Management of Retinal Vein Occlusion : Current Concepts [1 ed.] 9781630910259, 9781617116162

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Current Concepts

Hariprasad

Management of Retinal Vein Occlusion Management of retinal venous occlusions (RVO) has changed dramatically in recent years. With an increase in medical information, technological advances, and clinical trials, ophthalmologists need a concise, updated reference. Management of Retinal Vein Occlusion: Current Concepts fills this current need in the market.

• Background: The epidemiology, risk factors, and classification of RVO • History: Seven large clinical trials involving RVO and the pros and cons of earlier treatment modalities • Anti-VEGF Therapies: The rationale and outcomes of large clinical trials • Corticosteroid Therapies: The rationale and outcomes of various steroid treatment modalities • Imaging: Case presentations and emerging technology that highlights the relationship between peripheral ischemia and macular edema • Difficult Cases: Combination therapies, management of recalcitrant cases, and surgical approaches for cases that do not respond to standard management • Future of RVO: A summary overview of the subject and future directions

With an unparalleled list of contributors that are leaders in the retina field, Management of Retinal Vein Occlusion goes beyond the conclusions of clinical trials and delves deeper into practical recommendations for patient management in daily practice. With abundant illustrations, fundus photographs, and concise tables that enhance the written text, Management of Retinal Vein Occlusion: Current Concepts is a valuable resource.

Management of Retinal Vein Occlusion: Current Concepts

In Management of Retinal Vein Occlusion, Dr. Seenu Hariprasad is joined by multiple section editors to provide this easy-to-read and nicely formatted resource, which is divided into organized sections:

Management of Retinal Vein Occlusion Current Concepts

EDITOR | Seenu M. Hariprasad ISBN 978-1-61711-616-2 90000

MEDICAL/Ophthalmology

9

781617

116162

SECTION EDITORS | Sophie J. Bakri | Dean Eliott | Nancy M. Holekamp | Michael S. Ip | Tamer H. Mahmoud | SriniVas R. Sadda

SLACK Incorporated

Editor

Seenu M. Hariprasad, MD Professor of Ophthalmology and Director of Clinical Research Chief, Vitreoretinal Service University of Chicago Department of Ophthalmology and Visual Sciences Chicago, Illinois

Section Editors Sophie J. Bakri, MD ◆ Dean Eliott, MD ◆ Nancy M. Holekamp, MD Michael S. Ip, MD ◆ Tamer H. Mahmoud, MD, PhD ◆ SriniVas R. Sadda, MD

www.Healio.com/books Copyright © 2014 by SLACK Incorporated Cover image of BRVO and peripheral nonperfusion reproduced with permission from Dr. Barb Blodi. 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:

SLACK Incorporated 6900 Grove Road Thorofare, NJ 08086 USA Telephone: 856-848-1000 Fax: 856-848-6091 www.Healio.com/books

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 Management of retinal vein occlusion : current concepts / editor, Seenu M. Hariprasad. p. ; cm. Includes bibliographical references and index. ISBN 978-1-61711-616-2 (hardback) I. Hariprasad, Seenu M., - editor of compilation. [DNLM: 1. Retinal Vein Occlusion--therapy--Handbooks. WW 39] RE551 617.7’35--dc23 2013044794 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: [email protected]

DEDICATION This textbook is a token of my love and admiration for my parents, Mavidi and Raji, and my parents-in-law, Raghunath and Manju. For all their love and support, this work is also dedicated to Jaya, Anya, and Ishani—the best family I could hope for. S.M.H.

CONTENTS Dedication ....................................................................................................................................v About the Editor ........................................................................................................................ ix About the Section Editors...........................................................................................................xi Contributing Authors ................................................................................................................xv Foreword by Harry W. Flynn Jr, MD ................................................................................... xvii Introduction ............................................................................................................................. xix Chapter 1

Retinal Vein Occlusion: Background .................................................................. 1 Kapil G. Kapoor, MD and Sophie J. Bakri, MD

Chapter 2

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance ................................................................................................ 19 Yewlin E. Chee, MD and Dean Eliott, MD

Chapter 3

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion ............................................................................................................... 33 Nancy M. Holekamp, MD and Shaun T. Ittiara, MD

Chapter 4

Corticosteroid Therapies in the Management of Macular Edema Secondary to Retinal Vein Occlusion ................................................................................... 63 Amol Kulkarni, MD and Michael S. Ip, MD

Chapter 5

Role of Imaging in the Management of Macular Edema Secondary to Retinal Vein Occlusion........................................................................................ 79 Pearse A. Keane, MD, MSc, FRCOphth, MRCSI; Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth); Michael A. Singer, MD; and SriniVas R. Sadda, MD

Chapter 6

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches .......................................................................................................... 121 Eric W. Schneider, MD and Tamer H. Mahmoud, MD, PhD

Financial Disclosures...............................................................................................................159

ABOUT THE EDITOR Seenu M. Hariprasad, MD is a Professor at the University of Chicago, Department of Ophthalmology and Visual Sciences, Pritzker School of Medicine in Illinois, where he serves as Chief of the Vitreoretinal Service. After receiving his Bachelor of Arts degree from Cornell University in Ithaca, NY and graduating with Distinction in Neuroscience, Dr. Hariprasad went on to receive his Medical Degree from the University of Pennsylvania in Philadelphia, where he was elected into Alpha Omega Alpha. He completed both his transitional internship and ophthalmology residency at Baylor College of Medicine’s Cullen Eye Institute in Houston, TX, where he received numerous research awards. Dr. Hariprasad then spent 2 years at Washington University’s Barnes Retina Institute in St. Louis, MO, where he completed a Fellowship in the Diseases and Surgery of the Retina, Macula, and Vitreous. Dr. Hariprasad is actively involved in clinical research, having been principal investigator or sub-investigator in nearly 50 national clinical trials evaluating new drugs, devices, and surgical innovations for age-related macular degeneration, retinal vascular occlusion, uveitis, endophthalmitis, and diabetic eye disease. His efforts in research have resulted in more than 140 peer-reviewed publications, meeting abstracts, and textbook chapters. He currently holds the position of Director of Ophthalmic Clinical Research at the University of Chicago. In addition to serving on the Editorial Board for the American Journal of Ophthalmology, Dr. Hariprasad is also a scientific referee for 12 major ophthalmology journals. Additionally, he serves on the Editorial Board for OSLI Retina, Retinal Physician, and Ocular Surgery News. He is also co-founder of the CONNECT Network, a collaborative association of academic vitreoretinal specialists dedicated to furthering the vitreoretinal subspecialty through various research and educational endeavors. Dr. Hariprasad has presented a vast number of lectures at scientific meetings, as well as guest lectureships both nationally and internationally. He has trained numerous residents and currently is Director of the Surgical Retina Fellowship Program at the University of Chicago. Dr. Hariprasad is board certified by the American Board of Ophthalmology and is a member of the American Medical Association, American Academy of Ophthalmology, Macula Society, Retina Society, American Society of Retinal Specialists, Association for Research in Vision and Ophthalmology, Club Vit, and the Chicago Ophthalmological Society. From 2007 to present, the Consumer Research Council of America has selected him as one of “America’s Top Ophthalmologists.” Becker’s ASC Review has named him as one of “135 Leading Ophthalmologists in America,” and he is listed as one of Castle Connolly/US News & World Report “America’s Top Doctors.” In 2014, he was listed in the Chicago Magazine Biennial List of Outstanding Doctors. Dr. Hariprasad has received Honor Achievement Awards from both the American Academy of Ophthalmology and the American Society of Retina Specialists.

ABOUT THE SECTION EDITORS Sophie J. Bakri, MD is Professor of Ophthalmology at the Mayo Clinic in Rochester, MN. Dr. Bakri completed a vitreoretinal fellowship at the Cleveland Clinic Foundation and her residency at Albany Medical College in New York after graduating from the University of Nottingham Medical School in England. She is board certified by the American Board of Ophthalmology. Dr. Bakri is a specialist in diseases and surgery of the retina and vitreous, in particular, age-related macular degeneration, diabetic retinopathy, and repair of complex retinal detachments. She undertakes both clinical and translational research in the pathogenesis and treatment of retinal diseases. She is active in teaching residents and fellows and is Director of the Vitreoretinal Surgery Fellowship at the Mayo Clinic. Dr. Bakri has authored over 110 peer-reviewed papers and 17 book chapters on retinal diseases. She is a principal investigator on numerous multicenter clinical trials on novel drugs for retinal disease. She serves on the editorial board of the American Journal of Ophthalmology, Retina, Seminars in Ophthalmology, and Clinical and Surgical Ophthalmology. She is an active participant in several ophthalmic societies and has received an Achievement Award from the American Academy of Ophthalmology, has received an Honor Award from the American Society of Retina Specialists, and is listed in Becker’s “135 Leading Ophthalmologists in America.”

Dean Eliott, MD is Associate Director of the Retina Service and the Stelios Evangelos Gragoudas Associate Professor of Ophthalmology at the Massachusetts Eye and Ear Infirmary and Harvard Medical School, both in Boston, MA. Dr. Eliott completed his residency at the Wilmer Eye Institute of Johns Hopkins Hospital in Baltimore, MD, and he received his vitreoretinal fellowship training at the Duke Eye Center of Duke University Medical Center in Durham, NC. Dr. Eliott has been a principal investigator for many clinical trials, and he has over 100 publications in the major ophthalmic journals and textbooks. Dr. Eliott is Co-Director of the Retina Fellowship at Massachusetts Eye and Ear Infirmary and he has received several teaching awards.

Nancy M. Holekamp, MD is a professor of Clinical Ophthalmology and Visual Sciences at the Washington University School of Medicine in St. Louis, MO. She is also Director of Retina Services at the Pepose Vision Institute in St. Louis. Dr. Holekamp received her undergraduate Bachelor of Arts degree from Wellesley College in Massachusetts Summa cum Laude. She received her Medical Degree from the Johns Hopkins School of Medicine in Baltimore, MD. Dr. Holekamp completed an internship in internal medicine and a residency in ophthalmology at the Washington University School of Medicine. Her fellowship training in vitreoretinal surgery was with the Retina Consultants in St. Louis. Dr. Holekamp is actively involved in clinical research, having been principal investigator or sub-investigator in 19 national clinical trials dealing with age-related macular degeneration, retinal vascular occlusion, and diabetic retinopathy. Her efforts in research have resulted in 64 peer-reviewed publications, 21 book chapters, and more than 100 speaking

xii  About the Section Editors

invitations both nationally and internationally. She is a member of the major subspecialty societies, including the Retina Society and the Macula Society. She acts as a reviewer for all of the major ophthalmology journals and as a consultant to several ophthalmic pharmaceutical companies. After 6 years on the American Academy of Ophthalmology Ethics Committee, she has developed an intereste in medical ethics.

Michael S. Ip, MD is Associate Professor, Department of Ophthalmology and Visual Sciences, and Co-Director of the Fundus Photograph Reading Center at the University of Wisconsin Medical School in Madison. He serves as Director of the Retina Service at the William S. Middleton Memorial Veterans Hospital in Madison. He also has an active clinical practice as a vitreoretinal surgeon that concentrates on the surgical management of retinal detachment and other conditions, as well as the treatment of age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and other conditions. Dr. Ip received his medical degree from New York University and completed his internship at Lenox Hill Hospital, both in New York, NY. He completed his residency at the University of Pittsburgh School of Medicine in Pennsylvania followed by a fellowship in vitreoretinal surgery at New England Eye Center, Tufts University, in Boston, MA. Dr. Ip’s research focuses on the design and conduct of clinical trials investigating treatments for diabetic retinopathy, AMD, and retinal venous occlusive disease. As Co-Director of the Fundus Photograph Reading Center, he has assisted with the collection, analysis, and dissemination of important secondary outcomes in ophthalmic clinical trials, such as the Eli Lilly trials for protein kinase C inhibitor for diabetic macular edema (MBBK), transpupillary thermotherapy of occult subfoveal choroidal neovascular membranes in patients with age-related macular degeneration trial (TTT4CNV), the Control Delivery Systems trials evaluating intravitreal fluocinolone implants, and the Bausch + Lomb trials investigating fluocinolone acetonide intravitreal implants. As a clinical site investigator, he has served as the principal investigator on over 15 clinical trials. He has also served as the protocol chair for the clinical trial conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema, as well as the National Principal Investigator for the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study. Dr. Ip received an award from the National Eye Institute, National Institutes of Health in 2003 to conduct the SCORE Study. He has authored more than 60 peer-reviewed articles, 20 book chapters, and more than 60 abstracts on these topics, as well as given many national and international presentations. Dr. Ip is also a reviewer for the following journals: Ophthalmic Surgery and Lasers, Investigative Ophthalmology and Visual Science, American Journal of Ophthalmology, Retina, and Ophthalmology. He is currently an associate editor for Archives of Ophthalmology. In addition, he serves on a variety of committees in the American Academy of Ophthalmology, including the Ophthalmic Technology Assessment Committee and the Curriculum Development Committee (COMPASS), and he is a member of the Food and Drug Administration (FDA) Panel on Orphan Drug Development. Dr. Ip has been recognized with several honors, including the Senior Achievement Award and the Leadership Development Program Award, both from the American Academy of Ophthalmology.

About the Section Editors  xiii

Tamer H. Mahmoud, MD, PhD graduated Valedictorian from Ain Shams University Medical School in Egypt. He is a member of the American Academy of Ophthalmology, the Association of Research in Vision and Ophthalmology (ARVO), the American Society of Retina Specialists, the Retina Society, and the United States Masters Swimming Association. Dr. Mahmoud is a reviewer for many ophthalmology journals and a principal investigator on many clinical trials sponsored by the industry and the National Eye Institute. He has been invited as a guest speaker at many lectures, besides being a consultant to the FDA. Dr. Mahmoud is certified by the American Board of Ophthalmology and is licensed in the states of California, Michigan, and North Carolina. He received the Edward K. Isbey Jr, MD Resident Award for “Excellence in Clinical Care, Ethics, and Research” from the Duke University Eye Center in Durham, NC, the Retina Research Foundation/“Joseph M. and Eula C. Lawrence” award from ARVO, the “Senior Honor Award” from the American Society of Retina Specialists, the prestigious Robert A. Machemer research award from the Duke University Eye Center, and the “Distinguished Teacher of the Year Award” from the Kresge Eye Institute in Detroit, MI, and he has been on the list of Best Doctors in America since 2009. He was the program director of the Vitreoretinal Surgery Fellowship at the Kresge Eye Institute before going back to Duke to join the retina faculty when the world renowned Brooks W. McCuen, MD retired. Wayne State University-Kresge Eye Institute established the “Tamer H. Mahmoud, MD endowed fellowship research award” in 2012. This award is bestowed yearly to the fellow presenting the best paper. Dr. Mahmoud is a co-founder of the Arab-African Society of Retina Specialists, co-director of the yearly popular Mid-West Chicagoland retina update conference, and director of the Duke Surgical Rounds Courses launched at national and international conferences in 2013. He serves on the national Therapeutic Safety Committee for monitoring of drugs and devices. Dr. Mahmoud founded the North Carolina Retina Club in 2012 to allow interaction and collaboration between retina specialists in the state of North Carolina.

SriniVas R. Sadda, MD is Professor of Ophthalmology at the University of Southern California (USC) Keck School of Medicine and the Doheny Eye Institute, both in Los Angeles, CA. He is also Director of the Medical Retinal Unit, Ophthalmic Imaging Unit, and Digital Image Reading Center at USC. He received his medical degree from Johns Hopkins University in Baltimore, MD. After an internship at the William Beaumont Hospital in Royal Oak, MI, he returned to Johns Hopkins University and the Wilmer Eye Institute in Baltimore for an ophthalmology residency as well as neuro-ophthalmology and medical retina fellowships. Dr. Sadda’s major research interests include quantitative, automated retinal image analysis; retinal substructure assessments; advanced retinal imaging technologies; genotype-phenotype correlative studies; and vision restoration technologies (eg, stem cells). In pursuit of these interests, Dr. Sadda is or has been the principal investigator on more than 30 trials, including phase III studies of ranibizumab, preservative-free triamcinolone acetonide, and a dexamethasone posterior segment drug delivery system. He has more than 170 publications in peer-reviewed journals and nearly 200 published abstracts. He authored the first edition of the textbook Emerging Technologies in Retinal Disease, as well as 11 book chapters. As an invited lecturer, he has given more than

xiv  About the Section Editors

150 presentations around the country and the world. Dr. Sadda also serves as an editorial board member of Ophthalmic Surgery, Lasers & Imaging, Retina, and Ophthalmology. He is an editor of the 5th edition of the Ryan’s Retina textbook and also serves as the editor for the electronic edition of this text. In addition, he serves as an ad hoc scientific referee for Investigative Ophthalmology and Visual Science, Archives of Ophthalmology, American Journal of Ophthalmology, Experimental Eye Research, and the Center for Scientific Review at the National Institutes of Health. Among Dr. Sadda’s many awards and honors are a Research to Prevent Blindness Physician-Scientist Award, a Senior Honor Award from the American Society of Retina Specialists, an Achievement Award and a Secretariat Award from the American Academy of Ophthalmology, John H. Zumberge Research and Innovation Award, and the Macula Society Young Investigator Award. He has been named to the “Best Doctors of America” list for several consecutive years.

CONTRIBUTING AUTHORS Yewlin E. Chee, MD (Chapter 2) Massachusetts Eye & Ear Infirmary Harvard Medical School Boston, Massachusetts

Amol Kulkarni, MD (Chapter 4) Retina Specialist Davis Duehr Dean Eye Clinic Madison, Wisconsin

Shaun T. Ittiara, MD (Chapter 3) Retinal Vitreal Consultants, Ltd Clinical Associate University of Chicago Chicago, Illinois

Eric W. Schneider, MD (Chapter 6) Vitreoretinal Fellow and Clinical Associate Faculty In-Training Duke University Eye Center Durham, North Carolina

Kapil G. Kapoor, MD (Chapter 1) Department of Ophthalmology Mayo Clinic Rochester, Minnesota

Michael A. Singer, MD (Chapter 5) Medical Center Ophthalmology Associates San Antonio, Texas

Pearse A. Keane, MD, MSc, FRCOphth, MRCSI (Chapter 5) NIHR Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital NHS Foundation Trust UCL Institute of Ophthalmology London, United Kingdom

Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth) (Chapter 5) National Healthcare Group Eye Institute Tan Tock Seng Hospital Fundus Image Reading Center National Healthcare Group Eye Institute Singapore

FOREWORD It is amazing to witness the change in management of retinal venous occlusions (RVO) in recent years. With the burgeoning of medical information, advanced technology, and new clinical trials, the need exists for a concise, up-to-date reference on RVOs using evidence-based medicine. This text, Management of Retinal Vein Occlusion: Current Concepts, meets that need very well. This text includes chapters dedicated to specific subtopics in the field of RVO. The background section includes epidemiology, risk factors, and classification of RVO. This is followed by the history of RVO clinical trials, including the pros and cons of earlier treatment modalities. In the next section on anti-vascular endothelial growth factor (VEGF) therapies, the rationale and outcomes of large clinical trials are reported. Next, the section on corticosteroid therapies provides the rationale and outcomes of various steroid treatment modalities used in clinical trials. Imaging, a vital part of evaluating RVO patients, is covered with case presentations and emerging technology to better understand the relationship between peripheral ischemia and macular edema. Combination therapies, management of recalcitrant cases, and surgical approaches are discussed in the next section, which describes the pros and cons of treatment strategies for these more difficult cases not responding to standard management. In the last section, the subject is summarized, and future directions are discussed. The significance of this text is that it concisely summarizes data from 7 large clinical trials (SCORE x 2, GENEVA, CRUISE, BRAVO, COPERNICUS, and GALILEO), all of which occurred in the past few years. As a matter of historical perspective, earlier clinical trials (CVOS and BVOS) are also included to demonstrate the natural history of untreated eyes and the value of laser photocoagulation. The section editors and chapter authors are leaders in the field of retina and include many principal investigators and project officers from various clinical trials. These retinal specialists go beyond the raw clinical trial data into how to implement these results into daily practice. The editors have covered the spectrum of management—from the background and pathophysiology of RVO through historical RVO clinical trials—and now move forward to contemporary anti-VEGF and corticosteroid studies and more recent techniques in imaging and combination therapies. This text will undoubtedly prove to be a valuable resource for all ophthalmologists, not just retinal specialists. The abundant illustrations, fundus photographs, concise tables, and summary boxes highlight and enhance its readability. Going beyond the simple conclusions of the various clinical trials, the authors provide practical recommendations for patient management in everyday practice. Although the management of RVO continues to change, I believe this text will stand the test of time as a frequently referenced, concise compendium on this topic. Harry W. Flynn Jr, MD Professor of Ophthalmology The J. Donald M. Gass Distinguished Chair in Ophthalmology Bascom Palmer Eye Institute Miami, Florida

INTRODUCTION The history of retinal vein occlusion (RVO) is a captivating saga of how knowledge of a disease develops. It is also a story of the relentless ingenuity of our colleagues to discover therapies for a disease, oftentimes thinking outside the box to help our patients despite numerous failed or suboptimal interventions. The story of RVO also demonstrates not only the community impetus for starting large, multicenter clinical trials, but also how the recent collaboration between clinicians and industry can ultimately help patients by developing therapies at lightning speed. Retinal vein obstruction was initially described as retinal apoplexy by Liebreich1 in 1855, followed by Leber’s2 description of this clinical entity as hemorrhagic retinitis in 1877. Soon after, in 1878, von Michel3 documented through microscopic analysis that this clinical entity was due to thrombosis of the trunk of the vena centralis retinae. The entire knowledge of RVO at the time was summarized in only 2 paragraphs in Nettleship’s4 ophthalmology textbook, Diseases of the Eye, in 1890.

It is fascinating that there was no reference to management in 1890; instead, the text focused on description of the disease. Over the next 35 years, the role of arteriosclerosis5 and the vulnerability of arteriovenous crossings6 advanced thinking in RVO. However, still no therapies existed. In the first chapter of Management of Retinal Vein Occlusions: Current Concepts, Drs. Kapil G. Kapoor and Sophie J. Bakri provide an overview of the pathogenesis of RVO.

xx  Introduction

It took more than 80 years from the initial descriptions of RVO for the first therapy to be suggested in the literature. Before the introduction of heparin in 1938, no therapy for RVO existed.7 Over the next 75 years, the community worked relentlessly to develop therapies to combat neovascularization and macular edema resulting from RVO. Although some of the therapies investigated would still be reasonable today, others go far outside the standard of care in 2014. Over the past 75 years, considered therapies included anticoagulation,8 panretinal and focal laser photocoagulation,9-12 vitrectomy (and associated procedures),13 laser anastomosis,14 optic nerve sheath decompression,15 hemodilution,16 intravitreal/intravascular thrombolysis,17,18 radial optic neurotomy,19 intraocular steroids,20-22 and intravitreal anti-vascular endothelial growth factor (VEGF) therapy.23-26 In Chapter 6 of this textbook, Drs. Eric W. Schneider and Tamer H. Mahmoud discuss details of many of these therapies. What is the impetus for performing large randomized, prospective clinical trials? This can be revealed by analyzing the discussions among retina specialists in the years preceding the Branch Vein Occlusion Study (BVOS)9,10 and Central Vein Occlusion Study (CVOS)11,12 of the 1980s and early 1990s. For instance, in 1971, Krill et al27 proposed that the use of laser to treat complications from branch RVO (BRVO) yielded results that were “encouraging and should stimulate further investigation of this mode of treatment.”27 However, a few years later, Wetzig28 stated, “I believe the use of photocoagulation in the proposed manner is not of obvious major benefit and the findings are inconclusive.”28 This back-and-forth discussion between retina specialists is one of numerous examples in the literature that likely spurred the undertaking of the 2 relatively large prospective BVOS and CVOS clinical trials. At the time, results from these 2 studies set the standard of care for managing the complications of RVO with the use of retina laser photocoagulation. Drs. Yewlin E. Chee and Dean Eliott will discuss the BVOS and CVOS in much greater depth in Chapter 2. We have come a long way in the management of the complications resulting from RVO, especially in the past 5 years. The outcomes are better than they have ever been, and the current treatments carry less morbidity than those that have been described in the past. What are some reasons that this landscape has evolved so rapidly, with recent unprecedented outcomes? First, advancements in laser technology have revolutionized not only management of RVO, but also management of other retinal diseases. For instance, in 1979, Wetzig 28 described the method in which laser therapy was used: “Two photocoagulators were used for treatment, the xenon photocoagulators and the argon laser photocoagulators… When the xenon photocoagulator was used, diazepam (Valium) was administered slowly intravenously, until the patient had a change in mental sensorium, usually 5 to 10 mg. Following this, 3 mL of 2% lidocaine (Xylocaine) was injected retrobulbarly.”28 This involved procedure with 2 different lasers, sedating a patient intravenously, and performing a retrobulbar block, is thankfully rarely necessary when performing laser today. Second, advances in imaging technology, especially optical coherence tomography (OCT), have revolutionized our management of macular edema secondary to RVO. It is hard to believe that the landmark BVOS and CVOS were performed before the availability of this technology. Imaging technologies used in the management of RVO—past, present, and future—will be reviewed extensively in Chapter 5 by Drs. Pearse A. Keane, Colin S. Tan, Michael A. Singer, and SriniVas R. Sadda.

Introduction  xxi

Third, the timing of intervention has changed, contributing to more successful outcomes than any time in the past. In 1974, Michels and Gass29 described the natural course of BRVO. They recommended that treatment for BRVO be withheld for at least 1 year. As we know today, subgroup analysis of modern-day clinical trials such as GENEVA, 20 CRUISE,23 BRAVO,24 COPERNICUS,25 and GALILEO26 all show us the same thing: early treatment of macular edema yields superior outcomes. Of course, in 1974, Michaels and Gass29 knew that retina laser was “destructive,” so their recommendations were sensible at the time. However, given the recent availability of intravitreal therapy and data from latest clinical trials, we must rethink the traditional dogma that treatment for RVO should routinely begin with a period of observation. Finally, collaboration with industry has moved the development of pharmacotherapies at a lightning speed. For instance, prior to 2009, there was no US Food and Drug Administration (FDA)-approved pharmacotherapy to treat macular edema secondary to RVO. However, in the past 5 years, there are now 3 FDA-approved therapies for this condition. Industry has helped provide our community with extensive funding to allow such therapies to exist and to help us navigate the FDA approval process. These therapies will be detailed by Drs. Nancy M. Holekamp and Shaun T. Ittiara (anti-VEGF) in Chapter 3 and Drs. Amol Kulkarni and Michael S. Ip (corticosteroids) in Chapter 4. Serving as editor of this textbook has allowed me a glimpse into the thought processes of some of the brightest minds researching RVO over the past 150 years. Despite the accelerating wealth of information being discovered on RVO, the reader will be amazed to know that Management of Retinal Vein Occlusions: Current Concepts is only one of a slim number of textbooks dedicated to this disease. I am very grateful to the numerous individuals who have made this textbook a reality: the section editors and coauthors, our publisher, and, most importantly, our patients. I truly hope that the reader will find Management of Retinal Vein Occlusions: Current Concepts to be a useful and up-to-date repository of knowledge in this landscape. Seenu M. Hariprasad, MD

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

Liebreich R. Apoplexia retinae. Albrect von Grafes Arch Ophthalmol. 1855;1:346-351. Leber T. Die Krankheiten der Netzhaut und des Sehnerven. Graefe-Seamisch Handbuch der Gestamtem Augenheilkunde. Leibzig, Germany: W. Englemann; 1877;531. von Michel J. de spontane Thrombose der Vena centralis des opticus. Graefes Arch Ophthalmol. 1878;24:37-70. Nettleship E. Diseases of the Eye. Philadelphia, PA: Lea Brothers & Co; 1890. Coats G. Thrombosis of the central vein of the retina. R Lond Ophthalmol Hosp Rep. 1904;16:62-81. Moore RF. Retinal vein thrombosis. Br J Ophthalmol. 1924;8(2):1-90. Holmin N, Ploman KG. Thrombosis of central vein of retina treated with heparin. Lancet. 1938;231(5977):664-665. Vannas S, Raitta C. Anticoagulant treatment of retinal venous occlusion. Am J Ophthalmol. 1966;62(5):874-884. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282.

xxii  Introduction 10. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104(1):34-41. 11. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102(10):1434-1444. 12. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):14251433. 13. Liang XL, Chen HY, Huang YS, et al. Pars plana vitrectomy and internal limiting membrane peeling for macular oedema secondary to retinal vein occlusion: a pilot study. Ann Acad Med Singapore. 2007;36(4):293-297. 14. Cohen SM. Vascular remodeling in central retinal vein occlusion following laser-induced chorioretinal anastomosis. JAMA Ophthalmol. 2013;131(3):403-404. 15. Maus M, Sergott RC. Optic nerve sheath decompression: a review. Int Ophthalmol Clin. 1992;32(3):179-196. 16. Glacet-Bernard A, Zourdani A, Milhoub M, Maraqua N, Coscas G, Soubrane G. Effect of isovolemic hemodilution in central retinal vein occlusion. Graefes Arch Clin Exp Opthalmol. 2001;239(12):909-914. 17. Murakami T, Takagi H, Kita M, et al. Intravitreal tissue plasminogen activator to treat macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2006;142(2):318-320. 18. Paques M, Vallée JN, Herbreteau D, et al. Superselective ophthalmic artery fibrinolytic therapy for the treatment of central retinal vein occlusion. British J Ophthalmol. 2000;84(12):1387-1391. 19. Opremcak EM, Bruce RA, Lomeo MD, Ridenour CD, Letson AD, Rehmar AJ. Radial optic neurotomy for central retinal vein occlusion: a retrospective pilot study of 11 consecutive cases. Retina. 2001;21(5):408-415. 20. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118(12):2453-2460. 21. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128. 22. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114. 23. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.e1. 24. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. 25. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032.

Introduction  xxiii 26. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278-284. 27. Krill AE, Archer D, Newell FW. Photocoagulation in complications secondary to branch vein occlusion. Arch Ophthalmol. 1971;85(1):48-60. 28. Wetzig PC. The treatment of acute branch vein occlusion by photocoagulation. Am J Ophthalmol. 1979;87(1):65-73. 29. Michels RG, Gass JD. The natural course of retinal branch vein obstruction. Trans Am Acad Ophthalmol Otolaryngol. 1974;78(2):OP166-177.

1 Retinal Vein Occlusion Background Kapil G. Kapoor, MD and Sophie J. Bakri, MD

In this chapter, we set the background for retinal vein occlusion (RVO) by initially describing the epidemiology and impact of RVO globally, and then delineating the classification scheme of central RVO (CRVO), branch RVO (BRVO), and hemi-RVO (HRVO) and their respective subtypes. We then analyze the risk factors that predispose our patients to develop retinal venous occlusive disease and formulate a plan for routine and individualized workup and assessment. Subsequently, we delve into studying the pathogenesis of macular edema, which is the greatest source of visual loss associated with RVO, and finally into understanding the prognosis and outcomes for our patients who develop RVO.

EPIDEMIOLOGY RVO is one of the most significant causes of visual loss from retinal vascular disease.1 Population-based studies have estimated the prevalence of BRVO to be between 0.6% and 1.1% and that of CRVO to be between 0.1% and 0.4%.2,3 The 15-year cumulative incidence is 1.8% for BRVO and 0.5% for CRVO.4 This translates to an estimated 16.4 million adults affected worldwide by RVOs (13.9 million by BRVO and 2.5 million by CRVO).5 The ageand sex-standardized prevalence for any RVO is 5.20 per 1000 persons (4.42 for BRVO and 0.80 for CRVO).5 This global impact is distributed relatively uniformly across countries, with a slightly higher prevalence of RVO in adults in Japan (2.1%) and Australia (1.6%) and a slightly lower prevalence in adults in Europe (0.8%) and Singapore (0.7%).3,5-7

-1-

Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 1-18). © 2014 SLACK Incorporated.

2  Chapter 1

Figure 1-1. Fundus photograph of the left eye shows BRVO with a prominently visible occlusion site. An inelastic sclerotic arteriole is demonstrated anteriorly in the adventitial sheath, causing posterior compression of the vein. Intraretinal hemorrhages and exudates are associated with the BRVO. Changes consistent with chronicity of the BRVO are evident, including narrowing, sheathing, and sclerosis of the vein distal to the occlusion site.

The prevalence of RVO is similar between men and women. The prevalence of RVO across ethnic groups is symmetric for CRVO but asymmetric for BRVO, with an incidence of 5.98 per 1000 persons in Hispanics, 4.98 in Asians, 3.53 in Blacks, and 2.82 in Whites.5,8 The incidence of a second RVO is estimated at 6.3% to 6.4%, with the risk of any vascular occlusion in the fellow eye estimated at 0.9% per year.1,4,9

PATHOPHYSIOLOGY Branch Retinal Vein Occlusion BRVO occurs secondary to a relative blockage of retinal veins at an arteriovenous crossing. This is believed to be secondary to compression of the retinal vein by a sclerotic arteriole.10 Two other anatomic considerations likely compound the arteriolar sclerosis to ultimately create venous obstruction. First, the arteriovenous crossings are contained within a shared adventitial sheath that is relatively inelastic and harbors varying degrees of fusion of the vascular wall, leading to deformation of the relatively distensible vein when juxtaposed with an inflexible sclerotic arteriole (Figure 1-1).11 A second anatomic consideration is the relative anteroposterior position of the retinal artery and vein within the adventitial sheath. In cases of BRVO, the artery is found anterior to the vein 97% to 99% of the time, whereas in subjects without BRVO, the artery is anterior to the vein only 60% of the time (see Figure 1-1).12 The consistent orientation of crossing retinal vessels in BRVO may facilitate posterior venous compression, leading to mechanical focal venous narrowing.13-15 This results in

Retinal Vein Occlusion: Background  3

local turbulent blood flow, which promotes endothelial vascular damage, platelet adherence and aggregation, intravascular thrombus formation, and ultimate RVO. The role of these anatomic predispositions to BRVO is underscored by studies corroborating that the maximal arteriovenous crossings mirror the retinal quadrants of BRVO frequency.16 As such, the superotemporal quadrant has the most arteriovenous crossings, consistent with BRVOs occurring superotemporally 52.3% of the time, inferotemporally 38.5% of the time, and nasally 9.2% of the time.4 Periphlebitis, or inflammation of the venous wall, has also been implicated in the pathogenesis of BRVO in some cases, likely secondary to foci of inflammatory cells in vessels, associated with venous sheathing, vessel necrosis, thrombosis, and ultimate RVO. This has been implicated in association with toxoplasmosis, Eales disease, Behçet’s syndrome, ocular sarcoidosis, tuberculosis, and collagen vascular disease.17-21

Central Retinal Vein Occlusion CRVO is associated with obstruction of the central retinal vein at or posterior to the lamina cribrosa. Histopathologic study of patients with acute CRVO has confirmed the presence of a thrombus consisting of fibrin and platelets in the central retinal vein.22 The pathophysiology of CRVO may be more obscure and multifactorial than that of BRVO.23,24 The central retinal artery and vein also share a common adventitial sheath but pass through a narrow opening in the lamina cribrosa upon exiting the optic nerve head. Thrombus formation in CRVO may be secondary to similar mechanisms causing BRVO, with arteriosclerosis of the adjacent central retinal artery leading to focal narrowing of the central retinal vein, turbulent venous flow, and ensuing endothelial damage and thrombus formation. Periphlebitis may also play a role in CRVO by similar vessel wall changes implicated in BRVO.21 In some cases, CRVO may be secondary to mechanical pressure from structural changes in the lamina cribrosa, as the lamina cribrosa may further limit space for displacement of the pliable central retinal vein, accentuating its occlusion in this tight compartment, such as in glaucomatous cupping, optic disc drusen, inflammatory swelling of the optic nerve, and orbital disorders.22,25,26 It is alternatively possible that the pathogenesis of CRVO in some cases implicates unique aspects of the relatively high-resistance and low-flow retinal venous circulation, which makes the retinal venous circulation particularly sensitive to hemodynamic disturbances associated with hyperdynamic or sluggish circulation, increases in blood-clotting factors (eg, elevated hematocrit, homocysteine, or fibrinogen; increased blood viscosity; presence of lupus anticoagulant or another antiphospholipid antibody), or deficiency of thrombolytic factors, such as protein C.23,24,27-29

RISK FACTORS Branch Retinal Vein Occlusion The Eye Disease Case-Control Study Group identified the major risk factors for BRVO as systemic hypertension, history of cardiovascular disease, increased body mass index at age 20 years, history of glaucoma, and higher serum alpha-2 globulin (Table 1-1).30

4  Chapter 1

TABLE 1-1. RISK FACTORS FOR BRANCH RETINAL VEIN OCCLUSION (LEVEL III EVIDENCE) SYSTEMIC Systemic hypertension History of cardiovascular disease Increased body mass index at age 20 years Serum alpha-2 globulin Age Diabetes mellitus Peripheral artery disease Cerebrovascular disease Chronic obstructive pulmonary disease Peptic ulcer disease Thyroid disorder Chronic kidney disease Obstructive sleep apnea High total cholesterol High low-density lipoprotein High triglycerides Less education

OCULAR Glaucoma or ocular hypertension Retinal arteriovenous nicking Focal arteriolar narrowing

Subsequent large studies identified additional risk factors for BRVO, including diabetes mellitus, peripheral artery disease, cerebrovascular disease, chronic obstructive pulmonary disease, peptic ulcer disease, thyroid disorder, chronic kidney disease, obstructive sleep apnea, higher total cholesterol, high low-density lipoprotein, high triglycerides, less education, retinal arteriovenous nicking, and focal arteriolar narrowing.31-36 Level IV and level V evidence, which include small case series and case reports, have elicited additional risk factors for BRVO that have yet to be confirmed in larger studies, such as migraine headache, hyperopia, elevated homocysteine, and decreased serum folate.37-40

Central Retinal Vein Occlusion The Eye Disease Case-Control Study Group identified the major risk factors for CRVO as systemic hypertension, diabetes mellitus, and open-angle glaucoma (Table 1-2).41

Retinal Vein Occlusion: Background  5

TABLE 1-2. RISK FACTORS FOR CENTRAL RETINAL VEIN OCCLUSION (LEVEL III EVIDENCE) SYSTEMIC Systemic hypertension Diabetes mellitus Hypercoagulability Age Peptic ulcer disease Thyroid disorder Chronic kidney disease Obstructive sleep apnea High total cholesterol High low-density lipoprotein High triglycerides Blood dyscrasias Paraproteinemias and dysproteinemias Vasculitis Less education

OCULAR Glaucoma or ocular hypertension Retinal arteriovenous nicking Focal arteriolar narrowing

Subsequent large studies identified additional major risk factors for CRVO, including thyroid disorder, peptic ulcer disease, chronic kidney disease, hypercoagulable state, obstructive sleep apnea, high total cholesterol, high low-density lipoprotein, high triglycerides, blood dyscrasias (eg, polycythemia vera, lymphoma, leukemia, and paraproteinemias) and dysproteinemias (eg, multiple myeloma and cryoglobulinemia), vasculitis (eg, from syphilis and sarcoidosis), autoimmune disease (eg, systemic lupus erythematosus), retinal arteriovenous nicking and focal arteriolar narrowing, and less education.32-36,42 Although most studies identified that race was not a major risk factor for CRVO, one large study identified that the Black race conferred a 58% higher risk of CRVO compared with the White race. It also elucidated that diabetes mellitus with end-organ damage was a risk factor for CRVO, whereas uncomplicated diabetes mellitus was not.43 Level IV and level V evidence have elicited additional risk factors for CRVO that have yet to be confirmed in larger studies, such as oral contraceptives,44-46 migraine headache,37 dehydration secondary to strenuous exercise or high-protein diet,47-55 prolonged Valsalva maneuver (eg, as in deep-sea diving or playing a wind instrument),56-58 and interferon beta treatment.59,60

6  Chapter 1

Hemiretinal Vein Occlusion The Eye Disease Case-Control Study Group identified the major risk factors for HRVO as systemic hypertension and diabetes mellitus.61 A subsequent large study identified additional major risk factors for HRVO, including thyroid disorder and peptic ulcer disease.32 Controversy persists regarding the classification of HRVO, and fewer studies have investigated its independent risk factors, variably grouping them as variants of BRVO or CRVO in different studies.

CLASSIFICATION RVOs are anatomically classified into 3 main groups based on the location of venous occlusion. BRVO occurs in one of the distal branches of the retinal venous system (Figure 1-2). CRVO describes an obstructed central retinal vein as it exits the optic nerve at the level of the lamina cribrosa (Figure 1-3). HRVO occurs when the blockage is in a vein that drains either the superior or inferior half of the retina. Hemicentral RVO (HCRVO) is a distinct entity that is sometimes grouped with HRVO. In approximately 20% of patients, a congenital anomaly exists that involves postnatal persistence of both trunks of the central retinal vein. HCRVO involves occlusion of one of these trunks within the substance of the optic nerve before they merge into a single trunk posterior to the lamina cribrosa (Figure 1-4). Evidence supports that HCRVO is a variant of CRVO because of similar sites of occlusion (central retinal vein or its trunk), similar risk factor profiles (particularly glaucoma and ocular hypertension), similar clinical characteristics (both have ischemic and nonischemic subtypes), and similar sites of collaterals (connecting occluded to unoccluded trunk of central retinal vein on optic disc, rather than occurring proximal to the arteriovenous site of occlusion as in BRVO). HCRVOs are uncommon, and in many studies, the distinction between HCRVO and HRVO is not identified or they are grouped together. For instance, for the purpose of the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) trial, all HRVOs were classified as BRVOs.62 Papillophlebitis or optic disc vasculitis likely represents another distinct type of mild CRVO that occurs in patients younger than 50 years. This is characterized by optic disc edema out of proportion to other retinal findings and is thought to be secondary to an inflammatory optic neuritis or vasculitis. Spontaneous improvement is common, but up to 30% of patients may develop ischemic occlusions, signaling a worse prognosis for visual acuity and neovascular complications.63,64 CRVO can be further classified into ischemic or nonischemic subtypes. Distinction between these subtypes can have implications for visual prognosis and risk of ocular neovascularization. Nonischemic CRVO represents 75% to 80% of all CRVOs and is characterized by less than 10 disc diameters of capillary nonperfusion on fluorescein angiography; absence of a relative afferent pupillary defect; visual acuity typically better than 20/200; and ophthalmoscopic examination consisting of dilated and tortuous veins, possible optic disc edema and macular edema, and variable retinal hemorrhages associated with rare, if any, cotton wool spots.1,9

Retinal Vein Occlusion: Background  7

Figure 1-2. (A) Fundus photograph of the left eye shows acute left superotemporal macular BRVO with a wedge of intraretinal hemorrhages and cotton wool spots, with the apex pointed at the site of occlusion. (B) Fluorescein angiogram (early frame 24s) shows blockage from hemorrhages from BRVO. (C) Fluorescein angiogram (late frame 8 min 55s) shows hyperfluorescence from diffuse leakage and no capillary nonperfusion. (D) Optical coherence tomography image shows cystoid macular edema superior to the fovea with minimal subfoveal subretinal fluid.

