge injector will also lesson the degree of induced astigmatism that may be created with a 6.0- or 7.0-mm all polymethylmethacrylate lens.

Iridodialysis Repair Through a Scleral Pocket Repair of the traumatic iridodialysis can be accomplished by means of single or multiple McCannel sutures through an ab externo approach or using one or more double-armed sutures with an ab interno method. When fixating anything to the sclera, it is important to rotate the suture knots into the sclera or cover the suture knots under a scleral flap to prevent erosion of the overlying conjunctiva, which could then allow for the development of subsequent endophthalmitis. Although suture knot rotation is relatively simple and straightforward, an alternative method of repairing a traumatic iridodialysis uses one or more scleral pockets that eliminate the need for a conjunctival peritomy but enable covering of the suture knot without the need for knot rotation. If the iridodialysis is 3 clock hours or less, one double-armed Prolene suture and one pocket is all that is required. For larger dialyses, 2 pockets will be needed (Figure 22-7). The first step is to place a 350-μm-deep grooved incision at the clear cornea limbus overlying the middle third of the dialysis. For large dialyses, 2 grooves of 2-clock-hour-lengths are placed. Each grooved incision is then dissected posteriorly in the plane of the sclera for approximately 2 mm to create a scleral pocket. Using a metal crescent blade and lifting up on the posterior edge of the grooved incision during the dissection facilitates creation of the scleral pocket. Once the pockets are dissected, the conjunctival surface overlying the lateral extent of each pocket is marked with gentian violet to assist in correct suture needle placement. A paracentesis is then made 3 to 4 clock hours from the site of fixation, and viscoelastic is injected into the anterior chamber. A 10-0 Prolene suture on a double-armed CIF4 needle (Ethicon) is passed through the paracentesis, incorporating the edge of the dialysed iris root onethird the lateral distance from the attached edge of the iris root. The needle is then passed through the full thickness of the globe, exiting approximately 2 mm posterior to the limbus within the area of the dissected pocket. The second arm of the double-armed suture is passed through the

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Figure 22-7. Intraoperative view of a 120-degree nasal iridodialysis.

same paracentesis, through the iris root edge, 3 mm adjacent to the first pass, and out through the sclera 2 to 3 mm adjacent to the first pass and 2 mm posterior to the limbus. It is better to err on passing the needle posterior to the original insertion rather than anterior to avoid obstructing the trabecular meshwork. Wiggling the needle tip back and forth as it goes through the paracentesis will avoid accidently passing the suture needle through the corneal stroma. Placing the viscoelastic cannula into the paracentesis to hold the paracentesis open while passing the needle into the anterior chamber will also facilitate entry if this step becomes difficult. For a single-pocket dialysis of less than 90 degrees, the 2 needle passes should trisect the dialysis into thirds. After the sutures have been placed, the needles are removed, and the suture ends are retrieved through the external opening of the scleral pocket by placing a Sinskey hook into the pocket and pulling each suture end out. After both suture ends of the double-armed suture have been externalized, the suture is tightened and tied, allowing the knot to slide under the protective roof of the scleral pocket. The suture ends are then trimmed, and no additional wound closure of the pockets is required (Figure 22-8). These repairs are usually performed in combination with cataract extraction, and it is best to repair the iridodialysis before phacoemulsification to facilitate access to the lens and avoid inadvertent aspiration and enlargement of the iridodialysis. Following phacoemulsification, IOL implantation, and viscoelastic removal, the pupil should be constricted intraoperatively to determine whether significant corectopia has been created from the iridodialysis repair. If so, a single suture can be placed through the pupillary margin using a Siepser slip-knot technique to pinch the pupil into a rounder and smaller size if desired.

Conclusion By using a scleral pocket for scleral fixation and repair of iridodialyses, scleral cauterization and collagen denaturation can be avoided. In addition, by avoiding conjunctival dissection, patients who have filtering blebs or may require filtering blebs in the future may be better served.

References 1. McCannel MA. A retrievable suture idea for anterior uveal problems. Ophthalmic Surg. 1976;7(2):98-103. 2. Ashraf MF, Stark WJ. McCannel sutures and secondary iris-fixated intraocular lenses. In: Azar DT, ed. Intraocular Lenses in Cataract and Refractive Surgery. Philadelphia, PA: WB Saunders; 2001:165-170. 3. Chang DF. Siepser slipknot for McCannel iris-suture fixation of subluxated intraocular lenses. J Cataract Refract Surg. 2004;30(6):1170-1176.

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Figure 22-8. Appearance of the dilated pupil following iridodialysis repair and prior to phacoemulsification.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Nakashizuka H, Shimada H, Iwasaki Y, Matsumoto Y, Sato Y. Pars plana suture fixation for intraocular lenses dislocated into the vitreous cavity using a closed-eye cow-hitch technique. J Cataract Refract Surg. 2004;30(2):302-306. Teichmann KD. Pars plana fixation of posterior chamber intraocular lenses. Ophthalmic Surg. 1994;25(8):549-553. Girard LJ. Pars plana phacoprosthesis (aphakia intraocular implant): a preliminary report. Ophthalmic Surg. 1981;12(1):19-22. Moreno-Montañés J, Heras H, Fernández-Hortelano A. Surgical treatment of a dislocated intraocular lens-capsular bag-capsular tension ring complex. J Cataract Refract Surg. 2005;31(2):270-273. Gross JG, Kokame GT, Weinberg DV; Dislocated In-The-Bag Intraocular Lens Study Group. In-the-bag intraocular lens dislocation. Am J Ophthalmol. 2004;137(4):630-635. Jehan FS, Mamlis N, Crandall AS. Spontaneous late dislocation of intraocular lens within the capsular bag in pseudoexfoliation patients. Ophthalmology. 2001;108(10):1727-1731. Smiddy WE, Sawusch MR, O’Brien TP, Scott DR, Huang SS. Implantation of scleral-fixated posterior chamber intraocular lenses. J Cataract Refract Surg. 1990;16(6):691-696. Grigorian R, Chang J, Zarbin M, Del Priore L. A new technique for suture fixation of posterior chamber intraocular lenses that eliminates intraocular knots. Ophthalmology. 2003;110(7):1349-1356. Apple DJ, Price FW, Gwin T, et al. Sutured retropupillary posterior chamber intraocular lenses for exchange or secondary implantation. The 12th annual Binkhorst lecture, 1988. Ophthalmology. 1989;96(8):1241-1247. Kumar M, Arora R, Sanga L, Sota LD. Scleral-fixated intraocular lens implantation in unilateral aphakic children. Ophthalmology. 1999;106(11):2184-2189. Sharpe MR, Biglan AW, Gerontis CC. Scleral fixation of posterior chamber intraocular lenses in children. Ophthalmic Surg Lasers. 1996;27(5):337-341. Lewis JS. Ab externo sulcus fixation. Ophthalmic Surg. 1991;22(11):692-695. Eryildirim A. Knotless scleral fixation for implanting a posterior chamber intraocular lens. Ophthalmic Surg. 1995;26(1):82-84. Shapiro A, Leen MM. External transscleral posterior chamber lens fixation. Arch Ophthalmol. 1991;109(12):1759-1760. Horiguchi M, Hirose H, Koura T, Satou M. Identifying the ciliary sulcus for suturing a posterior chamber intraocular lens by transillumination. Arch Ophthalmol. 1993;111(12):1693-1695. Kirk TQ , Condon GP. Simplified ab externo scleral fixation of late in-the-bag IOL dislocation. J Cataract Refract Surg. 2012;38(10):1711-1715. Heilskov T, Joondeph BC, Olsen KR, Blankenship GW. Late endophthalmitis after transscleral fixation of a posterior chamber intraocular lens. Arch Ophthalmol. 1989;107(10):1427.

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21. Hoffman RS, Fine IH, Packer M. Scleral fixation without conjunctival dissection. J Cataract Refract Surg. 2006;32(11):1907-1912. 22. Por YM, Lavin MJ. Techniques of intraocular lens suspension in the absence of capsular/zonular support. Surv Ophthalmol. 2005;50(5):429-462. 23. Schecter RJ. Suture-wick endophthalmitis with sutured posterior chamber intraocular lenses. J Cataract Refract Surg. 1990;16(6):755-756. 24. Bucci FA Jr, Holland EJ, Lindstrom RL. Corneal autografts for external knots in transsclerally sutured posterior chamber lenses. Am J Ophthalmol. 1991;112(3):353-354. 25. Bashshur Z, Ma’luf R, Najjar D, Noureddin B. Scleral fixation of posterior chamber intraocular lenses using fascia lata to cover knots. Ophthalmic Surg Lasers. 2002;33(6):445-449. 26. Rao SK, Gopal L, Fogla R, Lam DS, Padmanabhan P. Ab externo 4-point scleral fixation. J Cataract Refract Surg. 2000;26(1):9-10. 27. Ramocki JM, Shin DH, Glover BK, Morris DA, Kim YY. Foldable posterior chamber intraocular lens implantation in the absence of capsular and zonular support. Am J Ophthalmol. 1999;127(2):213-216. 28. Basti S, Tejaswi PC, Singh SK, Sekhar GC. Outside-in transscleral fixation for ciliary sulcus intraocular lens placement. J Cataract Refract Surg. 1994;20(1):89-92. 29. Hu BV, Shin DH, Gibbs KA, Hong YJ. Implantation of posterior chamber lens in the absence of capsular and zonular support. Arch Ophthalmol. 1988;106(3):416-420. 30. Bergren RL. Four-point fixation technique for sutured posterior chamber intraocular lenses. Arch Ophthalmol. 1994;112(11):1485-1487. 31. Friedberg MA, Berler DK. Scleral fixation of posterior chamber intraocular lens implants combined with vitrectomy. Ophthalmic Surg. 1992;23(1):17-21. 32. Lin CP, Tseng HY. Suture fixation technique for posterior chamber intraocular lenses. J Cataract Refract Surg. 2004;30(7):1401-1404. 33. Lewis JS. Sulcus fixation without flaps. Ophthalmology. 1993;100(9):1346-1350. 34. Buckley EG. Scleral fixated (sutured) posterior chamber intraocular lens implantation in children. J AAPOS. 1999;3(5):289-294. 35. Cordovés L, Gómez A, Mesa CG, Abreu JA. Sulcus transscleral sutured posterior chamber lenses. J Cataract Refract Surg. 1999;25(2):156-157. 36. Price MO, Price FW Jr, Werner L, Berlie C, Mamalis N. Late dislocation of scleral-sutured posterior chamber intraocular lenses. J Cataract Refract Surg. 2005;31(7):1320-1326. 37. Cionni RJ, Osher RH, Marques DM, Marques FF, Snyder ME, Shapiro S. Modified capsular tension ring for patients with congenital loss of zonular support. J Cataract Refract Surg. 2003;29(9):1668-1673. 38. Duffey RJ, Holland EJ, Agapitos PJ, Lindstrom RL. Anatomic study of transsclerally sutured intraocular lens implantation. Am J Ophthalmol. 1989;108(3):300-309. 39. Ahmed II, Chen SH, Kranemann C, Wong DT. Surgical repositioning of dislocated capsular tension rings. Ophthalmology. 2005;112(10):1725-1733. 40. Koh HJ, Kim CY, Lim SJ, Kwon OW. Scleral fixation technique using 2 corneal tunnels for a dislocated intraocular lens. J Cataract Refract Surg. 2000;26(10):1439-1441. 41. Cionni RJ, Osher RH. Management of profound zonular dialysis or weakness with a new endocapsular ring designed for scleral fixation. J Cataract Refract Surg. 1998;24(10):1299-1306. 42. Erakgun T, Kaskaloglu M, Kayikcioglu O. A simple closed chamber technique for repair of traumatic iridodialysis in phakic eyes. Ophthalmic Surg Lasers. 2001;32(1):83-85. 43. Brown SM. A technique for repair of iridodialysis in children. J AAPOS. 1998;2(6):380-382. 44. Kaufman SC, Insler MS. Surgical repair of a traumatic iridodialysis. Ophthalmic Surg Lasers. 1996;27(11):963-966. 45. Kervick GN, Johnston SS. Repair of inferior iridodialysis using a partial-thickness scleral flap. Ophthalmic Surg. 1991;22(6):354-355. 46. Kaiura TL, Seedor JA, Koplin RS, Rhee MK, Ritterband DC. Complications arising from irisfixated posterior chamber intraocular lenses. J Cataract Refract Surg. 2005;31(12):2420-2422. 47. Chen SX, Lee LR, Sii F, Rowley A. Modified cow-hitch suture fixation of transscleral sutured posterior chamber intraocular lenses: long-term safety and efficacy. J Cataract Refract Surg. 2008;34(3):452-458.

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Section IV Miscellaneous

23 Intrastromal Corneal Ring Segments and the Turnaround Technique for Overcoming False Channel Dissection During Intacs Implantation Saraswathy Karnati, MS; Soosan Jacob, MS, FRCS, DNB, MNAMS; and Amar Agarwal, MS, FRCS, FRCOphth Intrastromal corneal ring segments (ICRSs) have been used for the treatment of mild to moderate myopia and keratoconus.1-6 They act as passive spacing agents, shortening the arc length of the cornea. They also create a second limbus, thereby producing corneal flattening. ICRSs are available in various segment thicknesses, different arc lengths, and different diameters. The thicker the inserted segment, the greater the flattening effect. The greater the arc length, the greater the effect. Similarly, the greater the curvature, the smaller the optic zone and greater the effect.

Intrastromal Corneal Ring Segment Types Intacs Intacs (Addition Technology, Inc) are micro-thin prescription inserts made of polymethylmethacrylate (PMMA) (Figure 23-1). They are 150 degrees in arc length and available in various thicknesses. Each segment has 2 positioning holes that assist in implantation and, if required, explantation of the rings. They are available in 2 different optic zones: Intacs, which are hexagonal in cross section and have an outer diameter of 8.1 mm and an inner diameter of 6.8 mm; and Intacs SK (Addition Technology, Inc), which are oval in cross section and have an outer diameter of 7.3 mm and inner diameter of 6 mm. Because they have a smaller optic zone, Intacs SK are used for more severe keratoconus. - 253 -

Agarwal A, John T, eds. Mastering Corneal Surgery: Recent Advances and Current Techniques (pp 253-262). © 2015 SLACK Incorporated.

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Figure 23-1. Intacs implantation may be done with asymmetric segments for ectatic cones.

Ferrara Rings Ferrara rings (Mediphakos Inc) are PMMA camphorquinone-acrylic segments with a triangular cross section, which leads to a prismatic effect–induced decrease in edge-related photic phenomena. They are available in 2 optic zones: 6.0 and 5.0 mm. They vary in thickness from 150 to 350 μm and have a constant 600-μm base and an arc of 160 degrees for all segments.

Kerarings Kerarings (Mediphakos Inc) were designed specifically for keratoconus and are similar to Ferrara rings. However, they are available in varying arc lengths ranging from 90 to 210 degrees. They have an internal diameter of 4.4 mm and an external diameter of 5.6 mm. The smaller optical zones and the greater arc lengths lead to a greater neutralization of astigmatism. The longer arc length models are sometimes more difficult to implant.

Bisantis Bisantis (Optikon 2000 SpA and Soleko SpA) are segmented perioptic PMMA implants with an oval cross section. Four segments, each 80 degrees, are implanted. Segments of different curvatures are available to obtain optic zones of 3.5, 4.0, and 4.5 mm.

Myoring The Myoring (Dioptex GmbH) is a flexible, ring-shaped intracorneal PMMA implant that is inserted into a closed intracorneal pocket. Its diameter ranges from 5 to 8 mm and its thickness ranges from 100 to 400 μm.

Advantages The advantages of the ICRS include its ease, simplicity, and safety. It is a minimally invasive procedure with no tissue removal. It maintains the prolate shape of the cornea, and the central optic zone is untouched. It gives immediate visual recovery and is easily adjustable and reversible. It can restore contact lens tolerance and allow the patient to achieve improved levels of uncorrected visual acuity and best corrected visual acuity (BCVA). The option of undergoing a deep anterior lamellar keratoplasty or penetrating keratoplasty (PK) at a later date is preserved. It can be easily used as a combined treatment strategy along with cross-linking, phakic intraocular lenses (IOLs), or refractive lens exchange.

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Figure 23-2. (A) Intacs are used for the treatment of keratoconus and other ectatic disorders. (B) Intacs are passive spacing agents that act by creating a second limbus. They cause flattening of the cornea and have a refractive effect.

Indications ICRSs were originally used for the treatment of myopia and corneal ectasia. Indications for the treatment of myopia included stable refraction with astigmatism less than 1 diopter in patients older than 18 years. ICRSs produced a predicted nominal correction based on a cycloplegic spherical equivalent of between – 1.3 to – 4.0 diopters. More recently, the use of ICRSs is limited to ectatic disorders of the cornea, such as keratoconus, post-LASIK ectasia, and pellucid marginal degeneration. They have also been used for correction of irregular astigmatism following PK, radial keratotomy, and corneal scars. The most common indication is keratoconus with poor BCVA and contact lens intolerance.

Contraindications Contraindications include patients with collagen vascular diseases, and pregnant or lactating women. Local contraindications related to the eye include recurrent corneal erosions and dystrophies, severe keratoconus with extreme thinning, central corneal opacity affecting vision, and severe atopy. ICRSs should not be implanted for the correction of myopia in patients with high expectations for uncorrected emmetropia.