8  Chapter 1

Figure 1-3. (A) Fundus photograph of the left eye shows a nonischemic CRVO with optic disc edema, few peripapillary cotton wool spots, diffuse intraretinal hemorrhages, and dilated and tortuous veins. (B) Fluorescein angiogram (early frame 20s) shows delayed venous filling and blockage from hemorrhages. (C) Fluorescein angiogram (late frame 9 min) shows late diffuse leakage and no capillary nonperfusion. (D) Optical coherence tomography image shows significant cystoid macular edema.

Retinal Vein Occlusion: Background  9

Figure 1-4. Schematic representation of a 2-trunked central retinal vein in the optic nerve. Length of intraneural duplicate trunk could vary widely. Abbreviations: A, arachnoid; C, choroid; CRA, central retinal artery; CRV, central retinal vein; D, dura; LC, lamina cribrosa; OD, optic disc; ON, optic nerve; PCA, posterior ciliary artery; PR, prelaminar region; R, retina; S, sclera. (Reproduced from Hayreh SS, Zimmerman MB. Hemicentral retinal vein occlusion: natural history of visual outcome. Retina. 2012;32[1]:68-76, with permission of Lippincott Williams & Wilkins.)

Ischemic CRVO accounts for 20% to 25% of all CRVOs and is characterized by greater than 10 disc diameters of capillary nonperfusion on fluorescein angiography; the presence of a relative afferent pupillary defect; visual acuity typically 20/200 or worse; and ophthalmoscopic examination consisting of dilated and tortuous veins, possible optic disc edema and macular edema, and extensive retinal hemorrhages in all 4 quadrants associated with numerous cotton wool spots.1,9 In some cases, the subtype of CRVO cannot be resolved due to masking by significant intraretinal hemorrhages, and this is termed indeterminate CRVO. HCRVO can also be subdivided into ischemic and nonischemic subtypes, with similar prognostic implications.65 BRVO can be categorized as major BRVO or macular BRVO, the latter of which has also been referred to as twig BRVO. Major BRVO typically involves a quarter or more of the retina, whereas macular BRVO involves only a segment of the macular retina. BRVO has also been subdivided in some studies as ischemic (more than 5 disc diameters of capillary nonperfusion) and nonischemic subtypes, but these classifications are not used routinely, and neither of the BRVO classifications are used as routinely as the CRVO classifications, likely due to the impact of their clinical and prognostic implications.65,66

PATHOGENESIS OF MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION Macular edema can develop in up to 100% of patients with RVO at some point in their clinical course and is a significant source of visual loss.67,68 It is characterized by fluid

10  Chapter 1

accumulation in the outer plexiform and inner nuclear layers of the retina that frequently pools into cystic spaces. In chronic stages, this cystoid macular edema can be associated with retinal thinning and fibrosis. Macular edema in RVO has a complex multifactorial pathophysiology. Increased hydrostatic pressure behind the occlusion causes damage to tight junctions of capillary endothelial cells, which deteriorates the integrity of the bloodretinal barrier. This leads to an efflux of vascular fluid and protein, which have a proclivity for macular accumulation and thus visual loss.69 Hypoxia from RVO is associated with upregulation of vascular endothelial growth factor (VEGF) and interleukin 6, both of which contribute to blood-retinal barrier breakdown and increased vascular permeability, compounding macular edema.70 Recent evidence also suggests a cyclic cascade, such that although hypoxia may upregulate VEGF, VEGF contributes to progressive retinal nonperfusion, which further worsens retinal ischemia and potentially macular edema.71 Inflammatory mediators likely play an integral role in this process, as evidenced by typically elevated C-reactive proteins in RVO.72 This perivenular inflammation likely leads to impaired recruitment of macrophages, with increased migration of leukocytes releasing inflammatory cytokines such as intracellular adhesion molecule-1. Intracellular adhesion molecule-1 facilitates leukocyte adherence to the inside of the blood vessel, triggering monocyte chemoattractant protein-1 to promote leukocyte activation and vascular migration. This triggers a cascade of inflammatory mediators that include interleukin 1, tumor necrosis factor alpha, VEGF, and possibly prostaglandins and integrins, all of which compound macular edema.73 RVO may also increase vitreoretinal adhesion, potentially through hypoxia, which can also contribute to macular edema.74 The multifactorial pathophysiology of macular edema in RVO is further supported by the multifaceted treatment approach that has evolved, which will be outlined in Chapter 6.

LABORATORY ASSESSMENTS AND SYSTEMIC WORKUP Little evidence exists to guide or support extensive laboratory assessments or systemic workup in RVO.75 All patients with RVO should have a complete history and physical examination, including a complete ophthalmic examination with gonioscopy (Table 1-3). Fluorescein angiography and optical coherence tomography are routinely performed in RVO evaluation. Expert consensus indicates that systemic workup should be pursued for bilateral RVO, for patients younger than 50 years with no known risk factors for RVO, or for unusual presentations of RVO. This includes a general medical evaluation with medical history and physical examination, including blood pressure evaluation.76 Laboratory studies include complete blood count with differential, chemistry profile, coagulation factors, fasting glucose, hemoglobin A1c, and a fasting lipid profile. In the setting of a medical or family history of thrombotic events, a hypercoagulable workup should be pursued that includes factor V Leiden, homocysteine, anticardiolipin antibody, lupus anticoagulant, protein C, and protein S.77,78 If clinically indicated or supported by the medical history, laboratory evaluation may include venereal disease research laboratory, fluorescent treponemal antibody absorption, cryoglobulins, and serum protein electrophoresis.

Retinal Vein Occlusion: Background  11

TABLE 1-3. WORKUP FOR RETINAL VEIN OCCLUSION ROUTINE Complete history and physical examination Blood pressure evaluation Complete ophthalmic examination Gonioscopy Fluorescein angiography Optical coherence tomography

IF SUGGESTED BY HISTORY/EXAMINATION Complete blood count Chemistry profile Coagulation factors Fasting blood glucose and hemoglobin A1c Lipid profile

IF INDICATED, HYPERCOAGULABLE WORKUP Factor V Leiden Homocysteine Anticardiolipin antibody Lupus anticoagulant Protein C Protein S

PROGNOSIS AND OUTCOMES The prognosis and outcomes for RVO vary widely depending on the classification of RVO, the specific site and degree of occlusion, and the integrity of perfusion.79 In BRVO, patients can range from being asymptomatic from a nasal BRVO to having significant vision loss from macular edema in macular BRVO. Macular edema develops in 15% of BRVO eyes in the first year, but between 18% and 41% of patients may experience visual improvement without intervention, particularly within the first 3 months.80 The natural history without intervention for patients with BRVO-associated macular edema presenting with visual acuity of 20/40 or worse at 3 months is an average visual acuity of 20/70 at 3 years, with 34% retaining visual acuity of 20/40 or better and 23% having visual acuity of 20/200 or worse.81 Overall, 74% of patients with acute BRVO experience at least 2-line improvement in vision within the first 6 months.80 CRVO patients can have variable visual acuity upon diagnosis but typically have lower visual acuity than BRVO patients. The presenting visual acuity is an important prognosticator for final visual acuity outcomes, with a higher risk for lower visual acuity outcomes conferred to ischemic CRVO eyes compared with their nonischemic counterparts. Nonischemic CRVO eyes present with macular edema in 30% of cases, and ischemic

12  Chapter 1

CRVO eyes present with macular edema in 73% of cases.82 The natural history without intervention for patients with CRVO who presented with visual acuity equal to or better than 20/40 is that two-thirds of patients maintain visual acuity in the same range and 10% worsen to visual acuity of less than 20/200.1,9 In patients who present with visual acuity between 20/50 and 20/200, nearly 50% maintain visual acuity in the same range and 33% deteriorate to visual acuity less than 20/200.82 Up to 20% of patients with initial visual acuity less than 20/200 can experience some improvement in vision.8 Up to 34% of eyes with nonischemic CRVO convert to ischemic CRVO over 3 years.82 Reports in the literature conflict on the impact of developing retinochoroidal collaterals on final visual acuity outcomes; however, in the SCORE study, no association was found between the development of collateral vessels and visual acuity outcomes.83,84 In patients with CRVO, increasing age may be associated with worse visual acuity outcomes. This is particularly evident in the subset of young patients (younger than 45 years) developing CRVO, in whom the visual prognosis is markedly better than in those older than 45 years. In one study, 80% of young patients with CRVO presenting with visual acuity of 20/70 or worse had improvement, whereas only 56% of patients older than 45 years had improvement.84 The natural course of HRVO is more challenging to elucidate due to the heterogeneity of its classification in the literature. As stated previously, many studies group HRVO with either CRVO or BRVO, and many do not distinguish between HRVO and HCRVO. The best data are available for patients with the distinct entity of HCRVO. HCRVO occurs inferiorly more than superiorly, and its natural history and visual acuity outcomes are largely contingent on whether the ischemic (15%) or nonischemic (85%) subtype is implicated.85 In one study, visual acuity was better than or equal to 20/60 in 73.7% of patients with nonischemic HCRVO, compared with only 40% in patients with ischemic HCRVO. Overall, patients with nonischemic HCRVO had a more favorable visual prognosis, with only 6% experiencing a deterioration.85 Ocular neovascularization is an important complication of RVO and can occur in the form of neovascularization of the iris (NVI), anterior chamber angle (NVA), or disc (NVD), or neovascularization elsewhere in the retina (NVE; Table 1-4). The overall incidence of ocular neovascularization in BRVO is estimated at 20%, occurring most frequently in the first 3 months.80 In one study, 28.8% of patients with major BRVO developed ocular neovascularization, compared with 0% of patients with macular BRVO.86 NVI and NVA can be associated with neovascular glaucoma (NVG), which can be particularly difficult to treat and may even necessitate enucleation, but it is particularly uncommon in patients with BRVO. The SCORE trial estimated the 36-month incidence of NVI to be 0.3%, NVG to be 2.2%, NVD and NVE to be 5.8%, and preretinal or vitreous hemorrhages to be 3.8% in BRVO.87 NVI and NVA occur with greater frequency in CRVO than in BRVO, and they occur most frequently within the first 6 months.9,87 In the Central Vein Occlusion Study, 16% of patients with CRVO developed NVI or NVA, with 35% occurring in ischemic/indeterminate eyes and 10% occurring in eyes initially classified as nonischemic.9 The SCORE trial estimated the 36-month incidence of NVI to be 3.2%, NVG to be 5.8%, NVD and NVE to be 3.6%, and preretinal or vitreous hemorrhage to be 7.6% in CRVO.87

Retinal Vein Occlusion: Background  13

TABLE 1-4. OCULAR NEOVASCULARIZATION IN RETINAL VEIN OCCLUSION % RVO TYPE

NVI/NVA

NVG

NVD

NVE

PRH/VH

CRVO

3.2 to 16

5.8 to 21

1.1 to 3.6

1.6 to 3.6

7.6

BRVO (major)

0.3 to 1.6

0.8 to 2.2

5.8 to 10.6

5.8 to 20.7

3.8

BRVO (macular)

0

0

0

0

0

HCRVO

3.2

1

9.3

13.4

N/A

HRVO

9

3

11

9

3.8

Abbreviations: N/A, not applicable; PRH, preretinal hemorrhage; VH, vitreous hemorrhage.

Another important complication of RVO is epiretinal membranes (ERM). Chronic macular edema and hypoxia from the occlusion itself may both play a role in the pathogenesis of ERM. Hypoxia can also promote vitreoretinal adhesion, adding complexity to the surgical management of ERM associated with RVO. The development of ERM and foveal pigmentation following chronic macular edema can both adversely affect visual acuity outcomes in RVO, particularly in nonischemic CRVO.84 Two studies have assessed the impact of CRVO and BRVO on vision-related quality of life using the National Eye Institute Visual Function Questionnaire (NEI VFQ-25).88,89 CRVO was found to have a detrimental effect on vision-related quality of life because patients in the study scored significantly lower than controls.88 A subset of individuals with bilateral CRVO had lower scores that were comparable with those in a population with low vision.88 The impact of BRVO appeared to be less than that of CRVO, with significantly higher scores in nearly all subscales when compared with individuals with CRVO.89 Evidence suggests that patients with vision loss due to macular edema following RVO report meaningful reduction in multiple dimensions of health-related quality of life measured by the Short Form 36 and NEI VFQ-25.90 Some studies have suggested a higher prevalence of stroke and cardiovascular disease in patients with RVO compared with age-matched controls.3,91 However, population-based studies and a large systematic review suggest that RVO is not an independent predictor of stroke or myocardial infarction.92-94 Further, data on the impact of RVO on vascular mortality are conflicting. Whereas one study showed a higher rate of mortality from myocardial infarction in patients with RVO, other studies found that RVO does not predict cardiovascular or cerebrovascular mortality.92-94 Despite these discrepancies, these large studies serve as further reminders of the importance of evaluating and managing systemic risk factors in patients with RVO.

ACKNOWLEDGEMENT The authors would like to acknowledge Dr. Andrew J. Barkmeier for his photographic contributions in Figure 1-2A through D.

14  Chapter 1

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14. 15. 16. 17.

18. 19. 20. 21. 22.

Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol. 2006;124(5):726-732. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133-141. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch Ophthalmol. 1996;114(10):1243-1247. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4):513-518. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319. Yasuda M, Kiyohara Y, Arakawa S, et al. Prevalence and systemic risk factors for retinal vein occlusion in a general Japanese population: the Hisayama study. Invest Ophthalmol Vis Sci. 2010;51(6):3205-3209. Lim LL, Cheung N, Wang JJ, et al. Prevalence and risk factors of retinal vein occlusion in an Asian population. Br J Ophthalmol. 2008;92(10):1316-1319. Laouri M, Chen E, Looman M, Gallagher M. The burden of disease of retinal vein occlusion: review of the literature. Eye (Lond). 2011;25(8):981-988. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997;115(4):486-491. Bowers DK, Finkelstein D, Wolff SM, Green WR. Branch retinal vein occlusion. A clinicopathologic case report. Retina. 1987;7(4):252-259. Hamid S, Mirza SA, Shokh I. Etiology and management of branch retinal vein occlusion. World Appl Sci J. 2009;6(1):94-99. Sekimoto M, Hayasaka S, Setogawa T. Type of arteriovenous crossing at site of branch retinal vein occlusion. Jpn J Ophthalmol. 1992;36(2):192-196. Zhao J, Sastry SM, Sperduto RD, Chew EY, Remaley NA. Arteriovenous crossing patterns in branch retinal vein occlusion. The Eye Disease Case-Control Study Group. Ophthalmology. 1993;100(3):423-428. Weinberg D, Dodwell DG, Fern SA. Anatomy of arteriovenous crossings in branch retinal vein occlusion. Am J Ophthalmol. 1990;109(3):298-302. Duker JS, Brown GC. Anterior location of the crossing artery in branch retinal vein obstruction. Arch Ophthalmol. 1989;107(7):998-1000. Weinberg DV, Egan KM, Seddon JM. Asymmetric distribution of arteriovenous crossings in the normal retina. Ophthalmology. 1993;100(1):31-36. Wong R, dell’Omo R, Marino M, Hussein B, Okhravi N, Pavesio CE. Toxoplasma gondii: an atypical presentation of toxoplasma as optic disc swelling and hemispherical retinal vein occlusion treated with intravitreal clindamycin. Int Ophthalmol. 2009;29(3):195-198. Momtchilova M, Pelosse B, Ngoma E, Laroche L. Branch retinal vein occlusion and sarcoidosis in a child: a case report [in French]. J Fr Ophthalmol. 2011;34(4):243-247. Atmaca LS, Batioglu F, Atmaca Sonmez P. A long-term follow-up of Eales’ disease. Ocul Immunol Inflamm. 2002;10(3):213-221. El Fekih L, Khaldi N, Hmaied W, Ksantini I, Mestiri A, Doggi M. Retinal venous occlusion in Behçet disease [in French]. Rev Med Interne. 2007;28(11):742-745. Paovic‫ ׳‬J, Paovic‫ ׳‬P, Vukosavljevic‫ ׳‬M. Clinical and immunological features of retinal vasculitis in systemic diseases. Vojnosanit Pregl. 2009;66(12):961-965. Green WR, Chan CC, Hutchins GM, Terry JM. Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases. Retina. 2005;25(5 Suppl):27-55.

Retinal Vein Occlusion: Background  15 23. Hayreh SS. Retinal vein occlusion. Indian J Ophthalmol. 1994;42(3):109-132. 24. David R, Zangwill L, Badarna M, Yassur Y. Epidemiology of retinal vein occlusion and its association with glaucoma and increased intraocular pressure. Ophthalmologica. 1988;197(2):69-74. 25. Komolafe OO, Ashaye AO. Combined central retinal artery and vein occlusion complicating orbital cellulitis. Niger J Clin Pract. 2008;11(1):74-76. 26. Foroozan R. Combined central retinal artery and vein occlusion from orbital inflammatory pseudotumour. Clin Experiment Ophthalmol. 2004;32(4):435-437. 27. Dhôte R, Bachmeyer C, Horellou MH, Toulon P, Chrisoforov B. Central retinal vein thrombosis associated with resistance to activated protein C. Am J Ophthalmol. 1995;120(3):388-389. 28. Glacet-Bernard A, Chabanel A, Lelong F, Samama MM, Coscas G. Elevated erythrocyte aggregation in patients with central retinal vein occlusion and without conventional risk factors. Ophthalmology. 1994;101(9):1483-1487. 29. Vine AK. Hyperhomocysteinemia: a new risk factor for central retinal vein occlusion. Trans Am Ophthalmol Soc. 2000;98:493-503. 30. Risk factors for branch retinal vein occlusion. The Eye Disease Case-Control Study Group. Am J Ophthalmol. 1993;116(3):286-296. 31. Bertelsen M, Linneberg A, Rosenberg T, et al. Comorbidity in patients with branch retinal vein occlusion: case-control study. BMJ. 2012;345:e7885. 32. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol. 2001;131(1):61-77. 33. Arakawa S, Yasuda M, Nagata M, et al. Nine-year incidence and risk factors for retinal vein occlusion in a general Japanese population: the Hisayama Study. Invest Ophthalmol Vis Sci. 2011;52(8):5905-5909. 34. Lim LL, Cheung N, Wang JJ, et al. Prevalence and risk factors of retinal vein occlusion in an Asian population. Br J Ophthalmol. 2008; 92(10):1316-1319. 35. Cheung N, Klein R, Wang JJ, et al. Traditional and novel cardiovascular risk factors for retinal vein occlusion: the multiethnic study of atherosclerosis. Invest Ophthalmol Vis Sci. 2008;49(10):4297-4302. 36. Chou KT, Huang CC, Tsai DC, et al. Sleep apnea and risk of retinal vein occlusion: a nationwide population-based study of Taiwanese. Am J Ophthalmol. 2012;154(1):200-205. e1. 37. Tilleul J, Glacet-Bernard A, Coscas G, Soburane G, Souied EH. Underlying conditions associated with the occurrence of retinal vein occlusion [in French]. J Fr Ophthalmol. 2011;34(5):318-324. 38. Timmerman EA, de Lavalette VW, van den Brom HJ. Axial length as a risk factor to branch retinal vein occlusion. Retina. 1997;17(3):196-199. 39. Goldstein M, Leibovitch I, Varssano D, Rothkoff L, Feitt N, Loewenstein A. Axial length, refractive error, and keratometry in patients with branch retinal vein occlusion. Eur J Ophthalmol. 2004;14(1):37-39. 40. Weger M, Stanger O, Deutschmann H, et al. Hyperhomocyst(e)inemia, but not methylenetetetrahydrofolate reductase C677T mutation, as a risk factor in branch retinal vein occlusion. Ophthalmology. 2002;109(6):1105-1109. 41. Risk factors for central retinal vein occlusion. The Eye Disease Case-Control Study Group. Arch Ophthalmol. 1996;114(5):545-554. 42. Gutman FA, Evaluation of a patient with central retinal vein occlusion. Ophthalmology. 1983;90(5):481-483. 43. Stern MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology. 2013;120(2):362-370.

16  Chapter 1 44. Güven D, Sayinalp N, Kalayci D, Dündar S, Hasiripi H. Risk factors in central retinal vein occlusion and activated protein C resistance. Eur J Ophthalmol. 1999;9(1):43-48. 45. Thapa R, Paudyal G. Central retinal vein occlusion in young women: rare cases with oral contraceptive pills as a risk factor. Nepal Med Coll J. 2009;11(3):209-211. 46. Kirwan JF, Tsaloumas MD, Vinall H, Prior P, Kritzinger EE, Dodson PM. Sex hormone preparations and retinal vein occlusion. Eye (Lond). 1997;11(Pt 1):53-56. 47. Hedreville M, Connes P, Romana M, et al. Central retinal vein occlusion in a sickle cell trait carrier after a cycling race. Med Sci Sports Exerc. 2009;41(1):14-18. 48. Labriola LT, Friberg TR, Hein A. Marathon runner’s retinopathy. Semin Ophthalmol. 2009;24(6):247-250. 49. Gaudard A, Varlet-Marie E, Monnier JF, et al. Exercise-induced central retinal vein thrombosis: possible involvement of hemorheological disturbances. A case report. Clin Hemorheol Microcirc. 2002;27(2):115-122. 50. Jampol LM, Fleischman JA. Central retinal-vein occlusion five days after a marathon. N Engl J Med. 1981;305(13):764. 51. Disdier P, Harlé, Swiader L, Gambarelli-Mouillac N, Weiller PJ. Retinal vein occlusions in a marathon runner [in French]. Presse Med. 1992;21(12);582. 52. Jacobs DJ, Ahmad F, Pathengay A, Flynn HW Jr. Central retinal vein occlusion after intense exercise; response to intravitreal bevacizumab. Ophthalmic Surg Laser Imaging. 2011;42 Online:e59-e62. 53. Francis PJ, Stanford MR, Graham EM. Dehydration is a risk factor for central retinal vein occlusion in young patients. Acta Ophthalmol Scand. 2003;81(4):415-416. 54. Alghadyan AA. Retinal vein occlusion in Saudi Arabia: possible role of dehydration. Ann Ophthalmol. 1993;25(10):394-398. 55. Quintyn JC. Central retinal vein occlusion caused by high-protein diet [in French]. J Fr Ophthalmol. 2012;35(5):358.e1-2. 56. Merle H, Drault JN, Gerard M, Alliot E, Mehdaoui H, Elisabeth L. Retinal vein occlusion and deep-sea diving [in French]. J Fr Ophthalmol. 1997;20(6):456-460. 57. Sbeity ZH, Mansour AM. Recurrent retinal vein occlusion after playing a wind instrument. Graefes Arch Clin Exp Ophthalmol. 2004;242(5):428-431. 58. Küper KD, De Laey JJ, Herzeel R. Subhyaloid hemorrhage in association with an atypical central retinal vein occlusion [in German]. Klin Monbl Augenheilkd. 2002;219(11):810-812. 59. Jenisch T, Dietrich-Ntoukas T, Renner AB, Helbig H, Gamulescu MA. Combined retinal artery and vein occlusions associated with interferon beta therapy [in German]. Ophthalmologe. 2012;109(1):71-75. 60. Rachitskaya AV, Lee RK, Dubovy SR, Schiff ER. Combined central retinal vein and central retinal artery occlusions and neovascular glaucoma associated with interferon treatment. Eur J Ophthalmol. 2012;22(2):284-287. 61. Sperduto RD, Hiller R, Chew E, et al. Risk factors for hemiretinal vein occlusion: comparison with risk factors for central and branch retinal vein occlusion: the eye disease case-control study. Ophthalmology. 1998;105(5):765-771. 62. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128. 63. Lyle TK, Wybar K. Retinal vasculitis. Br J Ophthalmol. 1961;45(12):778-788. 64. Lonn LI, Hoyt WF. Papillophlebitis: a cause of protracted yet benign optic disc edema. Eye Ear Nose Throat Mon. 1966;45(10):62 passim. 65. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res. 2005;24(4):493-519.

Retinal Vein Occlusion: Background  17 66. Parodi MB, Di Stefano G, Ravalico G. Grid laser treatment for exudative retinal detachment secondary to ischemic branch retinal vein occlusion. Retina. 2008;28(1):97-102. 67. Michels RG, Gass JD. The natural course of retinal branch vein obstruction. Trans Am Acad Ophthalmol Otolaryngol. 1974;78(2):OP166-177. 68. Coscas G, Gaudric A. Natural course of nonaphakic cystoid macular edema. Surv Ophthalmol. 1984;28 Suppl:471-484. 69. Silva RM, Faria de Abreu JR, Cunha-Vaz JG. Blood-retina barrier in acute retinal branch vein occlusion. Graefes Arch Clin Exp Ophthalmol. 1995;233(11):721-726. 70. Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2006;244(3):309-315. 71. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio RG. Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology. 2013;120(4):795-802. 72. Lee HB, Pulido JS, McCannel CA, Buettner H. Role of inflammation in retinal vein occlusion. Can J Ophthalmol. 2007;42(1):131-133. 73. Funk M, Kriechbaum KF, Prager F, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci. 2009;50(3):1025-1032. 74. Saika S, Tanaka T, Miyamoto T, Ohnishi Y. Surgical posterior vitreous detachment combined with gas/air tamponade for treating macular edema associated with branch retinal vein occlusion: retinal tomography and visual outcome. Graefes Arch Clin Exp Ophthalmol. 2001;239(10):729-732. 75. Hayreh SS. Management of central retinal vein occlusion. Ophthalmologica. 2003;217(3):167-188. 76. Lam HD, Lahey JM, Kearney JJ, Ng RR, Lehmer JM, Tanaka SC. Young patients with branch retinal vein occlusion: a review of 60 cases. Retina. 2010;30(9):1520-1523. 77. Rehak M, Rehak J, Müller M, et al. The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis. Thromb Haemost. 2008;99(5):925-929. 78. Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ. Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost. 2005;93(6):1021-1026. 79. Scott IU, VenVeldhuisen PC, Oden NL, et al. SCORE Study report 1: baseline associations between central retinal thickness and visual acuity in patients with retinal vein occlusion. Ophthalmology. 2009;116(3):504-512. 80. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1094-1101.e5. 81. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282. 82. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2010;117(6):1113-1123.e15. 83. Weinberg DV, Wahle AE, Ip MS, et al. SCORE Study Report 12: development of venous collaterals in the Score Study. Retina. 2013;33(2):287-295. 84. Hayreh SS, Podhajsky PA, Zimmerman MB. Natural history of visual outcome in central retinal vein occlusion. Ophthalmology. 2011;118(1):119-133.e1-2. 85. Hayreh SS, Zimmerman MB. Hemicentral retinal vein occlusion: natural history of visual outcome. Retina. 2012;32(1):68-76.

18  Chapter 1 86. Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovascularization with retinal vascular occlusion-III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983;90(5):488-506. 87. Chan CK, Ip MS, Vanveldhuisen PC, et al. SCORE Study report #11: incidences of neovascular events in eyes with retinal vein occlusion. Ophthalmology. 2011;118(7):1364-1372. 88. Deramo VA, Cox TA, Syed AB, Lee PP, Fekrat S. Vision-related quality of life in people with central retinal vein occlusion using the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2003;121(9):1297-1302. 89. Awdeh RM, Elsing SH, Deramo VA, Stinnett S, Lee PP, Fekrat S. Vision-related quality of life in persons with unilateral branch retinal vein occlusion using the 25-item National Eye Institute Visual Function Questionnaire. Br J Ophthalmol. 2010;94(3):319-323. 90. Rentz AM, Kowalski J, Revicki D, et al. Normative comparison of generic and visiontargeted health-related quality of life (HRQL) outcomes in patients with vision loss due to macular edema following retinal vein occlusion. Invest Ophthalmol Vis Sci. 2010;51:e-abstract 4728. 91. Martin SC, Butcher A, Martin N, et al. Cardiovascular risk assessment in patients with retinal vein occlusion. Br J Ophthalmol. 2002;86(7):774-776. 92. Hu CC, Ho JD, Lin HC. Retinal vein occlusion and the risk of acute myocardial infarction: a 3-year follow-up study. Br J Ophthalmol. 2009;93(6):717-720. 93. Mansour AM, Walsh JB, Henkind P. Mortality and morbidity in patients with central retinal vein occlusion. Ophthalmologica. 1992;204(4):199-203. 94. Tsaloumas MD, Kirwan J, Vinall H, et al. Nine year follow-up study of morbidity and mortality in retinal vein occlusion. Eye (Lond). 2000;14(Part 6):821-827.

2

Retinal Vein Occlusion Clinical Trials Historical Perspective and Current Relevance Yewlin E. Chee, MD and Dean Eliott, MD

The Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study (CVOS) represented significant advances in the understanding of the natural history of retinal vein occlusion (RVO) and the role of laser photocoagulation in its treatment. Before these trials, numerous therapies for RVO had been investigated, including anticoagulation with heparin,1 streptokinase fibrinolysis,2-4 hemodilution,5-7 clofibrate,8 and laser photocoagulation.9-27 Despite these varied investigations, no consensus existed regarding whether any of these treatments were beneficial. Multiple studies had described the use of laser photocoagulation to treat RVO with variable success. Some of these studies concluded that photocoagulation was useful to treat macular edema and help prevent neovascularization,9-25 but other investigations reported no treatment benefit.19,26,27 The studies demonstrating treatment efficacy were small. Furthermore, because these studies had no matched controls (and spontaneous improvement in vision after RVO had previously been reported), the benefit of laser photocoagulation remained uncertain.28 A need existed for a prospective, randomized, controlled clinical trial to evaluate the safety and efficacy of laser photocoagulation for treating RVO and associated complications. In the 1980s and early 1990s, the BVOS and CVOS addressed this need.29-31

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Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 19-32). © 2014 SLACK Incorporated.

20  Chapter 2

OVERVIEW OF THE BRANCH VEIN OCCLUSION STUDY Macular Edema Study The BVOS was a multicenter, randomized, controlled clinical trial sponsored by the National Eye Institute designed to evaluate the role of argon laser photocoagulation in treating macular edema and preventing neovascularization and vitreous hemorrhage after branch RVO (BRVO).32,33 Four groups of patients with BRVO were recruited for the study, one of which comprised patients with vision loss from macular edema secondary to BRVO. To meet eligibility criteria for the macular edema group, patients were required to have experienced onset of BRVO within 3 to 18 months prior to enrollment and to have the presence of foveal-involving macular edema on fluorescein angiography and best corrected visual acuity (BCVA) of 20/40 or worse. By excluding patients who had experienced the onset of BRVO less than 3 months prior to enrollment, the group was less likely to include patients who would experience spontaneous recovery of vision. Patients with hemorrhage at the fovea, foveal capillary nonperfusion on fluorescein angiography, or any ocular disease that threatened visual acuity were also excluded from the study. In addition, patients using a systemic anticoagulant that could not be discontinued were excluded. Patients who met eligibility criteria were randomized to treatment with focal grid laser or observation. Treatment consisted of argon laser photocoagulation performed in a grid pattern over the area of capillary leakage identified by a fluorescein angiogram performed within 1 month of treatment. Laser burns of 50 to 100 μm in diameter with 50- to 100-ms exposure time were used to create light- to medium-white burns. Laser treatment could extend to the outer edge of the foveal avascular zone but no closer to the fovea and it was required to remain within the vascular arcades. Patients were evaluated at 4-month intervals. At each patient visit, a certified masked visual acuity examiner measured the BCVA, color fundus photographs were obtained, and an ophthalmic examination was performed. Fluorescein angiography was performed at the time of initial examination, at the first return visit in 4 months, and on an annual basis thereafter. For patients assigned to the laser treatment group, if fluorescein angiography 4 months after grid laser demonstrated persistent foveal edema (and the patient continued to have decreased visual acuity), additional photocoagulation was mandated. A total of 139 eyes (139 patients) were enrolled in the study group, 71 of which were randomized to macular laser treatment. Fifty-three of 69 treated eyes (77%) required only one treatment, whereas the remaining treated eyes met criteria for additional photocoagulation after the initial treatment. Of the 86 eyes with 3 years of follow-up, average visual acuity at 3 years was 20/70 in the untreated group and 20/40 to 20/50 in the treated group. Compared with untreated eyes, eyes that received grid laser treatment were more likely to gain at least 2 lines of vision from baseline (28 eyes [65%] in the treated group vs 13 eyes [37%] in the untreated group). Both untreated and treated eyes were more likely to improve within the first year after the onset of BRVO than in subsequent years. Although there was a trend toward patients with systemic hypertension showing a greater response to laser treatment than patients without hypertension, this was not statistically significant. Given these findings, the study group recommended argon grid laser for patients with macular edema secondary to BRVO and vision loss of 20/40 or worse who met study inclusion criteria (Table 2-1).

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  21

TABLE 2-1. BRANCH VEIN OCCLUSION STUDY MACULAR EDEMA TREATMENT GUIDELINES FOR BRANCH RETINAL VEIN OCCLUSION ●

Visual acuity of 20/40 or worse

●

No spontaneous improvement in 3 months

●

●

●

Macular edema involving central fovea on fluorescein angiography performed within 1 month of treatment No evidence of foveal capillary nonperfusion, foveal hemorrhage, or other cause of decreased visual acuity

If all of the above are true, then treat with focal grid laser to the area of capillary leakage identified on fluorescein angiography ○

●

Focal grid laser: light- to medium-white burns/50- to 100-µm spot size/50- to 100-ms duration. Laser burns should not extend beyond vascular arcades or within foveal avascular zone

Follow up in 4 months after focal laser with repeat fluorescein angiography. If foveal edema persists and visual acuity is still poor, additional treatment to untreated leaking areas may be performed

Neovascularization and Vitreous Hemorrhage Study The BVOS also evaluated the efficacy of argon laser scatter photocoagulation for the prevention of retinal neovascularization and vitreous hemorrhage after BRVO.33 Two groups of eyes were evaluated: recent BRVO without neovascularization and recent BRVO with retinal neovascularization. To be eligible for the former group, patients were required to have experienced onset of BRVO within 3 to 18 months prior to enrollment and to have at least 5 disc diameters of retinal involvement, enough clearing of retinal hemorrhages to allow safe laser photocoagulation treatment, and no other ocular disease that could affect visual acuity. The degree of nonperfusion on fluorescein angiography was evaluated for this group; patients with more than 5 disc diameters of capillary nonperfusion were defined as having a nonperfused BRVO, whereas those with a smaller area of capillary nonperfusion were considered perfused. Patients in the neovascularization group were required to have experienced onset of BRVO within 3 to 18 months prior to enrollment and to have sufficient clearing of retinal hemorrhages to allow safe laser treatment, no ocular disease, and disc and/or retinal neovascularization documented on color fundus photography and fluorescein angiography. A total of 319 eyes (316 patients) were recruited for the group without neovascularization, and 82 eyes (82 patients) were recruited for the group with neovascularization. Patients in each group were randomized to treatment with scatter laser photocoagulation or observation. The treatment consisted of argon laser scatter photocoagulation to the entire involved segment, with medium-white burns 200 to 500 μm in diameter spaced 1 burn-width apart. Laser burns could be no closer than 2 disc diameters from the foveal center. The primary outcome measures were the development of neovascularization and/ or vitreous hemorrhage in the group of patients without preexisting neovascularization

22  Chapter 2

TABLE 2-2. BRANCH VEIN OCCLUSION STUDY RETINAL NEOVASCULARIZATION TREATMENT GUIDELINES FOR BRANCH RETINAL VEIN OCCLUSION ●

●

●

High-quality fluorescein angiography after sufficient clearing of retinal hemorrhage If > 5 disc diameters of nonperfusion, examine every 4 months for development of retinal neovascularization If neovascularization develops, perform scatter laser photocoagulation to the entire involved segment ○

Scatter laser: medium-white burns/200- to 500-µm spot size. Laser burns should be placed no closer than 2 disc diameters from foveal center

and the development of vitreous hemorrhage in the group of patients with neovascularization at baseline. Patients with neovascularization at baseline who were randomized to the observation group were recommended to undergo scatter laser photocoagulation if they developed vitreous hemorrhage. Eyes with retinal neovascularization treated with scatter photocoagulation were significantly less likely to develop vitreous hemorrhage compared with untreated controls (29% of treated eyes vs 61% of control eyes). In eyes without preexisting neovascularization, treatment reduced the risk of developing retinal neovascularization (19 [12%] treated eyes vs 35 [22%] control eyes). However, since many untreated eyes do not progress to neovascularization and prompt treatment of neovascularization with scatter laser photocoagulation is effective in preventing vision loss from vitreous hemorrhage, the study group recommended treatment only after the development of neovascularization.34 Eyes that concomitantly met criteria for enrollment in the macular edema group of the study had a greater probability of developing neovascularization, as were eyes with areas of capillary nonperfusion greater than 5 disc diameters on fluorescein angiography. As a result, the BVOS group recommended careful monitoring of patients with BRVO and large areas of capillary nonperfusion at 4-month intervals to evaluate for the development of retinal neovascularization such that treatment with scatter laser photocoagulation could promptly be initiated at the first sign of neovascularization (Table 2-2).

OVERVIEW OF THE CENTRAL VEIN OCCLUSION STUDY Macular Edema Study The CVOS was a multicenter, randomized, controlled clinical trial sponsored by the National Eye Institute that was designed to provide clinicians with information about the natural course of central RVO (CRVO) and to evaluate the role of focal grid laser photocoagulation and panretinal photocoagulation (PRP) in the treatment of macular edema and neovascularization after CRVO, respectively.35-39 Inclusion criteria for patients in the macular edema study group were confirmed CRVO of at least 3 months’

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  23

duration, foveal-involving macular edema verified by fluorescein angiography, visual acuity between 20/50 and 5/200 (with no other ocular pathology to explain the decreased vision), and intraocular pressure less than 30 mm Hg. If foveal nonperfusion existed on fluorescein angiography, the patient was excluded from the study. Patients on heparin or warfarin were required to discontinue their systemic anticoagulation prior to enrollment and were excluded if they were unable to do so. To decrease the likelihood of including patients with actively improving visual acuity at the time of enrollment, patients were required to undergo 2 evaluations spaced at least 2 weeks apart prior to enrollment. If their visual acuity improved by 2 or more lines at their second evaluation, they were not eligible for the study. Patients with a history of retinal laser photocoagulation, diabetic retinopathy, retinal neovascularization, aphakia or pseudophakia, or significant lens opacity were also excluded from the study. Patients were randomized to treatment with argon grid laser photocoagulation or observation. Treatment parameters consisted of argon laser in a grid pattern to the area of capillary leakage as determined on recent fluorescein angiography using a 100-μm spot size and 100-ms duration to create moderately intense retinal whitening. Treatment could not extend into the foveal avascular zone, and collateral vessels/retinal hemorrhages were to be avoided. Patients returned for follow-up visits every 4 months for 3 years, with fluorescein angiography performed at the first and second visits and then on an annual basis. Outcome measures included BCVA performed by a masked examiner and degree of macular edema on fluorescein angiography determined by a centralized reading center. Patients in the treatment group underwent additional grid laser treatment after their initial treatment if they had fewer than 9 letters of vision gain and persistent macular edema on fluorescein angiography at their follow-up visit. A total of 155 eyes of 155 patients were enrolled in the study, and 77 were randomized to grid laser treatment. There was a significant improvement in the degree of macular edema measured on fluorescein angiography in treated patients, with 21 of 68 treated eyes (31%) demonstrating complete resolution of edema 1 year after treatment. This was in contrast to the untreated control eyes, all of which still had some degree of edema at the end of 1 year. Despite the reduced edema in eyes that underwent grid laser photocoagulation, no significant difference existed in visual acuity between treated patients and untreated controls. There was a trend toward improved visual acuity in treated patients younger than 60 years and worsened visual acuity in older treated patients; however, this was not statistically significant. Given the latter findings, the CVOS group did not recommend macular grid photocoagulation to treat macular edema from CRVO.