Mechanism of Action The flattening effect of the ICRS on the cornea creates a refractive effect, hence its introduction for the treatment of myopia (Figure 23-2). Some of the major advantages of Intacs over LASIK in the treatment of myopia are the absence of surgery in the optic zone, the reversibility, and the ability of the procedure to maintain the prolate shape of the cornea as opposed to the oblate shape that occurs after LASIK. However, currently the use of Intacs is largely restricted to the treatment of keratoconus and other ectatic disorders of the cornea. The aim is to delay if not arrest the need for an eventual keratoplasty secondary to progressive ectasia and thinning. The flattening and smoothing of surface irregularities of the stretched cornea by the inserted segment improves the visual acuity of the keratoconic patient to a variable degree. ICRSs have a positive effect on the corneal topography and help to shift the corneal apex more centrally. Symmetric segments are used for central cones, whereas asymmetric segments are used for eccentric cones. By creating a second limbus, they redistribute corneal curvature and thereby biomechanical stress, having a positive effect on corneal biomechanics. The cycle of progression may be slowed or even halted by these rings; therefore, they are used to stabilize the shape of the cornea to a variable extent. They are also used in combination with cross-linking to achieve a greater flattening and stabilizing effect on the progression of ectasia.

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Figure 23-3. (A) The channel for the ICRS is created manually or (B) by the femtosecond laser.

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Figure 23-4. (A) A circumferential 360-degree IntraLase channel is created with a vertical entry incision. (B) The Intacs segment is pushed into the channel.

Surgical Technique ICRSs are inserted intrastromally into a track created by the surgeon at approximately twothirds the depth of the zone of implantation. The track can be created using either mechanical dissectors or a femtosecond laser (Figure 23-3). The femtosecond laser offers greater precision with regard to the channel size and depth and lesser chance of complications such as shallow placement or perforation into the anterior chamber or superficially. The laser can be programmed to create a 360-degree circumferential channel at the desired depth and a vertical entry incision at the desired axis (Figure 23-4). While inserting the first ICRS, the surgeon should go perpendicularly down to the depth of the incision (Figure 23-5) and then turn the segment horizontally, parallel to the channel, to introduce it into the channel. Once it is within the channel, it is advanced forward with short pushes in the direction of the tunnel plane while maintaining the arc of the tunnel (see Figures 23-4B and 23-5B). The same procedure is repeated on the other side with the second ICRS. This generally allows both segments to slide in smoothly into the IntraLase (Abbott Medical Optics) tunnel.

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Figure 23-5. (A) While inserting Intacs segments, the surgeon should go perpendicularly down to the depth of the incision. (B) It is then turned horizontally, parallel to the channel, and introduced into the channel using short pushes to move it forward.

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Figure 23-6. (A) An ICRS with overlying stromal melt. (B) ICRS removed due to melt. (C and D) Corneal vascularization extending from the limbus.

Complications Intraoperative complications include epithelial defects at the keratotomy site, anterior and posterior perforation during channel creation, false channel creation during segment insertion, decentered optical zone, segment breakage, and incisional gaping. Postoperative complications include stromal melt (Figures 23-6A and 23-6B), progressive thinning and segment extrusion (see Figures 23-6A and 23-6B), neovascularization (Figures 23-6C and 23-6D), segment migration (Figure 23-7), undercorrection, overcorrection, induced/residual astigmatism, pupil size/ optic zone mismatch, edge glare and haloes in mesopic conditions, channel opacification, channel deposits, and channel infections.

False Channel Creation False channel creation can occur during insertion and can be easily handled if the surgeon takes the necessary steps. Occasionally, difficulty may be experienced at any point along the arc of insertion. This happens if the ICRS, instead of following the femtosecond channel, enters and creates

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Figure 23-7. (A) Segment migration following difficult segment implantation. (B) Progressively increasing segment migration with overriding over 4 months. (C) Segment extrusion. (D) Anteriorsegment optical coherence tomography showing segment migration and overriding.

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Figure 23-8. (A) An eye in which one Intacs segment has been abandoned secondary to false channel creation. (B) An eye in which suboptimal positioning of the segments is seen secondary to difficult insertion. Both segments are seen lying close to the entry incision because further forward movement was impossible.

a false plane. This false channel can become enlarged on further pushing, with simultaneous collapse and loss of the femtosecond channel plane. Further pushing at this stage is pointless because it leads to the creation of a false channel, which is essentially a blind track. False channel creation is thus associated with difficult insertion, which may sometimes result in having to abandon the procedure (Figure 23-8A) or to accept a suboptimal positioning of the segments (Figure 23-8B). In our experience, this kind of excessive maneuvering and repeated attempts at insertion, even in the face of obstruction, can lead to complications.

Turnaround Technique Dr. Soosan Jacob described 2 new techniques—the turnaround technique and the double-pass turnaround technique—for handling such a situation and for placement in case of channel plane loss for both symmetric and asymmetric Intacs segments.7 Encountering any difficulty in insertion (Figure 23-9A) may imply the creation of a false channel (Figure 23-9B). At this point, instead of trying further pushing movements in the same direction, the segment is removed and turned around to be inserted in the opposite direction through the IntraLase channel (Figure 23-9C). It is then advanced forward as far as possible in the usual manner with forceps. Once it is completely lying within the channel and cannot be moved further forward with the forceps, the second Intacs segment is used as an instrument for pushing the first one further forward (Figure 23-9D). The arc shape of the second segment makes it the

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Figure 23-9. (A) A false channel is recognized by radial folds and a wave-like deformity at the advancing edge, as well as increasing difficulty in pushing the segment further forward. (B) The internal lip of the false channel. (C) The turnaround technique is used to overcome the blind track secondary to false channel creation. The Intacs segment is removed, turned around, and inserted from the other side. (D) The second segment is inserted and used to push the first segment further forward. (E) The leading edge of the second segment pushes the first segment forward. (F) The first segment is pulled into its final position using a reverse Sinskey hook, and the surgery is completed.

perfect instrument for doing so (Figure 23-9E). This maneuver automatically glides the leading edge of the first segment into the right plane by opening up the IntraLase-dissected channel (Figure 23-10). Because the femtosecond channel is a continuous, circular, 360-degree channel, it allows circumferential movement of the segment. The first segment is thus pushed forward through the IntraLase channel in the area of false dissection until it has reached the intended site of implantation. The second segment is then manipulated back into its intended site using a reverse Sinskey hook to engage its positioning hole (Figure 23-9F).

Recognizing False Channel Dissection When the advancing edge of the Intacs segment enters into a plane separate from that created by the IntraLase, further pushing maneuvers lead to the cleavage of a new plane. This new plane is a false channel, and its formation is recognized clinically as progressively increasing difficulty in insertion and forward movement of the segment. Resistance offered by the corneal stroma to the advancing edge of the segment is seen as a wave-like deformity and radiating folds at the advancing edge of the segment (Figure 23-11). Further forcible pushing by the surgeon leads to enlargement of this false channel until no further forward movement of the Intacs is possible. Creation of this false channel adjacent to the IntraLase-dissected channel leads to compaction of the adjacent lamellae with resultant collapse of the IntraLase channel. At its point of origin, the false channel is separated from the IntraLase channel by an internal lip in the corneal stroma (see Figure 23-10). This lip is open toward the direction of the entry incision through which the segments are introduced, and it can be identified clinically on careful examination (see Figure 23-9B). The Intacs segment or any other instrument that may be introduced through the entry incision in an attempt to reopen the IntraLase channel is guided away from the IntraLase channel and into the false channel by this internal lip. With the turnaround technique for false channel dissection, the segment approaches the obstruction from the opposite side. It flattens the lip, making the false channel collapse while reopening the IntraLase-dissected channel (see Figure 23-10B). The turnaround technique thus refers to turning the segment around and introducing it from the opposite side on encountering false channel dissection. This guides the segment from the opposite direction

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Figure 23-10. (A) The internal lip in the corneal stroma, which separates the false channel from the IntraLase channel at its point of origin. (B) With the turnaround technique for false channel dissection, the segment approaches the obstruction from the opposite side and flattens the lip, making the false channel collapse while reopening the IntraLase-dissected channel.

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Figure 23-11. (A) The presence of undue resistance to the insertion of the segment indicates false channel creation. (B) The segment is removed and reinserted from the opposite direction. (C) As the first segment approaches the obstruction from the opposite side, it flattens the lip of the false channel and opens up the original IntraLase-dissected channel. (D) The segment is then pulled into position using a reverse Sinskey hook.

into the right IntraLase-dissected plane. The segment can be seen to cross the internal lip when it is turned around and introduced from the opposite side.

Symmetric and Asymmetric Segments With symmetric segments, if it is the second segment that is causing false channel dissection, it is removed and used to push the first segment forward so that this now comes to lie in the area of obstruction. With asymmetric segments, if it is the first segment that has entered a false channel,

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it is removed and turned around to be inserted from the opposite direction. The second segment is then used as an intrachannel pushing instrument to make the first segment approach its intended site from the opposite direction.

Double-Pass Turnaround Technique With asymmetric segments, if it is the second segment that is not passing with ease, it is removed, and a double-pass turnaround technique is performed. The obstructed second segment is removed and used to push the other asymmetric (first) segment forward. Once this is accomplished, the position of the segments is the reverse of what is desired and needs to be corrected by doing a “double pass.” The first segment is manipulated out through the incision site. This externalized segment is again reintroduced and used to push the second segment forwards until both eventually come to rest in their respective planned sites. An alternative is to pull the first segment out and then perform a turnaround technique with the second segment.

Combination Surgery Intrastromal Corneal Ring Segments With Crosslinking and Contact Lens– Assisted Cross-Linking Combining ICRS with crosslinking augments the flattening effect of ICRS alone. It can be done as simultaneous surgery, where ICRS insertion is followed immediately by crosslinking, or as sequential surgery, where ICRS insertion is followed by crosslinking at a later date. It may also be combined with contact lens–assisted crosslinking for patients with minimal stromal thickness less than 400 μm.

Intrastromal Corneal Ring Segments With Phakic Intraocular Lenses The residual refractive error after ICRS may be corrected with the placement of phakic IOLs, either toric or nontoric. It may be preceded by crosslinking if required.

Intrastromal Corneal Ring Segments With Refractive Lens Exchange The residual refractive error after ICRS may be corrected by refractive lens exchange. This may be preceded by crosslinking if required.

Conclusion ICRSs are used as a treatment for keratoconus and other ectatic disorders. They are effective in increasing quality of vision and in stabilizing the cornea. Their insertion may sometimes be associated with complications. False channels, if not addressed appropriately, may result in having to abandon implantation of one or both Intacs segments or to accept a suboptimal positioning of the segments with respect to the plane/axis of implantation. The turnaround technique and the double-pass turnaround technique are useful additions to the surgeon’s armamentarium and can help overcome this difficult situation.

References 1.

Burris TE, Baker PC, Ayer CT, Loomas BE, Mathis ML, Silvestrini TA. Flattening of central corneal curvature with intrastromal corneal rings of increasing thickness: an eye-bank eye study. J Cataract Refract Surg. 1993;19 Suppl:182-187. 2. Asbell PA, Uçakhan OO. Long-term follow-up of Intacs from a single center. J Cataract Refract Surg. 2001; 27(9):1456-1468. 3. Nosé W, Neves RA, Burris TE, Schanzlin DJ, Belfort Júnior R. Intrastromal corneal ring: 12-month sighted myopic eyes. J Refract Surg. 1996;12(1):20-28. 4. Schanzlin DJ, Asbell PA, Burris TE, Durrie DS. The intrastromal ring segments. Phase II results for the correction of myopia. Ophthalmology. 1997;104(7):1067-1078.

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5.

Asbell PA, Uçakhan OO, Abbott RL, et al. Intrastromal corneal ring segments: reversibility of refractive effect. J Refract Surg. 2001;17(1):25-31. 6. Neuhann TH. Intrastromal corneal ring segments. In: Agarwal S, Agarwal A, Pallikaris IG, Neuhann TH, Knorz MC, Agarwal A, eds. Refractive Surgery. New Delhi, India: Jaypee Brothers; 2000:566-573. 7. Jacob S, Nair V, Prakash G, Kumar DA. Turnaround technique for intrastromal corneal ring implantation in eyes with false channel dissection. J Cataract Refract Surg. 2010;36(8):1253-1260.

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24 Corneal Inlays for the Surgical Correction of Presbyopia George O. Waring IV, MD and Fernando Faria-Correia, MD Presbyopia is a ubiquitous visual disability of the aging eye featuring a progressive loss of accommodation. Regardless of any underlying refractive error, this condition affects all individuals approximately 50 years old. Currently, there are more than 140 million people older than 40 years in the United States alone, and it is expected that by 2020, there will be 2.1 billion presbyopic patients worldwide. Based on these demographic trends, an increasing interest has been placed on the development of novel treatments for the surgical correction of presbyopia. Several options exist or are in development for the surgical correction of presbyopia, such as corneal inlays, multifocal or accommodative intraocular lenses (IOLs), monovision or blended vision strategies, conductive keratoplasty, presbyLASIK, intrastromal correction with the use of femtosecond technology (INTRACOR, Technolas Perfect Vision GmbH), and scleral expansion techniques. Corneal inlays have emerged as a promising corneal-based treatment for presbyopia. During the past century, Barraquer1 introduced refractive addition surgery by means of implanting a synthetic lenticule into the cornea (synthetic keratophakia) for the correction of aphakia and high myopia. Several studies led to the understanding that corneal inlays needed to be thin, small diameter, highly permeable, and implantable relatively deep in corneal stroma.2-7 The nutrient-permeable corneal endothelium and the gas-permeable corneal epithelium synergistically transport ions out of the stroma. The ideal inlay design would allow oxygen from tear film and glucose from aqueous humor to nourish corneal cells while catabolic waste products flowed out to the aqueous humor with minimal restriction to provide a healthy environment for corneal cells and to remain transparent after implantation of the inlay. This surgical concept and additional research led the way for the development of various types of implants with different mechanisms and designs. Corneal inlays offer several advantages compared with other surgical options: they are removable and repositionable and can be combined with other refractive procedures. There are also several implantation techniques and technologies—including both mechanical and femtosecond laser–enabled platforms—to create pockets and flaps to achieve the desired visual results.8 The current generation of inlays available for the treatment of presbyopia are different based on their mechanism of action (Figure 24-1): refractive inlays, which alter the index of refraction; inlays that change the corneal curvature; and inlays with a small aperture to increase the depth of focus. - 263 -

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Figure 24-1. Flow chart depicting classification of corneal inlays based on mechanism of action.

Refractive Optic Inlays Refractive optic corneal inlays are designed to change the eye’s refractive index, providing distance vision through a plano central zone surrounded by one or more rings of varying add power for near vision. Inlays are typically implanted in the nondominant eye. Based on a precursor known as the InVue lens (Biovision AG), the Flexivue Microlens (Presbia) is a transparent, 3.0-mm-diameter hydrogel implant containing an ultraviolet blocker. It has a central 0.15-mm opening to facilitate fluid and nutrient flow, surrounded by a plano central zone and a refractive peripheral zone with add power from + 1.25 to + 3.5 diopters, in 0.25-diopter increments. Depending on add power, the lens thickness varies between 15 and 20 μm. This inlay should be implanted in a corneal pocket at a depth of 280 to 300 μm. The Flexivue inlay is currently in US Food and Drug Administration clinical trials but is commercially available in a number of countries outside the United States. The literature published on this inlay is limited. A prospective study of 47 presbyopic emmetropes implanted with the Flexivue Microlens in a femtosecond laser–created corneal pocket in the nondominant eye found that uncorrected near visual acuity (UCNVA) was 20/32 or better in 75% of implanted eyes at 12 months (mean, 20/25).9 Mean uncorrected distance visual acuity (UCDVA) decreased 3 lines, from 20/20 to 20/50, although binocular UCDVA was not statistically affected. Thirty-seven percent of patients lost 1 line of best corrected distance visual acuity (BCDVA) in the operated eye, but no patient lost 2 lines. There was a statistically significant decrease in mesopic and photopic contrast sensitivity at a number of spatial frequencies and an increase in higher-order aberrations in the implanted eyes. Overall, patient satisfaction and spectacle independence was high, but 12.5% of patients experienced halos and glare 1 year postoperatively.9 Promising results were reported in a previous prospective study using the earlier version of the inlay (InVue lens) inserted in a corneal pocket created with a microkeratome.10 One year postoperatively, 98% of those patients had UCNVA of 20/32 or better in the operated eye. UCDVA was 20/40 or better in 93% of implanted eyes.10 The Icolens (Neoptics AG) is a 3-mm-diameter multifocal corneal inlay that uses the peripheral zone for near vision correction and a central zone for distance vision correction. This lens, made of a hydrophilic acrylic hydrogel, is the most recent inlay to be introduced. There are promising early reports from European clinical trials, but no details have yet been published in the peer-reviewed literature. The Icolens is currently under consideration for a US investigational device exemption in anticipation of embarking on a clinical trial.

Corneal Reshaping Inlays Corneal reshaping inlays are designed to reshape the anterior curvature of the cornea to enhance near and intermediate vision due to a multifocal effect. The Raindrop Near Vision Inlay (ReVision Optics), formerly known as the PresbyLens or Vue+ Lens (ReVision Optics), has a 1.5to 2.0-mm diameter and is made of clear hydrogel. This inlay has a hyperprolate shape that is 10

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Figure 24-2. Slit lamp biomicroscopic photograph of the Raindrop Near Vision Inlay.

Figure 24-3. Slit lamp biomicroscopic photograph of the KAMRA small-aperture inlay.