Neovascularization and Vitreous Hemorrhage Study Neovascularization of the iris (NVI) and neovascularization of the anterior chamber angle (NVA) are precursors to neovascular glaucoma (NVG), a serious complication of CRVO that can result in pain, vision loss, and enucleation.37 The CVOS evaluated the efficacy of early PRP for preventing and treating NVI and NVA from ischemic CRVO. Patients with confirmed CRVO of less than 1 year in duration, visual acuity of light perception or better, no NVI or NVA, intraocular pressure less than 30 mm Hg, and at least 10 disc areas of retinal nonperfusion on fluorescein angiography were included in the study. Exclusion criteria included a history of previous retinal photocoagulation, other

24  Chapter 2

ocular pathology that could cause decreased visual acuity, diabetic retinopathy, or the presence of peripheral anterior synechiae in the study eye. Patients on heparin or warfarin were required to discontinue their systemic anticoagulation prior to enrollment and were excluded if they were unable to do so. Outcome measures included the development of 2 or more clock hours of NVI/NVA, BCVA, neovascularization of the retina and/or optic disc, and the development of NVG. Patients were randomized to treatment with immediate prophylactic PRP or close observation. Treatment consisted of PRP to all quadrants with a 500- to 1000-μm spot size, 200-ms duration burn to yield moderately intense retinal whitening. Between 1000 and 2000 treatment spots were placed in the retinal periphery no closer than 2 disc diameters from the central fovea and no closer than 500 μm nasal to the optic disc. Patients returned monthly for follow-up visits for the first 6 months, then 2 months later for the following visit, then at 4-month intervals for the remainder of the study. All study patients underwent undilated gonioscopy and slit-lamp examination to evaluate for NVI/ NVA at their initial visit and at all subsequent visits. If 2 or more clock hours of NVI/NVA occurred, PRP was performed in both the treatment and the control groups. For eyes in the treatment group, supplementary PRP was performed and control eyes underwent full PRP using the treatment parameters described previously. Eyes that developed anterior segment neovascularization were followed monthly for at least 6 months after the appearance of abnormal blood vessels until they stabilized. A total of 181 eyes (180 patients) were enrolled in the study, with 90 eyes (90 patients) randomized to receive early PRP. There was a trend toward decreased anterior segment neovascularization in the eyes that received prophylactic PRP, but this was not statistically significant. Moreover, eyes that developed neovascularization were significantly more likely to demonstrate prompt regression of NVI/NVA with photocoagulation therapy if they had not received prophylactic treatment; 56% (18 of 32) of control eyes that received PRP for NVI/NVA demonstrated total regression of abnormal blood vessels in 1 month, compared with 22% (4 of 18) of eyes that had received early prophylactic treatment with PRP and later received supplementary PRP after the development of NVI/NVA. The degree of retinal capillary nonperfusion at the start of the study was the most important risk factor for developing anterior segment neovascularization. Sixteen percent of eyes with 10 to 29 disc areas of nonperfusion developed NVI/NVA, compared with 52% of eyes with 75 or more disc diameters of capillary nonperfusion on initial fluorescein angiography. No significant difference existed in the change in visual acuity, development of neovascularization of the retina and/or optic disc, or development of NVG between the treatment and control groups. Given these findings, the CVOS recommended frequent evaluation of eyes after CRVO, particularly if large areas of retinal capillary nonperfusion are present, and treatment with PRP at the first sign of anterior segment neovascularization (Table 2-3).

Natural History and Clinical Follow-up Recommendations As demonstrated previously, the study design of the CVOS divided patients with a history of CRVO into several different study groups to answer questions regarding the

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  25

TABLE 2-3. CENTRAL VEIN OCCLUSION STUDY NEOVASCULARIZATION TREATMENT GUIDELINES FOR CENTRAL RETINAL VEIN OCCLUSION ●

●

●

●

High-quality fluorescein angiography if possible Eye is considered nonperfused if > 10 disc diameters of capillary nonperfusion; neovascularization risk greater with increased nonperfusion

If presenting visual acuity 20/40 or better, follow up every 1 to 2 months for 6 months, then annually If presenting visual acuity 20/50 to 20/200, follow up every 1 to 2 months (at physician s discretion) for 6 months, then annually

●

If presenting visual acuity 20/200 or worse, follow up monthly

●

If ≥ 2 clock hours of NVI/NVA, treat with PRP ○

PRP: medium-white burns/500- to 1000-µm spot size/200-ms duration. Laser burns should be placed to or beyond equator in all 4 quadrants. In addition, burns should be placed no closer than 2 disc diameters from center of fovea and no closer than 500 µm nasal to disc

efficacy of laser photocoagulation to prevent and/or treat the complications of CRVO. After combining patients in all study groups, a total of 714 eyes of 711 patients with CRVO of less than 1 year in duration and no evidence of neovascularization at presentation were enrolled in the CVOS. Evaluation of this large cohort of patients yielded important information regarding prognostic factors for vision, development of NVI/NVA, likelihood of conversion to ischemia, and likelihood of fellow eye involvement.38 The study found that baseline visual acuity predicts visual acuity at 3 years for eyes with good (20/40 and better) and poor (worse than 20/200) visual acuity. Sixty-five percent of eyes that started with visual acuity of 20/40 or better remained at this level, whereas 79% of eyes with 20/200 vision at baseline continued to have poor vision at their final visit. Eyes with intermediate visual acuity at presentation have a variable course. Poor visual acuity, moderate to severe venous tortuosity, and capillary nonperfusion of 30 or more disc areas increase the risk of developing NVI of at least 2 clock hours and/or NVA. Of the 714 eyes enrolled in the study, 117 (16%) eventually developed NVI/NVA. During the 3-year follow-up period, 185 of 547 eyes (34%) that were initially perfused developed ischemia, defined as at least 10 disc diameters of capillary nonperfusion on fluorescein angiography; this progression occurred most rapidly within the first 4 months of follow-up. The annual risk of vascular occlusion in the fellow eye was determined to be approximately 0.9% based on the development of 9 CRVOs and 8 other types of vascular occlusions in previously unaffected fellow eyes. The study group recommended follow-up examinations every 1 to 2 months for 6 months after diagnosis and then annually for patients presenting with a visual acuity of 20/40 or better and monthly for the initial 6 months in patients with initial visual acuity of 20/200 or worse.

26  Chapter 2

ROLE OF FOCAL LASER TREATMENT Macular edema is the most common cause of vision loss after RVO.28,40-43 The BVOS and CVOS were designed in part to address the question of whether focal grid laser can improve visual acuity in patients with macular edema associated with RVO. The BVOS recommended that macular edema that persists 3 months after the onset of BRVO and results in visual acuity of 20/40 or worse should be treated with focal grid argon laser to areas of capillary leakage identified by fluorescein angiography. Eyes with hemorrhage in the fovea or foveal nonperfusion were excluded from the study. For patients with vision loss from macular edema after CRVO, focal laser promptly decreased the degree of macular edema on fluorescein angiography; however, it did not improve visual acuity. As a result, focal laser was generally not recommended in cases of CRVO. The possible exception was in patients younger than 60 years with persistent macular edema for more than 3 months and visual acuity of 20/50 or worse. In this subset of patients, there was a trend toward improved visual acuity; however, the sample size of patients in this age group was too small to demonstrate a statistically significant improvement with treatment. Since the BVOS and CVOS, intravitreal pharmacologic therapies such as triamcinolone acetonide, dexamethasone implant, and intravitreal anti-vascular endothelial growth factor (VEGF) agents have been shown to effectively improve vision in patients with macular edema after both BRVO and CRVO.44-47 Although intravitreal pharmacologic agents are now the first-line treatment in many of these patients, focal laser still plays a role in the treatment of venous occlusive disease. Focal laser can be useful in patients with macular edema from BRVO with discrete areas of leakage either as a stand-alone therapy or as an adjunct to intravitreal injections. Patients who are refractory to intravitreal steroids and anti-VEGF therapy or are unable to tolerate the treatments (eg, due to steroid-induced glaucoma) can benefit from focal laser treatment. Another group of patients in whom focal laser can have an important therapeutic role is those who are unwilling or unable to return for monthly intravitreal injections. Because most patients in the BVOS only required one session of focal laser before an effect was seen and those who required additional laser sessions received them at 4-month intervals, the frequency of office visits and treatments in patients who undergo focal laser is generally less than for those who are treated with intravitreal injections.48 Lastly, it is important to recognize that although CVOS did not recommend using focal laser when macular edema occurred in the setting of CRVO, focal laser decreased macular leakage (but did not improve vision) in this study. Furthermore, CVOS also showed a trend toward benefit in patients younger than 60 years. Given these findings (and the current availability of intravitreal pharmacologics), the community should evaluate the potential benefit of focal laser treatment when used in combination with injections in the setting of macular edema secondary to CRVO. Various combination treatment approaches will be discussed in much greater detail in Chapter 6 of this textbook.

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  27 Figure 2-1. Superotemporal BRVO with cystic macular edema. Note blood layered in macular intraretinal cysts.

CASE REPORT A 57-year-old African American woman with a history of hypertension presented with decreased vision in her left eye of 1 week’s duration. On examination, her visual acuity was 20/20 in her right eye and 20/100 in her left eye. Her intraocular pressures were 14 mm Hg bilaterally, and her anterior segment examination was unremarkable. No NVI or NVA existed on undilated examination. Her posterior segment examination in the right eye was normal. In her left eye, dilated tortuous veins existed along the superotemporal arcade with scattered intraretinal hemorrhages. She had cystic macular edema with areas of blood layered within the cysts (Figure 2-1). Fluorescein angiography at the time of presentation demonstrated less than 5 disc diameters of extrafoveal capillary nonperfusion with late diffuse leakage involving the central fovea (Figure 2-2). The patient was diagnosed with macular edema secondary to BRVO. Because the onset of her symptoms was only 1 week prior to her initial visit, the patient was monitored and asked to return for follow-up 3 months later to evaluate for spontaneous improvement. Her visual acuity remained at 20/100 in her affected eye. On funduscopic examination, the intraretinal hemorrhages had largely resolved; however, the cystic macular edema persisted. Because repeat fluorescein angiography again demonstrated diffuse leakage with central foveal involvement and an absence of foveal nonperfusion, the decision was made to proceed with focal grid laser treatment (Figure 2-3). She tolerated the procedure well, and at her 4-month follow-up appointment, her visual acuity had improved to 20/25 and there was complete resolution of her macular edema. She remained stable at this level of acuity.

28  Chapter 2

Figure 2-2. Fluorescein angiography shows areas of extrafoveal nonperfusion (< 5 disc diameters) and late diffuse macular leakage. Multiple large intraretinal macular cysts contain layered blood. Figure 2-3. BRVO after grid laser treatment for macular edema. Intraretinal hemorrhages present at presentation have largely resolved in the period between initial examination and treatment.

PROS AND CONS The BVOS and CVOS demonstrated that laser photocoagulation, in the form of grid laser for macular edema in BRVO and as scatter laser or PRP to treat neovascularization in BRVO and CRVO, respectively, is an effective method to treat the consequences of RVO. Few complications were reported in the BVOS and CVOS. One rupture of Bruch’s membrane was reported among patients with macular edema and BRVO treated with focal grid laser, and one occurrence of preretinal fibrosis was reported over an area of intraretinal hemorrhage that received scatter grid laser treatment with subsequent macular traction and decreased visual acuity that later improved spontaneously. In patients receiving scatter laser for neovascularization associated with CRVO, 1 choroidal hemorrhage, 1 vitreous hemorrhage, and 2 intraretinal hemorrhages were reported as a result of treatment.

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  29

Despite the low complication rate reported in the BVOS and CVOS, it is important to note that laser photocoagulation is not without risks. Retinal hemorrhage, choroidal neovascularization and hemorrhage, preretinal membrane contraction, tractional retinal detachment, exudative detachment, ischemic papillitis, and visual field defects have all been reported in association with argon laser photocoagulation treatment.49-51 Large visual field defects and exudative detachments are more commonly seen in the setting of scatter photocoagulation for the treatment of anterior segment neovascularization in CRVO, whereas inadvertent photocoagulation of the fovea is a serious complication of focal grid laser. At the time of the BVOS and CVOS trials, laser photocoagulation was the only proven method of therapy for RVO. As previously discussed, newer intravitreal pharmacologic agents have been investigated and proven to be efficacious since the publication of the BVOS and CVOS. However, it should be recognized that intravitreal injections of steroids and anti-VEGF agents have their own risk profile that should be considered when discussing treatment options with a patient. If the decision is made to proceed with either PRP for retinal neovascularization or focal laser photocoagulation for macular edema, it is important to adhere to the treatment guidelines of the BVOS and CVOS. For focal laser treatment, laser spots should not extend any closer to the central fovea than the edge of the foveal avascular zone. For PRP, treatment should be no closer than 2 disc diameters from the center of the fovea and no closer than 500 μm nasal to the optic disc. Areas of intraretinal hemorrhage should be avoided, and laser burns should be of the appropriate intensity because burns that are too hot can increase the risk of rupturing Bruch’s membrane. It is also worthwhile to point out that many of the CVOS and BVOS management recommendations were based on fluorescein angiography findings. In the past decade, the development of spectral domain optical coherence tomography and ultra-wide-field angiography has revolutionized the management of RVO. We can now detect and exquisitely characterize macular edema better than we could in the past. Furthermore, ultra-widefield angiography has given us hints regarding the role of peripheral nonperfusion and its possible contribution to recalcitrant macular edema. Given the recent development of these imaging technologies, the community may need to precisely define the role of traditional fluorescein angiography versus these new imaging modalities to manage RVO and its complications. Imaging in RVO will be discussed in greater detail in Chapter 5.

CONCLUSION The CVOS and BVOS were landmark studies that provided retina specialists with much-needed guidance regarding the use of laser to treat the complications of RVO. The recommendations regarding the use of PRP for the treatment of neovascularization have withstood the test of time. However, given the current availability of effective intravitreal pharmacologics to treat macular edema secondary to RVO, the precise role of focal laser may need to be reevaluated, either as a monotherapy or in combination with intravitreal injections.

30  Chapter 2

REFERENCES 1. 2. 3.

4. 5.

6.

7.

8.

9. 10. 11. 12. 13.

14.

15. 16. 17.

18. 19. 20.

Holmin N, Ploman KG. Thrombosis of central vein of retina treated with heparin. Lancet. 1938;231(5977):664-665. Rossmann H. The thrombolytic therapy of vascular occlusions of the retina [in German]. Klin Monbl Augenheilkd. 1966;149(6):874-880. Kohner EM, Hamilton AM, Bulpitt CJ, Dollery CT. Streptokinase in the treatment of central retinal vein occlusion. A controlled trial. Trans Ophthalmol Soc U K. 1974;94(2):599603. Kohner EM, Pettit JE, Hamilton AM, Bulpitt CJ, Dollery CT. Streptokinase in central retinal vein occlusion: a controlled clinical trial. Br Med J. 1976;1(6009):550-553. Hansen LL, Danisevskis P, Arntz HR, Hövener G, Wiederholt M. A randomised prospective study on treatment of central retinal vein occlusion by isovolaemic haemodilution and photocoagulation. Br J Ophthalmol. 1985;69(2):108-116. Hansen LL, Wiek J, Schade M, Müller-Stolzenburg N, Wiederholt M. Effect and compatibility of isovolaemic haemodilution in the treatment of ischaemic and non-ischaemic central retinal vein occlusion. Ophthalmologica. 1989;199(2-3):90-99. Hansen LL, Wiek J, Wiederholt M. A randomised prospective study of treatment of nonischaemic central retinal vein occlusion by isovolaemic haemodilution. Br J Ophthalmol. 1989;73(11):895-899. Clements DB, Elsby JM, Smith WD. Retinal vein occlusion. A comparative study of factors affecting the prognosis, including a therapeutic trial of Atromid S in this condition. Br J Ophthalmol. 1968;52(2):111-116. Krill AE, Archer D, Newell FW. Photocoagulation in complications secondary to branch vein occlusion. Arch Ophthalmol. 1971;85(1):48-60. Archer DB, Michalopoulos N. Treatment of neovascularization secondary to branch retinal vein obstruction. Int Ophthalmol. 1981;3(3):141-153. Cleasby GW, Hall DL, Fung WE, Webster RG Jr. Retinal branch vein occlusion. Treatment by photocoagulation. Mod Probl Ohthalmol. 1974;12(0):254-260. Campbell CJ, Wise GN. Photocoagulation therapy of branch vein obstructions. Am J Ophthalmol. 1973;75(1):28-31. Glacet-Bernard A, Mahdavi KN, Coscas G, Zourdani A, Fardeau C. Macular grid photocoagulation in persistent macular edema due to central retinal vein occlusion. Eur J Ophthalmol. 1994;4(3):166-174. Hayreh SS, Klugman MR, Podhajsky P, Servais GE, Perkins ES. Argon laser panretinal photocoagulation in ischemic central retinal vein occlusion. A 10-year prospective study. Graefe’s Arch Clin Exp Ophthalmol. 1990;228(4):281-296. Gitter KA, Cohen G, Baber BW. Photocoagulation in venous occlusive disease. Am J Ophthalmol. 1975;79(4):578-581. Van Hulst L, Deutman AF. Technique of laser treatment in branch vein occlusion with cystoid macular oedema. Bull Soc Belge Ophtalmol. 1981;197:81-83. Jalkh AE, Avila MP, Zakka KA, Trempe CL, Schepens CL. Chronic macular edema in retinal branch vein occlusion: role of laser photocoagulation. Ann Ophthalmol. 1984;16(6):526-529,532-533. Jalkh AE, Trempe CL. Macular edema in branch retinal vein occlusion: types and treatment. Ophthalmic Surg. 1989;20(1):26-32. Kelley JS, Patz A, Schatz H. Management of retinal branch vein occlusion: the role of argon laser photocoagulation. Ann Ophthalmol. 1974;6(11):1123-1126,1129-1134. Klein ML, Finkelstein D. Macular grid photocoagulation for macular edema in central retinal vein occlusion. Arch Ophthalmol. 1989;107(9):1297-1302.

Retinal Vein Occlusion Clinical Trials: Historical Perspective and Current Relevance  31 21. Kremer I, Hartman B, Siegal R, Ben-Sira I. Static and kinetic perimetry results of krypton red laser treatment for macular edema complicating branch vein occlusion. Ann Ophthalmol. 1990;22(5):193-197. 22. Morse PH. Prospective rationale for and results of argon laser treatment of patients with branch retinal-vein occlusion. Ann Ophthalmol. 1985;17(9):565-571. 23. Romem M, Isakow I. Photocoagulation in retinal vein occlusion. Ann Ophthalmol. 1981;13(9):1057-1058. 24. Roseman RL, Olk RJ. Krypton red laser photocoagulation for branch retinal vein occlusion. Ophthalmology. 1987;94(9):1120-1125. 25. Blankenship GW, Okun E. Retinal tributary vein occlusion. History and management by photocoagulation. Arch Ophthalmol. 1973;89(5):363-368. 26. Wetzig PC. The treatment of acute branch vein occlusion by photocoagulation. Trans Am Ophthalmol Soc. 1978;76:654-669. 27. Shilling JS, Jones CA. Retinal branch vein occlusion: a study of argon laser photocoagulation in the treatment of macular oedema. Br J Ophthalmol. 1984;68(3):196-198. 28. Gutman FA, Zegarra H. Macular edema secondary to occlusion of the retinal veins. Surv Ophthalmol. 1984;28 Suppl:462-70. 29. Clarkson JG. Photocoagulation for ischemic central retinal vein occlusion. Central Vein Occlusion Study. Arch Ophthalmol. 1991;109(9):1218-1219. 30. Orth DH, Patz A. Retinal branch vein occlusion. Surv Ophthalmol. 1978;22(6):357-376. 31. Patz A. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol. 1984;98(3):374-375. 32. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282. 33. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104(1):34-41. 34. Finkelstein D. Laser treatment of branch and central retinal vein occlusion. Int Ophthalmol Clin. 1990;30(2):84-88. 35. Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8):1087-1095. 36. Central vein occlusion study of photocoagulation therapy. Baseline findings. Central Vein Occlusion Study Group. Online J Curr Clin Trials. 1993;Doc No 95:[6021 words;81 paragraphs]. 37. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102(10):1434-1444. 38. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997;115(4):486-491. 39. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):14251433. 40. Gutman FA, Zegarra H. The natural course of temporal retinal branch vein occlusion. Trans Am Acad Ophthalmol Otolaryngol. 1974;78(2):OP178-192. 41. Zegarra H, Gutman FA, Conforto J. The natural course of central retinal vein occlusion. Ophthalmology. 1979;86(11):1931-1942. 42. Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinal photocoagulation in central retinal vein occlusion: a randomised controlled clinical study. Br J Ophthalmol. 1977;61(12):741-753. 43. Gutman FA. Macular edema in branch retinal vein occlusion: prognosis and management. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1977;83(3 Pt 1):488-495.

32  Chapter 2 44. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.e1. 45. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. 46. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128. 47. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114. 48. Shah AM, Bressler NM, Jampol LM. Does laser still have a role in the management of retinal vascular and neovascular diseases? Am J Ophthalmol. 2011;152(3):332-339.e1. 49. Little HL. Complications of argon laser retinal photocoagulation: a five-year study. Int Ophthalmol Clin. 1976;16(4):145-159. 50. Galinos SO, Asdourian GK, Woolf MB, Goldberg MF, Busse BJ. Choroido-vitreal neovascularization after argon laser photocoagulation. Arch Ophthalmol. 1975;93(7):524-530. 51. Fong DS, Girach A, Boney A. Visual side effects of successful scatter laser photocoagulation surgery for proliferative diabetic retinopathy: a literature review. Retina. 2007;27(7):816-824.

3

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion Nancy M. Holekamp, MD and Shaun T. Ittiara, MD

RATIONALE Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are currently a standard of care treatment for exudative age-related macular degeneration (AMD), diabetic macular edema, and macular edema due to retinal vein occlusion (RVO). Although it is remarkable that a single therapeutic intervention can prove so beneficial in treating 3 distinct retinal diseases, this fact suggests a common underlying pathophysiology mediated largely by VEGF. Of these diseases, macular edema due to RVO, in the acute phase, is perhaps the one most directly mediated by VEGF and, therefore, may be the most directly responsive to anti-VEGF therapy.

Vascular Endothelial Growth Factor as a Dual-Function Protein: Angiogenesis and Vascular Permeability In 1983, Senger et al1 published a study identifying the initial functional role of VEGF. Originally called vascular permeability factor, it facilitated leakage of plasma proteins such as fibrinogen whose purpose was to effectively form an extracellular fibrin matrix and thereby promote new blood vessel growth. In 1989, Leung and colleagues2 independently identified and characterized VEGF as an angiogenic factor. At the same time, Keck et al3 demonstrated that tumor-derived vascular permeability factor and VEGF were one and the same. It was a seminal discovery that a single vascular agent could have dual functions.

- 33 -

Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 33-61). © 2014 SLACK Incorporated.

34  Chapter 3

Figure 3-1. VEGF levels in both the aqueous and vitreous for exudative AMD, branch RVO, and central RVO.

It is interesting to note that, clinically, the damaging effects of RVO are also dual: macular edema and neovascularization (which can occur on the iris [NVI], angle [NVA], optic disc [NVD], and/or elsewhere in the retina [NVE]). Both effects are mediated by VEGF.

Vascular Endothelial Growth Factor Levels Are Elevated in Retinal Vein Occlusion The landmark report by Aiello et al4 in the New England Journal of Medicine in 1994 that identified VEGF as the ischemia-induced ocular angiogenic factor largely focused on VEGF levels in eyes with proliferative diabetic retinopathy. The report also included other retinal disorders, such as RVO. Four eyes undergoing surgery for ischemic central RVO (CRVO) were studied. Three of the 4 eyes had NVI. Although vitreous samples were not taken for the eyes with CRVO, the 3 eyes with NVI had statistically significant elevation of VEGF levels in the aqueous. Thus, VEGF, in response to retinal ischemia caused by RVO, was concluded to be the likely mediator of abnormal NVI. Because VEGF is also a vascular permeability factor, it is the likely mediator of macular edema secondary to RVO. Since 1994, this has become a well-accepted paradigm. Since the groundbreaking work of Aiello and colleagues4 in diabetic retinopathy, numerous investigators have replicated their study for choroidal neovascularization in AMD, branch RVO (BRVO), and CRVO. Figure 3-1 shows VEGF levels in both the aqueous and vitreous for exudative AMD, BRVO, and CRVO. Although VEGF levels vary across patient populations and disease states, the levels for RVO are elevated, with vitreous levels being much higher than aqueous levels.

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  35

Figure 3-2. (A) A hemorrhagic inferotemporal BRVO in the right eye. (continued)

Retinal Vein Occlusion Leads to Retinal Ischemia and Overexpression of Vascular Endothelial Growth Factor Acute RVO occurs when a thrombus forms in either the central retinal vein or branch retinal vein. Once the retinal vein is obstructed, proper drainage of the capillary bed is inhibited. There are few functional collaterals to compensate when retinal vessels are obstructed; thus, the retina becomes hypoxic.5 VEGF production is induced in cells that are not receiving enough oxygen. When a cell is deficient in oxygen, it produces hypoxiainducible factor (HIF), a transcription factor. HIF stimulates increased VEGF production. Thus, VEGF is upregulated and therefore overexpressed by hypoxia via the HIF-1 alpha pathway.6 VEGF promotes vascular endothelial cell growth and angiogenesis. New blood vessel growth can lead to NVI, neovascular glaucoma (NVG), and vitreous hemorrhage. Untreated, these conditions may lead to severe vision loss or loss of the eye. VEGF also induces vascular permeability. Vascular permeability leads to hemorrhage and edema, ultimately causing loss of vision. Macular edema accounts for the majority of vision loss in RVO.7 Clinically, fluorescein angiography reveals the compromise of the capillary bed that leads to tissue hypoxia and the overexpression of VEGF. Figure 3-2A shows a hemorrhagic inferotemporal BRVO in the right eye. The subsequent vascular damage to the capillary bed is easily seen in Figure 3-2B, an early frame of the fluorescein angiogram. The hypofluorescent areas indicate either blocking from the blood or areas of nonperfusion known as capillary dropout. The latter equates to regions of tissue hypoxia. In Figure 3-2C, a late frame of the fluorescein angiogram demonstrates late leakage of fluorescein, a direct biologic response to the hypoxia-induced upregulation and overexpression of VEGF and its vascular permeability properties. In Figure 3-1, there is no evidence of VEGF-mediated neovascularization. Currently, there is limited understanding regarding whether VEGF is predominantly a vascular permeability factor or an angiogenic factor.

36  Chapter 3

Figure 3-2 (continued). (B) An early frame of the fluorescein angiogram demonstrates damage to the vascular bed. The hypofluorescent areas indicate either blocking from the blood or areas of nonperfusion known as capillary dropout. (C) A late frame of the fluorescein angiogram demonstrates late leakage of fluorescein, a direct biologic response to VEGF and its vascular permeability properties.

Anti-Vascular Endothelial Growth Factor Injections Reduce Intraocular Vascular Endothelial Growth Factor Levels VEGF is the natural target when attempting to treat the complications of RVO (ie, macular edema and neovascularization). Good evidence exists in the diabetes literature that intraocular injection of an anti-VEGF agent reduces aqueous levels of VEGF. Sawada and colleagues8 studied 18 eyes in 18 patients with proliferative diabetic retinopathy in which intravitreal bevacizumab (IVB) was injected into the vitreous cavity 1 week prior to pars plana vitrectomy. At the time of surgery, aqueous samples were taken and VEGF was measured using an enzyme-linked immunosorbent assay. The mean aqueous humor VEGF concentration in eyes with proliferative diabetic retinopathy prior to bevacizumab

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  37

injection was 324 pg/mL and fell to less than 31 pg/mL in all eyes 1 week after bevacizumab injection. It is interesting to note that the bevacizumab injection was administered in the vitreous cavity and had a profound effect on aqueous VEGF levels. Based on this study, it is biologically plausible to extrapolate that the vitreous VEGF levels were likely decreased as well. It is also reasonable to extrapolate that injections of anti-VEGF agents in RVO would result in a similar profound decrease in intraocular VEGF levels.

Early Clinical Experience With Anti-Vascular Endothelial Growth Factor Agents in Retinal Vein Occlusion Were Positive In 2005, Rosenfeld et al9 published the first case report of IVB for treating macular edema due to CRVO. The authors injected 1.0 mg bevacizumab into the eye of a patient in which prior intravitreal injections of triamcinolone acetonide resulted in vision improvement but worsening cataract and borderline glaucoma. Within 1 week of the bevacizumab injection, visual acuity improved from 20/200 to 20/50, and optical coherence tomography (OCT) revealed resolution of the cystic maculopathy. The improvements were maintained for 4 weeks. Based on this single patient, the authors hypothesized that intravitreal injections of bevacizumab would be an effective treatment option for patients with macular edema from RVO. Shortly after Rosenfeld and colleagues9 published a single case report, Iturralde et al10 published a slightly larger retrospective series of 16 eyes in 15 patients with CRVO in which IVB injections resulted in an immediate reduction in cystoid macular edema as seen on OCT and a significant improvement in visual acuity without any serious adverse ocular or systemic events. These 2 initial studies of bevacizumab in treating macular edema due to CRVO had only a small number of patients with short-term follow-up. Nevertheless, they were the proof of concept needed by the retina community not only to begin widespread use of IVB for treating complications of RVO, but also to collaborate with industry on large, wellcontrolled clinical trials of other anti-VEGF agents in treating this disease.

RANIBIZUMAB Ranibizumab is a humanized, affinity-maturated VEGF antibody fragment that binds to and neutralizes all forms of VEGF.11,12 The clinical use of ranibizumab by retina specialists was pioneered in treating neovascular AMD, and ranibizumab is US Food and Drug Administration (FDA)-approved for that indication. Shortly following successful use of ranibizumab in AMD, clinicians began using it for macular edema due to CRVO. A small, uncontrolled trial of open-label intravitreal ranibizumab in 20 patients with BRVO and 20 patients with CRVO demonstrated visual acuity improvements of 10 to 18 letters and 90% improvement in macular edema on OCT after 3 monthly injections. The investigators found a positive association between higher levels of VEGF at baseline and a larger degree of clinical improvement.13 Another uncontrolled trial provided evidence of visual acuity and anatomical benefit for up to a year of treatment in a small group of 20 patients with CRVO.14 These initial reports provided evidence that macular edema secondary to BRVO and CRVO was mediated by VEGF and could be blockaded effectively with intravitreal

38  Chapter 3

Figure 3-3. CRUISE study design.15

ranibizumab injections for sustained clinical improvement. These early studies preceded large FDA-sanctioned registration trials examining ranibizumab for macular edema due to BRVO and CRVO.

CRUISE Food and Drug Administration Registration Trial Ranibizumab for the Treatment of Macular Edema After Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) was an industry-sponsored FDA registration trial intended to assess the efficacy and safety of intraocular injections of 0.3 or 0.5 mg of ranibizumab in patients with macular edema due to CRVO. Designed to meet FDA requirements for drug approval, CRUISE was a 12-month, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. Investigators at 95 clinical trial sites enrolled 392 patients with macular edema secondary to CRVO who were then randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections for 6 months. The primary efficacy outcome measure was mean change from baseline best corrected visual acuity (BCVA) at 6 months.15 The favorable 6-month primary endpoint results of this phase III study led to FDA approval of 0.5 mg of ranibizumab for macular edema due to CRVO.15 Consequently, only the data for the 0.5-mg dose of ranibizumab will be discussed in this chapter.

Study Design Figure 3-3 shows the CRUISE study design. To be enrolled in the study, each patient had macular edema due to CRVO and met the following inclusion criteria: Provided informed consent ●

●

●

Aged 18 years or older Foveal center-involved macular edema secondary to CRVO diagnosed within 12 months prior to screening

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  39 ●

●

●

●

BCVA of 20/40 to 20/320 Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts Mean central subfield thickness of 250 μm or more on time-domain OCT as assessed by both the investigating physician and a reading center Patients were excluded from participating if they met any of the following criteria: Prior episode of RVO in the study eye Laser photocoagulation for macular edema in the study eye 4 months or less prior to day 0

●

Intraocular corticosteroid use in the study eye 3 or more months prior to day 0

●

History of anti-VEGF treatment ○

Intravitreal treatment in either the study or fellow eye 3 months or less prior to day 0

○

Systemic treatment 6 months or less prior to day 0

●

Brisk afferent pupillary defect in the study eye

●

BCVA gain of more than 10 letters in the study eye between screening and day 0

Cerebrovascular accident (CVA) or myocardial infarction (MI) 3 months or less prior to day 0 Important aspects of the inclusion criteria for the CRUISE study included the following: eyes could have had macular edema secondary to CRVO for up to 12 months, thus allowing chronic cases to be enrolled; and the lower limit of poor visual acuity was 20/320, thus excluding severe cases of CRVO. Important aspects of the exclusion criteria for the CRUISE study included the following: eyes with a brisk afferent pupillary defect in the study eye were excluded, thus keeping severely ischemic eyes out of the study; and patients with a recent history of CVA or MI were excluded, which may have biased the study toward healthier patients. In the CRUISE study, 130, 132, and 130 patients received sham, 0.3-mg, and 0.5-mg ranibizumab injections, respectively. All patient groups were balanced with regard to age (sham group, 65.4 years; ranibizumab group, 67.6 years), baseline visual acuity (sham group, 49.2 ETDRS letters; ranibizumab group, 48.1 ETDRS letters), and baseline central foveal thickness (CFT) on time-domain OCT (sham group, 687.0 μm; ranibizumab group, 688.7 μm). Through month 6, 88.5% of sham-treated patients (n = 130) and 91.5% of 0.5-mg ranibizumab-treated patients (n = 130) completed all follow-up visits, receiving a mean of 5.5 and 5.6 injections, respectively. ●

Results The CRUISE study primary endpoint of mean change from baseline BCVA to month 6 was + 14.9 letters for the 0.5-mg ranibizumab group compared with + 0.8 letters for the sham group. The difference was statistically significant (P < .01) and led to FDA approval of 0.5 mg of ranibizumab for macular edema due to CRVO. Figure 3-4 shows a key secondary endpoint: the mean change from baseline BCVA over time. In the CRUISE study, treatment with monthly ranibizumab resulted in increases in mean visual acuity observed as early as 7 days following the first dose. Statistically significant mean visual acuity gains were sustained with monthly dosing for 6 months. Concomitant with the rapid improvement in BCVA was an immediate reduction in CFT

40  Chapter 3

Figure 3-4. Primary endpoint from the CRUISE study.15

Figure 3-5. Key secondary anatomical endpoint from the CRUISE study.15

after treatment with ranibizumab (Figure 3-5). At day 7, the mean reduction from baseline CFT was more than 250 μm in the ranibizumab group compared with no reduction in the sham group. A key secondary endpoint is that 47.7% of patients in the ranibizumab group gained 3 or more lines compared with 16.9% of patients in the sham group. Also, 9.2% and 5.4% of patients had a baseline visual acuity of 20/40 in the sham and ranibizumab groups, respectively, but by month 6, the proportion of patients achieving a BCVA of 20/40 or better in the ranibizumab group was 46.9% compared with 20.8% in the sham group. This difference was statistically significant (P < .01).

Safety The safety profile of 0.5 mg of ranibizumab in patients with CRVO was consistent with previous phase III trials of patients with exudative AMD. No new safety concerns were

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  41

raised by the CRUISE clinical trial. No serious events of endophthalmitis, intraocular inflammation, or retinal detachment occurred in the study eye. In fact, NVI, NVG, and vitreous hemorrhage were more common in the sham group than in the ranibizumab groups, suggesting a protective effect of anti-VEGF therapy. There were no safety signals regarding systemic adverse events. The incidence of thromboembolic events was low in both the sham and ranibizumab groups (< 1% for each event). The CRUISE study demonstrated that monthly intraocular ranibizumab injections were well tolerated for at least 6 months.

Limitations The CRUISE study was a 12-month study with limited inclusion criteria and a 6-month primary endpoint selected for FDA approval of ranibizumab. The study offers few guidelines for treating patients with the following conditions: vision better than 20/40 or worse than 20/320, patients with disease duration longer than 12 months at baseline, patients with a recent history of CVA or MI, and patients requiring treatment beyond the 6-month period of the CRUISE study. When to initiate anti-VEGF therapy in CRVO remains unanswered by the CRUISE study, although sooner is probably better than later due to the poor natural history of CRVO and the apparent safety of ranibizumab treatment. The CRUISE trial did not examine the use of ranibizumab for the neovascular complications of CRVO. Finally, a drawback to anti-VEGF therapy with ranibizumab is the need for monthly injections, a dosing interval restricted by the pharmacokinetics of the antibody fragment in the vitreous cavity.

Conclusion The investigators of the CRUISE study rightly concluded that ranibizumab does not affect the original thrombus in the central retinal vein. Anti-VEGF therapy blocks the mediator of retinal edema and neovascularization, thus preserving vision in CRVO. AntiVEGF blockade results in rapid and sustained improvement in macular edema and visual acuity. Because VEGF is induced by tissue hypoxia, this suggests that all central retinal veins are ischemic to differing degrees. Based on the safety and efficacy results of the CRUISE study, monthly intravitreal ranibizumab injections can be considered a standardof-care treatment for macular edema due to CRVO.

BRAVO Food and Drug Administration Registration Trial Ranibizumab for the Treatment of Macular Edema After Branch Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (BRAVO) was an industry-sponsored FDA registration trial intended to assess the efficacy and safety of intraocular injections of 0.3 or 0.5 mg of ranibizumab in patients with macular edema due to BRVO.16 Designed to meet FDA requirements for drug approval, BRAVO was a 12-month, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. Investigators at 93 clinical trial sites enrolled 397 patients with macular edema secondary to BRVO who were then randomized to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections for 6 months. The primary efficacy outcome measure was the mean change from baseline BCVA at month 6.16 The favorable 6-month primary endpoint

42  Chapter 3

Figure 3-6. BRAVO study design.16

results of this phase III study led to FDA approval of 0.5 mg of ranibizumab for macular edema due to BRVO. Consequently, only the data for the 0.5-mg dose of ranibizumab will be discussed in this chapter.

Study Design Figure 3-6 shows the BRAVO study design. To be enrolled in the study, each patient had macular edema due to BRVO and met the following inclusion criteria: Signed informed consent ●

●

●

●

●

●

Aged 18 years or older Foveal center-involved macular edema secondary to BRVO/hemi-RVO (HRVO) diagnosed within 12 months prior to screening BCVA of 20/40 to 20/400 approximate Snellen equivalent Mean central subfield thickness 250 μm or more from 2 time-domain OCT measurements Patients were excluded from participating if they met any of the following criteria: Prior episode of RVO

●

Laser photocoagulation for macular edema 4 months or less prior to day 0

●

Intraocular corticosteroid use 3 months or less prior to day 0

●

History of anti-VEGF treatment ○

Intravitreal 3 months or less prior to day 0

○

Systemic 6 months or less prior to day 0

●

Brisk afferent pupillary defect

●

BCVA gain of more than 10 letters between screening and day 0

●

Stroke or MI 3 months or less prior to day 0

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  43

Important aspects of the inclusion criteria for the BRAVO study included the following: eyes with HRVO were included; eyes could have had macular edema secondary to BRVO for up to 12 months, thus allowing chronic cases to be enrolled; and the lower limit of poor visual acuity was 20/400, thus excluding severe cases of BRVO or HRVO. Important aspects of the exclusion criteria for the BRAVO study included the following: eyes with a brisk afferent pupillary defect were excluded, thus keeping severely ischemic eyes out of the study, and patients with a recent history of CVA or MI were excluded, which may have biased the study toward healthier patients. In the BRAVO study, 132, 134, and 131 patients received sham, 0.3-mg, and 0.5-mg ranibizumab injections, respectively. All patient groups were balanced with regard to age (sham group, 65.2 years; ranibizumab group, 67.5 years), baseline visual acuity (sham group, 54.7 ETDRS letters; ranibizumab group, 53.0 ETDRS letters), and baseline CFT on time-domain OCT (sham group, 488.0 μm; ranibizumab group, 551.7 μm). Through month 6, 93.2% of sham-treated patients and 95.4% of 0.5-mg ranibizumab-treated patients completed all follow-up visits, receiving a mean of 5.6 and 5.7 injections, respectively. All patients were eligible for rescue laser treatment once during the treatment period (beginning month 3) and once during the observation period (beginning month 9) if they met the following criteria: BCVA of 20/40 or worse or CFT of 250 μm or more and, compared with the month 3 visit prior to the current visit, a BCVA gain of fewer than 5 letters or a decrease of less than 50 μm in CFT.

Results The BRAVO primary endpoint of mean change from baseline BCVA to month 6 was + 18.3 letters for the 0.5-mg ranibizumab group compared with + 7.3 letters for the sham group. The difference was statistically significant (P < .01) and led to FDA approval of 0.5 mg of ranibizumab for macular edema due to BRVO. Figure 3-7 shows a key secondary endpoint: the mean change from baseline BCVA over time. In the BRAVO study, treatment with monthly ranibizumab resulted in increases in mean visual acuity observed as early as 7 days following the first dose. Statistically significant mean visual acuity gains were sustained with monthly dosing for 6 months. Concomitant with the rapid improvement in BCVA was an immediate reduction in CFT after treatment with ranibizumab (Figure 3-8). At day 7, the mean reduction from baseline CFT was more than 250 μm in the ranibizumab group compared with no reduction in the sham group. It is important to note that the sham group demonstrated slow but sustained improvement over the 6-month study period, resulting in a visual acuity gain of 7.3 letters at month 6 (see Figure 3-7). For patients in the sham group, 54.5% received grid laser photocoagulation as early as month 3. This improvement reflects a combination of the natural history of BRVO and the mildly beneficial effects of laser surgery as seen in the 1984 Branch Vein Occlusion Study as described in Chapter 2 in this textbook.17 Nevertheless, as a group, the improvement seen in sham-/laser-treated eyes was inferior to that of ranibizumab-treated eyes. A key secondary endpoint is that 61.1% of patients in the ranibizumab group gained 3 lines or more compared with 28.8% of patients in the sham group. Also, 14.4% and 11.5% of patients had a baseline visual acuity of 20/40 in the sham and ranibizumab groups, respectively, but by month 6, the proportion of patients achieving a BCVA of 20/40 or

44  Chapter 3

Figure 3-7. Primary endpoint from the BRAVO study.16

Figure 3-8. Key secondary anatomical endpoint from the BRAVO study.16

better in the ranibizumab group was 64.9% compared with 41.7% in the sham group. This difference was statistically significant (P < .01).

Safety The safety profile of 0.5 mg of ranibizumab in patients with BRVO was consistent with previous phase III trials of patients with exudative AMD. No new safety concerns were raised by the BRAVO clinical trial. One patient developed endophthalmitis following ranibizumab injection, reaffirming this complication as a small but definite risk of intraocular injection. One patient developed a retinal tear and a detachment following ranibizumab injection, suggesting that repeated intravitreal injections can exacerbate underlying vitreous traction. NVI and vitreous hemorrhage were more common in the sham group than in the ranibizumab group, suggesting a protective effect of anti-VEGF

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  45

therapy. There were no safety signals regarding systemic adverse events. The incidence of thromboembolic events was low in both the sham and ranibizumab groups (less than 1% for each event). The BRAVO study demonstrated that monthly intraocular ranibizumab injections were well tolerated for at least 6 months.

Limitations The BRAVO study was a 12-month study with limited inclusion criteria and a 6-month primary endpoint selected for FDA approval of ranibizumab. The study offers few guidelines for treating patients with the following conditions: vision better than 20/40 or worse than 20/400, patients with disease duration longer than 12 months at baseline, patients with a recent history of CVA or MI, and patients requiring treatment beyond the 6-month study period. When to initiate anti-VEGF therapy in BRVO remains unanswered by BRAVO. A substantial number of eyes in the BRAVO clinical trial did well with observation with or without rescue laser treatment. Nevertheless, the results were still inferior to ranibizumab treatment, suggesting that anti-VEGF therapy sooner rather than later is preferable given the apparent safety of ranibizumab treatment. However, using this approach would undoubtedly result in unnecessary treatment for the small percentage of patients who undergo spontaneous resolution. The BRAVO study did not examine the use of ranibizumab for neovascular complications of RVO. Finally, a drawback to anti-VEGF therapy with ranibizumab is the need for monthly injections, a dosing interval restricted by the pharmacokinetics of the antibody fragment in the vitreous cavity.

Conclusion Although ranibizumab does not affect the original thrombus in the branch retinal vein, the BRAVO study demonstrates that sustained anti-VEGF blockade results in rapid and sustained improvement in macular edema and visual acuity. Because VEGF is induced by tissue hypoxia, this suggests that all branch retinal veins are ischemic to differing degrees. Anti-VEGF therapy blocks the mediator of retinal edema and neovascularization, thus preserving vision in BRVO. Based on the safety and efficacy results of the BRAVO study, monthly intravitreal ranibizumab injections can be considered a standard-of-care treatment for macular edema due to BRVO.

Twelve-Month Follow-up for the BRAVO and CRUISE Studies Both the CRUISE and BRAVO studies were 12-month clinical trials with primary endpoints at month 6 for purposes of FDA approval of ranibizumab. Patients in both trials continued to be followed through month 12. At month 6, all patients (even the shamtreated group) were to receive monthly intravitreal ranibizumab pro re nata (PRN) based on the investigator’s discretion if they met prespecified functional and anatomic criteria: Snellen equivalent BCVA of 20/40 or worse according to the ETDRS eye chart or mean central subfield thickness of 250 μm or more on OCT.15,16 Figure 3-9 shows the CRUISE study’s 6- to 12-month visual acuity results. In the CRUISE study, switching from monthly to PRN dosing of ranibizumab maintained visual acuity but did not result in additional visual acuity gains, with a mean change in BCVA of + 13.9 letters at month 12. However, maintenance in visual acuity was achieved with

46  Chapter 3

Figure 3-9. CRUISE trial 6- to 12-month visual acuity results.18

Figure 3-10. BRAVO trial 6- to 12-month visual acuity results.19

fewer ranibizumab injections (3.3 injections over 6 months). Delaying initial ranibizumab treatment for 6 months and then initiating PRN treatment resulted in a mean change in BCVA of + 7.3 letters at month 12. Again, fewer than monthly ranibizumab injections were required (3.7 injections over 6 months).18 Figure 3-10 shows the BRAVO trial’s 6- to 12-month visual acuity results. In the BRAVO study, switching from monthly to PRN dosing maintained visual acuity but did not result in additional visual acuity gains in the ranibizumab-treated group, with a mean change in BCVA of + 18.3 letters at month 12. However, maintenance in visual acuity was achieved with fewer ranibizumab injections (2.7 over 6 months). Delaying initial ranibizumab treatment for 6 months and then initiating PRN treatment resulted in a mean change in BCVA of + 12.1 letters at month 12. Again, fewer than monthly ranibizumab injections were required (3.6 injections over 6 months).19

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  47

HORIZON: The Extension Trial for CRUISE and BRAVO The HORIZON (An Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration) trial was designed to obtain additional information about the effects of ranibizumab in 2 patient cohorts. Cohort 1 included patients with neovascular AMD who had completed the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD)11 and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD)12 clinical trials. Cohort 2 included patients who had completed the CRUISE and BRAVO clinical trials.19 Therefore, the HORIZON trial was an open-label extension trial of the 12-month CRUISE and BRAVO trials whose purpose was to assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema due to RVO through month 24. A total of 304 CRUISE patients and 304 BRAVO patients were enrolled in the study and were evaluated at least every 3 months, or more frequently if needed. At each study visit, patients were eligible to receive PRN intravitreal 0.5 mg of ranibizumab according to the investigator’s discretion if they met prespecified functional and anatomic criteria: mean center subfield thickness of 250 μm or more on OCT or if evidence existed of persistent or recurrent macular edema deemed to be affecting the patient’s visual acuity. Patients with BRVO were eligible for rescue grid laser therapy if BCVA was 20/40 or worse caused by macular edema. In BRAVO and CRUISE patients who completed the second year of follow-up in the HORIZON trial, the mean number of injections in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (BRVO) and 2.9, 3.8, and 3.5 (CRVO), respectively.20 The mean change from baseline BCVA letter score at month 24 in BRVO patients was 0.9 (sham/ 0.5 mg), –2.3 (0.3/0.5 mg), and –0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 24 in CRVO patients was –4.2 (sham/0.5 mg), –5.2 (0.3/0.5 mg), and –4.1 (0.5 mg), respectively. No new safety events were identified with long-term use of ranibizumab through 24 months. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in CRVO patients, but vision in BRVO patients remained stable. The results suggest that, during the second year of ranibizumab treatment in RVO patients, follow-up and injections should be individualized, and CRVO patients may require more frequent follow-up than every 3 months.

BEVACIZUMAB Bevacizumab is a humanized monoclonal antibody that binds to all subtypes of VEGF and is successfully used in tumor therapy as a systemic drug.21 It is an FDA-approved treatment for colon, kidney, lung, and brain cancers. It is not FDA approved for treatment of any ocular condition. Although a large randomized, head-to-head clinical trial comparing ranibizumab with bevacizumab for treating exudative AMD has been completed, no large randomized, multicenter, prospective clinical trials examine bevacizumab’s use for the treatment of macular edema due to RVO.22 However, in a 2012 survey of the American Society of Retina Specialists, 71% of respondents claimed it was their first-line treatment for a patient with a recent nonischemic CRVO with a visual acuity of 20/100.23 In the

48  Chapter 3

same survey, 80% of retina specialists chose to reinitiate treatment with bevacizumab over other treatment options in a patient with recurrent macular edema 5 months after a fourth injection of bevacizumab. Thus, IVB has become a standard-of-care treatment for macular edema due to RVO without Level I evidence to support its use. However, many other factors support its widespread use around the globe: its similarity in structure and function to ranibizumab, a favorable comparison to ranibizumab for treating AMD in a well-done noninferiority clinical trial, cost of bevacizumab relative to other drugs, and easy accessibility. With no large randomized clinical trials and few small prospective case series, clinicians have few established guidelines for using bevacizumab in the treatment of macular edema due to RVO. Therefore, clinicians will necessarily extrapolate from the ranibizumab clinical trials. However, not all bevacizumab issues are addressed in those trials. For example, what is the ideal dose of bevacizumab? What is the correct dosing interval? Does it potentially work better than ranibizumab? Are there any unique safety concerns? Some of these questions can be answered by the existing literature and can guide treatment options. For example, Wu et al 24 compared 2 doses of IVB as primary treatment for macular edema due to CRVO and found no difference in the 1.25-mg dose compared with the 2.5-mg dose. In this interventional, retrospective, comparative, multicenter study of 86 eyes, no statistically significant differences existed in the number of injections, central macular thickness on OCT, or change in visual acuity at month 24 between the 2 doses. Thus, the authors concluded that 1.25 and 2.5 mg of bevacizumab were equally effective in improving vision and reducing central macular thickness on OCT. The dosing interval for bevacizumab is likely not 6 weeks. This is evidenced by a 3-month double-masked, randomized clinical trial on 81 patients with acute BRVO who were randomly assigned to 1 of 2 treatment groups: IVB (2 injections of 1.25 mg of IVB 6 weeks apart) or sham treatment.25 Although visual acuity initially improved at the 6-week endpoint, at the 12-week endpoint, visual acuity was not significantly different between the 2 groups. This is in contrast to the sustained improvement through week 12 in a large prospective clinical trial in which ranibizumab was injected every 4 weeks, implying that the ideal treatment interval for bevacizumab is also likely 4 weeks. In AMD eyes treated in the Comparisons of AMD Treatments Trials (CATT), the PRN treatment arms of the study resulted in the same number of bevacizumab and ranibizumab treatments being given, again suggesting the ideal dosing interval for bevacizumab is not clinically longer.22 Early investigations of IVB in diabetic retinopathy by Avery and colleagues26 found 2 cases in which a subtle decrease in leakage of retinal neovascularization or NVI in the fellow noninjected eye was noted after a bevacizumab injection in the first eye for proliferative diabetic retinopathy. This was the first published evidence suggesting the possibility that therapeutic systemic levels were achieved after intravitreal injection of bevacizumab. The CATT found a higher incidence of hospitalizations associated with IVB injection compared with intravitreal ranibizumab injection.22 Although these 2 studies were performed in patients with diabetes mellitus and AMD, respectively, they raise the possibility that IVB use may be associated with a higher incidence of systemic adverse events. This possibility may go undetected without a large, prospective clinical trial or a concerted postmarketing surveillance effort.

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  49

For clinicians treating macular edema due to RVO, bevacizumab appears to be safe and effective, with visual acuity and OCT results approximating those seen in large clinical trials that used ranibizumab. Figure 3-11 shows bevacizumab use in a 76-year-old male with an 8-month history of decreased vision of 20/200 due to a superotemporal BRVO. Two weeks after intravitreal injection of 1.25 mg of bevacizumab, there is a significant improvement in visual acuity and retinal thickness on OCT. However, at week 4, there is regression in both the vision and the OCT, necessitating another injection. This is a typical response to treatment with any of the anti-VEGF agents currently in use, including bevacizumab. It is rare for RVO to be successfully treated with a single injection of an antiVEGF agent. Multiple monthly injections are generally required, and edema can recur when injections are stopped. Thus, IVB injections can be a highly beneficial treatment for macular edema due to RVO, but, as with ranibizumab, prolonged treatment schedules are often required.

PEGAPTANIB Pegaptanib sodium is a 40-kilodalton ribonucleic acid aptamer that binds VEGF165 selectively, the isoform that predominantly exerts the pathogenic effects in animal models of ischemia-mediated ocular neovascularization.27 Intravitreal pegaptanib is FDA approved for the treatment of neovascular AMD. It is not FDA approved for the treatment of macular edema due to RVO. However, 2 well-executed prospective FDA phase II clinical trials examining the use of intravitreal pegaptanib for macular edema due to CRVO28 and BRVO,29 respectively, are published in the peer-reviewed literature. The first study assessed the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following CRVO.28 It was a dose-ranging, doublemasked, multicenter, phase II clinical trial in which patients with CRVO, for a duration of 6 months or less, were randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg, n = 33; 1 mg, n = 33; sham, n = 32). The primary outcome was BCVA at week 30. In the primary analysis at week 30, 12 (36%) of 33 patients treated with 0.3 mg and 13 (39%) of 33 patients treated with 1 mg of pegaptanib sodium gained 15 or more letters from baseline vs 9 (28%) of 32 sham-treated patients (P = .48 for 0.3 mg and P = .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, patients treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6% in 0.3- and 1-mg groups, respectively) compared with sham-treated eyes (31%; P = .03 for 0.3 mg and P = .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+ 7.1 and + 9.9, respectively, vs –3.2 letters with sham; P = .09 for 0.3 mg and P = .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3- and 1-mg pegaptanib sodium groups by 269 μm and 210 μm, respectively, vs 5 μm with sham (P < .001). Although the primary endpoint for this study was not met, intravitreous pegaptanib sodium appeared to provide visual and anatomical benefits in the treatment of macular edema following CRVO. A subsequent phase III clinical trial was not performed. The second study assessed the efficacy and safety of intravitreal pegaptanib sodium for macular edema secondary to BRVO.29 It was a prospective, randomized, dose-finding, FDA phase II clinical trial in which 20 patients from 3 clinical practices in the United

50  Chapter 3

Figure 3-11. (A) 76-year-old male with an 8-month history of decreased vision. Visual acuity is 20/200. (continued)

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  51

Figure 3-11 (continued). (B) Baseline OCT shows cystic intraretinal edema and some subretinal fluid at the fovea. (C) Two weeks after IVB injection, the fluid has resolved and vision has improved to 20/50. However, 4 weeks after IVB injection, the fluid has recurred and vision drops back to 20/200.

States with macular edema due to BRVO of between 1 and 6 months’ duration, BCVA between 20/40 and 20/320, and CFT of 250 μm or more were randomized 3:1 to intravitreous injections of 0.3 or 1 mg of pegaptanib at baseline, 6 weeks, and 12 weeks with subsequent injections at 6-week intervals at investigator discretion until week 48. Fifteen patients received 0.3 mg of pegaptanib and 5 received 1 mg of pegaptanib. Eighteen patients completed the 54-week follow-up. Results were similar in both the 0.3- and 1-mg groups. Overall improvements from baseline to week 54 occurred in mean BCVA (+ 14613 letters) and central subfield thickness (–2016153 mm). The response was rapid

52  Chapter 3

Figure 3-12. COPERNICUS and GALILEO study design.32,33

after the first injection, with a mean BCVA improvement of 1167 letters at week 1. As with the earlier pegaptanib study in eyes with CRVO, although the results appeared promising for using pegaptanib to treat macular edema due to BRVO, a subsequent phase III clinical trial was not performed.

AFLIBERCEPT Aflibercept is a 115-kilodalton decoy receptor fusion protein comprising the second domain of human VEGF receptor 1 and the third domain of VEGF receptor 2 fused to the Fc domain of human immunoglobulin G1.30 Its binding affinity for VEGF is substantially greater than that of either bevacizumab or ranibizumab.31 The clinical use of aflibercept by retina specialists was pioneered in treating neovascular AMD, and aflibercept is FDA approved for that indication. Following successful clinical trials of aflibercept in exudative AMD, 2 independent FDA-sanctioned registration trials for aflibercept in macular edema due to CRVO were executed: the COPERNICUS (Vascular Endothelial Growth Factor Trap-Eye for Macular Edema Secondary to Central Retinal Vein Occlusion) study32 in the United States and the GALILEO (VEGF Trap-Eye for Macular Edema Secondary to Central Retinal Vein Occlusion) study33 outside of the United States. The favorable 6-month primary endpoint results of these 2 phase III studies led to FDA approval of 2.0 mg of aflibercept for macular edema due to CRVO. Consequently, only the data for the 2.0-mg dose of aflibercept will be discussed in this chapter.

Study Design Figure 3-12 shows the study design for both COPERNICUS and GALILEO, industrysponsored FDA registration trials intended to assess the efficacy and safety of intravitreal

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  53

aflibercept in eyes with macular edema due to CRVO. Designed in collaboration with the FDA, they were multicenter, randomized, prospective controlled trials that randomly assigned eligible eyes 3:2 to receive intravitreal 2.0 mg of aflibercept injection or sham injection monthly for 6 months. The COPERNICUS trial enrolled 189 eyes and the GALILEO trial enrolled 177 eyes that met the following inclusion criteria: Treatment-naïve patients with macular edema following CRVO regardless of perfusion status ●

●

Center-involved macular edema following CRVO

●

Diagnosed within 9 months of study initiation

●

Mean central retinal thickness of 250 μm or more on time-domain OCT

●

BCVA of 20/40 to 20/320

●

●

Aged 18 years or older Key exclusion criteria included the following: History of prior vitreoretinal surgery

●

History of panretinal or macular laser surgery

●

Any other serious ocular disease in the study or fellow eye

●

Any intraocular surgery in the prior 3 months

●

History of periocular or intraocular corticosteroid in the prior 3 months

●

History of antiangiogenic treatment in the study eye in the prior 3 months

●

NVI, vitreous hemorrhage, or uncontrolled glaucoma

CVA or MI in the prior 6 months Important aspects of the inclusion criteria for the COPERNICUS/GALILEO studies included the following: eyes could have had macular edema secondary to CRVO for up to 9 months, thus allowing chronic cases to be enrolled, and the lower limit of poor visual acuity was 20/320, thus excluding severe cases of CRVO. Important aspects of the exclusion criteria for the COPERNICUS/GALILEO studies included the following: eyes with a brisk afferent pupillary defect or evidence of retinal nonperfusion on fluorescein angiography in the study eye were not excluded, thus potentially including severely ischemic eyes in the study, and patients with a recent history of CVA or MI were excluded, which may have biased the study toward healthier patients. In the COPERNICUS study, 115 patients received 2-mg aflibercept injections and 74 patients received sham injections every 4 weeks. All patient groups were balanced with regard to age (sham group, 67.5 years; aflibercept group, 65.5 years), baseline visual acuity (sham group, 48.9 ETDRS letters; aflibercept group, 50.7 ETDRS letters), and baseline central retinal thickness on time-domain OCT (sham group, 672.4 μm; aflibercept group, 661.7 μm). Through week 24, 81.1% of sham-treated patients and 95.7% of aflibercepttreated patients completed all follow-up visits.32 In the GALILEO study, 106 patients received 2-mg aflibercept injections and 71 patients received sham injections every 4 weeks. All patient groups were balanced with regard to age (sham group, 63.8 years; aflibercept group, 59.9 years), baseline visual acuity (sham group, 50.9 ETDRS letters; aflibercept group, 53.6 ETDRS letters), and baseline ●

54  Chapter 3

Figure 3-13. Primary endpoint for the COPERNICUS and GALILEO studies.32,33

central retinal thickness on time-domain OCT (sham group, 638.7 μm; aflibercept group, 683.2 μm). Through week 24, 78.9% of sham-treated patients and 90.6% of aflibercepttreated patients completed all follow-up visits.33

Results In the COPERNICUS study, more patients receiving aflibercept (56.1%) gained 15 or more letters compared with patients receiving sham injections (12.3%) at week 24 (P < .0001). Figure 3-13 shows that aflibercept-treated patients gained a mean of 17.3 letters compared with 4.0 letters in sham-treated patients (P < .0001). Figure 3-14 shows that mean central retinal thickness decreased by 457.2 μm in aflibercept-treated eyes compared with 144.8 μm in sham-treated eyes (P < .0001).32 In the GALILEO study, more patients receiving aflibercept (60.2%) gained 15 or more letters compared with patients receiving sham injections (22.1%) from baseline to week 24 (P < .0001). Figure 3-13 shows that aflibercept-treated patients gained a mean of 18.0 letters compared with 3.3 letters in sham-treated patients (P < .0001). Figure 3-14 shows that mean central retinal thickness decreased by 448.6 μm in aflibercept-treated eyes compared with 169.3 μm in sham-treated eyes (P < .0001).33

Safety The safety profile of 2.0 mg of aflibercept in patients with CRVO was consistent with previous phase III trials of patients with exudative AMD. No new safety concerns were raised by the COPERNICUS or GALILEO clinical trials. In the GALILEO study, no serious events of endophthalmitis or retinal detachment occurred in the study eye. One mild case of intraocular inflammation occurred in the aflibercept group that resolved without

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  55

Figure 3-14. Key secondary anatomical endpoint for the COPERNICUS and GALILEO studies.32.33

change in therapy. In the COPERNICUS study, one case of endophthalmitis occurred. Cases of vitreous hemorrhage (n = 4), NVG (n = 2), NVI (n = 2), and retinal hemorrhage (n = 2) occurred in the COPERNICUS study, all of which occurred in sham-treated eyes, suggesting a protective effect of aflibercept in eyes with CRVO. There were no safety signals regarding systemic adverse events. No thromboembolic events occurred in either of the aflibercept-treated groups through 24 weeks. The COPERNICUS and GALILEO clinical trials demonstrated that intraocular aflibercept injections every 4 weeks were well tolerated for at least 6 months.

Limitations The COPERNICUS and GALILEO clinical trials were 12-month studies with limited inclusion criteria and a 6-month primary endpoint selected for FDA approval of aflibercept. The studies offer few guidelines for treating patients with the following conditions: vision better than 20/40 or worse than 20/320, patients with disease duration longer than 9 months at baseline, and patients with a prior history of treatment. When to initiate antiVEGF therapy in CRVO remains unanswered by the COPERNICUS and GALILEO studies, although sooner is probably better than later due to the poor natural history of CRVO and the apparent safety of aflibercept treatment. The COPERNICUS and GALILEO trials did not examine the use of aflibercept for the neovascular complications of CRVO. Finally, a drawback to anti-VEGF therapy with aflibercept is the need for injections every 4 weeks. Although aflibercept has FDA approval for dosing every 8 weeks in the treatment of exudative AMD, this treatment interval was not studied in the COPERNICUS and GALILEO studies.

56  Chapter 3

Conclusion The investigators of the COPERNICUS and GALILEO studies rightly concluded that anti-VEGF blockade results in rapid and sustained improvement in macular edema and visual acuity in eyes with macular edema due to CRVO. Based on the safety and efficacy results of the COPERNICUS and GALILEO studies, injections of aflibercept every 4 weeks can be considered a standard-of-care treatment for macular edema due to CRVO. It is important to note that at the time of this writing, aflibercept is being studied in FDA registration trials for the treatment of macular edema due to BRVO but is not FDA approved.

ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR COMPLICATIONS OF RETINAL VEIN OCCLUSION Despite the fact that no large, randomized clinical trials demonstrate the efficacy of anti-VEGF therapy for neovascular complications of RVO, anti-VEGF injections have become, de facto, the standard-of-care treatment for NVI and NVG. Bevacizumab is, generally, the agent of choice due to the off-label, non–FDA-approved nature of this treatment and the high cost associated with the other anti-VEGF agents currently available.34 In the 2011 Preferences and Trends Survey of the American Society of Retina Specialists, 74.3% of retina specialists surveyed chose bevacizumab plus panretinal photocoagulation (PRP) as the first-line treatment for NVG due to ischemic CRVO, 17.6% chose bevacizumab alone as the first-line treatment, and only 1.9% chose PRP as the first-line treatment (Figure 3-15).35 This represents a seismic shift in the treatment paradigm for NVG secondary to RVO compared with a decade ago. Management pearls regarding the use of anti-VEGF therapy, usually bevacizumab, for treatment of neovascular complications of RVO can be gleaned from a limited number of small, single-center clinical trials; numerous small, retrospective case series; and other investigations from the world’s literature. It is known that doses as low as 0.1 mg of bevacizumab given intracamerally or intravitreally are as effective as larger doses (generally 1.0 to 2.5 mg) in eradicating iris vessels associated with ischemic retinopathy.36 The elimination of iris vessels can be seen as early as 1 day.37 After treatment, there is a significant improvement in patient-reported eye pain.38 If abnormal blood vessel growth on the iris has not yet involved the angle and caused significant peripheral anterior synechiae or NVG, an immediate and profound drop in intraocular pressure will occur.39 If the angle is already closed, anti-VEGF therapy will have little effect on intraocular pressure or pain. The benefit of anti-VEGF therapy for NVI due to RVO is temporary, lasting approximately 1 month or as long as pharmacokinetics allow the drug to remain in the eye at therapeutic levels.40 Therefore, anti-VEGF therapy for NVG due to RVO is a short-term, ameliorating measure that must be used in conjunction with PRP. PRP is the only long-term fix for the ischemic retinopathy driving the abnormal neovascularization. The rapid and complete response of NVI or NVG to anti-VEGF therapy can lead clinicians to underestimate the ischemic insult and, therefore, undertreat affected eyes with PRP.41 Close monitoring of

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  57

Figure 3-15. Results from the 2011 American Society of Retina Specialists Preferences and Trends Survey.

post-intravitreal VEGF injection and post-PRP eyes is required to carefully titrate the right amount of PRP laser surgery with the severity of ischemia due to RVO. Eyes receiving sufficient PRP laser surgery to match the degree of retinal ischemia do not require additional anti-VEGF injections long term. For eyes with irreversible NVG and persistently elevated intraocular pressure that ultimately require surgical glaucoma procedures, anti-VEGF therapy is currently being explored as a surgical adjunctive treatment.42 The early reports from the glaucoma literature are mixed but suggest that eyes undergoing trabeculectomy with or without mitomycin C, seton valve placement, or transscleral cyclodestructive procedures may experience less acute anterior segment hemorrhaging, but the long-term success of the surgical procedure is unaffected by the adjuvant use of intraocular bevacizumab.

SYSTEMIC SAFETY OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS Intravitreal anti-VEGF injections are currently a standard-of-care treatment for exudative AMD, diabetic macular edema, and macular edema due to RVO. These agents have thus become one of the most commonly performed treatments in the United States. In 2008, 824,525 anti-VEGF injections were given.43 This number predates FDA approval of ranibizumab for RVO and diabetic macular edema and aflibercept for RVO. Thus, in 2012, the number of anti-VEGF injections per year in the United States likely exceeds 1 million and is rising. What is known about the local and systemic safety of anti-VEGF agents? Ranibizumab has been studied monthly in more than 10,000 patients in 27 clinical trials over a 13-year span. The safety data from these clinical trials are favorable, but it is

58  Chapter 3

important to remember that most trials, including FDA phase III clinical trials, may not be primarily designed or adequately powered to conclusively detect small safety signals. Bevacizumab accounted for 58% of the anti-VEGF agents administered to Medicare feefor-service recipients in 2008.43 Bevacizumab lacks a rigorous clinical trial history examining it for safety. Aflibercept is relatively new to ophthalmology and has yet to be studied in tens of thousands of patients, a number likely needed to detect small safety concerns. Because ranibizumab was FDA approved for RVO in 2010 and aflibercept was FDA approved for RVO in 2012, most of the literature on the safety of anti-VEGF injections for ocular disease comes from the AMD literature. Curtis and colleagues44 reported higher risks of stroke and all-cause mortality with intravitreal injections of bevacizumab compared with ranibizumab when used for treating AMD in a retrospective analysis of 146,942 Medicare case records. Gower et al45 also reviewed a large Medicare database and found an 11% higher risk of all-cause mortality and a 57% higher risk of hemorrhagic stroke with bevacizumab compared with ranibizumab when used to treat AMD. No statistically significant differences existed in the risk of either MI or ischemic stroke between the 2 drugs.45 The landmark ranibizumab clinical trials found no increase in stroke rate among patients receiving the drug, but the SUSTAIN (Study of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration) trial in Europe found that 10% of patients who had a prior history of stroke suffered another stroke in the first 12 months of the study.46 These data from the AMD literature are remarkable when coupled with the finding by Werther et al47 that patients with RVO have a 2-fold higher incidence of stroke compared with age-matched control patients at baseline, even before being treated with anti-VEGF agents. The CATT trial 1-year results found that the proportion of patients with serious systemic events was 24.1% for bevacizumab and 19.0% for ranibizumab (P = .4).48 After adjustment for demographic features and coexisting illnesses at baseline, the risk of serious systemic adverse events for bevacizumab at 1 year was higher by 29% (P = .4).48 The results held during the second year of the CATT trial: the proportion of patients with one or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs 31.7%; adjusted risk ratio, 1.30; 95% confidence interval, 1.07 to 1.57; P = .009).22 The findings from the CATT trial are difficult to explain because no specific organ system consistently accounted for the differences in adverse events. In addition, most of the excess events had not been associated previously with systemic therapy targeting VEGF. Several large analyses comparing the safety of ranibizumab with bevacizumab suggest that the use of bevacizumab may be associated with increased systemic morbidity. This has biological plausibility based on the observation by Avery and colleagues26 of fellow-eye effects when IVB was given for diabetic retinopathy in the first eye. Bakri et al40 also found small amounts of bevacizumab in the serum and in the fellow uninjected eye. To date, most large Medicare claims database analyses of safety for intravitreal antiVEGF agents have been performed with AMD patients, a patient population different from RVO patients with possibly different underlying risk factors and comorbidities. An extrapolation of AMD data to RVO patients may be reasonable if done with caution. To date, no large Medicare claims database analyses of safety have examined aflibercept. Again, any extrapolation of ranibizumab and bevacizumab data to aflibercept should be done with caution. With increased use of all of these anti-VEGF agents to treat RVO and other ocular disease, more safety analyses will be forthcoming.

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  59

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Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983-985. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306-1309. Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309-1312. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-1487. Christoffersen NL, Larsen M. Pathophysiology and hemodynamics of branch retinal vein occlusion. Ophthalmology. 1999;106(11):2054-2062. Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signaling and therapeutic inhibition. Cell Signal. 2007;19(10):2003-2012. Noma H, Funatsu H, Mimura T, Harino S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor in macular edema with central retinal vein occlusion. Ophthalmology. 2009;116(1):87-93. Sawada O, Kawamura H, Kakinoki M, Sawada T, Ohji M. vascular endothelial growth factor in aqueous humor before and after intravitreal injection of bevacizumab in eyes with diabetic retinopathy. Arch Ophthalmol. 2007;125(10):1363-1366. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36(4):336-339. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. 2006;26(3):279-284. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implications of VEGF as a critical stimulator. Mol Ther. 2008;16(4):791-799. Pieramici DJ, Rabena M, Castellarin AA, et al. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions. Ophthalmology. 2008;115(10):e47-e54. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.e1. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. Shilling JS, Jones CA. Retinal branch vein occlusion: a study of argon laser photocoagulation in the treatment of macular oedema. Br J Ophthalmol. 1984;68(3):196-198. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041-2049.

60  Chapter 3 19. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118(8):1594-1602. 20. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012;119(4):802-809. 21. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342. 22. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398. 23. Jumper JM, Mittra RA, eds. ASRS 2012 Preferences and Trends Membership Survey. Chicago, IL: American Society of Retina Specialists; 2012 24. Wu L, Arevalo JF, Berrocal MH, et al. Comparison of two doses of intravitreal bevacizumab as primary treatment for macular edema secondary to central retinal vein occlusion: results of the pan American collaborative retina study group at 24 months. Retina. 2010;30(7):1002-1011. 25. Moradian S, Faghihi H, Sadeghi B, et al. Intravitreal bevacizumab vs. sham treatment in acute branch retinal vein occlusion with macular edema: results at 3 months (Report 1). Graefes Arch Clin Exp Ophthalmol. 2011;249:193-200. 26. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006;113(10):1695.e1-15. 27. Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006;5:123-132. 28. Wroblewski JJ, Wells JA III, Adamis AP, et al. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. Arch Ophthalmol. 2009;127(4):374-380. 29. Wroblewski JJ, Wells JA III, Gonzales CR. Pegaptanib sodium for macular edema secondary to branch retinal vein occlusion. Am J Ophthalmol. 2010;149(1):147-154. 30. Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multi-component, highaffinity blockers of cytokine action. Nat Med. 2003;9(1):47-52. 31. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393-11398. 32. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032. 33. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278-284. 34. Park SC, Su D, Tello C. Anti-VEGF therapy for the treatment of glaucoma: a focus on ranibizumab and bevacizumab. Expert Opin Biol Ther. 2012;12(12):1641-1647. 35. Jumper JM, Mittra RA, eds. ASRS 2011 Preferences and Trends Membership Survey. Chicago, IL: American Society of Retina Specialists; 2011. 36. Sasamoto Y, Oshima Y, Miki A, et al. Clinical outcomes and changes in aqueous vascular endothelial growth factor levels after intravitreal bevacizumab for iris neovascularization and neovascular glaucoma: a retrospective two-dose comparative study. J Ocul Pharmacol Ther. 2012;28(1):41-48. 37. Grisanti S, Biester S, Peters S, et al. Intracameral bevacizumab for iris rubeosis. Am J Ophthalmol. 2006;142(1):158-160. 38. Kotecha A, Spratt A, Ogunbowale L, et al. Intravitreal bevacizumab in refractory neovascular glaucoma: a prospective, observational case series. Arch Ophthalmol. 2011;129:145-150. .

Anti-Vascular Endothelial Growth Factor Therapies for Retinal Vein Occlusion  61 39. Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology. 2008;115(9):1571-1580.e1-3. 40. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114(5):855-859. 41. Gheith ME, Siam GA, de Barros DS, Garg SJ, Moster MR. Role of intravitreal bevacizumab in neovascular glaucoma. J Ocul Pharmacol Ther. 2007;23(5):487-491. 42. Horsley MB, Kahook MY. Anti-VEGF therapy for glaucoma. Curr Opin Ophthalmol. 2010;21:112-117. 43. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular agerelated macular degeneration: an analysis of the 100% 2008 Medicare fee-for-service part B claims file. Am J Ophthalmol. 2011;151(5):887-895.e1. 44. Curtis LH, Hammill BG, Schulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128(10):1273-1279. 45. Gower EW, Cassard S, Chu L, Varma R, Klein R. Adverse event rates following intravitreal injection of Avastin or Lucentis for treating age-related macular degeneration. Paper presented at: Association for Research in Vision and Ophthalmology (ARVO) annual meeting 2011; May 1-5, 2011; Fort Lauderdale, FL. 46. Chong NV. Should avastin be used to treat age-related macular degeneration in the NHS?—No. Eye (Lond). 2009;23(6):1250-1253. 47. Werther W, Chu L, Holekamp N, Do DV, Rubio RG. Myocardial infarction and cerebrovascular accident in patients with retinal vein occlusion. Arch Ophthalmol. 2011;129(3):326-331. 48. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.

4

Corticosteroid Therapies in the Management of Macular Edema Secondary to Retinal Vein Occlusion Amol Kulkarni, MD and Michael S. Ip, MD

RATIONALE The development of macular edema secondary to retinal vein occlusion (RVO) has been hypothesized to be caused by breakdown of the blood-retina barrier.1 This is mediated by the secretion of vasopermeability factors such as vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and others.1 Intravitreal steroids have been shown experimentally to reduce the breakdown of the blood-retina barrier by inhibiting factors such as IL-6, VEGF, prostaglandins, and protein kinase C.2 Several case studies have shown favorable anatomical response to intravitreal injection of triamcinolone acetonide (TA).3-7 This initial favorable response to TA introduced the use of intraocular corticosteroids in the management of macular edema secondary to RVO. The corticosteroid preparations currently available for intraocular delivery include TA and dexamethasone (DEX). These corticosteroids are selective and potent glucocorticoid (GR) agonists (Table 4-1). They have no mineralocorticoid activity. Extended delivery of these steroids can occur either by use of a controlled-release system (Table 4-2) or, in the case of TA, by the dissolution of insoluble TA crystals into soluble TA in the vitreous cavity. Fluocinolone acetonide (FA) and TA have a stable C16-C17 acetonide group, whereas DEX has a methyl group on the C16 position and a hydroxyl group on the C17 position.8 The vitreous elimination half-life for these 3 compounds in solubilized form is 2 to 3 hours. Therefore, for an extended duration of action, these compounds need to have slow

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Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 63-78). © 2014 SLACK Incorporated.

64  Chapter 4

TABLE 4-1. COMPARISON OF POTENCY OF INTRAOCULAR STEROIDS8 STEROID

GLUCOCORTICOID POTENCY

TA

1

FA

0.4

DEX

3

Prednisolone

8

Cortisol

72

TABLE 4-2. EXTENDED-RELEASE FORMULATIONS OF INTRAVITREAL STEROIDS9 STEROID

TRADE NAME

MANUFACTURER

FA

Retisert

Bausch + Lomb

FA

Iluvien

Alimera Sciences

DEX

Ozurdex

Allergan

TA

Kenalog

Bristol-Myers Squibb

TA

Triesence

Alcon

TA

Trivaris

Allergan

TA

I-vation

SurModics

dissolution of crystals or delivery from a controlled-release system. Intravitreal injection or implantation of these extended-release formulations creates a diffusional drug gradient from depot to macula with minimal systemic exposure. This promotes resolution of macular edema. Furthermore, intraocular steroids also have the potential to normalize glial and neuronal function of the diseased retina as compared with anti-VEGF agents.8 These unique attributes make intraocular steroids a suitable therapy in the management of macular edema secondary to RVO.

TRIAMCINOLONE ACETONIDE TA is a long-acting corticosteroid depot that is delivered by periocular or intravitreal injection. A human pharmacokinetics study of nonvitrectomized eyes found a single 4-mg intravitreal injection of TA to have a mean half-life of 18.6 days, with measurable concentrations expected to last approximately 3 months.10 Preliminary short-term results of intravitreal therapy with TA for macular edema associated with RVO showed transient anatomical and functional benefits. As a result, the National Eye Institute funded the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study in 2003.11 It was a multicenter, randomized, phase III trial that evaluated the safety and efficacy of standard care (observation or macular laser) vs intravitreal injection(s) of TA for macular

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  65

edema secondary to RVO. Individuals with branch RVO (BRVO) and central RVO (CRVO) with associated macular edema of up to 24 months’ duration and best corrected visual acuity (BCVA) between 19 and 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (corresponding to approximately 20/40 to 20/400 Snellen BCVA) were eligible for participation in the SCORE study.11 The 2 primary study objectives of the SCORE-BRVO trial were to (1) determine whether intravitreal TA at 1- and 4-mg doses produce greater visual benefit, with an acceptable safety profile, than grid photocoagulation (standard care) does, when appropriate, for the treatment of vision loss associated with macular edema secondary to BRVO; and (2) compare the safety and efficacy of the 1- and 4-mg TA doses.12 The results of the SCOREBRVO trial demonstrated no significant differences among the 3 treatment groups regarding a gain in visual acuity letter score of 15 or more at 12 months (29%, 26%, and 27% in the standard care and 1- and 4-mg TA groups, respectively).12 An early positive treatment response of a gain in visual acuity letter score of 15 or more was observed at month 4 in the 4-mg TA group compared with the 1-mg TA and standard care groups. After month 12 and through month 36, the mean improvement from baseline visual acuity letter score was greatest in the standard care group compared with the 2 TA groups. With respect to optical coherence tomography (OCT)-measured center point thickness, all 3 groups showed a decrease from baseline to month 12. Analogous to the visual acuity results, only at month 4 did the 4-mg TA group demonstrate a greater treatment effect on center point thickness than the 1-mg and standard care groups; at all other times investigated (months 8 through 36), the standard care group demonstrated the greatest overall median decrease in center point thickness from baseline. The rates of adverse events were higher in the 4-mg TA group compared with the 1-mg TA and standard care groups. There was a dose-dependent higher frequency of initiating intraocular pressure (IOP)-lowering medications in the TA groups (41% in the 4-mg group and 8% in the 1-mg group) compared with the standard care group (2%). The proportion of phakic eyes that had new-onset lens opacity or progression of an existing opacity through 12 months based on assessment at the clinical center was greater in the 2 TA groups (35% in the 4-mg group and 25% in the 1-mg group) compared with the standard care group (13%). Most cataract surgeries were performed during the second year of the study and occurred with the highest frequency in the 4-mg TA group (n = 35). The rates of adverse events with respect to cataract surgery and elevated IOP were similar between the standard care and 1-mg TA groups. Thus, the SCOREBRVO study results, at the time of their publication, supported grid photocoagulation as the continued standard of care for patients with decreased visual acuity associated with macular edema secondary to BRVO up to 12 months and possibly up to 36 months.12 The 2 primary study objectives of the SCORE-CRVO trial were to (1) compare 1- and 4-mg doses of intravitreal TA with standard care (observation) for the treatment of vision loss associated with macular edema secondary to perfused CRVO; and (2) evaluate the safety and efficacy of the 1- and 4-mg TA doses.13 The primary outcome of the SCORECRVO trial (ie, the percentage of participants with a gain in visual acuity letter score of 15 or more from baseline to month 12) was 6.8%, 26.5%, and 25.6% for the observation and 1- and 4-mg TA groups, respectively. More eyes in the 4-mg TA group (35%) initiated IOP-lowering medication through 12 months compared with eyes in the 1-mg TA (20%) and observation (8%) groups. During the first 12 months of the study, 2 participants in the 1-mg TA group underwent tube shunt surgery. Between 12 and 24 months, 2 participants

66  Chapter 4

in the 4-mg TA group underwent tube shunt surgery. Glaucoma surgery in all participants was deemed by the investigator to be necessary because of neovascular glaucoma (NVG) rather than secondary to steroid-induced IOP elevation. Among eyes that were phakic at baseline, the estimate through month 12 of new-onset lens opacity or progression of an existing opacity was 18% in the observation group compared with 26% and 33% in the 1- and 4-mg TA groups, respectively. Whereas no eyes in the observation or 1-mg TA groups had cataract surgery through month 12, 4 eyes in the 4-mg TA group had cataract surgery. Similarly, cataract surgery was more frequent between months 12 and 24 in the 4-mg TA group, with 21 eyes having cataract surgery, compared with 3 in the 1-mg TA group and 0 in the observation group. Through month 12, there were no reports of infectious or noninfectious endophthalmitis or retinal detachment in any of the 3 study groups. In summary, intravitreal TA in both 1- and 4-mg doses had better visual acuity outcomes over 1 year, and possibly 2 years, than the untreated natural history of macular edema secondary to perfused CRVO. The superior safety profile of the 1-mg dose compared with the 4-mg dose, particularly with respect to glaucoma and cataract, makes it the preferred dose. A favorable visual acuity response after intravitreal TA is more likely in patients with perfused rather than nonperfused macular edema. Retreatment may also be performed in some patients due to recurrent macular edema. Reported side effects with intravitreal TA include cataract, increased IOP, and injection-related complications, including noninfectious and infectious endophthalmitis, retinal detachment, vitreous hemorrhage, and lens injury.3-7 Commercially available formulations of TA include Kenalog, Triesence, and compounded triamcinolone (see Table 4-2). Kenalog-40 is a preserved formulation of TA. Triamcinolone can also be obtained in a preservative-free formulation from compounding pharmacies. Intravitreal injections of Kenalog and compounded TA are considered to be off-label use.14 Triesence is a preservative-free formulation of TA that is approved for intraocular use but not labeled specifically for use in RVO. Triesence suspension is packaged as a single-use 1-mL vial at a concentration of 40 mg/mL.14 Trivaris was evaluated in the SCORE study and has an approvable letter from the Food and Drug Administration (FDA) but is not commercially available. SurModics, Inc has developed the I-vation Sustained Drug Delivery system for the sustained release of TA to the posterior segment.15 The I-vation implant is currently experimental and consists of 3 components: a nonferrous metallic scaffold in the shape of a helix, a cap that is attached to the helix, and a drug-loaded polymer coating that encapsulates the helix (Figure 4-1). The implantation is performed under local anesthesia in the operating room and begins with a 2- to 3-mm circumferential dissection of the conjunctiva and Tenon’s capsule, followed by a sclerotomy using a 25- to 30-g needle. The I-vation implant is inserted through the sclerotomy into the vitreous cavity and rotated clockwise such that the thin cap of the implant abuts the sclera. The overlying conjunctival incision is sutured with Vicryl (polyglactin 910) sutures (Ethicon, Inc). The unique implant design allows a constant rate of drug release for up to 2 years while maintaining the ability to discontinue treatment by removing the implant. A phase II prospective study to evaluate the safety and tolerability of the I-vation TA implant is underway in 31 patients with diabetic macular edema.16 These patients were randomized to receive a slow-release (1 μg/day) or fast-release (3 μg/day) formulation containing 925 μg of TA. Participants in the study will be monitored for 3 years. A preliminary

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  67 Figure 4-1. SurModics Inc’s I-vation controlled release triamcinolone acetonide drug delivery system is a removable intravitreal implant. (Reprinted with permission of SurModics, Inc.)

safety and efficacy review of data at 9 months after implantation was reported on 27 of the 31 patients enrolled in the study. The mean change in central retinal thickness was 100.2 μm (± 158.9) from baseline (n = 27) and BCVA improved to 20/80 or better (ETDRS Snellen equivalent) in 18 (67%) of 27 patients. The mean increase in IOP was 4 mm Hg at 9 months, and IOP-lowering medications were prescribed to 4 patients. All patients were evaluated for cataract formation and/or progression, and one phakic patient underwent cataract surgery. The implant was well tolerated in a majority of patients and required explantation in 2 patients for exposure of the cap through the conjunctiva. SurModics, Inc has partnered with Merck to develop and commercialize the I-vation TA system. Icon Bioscience, Inc has developed a sustained-release intravitreal liquid drug delivery of TA (IBI-20089) designed to deliver the TA for up to 1 year with a single intravitreal injection.17 A prospective, phase I clinical trial consisting of 10 patients (6.9 mg in 5 patients and 13.8 mg in 5 patients) with chronic macular edema resulting from RVO showed significant reduction in OCT central subfield thickness in both groups (477 μm to 251 μm in the 6.9-mg group and 518 μm to 278 μm in the 13.8-mg group). Elevation of IOP occurred in 3 patients—in 2 patients due to NVG (not related to the study drug) and in 1 who required a glaucoma tube shunt due to steroid-induced glaucoma.