μm thick at the edge and approximately 30 μm thick at the center. It also has no refractive power. Its water content and refractive index are similar to the native cornea (Figure 24-2). It is intended for implantation under a 130- to 150-μm LASIK flap or in a corneal pocket in the nondominant eye. The Raindrop Near Vision Inlay is available in Europe and is currently in a phase III clinical trial in the United States. Porter et al11 described the visual results in a series of hyperopic eyes implanted with the 2.0-mm design. There was an average UCNVA improvement of more than 5 lines 1 month postoperatively, with 78% of the implanted eyes achieving 20/25 or better. Uncorrected intermediate visual acuity (UCIVA) improved by an average of 4 lines, and mean distance UCDVA was 20/25.11 In another study, 25 hyperopic presbyopic patients underwent implantation of the 2.0-mm corneal inlay combined with LASIK.12 At 1 month postoperatively, more than 80% of eyes achieved J1 or better UCNVA. There was also an average of 5 lines of UCIVA improvement, to 20/25. Improvement in UCDVA averaged 2 lines, with one patient losing 1 line.12

Small-Aperture Inlays The KAMRA Inlay (AcuFocus, Inc) is an opaque inlay made of polyvinylidene fluoride (Figure 24-3) that uses the pinhole effect to increase depth of field by selecting central light rays and minimizing refraction. It is just 5 μm thick and has 8400 laser-etched porosity holes to maintain the metabolic flow to the anterior cornea; the holes are distributed in a designed pseudorandom pattern to prevent diffraction issues at night. The 1.6-mm central annulus acts as a pinhole, and the outer diameter measures 3.8 mm. It should be implanted in a lamellar pocket or under a 200-μm femtosecond laser flap. Unlike other nonlens-based presbyopic treatments, including inlays in development, the KAMRA continuously compensates for the progressive loss of accommodative amplitude by means of improvement in depth of focus with a small aperture. A contralateral comparison with

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the Optical Quality Analysis System (Visiometrics) shows a broadened defocus curve and reduced simulated retinal blur in the implanted eye. The KAMRA inlay is an attractive option for several types of patients: natural emmetropes, post-LASIK emmetropes, patients also undergoing LASIK correction as a simultaneous or 2-step procedure, and pseudophakic patients after implantation of a monofocal IOL.13 This implant completed US phase III clinical trials but is commercially available in many countries outside the United States, with more than 18,000 inlays implanted worldwide to date. Animal studies showed an early increase in stromal cell death and inflammation 48 hours postoperatively in eyes that underwent a femtosecond laser pocket creation and KAMRA inlay insertion compared with eyes with the pocket only. This inflammatory reaction dissipated by 6 weeks postoperatively.14 In previous human studies, there were no reports of inflammatory reactions, such as ulceration or stromal fibrosis. There was also no negative effect on endothelial cell density.15,16 Published clinical data demonstrate that monocular implantation of the KAMRA inlay results in sustained improvement of near and intermediate vision while maintaining good distance vision.17 Tomita et al18 reported a series of 180 eyes implanted with the current version of the KAMRA inlay that also underwent simultaneous LASIK. At 6 months, with data available for approximately one-third of the eyes, mean UCNVA improved by 7 lines in hyperopic eyes, 6 lines in emmetropic eyes, and 2 lines in myopic eyes; mean UCDVA improved by 3 lines, 1 line, and 10 lines, respectively. All patients had binocular UCDVA of 0.00 logMAR (20/20) or better. There are also long-term studies on the earlier version of the KAMRA inlay. Despite recent improvements in the inlay and surgical technique, these studies showed that the mean UCNVA improved and there was no significant loss of binocular UCDVA.15,16 Concerning UCIVA, 91% of implanted eyes saw at least 20/3216 and had significant improvements in the ability to perform intermediate tasks without correction.18,19 This is a major advantage over multifocal options for presbyopic patients, which typically provide relatively poor intermediate acuity. Despite the small loss of monocular contrast sensitivity, it remains within normal limits, and the loss is minor compared with the gain in near and intermediate vision.16,20 A prospective study described no significant change in stereopsis 6 months after implantation.20 The ability to perform common tasks without spectacles may be a better measure of functional success than visual acuity. Through 1- to 2-year follow-up prospective and interventional case series, Dexl et al 21,22 reported that emmetropic presbyopic patients implanted with the KAMRA inlay had sustained and even slightly improved on all measures of reading performance. Other studies reported that patient satisfaction with the KAMRA inlay has been especially high among emmetropes and hyperopes.18,19 After small-aperture inlay implantation, patients reported a statistically significant reduction in their dependence on glasses for near and intermediate tasks. The ability to perform these tasks was better in bright than in dim light conditions.19,22 Casas-Llera et al 23 demonstrated good quality visualization of the central and peripheral fundus in eyes after small-aperture inlay. Other authors pointed out that retina examination was a difficult task. Regarding visual field analysis, the inlay did not appear to cause any localized changes or scotomas.16 Recently available in the literature are the first series of patients with corneal inlays who underwent cataract surgery.15 After monofocal IOL implantation, the patients continued to have good vision at near and intermediate distances.

Pockets, Flaps, and Dual Interfaces The femtosecond laser–assisted pocket technique provides a number of potential advantages.8,9 First, the majority of peripheral corneal nerves are preserved, which allows for maintained corneal sensitivity and potentially quicker visual recovery. The pocket procedure has more biomechanical stability and does not induce striae. The new generation of femtosecond lasers features increased repetition rates and tighter laser spots, allowing for more predictable refractive outcomes by modulating the wound-healing response and decreasing forward light scatter. Another insertion technique is the lamellar flap option. This modality is an attractive alternative because it offers access to a stromal bed for excimer ablation, allowing for full control of the

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refractive target and the ability to treat ametropia. When repositioning or removal is warranted, this option allows easy access to the inlay. The dual interface is another insertion technique. In this procedure, the pocket is created deeper to a previously made thin flap, either sequentially or from a preexisting LASIK. This procedure combines the benefits of the pocket and flap techniques.

Complications and Management There have been no serious, sight-threatening complications with the current surgical techniques for implanting the small-aperture inlay. A few cases of epithelial ingrowth have been reported but were resolved and/or did not affect the visual axis and were likely not related to the technology.15,16 Previous studies reported complications associated with early-generation implants, such as corneal stromal opacity, haze variants, para-inlay epithelial or extracellular matrix deposits, infiltration, and keratolysis.19-21 Because the understanding of biocompatibility and wound-healing modulation has improved significantly, these complications have decreased significantly. Other strategies that have enhanced results are modifications in postoperative medical regimens and ocular surface optimization, including the correct use of postoperative steroids, topical cyclosporine, preservative-free artificial tears, and omega-3 fatty acid supplements. The ocular surface should be treated aggressively before and after inlay implantation because preexisting dry eye is common in the presbyopic population and will likely be exacerbated by the creation of a flap or pocket. These modalities may play a role in the tolerance and refractive stability of current inlay designs. Early recognition of focal surface irregularity in the form of epitheliopathy or paracentral irregular dellen-like curvature changes associated with inlay location may alert the practitioner to more aggressively monitor and treat the ocular surface. In the literature, the most commonly reported complaints are glare and halo, dry eye, and night vision problems.16,18 Other studies report that inlays are removed for various reasons, including dissatisfaction with vision or visual symptoms, refractive shift, and flap problems.15 Removal was easily accomplished, even years after implantation, and vision recovered with little residual effect. Centration of any corneal inlay is important to achieve the best refractive result. Optical modeling suggests that, even with a small aperture inlay, 0.5-mm decentration can deteriorate image quality.18 To achieve a perfect inlay centration, it should be centered on the visual axis, which is typically slightly inferonasal to the center of the pupil. The precise location of the visual axis is difficult to assess. It is best identified by marking the first Purkinje reflection or the coaxially sighted corneal reflex.24 Regarding this point, devices are available to aid in centration of the inlay intraoperatively. In the case of decentration, inlays may be easily repositioned concentric with the estimated line of sight to dramatically improve distance and near acuities. In cases with visually significant epithelial ingrowth or deep lamellar keratitis, removing the inlay is warranted.

Conclusion Thanks to recent improvements in design and materials, corneal inlays have become a promising non-IOL–based treatment of presbyopia. This modality is considered safe and effective for presbyopic patients, achieving high satisfaction levels and low complication rates. Compared with other presbyopic surgeries, corneal inlays offer several advantages because they are removable and repositionable. These implants can also be combined with other refractive procedures and do not exhibit the risks of intraocular surgery. Several implantation techniques and technologies are available, including both mechanical and femtosecond laser assisted, to create pockets and flaps to achieve the desirable visual results. As a result, we are observing excellent outcomes, which will surely improve as the technologies and techniques continue to evolve.

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References 1. Barraquer JI. Queratoplatica Refractiva. Estudios e informaciones. Oftalmologicas. 1949;2:10. 2. Choyce P. The present status of intra-cameral and intra-corneal implants. Can J Ophthalmol. 1968;3(4):295-311. 3. Dohlman CH, Refojo MF, Rose J. Synthetic polymers in corneal surgery. I. Glyceryl methacrylate. Arch Ophthalmol. 1967;77(2):252-257. 4. Klyce SD, Dingeldein SA, Bonanno JA, et al. Hydrogel implants: evaluation of first human trial. Invest Ophthalmol Vis Sci. 1988;29 Suppl:393. 5. McCarey BE. Alloplastic refractive keratoplasty. In: Sanders DR, Hofmann RF, Salz JJ, eds. Refractive Corneal Surgery. Thorofare, NJ: SLACK Incorporated; 1986:531-548. 6. Klyce SD, Russell SR. Numerical solution of coupled transport equations applied to corneal hydration dynamics. J Physiol. 1979;292:107-134. 7. Larrea X, De Courten C, Feingold V, Burger J, Büchler P. Oxygen and glucose distribution after intracorneal lens implantation. Optom Vis Sci. 2007;84(12):1074-1081. 8. Binder PS. New femtosecond laser software technology to create intrastromal pockets for corneal inlays. ARVO. 2010;51:2868. 9. Limnopoulou AN, Bouzoukis DI, Kymionis GD, et al. Visual outcomes and safety of a refractive corneal inlay for presbyopia using femtosecond laser. J Refract Surg. 2013;29(1):12-18. 10. Bouzoukis DI, Kymionis GD, Panagopoulou SI, et al. Visual outcomes and safety of a small diameter intrastromal refractive inlay for the corneal compensation of presbyopia. J Refract Surg. 2012;28(3):168-173. 11. Porter T, Lang A, Holliday K, et al. Clinical performance of a hydrogel corneal inlay in hyperopic presbyopes. Invest Vis Ophth Sci. 2012;53:e-abstract 4056. 12. Lang AJ, Porter T, Holliday K, et al. Concurrent use of the ReVision Optics intracorneal inlay with LASIK to improve visual acuity at all distances in hyperopic presbyopes. Invest Ophthalmol Vis Sci. 2011;52:e-abstract 5765. 13. Tomita M, Kanamori T, Waring GO IV, Nakamura T, Yukawa S. Small-aperture corneal inlay implantation to treat presbyopia after laser in situ keratomileusis. J Cataract Refract Surg. 2013;39(6):898-905. 14. Santhiago MR, Barbosa FL, Agrawal V, Binder PS, Christie B, Wilson SE. Short-term cell death and inflammation after intracorneal inlay implantation in rabbits. J Refract Surg. 2012;28(2):144-149. 15. Yilmaz OF, Alagöz N, Pekel G, et al. Intracorneal inlay to correct presbyopia: long-term results. J Cataract Refract Surg. 2011;37(7):1275-1281. 16. Seyeddain O, Hohensinn M, Riha W, et al. Small-aperture corneal inlay for the correction of presbyopia: 3-year follow-up. J Cataract Refract Surg. 2012;38(1):35-45. 17. Waring GO IV. Correction of presbyopia with a small aperture corneal inlay. J Refract Surg. 2011;27(11):842-845. 18. Tomita M, Kanamori T, Waring GO IV, et al. Simultaneous corneal inlay implantation and laser in situ keratomileusis for presbyopia in patients with hyperopia, myopia, or emmetropia: six-month results. J Cataract Refract Surg. 2012;38(3):495-506. 19. Dexl AK, Seyeddain O, Riha W, et al. One-year visual outcomes and patient satisfaction after surgical correction of presbyopia with an intracorneal inlay of a new design. J Cataract Refract Surg. 2012;38(2):262-269. 20. Linn S, Hoopes PC. Stereopsis in patients implanted with a small aperture corneal inlay. Invest Ophthalmol Vis Sci. 2012;53:e-abstract 1392. 21. Dexl AK, Seyeddain O, Riha W, et al. Reading performance and patient satisfaction after corneal inlay implantation for presbyopia correction: two-year follow-up. J Cataract Refract Surg. 2012;38(10):1808-1816. 22. Dexl AK, Seyeddain O, Riha W, et al. Reading performance after implantation of a modified corneal inlay design for the surgical correction of presbyopia: 1-year follow-up. Am J Ophthalmol. 2012;153(5):994-1001.e2. 23. Casas-Llera P, Ruiz-Moreno JM, Alió JL. Retinal imaging after corneal inlay implantation. J Cataract Refract Surg. 2011;37(9):1729-1731. 24. Gatinel D, El Danasoury A, Rajchles S, Saad A. Recentration of a small-aperture corneal inlay. J Cataract Refract Surg. 2012;38(12):2186-2191.

25 Pterygium Surgery Raising Ocular Surface Surgery to Cosmetic Outcomes Arun C. Gulani, MD, MS and Aaishwariya Gulani, BS Pterygium is one of the oldest pathologies known to eye surgeons. Surgery for this condition can range from simple excision to techniques with exotic detail and meticulous maneuvers with task-specific instruments beckoning an era of raised expectations and cosmetic outcomes in the field of ocular surface surgery itself.1-4

Clinical Appearance of Pterygium and Its Surgical Application Head/Neck Adhesion Peripheral/central adhesion (diffuse or focal) is usually seen (Figures 25-1 and 25-2). In cases of peripheral adhesion, the pterygium easily peels off the cornea.

Vascularity Engorged, tortuous vessels and simultaneous conjunctival fold contracture signifies a more aggressive pterygium (Figure 25-3). This concept can be used to determine outcomes postoperatively.

Deep Pterygium A hard, thick, and deep pterygium can lead to a thin residual cornea after excision. Amniotic membrane can be used as a lamellar graft in those eyes. On performing the draw test and tugging on the cornea, a pterygium may be small in size but outright gritty and deep into the cornea, resulting in a thin cornea when removed.

Surgical Criteria • Extent of pterygium • Density of pterygium - 269 -

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A

B

Figure 25-1. (A) Central, focal, dense pterygium preoperatively and (B) 1 day postoperatively.

Figure 25-2. (A) Focal, (B) diffuse, and (C) central diffuse dense peripheral adhesion.

Figure 25-3. (A) Vascular pterygium. (B) Dense hard pterygium. (C) Vascular engorgement with carcinoma in situ appearance.

• • • •

Involvement of adjacent structures Head/neck adhesion Vascularity Depth of pterygium/draw test

Surgical Technique Topical anesthesia in the form of tetracaine hydrochloride is applied with preoperative topical moxifloxacin. Intralesional anesthesia in the form of 1 to 2 cc of lidocaine with epinephrine is used (this can also delineate the extent of the pterygium in obscure or recurrent cases). Depending on the appearance and draw test, the approach can be from the contracted medial conjunctival fold and can proceed medial to limbal or from the head toward the medial conjunctival fold. At

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Figure 25-4. (A) High-magnification photograph of the pterygium area at the medial canthus postoperatively. Note the cut end of the remnant stump. (B) High-magnification photograph of the pterygium area at the limbus postoperatively. (C) Iceberg concept: The small lesion is the clinically visible pterygium, and the lesion next to it is its actual size on removal. (D) One day postoperatively.

the start of the procedure, the head of the pterygium is delineated from the cornea underneath. This can be done with a posterior-to-anterior sweep using the Gulani Pterygium Cross-Action Spreader (Storz). In cases of mild adhesions, the pterygium can be easily separated from the cornea (mostly peripheral pterygia) or effectively peeled in a single centrifugal movement. After smoothing the cornea with a specially designed blunt blade, remnant tissue (especially in the gritty pterygium) is meticulously removed with toothed forceps in a medial-to-limbal direction. The blade is used again to smooth the limbus. A Weck-Cel sponge (Medtronics) soaked in 1:1000 epinephrine is tucked into the nasal crevice where the cut pterygium is pressured into hemostasis. The whole plane of the pterygium is delineated subconjunctivally as if separating a fan-shaped scar with tentacles into the fornices and medial angle. The pull is kept superior and vertical to avoid damage to the underlying medial rectus. By cutting vertically instead of horizontally, bleeding, unnecessary involvement of orbital fat, and accidental damage to the medial rectus can be avoided. In cases of a recurrent pterygium, a muscle hook is used to ascertain the anatomy by hooking the medial rectus. When the pterygium mass is removed, it resembles a spreading mass of tentacles. It is important to remove the entire mass to avoid recurrence (Figure 25-4). The pterygium is dissected carefully superiorly to avoid buttonholing the conjunctiva and invading the orbital septum and inferiorly to avoid cutting the underlying muscles, which are rechecked after the pterygium is removed. The episcleral remnants are carefully picked through to clear the underlying sclera in an attempt to remove all pterygium tissue from the area of impact. Weck-Cel sponge pieces are soaked in mitomycin C 0.04%, placed under the conjunctiva in the area of the dissection, and left in place for 30 seconds. Application to the sclera is avoided; dry the sclera with a clean Weck-Cel sponge. After a full count of the sponges, they are removed and the area is flushed with copious balanced salt solution. The cornea can be used as an illuminated receiving table on which to drape the amniotic membrane, which is then placed on the raw area and accepted with a Tyre-Tool technique (the

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Figure 25-5. (A) Recurrent, aggressive pterygium preoperatively. (B) Same patient 1 day postoperatively. (C) Same patient with multiple recurrent, aggressive pterygium preoperatively. (D) Same patient 1 year postoperatively.

conjunctiva is draped over the amniotic graft with minimal handling to avoid touching the membrane with any instrument) so it slips under the surrounding cut edge of the conjunctiva medially, superiorly, and inferiorly. This is then milked to adhere to the globe contour using a specially designed forceps that literally squeegees the graft as it lays on the sclera. Tisseel glue (Baxter) is applied under the membrane (subamniotic, controlled delivery) as 2 separate components (fibrinogen and thrombin), and the membrane is milked again in 2 quick sweeps to a pearly white and smooth appearance, beginning with the medial fornix and the underlying tenons to ensure closure of any potential space in between. A #64 Bard-Parker blade (Becton, Dickinson and Company) is used in a single sweeping action to cut the excess graft at the limbus. That excess graft is then peeled away as it clears the cornea and confirms adhesion of the remaining graft. This prevents bumpy anatomy at the limbus, and patients can resume contact lens wear early.