68  Chapter 4

Figure 4-2. Ozurdex implant. (Copyright—Allergan, Inc, used with permission.)

Figure 4-3. Ozurdex intravitreal implant. (Left) As the polymer breaks down into inert compounds over time, the drug is released. (Right) Scanning electron microscopy of implant surface in an animal model.

OZURDEX DEX is 3 times more potent a GR than TA. However, it is rapidly cleared from the vitreous cavity (half-life of 5.5 hours) in humans. Ozurdex is an extended-delivery bioerodible DEX polylactic acid polyglycolic acid copolymer complex (Figures 4-2 and 4-3).18 The poly(D,L-lactide-co-glycolide) degrades into lactic acid and glycolic acid (Figure 4-4). The release of DEX depends on the diffusion through the polymer matrix, solubility of the polymer, and rate of degradation of polymer matrix. Pharmacokinetics and pharmacodynamics studies of a 0.7-mg Ozurdex implant were performed in monkeys. Samples of blood, vitreous humor, and retina were obtained at days 7, 30, 60, 90, 120, 150, 180, 210, 240, and 270 after implantation.8 DEX was detected in the retina and vitreous humor for 6 months, with peak concentrations during the first 2 months. DEX concentrations in the retina were characterized by 2 distinct phases: (1) high concentrations of DEX (Cmax) from days 7 to 60 (Cmax=1110 ± 284 ng/g at day 60) and (2) low concentrations of DEX (Clast) (Clast=0.0167 ± 0.0193 ng/g at day 210).8 DEX concentrations in the vitreous humor were also characterized by 2 distinct phases: (1) days 7 to 60 (Cmax = 213 ± 49 ng/mL at day 60) and (2) days 90 to 180 (Clast = 0.00131 ± 0.00194 ng/mL at day 180). A specially designed proprietary instrument is used for the intravitreal injection of the Ozurdex implant, thus obviating the need for surgery. It consists of a 22-g, 1-inch–long hypodermic needle mounted on a device measuring 165 × 13 mm and preloaded with the implantable drug product (see Figure 4-2).18 The drug implant is injected into the pars plana by pressing a button. The implant releases a total dose of 0.7 mg of DEX. Adverse events associated with this implant include anterior chamber flare, conjunctival hyperemia, conjunctival hemorrhage, eye pain, floaters, IOP increase, vitreous hemorrhage, vitritis, and migration of the

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  69

Figure 4-4. The Ozurdex drug delivery technology. (Copyright—Allergan, Inc, used with permission.)

implant into the anterior chamber in aphakic eyes. The majority of these events occurred within the first 7 days after injection.18 The Ozurdex implant is the first FDA-approved pharmacologic for the treatment of macular edema secondary to RVO. The Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion With Macular Edema (GENEVA) studies were 2 identical randomized, prospective, multicenter, masked, sham-controlled, parallel-group, phase III clinical trials showing the efficacy of the DEX implant compared with sham treatment for macular edema associated with BRVO or CRVO.19 The trials enrolled 1267 patients aged 18 years or older with a BCVA between 20/50 and 20/200 secondary to edema of 300 μm or more in the central 1-mm macular subfield associated with RVO. The duration of macular edema was at least 6 weeks and up to 9 months for CRVO and up to 12 months for BRVO. The study consisted of a 6-month primary phase followed by a 6-month openlabel follow-up phase in which all eyes with visual acuity worse than 20/20 or OCT thickness greater than 250 μm were offered the 700-μg implant. In the primary phase, enrolled patients were randomized 1:1:1 to receive either a 700-μg DEX implant (n = 427), a 350-μg DEX implant (n = 412), or a sham injection (n = 423). The exclusion criteria included the presence of clinically significant epiretinal membrane; active retinal or optic disc neovascularization; active or history of choroidal neovascularization; presence of rubeosis iridis; any active infection; aphakia or anterior chamber intraocular lens; clinically significant media opacity, glaucoma, or glaucoma requiring more than one medication to control IOP in the study eye; or a history of steroid-induced IOP rise in either eye. Patients were also excluded if they had diabetic retinopathy in either eye, had any uncontrolled systemic disease, were currently using or anticipating the use of systemic steroids or anticoagulants during the study, or had any ocular condition in the study eye, which, in the opinion of the investigator, would prevent a 15-letter improvement in BCVA. Ninety-four percent (1196) of patients completed the study through day 180, and 79% (997) of patients continued on with the open-label phase. One-third (437/1267) of each group had a diagnosis of CRVO, whereas the remaining two-thirds (830/1267) had a diagnosis of BRVO. The duration of macular edema was also similar between groups. Patients did not receive grid photocoagulation in the control arm. All patients were examined at baseline and at 1, 7, 30, 60, 90, and 180 days after treatment. The primary outcome for the

70  Chapter 4

first 6 months was the proportion of eyes achieving at least a 15-letter improvement from baseline. The FDA later changed the primary outcome for the second study to be the time to reach a 15-letter improvement from baseline. Following completion of the first portion of the study, patients were eligible to have open-label retreatment with 0.7 mg of Ozurdex regardless of which initial treatment group they were in (sham, 0.35 mg, or 0.7 mg), provided they demonstrated evidence of macular edema of more than 250 μm on OCT examination and visual acuity worse than 20/20 at 6 months. Both DEX implant groups showed significantly greater improvement in vision than did the sham treatment group.19 The cumulative response rate was 41% in the 0.7-mg Ozurdex group, 40% in the 0.35-mg Ozurdex group, and 23% in the sham injection group (P < .001). Although the proportion of eyes achieving at least a 15-letter improvement from baseline BCVA was greater in the treatment groups at month 1 (21% in the 0.7-mg Ozurdex group vs 18% in the 0.35-mg Ozurdex group vs 8% in the sham injection group; P < .001) and month 3 (22% in the 0.7-mg Ozurdex group vs 23% in the 0.35-mg Ozurdex group vs 13% in the sham injection group; P < .001), this effect was not statistically significant at month 6. The reduction in mean OCT central subfield retinal thickness was greater in the 0.7-mg (208 ± 201 μm) and 0.35-mg (177 ± 197 μm) Ozurdex groups than in the sham injection group (85 ± 173 μm) at month 3 (P < .001) but not statistically significant at month 6. It should be noted that 21% of BRVO eyes and 17% of CRVO eyes required only a single treatment through 12 months. The DEX implant was well tolerated, and most eyes had no significant increase in IOP at 6-month follow-up. Only 2 eyes (0.2%) in either DEX group had IOP of more than 35 mm Hg, and 10 eyes (1.2%) had IOP of more than 25 mm Hg at 6 months. At day 90, 237 eyes (29.7%) were treated with IOP-lowering medication, and the IOP returned to baseline by day 180 in all groups. Only 5 eyes (0.7%) required surgical intervention for IOP control, and 3 of these were for NVG due to the RVO disease process and not to Ozurdex. Rates of cataract progression up to 1 year did not differ significantly between the groups. The side effect profile was similar during the 6-month open-label extension, during which all eyes received a first (in the case of sham-treated eyes) or second DEX implant. In the extended follow-up, 108 eyes (32.8%) of retreated 0.7/0.7-mg DEX group patients had at least a 10-mm Hg increase in IOP from baseline at some point over the 12-month period. In this retreatment group, 14 eyes required laser or surgery to reduce IOP. Cataracts were reported in 29.8% (90/302) of phakic study eyes in the retreated 0.7/0.7-mg DEX group, in 19.8% (56/283) of the 0.35/0.7-mg DEX group, and in 10.5% (31/296) of the delayed treatment (sham/0.7-mg DEX) group (P = .001). A total of 11 patients underwent cataract surgery. The results from the GENEVA phase III trials have important clinical implications.19 Earlier treatment was associated with a better visual acuity outcome across subgroups. A 3-line gain following treatment with the 700-μg implant was seen in 48% (140/291) of eyes with BRVO in 90 or fewer days and in 67% (286) of eyes with baseline BCVA worse than 55 letters in the 90 or fewer days subset. In addition, there was up to a 2-fold greater risk of 3-line loss in sham-treated eyes compared with 0.7-mg DEX-treated eyes. Risk of vision loss persisted at 12 months, even after the sham group was treated with a 700-μg implant at the 6-month visit. In patients with BRVO treated with Ozurdex, mean change in visual acuity from baseline was approximately + 6.6 letters for retreated patients and + 6.5 letters for delayed treatment. In patients with CRVO treated with Ozurdex, mean change

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  71

Figure 4-5. Retisert fluocinolone implant. (Reprinted with permission of Bausch + Lomb.) (continued)

in visual acuity from baseline was approximately + 2.2 letters for retreated patients and − 1.2 letters for delayed treatment.

FLUOCINOLONE ACETONIDE FA is a glucocorticoid that can be delivered by polymer-based nonbiodegradable platforms to the posterior segment (Figures 4-5 and 4-6)—although no implant is FDA approved for use in RVO. Retisert is FDA approved for the treatment of uveitis and is designed to release 0.59 μg/ day of FA (see Figure 4-5). It has been evaluated for the treatment of macular edema secondary to CRVO in a pilot study but has not been FDA approved for this indication.20 In this prospective, noncomparative, interventional case series, 24 eyes of 23 patients with chronically persistent macular edema associated with CRVO underwent intraocular implantation of a 3-year FA sustained drug delivery system.20 At 1, 2, and 3 years postimplantation, mean visual acuity showed gains of 4.5 (P = .52), 8.2 (P = .07), and 3.4 (P = .64) letters, respectively, and 32% (6/19), 56% (10/18), and 50% (9/18) of study eyes, respectively, showed at least a 10-letter gain in ETDRS score. At these same time points, mean central foveal thickness improved by 247 (44%; P = .002), 212 (38%; P < .001), and 250 (45%; P < .001) μm, respectively. During the study period, all phakic eyes ultimately underwent cataract extraction, and 5 eyes underwent glaucoma surgery. It should be noted that a phase II, randomized, double-masked, pilot study of the safety and efficacy of 0.5 μg/day and 0.2 μg/day of Iluvien Fluocinolone Acetonide Intravitreal Inserts (see Figure 4-6) for Vein Occlusion in Retina (FAVOR study) was underway at the time of publication of this textbook.

72  Chapter 4

Figure 4-5 (continued). Retisert fluocinolone implant. (Reprinted with permission of Bausch + Lomb.)

COMPARISON OF THERAPIES Anti-Vascular Endothelial Growth Factor vs Corticosteroids Anti-VEGF therapies have become a widely accepted treatment of macular edema secondary to RVO.21 Unfortunately, no randomized, controlled trial compares antiVEGF agents directly with corticosteroids. As compared with corticosteroids, which have durability in the eye for several months, anti-VEGF recommended treatment interval is more frequent. It is important to differentiate between a partial response (more common) and nonresponse (rare) to intravitreal anti-VEGF therapy based on anatomic findings. Patients who have persistent macular edema despite monthly anti-VEGF injections for at least 3 months (partial response) can be considered for combination treatment with the DEX implant (on-label) or intravitreal triamcinolone (off-label). Patients with no changes in baseline visual acuity, central retinal thickness, and macular morphology on OCT despite monthly anti-VEGF injections for 3 consecutive months should be considered

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  73

Figure 4-6. Iluvien fluocinolone implant. (Reprinted with permission of Alimera Sciences, Inc.)

nonresponders. In these patients, switching the anti-VEGF agent (eg, switching from bevacizumab to aflibercept) can sometimes yield success. One may also consider combination therapy with Ozurdex because good evidence exists that RVO has both inflammatory and ischemic components, providing good rationale for using both a steroid and anti-VEGF to treat macular edema from this disease (Figures 4-7 and 4-8). Unfortunately, long-term studies on the safety and efficacy of these approaches are not yet available, and further studies need to be performed showing long-lasting improvement in vision with the use of combination approaches. Combination therapies will be discussed in much greater detail in Chapter 6 in this textbook.

74  Chapter 4

Figure 4-7. (A) Fundus photo and (B) OCT scan of patient with persistent macular edema secondary to CRVO treated with 2 intravitreal bevacizumab injections. The patient underwent intravitreal triamcinolone acetonide and there was resolution of macular edema as noted in the (C) 3-month follow-up fundus photo and (D) OCT scan.

Figure 4-8. (A) OCT scan of patient with persistent macular edema secondary to CRVO despite being treated with intravitreal injections of bevacizumab x 2, triamcinolone x 1, and ranibizumab x 2. (B) The patient underwent Ozurdex implant and there was resolution of macular edema at 1-month follow-up OCT scan. (C) The macular edema recurred at 3.5-month follow-up status post Ozurdex as noted in OCT scan. (D) The patient underwent a second Ozurdex implant and had no macular edema at 2-month follow-up as noted in OCT scan.

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  75

Ozurdex Versus Triamcinolone Acetonide No head-to-head comparison exists of Ozurdex (on-label) and TA (off-label).18 Ozurdex is more costly (approximately $1300) than TA (either Triescence, Kenalog, or a compounded formulation). Ozurdex (700 μg) has a significant impact on the resolution of macular edema secondary to RVO at 3 months postimplantation and up to 12 months in approximately 20% of eyes. On the other hand, the effect of a single intravitreal injection of TA (4 mg) can be seen to last only a few weeks in some patients and up to 3 months in other patients. When comparing the 2 therapies, Ozurdex has a lower rate of cataract formation and IOP elevation compared with TA. The worse side-effect profile of TA limits its longterm use. Furthermore, the aggregates of TA may cause floaters that bother some patients. Sterile endophthalmitis occurring after TA injection is caused by the vehicle in some formulations or can be due to dispersed TA crystals migrating into the anterior chamber causing pseudoendophthalmitis (Figure 4-9). In contrast, Ozurdex is preservative free and nondispersive. The other theoretical design advantages of the Ozurdex polymer over a bolus injection of TA include more consistent levels of steroid delivered, a smaller quantity of drug required for the duration of treatment, and avoidance of the pulse effect.

CONCLUSION Over the past 2 decades, notable advances have occurred in our understanding of the pathophysiology of macular edema secondary to RVO. One of these advances is the understanding that RVO has a multifactorial etiology (localized inflammation in addition to ischemia causing high VEGF levels) and that therapy with both corticosteroids and antiVEGF is necessary in some patients, especially those recalcitrant to a given monotherapy. Evolving corticosteroid preparations over the past decade have helped in our management of this disease. Newer-generation, FDA-approved corticosteroids such as Ozurdex provide us with a safer and more durable treatment option compared with older-generation steroid preparations. Minimal controversy exists that corticosteroids are an important tool that retina specialists use to manage this condition. With time, we believe that the controversy of anti-VEGF vs corticosteroids will evolve into a discussion of when to use what combination of therapies in a given patient. Undoubtedly, as new and improved therapies are developed, our treatment regimens will continue to evolve.

REFERENCES 1. 2. 3. 4.

Rehak J, Rehak M. Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. Curr Eye Res. 2008;33(2):111-131. Wolfensberger TJ, Gregor ZJ. Macular edema—rationale for therapy. Dev Ophthalmol. 2010;47:49-58. Lee H, Shah GK. Intravitreal triamcinolone as primary treatment of cystoid macular edema secondary to branch retinal vein occlusion. Retina. 2005;25(5):551-555. Yepremyan M, Wertz FD, Tivnan T, Eversman L, Marx JL. Early treatment of cystoid macular edema secondary to branch retinal vein occlusion with intravitreal triamcinolone acetonide. Ophthalmic Surg Lasers Imaging. 2005;36(1):30-36.

76  Chapter 4

Figure 4-9. Post-intravitreal Kenalog endophthalmitis vs pseudoendophthalmitis. (A) 4+ cell and flare with keratic precipitates and hypopyon within 1 day after intravitreal triamcinolone injection. (continued)

5.

6. 7.

8.

Ozkiris A, Evereklioglu C, Erkiliç K, Ilhan O. The efficacy of intravitreal triamcinolone acetonide on macular edema in branch retinal vein occlusion. Eur J Ophthalmol. 2005;15(1):96-101. Jonas JB, Akkoyun I, Kamppeter B, Kreissig I, Degenring RF. Branch retinal vein occlusion treated by intravitreal triamcinolone acetonide. Eye (Lond). 2005;19(1):65-71. Chen SD, Sundaram V, Lochhead J, Patel CK. Intravitreal triamcinolone for the treatment of ischemic macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2006;141(5):876-883. Edelman JL. Differentiating intraocular glucocorticoids. Ophthalmologica. 2010;224(Suppl 1):25-30.

Corticosteroid Therapies in the Management of Macular Edema Secondary to RVO  77

Figure 4-9 (continued). Post-intravitreal Kenalog endophthalmitis vs pseudoendophthalmitis. (B1) Treated with topical moxifloxacin every 2 hours and PO moxifloxacin 400 mg once per day on day 1 and daily thereafter. (B2) 2 days later, vision was 20/100 and pain resolved.

Kiernan DF, Mieler WF. The use of intraocular corticosteroids. Expert Opin Pharmacother. 2009;10(15):2511-2525. 10. Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB III, Miller M. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology. 2003;110(4):681-686. 11. Scott IU, Ip MS. It’s time for a clinical trial to investigate intravitreal triamcinolone for macular edema due to retinal vein occlusion: the SCORE study. Arch Ophthalmol. 2005;123(4):581-582. 9.

78  Chapter 4 12. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128. 13. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114. 14. Kiernan DF, Mieler WF. Intraocular corticosteroids for posterior segment disease: 2012 update. Expert Opin Pharmacother. 2012;13(12):1679-1694. 15. Christoforidis JB, Chang S, Jiang A, Wang J, Cebulla CM. Intravitreal devices for the treatment of vitreous inflammation. Mediators Inflamm. 2012;2012:126463. 16. Dugel PU, Eliott D, Cantrill HL, et al. I-Vation TA: 24-month clinical results of the Phase I safety and preliminary efficacy study. Paper presented at: ARVO Annual Meeting; May 3-7, 2009; Fort Lauderdale, FL. 17. Lim JI, Fung AE, Wieland M, Hung D, Wong V. Sustained-release intravitreal liquid drug delivery using triamcinolone acetonide for cystoid macular edema in retinal vein occlusion. Ophthalmology. 2011;118(7):1416-1422. 18. London NJ, Chiang A, Haller JA. The dexamethasone drug delivery system: indications and evidence. Adv Ther. 2011;28(5):351-366. 19. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.e3. 20. Jain N, Stinnett SS, Jaffe GJ. Prospective study of a fluocinolone acetonide implant for chronic macular edema from central retinal vein occlusion: thirty-six-month results. Ophthalmology. 2012;119(1):132-137. 21. Campochiaro PA. Anti-vascular endothelial growth factor treatment for retinal vein occlusions. Ophthalmologica. 2012;227 Suppl 1:30-35.

5

Role of Imaging in the Management of Macular Edema Secondary to Retinal Vein Occlusion

Pearse A. Keane, MD, MSc, FRCOphth, MRCSI; Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth); Michael A. Singer, MD; and SriniVas R. Sadda, MD

An understanding of the disease mechanisms underlying retinal vein occlusion (RVO) is fundamental to accurate interpretation of ocular imaging in patients with this disease.1 Therefore, we begin this chapter with a simple overview of these mechanisms: first, the processes leading to occlusion of the vein; and second, the anatomic and visual consequences. In most patients, RVO develops as a result of arteriosclerosis; hence, systemic cardiovascular risk factors (eg, hypertension) play a key role.2,3 Because retinal arterioles and venules share a common adventitial sheath at crossing points, thickening and hardening of the arterial walls impinges on the venules at these points, leading to venous narrowing. The resulting stasis—and then thrombosis—leads to venous occlusion. Less commonly, inflammation of the retinal veins (phlebitis) or hypercoagulable states can produce occlusion.4,5 Occlusion then causes elevation of first venous, and then intracapillary pressure, with subsequent slowing of arterial flow; the combination of these factors leads to extravasation of serous fluid and hemorrhage, as well as to capillary endothelial damage.6 Subsequent increases in interstitial pressure act as an impediment to capillary perfusion and leads to ischemia. Ischemia, in turn, leads to increased production of vascular endothelial growth factor (VEGF) with resulting increased hyperpermeability and creation of a vicious circle.7-9

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Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 79-120). © 2014 SLACK Incorporated.

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Vision loss in RVO occurs through a combination of 4 distinct mechanisms.6,10-13 First, serous exudation distal to the point of obstruction leads to macular edema. When the associated damage to the vascular architecture is severe, such edema may become prolonged or permanent with degenerative changes (eg, epiretinal membrane, lamellar holes). Second, extravasation of blood occurs distal to the point of obstruction; in severe cases, dissection of blood beneath the retina may lead to retinal pigment epithelium (RPE) atrophy and/or scarring, often in a subfoveal location. Finally, venous obstruction may be accompanied by ischemic damage to the retina. When extensive loss of the macular capillary bed exists, postischemic atrophy may develop, with irreversible vision loss. In addition, with extensive ischemia of the peripheral retina, pathologic neovascularization of the retina may ensue, resulting in vitreous hemorrhage and/or tractional retinal detachment, whereas neovascularization of the iris (NVI) may culminate in neovascular glaucoma (NVG).14 Building on this foundation, we begin the remainder of the chapter by discussing in detail the angiographic findings in RVO, a sound knowledge of which is a prerequisite for rational management. We next discuss the putative role for ultra-widefield angiography in redefining our understanding and treatment of this disorder. We then examine tomographic (cross-sectional) imaging and the manner in which objective measurements of retinal thickness have transformed management of RVO-associated macular edema. Finally, we highlight a number of new imaging modalities, still largely in development, that are likely to transform the diagnosis and management of RVO-associated macular edema in the near future.

FLUORESCEIN ANGIOGRAPHY Although an RVO diagnosis can usually be made on the basis of clinical findings alone, fluorescein angiography (FA) of the ocular fundus is an important adjunct, providing prognostic information and guiding treatment strategies. In this section, we examine the basic principles of FA, the qualitative and quantitative analysis of FA image sets in RVO, and the use of FA in RVO clinical trials. Throughout, we emphasize the role of FA in the assessment of retinal capillary nonperfusion, highlighting the strengths and weaknesses of this approach.

Basic Principles In 1961, Novotny and Alvis15 reported the first demonstration of fundus FA. They modified a standard fundus camera with monochromatic light filters and then obtained a series of fundal photographs following intravenous administration of a fluorescent contrast agent (sodium fluorescein). This technique allowed greatly enhanced visualization of the retinal vasculature, as well as assessment of its structural integrity. FA was initially used in patients with hypertensive and diabetic retinopathy but quickly became adopted for a variety of chorioretinal diseases, including RVO.16,17 Moreover, in 1977, FA imaging became a fundamental component of the first major clinical trial related to RVO: the Branch Vein Occlusion Study (BVOS).18 Since this time, fundus cameras (and thus FA) have undergone substantial refinements, including optimization for nonmydriatic and

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stereoscopic image acquisition and transition from analog to digital image capture.19,20 At present, fundus cameras are typically described by their external field of view, with an angle of 30 or 35 degrees most commonly used. In clinical practice, commonly used fundus cameras include the TRC-50DX (Topcon Medical Systems) and the FF 450plus (Carl Zeiss Meditec).21 Fundus cameras are dependent on the generation of a bright ring of white light.20 The peripheral portion of the camera’s objective lens is then used to focus this light and illuminate the fundus, whereas the central portion of the objective lens is used to create a real, inverted image of the fundus within the camera. This image is then projected onto the pixel array of a charge-coupled device, and all the pixels of the image are created in the same instant. In the 1980s, the introduction of a new device, the scanning laser ophthalmoscope (SLO), provided an alternative method for the acquisition of fundus images.19,22,23 In SLO systems, a single point of laser light at a specific wavelength is scanned across the retina in a raster pattern (ie, a series of parallel horizontal lines). As a result, images are created one pixel at a time. Because only a small area of the fundus is illuminated at any one time, the effects of light scatter are reduced; thus, SLO devices are capable of producing fundus images with higher contrast than are standard fundus cameras and are readily used for angiographic purposes. In clinical practice, commonly used SLO instruments include the Heidelberg Retina Angiograph-2 (HRA-2; Heidelberg Engineering) and the Nidek F-10. In FA, a rapid sequence of fundus photographs is obtained in a systematic fashion following intravenous administration of fluorescein. This leads to a number of generally defined phases of the angiogram.1,24 Shortly after injection of the dye, it first distributes within the choroidal and then the retinal vessels. In healthy subjects, the choroid quickly becomes permeated with the dye. However, this is not the case for the retinal parenchyma, where the retinal vessels and RPE act as barriers to permeation (the inner and outer bloodretina barriers, respectively). In normal eyes, the retinal vessels are thus sharply visible overlying the homogenous background fluorescence of the choroid, and no other distinctly fluorescent structures will be apparent. Pathological changes in the eye may cause alterations in this normal fluorescence pattern, with disease features primarily identified by their relative hyper- or hypofluorescent characteristics.

Qualitative Image Interpretation Overview Numerous RVO subtypes exist, including central RVO (CRVO), branch RVO (BRVO), and hemi-RVO (HRVO).3 Although the basic schema described in the beginning of this chapter applies to each, some caution is required because significant differences exist in their underlying mechanisms, clinical features, and prognoses.25 Such differences may be of particular importance in clinical research studies, where the grouping of these disorders as a single entity may lead to erroneous conclusions. In addition, it may be helpful to divide clinical and angiographic findings into those seen in acute and chronic settings.26

Central Retinal Vein Occlusion The central retinal vein is formed by the union of tributaries that correspond approximately to the branches of the central retinal artery. It leaves the globe by passing through

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the lamina cribrosa in company with the central retinal artery. The central retinal vein has multiple tributaries along its course in the optic nerve, none in the lamina cribrosa, and only one in the prelaminar region.27 The site of occlusion in CRVO may thus determine the potential for collateral circulation, and therefore, to a large extent, the severity of ensuing disease. For example, in occlusion at the level of the lamina cribrosa, little opportunity exists for collateral drainage, and the retinal circulation becomes, in effect, a closed loop. The almost complete cessation of retinal flow that ensues may lead to central retinal artery occlusion, profound visual loss, and neovascular consequences.28 In a series of eyes enucleated as a result of NVG, Green et al 29 demonstrated such thrombus formation at the level of the lamina cribrosa. However, because NVG only develops in approximately 10% of cases, this finding likely represents only the severest forms of the disease.29,30 In contrast, when occlusion occurs posterior to the lamina cribrosa, greater potential exists for collateral flow through the multiple tributaries to the vein in the optic nerve. As a result, in most patients with CRVO, some flow in the retinal vascular bed is retained, and severe neovascular consequences do not ensue. However, this hypothesis remains controversial, with some experts contending that incomplete obstruction at the level of the lamina cribrosa is responsible for the variations in clinical presentation.3 Nonetheless, it is clear that CRVO exists as 2 distinct clinical entities: ischemic and nonischemic.25 Nonischemic CRVO is a comparatively benign disease, with moderate vision loss due to macular edema and little chance of ocular neovascularization. Conversely, ischemic CRVO is a serious blinding disease with high risk of neovascularization. Awareness of this distinction is of vital importance in image interpretation and thus patient management. From his extensive experience with these disorders, Hayreh25 has argued that lumping these 2 entities together is like “combining benign and malignant tumors into one disease.”25(pp546-552) On FA, CRVO is characterized by a number of features.6,31 Impairment of central venous outflow leads to increased retinal circulation time; this is often markedly increased in patients with ischemic CRVO (circulation time may be recorded as the time when fluorescein first appears in retinal arterioles and when laminar flow first appears in retinal venules). The subsequent increase in intracapillary and venous pressures leads to extravasation of blood and serous fluid and damage to retinal vascular structures (Figure 5-1A). On FA frames, the accumulation of blood in the retina produces areas of blocked fluorescence corresponding to the areas of visible blood on clinical examination or color fundus photography. In ischemic CRVO, extensive confluent retinal hemorrhages may block fluorescence over large areas of the posterior pole and make assessment of other FA features difficult (Figure 5-1B).31 On FA, extravasation of fluid is manifested as leakage from the retina and optic disc (Figure 5-2). Such leakage may lead to fluid accumulation in the retina (macular edema) and in the subretinal space (serous retinal detachment). On FA, macular edema appears as an area of progressively increasing fluorescence and staining of the surrounding edematous retinal tissue. Over time, pooling of dye in the retina may lead to cystoid macular edema (CME), with sharply demarcated petalloid or honeycomb patterns on FA (see Figure 5-2A).32,33 The presence of serous retinal detachment may be difficult to detect angiographically in CRVO due to the widespread overlying retinal leakage. Damage to the retinal vascular structures that occurs following acute venous occlusion may be seen as transient vessel wall staining on FA. In patients with ischemic CRVO, more marked late staining along large veins is a characteristic finding.6

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Figure 5-1. (A) Color fundus photograph of the left eye of a patient with a CRVO demonstrating extensive areas of flame and blot hemorrhages. The margins of the disc are blurry due to significant disc edema. Some breakthrough vitreous hemorrhage has occurred in this patient, causing a slightly hazy view. (B) Fluorescein angiogram demonstrating areas of blocked fluorescence (dark areas), which correspond to the areas of hemorrhage seen in the color fundus images. The disc shows considerable leakage.

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Figure 5-2. (A) Fluorescein angiogram of the right eye of a patient with a BRVO associated with CME. (B) A midphase frame demonstrating early leakage from telangiectatic capillaries with accumulation of dye in cystoid spaces organized in a petalloid pattern in the late phases. Leakage from the disc and staining of an inferior branch retinal vein are also observed. Panretinal photocoagulation scars are noted superiorly.

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Figure 5-3. Fluorescein angiogram of a patient with an ischemic CRVO. Many areas of capillary nonperfusion are seen, with adjacent areas of telangiectasia and vessel pruning.

In CRVO, accumulation of blood and serous fluid in the extracellular space of the retina leads to reduced capillary perfusion and ischemia.6 On FA, areas of capillary nonperfusion are seen as well-demarcated areas of hypofluorescence, often with a different shade of grayness from that of adjacent intact capillary networks.24,31,34,35 These nonperfused areas can often be detected indirectly by the presence of adjacent lesions such as dilated capillaries and arteriolar abnormalities such as pruning (Figure 5-3).34 In eyes with ischemic CRVO, large areas of capillary nonperfusion may be seen, often extending from the posterior pole into the retinal periphery.31 Disruption of axoplasmic flow in the retinal nerve fiber layer may lead to the presence of cotton wool spots (whitish, ill-defined superficial lesions that cause blocked fluorescence on FA). Over time, the acute features of CRVO evolve, with the potential for both maladaptive and ameliorative responses. In response to impaired drainage of blood from the eye, collateral vessels may develop at the disc (Figure 5-4), facilitating an alternative drainage via the choroidal vascular system.12,36-40 Such vessels are often referred to as optociliary shunts or anastomoses and are likely preformed channels that enlarge when normal drainage is impaired. These vessels tend to be large and tortuous, and their path can often be traced from the retinal vein to a ciliary vessel. Using indocyanine green angiography, it is occasionally even possible to trace this drainage pathway in its entirety to the vortex veins.41 Unlike pathologic neovascularization, disc collaterals do not show intense late leakage on FA imaging (see Figure 5-4B), and this may be a helpful distinguishing feature (some underlying leakage from the optic disc is often present and may confuse the picture, although this is typically less intense than that seen with neovascularization). Of note, disc collaterals are not seen in more than 50% of eyes with nonischemic CRVO. This may be

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Figure 5-4. (A) Color fundus photograph of the optic disc demonstrating collateral vessels. (B) Corresponding fluorescein angiogram of the collateral vessels. In contrast to neovascularization, no leakage is observed from these vessels. Staining of atrophy due to damage from previous chronic macular edema is also observed in this case.

consistent with a location of occlusion posterior to the lamina cribrosa, with shunts occurring in the substance of the optic nerve.11 In ischemic CRVO, widespread areas of capillary nonperfusion often lead to the development of NVI. In contrast, neovascularization of the retina occurs much less commonly.12

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Figure 5-5. (A) BRVO. Color fundus photograph demonstrating flame and blot hemorrhages inferotemporally. An area of arteriovenous nicking with compression of the vein by the artery is observed and is likely a contributing factor to the occlusion. (continued)

In CRVO, severe macular ischemia may lead to retinal atrophy, with particular loss of inner retinal structures. This finding is easily documented on histopathology,6 but in vivo is better appreciated on optical coherence tomography (OCT) than on FA.1 In response to chronic CME, degenerative changes in the retinal architecture may arise, including localized foveal atrophy, lamellar or full-thickness macular holes, and epiretinal membrane. Again, these are best appreciated using OCT. Tracking a hemorrhage into the subretinal space in such cases may lead to foveal hyperpigmentation/scarring with blocked or mottled fluorescence on FA.

Branch Retinal Vein Occlusion In BRVO, occlusion occurs at arteriovenous crossing points, most commonly affecting the superotemporal vascular arcade, and typically where arterioles pass over (ie, superficially to) venules (Figure 5-5).26 The location of the venous blockage determines the severity and distribution of acute features, resulting in a quadrantic or wedge-shaped distribution (see Figure 5-5A). In addition, disease features are characteristically limited to one side of the horizontal raphe. If occlusion occurs peripheral to tributary veins draining the macula, the macula may be spared and visual acuity unaffected.13 On histopathologic examination, Frangieh et al42 demonstrated fresh or recanalized thrombi at arteriovenous crossing points in a series of eyes with BRVO.42 On high-quality FA, the presumed thrombus can occasionally be seen as a white mass immediately downstream from (proximal to) the arteriovenous crossing, causing slight expansion of the

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Figure 5-5 (continued). (B) Early-phase fluorescein angiogram demonstrating an area of capillary nonperfusion in the region of the BRVO, with associated telangiectasia and vessel pruning. Areas of blocked fluorescence correspond to the intraretinal hemorrhages seen.

retinal vein, and with staining in the late venous phase.43 Abnormal flow patterns, such as side stream and central tapered flow, may also be seen in the venous phase of angiography downstream from the site of occlusion.43 Many of these findings have recently been confirmed using OCT, including direct visualization of the thrombus, located downstream from the arteriovenous crossing in all cases.44 Using FA, increases in retinal circulation time distal to the site of obstruction can also be observed.26 In the involved quadrant, marked dilatation and tortuosity of the involved vein is typically seen, with narrowing of the accompanying arteriole. As with CRVO, the acute event leads to varying quantities of fluid leakage, hemorrhage, capillary nonperfusion, and vascular wall injury (with similar angiographic findings as described in detail previously). Over time, a variety of responses to the acute event may be clearly visualized on FA. Adjacent to areas of capillary nonperfusion, the capillary bed often becomes telangiectatic, with formation of microaneurysms and intraretinal microvascular abnormalities (see Figure 5-3).26,45 These intraretinal changes may be accompanied by diffuse leakage on FA. In a minority of cases, macroaneurysms (100 μm or larger in size) may develop, located in association with arterial, venous, capillary, or collateral vessels.46 Collateral vessels (typically veno-venous anastomoses) are most easily seen crossing the horizontal raphe temporal to the macula, but they may also be seen nasal to the macula and even directly bypassing the site of obstruction (Figure 5-6).47 These intraretinal responses, such as intraretinal collateral formation, are typically more marked in BRVO than in CRVO. In CRVO, all branches of the central retinal vein are affected, so no pressure gradient within

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Figure 5-6. Fluorescein angiogram of a patient with RVO, with vein-tovein collaterals linking one vein to another across the horizontal raphe.

the retinal circulation exists to drive formation of such changes.36,39 In BRVO eyes with more profound ischemia, these intraretinal changes may culminate in the development of pathologic neovascularization.13 On FA, such neovascularization at the disc or elsewhere in the fundus appears as a fine network of vessels on or above the retinal surface, often crossing/obscuring the underlying vasculature (Figure 5-7). New vessels show early, prominent hyperfluorescence with intense late leakage. Blocked fluorescence from associated preretinal and/or vitreous hemorrhage may also be present. As the neovascular complex matures, the vessels may attain a larger, more loopy caliber and be associated with whitish fibrous tissue. Rarely tractional retinal detachment may develop. NVI occurs only rarely in isolated BRVO.48 As with CRVO, chronic CME commonly develops, along with its standard sequelae (eg, lamellar hole formation).6 Serous retinal detachment is also a common finding, and although much more readily evident on OCT, it can be seen on FA in severe cases.26 Tracking of hemorrhage into the subretinal space in such cases may lead to scarring of the RPE, with blocked fluorescence on FA.

Hemiretinal Vein Occlusion HRVO has a similar appearance to BRVO, but the entire superior or inferior hemisphere is involved as opposed to a single quadrant (Figure 5-8).49-51 HRVO has previously been classified as (1) hemi-CRVO, in which the central retinal vein forms posterior to the lamina cribrosa from a dual trunk, with occlusion affecting a single trunk (thus a variant of CRVO), or (2) hemispheric RVO, in which a major branch of the central retinal vein is occluded at or near the optic disc (thus a variant of BRVO). However, use of this classification is limited by difficulty identifying the site of occlusion in many cases of HRVO. Differentiation of HRVO from BRVO is nonetheless important because the type and

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Figure 5-7. (A) Color fundus photograph of an eye with an RVO illustrating neovascularization at the disc. (B) Early-phase fluorescein angiogram showing the outlines of the neovascular complex and early leakage from these vessels. (continued)

relative risk of neovascular complications differs.25 For example, severe HRVO appears to have an intermediate risk of rubeosis when compared with BRVO and CRVO but a greater risk of neovascularization at the disc than either. It is also interesting to note that HRVO can result in both intraretinal collaterals and disc collaterals. In the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study, HRVO was treated as BRVO and demonstrated a similar response to treatment.52

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Figure 5-7 (continued). (C) Late-phase fluorescein angiogram illustrating extensive leakage from neovascularization at the disc.

Figure 5-8. (A) Color fundus photograph of the right eye of a patient with an inferior HRVO. The superior retina is normal. (continued)

Capillary Nonperfusion Quantitative analysis of angiographic parameters has played a central role in the management of RVO since the 1970s. In particular, it has become commonplace for FA-derived measurements of capillary nonperfusion to be used for differentiation of disease subtypes. It is important for retina specialists to be aware of both the strengths and shortcomings of this approach.

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Figure 5-8 (continued). (B) Corresponding fluorescein angiogram illustrating blocked fluorescence caused by the intraretinal hemorrhages. The blockage precludes accurate assessment of the extent of capillary nonperfusion. (C) The left eye of another patient with an inferior HRVO with severe ischemia. Nearly the entire inferior retina, including the macula, is nonperfused. This eye is at high risk for the development of neovascularization.