Recurrent Pterygium The surgery is the same no matter how aggressive and recurrent the pterygium (Figure 25-5). The bleeding is minimal if these pearls are followed for recurrent cases: • Select an area that is more amenable to approach and dissect down into this area until the scleral bed is reached. Usually the previous ophthalmologist will have performed a meticulous clearing of the sclera. Once the sclera is reached, dissection is performed from behind forward, and the whole pterygium mass lifts up (armor technique). • Avoid trying to cut and dissect vigorously. That will lead to bleeding and losing the plane of easy dissection.

Cosmetic Surgery The cosmetic appeal of the outcome with the no-stitch, no-patch, and no-red approach, along with the absence of visual deficit, is raising the bar in patients now seeking this approach for related ocular surface conditions such as pinguecula and conjunctivochalasis. Additionally, these patients will undergo laser vision surgery and/or cataract surgery with premium lens technologies

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Figure 25-6. (A) Bitemporal pterygium. (B) Left eye postoperatively.

B

in quick succession because the cornea is cleared (for laser photo-refractive keratectomy) with excellent globe contour or for the suction ring during LASIK and Intacs.5,6 Pterygium surgery has led to an increase in requests for pinguecula removal in patients whose appearance may trouble them or threaten their livelihood (eg, models or sales personnel). Because the bar has been raised for outcomes, pinguecula removal follows the same principle as pterygium surgery. If performed with the methods described previously, pterygium and pinguecula surgery outcomes on the first postoperative day have made aesthetic outcomes a reality.

Postoperative Period Complicated pterygium-like bitemporal presentation can cause postoperative scarring or strabismus after extensive surgery (Figure 25-6). Scarring and keloid formation may be high in patients with a tendency to form keloids or in deep pterygium (Figure 25-7). Clinical evaluation of the surgical site postoperatively is required to detect early complications (Table 25-1). Eyes with amniotic membrane graft may rarely have the bubble wrap sign or subgraft hematoma (Figures 25-8 and 25-9). Hence, detailed patient education, including informed consent about the seriousness of surgery, should be undertaken preoperatively. It is our responsibility to ensure that we are not jeopardizing vision in any way and to provide options for vision correction using modalities like LASIK, photo-refractive keratectomy, premium cataract surgery (Figure 25-10), and Intacs (Oasis Inc) using Corneoplastique principles (Figure 25-11) for an early visual rehabilitation of the operated eye.7-9

Conclusion Some patients undergoing LASIK or cataract surgery will need surgery for pterygia or pingueculas afterward. Ocular surface surgeries have good cosmetic outcomes and lead to ocular surface suitability for laser vision correction, thus becoming an integral part of every refractive surgery practice.

References 1. Gulani AC. Gulani iceberg technique. Cataract Refractive Surg Today Eur. 2014;9(3):48-49. 2. Gulani AC. A cornea-friendly pterygium procedure. Review of Opthalmology. June 7, 2012:52-56. http://www.revophth.com/content/i/1979/c/34837/. 3. Gulani A, Dastur YK. Simultaneous pterygium and cataract surgery. J Postgrad Med. 1995;41(1):8-11. 4. Trelford JD, Trelford-Sauder M. The amnion in surgery, past and present. Am J Obstet Gynecol. 1979;134(7):833-845.

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A

B

D

C

E

Figure 25-7. (A) Aggressive pterygium with skin keloid tendency. (B) Aggressive pterygium with deep corneal scar. (C) Postoperatively aggressive pterygium with amniotic lamellar fill. Amniotic grafts can be used in such cases as an extension of lamellar fill, which gradually resolves over time and can be followed by laser vision surgery. (D) Bitemporal aggressive pterygia in a patient with keloids. (E) One day postoperatively.

TABLE 25-1

Objective Grading of the Postoperative Site on the Basis of External and Slit Lamp Examination OBJECTIVE GRADE

EXAMINATION FINDINGS

1

Better-than-normal appearance of operative site (pearly white)

2

Normal appearance of the eye and scleral area

3

Presence of fine episcleral vessels in the excised area

4

Episcleral vessels reaching the limbus

5

Fibrovascular tissue in the excised area reaching to the limbus

6

Fibrovascular tissue invading the cornea

7

Worse than preoperative appearance

8

Symblepharon and restrictive eye movements in addition to grade 7

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A

B

C

D

Figure 25-8. (A) Amniotic bubble wrap sign, which was self-resolving. (B) Scleral melt. (C) Scleral melt at 1 month. (D) Scleral melt at 6 months.

A

B

C

D

Figure 25-9. Subamniotic blood at (A) 1 day, (B) 1 week, (C) 1 month, and (D) 3 months. Notice that the blood is clotted and well contained under the amniotic graft limited by the glued rectangular boundary of the graft. It selfresolved over 1 week.

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Figure 25-10. (A) Post-extensive central pterygium surgery with lamellar amniotic fill. (B) Three years postoperatively. (C) High-magnification image 3 years postoperatively. (D) Cataract with thin amniotic fill. (E) Post-cataract surgery with multifocal ReSTOR IOL. (F) Post-laser vision surgery through the amniotic membrane after ReSTOR IOL (Alcon) surgery.

A

E

D B F

C

Figure 25-11. Embedded corneal scar (A) preoperatively and (B) postoperatively. Embedded corneal scar (C) preoperatively and (D) postoperatively. These scars can be used as masking agents, and refractive laser surgery can be performed following Corneoplastique principles.

A

B

C

D

5.

Gulani AC. Shaping the future and reshaping the past: The art of vision surgery. In: Copeland RA, Afshari NA. Copeland and Afshari’s Principles and Practice of Cornea. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd; 2013:1252-1273. 6. Gulani AC. Using excimer laser PRK — not PTK — for corneal scars. Straight to 20/20 vision. Adv Ocul Care. 2012:1-3. http://eyetubeod.com/advancedocularcare/pdfs/aoc0912_cornea_Gulani.pdf. 7. Gulani AC. Corneoplastique: art of vision surgery. Ind J Opthalmol. 2014;62:3-11. 8. Gulani AC. Corneoplastique video. J Cataract Refract Surg. 2006;22(3). 9. Gulani A. Principles of surgical treatment of irregular astigmatism in unstable corneas. Irregular Astigmatism: Diagnosis and Treatment. Thorofare, NJ: SLACK Incorporated; 2007:251-261.

Please see video on the accompanying website at

www.healio.com/books/cornealvideos

26 Limbal Dermoids Susan Huang, MD; Roy S. Chuck, MD, PhD; and Jimmy K. Lee, MD Epibulbar dermoids are congenital choristomas consisting of tissue from ectodermal and mesodermal derivatives. They present as slow-growing, minimally vascularized, smooth, yellowishwhite bulbous lesions (Figure 26-1). They are most commonly found in the bulbar conjunctiva and limbus and less frequently in the cornea, caruncle, and palpebral conjunctiva.1 They typically grow as a child matures and have no malignant potential.

Epidemiology Limbal dermoids occur at a prevalence of 1 in 10,0001 and make up approximately 10% to 29% of pathologic lesions at the limbus.2,3 They are most commonly located in the inferotemporal globe or limbus.4 They may be associated with additional systemic anomalies such as Goldenhar’s syndrome (oculoauriculovertebral dysplasia), a sporadic or autosomal-dominant syndrome characterized by epibulbar dermoid, upper eyelid coloboma, preauricular skin tags, aural fistulae, and vertebral anomalies.5 They may also be associated with ring dermoid syndrome and mandibulofacial dysostosis of Franceschetti syndrome.6,7 Thirty-three percent of epibulbar choristomas are removed before age 16, and 2.2% are removed after age 16.6

Pathophysiology Limbal dermoids consist of a superficial stratified squamous epithelium and underlying mass of mesodermal derivatives, which include hair follicles, sebaceous glands, muscle, dense connective tissue, blood vessels, cartilage, and fat.8 It has been proposed that epibulbar choristomas occur due to an embryologic error of metaplastic transformation of the mesoblast between the optic nerve rim and surface ectoderm at 5 to 10 weeks of gestation.9 Epibulbar dermoids have been classified into 3 anatomic grades.9 The grading system enables clinicians to proceed with clinical and surgical management with a more systematic approach. • Grade I: a superficial limbal dermoid less than 5 mm and localized onto the corneal limbus • Grade II: large dermoid that covers most of the cornea, extends deep into the stroma, and spares Descemet’s membrane (Figure 26-2) • Grade III: large dermoid that covers the entire cornea and extends through all histological structures between the anterior surface of the globe and pigmented epithelium of the iris (least common) - 277 -

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Figure 26-1. Limbal dermoid in the inferotemporal region. (Reprinted with permission from Sherman Reeves, MD.)

Figure 26-2. Grade II limbal dermoid. (Reprinted with permission from Amir Pirouzian, MD.)

Management Conservative or surgical approach with limbal dermoids depends on multiple factors, such as the presenting size of the lesion, rate of growth, anatomical location involved, cosmetic requests, and consideration of the patient’s support system.10-12

Medical Management Grade I dermoids can typically be managed conservatively because of their small size. Close observation may suffice if the dermoid is asymptomatic with minimal surface irregularity, and the astigmatism can be addressed with spectacle correction.13 Contact lenses, particularly hybrid lenses, can also be an option for patients who can be fitted and trained to use them. Patients managed conservatively should be followed every 2 to 3 months. Visual acuity and evaluation for amblyopia should be performed. The size of the lesion should be monitored with serial photography and cycloplegic refraction.

Surgical Management Surgical intervention for the pediatric patient is generally reserved as the last resort, considering the risks and postoperative commitment required by the patient and guardian. Indications for surgical excision include cosmetic deformity, high corneal astigmatism resulting in anisometropic amblyopia, extension to the visual axis, dellen formation, and severe ocular irritation. Superficial grade I dermoids may be considered for excision if the patient is not compliant with wearing spectacles in the setting of progressive amblyopia.13 It is important to note that complete excision

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of the lesion (area and depth) may not be necessary to achieve the goals of reducing astigmatism or symptoms. For preoperative evaluation, gonioscopy may be helpful in determining whether a full-thickness procedure will be necessary. Ultrasound biomicroscopy may be obtained to determine the depth and extent of the lesion for surgical planning.14 Due to strong sound attenuation produced by dermoids, there is decreased visibility of deep corneal structures, particularly Descemet’s membrane.15 Anterior-segment optical coherence tomography is another option to assess the depth of the lesion.

Simple Excision Simple excision is one of the most commonly used techniques for removal of grade I limbal dermoids (Video 26-1). In the first step, conjunctival peritomy is performed around the dermoid using scissors. Hemostasis is achieved with cauterization. A straight or angled blade is then used to shell out or shave off the dermoid. In a lamellar fashion, sharp dissection using a lamellar blade (Martinez, Troutman) is performed. Dissection along the corneoscleral plane is typically adequate to remove the lesion. Superficial irregularities may be smoothed with a diamond corneal burr. If the conjunctival defect is large, the surrounding conjunctival tissue can be mobilized with blunt dissection and be brought together, and the conjunctival defect can be closed with absorbable sutures or fibrin glue. Peripheral corneal vascularization, residual opacity, and pseudopterygium formation are not uncommon after simple excision.11,16 However, if the objectives of the surgery are achieved (ie, improved vision, cosmesis, less irritation), additional surgery is not necessary.

Lamellar Keratoplasty Larger lesions may require lamellar keratoplasty, in which the dermoid is entirely excised and the defect filled with a lamellar donor corneoscleral graft. A corneoscleral graft has the benefit of providing similar tectonic force and color in the junctional area of the cornea, limbus, and sclera. It also has the advantage over simple excision in improved cosmetic results, less scarring and vascularization, and decreased risk of pseudopterygium development. Astigmatism induced by the lesions usually has minus cylinder axis in the dermoid location.18 The astigmatism and central corneal flattening in the axis of the dermoid can theoretically be improved through titrating the suture tension of the lamellar graft, steepening the cornea. Published reports have shown variable results with increased,19 decreased,17,20 or no change11 in astigmatism.

Dissection A conjunctival peritomy is performed with scissors surrounding the conjunctival side of the dermoid. The cutting margin is defined by the smallest-sized trephine able to fit the entire lesion. A partial-thickness cut is made, and the dissection can be made deeper with a crescent blade or diamond knife until reaching the corneal stroma. A lamellar dissection is performed from the direction of the corneal to the scleral side of the lesion. Dissection is repeated in a deeper plane with a trephine for any remaining deeper opacities.

Donor Corneoscleral Tissue Preparation The graft is usually obtained from either a whole globe or a corneoscleral button with an adequate amount of scleral rim.21-23

Manual Dissection For grafts from a whole donor globe, with the donor eye wrapped in gauze, the globe is compressed either manually or with a hemostat to increase the intraocular pressure. A small incision is made with a crescent blade or diamond knife at the limbus to a depth that is mildly thicker than the recipient bed’s depth. A deeper donor depth incision, as compared with the recipient’s defect depth, is required due to the initial swelling of the donor. The graft is dissected in a lamellar fashion with a dissection spatula or a Gill knife. The donor cornea is then cut through with a trephine. This technique with the trephine produces a donor button that is equal in diameter

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size to the trephine blade used, as compared with a 0.2-mm smaller size when a donor button is punched through from the endothelial to epithelial surface. For small lesions, the same-sized trephine should be used for the recipient and donor. For large lesions with a recipient bed 6 mm or greater, the donor should be 0.2 mm larger in diameter. The graft is then sutured on with interrupted 10-0 nylon sutures to the cornea and 9-0 nylon sutures to the sclera. The donor button can be truncated at the limbus if only the superficial sclera is involved with the dermoid. The surrounding conjunctiva can be brought together over the exposed sclera and sutured to the edge of the graft. If conjunctival tissue is removed with a larger dermoid, free autograft of conjunctiva can be harvested from the same eye and sutured over the exposed sclera.

Graft From a Corneoscleral Button The corneoscleral button is anchored and sutured on a cloth-covered, size-14 glass ball. The button is marked with a trephine matching the recipient corneoscleral defect size.24 The graft is dissected in a lamellar fashion with a dissection spatula or Gill knife. The stepwise approach continues as described previously.

Microkeratome Harvesting graft for lamellar keratoplasty with a microkeratome may be beneficial to provide a more uniform, matching lamellar thickness and intact epithelium. The preparation of a donor corneoscleral button is less time consuming. It avoids possible wound discontinuities that can be seen in manually dissected lamellar keratoplasty. Wiley et al 25 described the use of the Automated Lamellar Therapeutic Keratoplasty system (Moria/Microtek Inc) in lamellar keratoplasty for limbal dermoids. Lamellar dissection of the limbal dermoid is completed in the same method as described above. After dissection completion, the depth and diameter of the lamellar bed are determined with calipers. An appropriate microkeratome head for the LSK 1 microkeratome (Moria/Microtek Inc) is selected, with the most common being 150 or 250 μm. A corneoscleral rim with at least 2 mm of sclera is mounted in the Moria artificial anterior chamber. The chamber is pressurized with balanced salt solution that is hung from an adjustable pole. A Barraquer tonometer is used to confirm the intrachamber pressure. A lamellar graft of the appropriate diameter is prepared with the adjusted height of the microkeratome guide in place. The microkeratome is used to resect the tissue, which can be trimmed to the appropriate size with a trephine.

Full-Thickness Central Corneal Graft Full-thickness central corneal grafts can be used if corneoscleral grafts are not available. Shen et al 26 described this method, which could be technically easier and less time consuming. The cosmetic appearance has been reported as satisfactory. However, the transparent corneal graft may result in the scleral bluish hue possibly being seen. The graft could also develop stromal haze and have delayed epithelial healing due to lack of limbal stem cell transfer. Lesion dissection is performed as described above. A full-thickness central corneal graft is harvested from a corneoscleral button with a trephine 0.25 mm larger than the recipient trephine. The graft corneal endothelial cells are removed with a dry cellulose sponge. It is then placed and sutured on with 10-0 nylon interrupted sutures onto the corneal side and 9-0 nylon interrupted sutures onto the scleral side. The conjunctiva is attached to the limbus with 10-0 nylon.

Penetrating Keratoplasty Penetrating keratoplasty may be required in a grade II or III dermoid (Figure 26-3) or in cases of perforation that occur during lamellar dissection. A second full-thickness transplant is often required. A 2-stage procedure may be preferred if a grade II or III dermoid necessitates a graft greater than 7 mm in size.10 This approach decreases the risk of anterior synechiae, vascularization, and graft rejection related to the large-sized graft. In the first part of the procedure, the external bulk of the dermoid is excised and a large lamellar keratoplasty is placed. A manual freehanded dissection may be required if the dermoid is too large to fit a trephine. A second procedure is performed after the lamellar graft has healed after several months. The goal of the

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Figure 26-3. Postoperative photograph of limbal dermoid removal with penetrating keratoplasty. (Reprinted with permission from Sherman Reeves, MD.)

Figure 26-4. Limbal dermoid removal using amniotic graft and fibrin glue. (A) Intraoperative photograph of a left inferotemporal limbal dermoid. (B) Intraoperative multilayering of amniotic membrane after dermoid resection. (C) Threemonth postoperative appearance. (D) One-year postoperative appearance. (Reprinted with permission from Amir Pirouzian, MD.)

second procedure is to form a clear visual axis by excising the residual internal tumor and placing a smaller-sized central penetrating graft.

Other Approaches for Grade I Limbal Dermoids For pericardial graft placement, after the limbal dermoid is dissected, a 400-μm pericardial graft is placed over the perlimbal excised area.27 Amniotic membrane is then placed over the pericardial graft and mounted to the cornea over the excised area. This surgical approach may be considered with large dermoid lesions or when the junction between the abnormal and normal tissue is unclear intraoperatively.

Fibrin Glue-Assisted Multilayered Amniotic Membrane Transplantation After complete dissection and excision of the dermoid, fresh amniotic membrane can be used to fill in the corneal defect (Figure 26-4). The graft is folded in a 3-layered sandwich pattern with the orientation of stromal side on the corneal surface and epithelial side up. It is then trimmed to the same measured corneal defect size. This fully fills the corneal depth defect and results in a similar height with the surrounding normal corneal tissue. A second amniotic membrane is cut with a trephine into a larger diameter than the first amniotic membrane placed. The second membrane is glued and fully covers both the bare sclera and the first secured amniotic membrane. The surrounding normal conjunctival tissue is mobilized and repositioned to have its edge meet the amniotic membrane edge and is secured with fibrin glue.28,29

Future Directions With new technology, the surgical management of limbal dermoids continues to evolve. Femtosecond laser technology, widely used in corneal refractive surgery, can also be used to construct nonplanar combinations of vertical and lamellar cuts for both donor and host corneas. These wound configurations create more surface area for healing, improve tissue alignment and

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distribution, require less suture tension for alignment of tissue, and have superior biomechanical strength. Studies of femtosecond laser–enabled keratoplasty have shown rapid visual recovery and reduction of astigmatism comparable with or often better than traditional blade trephination.30 Most recently, femtosecond laser settings have been configured to dissect dense lens planes for cataract surgery. As femtosecond laser technology continues to evolve, limbal and scleral tissue should be penetrable as well, allowing safer and more accurate grafting for limbal dermoids.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

Mansour AM, Barber JC, Reinecke RD, Wang FM. Ocular choristomas. Surv Ophthalmol. 1989;33(5):339-358. Garner A. The pathology of tumors at the limbus. Eye (Lond). 1989;3(Pt 2):210-217. Sunderraj PP, Viswanathan RK, Balachander R. Neoplasms of the limbus. Indian J Ophthalmol. 1991;39(4):168-169. Nevares RL, Mulliken JB, Robb RM. Ocular dermoids. Plast Reconstr Surg. 1988;82(6):959-964. External Disease and Cornea. Basic and Clinical Science Course. Section 8. 2012-2013. San Francisco: American Academy of Ophthalmology, 2012. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults. A clinical and histopathological review. Cornea. 1987;6(2):78-116. Mattos J, Contreras F, O’Donnell FE Jr. Ring dermoid syndrome. A new syndrome of autosomal dominantly inherited, bilateral, annual limbal dermoids with corneal and conjunctival extension. Arch Ophthalmol. 1980;98(6):1059-1061. Neumann R, Dutt CJ, Foster CS. Immunohistopathological features and therapy of conjunctival lichen planus. Am J Ophthalmol. 1993;115(4):494-500. Mann I. Developmental Abnormalities of the Eye. Cambridge, UK: Cambridge University Press; 1937. Zaidman GW, Johnson B, Brown SI. Corneal transplantation in an infant with corneal dermoid. Am J Ophthalmol. 1982;93(1):78-83. Panton RW, Sugar J. Excision of limbal dermoids. Ophthalmic Surg. 1991;22(2):85-89. Kaufman A, Medow N, Phillips R, Zaidman G. Treatment of epibulbar limbal dermoids. J Pediatr Ophthalmol Strabismus. 1999;36(3):136-140. Pirouzian A. Management of pediatric corneal limbal dermoids. Clin Ophthalmol. 2013;7:607-614. Grant CA, Azar D. Ultrasound biomicroscopy in the diagnosis and management of limbal dermoid. Am J Ophthalmol. 1999;128(3):365-367. Hoops JP, Ludwig K, Boergen KP, Kampik A. Preoperative evaluation of limbal dermoids using high-resolution biomicroscopy. Graefes Arch Clin Exp Ophthalmol. 2001;239(6):459-461. Mohan M, Mukherjee G, Panda A. Clinical evaluation and surgical intervention of limbal dermoid. Indian J Ophthalmol. 1981;29(2):69-73. Burillon C, Durand L. Solid dermoids of the limbus and the cornea. Ophthalmologica. 1997;211(6):367-372. Robb RM. Astigmatic refractive errors associated with limbal dermoids. J Pediatr Ophthalmol Strabismus. 1996;33(4):241-243. Watts P, Michaeli-Cohen A, Abdolell M, Rootman D. Outcome of lamellar keratoplasty for limbal dermoids in children. J AAPOS. 2002;6(4):209-215. Panda A, Ghose S, Khokhar S, Das H. Surgical outcomes of epibulbar dermoids. J Pediatr Ophthalmol Strabismus. 2002;39(1):20-25. Glasser D. Surgery of limbal dermoids. In: Brightbill FS, ed. Corneal Surgery: Theory, Technique, and Tissue. 3rd ed. St Louis, MO: Mosby; 1999:197-201. Vrabec MP, Jordan JJ, Lawlor PP. Lamellar keratoplasty performed with a corneal scleral button. Ophthalmic Surg. 1994;25(6):389-391. Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea. 1998;17(1):66-67. Scott JA, Tan DT. Therapeutic lamellar keratoplasty for limbal dermoids. Ophthalmology. 2001;108(10):1858-1867. Wiley LA, Joseph MA, Springs CL. Tectonic lamellar keratoplasty utilizing a microkeratome and an artificial anterior chamber system. Cornea. 2002;21(7):661-663. Shen YD, Chen WL, Wang IJ, Hou YC, Hu FR. Full-thickness central corneal grafts in lamellar keratoscleroplasty to treat limbal dermoids. Ophthalmology. 2005;112(11):1955. Lazzaro DR, Coe R. Repair of limbal dermoid with excision and placement of a circumlimbal pericardial graft. Eye Contact Lens. 2010;36(4):228-229.

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Pirouzian A, Ly H, Holz H, Sudesh RS, Chuck RS. Fibrin-glue assisted multilayered amniotic membrane transplantation in surgical management of pediatric corneal limbal dermoid: a novel approach. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):261-265. 29. Pirouzian A, Holz H, Merrill K, Sudesh R, Karlen K. Surgical management of pediatric limbal dermoids with sutureless amniotic membrane transplantation and augmentation. J Pediatr Ophthalmol Strabismus. 2012;49(2):114-119. 30. Chamberlain WD, Rush SW, Mathers WD, Cabezas M, Fraunfelder FW. Comparison of femtosecond laser-assisted keratoplasty versus conventional penetrating keratoplasty. Ophthalmology. 2011;118(3):486-491.

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27 Ocular Surface Squamous Neoplasia Dhivya Ashok Kumar, MD and Amar Agarwal, MS, FRCS, FRCOphth Ocular surface squamous neoplasia (OSSN) refers to precancerous and cancerous lesions of the epithelium of the ocular surface, namely the cornea and the conjunctiva. It includes dysplasia, carcinoma in situ, and invasive carcinoma. It is a distinct clinical entity, although it has been known by various names in the literature. It is also known as conjunctival intraepithelial neoplasia or corneal intraepithelial neoplasia.1-3 OSSN is uncommon, but it is important because of its potential effects on ocular and rarely, systemic morbidity. Reported risk factors for the disease include ultraviolet light exposure, fair skin, human papilloma virus infection, human immunodeficiency virus infection, dysfunctional DNA repair, and cigarette smoking.1,4-6 OSSN incidence varies from 0.13/100,0007 in one series to 1.9/100,000 in another.8 OSSN represents 4% to 29% of all orbito-ocular tumors and is the third most common neoplasia in older patients, after melanoma and lymphoma.1 It predominantly occurs in elderly patients.

Limbus and Histology The limbus is the transition zone from the conjunctival epithelium to the corneal epithelium. Stem cells located here have a high potential for clonagenic cell division. Conjunctivalization of the cornea or excessive conjunctival growth is often seen in OSSN. Histopathologically, it has been identified as overgrowth of the epithelium with associated goblet cells, accompanied by neovascularization, disruption of the basement membrane, and infiltration by inflammatory cells. An abnormal regulatory mechanism leads to altered epithelial phenotypes.1

Clinical Presentation The usual presentation is the slightly elevated lesion relatively demarcated from surrounding normal tissue with feeder blood vessels with or without surface changes. The color varies from pink (Figure 27-1A) to grey or reddish grey (Figure 27-1B) depending on the vascularity of the tumor. The tumor most commonly straddles the nasal or temporal limbus between the palpebral apertures. The gross appearance of the tumor can be papillomatous (Figure 27-2A), gelatinous (Figure 27-2B), or leukoplakic (Figure 27-2C). It can also be classified as nodular (Figure 27-3A) or diffuse (Figure 27-3B). It may also present as a solitary mass with a satellite lesion. Nodular is the most common type, which can be aggressive (Figure 27-4), with metastasis to regional lymph nodes. The diffuse type is rare and masquerades as chronic conjunctivitis.

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Figure 27-1. Clinical presentation of OSSN. (A) Pinkish mass with feeder blood vessel (arrow). (B) Greyish mass.

Figure 27-2. Morphological characteristics of OSSN. (A) Gelatinous. (B) Papillomatous. (C) Leukoplakic.

Figure 27-3. Depending on the region involved, OSSN can be (A) nodular or (B) diffuse.

Clinical symptoms include redness, irritation, or the sensation of a foreign body or mass in the eye. Complaints of diminution of vision are uncommon. There seems to be no correlation between the severity of the lesion and the rapidity of symptoms. The usual differential diagnoses are pterygium, papilloma, nevus, pingueculum, and dyskeratosis. Malignancy should be suspected in recurrent active pterygium when there is unusual extension or invasion with vascularity.

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Figure 27-4. Invasive OSSN encroaching the cornea with intraocular extension.

Hematological malignancies can predispose to OSSN, and defective DNA repair conditions like xeroderma pigmentosa can be associated with OSSN in younger patients.

Investigations Certain preoperative investigations help in the diagnosis of suspicious ocular surface lesions.

Exfoliative Cytology A sterile platinum spatula is used to obtain the exfoliated cells. The cells are fixed with 95% alcohol and examined after staining with Papanicolaou’s stain. Dysplasia is seen as enlarged nuclei with coarse granulation of the nuclear chromatin, scanty cytoplasm, and a clean background. Carcinoma in situ is noted as a variable number of dysplastic cells with an admixture of malignant cells, scanty cytoplasm, enlarged nuclei, and hyperchromatism.1 Grade 1 and 2 invasive carcinoma has bizarre malignant cells with tadpole tails, spindle cells, hyperkeratinized malignant cells with opaque refractile cytoplasm, and malignant nuclei. Grade 3 has scanty cytoplasm and nonkeratinized, large pleomorphic nuclei with features of deeper invasion, ulceration, or necrosis.

Impression Cytology In this simple, noninvasive test for OSSN, a cellulose nitrate filter paper is gently placed on the ocular surface lesion and removed. It is then stained with Papanicolaou’s stain and examined for surface epithelial cell changes. Dysplastic cells are characterized by enlarged, irregular, and hyperchromatic nuclei. Carcinoma in situ demonstrates syncytia-like groupings (loss of cellular boundaries and irregularly arranged enlarged nuclei). Carcinomatous change shows inflammatory cells and sheets of abnormal cells with enlarged nuclei with invasion.1 Impression cytology is also used for recurrent tumors and for follow-up care of patients treated with topical chemotherapy.9

Excision Biopsy Only histopathologic evaluation of excised lesions after incisional or excisional biopsy can differentiate the spectrum of lesions.

Dysplasia The lesions exhibit a mild, moderate, or severe degree of cellular atypia that may involve various thicknesses of the epithelium, starting from the basal layer outward.

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Figure 27-5. (A and B) Histopathology of a solitary nodular lesion that turned out to be a squamous cell carcinoma. Hemotoxylin and eosin stain was used and seen under 10X to 40X magnification.

Carcinoma In Situ Carcinoma in situ may exhibit all of the histologic features of squamous cell carcinoma; however, it usually remains confined to the epithelium, respecting the basement membrane, and most of these lesions do not follow the course of a true invasive carcinoma. Carcinoma in situ usually shows a total loss of normal cellular maturation, affecting the full thickness of the epithelium. The cells are large and usually elongated. Keratinized cells may be identified, and mitotic figures can be seen in all layers.

Squamous Cell Carcinoma Squamous cell carcinoma (Figure 27-5) shows features similar to carcinoma in situ, but the basement membrane of the epithelium is breached and the subepithelial tissue of the conjunctiva is invaded. Most conjunctival squamous cell carcinomas are well differentiated and show surface keratinization. The tumor may show various degrees of cellular pleomorphism, with variation in size and configuration of the cells. When examining such lesions, one may find hyperplastic and hyperchromatic cells, individually keratinized cells (dyskeratosis), concentric collections of keratinized cells (horn pearls), and loss of cellular cohesiveness. The spindle cell variant of squamous cell carcinoma exhibits spindle-shaped cells that may be difficult to distinguish from fibroblasts. Mucoepidermoid carcinoma is a variant of conjunctival squamous cell carcinoma that shows, in addition to squamous cells, mucous-secreting cells that stain positively with special stains for mucopolysaccharides, such as mucicarmine, alcian blue, and colloidal iron. Adenoid squamous carcinoma is another variant of conjunctival squamous cell carcinoma with aggressive behavior. Histologically, there is extracellular hyaluronic acid but no intracellular mucin.

Anterior-Segment Optical Coherence Tomography Ultra-high-resolution optical coherence tomography (OCT) is a noninvasive diagnostic tool for the evaluation of ocular surface lesions.9,10 In OCT, the lesion appears as a thickened, hyperreflective epithelium, and there will be an abrupt transition from normal to hyper-reflective epithelium (Figure 27-6).

Confocal Microscopy In vivo confocal microscopy analysis of cytological characteristics of OSSN is a safe, relatively noninvasive, and effective diagnostic tool in detecting characteristics of OSSN before surgical resection.11 Cellular anisocytosis, enlarged nuclei, and keratinization changes can be assessed by confocal microscopy.

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Figure 27-6. High-speed anterior-segment OCT image of OSSN showing hyperreflective epithelial growth.

Figure 27-7. Surgical excision of OSSN. (A) The epithelium is loosened by applying alcohol. (B) Approximately 4 mm of surgical margin measured from the lesion. (C) The epithelium is removed with a crescent blade.

Figure 27-8. (A) Surface marking is done to plan for the region to be excised, including the main lesion (black arrow) and the satellite lesion (yellow arrow). (B) The mass is excised carefully without manipulation. (C) Lamellar sclerectomy of the underlying scleral bed is performed.

Treatment Surgical Excision Excision of the tumor is the conventional treatment for OSSN.1,12-14 The 2 main goals in the surgical management of OSSN are (1) to excise the tumor with clear margins and (2) to make any remaining tumor cells nonviable. A wide surgical margin of 4 mm should be taken along with tumor excision. Initially, the corneal epithelium is loosened by applying a sponge soaked in absolute alcohol (Figure 27-7). The epithelium is carefully dissected along the required margin. Care must be taken not to violate Bowman’s layer. After removal of the alcohol-soaked sponge, a copious balanced salt solution wash is performed. The surgical clearance required is measured and marked with a marker pen, and the mass is excised. When the sclera or cornea is involved, deep sclerectomy or lamellar keratectomy is performed (Figure 27-8). After tumor excision, the remaining cells are made nonviable by alcohol treatment of the scleral bed and washed with balanced salt solution. Then the double freeze/slow thaw cycle of cryotherapy to the limbus and conjunctival

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Figure 27-9. (A) The epithelium, conjunctival mass, and lamellar sclera, along with a clear margin, is excised in toto. (B) The underlying scleral and corneal surface is washed with balanced salt solution. (C) Double freeze/thaw cryotherapy is performed in the excised margins. (D) Ocular surface reconstruction is performed with amniotic membrane graft.

Figure 27-10. (A) Preoperative photograph of a patient with squamous cell neoplasia. (B) Photograph after surgical excision with no recurrence.

edges are performed (Figure 27-9). Rapid freeze and slow thaw is advised. This method of surgical removal of OSSN has been termed the no-touch method by Shields et al.13,14 Frozen section of the surgical margin can also be done for confirmation. Mohs’ micrographic technique is another method of evaluating the tumor clearance in the surgical specimen. The specimen’s margins are carefully evaluated; if they show evidence of tumor cells, a second excision of the involved side, including deep sclera, is performed. Ocular surface can be reconstructed with amniotic membrane graft in the same sitting after surgical excision (Figure 27-9). Adequate surgical clearance and the no-touch method of excision would prevent recurrence and give good results postoperatively (Figure 27-10). However, in case of intraocular invasion, enucleation is recommended. Similarly, exenteration is required for orbital extension.

Cryotherapy Cryotherapy is thought to act by destroying the tumor cells and obliterating their microcirculation, resulting in ischemic infarction of normal and tumor tissue. It may also act by immunologic response. A nitrous oxide cryoprobe is used to form ice balls approximately 2 mm from the conjunctiva, 1 mm from the episcleral tissues or limbus, and 0.5 mm from the cornea. Rapid freeze and slow thaw is advised for adequate cellular destruction. Reported side effects include iritis, increased or decreased intraocular pressure, inflammation, edema and corneal scarring, sector iris

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atrophy, ablation of the peripheral retina, ectropion, and superficial corneal vascularization.15,16 To reduce recurrence after surgical excision alone, cryotherapy is combined with surgery.

Radiotherapy Radiotherapy has also been used for treatment of OSSN.1,12 Strontium-90, a beta source, is applied with a cup applicator on the tumor surface. For lesions smaller than 1 mm or postoperative lesions, a dose of 1 x 60 or 3 x 20 Gy is recommended, and for lesions larger than 1 mm, a dose of 4-7 x 20 Gy is recommended, both at weekly intervals.17 Isolated irradiation is not recommended; however, it may be used in a diffuse spreading lesion for which initial excision may be too extensive. Gamma radiation has also been used in OSSN treatment. Post-irradiation side effects include conjunctivitis, dry eye, and cataracts, especially after gamma radiation. Scleral ulceration or scarring can occur after irradiation.