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In the BVOS, a major question was whether scatter laser photocoagulation would be beneficial for prophylaxis of neovascularization and vitreous hemorrhage in BRVO patients.53 Eyes with “branch vein occlusion involving a retinal area of at least 5 disc diameters in diameter” were recruited. Of these, eyes with “capillary nonperfusion involving a retinal areas of at least 5 disc diameters in diameter” were labeled nonperfused, whereas all other eyes were labeled perfused. The findings from the BVOS demonstrated that the majority of eyes developing neovascularization were in the nonperfused category (specifically 19% of nonperfused eyes receiving prophylactic scatter laser and 31% of those in the control group). The BVOS thus recommended that FA imaging should be performed when retinal hemorrhages have cleared sufficiently to allow assessment of perfusion and that regular monitoring for neovascular complications should occur in those with greater than 5 disc diameters in diameter of nonperfusion. In the Central Vein Occlusion Study (CVOS), a major question was whether early panretinal photocoagulation (PRP) could prevent NVI in eyes with ischemic CRVO.54 In this study, CRVOs were classified as ischemic if FA demonstrated more than 10 disc areas of nonperfusion in the posterior pole and midperiphery, whereas all other eyes were labeled nonischemic. Images were attained using 5-field (for sites with Canon or Topcon fundus cameras) or 8-field (for sites with Zeiss fundus cameras) photographic sweeps, allowing approximately 75 degrees of the retina to be visualized.31 This cutoff was chosen because a number of smaller studies had identified 10 disc areas as a threshold degree of ischemia that could lead to NVI.55-57 Interestingly, these studies used a number of different methods for quantification of capillary nonperfusion, and measurements were typically confined to standard posterior pole images (ie, 30 to 50 degrees). Therefore, it is not surprising that in the CVOS, eyes with fewer than 30 disc areas of nonperfusion were actually found to be at a low risk of NVI. Conversely, eyes with more than 75 disc areas (of a potential 210) of nonperfusion were found to be at a high risk.54 Seemingly contrary to these findings (ie, despite having a sensitivity of only 52% and a specificity of 81%), 10 disc areas of retinal capillary nonperfusion was quickly adopted as the standard for designation of CRVO as ischemic.25,58 In the CVOS, the presence of significant retinal hemorrhage prevented assessment of perfusion at baseline, and these eyes were labeled indeterminate, thus representing a spectrum bias and further overestimating the sensitivity and specificity of the test.31 Consistent with this, in a large single-center study, FA imaging allowed accurate assessment of baseline nonperfusion in only 60% of cases.59 These findings clearly highlight the weakness of 10 disc areas as a gold standard for CRVO classification. In fact, use of a functional criterion, such as the presence of a relative afferent pupillary defect, may be the single most accurate method for making this designation and thus providing crucial prognostic information for the patient.59,60 It is also worth noting that measurements of capillary nonperfusion are subtly different in the BVOS vs the CVOS (more than 5 disc diameters in diameter vs more than 10 disc areas), and false equivalencies should not be drawn between nonperfused BRVO and ischemic CRVO, particularly given the many differences in clinical features described previously. Since 2000, a number of important trials have added to the seminal findings from the BVOS and CVOS. Although these studies have contributed greatly to our understanding of new therapeutics, their assessment of capillary nonperfusion raises a number of issues. In the SCORE study, and more recently in the Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study:

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Figure 5-9. Early-phase fluorescein angiogram of a patient with retinal vein occlusion. Note areas of capillary nonperfusion.

Evaluation of Efficacy and Safety (CRUISE) studies, retinal capillary nonperfusion was assessed using a modification of a methodology designed for diabetic macular edema in the Early Treatment Diabetic Retinopathy Study (ETDRS; Figure 5-9).34,61 In this system, measurements of nonperfusion were made within a template centered on the fovea and consisting of the center, inner, and outer ETDRS subfields. In this system, measurement of retinal capillary nonperfusion is essentially confined to the macula rather than to the posterior pole and midperiphery, as in the CVOS. This discrepancy may be missed by the casual reader but becomes readily apparent when actual measurements are compared. For example, in a random sample of 40 FA image sets from the SCORE study, a mean area of capillary nonperfusion of 0.45 disc areas was measured, with a standard deviation of 1.26 disc areas.34 Similarly, in the CRUISE study, only 6 of 392 eyes (1.8%) had more than 5 disc areas of nonperfusion at baseline, and only 2 eyes (0.6%) had more than 10 disc areas.61 Although their inclusion criteria have significant differences, this stands in marked contrast to the findings from the CVOS, where 181 eyes had greater than 10 disc areas of retinal nonperfusion at baseline.54 Although direct comparisons are not possible, this newer methodology has nonetheless revealed many exciting findings. In particular, in CRVO eyes with significant capillary nonperfusion at baseline, 30% of those treated with ranibizumab showed evidence of reperfusion.61 These findings were mirrored in eyes with BRVO. Similarly, in both CRVO and BRVO eyes switched from sham treatment to ranibizumab at month 6 of the study, progression of retinal nonperfusion was halted, and some improvement was seen. To allow more direct comparison with the CVOS, the Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion With Macular Edema (GENEVA) study of intravitreal dexamethasone assessed global retinal capillary nonperfusion, a parameter combining macular and peripheral nonperfusion.62 The Controlled Phase 3 Evaluation of

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Repeated Intravitreal Administration of VEGF Trap-Eye in Central Retinal Vein Occlusion: Utility and Safety (COPERNICUS) and General Assessment Limiting Infiltration of Exudates in Central Retinal Vein Occlusion With VEGF Trap-Eye (GALILEO) studies of intravitreal aflibercept also evaluated retinal nonperfusion in a manner similar to the CVOS.63,64 Despite this, evaluation of nonperfusion in the midperiphery using conventional fundus cameras is often difficult due to the requirements for skilled photographers, cooperative patients, and clear ocular media. Even in ideal circumstances, image quality is reduced by the smaller size of the entrance pupil, induced astigmatism, and vignetting (a style of photographic portrait that is clear in the center but fades off in the periphery).58 Moreover, these systems, being typically limited to a range of approximately 75 degrees, do not allow assessment of the far retinal periphery, and thus the full extent of nonperfusion cannot be measured. In future clinical trials, use of ultra-widefield imaging systems may allow more standardized measurements of retinal nonperfusion in its entirety.

ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY In the previous section, we described long-established methods for assessment of RVO using conventional angiographic systems. We emphasized the role of quantitative assessment of retinal capillary nonperfusion but highlighted the difficulties in assessing this parameter in the retinal periphery. Recent advances in fundus imaging systems have addressed this issue, and now routine, noncontact acquisition of ultra-widefield images is possible.65 In this section, we describe the basic principles underlying these devices and their potential to greatly alter the future management of patients with RVO.

Basic Principles Conventional FA, whether performed with a fundus camera or an SLO, typically generates images with a 30- to 50-degree external field of view; this corresponds to approximately 5% to 15% of the retinal surface area. Although this allows optimal visualization of the posterior pole, a large area of the peripheral retina is not captured, even with 7-field acquisition protocols. In recent years, this shortcoming has been addressed with the release of noncontact ultra-widefield imaging systems such as the 200Tx system (Optos plc).66 The Optos system uses an SLO with 2 wavelengths of laser light (green [532 nm] and red [633 nm]) to recreate a composite color image of the posterior segment. Through the use of a large ellipsoid mirror with 2 focal lengths allowing wide scanning angles, images with a 200-degree internal field of view (approximately equivalent to a 135-degree external field of view) can be obtained through an undilated pupil. In this manner, approximately 80% of the total retinal surface area can be visualized, assuming the equator is located at 180 degrees and the ora serrate at 230 degrees (Figure 5-10). Furthermore, with a compliant patient and with a well-dilated pupil, it is possible to capture images to the ora serrata, although ora-to-ora coverage is not possible in a single image. A noncontact ultrawidefield imaging system has also recently been introduced by Heidelberg Engineering, although its technical specifications are not publicly available and its field of view appears to be considerably smaller.

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Figure 5-10. (A) Ultra-widefield fluorescein angiogram of a patient with an RVO. The periphery is distorted due to the nature of the imaging technique. (B) Stereographic projection image of the same fluorescein angiogram in which the peripheral distortion has been corrected and all areas on the fluorescein angiogram are anatomically correct.

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Quantitative analysis of ultra-widefield images in RVO and other diseases poses challenges.65 For example, in any theoretical fundal imaging, distortion is generated when images of the nearly spherical inner surface of the eye are mapped to a flat surface (ie, for representation on a computer display). In this so-called azimuthal projection, increased eccentricity from the image center results in larger distortion in size and shape of structures (see Figure 5-10A). In an ideal image modality, radial measurements from the flat projection will remain proportional to arc measurements from the spherical surface (ie, distances and directions from the foveal center will be retained). However, in uncorrected Optos imaging, small deviations in eye position can have large effects on the projected image, producing varying amounts of distortion at different points within each image.58 As a result, measurement of retinal surface area directly from Optos images can have a variable and unknown relationship with the actual dimensions of the eye. This varying distortion also makes registration of Optos images difficult (eg, for generation of montages covering the entire retinal surface: ora-to-ora). In 2011, Spaide58 described a method to address these issues, allowing images taken with the eye in different cardinal positions to be registered to a single base image and for measurements of retinal surface area to be obtained. It is expected that software using a stereographic projection method to allow production of anatomically correct images will soon become available on the commercial instrument market (see Figure 5-10). As with standard fundus cameras and other SLO systems, noncontact ultra-widefield imaging systems can be modified to provide additional information. For example, the use of appropriate filters allows both ultra-widefield autofluorescence and angiographic imaging.67-69 Ultra-widefield FA may be of particular value in diseases with peripheral neovascularization of the retina, peripheral retinal vasculitis, or abnormal retinal vascular development. Ultra-widefield FA may also be of use in retinal vascular disorders such as CRVO and BRVO, where putative relationships between peripheral retinal ischemia, pathologic neovascularization, and macular edema are currently being explored.

Qualitative Image Interpretation In 2009, Prasad et al70 reported use of Optos ultra-widefield angiography in patients with BRVO and HRVO. Many of the patients in this retrospective cohort had previously been treated with scatter laser photocoagulation. However, on imaging with ultrawidefield angiography, significant areas of untreated, peripheral nonperfusion were seen. A significant association was also found between the presence of untreated peripheral nonperfusion and macular edema, with 86% of such cases demonstrating nonperfusion anterior to the equator, which was defined using the vortex vein ampullae as landmarks. The authors also noted that retinal nonperfusion peripheral to the equator encompassed an area at least twice that of posterior nonperfusion.70 Numerous studies have previously demonstrated that the severity of ocular findings in CRVO is related to intraocular levels of VEGF and that intraocular injection of VEGF in animal models can reproduce many of the abnormalities seen in CRVO.7-9,71-73 Thus, it seems plausible that production of VEGF by previously undetected areas of peripheral nonperfusion may drive the persistence of many disease features in CRVO. Indeed, in the work by Prasad et al,70 macular edema was often present despite previous macular grid laser, and the authors hypothesized that a combination of scatter laser to peripheral nonperfusion and conventional therapy would

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Figure 5-11. (A) Ultra-widefield fluorescein angiogram illustrating areas of capillary nonperfusion. (continued)

lead to improved outcomes. Interestingly, these findings may be in accordance with studies in which patients with RVO with no observable nonperfusion on conventional angiography required repeated retreatment with anti-VEGF agents to prevent recurrence of CME.74,75 In 2010, Tsui and colleagues76 published a companion study involving ultra-widefield imaging of CRVO. In this work, they described a semiquantitative parameter called the ischemic index (ISI), defined as the total area of retinal nonperfusion seen in the arteriovenous phase of Optos angiography divided by the total image area (Figure 5-11). Of the 69 eyes evaluated, 15 eyes with coexisting neovascularization had a mean ISI of 75% (range, 47% to 100%), whereas those without neovascularization had a mean ISI of 6% (range, 0% to 43%). The authors also observed that use of ultra-widefield angiography allowed assessment of perfusion status even in CRVO eyes with large areas of retinal hemorrhage. In this study, for areas of blocked fluorescence, the authors used the perfusion status of the surrounding retina to determine perfusion status.76 A similar methodology is commonly used in image reading centers for diseases such as neovascular age-related macular degeneration.77 In 2011, Spaide58 described a method for the creation of Optos montage images that allowed for ora-to-ora visualization and measurement of retinal surface area. In this work, he performed Optos angiography on 22 patients with CRVO enrolled in a prospective study evaluating the use of ranibizumab. In this cross-sectional analysis, only 7 patients met the CVOS gold standard for classification as an ischemic CRVO; surprisingly, all patients were seen to have confluent areas of peripheral nonperfusion on ultra-widefield imaging. These confluent areas ranged in size from 16 to 242 disc areas. Abrupt boundaries were seen between areas of posterior perfusion and areas of anterior nonperfusion (unlike posterior pole nonperfusion, where affected areas are commonly surrounded by

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Figure 5-11 (continued). (B) Corresponding grading diagram for calculation of the ischemic index. Areas colored orange are perfused and areas shaded blue are nonperfused.

perfused retina). Retinal vessels at the border zones of peripheral nonperfusion often showed little or no leakage, suggesting that such vessels are not subject to hyperpermeability from locally produced VEGF, in contrast to islands of posterior pole nonperfusion where perfused border zones typically demonstrate leakage. Spaide58 also noted that the area of peripheral nonperfusion was not correlated with the number of anti-VEGF injections previously received but was correlated with visual acuity. To test the hypothesis that previously undetected peripheral nonperfusion is a driver of disease in eyes with CRVO, Spaide58 performed PRP to areas of peripheral nonperfusion in 10 eyes receiving ranibizumab for CRVO-associated macular edema. The results of this study, published in 2011, failed to demonstrate a reduction in injection frequency or an improvement in visual acuity after Optos-guided PRP (Figure 5-12). Although the sample size was small, these findings raise the possibility that peripheral nonperfused areas have actually been infarcted and are not producing clinically relevant quantities of VEGF. Spaide58 also speculated that other areas appearing perfused on angiography may be the source of VEGF production (ie, that FA simply provides evidence that capillaries are present in a tissue bed but does not necessarily mean sufficient perfusion exists to avoid ischemia). Later in this chapter, we discuss the latest developments in imaging of retinal vascular disease, with a particular emphasis on modalities that will address this issue.

OPTICAL COHERENCE TOMOGRAPHY Until now, we have focused on topographic imaging of the retinal vasculature in RVO (ie, the use of fundus cameras and/or SLOs to obtain 2-dimensional images of the

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Figure 5-12. (A) Ultra-widefield fluorescein angiogram showing extensive areas of nonperfusion in the periphery. (B) Follow-up fluorescein angiogram after selective PRP to the areas of nonperfusion. The laser scars can be seen.

ocular fundus with an emphasis on structural integrity of the retinal vascular network). With the introduction of a wholly new imaging modality in the 1990s—OCT—tomographic imaging is now possible (ie, cross-sectional and 3-dimensional visualization of the retina and underlying structures). High-resolution tomographic imaging offers the opportunity to visualize intraretinal fluid accumulation and objectively quantify changes in retinal thickness. With the recent introduction of many new therapeutic options for

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RVO-associated macular edema, it is not surprising that OCT has attained a crucial role in disease management. Moreover, unlike FA, the presence of intraretinal hemorrhage has only a minimal effect on the OCT images, making this imaging modality of particular usefulness in acute settings. In this section, we begin by describing the basic principles underlying OCT and current technologies before detailing the OCT features of RVO, both qualitative and quantitative. Throughout, we highlight patterns of serous fluid accumulation in the retina and their resulting appearances on OCT. We also attempt to move beyond the use of OCT as a simple measure of retinal thickness and to highlight other, more novel OCT-derived morphologic parameters of potential clinical significance.

Basic Principles OCT is analogous to ultrasonography but measures reflection of light waves rather than sound. These measurements are achieved indirectly using low-coherence tomography, an approach first described by Huang et al in 1991.78 In this technique, the combination of light reflected from a tissue of interest and light reflected from a reference path produces characteristic patterns of light interference dependent on the mismatch between the reflected waves. Because the time delay and amplitude of one of the waves (ie, the reference path) is known, the time delay and intensity of light returning from the sample tissue may then be extracted. A plot of the amplitude of the returning light against its time delay yields the characteristic A-scan (axial) describing the anatomy of the eye tissue at a specific point. In OCT, these scans are repeated at multiple transverse locations and mapped to a gray or pseudocolor scale, giving rise to 2-dimensional cross-sectional images of the retina (termed B-scans). Because the wavelength of light is so much shorter than that of sound, OCT imaging generates image sets with considerably superior resolution to those of ultrasonography (eg, axial resolutions of 3 to 8 μm in commercially available systems). Light waves traveling through tissue can be reflected, scattered, or absorbed at each tissue interface; as a result, the multilayered structure of the retina is particularly well suited to assessment using OCT. On pseudocolor B-scans, highly reflective tissue is reddishwhite in color, whereas hyporeflective tissue is blue-black in color; alternatively, images can be shown in 256 shades of gray, corresponding to different optical reflectivities. On most OCT scans (Figure 5-13), the first hyperreflective layer detected is the internal limiting membrane at the vitreoretinal interface. In a subset of the population, the posterior hyaloid may be seen as a thin hyperreflective layer above the internal limiting membrane. Within the retina, the retinal nerve fiber layer and the plexiform layers, both inner and outer, are seen as hyperreflective, whereas the ganglion cell layer and the nuclear layers, both inner and outer, are hyporeflective. Retinal vessels may sometimes be seen on OCT images as circular hyperreflective foci located in the inner retina with a vertically oriented zone of shadowing or reduced reflectivity extending into the deeper layers. The first continuous, strongly hyperreflective line seen in the outer retina has historically been designated as the junction of the inner and outer segments of the photoreceptors (IS-OS junction), but more recently has been reclassified as the ellipsoid zone, with the ellipsoid corresponding to a dense aggregation of mitochondria located in the apical region of the photoreceptor inner segment. A faint hyperreflective line is often seen above this and is thought to represent the external limiting membrane (ELM). Beneath the ellipsoid zone

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Figure 5-13. Spectral-domain OCT B-scan of a normal fundus illustrating the retinal and choroidal layers.

are 2 more closely opposed hyperreflective bands representing the interdigitation zone, thought to be the contact cylinder where the RPE apical processes envelop the tips of the cone outer segment, and the RPE-Bruch’s membrane complex (see Figure 5-13). In poorerquality OCT scans with loss of resolution, these 2 outer bands may appear to fuse to yield a single wider band.

Current Technology In the original OCT systems, interference patterns generated were varied as a function of time using a moving mirror in the reference pathway; such devices were commonly referred to as time-domain OCT. In more recent OCT devices, interference patterns are measured as a function of frequency using a spectrometer. These spectral-domain OCT devices remove the need for a moving reference mirror and thus facilitate greatly enhanced image acquisition speed. For example, time-domain OCT systems (eg, Stratus OCT, Carl Zeiss Meditec) acquire images at 400 A-scans per second, whereas spectral-domain OCT systems (eg, Spectralis OCT, Heidelberg Engineering) typically acquire images at speeds in excess of 20,000 A-scans per second. As a result, greater sampling of the macula is possible for any given image set (eg, 128 line scans in a horizontal raster pattern), and areas of focal pathology are less likely to be missed. In 2013, the next generation of commercial OCT systems is beginning to be introduced (eg, DRI OCT-1, Topcon Medical Systems).79,80 This generation of so-called swept-source OCT will still evaluate interference patterns as a function of frequency but will use rapidly tunable lasers in the place of broadband light sources and spectrometry.81 This advance will allow further increases in image acquisition speed and thus coverage of wider areas of the ocular fundus in single image sets. The use of long-wavelength light sources (eg, 1050 nm) will also allow improved depth penetration for enhanced visualization of sub-RPE pathology, choroid, and sclera.82,83

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Figure 5-14. Spectral-domain OCT of a patient with massive CME. A small pocket of subretinal fluid is noted under the foveal center.

Qualitative Image Interpretation Vision loss in RVO commonly occurs as a result of extravasation of serous fluid distal to the point of RVO. The degree of accompanying capillary endothelial damage then determines the composition and axial location of the extracellular fluid collection6 and thus the acute OCT appearance.1,84-88 If the capillary damage is mild, serous exudation may be confined to the inner retinal layers without the formation of cystoid spaces. On OCT, these changes may be visualized as diffuse retinal thickening, a sponge-like retinal thickening associated with decreased optical backscattering. If the capillary damage is moderate, and particularly if the deeper plexus of retinal capillaries is affected, the serous fluid extends posteriorly and laterally, where it accumulates in the inner nuclear and outer plexiform layers and forms CME. On OCT, these changes may be seen as round or oval hyporeflective areas in the outer retina (outer plexiform layer and outer nuclear layer; Figure 5-14). As the severity of leakage increases, these cystoid spaces may form in the more superficial retinal layers, first in the inner nuclear layer and subsequently in the ganglion cell layer. The axial location of cystoid spaces may thus provide some indication of disease severity.89 Conversely, in some cases, leakage may be of sufficient severity to breach the ELM of the outer retina, leading to subretinal fluid accumulation and serous retinal detachment. On OCT, subretinal fluid is seen as an optically clear/hyporeflective space between the outer layer of photoreceptors and the highly hyperreflective RPE band (see Figure 5-14).85,88,90 In eyes with RVO and chronic edema, additional features may be seen on OCT. In areas of long-standing stagnant fluid, lipid and protein may precipitate in the outer retina, forming hard exudates that appear on OCT as focal areas of hyperreflectivity with posterior shadowing (Figure 5-15).91-94 Long-standing and/or severe CME may also lead to degenerative changes occurring in the retinal parenchyma, with damage to photoreceptors and disruption of the normal architecture. The former may be seen on OCT as focal or confluent loss of the ELM and/or ellipsoid zone (Figure 5-16).95-100 The latter may result in cystoid macular degeneration, where cystoid spaces are seen in the absence of retinal thickening.101,102 In such eyes, foveal retinal atrophy may occur and be seen on OCT as discrete areas of marked retinal thinning. Deroofing of cystoid spaces may lead to lamellar hole formation, seen on OCT as a discontinuity in the inner retina, often with wedgeshaped separation of the inner and outer foveal layers and the absence of a full-thickness defect (Figure 5-17).103,104

104  Chapter 5

Figure 5-15. Spectral-domain OCT demonstrating macular edema. Areas of hyper-reflectivity are seen intraretinally with posterior shadowing. These correspond to lipid deposits.

Figure 5-16. Spectral-domain OCT of a patient with chronic macular edema secondary to RVO. There is loss of the ELM and ellipsoid zone. However, the RPE-Bruch’s membrane complex is still intact.

Patients with long-standing CME commonly develop other abnormalities of the vitreoretinal interface.103 On OCT, the partially attached vitreous (posterior hyaloid) may be seen as a thin hyperreflective membrane with a broad or focal adhesion to the retinal surface. This membrane may be thickened and taut, exerting obvious traction on the retina and resulting in a characteristic peaked appearance of the retinal surface (vitreomacular traction).105 Epiretinal membrane formation on the retinal surface is also common and is best visualized on OCT.106 Centripetal contraction of an epiretinal membrane may lead to pseudohole formation. On OCT, a pseudohole appears as a steepened foveal pit with thickened edges, reduced foveal pit diameter, normal or slightly increased foveal thickness, and an obvious causative epiretinal membrane.107 Finally, it should be noted that the qualitative OCT features described previously are not specific to eyes with RVO. In fact, many of these features can be seen in other retinal vascular diseases, including diabetic retinopathy, hypertensive retinopathy, and retinal arteriolar macroaneurysms. However, a characteristic finding in patients with BRVO is that disease features such as CME should respect the horizontal raphe on volume raster scanning (Figure 5-18).

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Figure 5-17. OCT macular B-scan of the right eye of a patient with a central retinal vein occlusion. An epiretinal membrane and cystoid edema are noted. The central large cysts show a small defect in the inner surface resulting in an early lamellar hole.

Figure 5-18. Reconstructed vertically oriented spectral-domain OCT B-scan of the eye of a patient with BRVO. Although there is marked retinal edema inferiorly (left half of the image), the superior macula is relatively normal.

106  Chapter 5

Quantitative Assessment The high axial resolution offered by OCT is well suited to the objective, accurate measurement of retinal thickness in disorders such as RVO.108 Commercial OCT systems use image processing techniques to automatically detect the inner and outer retinal boundaries on OCT B-scans (segmentation) and thus provide measurements of retinal thickness.109,110 Retinal thickness is then measured at multiple locations, and retinal thickness maps corresponding to the ETDRS grid can then be constructed (Figure 5-19). However, caution is required because errors in automated measurements may occur, particularly in eyes with vitreoretinal interface abnormalities and/or subretinal fluid.110,111 Fortunately, these errors are typically less common and less marked in retinal vascular diseases such as RVO than in disorders with more complex structural disruption such as neovascular age-related macular degeneration.112 Numerous commercial OCT devices are currently available from multiple vendors, including Cirrus HD-OCT (Carl Zeiss Meditec), 3D OCT-2000 (Topcon Medical Systems), Spectralis OCT (Heidelberg Engineering), OCT HS-100 (Canon), Envisu (Bioptigen), RTVue-100 (Optovue), RS-3000 (Nidek), and Optos OCT SLO (Optos).113 For each device, segmentation of the outer retinal boundary differs, leading to slight discrepancies in retinal thickness measurements.

Structure-Function Correlation The correlation between OCT-derived measurements of central retinal thickness and visual acuity has been extensively investigated in the SCORE study.114-120 In the SCORECRVO trial, the 262 patients had a mean ETDRS visual acuity score at baseline of 51 letters and a mean retinal thickness of 656 μm.114 The correlation between these parameters was modest (correlation coefficient, r = −0.27), with every 100-μm increase in thickness only estimated to result in the loss of 1.7 letters. In the SCORE-BRVO trial, the 403 patients had a mean ETDRS visual acuity score at baseline of 57 letters and a mean retinal thickness of 526 μm.114 As with CRVO patients, the correlation between these parameters was modest (correlation coefficient, r = −0.28). In the SCORE-CRVO trial, the median decrease in center point retinal thickness was 196 μm in the 4-mg triamcinolone group, 77 μm in the 1-mg triamcinolone group, and 125 μm in the observation group at the first follow-up visit (month 4).116 Changes in center point retinal thickness from baseline in all 3 groups showed a moderate negative correlation with changes in visual acuity from baseline, at both first follow-up and primary endpoint (r values of −0.39, −0.32, and −0.32 at month 12 for observation, 1-mg, and 4-mg groups, respectively). The OCT outcomes from the SCORE-BRVO trial were broadly similar, with similar OCT and visual acuity correlations.117 The lack of a strong correlation between visual acuity and OCT measurements in the SCORE study is interesting given that current treatment for RVO-associated macular edema is aimed at reducing retinal thickness with the expectation that such reduction will positively affect visual acuity. Although OCT-derived central retinal thickness helps guide RVO retreatment strategies and provides insight into the pharmacodynamics and mechanism of action of new therapies, it is clear that it cannot yet serve as a validated surrogate endpoint for clinical trials (ie, an endpoint that is reasonably likely to predict clinical benefit).121 Such an

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Figure 5-19. (A) Typical retinal thickness map output from an OCT device. (B) Corresponding retinal thickness map. The numbers in various sectors of the ETDRS grid illustrate the mean retinal thickness in each of these sectors.

108  Chapter 5

endpoint could be used to increase the accuracy, decrease the costs, and potentially shorten the duration of such trials. For a number of years, efforts have been underway to identify novel OCT-derived morphologic parameters that show stronger correlations with visual function.122-124 In a recent OCT study of diabetic and uveitic patients with CME, much stronger correlations were detected when the cross-sectional area of retinal tissue between the plexiform layers (as measured from en face scans) was correlated with visual acuity.125 Diabetic correlative studies have also focused on evaluation of other novel OCT parameters, such as intensity data.126-128 In RVO, a number of smaller single-center, retrospective studies have found interesting correlations between disruption of the ELM/ photoreceptor IS-OS junction and decreases in VA.96-100 These findings are supported by a SCORE ancillary study, where disruption of the photoreceptor IS-OS junction was associated with increased retinal thickness and worse visual outcomes at the primary endpoint.120 Further work is required; fortunately, the imminent introduction of new imaging modalities is likely to provide a boost to these efforts. In the next section, we describe these technologies.

FUTURE DIRECTIONS In this section, we highlight attempts to address the shortcomings of current retinal imaging modalities in the management of RVO-associated macular edema. We focus on 4 main areas: (1) objective quantification of retinal blood flow, (2) measurement of tissue oxygenation, (3) imaging of single cells in the retina, and (4) noninvasive retinal angiography.

Objective Quantification of Retinal Blood Flow Measurement of retinal blood flow is currently possible using quantitative angiography, based on the use of dye-dilution techniques.129 In this method, the concentration of fluorescent dye within the blood at a specific observation point is graphed over time, producing a dye-dilution curve and allowing calculation of blood-flow velocities. However, without measurement of corresponding vascular diameters, it is not possible to measure absolute blood flow, which is the most clinically relevant parameter because changes in blood velocity can occur in nondisease states due to retinal autoregulation. In addition, the invasive nature of the dye injections required for these approaches precludes their routine use in many clinical scenarios. As a result, many current efforts are focused on use of the Doppler effect in OCT systems to allow noninvasive quantification of blood flow. The Doppler effect is the change in frequency of a wave as it is reflected off a moving object. As the frequency shift is dependent on the velocity of the moving object, this effect can be used to measure the velocity of blood flowing in the eye. Use of the Doppler effect in OCT systems may thus allow calculation of blood-flow velocities.81 If blood-flow velocity is known and the diameter of the blood vessel can also be measured, then absolute values for blood flow may be determined (Figure 5-20). Since the mid-1990s, Doppler measurements have been incorporated into prototype OCT imaging systems.130-132 Although OCT can generate cross-sectional images of retinal blood flow, accurate quantification of this flow remains challenging. To achieve this, it is necessary to measure the geometry

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Figure 5-20. Doppler OCT B-scan image in an eye with an RVO. The B-scan is a circumpapillary circular scan that encircles the nerve and transects all vessels as they exit or enter the nerve area. The Doppler shift within the vessels is shown in color (red or blue).

of the vessel and, in particular, the Doppler angle.133 Furthermore, current Doppler OCT systems are limited in terms of the maximal velocities measurable and of the smallest vessel diameters measurable (capillary flow involves single erythrocyte movement rather than continuous fluid flow). Nevertheless, a number of commercial OCT systems (eg, Envisu) have begun to incorporate Doppler measurements. Although this is exciting, the complexity of retinal hemodynamics ensures that extensive validation studies will be required before widespread clinical application.

Measurement of Tissue Oxygenation Spectroscopy is the study of the interaction between any form of matter and radiated energy (eg, visible light). By measuring radiation intensity as a function of wavelength and through the identification of characteristic signatures, it is possible to determine the constituents of a material. In clinical settings, the application of spectroscopic principles has been of particular use for oximetry, the measurement of oxygen saturation in a patient’s blood. In the retina, spectral imaging is the combination of spectroscopy with conventional imaging techniques to allow determination of the spatial distribution of oximetry findings.134,135 Current spectral imaging devices typically use 1 of 2 different approaches: (1) multispectral imaging and (2) hyperspectral imaging (Figure 5-21). Fundus cameras and SLOs are most commonly used, although early attempts have been made to use OCT.135 Multispectral imaging involves the measurement of reflected light from images obtained at discrete and somewhat narrow spectral bands.135,136 The commercially available Oxymap T1 system uses this approach and has recently been used for the investigation of RVO. In patients with both CRVO and BRVO, considerable variations in oxygen saturation were found.137,138 Evidence of hypoxia was seen in some patients but not in others, potentially reflecting variable disease severity in terms of degree of occlusion, recanalization, collateral circulation, and coexistent tissue atrophy. Hyperspectral imaging involves the measurement of light from images obtained at narrow spectral bands over a contiguous spectral range.139 This approach may provide more accurate measurements of oxygen saturation than 2-wavelength multispectral approaches. However, this requires the use

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Figure 5-21. Hyperspectral image of the fundus. Capturing images of the retina at various individual spectra allows the relative amounts of oxygenated and deoxygenated hemoglobin to be determined in the retinal vessels and surrounding tissue. From this information, the oxygen tension within the tissue can be computed and displayed as a color-coded map. In this example of a patient with an HRVO (top), the oxygen tension is also noted to be reduced in the major vessels opposite from the occlusion (bottom insets). (Reprinted with permission of Amir Kashani and Mark Humayun.)

of sensitive detectors and powerful computers to enable fast and accurate processing of images. As with Doppler OCT, these modalities show great promise but require detailed validation and reproducibility studies.

Imaging of Single Cells in the Retina Our ability to obtain high-resolution images of the human retina is limited by the presence of defects or aberrations in the optical system of the eye.140,141 Using the technique of adaptive optics, it is now possible to measure and correct for these aberrations in real time. Adaptive optics involves precise measurements of ocular aberrations using wavefront sensors based on the Hartmann-Shack principle and the correction of these aberrations using highly deformable mirrors. As a result, it is now possible to acquire images of the retina with cellular-level resolution in a noninvasive fashion. Adaptive optics components have been adapted into fundus cameras and SLO systems; the rtx1 Adaptive Optics Retinal Camera (Imagine Eyes) is now commercially available

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Figure 5-22. Adaptive optics scanning laser ophthalmoscopic imaging. A 1 × 1-mm region of the parafoveal retina of a normal subject is shown. The wave-guiding properties of the photoreceptors allow the cone photoreceptor mosaic to be well seen.

and approved for use in clinical settings. They allow fundal images to be obtained with such resolution that individual cone photoreceptors can be visualized (Figure 5-22).142,143 The high scanning speed of adaptive optics SLO systems further allows retinal images to be captured at video rates, thus permitting measurement of dynamic retinal changes, such as blood flow.142,144,145 Using these systems, it is possible to directly visualize blood cells as they transit through retinal capillaries. As a consequence, direct noninvasive measurement of the velocity of retinal blood flow becomes possible. Current adaptive optics systems have limitations, including a small field of view (eg, 4 degrees × 4 degrees) and long image acquisition times. To date, their use has also been limited in diseases with profound disruption of normal anatomy, such as RVO.

Noninvasive Retinal Angiography The high speed of current state-of-the-art OCT technology (swept-source OCT) allows 3-dimensional mapping of the macula and posterior pole.81 The use of long-wavelength light sources (eg, 1050 nm) also allows enhanced visualization of the choroid.146 An important focus of current OCT research is the generation of 3-dimensional maps of the retinal and choroidal vasculature: so-called optical coherence angiography (OCA; Figure 5-23).81,147

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Figure 5-23. Phase-contrast OCT image. Reconstruction of the OCT data emphasizing the phase-variant information allows the retinal microvasculature to be well seen without the aid of an exogenous contrast agent. (Reprinted with permission of Jeff Fingler and Scott Fraser.)

A number of techniques for OCA are currently under development. In essence, they all involve high-speed, sequential acquisition of OCT A-scans or B-scans at the same retinal locus and then assessment of differences in the scans that occur as a result of blood flow. In Doppler OCT, measurement of phase shifts between sequential A-scans allows generation of contrast.147,148 In phase-contrast OCT, measurement of differences in sequential B-scans allows detection of motion (ie, blood flow).147,149,150 This may be achieved by 1 of 2 methods: (1) differential phase variance or (2) power Doppler phase shifts.151,152 After acquisition of OCA image sets, it is possible to generate 3-dimensional renderings of the vasculature or 2-dimensional fundal images with color coding of the vessel depth. The incorporation of adaptive optics with OCT/OCA will allow vascular mapping with the high axial resolutions of OCT/OCA and the high transverse resolutions of adaptive opticsSLOs. The first such adaptive optics-OCA device has recently been described.153

CONCLUSION In this chapter, we discussed in detail the role of imaging in the management of macular edema secondary to RVO. Throughout, we emphasized a number of key points. First, an understanding of disease pathophysiology is crucial to accurate interpretation of ocular

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imaging. Second, RVO is not a single disease but rather a number of distinct clinical entities with different clinical features and prognoses. We further highlighted the distinction between ischemic and nonischemic CRVO and the shortcomings in the use of 10 disc areas of nonperfusion as the gold standard in the differentiation of these forms. Third, we described the recent developments in noncontact imaging of the far retinal periphery (ie, ultra-widefield imaging) and the discovery of widespread peripheral retinal nonperfusion in many patients using this approach. Fourth, we detailed the cross-sectional visualization of RVO-associated macular edema and other features using OCT. We described the ubiquitous adoption of OCT-derived measures of retinal thickness in RVO clinical trials and highlighted the need for new OCT-derived anatomic endpoints that more strongly correlate with functional outcomes. Finally, we described the latest developments in stateof-the-art retinal imaging. In the near future, these changes are likely to allow rapid, noninvasive visualization of the retinal and choroidal circulation with resolution superior to that currently afforded by FA. They may also allow improved assessment of tissue perfusion status and help more clearly delineate the relationship between retinal morphology and VEGF upregulation in the eye.

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Role of Imaging in the Management of Macular Edema Secondary to RVO  115 39. Danis RP, Moorthy RS, Savage J. Microhemodynamics of retinal collateral vessel formation. Med Hypotheses. 1995;44(2):103-109. 40. Giuffrè G, Palumbo C, Randazzo-Papa G. Optociliary veins and central retinal vein occlusion. Br J Ophthalmol. 1993;77(12):774-777. 41. Takahashi K, Muraoka K, Kishi S, Shimizu K. Formation of retinochoroidal collaterals in central retinal vein occlusion. Am J Ophthalmol. 1998;126(1):91-99. 42. Frangieh GT, Green WR, Barraquer-Somers E, Finkelstein D. Histopathologic study of nine branch retinal vein occlusions. Arch Ophthalmol. 1982;100(7):1132-1140. 43. Kumar B, Yu DY, Morgan WH, Barry CJ, Constable IJ, McAllister IL. The distribution of angioarchitectural changes within the vicinity of the arteriovenous crossing in branch retinal vein occlusion. Ophthalmology. 1998;105(3):424-427. 44. Muraoka Y, Tsujikawa A, Murakami T, et al. Morphologic and functional changes in retinal vessels associated with branch retinal vein occlusion. Ophthalmology. 2013;120(1):91-99. 45. Christoffersen NL, Larsen M. Pathophysiology and hemodynamics of branch retinal vein occlusion. Ophthalmology. 1999;106(11):2054-2062. 46. Cousins SW, Flynn HW Jr, Clarkson JG. Macroaneurysms associated with retinal branch vein occlusion. Am J Ophthalmol. 1990;109(5):567-570. 47. Parodi MB, Da Pozzo S, Saviano S, Ravalico G. Branch retinal vein occlusion and macroaneurysms. Int Ophthalmol. 1997;21(3):161-164. 48. Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovascularization with retinal vascular occlusion-III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983;90(5):488-506. 49. Hayreh SS, Hayreh MS. Hemi-central retinal vein occulsion. Pathogenesis, clinical features, and natural history. Arch Ophthalmol. 1980;98(9):1600-1609. 50. Scott IU, Blodi BA, Ip MS, et al. SCORE Study Report 2: interobserver agreement between investigator and reading center classification of retinal vein occlusion type. Ophthalmology. 2009;116(4):756-761. 51. Hayreh SS, Zimmerman MB. Hemicentral retinal vein occlusion: natural history of visual outcome. Retina. 2012;32(1):68-76. 52. Scott IU, Vanveldhuisen PC, Oden NL, et al. Baseline characteristics and response to treatment of participants with hemiretinal compared with branch retinal or central retinal vein occlusion in the Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) Study: SCORE study report 14. Arch Ophthalmol. 2012;130(12):1517-1524. 53. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104(1):34-41. 54. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102(10):1434-1444. 55. Laatikainen L, Kohner EM. Fluorescein angiography and its prognostic significance in central retinal vein occlusion. Br J Ophthalmol. 1976;60(6):411-418. 56. May DR, Klein ML, Peyman GA, Raichand M. Xenon arc panretinal photocoagulation for central retinal vein occlusion: a randomised prospective study. Br J Ophthalmol. 1979;63(11):725-734. 57. Magargal LE, Brown GC, Augsburger JJ, Parrish RK II. Neovascular glaucoma following central retinal vein obstruction. Ophthalmology. 1981;88(11):1095-1101. 58. Spaide RF. Peripheral areas of nonperfusion in treated central retinal vein occlusion as imaged by wide-field fluorescein angiography. Retina. 2011;31(5):829-837. 59. Hayreh SS, Klugman MR, Beri M, Kimura AE, Podhajsky P. Differentiation of ischemic from non-ischemic central retinal vein occlusion during the early acute phase. Graefes Arch Clin Exp Ophthalmol. 1990;228(3):201-217.

116  Chapter 5 60. Servais GE, Thompson HS, Hayreh SS. Relative afferent pupillary defect in central retinal vein occlusion. Ophthalmology. 1986;93(3):301-303. 61. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio RG. Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology. 2013;120(4):795-802. 62. Sadda S, Danis RP, Pappuru RR, et al. Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion. Ophthalmology. 2013;120(7):1423-1431. 63. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013;97(3):278-284. 64. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032. 65. Witmer MT, Kiss S. Wide-field imaging of the retina. Surv Ophthalmol. 2013;58(2):143-154. 66. Friberg TR, Pandya A, Eller AW. Non-mydriatic panoramic fundus imaging using a noncontact scanning laser-based system. Ophthalmic Surg Lasers Imaging. 2003;34(6):488-497. 67. Tan CS, Heussen F, Sadda SR. Peripheral autofluorescence and clinical findings in neovascular and non-neovascular age-related macular degeneration. Ophthalmology. 2013;120(6):1271-1277. 68. Heussen FM, Tan CS, Sadda SR. Prevalence of peripheral abnormalities on ultra-widefield greenlight (532 nm) autofluorescence imaging at a tertiary care center. Invest Ophthalmol Vis Sci. 2012;53(10):6526-6531. 69. Wessel MM, Aaker GD, Parlitsis G, Cho M, D’Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina. 2012;32(4):785-791. 70. Prasad PS, Oliver SC, Coffee RE, Hubschman JP, Schwartz SD. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology. 2010;117(4):780-784. 71. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103(11):1820-1828. 72. Noma H, Funatsu H, Mimura T, Harino S, Sone T, Hori S. Increase of vascular endothelial growth factor and interleukin-6 in the aqueous humour of patients with macular oedema and central retinal vein occlusion. Acta Ophthalmol. 2010;88(6):646-651. 73. Noma H, Funatsu H, Mimura T, Harino S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor in macular edema with central retinal vein occlusion. Ophthalmology. 2009;116(1):87-93. 74. Ferrara DC, Koizumi H, Spaide RF. Early bevacizumab treatment of central retinal vein occlusion. Am J Ophthalmol. 2007;144(6):864-871. 75. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol. 2009;147(2):298-306. 76. Tsui I, Kaines A, Havunjian MA, et al. Ischemic index and neovascularization in central retinal vein occlusion. Retina. 2011;31(1):105-110. 77. Barbazetto I, Burdan A, Bressler NM, et al. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment—TAP and VIP report No. 2. Arch Ophthalmol. 2003;121(9):1253-1268. 78. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254(5035):1178-1181.