Chemotherapy Mitomycin-C, a noncell-cycle alkylating agent, can be used as a topical preparation. Topical mitomycin-C 0.02% applied 4 times daily for 10 to 22 days has been used to treat corneal intraepithelial neoplasia.18 Side effects include hyperemia, pain, and blepharospasm. The use of 5-flurouracil 1% 4 times daily for 4 weeks has shown a good response.19 Topical or intralesional recombinant alpha-2b interferon has been used in corneal and conjunctival neoplasia.20 Other chemotherapy drugs used for managing OSSN include dinitrochlorobenzene immunotherapy, topical urea treatment, antiviral cidofovir, and the anticancer drug ThioTEPA.

Prognosis OSSN is a low-grade malignancy. The course of OSSN may be evanescent, but it is more frequently slowly progressive and, if untreated, can lead to orbital and intraocular spread and require exenteration. Intraocular invasion or metastasis, although reported, is rare.21 Routine anterior segment evaluation along with anterior-segment OCT, gonioscopy, and slit lamp biomicroscopy, will rule out extension of the tumor. Systemic spread is rare with OSSN. Inadequate surgical marginal clearance or partial resection is known to cause recurrence.1 Repeat surgery can be performed in some cases. The use of a 193-nm excimer laser for ablation of corneal intraepithelial neoplasia recurrence has been reported.22 The recurrence rate after excision in OSSN ranges from 15% to 52%.1

Conclusion OSSN includes a spectrum of lesions, from dysplasia to carcinoma in situ and invasive squamous cell carcinoma. Preoperative tests such as cytology, anterior-segment OCT, and confocal microscopy aid in diagnosis and follow-up. Ocular surface cytologic analysis is a simple, safe, and relatively noninvasive diagnostic tool. Histopathology of the excised tissue confirms the preoperative diagnosis. Surgical excision with clearance of 2 to 3 mm gives a good prognosis. The no-touch technique for tumor excision prevents metastasis and recurrence.

References 1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995;39(6):429-450. 2. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea. 1987;6(2):78-116. 3. Waring GO III, Roth AM, Ekins MB. Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia. Am J Ophthalmol. 1984;97(5):547-559. 4. Napora C, Cohen EJ, Genvert GI, et al. Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg. 1990;21(1):27-30. 5. Nagaiah G, Stotler C, Orem J, Mwanda WO, Remick SC. Ocular surface squamous neoplasia in patients with HIV infection in sub-Saharan Africa. Curr Opin Oncol. 2010;22(5):437-442. 6. Hamam R, Bhat P, Foster CS. Conjunctival/corneal intraepithelial neoplasia. Int Ophthalmol Clin. 2009;49(1):63-70.

292 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Chapter 27 Templeton AC. Tumors of the eye and adnexa in Africans of Uganda. Cancer. 1967;20(10):1689-1698. Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol. 1992;110(4):525-527. Semenova EA, Milman T, Finger PT, et al. The diagnostic value of exfoliative cytology vs histopathology for ocular surface squamous neoplasia. Am J Ophthalmol. 2009;148(5):772-778.e1. Shousha MA, Karp CL, Perez VL, et al. Diagnosis and management of conjunctival and corneal intraepithelial neoplasia using ultra high-resolution optical coherence tomography. Ophthalmology. 2011;118(8):1531-1537. Xu Y, Zhou Z, Xu Y, et al. The clinical value of in vivo confocal microscopy for diagnosis of ocular surface squamous neoplasia. Eye (Lond). 2012;26(6):781-787. Pe’er J. Ocular surface squamous neoplasia. Ophthalmol Clin North Am. 2005;18(1):1-13. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol. 1997;115(6):808-815. Shields JA, Shields CL, De Potter P. Surgical management of circumscribed conjunctival melanomas. Ophthal Plast Reconstr Surg. 1998;14(3):208-215. DuttonJJ, Anderson RL, Tse DT. Combined surgery and cryotherapy for scleral invasion of epithelial malignancies. Ophthalmic Surg. 1984;15(4):289-294. Peksayar G, Soytürk MK, Demiryont M.Long-term results of cryotherapy on malignant epithelial tumors of the conjunctiva. Am J Ophthalmol. 1989;107(4):337-340. Cerezo L, Otero J, Aragón G, Polo E, de la Torre A, Valcárcel F, et al.Conjunctival intraepithelial and invasive squamous cell carcinomas treated with strontium-90.Radiother Oncol. 1990;17(3):191-197. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol. 1994;117(2):164-168. Midena E, Angeli CD, Valenti M, de Belvis V, Boccato P. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84(3):268-272. Vann RR, Karp CL. Perilesional and topical interferon alfa-2b for conjunctival and corneal neoplasia. Ophthalmology. 1999;106(1):91-97. lliff WJ, Marback R, Green WR. Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol. 1975;93(2):119-122. Dausch D, Landesz M, Schroder E. Phototherapeutic keratectomy in recurrent corneal intraepithelial dysplasia. Arch Ophthalmol. 1994;112(1):22-23..

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28 Collagen Cross-Linking and Contact Lens–Assisted Collagen Cross-Linking for Corneal Ectatic Disorders Soosan Jacob, MS, FRCS, DNB, MNAMS; Kaladevi Satish, MS; and Amar Agarwal, MS, FRCS, FRCOphth In the human body, collagen fibers are normally bonded together and thus stabilized by covalent cross-links. The tensile strength of mature collagen fibers is largely due to intermolecular covalent cross-links. Collagen cross-linking (CXL) is a relatively new technique described by Spoerl et al1 as a means to strengthen a weak and ectatic cornea. This was done by creating an increased number of covalent bonds between collagen fibers in the corneal stroma. The technique is also known by other names, such as corneal collagen cross-linking (C3R) and collagen crosslinking (CCL).

Mechanism of Action Topical riboflavin is used as a photosensitizer. The application of 370 nm of ultraviolet A (UVA) in the presence of riboflavin leads to the production of oxygen free radicals. These free radicals lead to the induction of collagen cross-links, which in turn leads to more compact interlamellar connections.

Role of Riboflavin The photosensitizing effect of riboflavin causes damage at a lower UVA level of 0.36 mW/cm 2. Despite having a photosensitizing effect, riboflavin has an additional protective role in CXL by means of increasing the absorption coefficient. This absorption coefficient reaches a plateau at a riboflavin concentration of 0.1%. With an irradiance of 3 mW/cm 2 of UVA (at the corneal surface) and 0.1% riboflavin, 95% of UVA light is absorbed within the cornea, resulting in a reduction of final irradiance at the endothelial level down to 0.18 mW/cm 2 , whereas at a depth of 300 μm, irradiance is 0.37 mW/cm 2. Therefore, 400 μm of riboflavin-saturated stroma above the endothelium is considered safe to avoid adverse effects. Also, as concluded by Wollensak et al, 2 the cornea - 293 -

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and a precorneal riboflavin film together are considered a composite 2-compartment system, and the riboflavin film is an integral part of the CXL procedure to achieve the correct stromal and endothelial UVA irradiance.

Indications The main indication for CXL is progressive keratoconus. It is also used for the treatment of other progressive corneal ectatic disorders, such as post–LASIK ectasia and pellucid marginal degeneration. CXL has also been used for infectious corneal melts because of the collagen-stabilizing effect of CXL and the anti-infective effect of UVA light. It has been used for the treatment of pseudophakic bullous keratopathy by applying CXL after dehydrating the cornea in an attempt to delay or avoid the need for a penetrating keratoplasty. Traditional age criteria is older than 18 years, but it has been used in pediatric patients with good results.3

Contraindications A minimum stromal thickness of 400 μm after epithelial removal is required for safe CXL. In patients with corneas thinner than this, conventional CXL cannot be performed. For such patients, either contact lens–assisted CXL (CACXL) or hypotonic CXL is performed. CXL is also not performed in patients with stable, nonprogressive keratoconus. Keratoconus is generally likely to be nonprogressive in patients older than 35 years because of naturally occurring cross-linking occurring with age. In such patients, it is indicated only if progression is documented.

Cross-Linking in Corneas With Minimum Thickness More Than 400 μm After Epithelial Removal Epi-Off Technique Preoperatively, topical anesthetic drops and pilocarpine are applied. The topical anesthetic makes epithelial removal less painful and easier by loosening the tight junction between corneal epithelial cells. Pilocarpine constricts the pupil and thus decreases the amount of UVA light passing beyond the iris to the lens and retina. The epithelium is then removed over the central 9 mm of the cornea, and 0.1% isotonic riboflavin in dextran T500 drops are applied to the cornea every 3 minutes for 30 minutes. After confirming adequate saturation of the cornea with riboflavin and checking for the presence of a green flare in the aqueous, the cornea is exposed to UVA light of 370 nm at an irradiance of 3 mW/cm 2 for 30 minutes. Irradiance to the limbal stem cells is avoided. A bandage contact lens is applied and the patient is put on postoperative topical lubricants and antibiotic drops until epithelial healing, followed by lubricants and antibiotic steroid eye drops thereafter. The patient is advised to wear UV protective glasses postoperatively.

Epi-On Technique The epi-on technique is similar to the epi-off technique except that the epithelium is not removed. This is done in an attempt to decrease postoperative pain and haze formation associated with CXL, and good results have been reported.4

Complications Complications can include postoperative delayed epithelial healing, sterile infiltrates, infectious keratitis, corneal stromal haze, endothelial damage, and reactivation of herpes simplex virus. Stromal haze that occurs after CXL generally decreases in intensity with time. Continued progression despite CXL is another possible complication.

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Cross-Linking in Corneas With Minimum Thickness Less Than 400 μm After Epithelial Removal Hypotonic Collagen Cross-Linking Hypo-osmolar cross-linking was described in 2009 by Hafezi et al 5 for thin corneas. Two solutions (iso-osmolar and hypo-osmolar) of 0.1% riboflavin are used. Epithelial debridement and application of iso-osmolar riboflavin 0.1% every 3 minutes for 30 minutes is followed by application of hypo-osmolar solution every 20 seconds for 5 more minutes or until corneal pachymetry showed a minimum corneal thickness more than 400 μm. According to the authors, stromal swelling shows distinct interindividual variation, ranging from 36 to 105 μm and from 3 to 20 minutes in different corneas.

Contact Lens–Assisted Collagen Cross-Linking Contact lens–assisted collagen cross-linking was described by one of the authors (Soosan Jacob)6 as a means to cross-link thin corneas safely and effectively. A precorneal riboflavin film, a riboflavin-soaked (UV barrier–free) soft contact lens of negligible power, and a pre–contact lens riboflavin film are used to attain attenuation of UV irradiance to safe levels at the level of endothelium.

Background It is possible that some corneas do not swell enough to make hypo-osmolar CXL possible. CACXL has the advantage of not being dependent on the swelling properties of the cornea and therefore makes CXL possible in a larger group of patients. Additionally, Wollensak et al 2 reported that the cornea and a precorneal riboflavin film of approximately 70 μm together create a composite 2-compartment system, and the riboflavin film is an integral part of the CXL procedure. They also stressed the importance of a stable riboflavin film for the absorption and shielding of UVA and stated that the unstable hypo-osmolar riboflavin film used for thin corneas results in higher irradiance at the endothelial level than the dextran-riboflavin film, putting the endothelium at possible risk if the stroma is swollen to only 400 μm. In CACXL, the thickness of the cornea is artificially increased by increasing the amount of riboflavin-containing substance anterior to the stroma, thereby increasing functional corneal thickness.. This is done by using the precorneal riboflavin film, a riboflavin-soaked (UV barrier– free) soft contact lens of negligible power, and a pre–contact lens riboflavin film.

Technique Preoperatively, lidocaine 2% and pilocarpine 2.0% are instilled twice to aid in epithelial removal and to promote miosis and reduce UVA exposure to the lens and retina. The central 9 mm of corneal epithelium is abraded. Iso-osmolar riboflavin 0.1% in dextran T500 drops is applied every 3 minutes for 30 minutes. At the same time, a Soflens Daily Disposable soft contact lens (Bausch + Lomb) made of hilafilcon without a UV filter and of negligible power is immersed in isotonic riboflavin for 30 minutes. At the end of 30 minutes, adequate corneal saturation with riboflavin is confirmed by visualization of a green flare in the anterior chamber using a slit lamp. The riboflavin-soaked contact lens is then applied on the corneal surface and the thickness is remeasured. Once confirmed to be more than 400 μm, treatment is continued. The central 9 mm of the cornea is exposed to UVA light of 370 nm with an irradiance of 3 mW/cm 2 for 30 minutes. During CACXL, hot and cold spots may be avoided by reapplying sufficient riboflavin solution under and above the contact lens when required and allowing it to spread uniformly. The layer of solution is also applied over the contact lens fills any persistent troughs on the lens surface and provides a uniform layer over the lens as required by Wollensak et al.2 Postoperatively, antibiotic drops are given until epithelial healing, followed by a bandage contact lens that is retained until corneal epithelial healing. Fluorometholone-tobramycin eye drops are applied once epithelial healing is complete. The patient is also advised to wear UV protective glasses (Figures 28-1 to 28-5).

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Figure 28-1. (A) The epithelium is removed for an epi-off procedure. (B) The cornea is saturated with 0.1% riboflavin in dextran every 3 minutes for 30 minutes. (C) The contact lens is soaked in the same solution of riboflavin for 30 minutes. (D) The riboflavin-soaked contact lens is applied on the cornea. Anterior-segment optical coherence tomography confirms that minimum pachymetry of the stroma with the contact lens is now above 400 µm.

Figure 28-2. (A) The riboflavin solution is applied under the contact lens. (B) Any troughs on the contact lens are smoothed out with a pre‒contact lens riboflavin film. (C) The cornea is exposed to 370 nm of UVA light for 30 minutes. (D) At the end of 30 minutes, the riboflavin-soaked contact lens is removed, balanced salt solution is used to wash the eye, and a new contact lens is applied until complete epithelial healing.

Figure 28-3. (A) In conventional cross-linking, the precorneal riboflavin film is 70 µm. (continued)

A

Advantages Using the CACXL technique, an average additional thickness of approximately 100 to 110 μm is obtained (Figure 28-6). It is important to use a contact lens that does not have a UV barrier built in for this technique. This can be simply checked by placing the contact lens under the UV

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Figure 28-3 (continued). (B) In CACXL, a 90-µm riboflavin-soaked contact lens is placed on the cornea. (C) The pre‒contact lens riboflavin film applied on the contact lens contributes about 70 µm.

C

beam of a UV light source. Contact lenses that block and decrease UV irradiance cannot be used (Figure 28-7). In studies by Wollensak et al, 2 the breakup times and thickness of 3 different solutions of riboflavin were studied: dextran-riboflavin as used in standard CXL and methylcellulose riboflavin and hypo-osmolar riboflavin without dextran as used in hypo-osmolar CXL. The standard CXL dextran-riboflavin film was found to be 70 μm after 1 minute and had a breakup time of 22 minutes. Showing the importance of a precorneal riboflavin film in CXL (which corresponds with the pre–contact lens riboflavin film in CACXL), Wollensak et al 2 reported that the mean UV irradiance with a 400-μm stroma was 0.68 mW/cm 2 (above the level toxic to the endothelium of 0.36 mW/cm 2) without the film and 0.21 mW/cm 2 with the film (below the level toxic to the endothelium of 0.36 mW/cm 2). With the hypo-osmolar solution, the mean UV irradiance with a 400-μm stroma was 0.63 mW/cm 2 (above toxic level) without the film and 0.36 mW/cm 2 (close to toxic level) with the film. With the CACXL technique, as we add artificially to the corneal stromal thickness with the use of a precorneal isotonic riboflavin film (dextran-riboflavin), a contact lens, and a pre–contact lens riboflavin film, the irradiance at the level of 400 μm measured from the anterior surface of the contact lens will be below the endothelial toxic level. Though the ultraviolet-A irradiance at the level of the stroma is also correspondingly decreased, we observed good clinical results with CACXL.

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Figure 28-4. (A) The contact lens shows good absorption of riboflavin, even after thorough washing with balanced salt solution. (B) The precorneal riboflavin film is shown.

Figure 28-5. (A) Troughs may sometimes appear on the surface of the contact lens. (continued)

Accelerated Contact Lens–Assisted Collagen Cross-Linking Accelerated CACXL is based on the reciprocity law of Bunsen Roscoe and has advantages of decreasing treatment time while increasing intensity, keeping the total energy constant. This also has additional advantage of decreasing the intraoperative dehydration that occurs with the use of Dextran T500 solution (Figure 28-8). This intraoperative dehydration can also be further

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Figure 28-5 (continued). (B) The troughs are filled by the posterior portion of a pre‒contact lens riboflavin film. (C) The solution is also applied uniformly over the entire contact lens. The anterior portion of the pre‒contact lens riboflavin film corresponds with the composite 2-compartment system of the cornea and a precorneal riboflavin film, as described by Wollensak et al.2

Figure 28-6. (A and B) Intraoperative anteriorsegment optical coherence tomography images of 2 patients after placement of the contact lens and during measurement of the thickness of the contact lens and the precorneal riboflavin film.

avoided by using 0.1% riboflavin in HPMC and BSS (Vibex Rapid TM; Avedro, USA) instead of 0.1% riboflavin in Dextran T500.

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Figure 28-7. (A) Two different contact lenses are tested for UV transmittance. (B) The UVA light source is tested with a digital UV meter. (C) The digital UV meter shows a low reading for a contact lens with a built-in UV blocker. (D) The digital UV meter shows good transmission of UV through a UV barrier‒free soft contact lens.

Figure 28-8. Accelerated CXL and CACXL may be performed with newer machines. The figure shows the power of 10mW/cm2 for 9 minutes giving a total energy of 5.4J/cm2 (CL-UVR rapid; Appasamy Associates; India).

Conclusion In CXL corneas thinner than 400 μm, despite a reduction in irradiance from the corneal surface toward the deeper layers of the corneal stroma, irradiation levels still exceed the endothelial toxic threshold. CACXL adds artificially to corneal thickness using a riboflavin-soaked contact lens and a precorneal riboflavin film of known thickness, thereby increasing safety. It extends the benefit of safely undergoing cross-linking to a larger number of patients with thin corneas and with a greater chance of successfully and safely completing the procedure. However, CACXL should not be used indiscriminately in all patients with thin corneas, rather only in patients where a combined thickness above 400 μm has been achieved. In patients with very thin corneas, it may be more appropriate to perform a deep anterior lamellar keratoplasty considering the severity of the disease.

References 1. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66:97-103. 2. Wollensak G, Aurich H, Wirbelauer C, Sel S. Significance of the riboflavin film in corneal collagen cross-linking. J Cataract Refract Surg. 2010;36:114-120.

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3. Gadelha DN, Cavalcanti BM, Bravo Filho V, Andrade Júnior N, Batista NN, Escarião AC, Urbano RV. Therapeutic effect of corneal cross-linking on symptomatic bullous keratopathy. Arq Bras Oftalmol. 2009;72(4):462-466. 4. Ertan A, Karacal H, Kamburoğlu G. Refractive and topographic results of transepithelial crosslinking treatment in eyes with intacs. Cornea. 2009 Aug;28(7):719-723. 5. Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg. 2009;35(4):621-624. 6. Jacob S, Kumar DA, Agarwal A, Basu S, Sinha P, Agarwal A. Contact lens–assisted collagen cross linking: A new technique for cross liking thin corneas. J Refract Surg. In press.

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29 Platelet-Rich Plasma in Corneal Surgery Jorge L. AliÓ, MD, PhD; Francisco Arnalich, PhD; Alejandra E. Rodriguez, MSc; and Alvaro Luque, BSc Platelet-rich plasma (PRP) is defined by Marx1 as a portion of the plasma fraction of autologous blood having a platelet concentration above baseline. He uses a PRP device, concentrate platelets using a double centrifugation technique, and activate PRP just when they are ready to use it. The final concentration is at least 1.000.000 platelets/μm. Therefore, it is an autologous concentration of platelets and growth factors. After the complete release of growth factors, platelets are able to synthesize and secrete additional growth factors for the remaining several days of their lifespan, thus expanding the wound-healing effect.1 The eye PRP (E-PRP) used in ophthalmology is an autologous preparation of plasma rich in platelets but different from the PRP described by Marx1 and slightly different from plasma-rich growth factor (PRGF).2 E-PRP uses sodium citrate as an anticoagulant, and, when necessary, calcium chloride is used for the activation of the E-PRP clot. The main difference with PRGF is that the E-PRP preparation uses commercial tubes to obtain the blood, and a typical laboratory centrifuge is used for plasma separation. E-PRP does not require specific devices (Figure 29-1). E-PRP fabrication is performed using a one-step centrifugation process, and the final rate of the platelet concentration depends on whether it will be used as eye drops (without activation) for ocular surface applications or as a clot (activated) for surgical procedures such as ocular reconstruction or treatment of corneal perforations.

Rationale of Use Different blood-derived formulations, such as autologous serum, plasma enriched with platelets, and preparations rich in growth factors, have been used to promote wound healing in multiple tissues. Blood-derived products have demonstrated their capacity to enhance healing and stimulate the regeneration of different tissues, providing growth factors and other bioactive proteins that are synthesized and present in the blood.3 The serum is the clear liquid part of full blood after cellular components and clotting proteins have been removed. Since Fox et al4 first used autologous serum eye drops in the treatment of keratoconjunctivitis sicca, it has been the preferred blood-derived topical preparation in the treatment of ocular surface diseases. Autologous serum is commonly used and has been found to be - 303 -

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Figure 29-1. Procedure for obtaining E-PRP.

effective for the treatment of persistent epithelial defects,5 neurotrophic ulcers,6 superior limbic keratoconjunctivitis,7 and other types of dry eye symptoms such as graft versus host disease8 or after LASIK.9 Autologous serum has also been used as an adjunctive treatment in ocular surface reconstruction with different results.10,11 Unlike artificial tears, serum eye drops have pH, osmolarity, and biomechanical properties that resemble natural tears, and they are nonpreserved. Used topically, they supply essential nutrients, such as growth factors, vitamins, and bacteriostatic products (eg, immunoglobulin G, lysozyme, and complement) to the ocular surface.12 Therefore, not only do they provide lubrication, but they also have epitheliotrophic and antimicrobial properties that cannot be found in commercialized artificial tears. Plasma, unlike serum, contains clotting proteins of full blood such as fibrin. Although the acellular component of blood contains growth factors, it is well known that platelets are great reservoirs of growth factors that enhance proliferation and wound healing. The alpha-granules in platelets contain more than 30 bioactive proteins, such as epidermal growth factor (EGF), platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and transforming growth factor beta (TGF-β), as well as cytokines, including proteins such as PF4 and CD40L, which promote tissue repair and influence the reactivity of vascular and other blood cells in angiogenesis and inflammation.3 Growth factors released from activated platelets initiate and modulate wound healing in both soft and hard tissues.13,14 The plasma also contains concentrated quantities of some important cell-adhesion molecules, such as fibrin, fibronectin, and vitronectin, which promote epithelial migration.15 Laboratory research with different cultured cellular lines, such as tendon cells, synovial and skin fibroblasts, and corneal epithelial cells, shows the multiple benefits and biological effects of growth factors.12,16-18

Use of Platelet-Rich Plasma in Ocular Surface Disorders The ocular surface comprises the conjunctival mucosa that lines the globe and palpebral surfaces, the corneoscleral limbus, the corneal epithelium, and the tear film. This complex structure needs a stable tear film, normal blink, functioning lacrimal system, and healthy eyelids to maintain a balanced homeostasis. Several diseases can compromise the stability of the ocular surface, ranging from chemical or physical injuries such as LASIK to autoimmune diseases such as Sjögren’s disease or ocular cicatricial pemphigoid. If corneal wound healing does not occur promptly, it can lead to visual loss, severe scarring, infection, and even corneal perforation. Autologous E-PRP in the form of topical eye drops is used for ocular surface applications, and the E-PRP clot can be used to enhance ocular reconstruction procedures. The advantage of E-PRP over autologous serum is that E-PRP has a large quantity of growth factors that are released from the platelets once these are activated in the ocular surface.19

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Figure 29-2. (A) A patient with a neurotrophic ulcer before treatment with E-PRP. (B) The same patient after 1 month of treatment with topical E-PRP.

Dormant ulcers are epithelial defects of the cornea that fail to heal in spite of at least 2 weeks of conventional treatment and are most commonly caused by neurotrophic keratopathy (including metaherpetic disease), dry eye, or immunological disorders such as rheumatoid arthritis or ocular cicatricial pemphigoid. In a prospective study, AliÓ et al19 included 26 eyes with dormant corneal ulcers with neurotrophic keratopathy (n = 12) (Figure 29-2A), herpetic keratopathy (n = 9), and ulcers of immunological origin (n = 5). They were treated with E-PRP eye drops 6 times a day in addition to routine medication. Primary outcome measures were the reduction in size or depth of the corneal ulcer and improvement in best corrected vision. Secondary outcome measures were the reduction of pain or discomfort, decrease in conjunctival or ciliary hyperemia, or conjunctival edema if present. Significant clinical improvement was found in 92% (24/26) of the eyes, with a complete resolution of the ulcer in 50% (13/26) of the cases (Figure 29-2B). Only 2 eyes showed no significant changes after treatment. Reduction in inflammation and decrease in ocular pain were other parameters that improved in the majority of cases. Two eyes with a relapsing epithelial defect, defined as observation of a new epithelial defect located at the level of the previous ulcer with positive fluorescein staining under slit lamp examination, occurred after 6 months to 1 year and were treated successfully by keratoplasty. Visual acuity also improved in more than half of the patients, with 31% of the eyes gaining 1 to 3 lines of visual acuity, 15% gaining 4 to 5 lines of visual acuity, and 12% gaining more than 6 lines of visual acuity. A reduction in inflammation occurred in 1 to 2 weeks, with a decrease in ocular pain. This study shows that E-PRP improved photophobia, pain, and inflammation; facilitated re-epithelialization; promoted corneal wound healing; and improved the clinical condition, which resulted in improved vision in the majority of studied patients. Dry eye is a disorder of the tear film caused by a disturbance in the composition and quantity of tears and can be due to (1) deficiency of the aqueous phase of the tear, as in Sjögren’s syndrome or lacrimal gland disease; (2) deficiency of the mucin layer caused by a vitamin A deficiency, trachoma, diphtheric keratoconjunctivitis, mucocutaneous disorders, and certain topical medications; or (3) abnormalities of the lipid tear layer caused by blepharitis and rosacea. Dry eye is common in ophthalmology and causes disturbing subjective symptoms such as dryness, burning, and a sandygritty eye irritation and is accompanied by superficial punctate keratopathy (Figure 29-3A), tiny abrasions on the surface of the eyes, and conjunctival hyperemia. Dry eye can also compromise visual acuity if it is severe enough. Artificial tears are the main standard treatment for this disease but are often not sufficient to stop all the symptoms and signs of the disease. Some studies have shown that dry eye is often associated with a low-grade inflammatory reaction on the ocular surface with the production of proinflammatory cytokines, activation of T-cells in the lacrimal glands, and conjunctiva with or without Sjögren’s syndrome.20,21 Dry eye symptoms usually correlate with the severity of the disease; however, when accompanied by inflammation, they may cause a downregulation of sensory receptors, leading to a decrease in symptoms, whereas milder conditions may cause the opposite effect. AliÓ et al 22 conducted a prospective, nonrandomized, consecutive, observational pilot study that included 36 eyes in 18 patients with moderate to severe dry eye syndrome according to the Madrid triple classification.23 Twelve

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Figure 29-3. (A) A patient with dry eye syndrome presenting with punctate keratitis. (B) The same patient after 1 month of treatment with topical E-PRP, with no evidence of keratitis at slit lamp examination.

patients had moderate dry eye, and 6 patients had severe dry eye related to Sjögren’s syndrome or Stevens-Johnson syndrome. All patients had punctate keratitis, with fluorescein staining on at least 50% of the corneal surface; were highly symptomatic; and showed severe ocular surface disturbances. Main outcome measurements included the disappearance of subjective symptoms after treatment; an increase in visual acuity, tear meniscus height, and tear breakup time; a decrease in inflammation and fluorescein staining; and an improvement of impression cytology. E-PRP was given topically as eye drops (4 to 6 times a day per eye). Patients were monitored for improvement every week. Data were analyzed after 1 month of treatment. After 1 month, 89% (16/18) of patients experienced relevant improvement or full disappearance of subjective symptoms, and no patient’s symptoms deteriorated while receiving treatment (Figure 29-3B). Twenty-eight percent (5/18) of patients had at least 1 line or more of visual acuity, with no cases of visual loss documented. Improvement in the quality of the tear film was also reported in more than half of the patients, with an increase of the tear meniscus height and tear breakup time. A significant reduction in inflammation was found in 89% (6/7) of patients suffering from conjunctival inflammation. Moreover, improvement of fluorescein staining of the cornea due to superficial punctate keratitis was found in 72% (13/18) of patients. Lastly, with the available data of impression cytology, 12 of 18 patients presented a statistically significant increase in the density of goblet cells (mucinproducing cells) on the superior bulbar conjunctiva and an almost statistically significant increase (P = .053) in the inferior bulbar conjunctiva. In this clinical study, E-PRP eye drop application improved regeneration of the ocular surface and relieved symptoms in patients with symptomatic dry eye, with no adverse events during a follow-up of up to 6 months.22 Topical steroids have also been proven to quickly relieve symptoms, but their long-term use may result in side effects such as an increased risk of infection, intraocular pressure elevation, and cataract formation.24 The preservative component present in these steroid solutions can also affect the bonds between epithelial cells in the cornea, inducing punctate keratopathy that may develop into a corneal ulcer.24 Ocular surface syndrome is a well-known side effect after refractive procedures with LASIK technology. Clinically it is characterized by dry eye, micropunctate keratitis, decreased and unstable tear film, and decreased best spectacle-corrected visual acuity (BSCVA). Although the exact mechanism for this disease is not completely understood, it is thought to be secondary to corneal nerve damage, which occurs in refractive procedures that involve corneal flap creation. One of the main functions of the ocular nerves is the regulation of secretion activities of the lacrimal and meibomian glands. Their damage causes neurotrophic epitheliopathy and affects tear composition.25 All lipidic, aqueous, and mucus components of tears are involved in the quality of the tear film, and any misbalance can compromise the ocular surface. When a deficiency on the aqueous phase is present in the tear film, the risk of infection by pathogens increases. A decrease in the quantity or quality of the mucus associated with goblet cells of the conjunctiva decreases tear stability. The same is observed when the alteration of the lipid composition of the tears affects the tears’ evaporation control.26 Treatment of ocular surface syndrome after LASIK surgery with artificial tears is often disappointing.27 A prospective study by AliÓ et al 28 included 26 eyes in

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Figure 29-4. (A) A patient with ocular surface syndrome after LASIK and before treatment with E-PRP, showing positive staining of fluorescein in more than 50% of the cornea. (B) The same patient after 1 month of treatment with E-PRP showing negative staining of fluorescein.

13 patients who had undergone LASIK surgery to correct myopia. All surgeries were performed using a mechanical microkeratome (Moria M2 with disposable head; Moria SA). A 9.5-mm flap was created with a superior hinge of 3.5 to 4 mm. Flaps were tentatively programmed to be 130 μm thick based on an intended flap thickness of 160 μm.7 LASIK was performed using the Esiris excimer laser (Schwind eye-tech-solutions GmbH & Co KG). They were all affected by severe to moderate dry eye syndrome (according to the Madrid triple classification 23) for at least 6 months postoperatively. Six of the 13 patients suffering from moderate ocular surface symptoms prior to treatment showed severe symptoms. BSCVA for all patients decreased from 1 line to 4 lines. All patients were positive for fluorescein staining (Figure 29-4A) and had a tear breakup time between 4 and 9 seconds. Main outcome measures included subjective symptom disappearance, increased visual acuity, increased tear meniscus and tear breakup time, decreased inflammation and fluorescein staining, and improvement in impression cytology. E-PRP eye drops applied 6 times daily improved subjective symptoms in the majority of patients, and the improvement was considered good or excellent in 84% (11/13) of patients. Fluorescein staining analysis showed complete resolution of punctate keratitis in 69% (18/26) of eyes (Figure 29-4B) and almost complete in another 23% (6/26) of eyes. E-PRP also improved visual acuity, providing a gain in vision ranging from 1 to 4 lines of improvement in visual acuity in 69% (18/26) of eyes. Tear breakup time increased 2 seconds in 46% (12/26) of eyes. Fourteen (54%) eyes showed a 0- to 2-second tear breakup time increase. One (8%) patient developed intolerance after 4 weeks and has been the only case reported in the literature. Autologous E-PRP adds a new tool for ocular surface syndrome treatment after LASIK because it provides subjective and objective improvement. E-PRP is rich in vitamins and growth factors.

Platelet-Rich Plasma as a Joint Adjuvant E-PRP and PRGF have been successfully used for more than a decade as a component for tissue regeneration procedures such as oral and maxillofacial surgery, reconstructive orthopedics, and plastic surgery.29-31 Dental implant surgery with guided bone regeneration is an example in which an autologous platelet-rich clot has been shown to accelerate ossification after a tooth extraction and/or around titanium implants, with marked reductions in the time required for implant stabilization and an improved success rate.32-34 Articular surgery 35 and tendon repair36 are other situations in which autologous platelets have shown to accelerate healing. Concentrated platelet preparations are also used to induce bone regeneration when prosthetic devices are to be implanted37 in maxillofacial and implant surgery and also in traumatology, combined with hydroxyapatite, autologous bone, and other biomaterials.38-40

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Figure 29-5. Photograph of E-PRP clot immediately after preparation.

Difficult Cases of Corneal Surgery: Solid Eye Platelet-Rich Plasma E-PRP can be used to promote and enhance healing of ocular surface reconstruction procedures or to treat impending perforation or even frank perforations. In theory, an E-PRP clot should provide a higher amount of growth factors in an initial burst as well as late synthesis and secretion of growth factors for the remaining 7 days of the life span of a platelet. For preparation of an E-PRP clot, 40 to 60 mL of blood is obtained from the patient just before surgery and centrifuged by the 1-step process used for E-PRP eye drop formulation; however, in this case, only the plasma nearest to the red cells is harvested, avoiding the white blood cell layer due to the undesirable proinflammatory effects of leucocytes. One mL of E-PRP is placed into each 4-well tissue culture plate, and 50 μL of 10% calcium chloride is added to each well for activation. After mixing carefully with a sterile pipette, the plates are incubated at 37ºC for 30 minutes. After that time, the E-PRP clot is formed and it is ready to be applied immediately onto the ocular defect (Figure 29-5). In the E-PRP clot, the rate of the platelets’ enrichment is approximately 2 to 3 times over the full blood values. The manipulation of the tubes to obtain the E-PRP must be done under strict sterile conditions using a laminar flow hood.