Role of Imaging in the Management of Macular Edema Secondary to RVO  117 79. Hirata M, Tsujikawa A, Matsumoto A, et al. Macular choroidal thickness and volume in normal subjects measured by swept-source optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(8):4971-4978. 80. Spaide RF, Akiba M, Ohno-Matsui K. Evaluation of peripapillary intrachoroidal cavitation with swept source and enhanced depth imaging optical coherence tomography. Retina. 2012;32(6):1037-1044. 81. Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retin Eye Res. 2008;27(1):45-88. 82. Ohno-Matsui K, Akiba M, Ishibashi T, Moriyama M. Observations of vascular structures within and posterior to sclera in eyes with pathologic myopia by swept-source optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53(11):7290-7298. 83. Ohno-Matsui K, Akiba M, Moriyama M, Ishibashi T, Hirakata A, Tokoro T. Intrachoroidal cavitation in macular area of eyes with pathologic myopia. Am J Ophthalmol. 2012;154(2):382-393. 84. Catier A, Tadayoni R, Paques M, et al. Characterization of macular edema from various etiologies by optical coherence tomography. Am J Ophthalmol. 2005;140(2):200-206. 85. Karacorlu M, Ozdemir H, Karacorlu SA. Resolution of serous macular detachment after intravitreal triamcinolone acetonide treatment of patients with branch retinal vein occlusion. Retina. 2005;25(7):856-860. 86. Lerche RC, Schaudig U, Scholz F, Walter A, Richard G. Structural changes of the retina in retinal vein occlusion—imaging and quantification with optical coherence tomography. Ophthalmic Surg Lasers. 2001;32(4):272-280. 87. Spaide RF, Lee JK, Klancnik JK Jr, Gross NE. Optical coherence tomography of branch retinal vein occlusion. Retina. 2003;23(3):343-347. 88. Otani T, Yamaguchi Y, Kishi S. Serous macular detachment secondary to distant retinal vascular disorders. Retina. 2004;24(5):758-762. 89. Ouyang Y, Heussen FM, Keane PA, Pappuru RK, Sadda SR, Walsh AC. Evaluation of the axial location of cystoid spaces in retinal vein occlusion using optical coherence tomography. Retina. 2013;33(5):1011-1019. 90. Ozdemir H, Karacorlu M, Karacorlu S. Serous macular detachment in central retinal vein occlusion. Retina. 2005;25(5):561-563. 91. Ogino K, Murakami T, Tsujikawa A, et al. Characteristics of optical coherence tomographic hyperreflective foci in retinal vein occlusion. Retina. 2012;32(1):77-85. 92. Kang HM, Chung EJ, Kim YM, Koh HJ. Spectral-domain optical coherence tomography (SD-OCT) patterns and response to intravitreal bevacizumab therapy in macular edema associated with branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2013;251(2):501-508. 93. Sekiryu T, Iida T, Sakai E, Maruko I, Ojima A, Sugano Y. Fundus autofluorescence and optical coherence tomography findings in branch retinal vein occlusion. J Ophthalmol. 2012;2012:638064. 94. Christoffersen N, Sander B, Larsen M. Precipitation of hard exudate after resorption of intraretinal edema after treatment of retinal branch vein occlusion. Am J Ophthalmol. 1998;126(3):454-456. 95. Murakami T, Tsujikawa A, Ohta M, et al. Photoreceptor status after resolved macular edema in branch retinal vein occlusion treated with tissue plasminogen activator. Am J Ophthalmol. 2007;143(1):171-173. 96. Horio N. Can the integrity of the photoreceptor layer explain visual acuity in branch retinal vein occlusion? Br J Ophthalmol. 2007;91(12):1575-1576. 97. Ota M, Tsujikawa A, Murakami T, et al. Association between integrity of foveal photoreceptor layer and visual acuity in branch retinal vein occlusion. Br J Ophthalmol. 2007;91(12):1644-1649.

118  Chapter 5 98. Ota M, Tsujikawa A, Kita M, et al. Integrity of foveal photoreceptor layer in central retinal vein occlusion. Retina. 2008;28(10):1502-1508. 99. Ota M, Tsujikawa A, Murakami T, et al. Foveal photoreceptor layer in eyes with persistent cystoid macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2008;145(2):273-280. 100. Yamaike N, Tsujikawa A, Ota M, et al. Three-dimensional imaging of cystoid macular edema in retinal vein occlusion. Ophthalmology. 2008;115(2):355-362.e2. 101. Wallow IH, Danis RP, Bindley C, Neider M. Cystoid macular degeneration in experimental branch retinal vein occlusion. Ophthalmology. 1988;95(10):1371-1379. 102. Iida T, Yannuzzi LA, Spaide RF, Borodoker N, Carvalho CA, Negrao S. Cystoid macular degeneration in chronic central serous chorioretinopathy. Retina. 2003;23(1):1-7. 103. Mirza RG, Johnson MW, Jampol LM. Optical coherence tomography use in evaluation of the vitreoretinal interface: a review. Surv Ophthalmol. 2007;52(4):397-421. 104. Witkin AJ, Ko TH, Fujimoto JG, et al. Redefining lamellar holes and the vitreomacular interface: an ultrahigh-resolution optical coherence tomography study. Ophthalmology. 2006;113(3):388-397. 105. Koizumi H, Spaide RF, Fisher YL, Freund KB, Klancnik JM Jr, Yannuzzi LA. Threedimensional evaluation of vitreomacular traction and epiretinal membrane using spectral-domain optical coherence tomography. Am J Ophthalmol. 2008;145(3):509-517. 106. Legarreta JE, Gregori G, Knighton RW, Punjabi OS, Lalwani GA, Puliafito CA. Threedimensional spectral-domain optical coherence tomography images of the retina in the presence of epiretinal membranes. Am J Ophthalmol. 2008;145(6):1023-1030. 107. Chen JC, Lee LR. Clinical spectrum of lamellar macular defects including pseudoholes and pseudocysts defined by optical coherence tomography. Br J Ophthalmol. 2008;92(10):1342-1346. 108. Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol. 1995;113(8):1019-1029. 109. Keane PA, Liakopoulos S, Jivrajka RV, et al. Evaluation of optical coherence tomography retinal thickness parameters for use in clinical trials for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50(7):3378-3385. 110. Keane PA, Mand PS, Liakopoulos S, Walsh AC, Sadda SR. Accuracy of retinal thickness measurements obtained with Cirrus optical coherence tomography. Br J Ophthalmol. 2009;93(11):1461-1467. 111. Sadda SR, Wu Z, Walsh AC, et al. Errors in retinal thickness measurements obtained by optical coherence tomography. Ophthalmology. 2006;113(2):285-293. 112. Keane PA, Patel PJ, Liakopoulos S, Heussen FM, Sadda SR, Tufail A. Evaluation of agerelated macular degeneration with optical coherence tomography. Surv Ophthalmol. 2012;57(5):389-414. 113. Kiernan DF, Mieler WF, Hariprasad SM. Spectral-domain optical coherence tomography: a comparison of modern high-resolution retinal imaging systems. Am J Ophthalmol. 2010;149(1):18-31. 114. Scott IU, VanVeldhuisen PC, Oden NL, et al. SCORE Study report 1: baseline associations between central retinal thickness and visual acuity in patients with retinal vein occlusion. Ophthalmology. 2009;116(3):504-512. 115. Ip MS, Oden NL, Scott IU, et al. SCORE Study report 3: study design and baseline characteristics. Ophthalmology. 2009;116(9):1770-1777.e1. 116. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101-1114.

Role of Imaging in the Management of Macular Edema Secondary to RVO  119 117. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115-1128. 118. Domalpally A, Blodi BA, Scott IU, et al. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study system for evaluation of optical coherence tomograms: SCORE study report 4. Arch Ophthalmol. 2009;127(11):1461-1467. 119. Scott IU, VanVeldhuisen PC, Oden NL, et al. Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10. Ophthalmology. 2011;118(2):345-352. 120. Domalpally A, Peng Q, Danis R, et al. Association of outer retinal layer morphology with visual acuity in patients with retinal vein occlusion: SCORE Study Report 13. Eye (Lond). 2012;26(7):919-924. 121. Csaky KG, Richman EA, Ferris FL III. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci. 2008;49(2):479-489. 122. Keane PA, Patel PJ, Ouyang Y, et al. Effects of retinal morphology on contrast sensitivity and reading ability in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(11):5431-5437. 123. Keane PA, Liakopoulos S, Chang KT, et al. Relationship between optical coherence tomography retinal parameters and visual acuity in neovascular age-related macular degeneration. Ophthalmology. 2008;115(12):2206-2214. 124. Keane PA, Sadda SR. Predicting visual outcomes for macular disease using optical coherence tomography. Saudi J Ophthalmol. 2011;25(2):145-158. 125. Pelosini L, Hull CC, Boyce JF, McHugh D, Stanford MR, Marshall J. Optical coherence tomography may be used to predict visual acuity in patients with macular edema. Invest Ophthalmol Vis Sci. 2011;52(5):2741-2748. 126. Alasil T, Keane PA, Updike JF, et al. Relationship between optical coherence tomography retinal parameters and visual acuity in diabetic macular edema. Ophthalmology. 2010;117(12):2379-2386. 127. Forooghian F, Stetson PF, Meyer SA, et al. Relationship between photoreceptor outer segment length and visual acuity in diabetic macular edema. Retina. 2010;30(1):63-70. 128. Gibran SK, Khan K, Jungkim S, Cleary PE. Optical coherence tomographic pattern may predict visual outcome after intravitreal triamcinolone for diabetic macular edema. Ophthalmology. 2007;114(5):890-894. 129. Schmetterer L, Garhofer G. How can blood flow be measured? Surv Ophthalmol. 2007;52 Suppl 2:S134-S138. 130. Izatt JA, Kulkarni MD, Yazdanfar S, Barton JK, Welch AJ. In vivo bidirectional color Doppler flow imaging of picoliter blood volumes using optical coherence tomography. Opt Lett. 1997;22(18):1439-1441. 131. Yazdanfar S, Rollins AM, Izatt JA. In vivo imaging of human retinal flow dynamics by color Doppler optical coherence tomography. Arch Ophthalmol. 2003;121(2):235-239. 132. Leitgeb R, Schmetterer L, Drexler W, Fercher A, Zawadzki R, Bajraszewski T. Real-time assessment of retinal blood flow with ultrafast acquisition by color Doppler Fourier domain optical coherence tomography. Opt Express. 2003;11(23):3116-3121. 133. Wang Y, Fawzi AA, Varma R, et al. Pilot study of optical coherence tomography measurement of retinal blood flow in retinal and optic nerve diseases. Invest Ophthalmol Vis Sci. 2011;52(2):840-845. 134. Harris A, Dinn RB, Kagemann L, Rechtman E. A review of methods for human retinal oximetry. Ophthalmic Surg Lasers Imaging. 2003;34(2):152-164.

120  Chapter 5 135. Mordant DJ, Al-Abboud I, Muyo G, et al. Spectral imaging of the retina. Eye (Lond). 2011;25(3):309-320. 136. Hardarson SH, Harris A, Karlsson RA, et al. Automatic retinal oximetry. Invest Ophthalmol Vis Sci. 2006;47(11):5011-5016. 137. Hardarson SH, Stefánsson E. Oxygen saturation in central retinal vein occlusion. Am J Ophthalmol. 2010;150(6):871-875. 138. Hardarson SH, Stefánsson E. Oxygen saturation in branch retinal vein occlusion. Acta Ophthalmol. 2012;90(5):466-470. 139. Mordant DJ, Al-Abboud I, Muyo G, et al. Validation of human whole blood oximetry, using a hyperspectral fundus camera with a model eye. Invest Ophthalmol Vis Sci. 2011;52(5):2851-2859. 140. Doble N. High-resolution, in vivo retinal imaging using adaptive optics and its future role in ophthalmology. Expert Rev Med Devices. 2005;2(2):205-216. 141. Williams DR. Imaging single cells in the living retina. Vision Res. 2011;51(13):1379-1396. 142. Roorda A, Williams DR. The arrangement of the three cone classes in the living human eye. Nature. 1999;397(6719):520-522. 143. Kitaguchi Y, Fujikado T, Bessho K, et al. Adaptive optics fundus camera to examine localized changes in the photoreceptor layer of the fovea. Ophthalmology. 2008;115(10):1771-1777. 144. Tam J, Martin JA, Roorda A. Noninvasive visualization and analysis of parafoveal capillaries in humans. Invest Ophthalmol Vis Sci. 2010;51(3):1691-1698. 145. Tam J, Tiruveedhula P, Roorda A. Characterization of single-file flow through human retinal parafoveal capillaries using an adaptive optics scanning laser ophthalmoscope. Biomed Opt Express. 2011;2(4):781-793. 146. Keane PA, Ruiz-Garcia H, Sadda SR. Clinical applications of long-wavelength (1,000-nm) optical coherence tomography. Ophthalmic Surg Lasers Imaging. 2011;42 Suppl:S67-S74. 147. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express. 2006;14(17):7821-7840. 148. Schmoll T, Kolbitsch C, Leitgeb RA. Ultra-high-speed volumetric tomography of human retinal blood flow. Opt Express. 2009;17(5):4166-4176. 149. Fingler J, Readhead C, Schwartz DM, Fraser SE. Phase-contrast OCT imaging of transverse flows in the mouse retina and choroid. Invest Ophthalmol Vis Sci. 2008;49(11):5055-5059. 150. Fingler J, Zawadzki RJ, Werner JS, Schwartz D, Fraser SE. Volumetric microvascular imaging of human retina using optical coherence tomography with a novel motion contrast technique. Opt Express. 2009;17(24):22190-22200. 151. Motaghiannezam R, Schwartz DM, Fraser SE. In vivo human choroidal vascular pattern visualization using high-speed swept-source optical coherence tomography at 1060 nm. Invest Ophthalmol Vis Sci. 2012;53(4):2337-2348. 152. Makita S, Jaillon F, Yamanari M, Yasuno Y. Dual-beam-scan Doppler optical coherence angiography for birefringence-artifact-free vasculature imaging. Opt Express. 2012;20(3):2681-2692. 153. Kurokawa K, Sasaki K, Makita S, Hong YJ, Yasuno Y. Three-dimensional retinal and choroidal capillary imaging by power Doppler optical coherence angiography with adaptive optics. Opt Express. 2012;20(20):22796-22812.

6

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches Eric W. Schneider, MD and Tamer H. Mahmoud, MD, PhD

In the nearly 2 decades following the publication of the Branch Retinal Vein Occlusion Study (BVOS) and Central Retinal Vein Occlusion Study (CVOS), pharmacologic therapy for retinal vein occlusion (RVO) was almost nonexistent. Although a few investigators explored the potential of tissue plasminogen activator (tPA)-assisted thrombolysis delivered intravenously1 or intravitreally,2 clinicians largely adhered to the BVOS/CVOS-vetted options of macular grid laser (MGL) and observation.3 With the introduction of new classes of intravitreal agents—namely corticosteroids and anti-vascular endothelial growth factor (VEGF) agents—in the middle of the last decade, a host of viable pharmacologic options became available to clinicians. As detailed in the preceding chapters, agents such as triamcinolone, ranibizumab, aflibercept, and dexamethasone implant have proven to be efficacious when given as intravitreal monotherapy for the treatment of RVO-associated macular edema in several large, randomized, prospective clinical trials. As evidenced by these trials and numerous smaller studies, intravitreal monotherapy is effective for the vast majority of RVO patients, and this fact is reflected in its predominant use as a primary therapy by retina specialists.4 However, a number of patients display recalcitrant macular edema with attendant poor visual results despite frequent intravitreal monotherapy dosing. In the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) trials, 11.6% to 12.0% of patients treated with repeated intravitreal triamcinolone (IVTA) lost 15 or more letters, and more than 20% had central point thickness of more than 500 μm at 12-month follow-up.5,6 Although the rate of refractory edema was lower in the Ranibizumab for the Treatment of Macular Edema Branch Retinal Vein Occlusion: Evaluation of Safety and Efficacy (BRAVO)/Ranibizumab for the Treatment of Macular Edema After Central Retinal Vein Occlusion Study: Evaluation - 121 -

Hariprasad SM, ed. Management of Retinal Vein Occlusion: Current Concepts (pp 121-157). © 2014 SLACK Incorporated.

122  Chapter 6

of Safety and Efficacy (CRUISE) trial—0.7% to 3.8% lost 15 or more letters and 6.7% to 15.9% had central foveal thickness of more than 400 μm at 12-month follow-up—frequent ranibizumab monotherapy was not universally successful.7,8 Such recalcitrant cases have led investigators to explore more aggressive therapeutic alternatives, most notably combination pharmacologic and pharmacolaser treatments. Nonsurgical interventional therapies and vitrectomy-based options have provided yet another strategy for managing refractory cases. This chapter reviews these alternative approaches. Following a discussion of the rationale for combination treatment, the current evidence in support of various combination therapies is reviewed. The remainder of the text will focus on reported outcomes with various interventional strategies, with particular attention paid to the role of vitrectomy. For the purposes of this review, combination therapy will be defined as the administration of 2 disparate therapies either concurrently (ie, same visit) or sequentially such that the secondary therapy is administered during the presumed highly active phase of the primary therapy. This is to differentiate combination treatment from alternating treatment strategies in which subsequent therapies are administered during the terminal phase of initial therapy activity.

PHARMACOLOGIC/PHARMACOLASER COMBINATION THERAPY Rationale for Combination Therapy and the Treatment Burden of Monotherapy In discussing the rationale for pharmacologic/pharmacolaser combination therapy, several therapeutic factors must be considered: mechanism of action, pharmacokinetics, and side-effect profiles (Table 6-1). An additional important consideration is whether combination therapy is to be used as an alternative in monotherapy-responsive patients (to reduce dosing frequency/intensity, avoid cumulative dose-limiting side effects, or minimize reductions in efficacy due to tachyphylaxis) or as an escalation strategy in monotherapy-resistant cases. In either scenario, the ideal combination therapy would use agents with activity targeted to disparate components of RVO pathophysiology and complementary pharmacokinetic profiles. Such a combination should, in theory, allow for greater therapeutic efficacy and/or higher trough activity, thereby minimizing the frequency and/or intensity of therapy required and lowering the incidence of adverse effects. As seen in Table 6-1, significant diversity exists in the mechanism of action of the various candidate combination agents to reduce macular edema. This diversity provides ample opportunity to achieve synergistic treatment effects. For example, combination therapy with corticosteroids and anti-VEGF agents target both the inflammatory (via decreased leukotriene/prostaglandin production and intercellular adhesion molecule 1 [ICAM-1] expression9,10) and ischemic (via robust VEGF inhibition11) drivers of RVO-related macular edema. Although all agents appear to target VEGF activity, each works at a distinct site along the pathway mediating VEGF effects: laser reduces retinal hypoxia, leading to a

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  123

TABLE 6-1. CHARACTERISTICS OF CANDIDATE COMBINATION THERAPY AGENTS TRIAMCINOLONE ⇩ Leukotriene/prostaglandin production9 ⇩ Inflammatory markers 10 Mechanism (ICAM-1) of action ⇩ Vascular permeability10 ⇩ Permeability of RPE barrier10 ⇩ VEGF production12

ANTI-VEGF

VEGF inhibition11 ⇩ Vascular permeability11 ⇧ Permeability of RPE barrier13

MACULAR GRID LASER ⇩ Retinal O2 consumption14 ⇧ Inner retinal oxygenation14 ⇩ Hydrostatic pressure in capillaries/venule15 ⇩ Permeability of RPE barrier16

Elimination half-life

Triamcinolone/ Dexamethasone=18.6 d17

IVR: 7.19 d18 IVB: 9.92 d19

n/a

Latency to peak effect

Minimal20

Minimal20

Long21

Side effects

Cataract Glaucoma

? Glaucoma ? Cardiovascular events

Macular ischemia Paracentral scotoma

Abbreviations: ?, putative but unconfirmed; RPE, retinal pigment epithelium.

reduction in VEGF production14; anti-VEGF agents bind to and directly inhibit VEGF11; and corticosteroids appear to reduce VEGF production while also decreasing production of downstream effectors.12 When used in combination, clinicians can potentially achieve synergistic gains in efficacy due to multisite inhibition. From a pharmacokinetic standpoint, combining agents with differing peak activities and intravitreal half-lives may allow for a prolonged treatment effect of rapid, shortacting agents (eg, corticosteroids/anti-VEGF agents) and/or a shortening of effect latency for delayed, longer-acting therapies (eg, laser).22 Moreover, early intervention with rapid, short-acting agents such as IVTA or anti-VEGF agents—which, unlike laser, can be administered regardless of the extent of associated macular hemorrhage or edema—may allow for earlier laser therapy (due to enhanced clearance of macular hemorrhages)7,8,23 with greater efficacy and/or safety (due to greater laser uptake at lower powers in the setting of reduced edema).24 Avoiding the treatment delay associated with laser monotherapy is particularly important because multiple investigators have demonstrated improved outcomes with early intervention.25,26 As previously mentioned, combination therapy can be applied in both monotherapyresponsive and monotherapy-resistant patients. In the latter case, the goal is to achieve greater therapeutic efficacy via synergistic effects. In the former case, the goal is to limit the burdens of monotherapy, including frequent treatments/visits and adverse effects related to cumulative therapeutic exposure. The burden of visits/interventions associated with intravitreal therapy can be especially arduous. In several recent prospective trials,

124  Chapter 6

patients with RVO-related macular edema required, on average, injections at over half of their monthly visits during the pro re nata (PRN) study phase despite receiving 3 to 6 requisite monthly injections at study outset.7,8,27 Additionally, in the SCORE trials, a similar group of patients were treated, on average, at over half of study-mandated visits following a required baseline injection.5,6 Although laser is often considered a more durable option for branch RVO (BRVO)-related macular edema, laser treatments were again administered at just under half of study visits for patients in the laser arm of the SCORE trial.6 In addition to the associated psychosocial, physical, and financial burden associated with frequent retreatment, several factors are specific to frequent monotherapy dosing that may limit efficacy or directly contribute to the development of adverse effects. Some investigators have suggested that repeated intravitreal therapy can lead to diminishing anatomic/functional improvement due to tachyphylaxis.28,29 Others have proposed that “rebound macular edema”—characterized by edema in excess of initial presentation following initial improvement with anti-VEGF treatment—may occur in patients receiving frequent intravitreal monotherapy. Both phenomena may be mediated upregulation of VEGF receptors.30 Repeated monotherapy may also increase the incidence of certain adverse effects due to increased cumulative toxicity. Multiple reports have linked increased rates of cataract progression to the receipt of multiple IVTA injections. The data regarding a possible correlation between increased rates of elevated intraocular pressure (IOP) and multiple IVTA injections are less clear. Two retrospective studies examined this issue and found no increased incidence of elevated IOP after multiple injections31,32; however, follow-up was limited in these studies (minimum of 3 to 6 months). Substantial circumstantial evidence suggests that chronic, repeated exposure to intravitreal corticosteroid may induce ocular hypertension. In large clinical trials examining the use of 2 different formulations of sustained-release fluocinolone implants, rates of IOP elevation requiring incisional glaucoma surgery ranged from 4.8% to 26.2% at 2- to 3-year follow-up, suggesting that chronic exposure leads to intractable IOP rise.33,34 Moreover, repeated aqueous sampling of patients after fluocinolone implant placement demonstrated a dose-dependent increase in the incidence of steroid-induced ocular hypertension associated with increasing aqueous levels of fluocinolone.35 Because triamcinolone has been detected in measurable concentrations up to 1.5 years after injection, it is conceivable that repeated injections could result in the stepwise accumulation of IOP-altering concentrations. There appear to be less safety concerns regarding repetitive anti-VEGF dosing with reports of acceptable midterm safety,36 but theoretical concerns remain with regard to the potential for increased rates of arteriothrombotic events or glaucoma with frequent dosing.37 In light of the many potential pitfalls of repeated monotherapy, clinicians are increasingly turning to combination therapy, particularly laser plus intravitreal anti-VEGF agents.4 Unfortunately, the currently available data regarding combination therapy have lagged somewhat behind its implementation in clinical practice. Of the handful of studies published to date, the majority are small, short term, and/or retrospective. The next 3 sections will review these studies in detail.

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  125

Combined Anti-Vascular Endothelial Growth Factor and Corticosteroid Therapy As detailed previously, the combination of corticosteroid and anti-VEGF treatments meet the criteria for ideal combination therapy because these agents exhibit notable differences in mechanism and duration of action (see Table 6-1). Interestingly, recent in vitro work suggests that anti-VEGF agents may reduce retinal pigment epithelial (RPE) barrier function, while triamcinolone demonstrates the opposite effect.10,13 Combining intravitreal steroid (IVTA/dexamethasone implant) with intravitreal bevacizumab (IVB), intravitreal ranibizumab (IVR), or intravitreal aflibercept (IVA) may result in greater reductions in macular edema due to neutralization of this negative anti-VEGF agent-induced effect on the RPE. Moreover, recent evidence suggests that anti-VEGF administration is associated with an increase in the expression of retinal inflammatory markers, which makes the argument for combining the anti-inflammatory properties of IVTA with anti-VEGF agents all the more compelling.38 Ekdawi and Bakri39 first reported the application of this combination approach in a single case of central RVO (CRVO)-related macular edema that became resistant to both IVTA and IVB monotherapy.39 Rapid improvement in both retinal thickness and visual acuity occurred following sequential administration 1 week apart, providing evidence that concurrent administration may overcome tachyphylaxis. Two subsequent, small, retrospective studies also examined the use of IVTA plus IVB in patients with persistent edema despite prior intravitreal monotherapy and/or laser. Both groups noted minimal functional improvement in CRVO patients,40,41 whereas BRVO patients, which were included only in the study by Ehrlich et al, were found to have an initial benefit that waned at 3 months.40 Anatomic results were mixed, with one group reporting no change in macular thickness41 and the second group reporting significant improvement in both the CRVO and BRVO patients.40 Interestingly, both groups chose to use a smaller dose of IVTA (2 mg), which appeared to result in lower rates of IOP elevation requiring treatment (31%40 and 9%,41 respectively). Although both groups claimed a longer retreatment interval, injections were required every 2.9 to 3.0 months, consistent with the accepted reinjection range (ie, 3 months) for IVTA alone (Table 6-2). The use of combination corticosteroid/anti-VEGF as primary therapy was examined in 2 prospective, comparative trials, also with mixed results. Wang et al42 compared a combination of IVB and reduced-dose IVTA (2 mg) with IVB monotherapy in BRVO patients and found no intergroup differences in visual outcome, macular edema reduction, frequency of retreatment, or IOP-related adverse effects. In contrast, Cho et al,43 using a combination of periocular corticosteroid (40 mg of posterior sub-Tenon’s Kenalog [PSTK]) and IVB, reported significantly greater visual acuity improvement and macular edema reduction with significantly less injections with combination treatment in BRVO patients when compared to IVB alone. Possible explanations for these disparate results may relate to the differences in study populations (CRVO vs BRVO), duration of follow-up (12 weeks vs 6 months), and/or corticosteroid dose and route of administration (half-dose IVTA vs full-dose PSTK; see Table 6-2). The impact of steroid-induced cataract formation may also play a greater or lesser role in functional outcomes depending on the timing of the primary endpoint.

Mean: 14.64 mo

6 mo

CRVO: n = 11

BRVO: n = 22 CRVO: n = 12

Mono: n = 30 (all BRVO) Combo: n = 30 (all BRVO)

1.25 mg IVB + 2 mg IVTA (0 d)

1.25 mg IVB + 0.7 mg Ozurdex (Allergan)

Mono: 1.25 mg IVB Combo: 1.25 mg IVB + 40 mg PSTK (0 d)

Gupta 201141 (Re)a

Singer 201244 (P)

Cho 201243 (P, Ra) 6 mo

Min: 6 mo

BRVO: n=8 CRVO: n=8

1.25 mg IVB + 2 mg IVTA (0 d)

Ehrlich 201040 (Re)

F/U

Patients

Therapeutic Combination (Tx Delay)

Study (Design)

NONCOMPARATIVE STUDIES

Y

N

N

N

Tx Naïve

Mono: ⇧ BCVA @ 1 mo, 3 mo, 6 mo (all P < .001) Combo: ⇧ BCVA @ 1 mo, 3 mo, 6 mo (all P < .001) Intergroup: BCVA combo > mono @ 1 mo (P = .025), 6 mo (P = .002)

Letters gained @ 1 mo = 12.3; 2 mo = 14.1; 3 mo = 11.0; 6 mo = 16.8c Mono: ⇩ CMT @ 1 mo, 3 mo, 6 mo (all P < .001) Combo: ⇩ CMT @ 1 mo, 3 mo, 6 mo (all P < .001) Intergroup: CMT combo > mono @ 1 mo (P = .026), 3 mo (P = .005), 6 mo (P ≤ .001)

No change in final CMT (P = .31)

BRVO: ⇩ CMT @ 6 mo (P = .017) CRVO: ⇩ CMT @ 6 mo (P = .005)

BRVO: ⇧ BCVA @ 1 mo (P = .05), 3 mo (P = .03); no change in BCVA @ 6 mo CRVO: no change in BCVA @ 1 mo, 3 mo, 6 mo No change in final BCVA (P = .69)

Anatomic Outcomes

Functional Outcomes

Combo < mono (P = 23 in 6/34

⇧ IOPb = 1/11

BRVO: IOP > 21 in 3/8 patients during F/U CRVO: IOP > 21 in 2/8 patients during F/U

Adverse Events

TABLE 6-2. OUTCOMES OF CORTICOSTEROID AND ANTI-VEGF TREATMENT FOR RVO-RELATED MACULAR EDEMA

126  Chapter 6

Mono: 1.25 mg IVB Combo: 1.25 mg IVB + 2 mg IVTA (0 d)

Therapeutic Combination (Tx Delay) F/U

12 wk

Patients

Mono: n = 36 (all CRVO) Combo: n = 39 (all CRVO) Y

Tx Naïve

Anatomic Outcomes

Mono: no change in CRT @ at any time point Combo: no change in CRT @ at any time point Intergroup: no difference in CRT (P = .544)

Functional Outcomes

Mono:⇧ BCVA @ 4 wk (P < .01), 6 wk (P < .03), and 12 wk (P < .04) Combo: ⇧ BCVA @ 4 wk, 6 wk, and 12 wk (all P < .01) Intergroup: no difference in mean BCVA (P = .836)

NGd

Injection Number

Mono: ⇧ IOP requiring Tx = 5/36 Combo: ⇧ IOP requiring Tx = 6/39

Adverse Events

only. bDefinition of IOP elevation not defined. cNo statistical analysis presented. dNo intergroup difference in need for retreatment.

aAbstract

Abbreviations: BCVA, best corrected visual acuity; CMT, central macular thickness; CRT, central retinal thickness; F/U, follow-up; NG, not given; P, prospective; Ra, randomized; Re, retrospective; Tx, treatment.

Wang 201142 (P, Ra)

Study (Design)

TABLE 6-2 (CONTINUED). OUTCOMES OF CORTICOSTEROID AND ANTI-VEGF TREATMENT FOR RVO-RELATED MACULAR EDEMA

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  127

128  Chapter 6

Another option includes the use of the longer-acting dexamethasone implant (Ozurdex, Allergan) in conjunction with anti-VEGF therapy. Singer et al44 explored this combination in a small prospective, noncomparative trial and reported robust visual acuity gains up to 6 months (12.3 to 16.8 letters gained) with infrequent retreatment (mean time to retreatment, 125.9 ± 25.5 days). IOP extending 23 mm Hg occurred in 18% of patients. Anatomic improvement was initially excellent through 3 months, with more than 75% of patients achieving normalization of retinal thickness; however, this waned in the final 3 months of the study, with just under one-half of patients maintaining this level of macular edema reduction (see Table 6-2).

Combined Anti-Vascular Endothelial Growth Factor and Laser Therapy Combining intravitreal therapy with focal laser treatment has likely been a more natural transition for clinicians due in large part to decades of subtle dissatisfaction with MGL following BVOS/CVOS. Although undoubtedly an effective therapy, MGL has several limitations. First, laser treatment must be withheld until adequate clearance of macular hemorrhage occurs. Second, visual gains are limited, particularly when eyes are treated multiple times.21 Finally, excess laser power is often required when significant edema is present, leading to unwanted collateral damage, which may further limit visual gains. Intravitreal therapy provides a remedy to many of these issues. Intravitreal agents can be administered at presentation, regardless of the extent of macular edema or hemorrhage. Macular edema reduction occurs quickly in responsive patients, and some evidence suggests that anti-VEGF agents lead to more rapid clearance of macular hemorrhage,7,8,23 both of which could allow for earlier laser treatment at lower powers. In addition, visual gains with anti-VEGF monotherapy may exceed those with MGL alone,45 although robust comparative clinical trial data are not available.7 All of these factors hint at significant potential for combination anti-VEGF and MGL therapy. Many clinicians have already adopted this approach based on the logic that intravitreal therapy provides short-term, temporary resolution of macular edema whereas subsequent laser therapy offers more permanent control.4 Also of interest is the impact of intravitreal therapy prior to MGL in CRVO. Although CVOS demonstrated no visual benefit from MGL in CRVO—hence the recommendation against its use—there was documented improvement in anatomic outcomes, especially in patients younger than 60 years.16 The limited visual benefit from MGL may be related to excess laser power and associated collateral damage, which could be mitigated by anti-VEGF pretreatment. To date, the evidence regarding combination anti-VEGF and laser therapy is mixed, and large-scale prospective data are lacking. A further hindrance to interpreting these data is the heterogeneous definition of laser therapy, with substantial differences in laser pattern, settings, timing, and frequency. In a small retrospective, noncomparative study, Ogino et al46 examined the usefulness of combining IVB with subsequent MGL (mean time to treatment, 15 days) and reported significant anatomic improvement in both BRVO and CRVO patients.46 However, visual gains were limited, with a significant improvement noted at only the 1-month time point in the BRVO group. Of note, a modest number of injections (2.8 ± 0.7 over a mean of 22.0 to 23.0 months of follow-up) were required, suggesting that combination therapy may limit the need for retreatment (Table 6-3).

BRVO: n=9

1.25 mg IVB + PRP + MGL (21 d)

1.25 mg IVB + PRP + MGL (28 d)

Shah 201123 (P)

SalinasAlaman 201147 (P)

Shimuraa 201024 (P, Ra)

Mono: 1.25 mg IVB Combo: 1.25 mg IVB + PRP (7 to 14 d)

Mono: n = 10 (all CRVO) Combo: n = 10 (all CRVO)

CRVO: n=9

1.25 mg IVB + MGL (15 ± 29 d)

Oginoa 201146 (Re)

COMPARATIVE STUDIES

Mean: BRVO: 22.0 mo CRVO: 23.3 mo

BRVO: n = 19 CRVO: n=9

NGc

Min: 12 mo

Mean: 21.3 mo

F/U

Therapeutic Combination (Tx Delay)

Patients

Study (Design)

NONCOMPARATIVE STUDIES

N

Y

Y

N

Tx Naïve

NG

Initial LogMAR BCVA 1.2 Final LogMAR BCVA 0.5 (P = NG)

Intergroup: no Intergroup: no sigsignificant differnificant difference ence in final BCVA in final FT (P = NG) (P = NG)

⇩ CFT @ 1 mo, ⇧ BCVA @ 6 mo, 12 mo (all 1 mo, 3 mo, 6 mo, P = .008), no change 12 mo (all P < .02) at 3 mo

BRVO: ⇩ CMT @ 1 mo, 3 mo, 6 mo, 12 mo (all P < .01) CRVO: ⇩ CMT @ 1 mo, 6 mo, 12 mo (all P < .01)

Anatomic Outcomes

BRVO: ⇧ BCVA @ 1 mo (P < .05), no change @ 3 mo, 6 mo, 12 mo CRVO: no change in BCVA @ 1 mo, 3 mo, 6 mo, 12 mo

Functional Outcomes

Combo mono @ 12 mo (P < .05) Mono: ⇧ BCVA @ 6 mo (P = .05) Combo 1: ⇧ BCVA @ 6 mo (P = .05) Combo 2: ⇧ BCVA @ 6 mo (P = .05) Intergroup: no significant differences in BCVA

Anatomic Outcomes

Functional Outcomes

NGe

Combo < mono (P = .03)

Injection Number

(continued)

NG

No endophthalmitis, rhegmatogenous retinal detachments, vitreous hemorrhages

Adverse Events

TABLE 6-3 (continued). OUTCOMES OF ANTI-VEGF AND LASER TREATMENT FOR RVO-RELATED MACULAR EDEMA

130  Chapter 6

Mono: 0.5 mg IVR Combo: 0.5 mg IVR + PRP (NG)

Therapeutic Combination (Tx Delay)

Mono: n = 10 (all CRVO) Combo: n = 10f (all CRVO)

Patients

F/U

Tx Naïve

Intergroup: no significant differences in BCVA

Functional Outcomes

Intergroup: no significant differences in BCVA

Anatomic Outcomes

Mono = combo (P = .26)

Injection Number

NG

Adverse Events

fMono

was up to 24 months, but mean or minimum follow-up not provided.

and combo patients are the same but were compared before (mono) and after (combo) PRP treatment.

number was predetermined by study protocol.

IVR injection followed 7 d later by MGL, then 2 additional monthly IVR injections.

eInjection

dInitial

cFollow-up

not allowed per protocol.

to IVB monotherapy.

bReinjections

aRefractory

Abbreviations: BCVA, best corrected visual acuity; CFT, central foveal thickness; CMT, central macular thickness; FT, foveal thickness; F/U, follow-up; LogMAR, logarithm of the minimum angle of resolution; NG, not given; NR, not randomized; P, prospective; PRP, panretinal photocoagulation; Ra, randomized; Re, retrospective; Tx, treatment.

Spaide 201350 (P, NR)

Study (Design)

TABLE 6-3 (continued). OUTCOMES OF ANTI-VEGF AND LASER TREATMENT FOR RVO-RELATED MACULAR EDEMA

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  131

132  Chapter 6

Donati et al48 used the same combination in a small prospective trial and compared it with IVB alone for BRVO-related macular edema. Although both IVB monotherapy and IVB-MGL combination therapy resulted in significant posttreatment improvements in visual acuity and retinal thickness, the authors reported significantly greater improvements in patients receiving combination treatment. Combination therapy also was associated with significantly fewer injections over the study period (see Table 6-3). Azad et al49 examined outcomes with combined IVR-MGL but compared it instead with MGL alone in a subsequent prospective trial. This study used 2 different combination approaches: (1) single-dose IVR followed by MGL 1 week later, and (2) the same, plus 2 additional IVR at monthly intervals. At 6-month follow-up, all 3 groups (MGL alone, IVRx1 + MGL, and IVRx3 + MGL) experienced significant gains in visual acuity and significant reductions in macular edema; however, no intergroup differences were noted. Reinjection frequency was predetermined (see Table 6-3). With the widespread introduction of anti-VEGF therapy, much thought has centered on reducing the drivers of VEGF production in an effort to reduce treatment burden. To that end, several investigators have examined the use of panretinal photocoagulation (PRP)— with the objective of reducing VEGF production by ischemic peripheral retina—in conjunction with anti-VEGF therapy. Shimura et al24 compared IVB monotherapy with IVB plus subsequent (7 to 14 days) PRP in CRVO-related macular edema and found no difference in functional or anatomic outcomes, but a significant reduction in the need for retreatment. In contrast, Spaide50 found no difference in injection frequency after PRP in 10 patients with CRVO and evidence of peripheral nonperfusion on widefield angiography who received PRP plus PRN IVR treatment after 6 months of IVR monotherapy (see Table 6-3). Two prospective, noncomparative studies investigated a combination of IVB with subsequent (7 to 28 days) PRP and MGL in treatment-naïve patients.23,47 Shah and Shah23 reported impressive visual gains in CRVO, although no statistical analysis or anatomic data were included. In BRVO patients, Salinas-Alaman et al47 found significant improvement in visual acuity and foveal thickness at 12-month follow-up with a minimum number of required injections (mean, 2.13; see Table 6-3).47 A final consideration is the use of rescue laser in the BRAVO clinical trial. Although this may potentially be a rich source of data on outcomes for IVR-MGL combination therapy, subgroup analysis of patients undergoing rescue laser and those not receiving such ancillary treatment is not currently available.7 Moreover, the rate of rescue laser was relatively low (18.7% to 19.8% at 6 months), and its application was somewhat heterogeneous (investigators could apply MGL at months 3, 4, or 5).