Solid Eye Platelet-Rich Plasma Associated With Amniotic Membrane Transplantation Ocular surface reconstruction includes limbal autograft or allograft keratoplasty, amniotic membrane transplantation (AMT), and sectorial epitheliectomy, among others. Theoretically, the adjuvant use of E-PRP would enhance the regenerative effect of these interventions by release of growth factors that promote wound healing and decrease inflammation. Other biologically active products, such as autologous serum, have been used successfully for this purpose.10 AliÓ et al19 presented a series of patients with perforated eyes or a high risk of perforation due to deep chronic corneal ulcers treated with AMT combined with a clot of autologous E-PRP. Surgery consisted of wound debridement, excision and removal of devitalized tissue, and application of amniotic membrane to the wound site with the epithelial side up. A clot of autologous PRP was placed under the amniotic membrane to seal the impending or actual corneal perforation and to increase the therapeutic effect of the amniotic membrane (Figure 29-6). The membrane was sutured to the conjunctiva with a 10-0 nylon suture, and a running purse-string suture was applied so that the membrane tightly adhered to the entire corneal surface. The eye was closed with a temporary tarsorrhaphy. Primary outcome measures were a reduction in the size or depth of the corneal ulcer and improvement in best corrected visual acuity. All patients showed an improvement in the size of the ulcer, and 71% (10/14) of eyes had a complete resolution of the ulcer. Vision also improved in 57% (8/14) of eyes, along with a decrease in inflammation that occurred 1 to

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Figure 29-6. (A) A patient with a corneal perforation before AMT. (B) Application and partial suture of the amniotic membrane on the corneal perforation. (C) Placement of the E-PRP clot below the amniotic membrane. (D) Final result after AMT with the E-PRP clot in the perforated eye.

Figure 29-7. (A) A patient with limbal deficiency preoperatively. (B) Limbal keratoplasty before application of an E-PRP clot and collagen membrane. (C) Placement of a Tutopatch (Tutogen Medical GmbH) on the limbal keratoplasty. (D) Application of the E-PRP clot under the Tutopatch after limbal keratoplasty.

2 weeks postoperatively. It cannot be ascertained in this study whether the healing effect of the E-PRP in combination with AMT was higher than using AMT alone. However, theoretically, E-PRP combined with AMT should further promote the corneal wound-healing processes and further decrease inflammation due to the intrinsic characteristics of E-PRP. We also have experience with the use of E-PRP clots in other surgical interventions, such as limbal keratoplasty, to restore the ocular surface with good results (unpublished data) (Figure 29-7), as seen by other authors with autologous serum.10,11 We believe that the prolonged synthesis and release of growth factors by the E-PRP clot provides additional long-acting effects that would increase the benefit of E-PRP over autologous serum.

Solid Eye Platelet-Rich Plasma Associated With Tutopatch In the previous section, we described the use of combined solid E-PRP and amniotic membrane for the management of perforations or impending perforations. The autologous PRP was used to stimulate tissue regeneration and to induce mesenchymal and epithelial cells to migrate and proliferate to restore the damaged ocular surface. The role of the antibiotic membrane was to maintain the solid clot attached at the site of injury. We designed and published a pilot study using a commercially available collagenous membrane obtained from bovine pericardium as an alternative to amniotic membrane for emergency management.41 This membrane was designed to support, repair, and substitute connective tissue structures and act as a guide for tissue regeneration. Unlike amniotic membrane, the commercially available bovine pericardium does not need specific authorization to be used as a graft, and it is a completely inert material submitted to a process of purification, deantigenation, dehydration, and sterilization, resulting in an acellular tissue free of

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Figure 29-8. (A) A neurotrophic corneal ulcer with a high risk of perforation. (B) Application of a Tutopatch on the ulcer and partial suture. (C) Placement of an E-PRP clot under the collagen membrane. (D) The same patient 1 month postoperatively.

antigens, pathogens, prions, and any other noncollagen protein. Moreover, there are no interdonor variations because it has been observed with amniotic membrane.42 The bovine pericardium patch used was the Tutopatch (Tutogen Medical GmbH). The use of the Tutopatch has been described for the closure of ventricular septal defects in cardiovascular surgery,43 for dural substitution in various neurosurgical procedures,44 and for orbital fracture repair in ophthalmology, in cases in which the floor fracture can be repositioned to obtain an orbital floor with a smooth surface.45 The wrap of hydroxyapatite implants with the Tutopatch has been suggested as a safe alternative in patients who undergo enucleation for uveal melanoma, with a low rate of complications and a decreased surgical time compared with the wrap with autologous tissue that needs to be harvested.46 In glaucoma surgery, a double layer of the Tutopatch has been suggested to be useful for the implantation of an Ahmed valve in a patient with anterior necrotizing scleritis.41 Our pilot study included 6 patients with different types of corneal perforations caused by a chronic corneal ulcerative disorder.41 Perforation size ranged from 0.5 to 1.5 mm. There were 3 cases of ocular cicatricial pemphigoid, 2 neurotrophic ulcers, and 1 corneal decompensation. None of them demonstrated signs of active infection at the time of surgery. In all cases, surgery was performed under retrobulbar anesthesia using a maximum of 4 mL. The eyelids were opened with an eyelid speculum, and the epithelium was debrided with a sponge 1.0 to 1.5 mm from the perforation. The pericardium patch membrane was then moistened with an antibiotic solution with 1% cefuroxime until it became a flexible membrane. The pericardium membrane was then trimmed to conform to the shape of the eye. A 10-0 nylon running suture was used to suture the Tutopatch to the 180 degree inferior conjunctiva (Figure 29-8). Solid PRP clots were then placed onto the corneal perforation and the epithelial debrided area underneath the collagenous membrane. Additional stitches were used to fixate the membrane to the remainder of the conjunctiva. At the end of the procedure, a temporal partial tarsorrhaphy was performed to allow observation of the central cornea with the slit lamp. In all cases, a firm, nonhypotonic ocular globe was assessed by digital examination. No evidence of infection or inflammation was detected in any case. No patient reported pain, discomfort, or other symptoms during the postoperative period. Between 2 and 3 weeks postoperatively, the temporal tarsorrhaphy was opened in all patients, and the ocular surface was inspected. In all cases, the corneal perforation was sealed with no evidence of leakage, even when moderate pressure was applied to the globe. No relapses of the ulcerative corneal condition or perforation occurred in 5 patients before the definitive corneal grafting surgery. Only one patient with severe ocular cicatricial pemphigoid and a long history of limbal stem cell deficiency with 2 previous limbal stem cell transplantations experienced a relapse, and a penetrating keratoplasty was performed 1 month after the Tutopatch procedure. In summary, both bovine pericardium and E-PRP clots can be successfully combined for the management of all perforations to take advantage of the effect of E-PRP growth factors and the tectonic properties of the Tutopatch. This technique has a low biologic risk and is an accessible and biologically active solution for the urgent management of perforated corneal ulcers.

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Figure 29-9. Photograph of 2 pieces of fibrin membrane immediately after preparation.

Solid Eye Platelet-Rich Plasma Associated With Autologous Fibrin Membrane Corneal perforation constitutes a major ophthalmic emergency necessitating surgical intervention because of the severity and major consequences, such as infection, severe anatomic distortion of the anterior segment of the eye, retinal detachment, phthisis bulbi, and total blindness.47 These perforations are the result of trauma and ulcerative diseases of different conditions. Perforation can be managed with the use of sealants such as cyanoacrylate48 or with different types of patches, such as autologous conjunctival flaps49 or, more commonly, multilayer amniotic membrane transplants.50 Corneal grafting is usually delayed as much as possible to improve the clinical condition and therefore surgical success.51 Moreover, in many cases there may not be corneal tissue readily available. Amniotic membrane transplants are considered to be a preferred option to treat corneal perforations, especially if the size of the perforation is large for ocular adhesives like cyanoacrylate. However, amniotic membrane is an uneven biological tissue with different properties and efficacy depending on the method of processing and preservation.42 It may harbor major biological hazards, such as the presence of viral contaminants and prions,50 and in some countries it needs specific authorization to be used as a grafting tissue. For all of these reasons, we developed a 100% autologous fibrin patch that can be easily handled due to its consistency and thickness (Figure 29-9) and can be used with an E-PRP clot as we have done with amniotic membrane15 or the Tutopatch.41 Fibrin (also called Factor Ia) is a fibrous, nonglobular protein involved in the clotting of blood. It is formed from fibrinogen by the protease thrombin and is then polymerized to make a mesh that forms a hemostatic plug or clot, in conjunction with platelets, over a wound site. The fibrin strands of the patch can bind simultaneously to the clot and the stromal collagen fibers of the cornea, thus contributing to sealing the defect. The fibrin patch and platelet clot gradually disappear over the wound, constituting an autologous, physiologically and biologically active solution for corneal perforation. Preparation of the autologous fibrin membrane requires an appropriate glass beaker previously sterilized. Working inside the laminar flow hood, 5 mL of platelet-poor plasma is placed in the beaker together with 500 μL of 10% calcium chloride and 1 mL of previously prepared autologous thrombin. Autologous thrombin is obtained by activation of 3 mL of E-PRP with 300 μL of 10% calcium chloride and incubation at 37°C for 30 minutes. After the contents are mixed carefully, the beaker is incubated at 37°C for 1 hour. During this time, the plasma fibrinogen, which is soluble, converts into fibrin, which is insoluble and viscous. After the incubation period, the fibrin membrane obtained is circular, with a diameter between 18 and 22 mm and a thickness of approximately 1 mm. With this shape and size, the fibrin membrane is perfectly manageable and suitable for applying to the damaged ocular surface. Combined autologous fibrin membrane and E-PRP clots have been used with success in our clinic.47 We included 11 patients with central corneal perforations caused by a chronic corneal

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Figure 29-10. (A) A large central corneal perforation. (B) The fibrin membrane is extended over the perforated cornea and sutured to the inferior conjunctiva. (C) The E-PRP clot is placed underneath the fibrin membrane. (D) The upper portion of the membrane is sutured to the conjunctiva.

Figure 29-11. (A) A corneal perforation before treatment. (B) The same eye 1 month after the combined use of an E-PRP clot and autologous fibrin membrane.

ulcerative disorder.47 The size of the perforations ranged from 1.0 to 2.0 mm. In 3 patients, the perforation was partially blocked by intraocular tissue, particularly the iris. No patient demonstrated signs of active infection at the time of surgery. In all cases, surgery was performed under a maximum of 4 mL of retrobulbar anesthesia. The eyelids were opened with an eyelid speculum, and the epithelium was debrided with a sponge 1.0 to 1.5 mm from the perforation (Figure 29-10). The fibrin membrane was then dried on absorbent sterile paper until it appeared to be a solid, fibrous structure. A 10-0 nylon running suture was used to sew the fibrin membrane to the 180 degree inferior conjunctiva. Solid PRP clots were then placed onto the corneal perforation and the epithelial debrided area underneath the fibrin membrane. Additional stitches were used to fixate the fibrin membrane to the remainder of the conjunctiva. The fibrin and E-PRP clots were placed in the same manner when there was iris or other intraocular tissue blocking the perforation. At the end of the procedure, a temporal partial tarsorrhaphy was performed to allow observation of the central cornea with the slit lamp. In all cases, the corneal perforation was sealed. The fibrin membrane was present on the corneal surface for the first 3 to 5 days and then gradually disappeared. No evidence of infection or inflammation was detected in any patient. Finger pressure confirmed the presence of acceptable levels of ocular tonus in all patients from postoperative day 2. No patient reported pain, discomfort, or other symptoms during the postoperative period. After 7 days, the temporal tarsorrhaphy was removed from all patients, and the ocular surface was inspected. In all cases, the corneal perforation was sealed with no evidence of leakage, even when moderate pressure was applied to the globe (Figure 29-11). No relapses of the ulcerative corneal condition or perforation occurred in any patient.

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Our findings suggest that the combined use of autologous fibrin membrane and E-PRP clots is a safe and effective alternative for the closure of corneal perforations. The obvious advantage of this technique is the use of autologous material for surgery. We believe that with specialized technicians and resources, the preparation of E-PRP and autologous fibrin membrane is possible in most tertiary hospitals.

Conclusion E-PRP is a reliable and effective therapeutic tool to enhance wound healing in ocular surface disease, ocular surface reconstruction procedures, and ocular perforations. E-PRP provides a high concentration of essential growth factors and cell adhesion molecules by concentrating platelets in a small volume of plasma. These growth factors and cell adhesion molecules play a major role in wound healing and enhance the physiological process at the site of the injury/surgery. Different materials are used to maintain the solid clot attached to the site where treatment is necessary. Although amniotic membrane could be used for this purpose, other materials such as bovine pericardium or autologous fibrin membrane are at least as effective with fewer interdonor variations, no biological hazards, and no need for specific authorization to be used as a graft.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

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Financial Disclosures

Dr. Ahmed Abdou has not disclosed any relevant financial relationships. Dr. Natalie A. Afshari has no financial or proprietary interest in the materials presented herein. Dr. Amar Agarwal has no financial or proprietary interest in the materials presented herein. Ashvin Agarwal has no financial or proprietary interest in the materials presented herein. Dr. Athiya Agarwal has no financial or proprietary interest in the materials presented herein. Dr. Elena Albè has not disclosed any relevant financial relationships. Dr. Jorge L. Alió has no financial or proprietary interest in the materials presented herein. Dr. Francisco Arnalich has no financial or proprietary interest in the materials presented herein. Dr. Alexander Bachernegg has no financial or proprietary interest in the materials presented herein. Dr. Perry S. Binder is currently the Medical Monitor for AcuFocus, Inc. He was a previous Medical Monitor for Abbott Medical Optics, Inc. Dr. Massimo Busin has not disclosed any relevant financial relationships. Dr. Alan N. Carlson has not disclosed any relevant financial relationships. Dr. Alejandro Cerda has no financial or proprietary interest in the materials presented herein. Dr. Roy S. Chuck has no financial or proprietary interest in the materials presented herein. Dr. Paolo Colliardo has not disclosed any relevant financial relationships. Dr. Robert A. Copeland Jr has not disclosed any relevant financial relationships. - 317 -

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Financial Disclosures

Dr. H. Burkhard Dick is consultant and advisor for Abbott Medical Optics Inc, a consultant for Aquesys, Bausch and Lomb, Ocular Surgery News, Acufocus, Domilens and Optical Express, an equity owner in Calhoun Vision Inc, owns patents in Morcher GmbH, owns patents in Oculus Inc, is a consultant and employee of Calhoun Vision, and receives grant support from Novartis, PowerVision, Allergan, and Ophtec. Dr. Harminder S. Dua has no financial or proprietary interest in the materials presented herein. Dr. Giancarlo Falcinelli has not disclosed any relevant financial relationships. Dr. Giovanni Falcinelli has not disclosed any relevant financial relationships. Dr. Fernando Faria-Correia has no financial or proprietary interest in the materials presented herein. Dr. I. Howard Fine has no financial or proprietary interest in the materials presented herein. Dr. Andrea Gabrielli has not disclosed any relevant financial relationships. Sunil Ganekal has not disclosed any relevant financial relationships. Dr. Ronald D. Gerste has not disclosed any relevant financial relationships. Dr. Ian Gorovoy has no financial or proprietary interest in the materials presented herein. Dr. Günther Grabner has no financial or proprietary interest in the materials presented herein. Dr. Aaishwariya Gulani has no financial or proprietary interest in the materials presented herein. Dr. Arun C. Gulani has no financial or proprietary interest in the materials presented herein. Dr. Richard S. Hoffman has no financial or proprietary interest in the materials presented herein. Dr. Susan Huang has no financial or proprietary interest in the materials presented herein. Dr. Soosan Jacob has no financial or proprietary interest in the materials presented herein. Dr. Bennie H. Jeng has not disclosed any relevant financial relationships. Dr. Vishal Jhanji has not disclosed any relevant financial relationships. Dr. Thomas John is a consultant and is on the speakers’ bureau for Bausch + Lomb Inc., Allergan Inc., iScience Surgical Corp., and Bio-Tissue, Inc., and he receives small royalties from JaypeeHighlights Medical Publishers, Inc., and ASICO Inc. Saraswathy Karnati has no financial or proprietary interest in the materials presented herein. Dr. Terry Kim has not disclosed any relevant financial relationships. Dr. Dhivya Ashok Kumar has no financial or proprietary interest in the materials presented herein. Rachel Kwok has no financial or proprietary interest in the materials presented herein.

Financial Disclosures

319

Dr. Jimmy K. Lee has no financial or proprietary interest in the materials presented herein. Dr. W. Barry Lee has not disclosed any relevant financial relationships. Alvaro Luque has no financial or proprietary interest in the materials presented herein. Dr. Prafulla K. Maharana has no financial or proprietary interest in the materials presented herein. Dr. Yuri McKee has received lecture honoria in the past from Haag-Streit, is a consultant for Mastel Precision Instruments, and has ownership interest in Interactive Medical Publishing. Priya Narang has no financial or proprietary interest in the materials presented herein. Dr. Francis W. Price, Jr has not disclosed any relevant financial relationships. Dr. Saima M. Qureshi has not disclosed any relevant financial relationships. Alejandra E. Rodriguez has no financial or proprietary interest in the materials presented herein. Dr. Theresa Rückl has not disclosed any relevant financial relationships. Dr. Bishoy Said has no financial or proprietary interest in the materials presented herein. Kaladevi Satish has no financial or proprietary interest in the materials presented herein. Dr. Tim Schultz has not disclosed any relevant financial relationships. Dr. Vincenzo Scorcia has not disclosed any relevant financial relationships. Dr. Namrata Sharma has not disclosed any relevant financial relationships. Dr. Yichieh Shiuey is the inventor of the KeraKlear Artificial Cornea. Dr. Annette Chang Sims has no financial or proprietary interest in the materials presented herein. Dr. Felipe Soria has no financial or proprietary interest in the materials presented herein. Dr. Maurizio Taloni has not disclosed any relevant financial relationships. Dr. Charles L. Thompson has no financial or proprietary interest in the materials presented herein. Dr. Jose M. Vargas has no financial or proprietary interest in the materials presented herein. Dr. Alfredo Vega-Estrada has no financial or proprietary interest in the materials presented herein. Dr. Laura Vickers has not disclosed any relevant financial relationships. Dr. George O. Waring IV is a consultant and on the Medical Advisory Board for AcuFocus.