Combined Corticosteroid and Laser Therapy The rationale for combining intravitreal therapy with focal laser is covered extensively in the preceding section. This reasoning applies equally to intravitreal corticosteroids and will not be repeated here. Unfortunately, the data regarding combination corticosteroids and laser therapy are somewhat sparse, and use of this combination is less common in clinical practice.4 Several possible explanations can be offered: (1) anti-VEGF agents appear to provide similar edema reduction but have a lesser side-effect profile; (2) corticosteroids have not been reported to have the same effect on clearance of macular hemorrhages as have anti-VEGF agents7,8,23; (3) functional outcomes for IVTA monotherapy

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  133

were equivalent, but not superior, to MGL monotherapy in the BRVO arm of the SCORE study6; and (4) laser and, to a lesser extent, corticosteroids are considered longer-acting agents with greater effect latency, whereas anti-VEGF agents have a shorter duration of action and effect latency; thus, combining a shorter-, quicker-acting agent with a longer-, slower-acting one would appear to be a more balanced approach. Only 2 studies have examined combination therapy with traditional IVTA and MGL. In a prospective, noncomparative analysis, Riese et al 22 reported significant functional and anatomic improvements with IVTA followed by MGL in patients with BRVO-related macular edema. This occurred after a mean of 1.13 IVTA injections over 6 months. Using a prospective, comparative design, Cakir et al51 came to different conclusions. Significant improvement in visual acuity and retinal thickness were present at early time points (3 months and 1 month, respectively) in a combination group consisting of BRVO patients receiving IVTA 3 to 7 months after failed MGL. Results were better in the IVTA monotherapy group, with significant functional and anatomic gains at nearly all time points; however, these patients had not previously failed monotherapy. No intergroup analysis was provided. In both studies, combination therapy did not appear to reduce the rates of IOP elevation relative to previously published rates with IVTA monotherapy (Table 6-4). The use of the dexamethasone implant Ozurdex in combination with MGL was examined in 2 abstracts presented in 2012. Both reported significant improvement in retinal thickness at all analyzed timepoints52,53 although only one study found similar improvements in visual acuity.52 No data were available regarding the impact of combining therapies on injection frequency (see Table 6-4). Parodi et al54 examined the effect of adding a single IVTA injection to subthreshold micropulse grid laser (MPGL) for BRVO-related macular edema in a prospective, comparative study. Significant improvement in foveal thickness was detected in both the MPGL monotherapy and combination groups; however, only the combination group experienced a significant functional improvement. IOP more than 21 mm Hg requiring medical therapy occurred in 55% of IVTA-treated patients (see Table 6-4). The authors postulated that IVTA pretreatment led to prompt reduction in macular edema relative to MPGL alone, and the shorter edema duration lessened the extent of photoreceptor damage.

NONSURGICAL EARLY INTERVENTIONAL THERAPIES Prior to the publication of the BVOS/CVOS results, few therapeutic options were available for RVO-related vision loss. Even after BVOS/CVOS, effective treatment strategies for CRVO were scarce given the poor functional responses associated with MGL in CRVO.16 This discouraging therapeutic environment led many investigators to explore a host of early interventional treatments, which are defined here as treatments aimed at the underlying pathophysiology of RVO. Such strategies are intended to prevent or attenuate the development of visually significant RVO sequelae, namely macular edema and macular ischemia. In theory, this may be accomplished either indirectly, by improving retinal blood flow through occluded vasculature, or directly, by addressing the causative occlusion. Changes in retinal blood flow may be achieved via hemorheological manipulation, whereas venous occlusion can be managed with thrombolysis and/or prevention of clot propagation by anticoagulation and antiplatelet therapy.

Parodi 200854 (P, Ra)

Mono: 4 mg IVTA Combo: 4 mg IVTA + MPGL (14 d)

Mono: n = 13 (all BRVO) Combo: n = 11 (all BRVO)

BRVO: n = 9

0.7 mg Ozurdex Cetina 201253 (NG) + MGL

COMPARATIVE STUDIES

F/U

12 mo

Mean: 8.8 mo

12 mo

BRVO: n = 24 6 mo

Patients

BRVO: n = 7 CRVO: n = 7

4 mg IVTA + MGL (21 d)

Therapeutic Combination (Tx Delay)

0.7 mg Ozurdex Fernandesa + MGL 52 2012 (P) (14 to 28 d)

Riese 200822 (P)

Study (Design)

NONCOMPARATIVE STUDIES

Y

NG

N

N

Tx Naïve

Mono: no difference in BCVA at any time point Combo: ⇧ BCVA @ 9 mo (P < .009), 12 mo (P < .011) Intergroup: BCVA combo > mono @ 12 mo (P = significant )

No significant difference in BCVA at 12 mo

NG

4.0b

1.13

Injection Number

Mono: ⇩ MFT @ 6 mo, 9 mo, 12 mo (all P < .001) Combo: ⇩ MFT @ 3 mo, 6 mo, 9 mo, 1.0b 12 mo (all P < .001) Intergroup: no significant differences in MFT

⇩ CFT at 12 mo (P = .05)

⇩ CMT @ 12 mo (P < .01)

⇩ CFT @ 1 mo (P < .0001), 3 mo (P < .0001), 6 mo (P = .001)

⇧ BCVA @ 1 mo (P = .001), 3 mo (P = .002), 6 mo (P = .016) ⇧ BCVA @ 12 mo (P < .01)

Anatomic Outcomes

Functional Outcomes

(continued)

Mono: NG Combo: IOP > 21 = 6/11

NG

⇧ IOP > 10 over baseline = 4/14

⇧ IOP requiring Tx = 10/24

Adverse Events

TABLE 6-4. OUTCOMES OF CORTICOSTEROIDS AND LASER TREATMENT FOR RVO-RELATED MACULAR EDEMA

134  Chapter 6

Patients

Mono: n = 25 (all BRVO) Combo: n = 12c (all BRVO)

Therapeutic Combination (Tx Delay)

Mono: 4 mg IVTA Combo: MGL + 4 mg IVTA (3 to 7 mo) Mean: 9.6 mo

F/U

NG

Tx Naïve

Mono: ⇩ CMT @ 1 mo, 3 mo, 6 mo (all P = significant ) Combo: ⇧ CMT @ 1 mo only (P = significant ) Intergroup: NG

Mono: ⇧ BCVA @ 1 mo, 3 mo, 6 mo, 12 mo (all P = significant ) Combod: ⇧ BCVA @ 3 mo only (P = significant ) Intergroup: NG

NG

Injection Anatomic Outcomes Number

Functional Outcomes

All: IOP > 25 = 8/37

Adverse Events

dCombo

group had significantly worse pre-IVTA BCVA compared with mono group.

eyes that failed primary MGL were eligible for combination therapy with follow-up IVTA.

number was predetermined.

bInjection

cOnly

only.

aAbstract

Abbreviations: BCVA, best corrected visual acuity; CFT, central foveal thickness; CMT, central macular thickness; F/U, follow-up; MFT, mean foveal thickness; NG, not given; NR, not randomized; P, prospective; R, retrospective; Ra, randomized; Tx, treatment.

Cakirb 200851 (P, NR)

Study (Design)

TABLE 6-4 (CONTINUED). OUTCOMES OF CORTICOSTEROIDS AND LASER TREATMENT FOR RVO-RELATED MACULAR EDEMA

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  135

136  Chapter 6

Because these therapies were largely investigated prior to the widespread acceptance of pharmacolaser therapy for RVO-associated macular edema, the published data reviewed hereafter are somewhat difficult to compare with the current standard of care. Few of the associated studies compared these interventional therapies with MGL or intravitreal therapies, and even fewer evaluated anatomic responses with optical coherence tomography (OCT). Nonetheless, these strategies may still have some relevance in the age of pharmacolaser therapy, particularly as adjuncts to reduce treatment burden.

Hemorheological Therapy: Isovolemic Hemodilution and Pharmacologic Agents Based on the characteristic prolongation of arteriovenous transit time seen on fluorescein angiography (FA), it is clear that local blood flow velocity is decreased in RVO. Moreover, some investigators have reported systemic hematologic abnormalities, including increased blood/plasma viscosity, hematocrits, and fibrinogen levels as well as abnormal erythrocyte deformability/aggregation in patients with RVO.55 Such abnormalities could contribute to retinal hypoperfusion and increased intravascular pressure, exacerbating macular edema and ischemia. Reversal of these negative-flow parameters can be achieved either by lowering of the hematocrit—a process called hemodilution—or by altering the aggregation/deformability of erythrocytes via pharmacotherapy. Isovolemic hemodilution (IVHD) involves sequential venesection with infusion of an equal volume of plasma substitute to reduce hematocrit to a target level. This reduction allows for improved retinal microvascular blood flow, decreased erythrocyte aggregation and intravascular pressure, and ultimately enhanced tissue oxygenation. Hansen et al56 examined outcomes with IVHD in CRVO in 3 separate studies. In the first, IVHD plus PRP was shown to result in significantly greater acuity gains compared to PRP alone in patients with CRVO.56 No intergroup difference was noted in the extent of macular edema or neovascularization. Of note, ischemic eyes demonstrated substantially—although not significant due to small numbers—greater functional improvement than nonischemic eyes. This finding was confirmed in a noncomparative follow-up study.57 The use of IVHD in nonischemic eyes was investigated in a third trial comparing IVHD alone with observation. This study reported significantly greater functional gains in nonischemic, IVHD-treated patients, although the authors concluded that, considering all 3 studies, greater visual improvements can be expected in ischemic CRVO.58 In a later study using IVHD alone for hemi-RVO (HRVO) and CRVO, Glacet-Bernard et al59 found that patients treated within 2 weeks of symptom onset had significantly greater final visual acuities compared with those treated later. Significantly better visual outcomes were also reported in IVHD-treated patients with BRVO as compared with control patients.60 In this study, all patients with a symptom duration longer than 3 months and acuity less than 20/40 were eligible for MGL; however, this is unlikely to account for the discrepant functional outcomes because significantly more control patients (44%) required MGL compared with those treated with IVHD (28%). In contrast to these studies, Luckie et al61 found no difference in visual improvement with significantly higher rates of visual deterioration following IVHD as compared with no treatment in CRVO.61 Of note, these authors excluded patients with low central vein closing pressure, which

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  137

is associated with a better prognosis, and used crystalloid as a plasma substitute, which rapidly redistributes into extravascular space following infusion, likely resulting in hypovolemic hemodilution. Although functional outcomes reported with IVHD were promising, the studies had significant limitations. All studies excluded patients with complicating systemic conditions, including congestive heart failure, respiratory/renal insufficiency, and anemia. IVHD is relatively invasive and requires frequent treatment visits, and it involved hospitalization in all but 2 of the studies.60,61 Although no serious systemic complications were documented, syncope, hypotension, and fatigue are not uncommon.56,57,59,60 Limited studies have examined the feasibility of enhancing retinal blood flow with pharmacologic agents such as troxerutin and pentoxifylline, which act to increase erythrocyte deformability and inhibit aggregation. Glacet-Bernard et al59 performed a small prospective trial comparing oral troxerutin with placebo for BRVO/CRVO and reported a greater, but nonsignificant, proportion of patients achieving 20/40 or better vision at the end of the 4-month randomized comparison period. All patients (including placebo) were subsequently given oral troxerutin for a mean follow-up of 23 months. At final follow-up, visual acuity and macular edema were significantly improved in the initial treatment group only. Similarly equivocal results were reported in a small, noncomparative, retrospective study investigating oral pentoxifylline in CRVO patients.62 At final follow-up, a trend existed toward improved visual acuity (P = .07) in all patients, with significantly reduced macular edema in patients with OCT data. Results of pentoxifylline combined with IVHD were mixed. Wolf et al63 reported a visual gain of 1.5 lines at 12 months after combined IVHD/pentoxifylline, which was significantly improved vs placebo.63 In contrast, 2 later studies in recent-onset (fewer than 11 days) RVO described disappointing functional results, with few patients gaining vision and a substantial proportion (23% to 32%) losing 2 or more lines of acuity.64,65 Both of these studies compared IVHD/pentoxifylline therapy with low-dose intravenous (IV) tPA plus heparin anticoagulation and reported significantly better visual results with the latter.

Anticoagulation and Antiplatelet Treatments Although considered standard of care for venous thromboembolism elsewhere in the body, anticoagulation and antiplatelet therapies remain unproven for RVO.66 Early investigators demonstrated little functional benefit from IV heparin and/or oral vitamin K antagonists in nonrandomized comparisons with observation, although no statistical analyses were performed.67-69 Serious systemic hemorrhagic complications were reported in 1% to 15% of patients, with multiple deaths attributed directly to therapy.67,69 Two later prospective, randomized trials comparing subcutaneous dalteparin with oral aspirin therapy in recent-onset (fewer than 30 days) CRVO70 and BRVO71 reported conflicting outcomes based on RVO subtype. In the CRVO study, investigators found significantly greater acuity gains at 6 months following dalteparin treatment as compared with aspirin.63 In contrast, no functional or anatomic benefit was detected in BRVO patients treated with dalteparin when compared with those treated with aspirin.71 A third, more recent trial comparing subcutaneous parnaparin with oral aspirin in a mixed RVO cohort demonstrated a significantly lower rate of functional worsening (based on a combination of visual acuity, FA, and visual field findings) in the total and CRVO subgroup, but not the

138  Chapter 6

BRVO subgroup.72 No significant hemorrhagic complications were reported in association with anticoagulation. These latter studies had several limitations, including an unmasked design70,71 and an unequal distribution of unfavorable baseline characteristics.70,72 In addition, the choice of aspirin, which some investigators feel leads to worse outcomes due to exacerbation of macular hemorrhage,66 as the comparator treatment may have led to an overestimation of the benefits of anticoagulation. As detailed previously, antiplatelet therapy with aspirin alone has resulted in little functional/anatomic benefit and may induce further visual deterioration in the setting of RVO.66,70,72,73 Ticlopidine, an antiplatelet agent with more potent inhibitory effects on platelet aggregation, has been shown in a prospective, randomized trial to result in greater visual improvement compared with placebo.74 Adverse effects were limited to mild gastrointestinal upset and rash.

Thrombolytic Therapy Similar to anticoagulation, thrombolytic therapy for RVO has its origin in the treatment of systemic vascular occlusions, including acute myocardial infarction, ischemic stroke, and pulmonary embolism. The rationale for thrombolysis relates to the ability of plasminogen activators to accelerate lysis of the presumed pathogenic occlusive clot in the central retinal vein,75 thereby restoring physiologic retinal blood flow. Given the cumulative and often irreversible damage that occurs with persistent impairment in retinal perfusion, such therapy has maximal benefits if used shortly following acute RVO. Nonetheless, thrombolysis may provide some benefit even if used subacutely because restoration of normal perfusion may prevent further visual loss due to ischemic damage or progressive macular edema. Multiple routes of administration are available. Although IV administration remains the most widely used in systemic occlusive disease, it is also accompanied by the highest risk of systemic hemorrhagic complications. Thus, other routes, including intravitreal, superselective intra-arterial, and transvitreal selective IV therapy, have been explored for the treatment of RVO. Although all routes of administration provide for some degree of thrombolysis, intravitreal tPA has the potential to provide the added benefit of vitreoretinal traction relief if plasmin (converted from plasminogen by tPA) activity induces a posterior vitreous separation. Systemic IV thrombolysis with tPA has demonstrated modest visual gains, most prominently in recent-onset (fewer than 7 to 30 days) CRVO; however, such treatment has been associated with concerning systemic and intraocular complications despite attempts to exclude high-risk patients. Kohner et al76 reported significantly greater visual gains in recent-onset (fewer than 7 days) CRVO treated with 100 mg of IV tPA followed by 6 months of anticoagulation compared with no treatment. Three (15%) patients suffered massive vitreous hemorrhage shortly after tPA administration, leading to permanent blindness. A subsequent larger noncomparative study by Elman1 demonstrated more modest visual gains at the same dose of IV tPA with variable use of anticoagulation/aspirin. Although the authors reported a significantly greater proportion of patients gaining 3 lines of vision compared with the historical CVOS cohort, the severity of hemorrhagic complications, including a fatal hemorrhagic stroke, gastrointestinal bleed, and multiple vitreous hemorrhages, was disconcerting. Two later studies using a lower dose (50 mg) of

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  139

tPA followed by 8 days of IV heparin resulted in 36% to 44% of RVO patients gaining 2 or more lines of vision.65,77 No major hemorrhagic complications occurred, although cohort numbers were small. Superselective intra-arterial tPA administration—perfused over 40 minutes after cannulation of the ophthalmic artery ostium with an intravascular catheter—was examined retrospectively in 2 small CRVO cohorts. Many of the included patients had a combined central retinal vein-central retinal artery occlusion, the latter of which is a more natural target for this route of administration. In patients with isolated CRVO findings, visual improvement was disappointing, with only 14% to 21% of patients gaining 2 or more lines of vision.78,79 Vitreous hemorrhage occurred in 1 (5%) patient. Whereas the relative risks and benefits of intravascular tPA had been previously established through work on systemic vascular occlusion, similar safety data were not available for intravitreal administration. Early investigations into the safety of intravitreal tPA demonstrated dose-dependent retinal toxicity, including distinct tapetal pigmentary alterations and decreased electroretinogram amplitudes, in rabbit80 and cat81 eyes, most prominent at doses larger than 50 μg. Interestingly, direct retinotoxic effects were not documented in a review of 18 studies in which tPA was used in the treatment of submacular hemorrhage in humans.82 Moreover, electroretinographic studies in humans treated with intravitreal tPA have not detected abnormalities to date.83,84 Intravitreal administration also raises concerns about the penetration of tPA into the retinal circulation. In theory, intravitreal tPA gains access to the retinal circulation via diffusion through the internal limiting membrane (ILM) and into damaged intraretinal capillaries.2 However, data regarding intraretinal penetration of tPA have been mixed. After intravitreal injection, Kamei et al85 found that tPA did not diffuse past the ILM to the subretinal space in a rabbit model.85 Conversely, Takeuchi et al86 demonstrated ready movement of intravitreal albumin—with molecular weight similar to that of tPA—across the neurosensory retina and into the subretinal space, and Mahmoud et al87 detected tPA within retinal veins in pigs with and without vascular occlusion after intravitreal injections. The efficacy of tPA in displacing submacular hemorrhage in humans would seem to support these latter findings.82 Four small noncomparative pilot studies investigated the use of intravitreal tPA for recent-onset (3 to 28 days) CRVO and noted generally positive results.2,88-90 The effects of intravitreal tPA were most notable in patients with moderate to severe pretreatment vision loss. Combining the 4 study cohorts, baseline acuities of 20/50 to 20/200 and worse than 20/200 were noted in 27 and 35 patients, respectively. At final follow-up, best corrected visual acuity (BCVA) of 20/40 or better was achieved in 66.6% of the baseline 20/50 to 20/200 group and 8.3% of the worse than 20/200 group. These figures compare favorably with the natural history of CRVO based on CVOS, in which similar cohorts achieved BCVA of 20/40 or better in only 19% and 1% of patients, respectively.2,88-90 Surprisingly, patients with good baseline BCVA (20/40 or better) had inferior outcomes, with only 44.4% maintaining baseline vision compared with 65% in the analogous CVOS cohort. Anatomic data were limited. Adverse effects were limited to transient serous retinal detachments (n = 2), increased macular hemorrhage (n = 9), and increased macular edema (n = 2). It is difficult to determine whether these latter 2 complications are related to treatment or due to progression of CRVO-related ischemia.2,88,90 Yamamoto et al91 used combined intravitreal tPA and triamcinolone acetonide (TA) and found significant visual

140  Chapter 6

gains, with 53% of patients gaining 3 or more lines of BCVA, which compares favorably with observation (CVOS, 6%) and IVTA alone (SCORE, 26% to 27%). Foveal thickness was significantly decreased at all time points.91 A subsequent retrospective trial looked at outcomes for CRVO following intravitreal tPA compared with IVB and pars plana vitrectomy (PPV).92 All 3 treatments resulted in significant anatomic and functional gains at 12 months, but the only significant intergroup difference was a greater decrease in foveal thickness in the tPA group vs IVB or PPV. Murakamai et al93 investigated intravitreal tPA for recent-onset (mean, 3.6 weeks) BRVO and found significant improvements in mean BCVA and foveal thickness at 1 and 6 months. Of note, one patient developed a focal pigmentary alteration similar to that seen in the cat model.81 One small, comparative, retrospective trial examined outcomes following BRVO, HRVO, or CRVO in patients receiving intravitreal anti-VEGF therapy and/or IVTA with or without early (less than 21 days from symptom onset) tPA. In this study, patients receiving early tPA experienced significant improvements in visual acuity and central macular thickness with fewer subsequent intravitreal anti-VEGF or corticosteroid treatments compared with those not treated with tPA (2.2 ± 2.5 vs 8.1 ± 8.2 injections).94

THE ROLE OF VITRECTOMY IN RETINAL VEIN OCCLUSION THERAPY A more traditional interventional modality, PPV has many potential benefits that recommend it as a therapeutic option for treatment of RVO-related macular edema. Several early cross-sectional studies identified an association between persistent vitreomacular adhesion (VMA) and RVO-related macular edema,95-97 prompting the authors to postulate a role for VMA in the pathogenesis of edema. PPV was subsequently proposed as a logical treatment for such persistent edema as a means to induce a complete posterior vitreous detachment (PVD). Although the exact mechanism whereby PPV (and/or PVD) may influence the course of macular edema remains unclear, several possible factors are likely involved. Postvitrectomy eyes have higher intravitreal and preretinal oxygen tensions,98,99 which attenuates hypoxia-driven VEGF and interleukin-6 production from ischemic retina.14 Moreover, increased preretinal oxygen levels induce retinal arteriolar vasoconstriction, leading to decreased IV pressure and edema.100 Removal of the posterior hyaloid further reduces the impact of pathogenic factors such as VEGF via increased diffusion away from the retinal surface.96 Exacerbating tractional forces contributing to RVO-related macular edema can also be relieved by PPV.95,101 Unlike thrombolytic therapy and hemodilution, PPV has no direct impact on retinal blood flow and does not address the causative occlusion. However, with the addition of intraoperative maneuvers such as retinal vein cannulation with tPA infusion, arteriovenous sheathotomy (AVS), and radial optic neurotomy (RON), PPV can be used to alter blood flow directly. Like much of the data on exploratory interventional therapies for RVO, the studies discussed hereafter have several limitations. Most were noncomparative pilot studies with small cohorts, limited follow-up, and diverse inclusion criteria. Many of the studies, particularly those from Asia, combined cataract extraction with vitrectomy, which

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  141

significantly muddles analysis of functional outcomes. Exclusion of patients with a preoperative PVD was also not uniform, which may lead to underestimation of the effect of PPV in those patients most likely to benefit from PPV (eg, patients without a PVD). As in any surgery-based study, outcomes are dependent on specific surgical technique and surgeon skill/experience, which makes interstudy comparison difficult.

Pars Plana Vitrectomy With and Without Internal Limiting Membrane Peeling Four noncomparative pilot studies examined outcomes of simple PPV with posterior hyaloid removal in RVO. Both BRVO and CRVO appeared to respond well to such therapy, with 2 groups reporting significantly improved BCVA after PVD induction alone.101,102 A third group noted a 2-line visual gain in 68% of patients with nonischemic CRVO.103 Visual improvement was superior in BRVO101 and was dependent on the chronicity of macular edema; one group demonstrated a significant improvement only in the subgroup with BRVO duration less than 11 months,104 whereas a second group found that time to edema resolution was inversely correlated with BRVO duration.101 The authors felt this finding related to photoreceptor and RPE damage from chronic edema. In general, both anatomic and functional gains were gradual, with one study reporting a mean time to edema resolution of 4.5 months.102 Resolution of edema tended to precede visual recovery. Of note, all 4 studies combined cataract extraction with PPV. Later investigators added ILM peeling to the standard PPV technique in a series of small pilot studies. In theory, ILM removal allows for decompression of extracellular fluid into the vitreous cavity and reduces the diffusion barrier to oxygen and pathogenic molecules (eg, VEGF, interleukin-6) between the retina and vitreous cavity.105,106 Removal of the ILM may also prevent subsequent formation of epiretinal membranes, which could generate traction, leading to recurrence of macular edema. In addition, some investigators used air or gas tamponade following ILM removal in an effort to “squeegee” out additional intraretinal fluid.106,107 In general, results for CRVO were superior to natural history (based on the CVOS), with 29.4% to 50.0% of patients with a baseline BCVA worse than 20/200 achieving a final BCVA of 20/200 or better (compared with 20% in the CVOS) and 25.0% to 80.0% of patients with a baseline BCVA of 20/50 to 20/200 achieving a final BCVA of better than 20/50 (compared with 19% in the CVOS).16,107-109 One small retrospective study, which included largely chronic CRVO (mean duration, 12.3 months) refractory to IVTA monotherapy, reported no difference in postoperative BCVA despite significant anatomic improvement.100 Outcomes for BRVO were also superior to natural history and comparable, if not superior, to MGL (based on BVOS). Two-line visual gains were noted in 57% to 100% of patients in 3 studies (compared with 37% of observation eyes and 65% of MGL-treated eyes in the BVOS),21,107,108,110 and a mean visual gain of 1.8 lines was documented in a fourth study (compared with 0.23 lines for observation and 1.33 lines for MGL in the BVOS).21,106 A single retrospective study compared outcomes of PPV with and without ILM peeling for BRVO and found no difference in either anatomic or functional results.105 Unfortunately, nonuniform use of combined cataract extraction, as well as ILM staining with indocyanine green dye, which has been linked to retinal toxicity,111 complicates interstudy comparison.

142  Chapter 6

Several groups have added IVTA at the conclusion of vitrectomy surgery,112-114 but results appear to be similar to PPV or IVTA alone. One comparative study found no difference in anatomic or functional outcomes with the addition of intraoperative IVTA,114 whereas a second study found no benefit to PPV-IVTA compared with IVTA alone.113 Although it was posited that IVTA might speed up resolution of edema following PPV, rebound/recurrent edema was common, as was the need for retreatment. This may relate to the short half-life of TA in vitrectomized eyes.

Pars Plana Vitrectomy With Intravascular Thrombolysis and Arteriovenous Sheathotomy In addition to providing access to the posterior hyaloid and ILM for removal, PPV allows surgeons to manipulate retinal vasculature directly. With such an approach, causative occlusions can be targeted using 2 adjuvant vitreoretinal techniques: (1) retinal vein cannulation with intravascular tPA infusion for CRVO, and (2) AVS for BRVO. Both techniques aim to restore normal venous blood flow via recanalization of occluded veins, although the former does so by means of thrombolysis and the latter relies on relief of external venous compression. Restoration of venous flow should, in theory, reduce retinal ischemia and intravascular pressure with resultant reductions in macular edema, macular hemorrhage, and disc edema. For retinal vein cannulation, a small microcannula is used to pierce a branch retinal vein adjacent to the optic nerve to provide access for local tPA infusion direct to the site of occlusion posterior to the lamina cribrosa. In theory, this technique should allow for delivery of very high local concentrations of tPA (with minimal systemic exposure) under direct visualization to effect thrombolysis. The high bulk flow rate (several hundred-fold higherthan-normal venous flow) may dislodge the thrombus and/or dilate the central retinal vein, further enhancing venous outflow.115 Benefits of PVD induction may also contribute to physiologic improvement. Two small, uncontrolled pilot studies reported impressive initial functional outcomes.115,116 Visual acuity gains of 3 lines or more were reported in 50% to 57% of patients with mixed perfusion status (excluding patients receiving perioperative TA) at final follow-up.115,116 No clear angiographic data were presented confirming improvement in retinal blood flow or ischemia. Poor results were obtained in a third uncontrolled trial in ischemic CRVO.117 In this study, patients lost a mean 1.9 lines at 12 months, with only 23.1% gaining 3 or more lines.117 Complications were frequent, with retinal detachment occurring in 7.6% of eyes, vitreous hemorrhage in 12.1% of eyes, and cataract in 27.8% of eyes.115-117 Other investigators have questioned the theoretical basis of this treatment. Two concerns were raised: (1) infused tPA should preferentially flow through established venous collaterals (ie, the path of least resistance), thus not reaching the thrombus, and (2) chronic thrombi such as those included in the previously mentioned studies (mean RVO duration: 2.9 to 4.9 months) will have organized into a fibrovascular scar and are thus not truly amenable to “flushing” by bulk flow.118 Additional challenges with this therapy relate to its technical difficulty and need for specialized equipment. AVS is based on the knowledge that most BRVOs occur at arteriovenous crossings, particularly when the artery crosses over the vein.119 Early histopathologic studies identified the presence of a common wall shared between these crossing vessels, and follow-up studies recognized this shared wall as a source of venous compression due to arteriolosclerotic

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  143

thickening of the overlying artery.120,121 BRVO results because venous compression induces downstream turbulence, endothelial damage, and eventually secondary thrombosis.122 In an effort to relieve this compression, surgeons devised AVS in which the common adventitial sheath is opened and the overlying artery is removed from atop the vein. Such a maneuver may restore local venous flow by either dislodging a thrombus or, more likely, increasing the luminal diameter of a partially recanalized branch vein. Initial pilot studies revealed promising functional outcomes, with improvement noted in 60% to 85% of patients with a mean acuity gain of 4.1 to 4.6 lines,123 as well as angiographic evidence of improved capillary perfusion.124-126 Unfortunately, interpretation of these results is confounded by the addition of various perioperative adjuvants, including IVHD,125 ILM peeling,125 and intravitreal tPA.126 Two uncontrolled follow-up studies failed to demonstrate a visual benefit following AVS alone.127,128 Much of the beneficial effect from AVS may in fact be attributable to simple PVD induction at time of PPV. Charbonnel et al129 found significantly greater visual gains in patients undergoing intraoperative PVD as compared with those with a preoperative PVD. Three comparative studies, one of which was randomized,130 later found no difference in postoperative acuity between groups undergoing AVS compared with those undergoing PPV with PVD induction alone.130-132 These data seem to indicate that AVS offers little additional benefit over PPV alone. Moreover, similar to branch vein cannulation, AVS is a technically challenging procedure, and complications are frequent.

Radial Optic Neurotomy Similar to AVS, RON is a vitrectomy-based technique used to relieve external venous compression and restore venous blood flow. AVS and RON relieve the source of external venous compression—arteriosclerotic crossing arteries in BRVO and the inelastic scleral ring and lamina cribrosa in CRVO, respectively—thereby increasing venous luminal diameter and blood flow. In the case of RON, a microvitreoretinal blade is used to create a radial incision at the nasal aspect of the optic nerve head, incising the peripapillary sclera, scleral ring, and lamina cribrosa adjacent to the major retinal vessels. This incision is intended to reverse a proposed compartment syndrome created within the tight confines of the scleral outlet with subsequent decompression of the central retinal vein.122 The compartment syndrome is thought to result from a bottleneck created by squeezing the retrobulbar optic nerve complex (diameter, 3 mm) through the 1.5-mm scleral outlet.122 However, the theoretical basis for RON has repeatedly been called into question. The apparent bottleneck configuration can be attributed to the loss of myelin as the nerve fibers enter the scleral outlet.133 Furthermore, a nasal incision is thought to be inadequate to decompress the central retinal vein due to the inelastic nature of the lamina cribrosa/ scleral ring134 and due to the temporal location of the central retinal vein relative to the artery within a common sheath that is not incised during RON.135 Even if decompression occurs, these same critics feel recanalization will not follow due to fibrovascular thrombus organization.134 The earliest attempts to relieve venous compression within the optic nerve used external approaches with decompression achieved via an incision through the posterior scleral ring136,137 or fenestration of the optic nerve sheath.138 In these small uncontrolled trials, visual gains were substantial, with 2 groups reporting improved acuity in 75% to 91% of

144  Chapter 6

eyes136,138 and a third finding a mean visual gain of 4.1 lines after treatment.137 Despite these promising results, larger follow-up studies were not pursued. Opremcak et al122 published the first results using a vitrectomy-based approach to scleral outlet decompression, which they termed RON. In this small retrospective study (n = 11), visual improvement was noted in 72.7% of eyes, with a mean gain of 5 lines after RON. Baseline BCVA was worse than 20/200 in all patients but increased to 20/200 or better in 63.6% of patients.122 This exceeds the 20% rate of 20/200 or better vision in the equivalent CVOS cohort, but comparison is difficult because Snellen (as opposed to ETDRS) acuity was used, and perfusion status in 2 studies differed widely.134,139 No adverse events were reported. Numerous uncontrolled trials followed, with variable functional outcomes. In a larger retrospective analysis of 117 patients, Opremcak et al140 reported visual improvement in 71% of eyes, with a mean gain of 2.5 lines. Although encouraging, these numbers were inferior to their initial report. Several other smaller uncontrolled trials found comparable functional gains with improved visual acuity in 50% to 92% of eyes and attainment of a BCVA of 20/200 or better in 40% to 63% of patients with a baseline BCVA worse than 20/200.141-144 Other investigators noted more modest visual improvements frequently inferior to CVOS natural history.145-149 Adjuvant perioperative therapies, including ILM peeling,150-152 gas/air tamponade,151 PRP,149,151 and IVTA,149-151,153,154 were included in several other noncomparative studies, although these did not result in substantially better outcomes compared with studies using RON alone. In general, RON appeared to result in significant reductions in macular thickness, but this often did not correlate with visual gains, likely due to significant ischemia.143,146,147 Indeed, patients with ischemic CRVO had worse outcomes following RON as compared with their nonischemic counterparts.143,147,151 On FA and color Doppler imaging, RON also did not appear to improve retinal blood flow (based on ΔT50,145 mean circulation times,148 or peak flow velocities155) or the extent of nonperfusion in these uncontrolled studies. The formation of retinociliary collaterals (eg, optociliary shunts) was noted in 8.5% to 60% of eyes (with more than two-thirds of studies reporting such collaterals in more than 40% of included eyes),140,141,143-145,147,151-154,156 which is on par with the incidence documented in larger natural history studies.157,158 Interestingly, in some reports, collaterals formed earlier (less than 3 months)145,156 after RON and were associated with greater functional gains145,152 and improved retinal blood flow.145 This led some investigators to propose that improvements after RON are related to enhanced venous outflow via collateralization as opposed to venous decompression. Limited comparative studies reported superior outcomes with RON when compared with observation or a single IVTA. Callizo et al152 reported significant visual improvement in the RON cohort but no difference in a control group. Improvement in retinal perfusion status, arteriovenous transit time, and the incidence of optociliary shunt formation was also significantly greater in the RON cohort.152 However, patients were not randomized, resulting in notable differences in visual acuity and perfusion status at baseline. A follow-up randomized study found that a significantly greater proportion of patients gained 3 or more lines of vision following RON as compared with a single IVTA or a sham injection. No difference in OCT-based retinal thickness was detected.159 The study was discontinued early due to poor recruitment following anti-VEGF introduction; thus, groups were unbalanced. The authors also acknowledged that better outcomes may have been obtainable with multiple IVTA injections.

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  145

To date, RON has largely been abandoned due to unconvincing clinical results. Given the lack of randomized trials comparing RON with PPV alone, it remains unclear how much additional benefit RON provides over simple surgical PVD induction. Moreover, RON is associated with many potentially serious complications. Numerous reports of subretinal/vitreous hemorrhage, choroidovitreal neovascularization,142,160 temporal wedge-shaped visual field defects,151,161,162 and retinal detachments149,151,159 have been attributed directly to RON. Two patients experienced iatrogenic central artery injuries with catastrophic visual loss.146,151

CONCLUSION Over the past few years, the use of intravitreal anti-VEGF and corticosteroids has become the preferred choice of retinal specialists for initial therapy of most RVO-related macular edema.4 Such an initial therapeutic approach appears logical because these agents are readily available, well studied, relatively easy to administer, and associated with few serious adverse effects. Given the generally good response of RVO-related macular edema to intravitreal monotherapy, the application of combination pharmacologic and pharmacolaser therapies would appear to be best suited as a secondary therapy in monotherapy-resistant cases or in monotherapy-responsive cases with dose-limiting adverse effects or practical limitations on dosing frequency (eg, transportation or other social issues limiting the frequency of office visits). In the latter group, combination therapy may allow for lower individual doses or less frequent administration. Recommendations regarding ideal pharmacologic/ pharmacolaser therapeutic approaches are difficult to provide because the currently available data are limited to a few small randomized, prospective, comparative trials, many of which report conflicting results.24,42,43,48,49,54 At the present time, selection of combined agents falls largely on individual providers, who are tasked with creating treatments customized for individual patients based on available clinical data with particular attention paid to previously documented responses to component agents, preexisting adverse effects or predisposition to adverse effects, and angiographic data documenting the extent of ischemia (Table 6-5). In the future, intravitreal cytokine profiling in treatment-naïve RVO patients may provide a greater level of customization of RVO therapy and allow for identification of candidates for initial combination therapy based on a particularly unfavorable intravitreal cytokine milieu.163 Based on currently available data, little evidence exists for the routine use of nonsurgical interventional therapies in RVO. Systemic treatments such as IVHD and systemic anticoagulation/thrombolysis are fraught with potential serious systemic adverse events and provide no clear benefit over safer intravitreal therapies. Although associated with a more favorable side-effect profile, systemic hemorheologic agents such as aspirin, pentoxifylline, and troxerutin have also shown limited efficacy in RVO. One notable exception within this group, intravitreal tPA, has shown promising efficacy when administered shortly following RVO onset (1 to 4 weeks) and may play a role in reducing subsequent monotherapy burden in this subset of patients. Finally, vitrectomy appears to provide a tertiary option for providers in treating only the most refractory patients who have previously failed intravitreal monotherapy and

146  Chapter 6

TABLE 6-5. PROS AND CONS OF PHARMACOLOGIC AND PHARMACOLASER COMBINATION THERAPY PROS ●

Allows for synergist effects based on differential mechanism of action of component therapies ○

○

○

●

●

●

●

●

●

May overcome tachyphylaxis May allow for reduced effective dosages

●

May allow for reduced dosing frequency

Takes advantage of different pharmacokinetic profiles of component therapies ○

●

CONS

●

Large-scale prospective clinical trial data not available Guidelines regarding retreatment intervals not established Volume of injected agents limited if concurrent administration desired (unless combined with aqueous paracentesis) Noncurrent administration requires 2 closely spaced office visits

May allow for reduced dosing frequency

No added technical difficulty in administration Component therapies are well studied in large prospective clinical trials Alternative for monotherapy-resistant patients Alternative for patients with doselimiting side effects or practical limitations on dosing frequency

combination therapy. Although the benefits of ILM peeling over PVD induction alone at the time of surgery are unclear, any added efficacy from AVS, RON, or retinal vein cannulation with tPA infusion seems to be outweighed by the significantly greater technical difficulty and potential for adverse effects associated with these vitrectomy adjuvants.

REPRESENTATIVE CASES Patient 1 An 81-year-old male with a history of hypertension, diabetes mellitus, and coronary artery disease as well as high myopia presented with a 4-month history of decreased vision in the right eye. Examination revealed a BCVA of 20/400 with a right afferent pupillary defect. Dilated fundus examination (Figure 6-1A) and FA were compatible with an ischemic CRVO. OCT showed diffuse intraretinal fluid with a large subfoveal collection of subretinal fluid (Figure 6-1B). The patient underwent IVB injection. At 1-month

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  147

Figure 6-1. Chronic (symptom duration, 4 months) ischemic CRVO treated with anti-VEGF monotherapy complicated by tachyphylaxis to both bevacizumab/ranibizumab monotherapy and responsive to combination dexamethasone implant and PRP. (A) Initial fundus examination revealed a myopic fundus with extensive intraretinal hemorrhages in all 4 quadrants. (B) OCT at presentation demonstrated extensive intraretinal fluid with a thin layer of subfoveal subretinal fluid. (C) A good response was noted following initial anti-VEGF monotherapy, with only mild residual intraretinal thickening; however, tachyphylaxis eventually developed in response to both bevacizumab/ranibizumab monotherapy. (D) Subsequent widefield FA revealed extensive peripheral nonperfusion. (E) Following combination dexamethasone implant and PRP, durable resolution of retinal thickening was achieved up to 3 months following treatment without further injections.

follow-up, BCVA had improved to 20/125 with complete resolution of subretinal fluid and a significant reduction in intraretinal fluid (Figure 6-1C). Further improvement in BCVA (to 20/64) and intraretinal fluid were noted with continued IVB monotherapy at 1-month intervals; however, the patient developed tachyphylaxis after 4 injections and was switched to IVR monotherapy. An initial response was noted to IVR, but the patient again developed tachyphylaxis after 2 injections. Widefield angiography demonstrated extensive peripheral nonperfusion (Figure 6-1D). Combination treatment with a dexamethasone implant followed by PRP was initiated. This resulted in near-complete resolution of intraretinal fluid with no additional intravitreal therapy 3 months after combination therapy (Figure 6-1E). BCVA at most recent follow-up was 20/160, likely limited by significant ischemia.

148  Chapter 6

Figure 6-2. Recent-onset (symptom duration, 5 days) HRVO treated with combination tPA and anti-VEGF therapy. (A) Extensive intraretinal hemorrhages were seen in the inferior hemifield on initial fundus examination. (B) FA demonstrated venous staining and tortuosity with microvascular changes inferiorly and large areas of nonperfusion. (C) OCT revealed extensive intraretinal fluid with a collection of subfoveal subretinal fluid. Ten weeks following tPA with subsequent (1-week intertreatment interval) anti-VEGF therapy, a dramatic improvement in (D) macular hemorrhages and (E) retinal vascular changes with good perfusion were seen. (F) This was associated with complete resolution of macular edema on OCT with recovery of external limiting membrane and outer segment/ inner segment lines.

Patient 2 A 78-year-old monocular male with a history of hypertension presented with a 5-day history of decreased vision in the right eye. Examination demonstrated BCVA of counting fingers at 2 feet with extensive intraretinal hemorrhages, macular edema, and tortuous retinal veins in the inferior hemifield on fundus ophthalmoscopy (Figure 6-2A). FA revealed a perfused macula with venous staining and severe telangiectatic vascular changes in the inferior hemifield with extensive peripheral nonperfusion (Figure 6-2B). OCT showed extensive intraretinal fluid with subfoveal subretinal fluid (Figure 6-2C). Given the recent onset of his symptoms, the patient was treated with combination tPA (50 μg/0.1 mL) followed by IVB 1 week later. This resulted in rapid improvement of macular hemorrhages (Figure 6-2D) and retinal vascular changes best seen on FA with markedly less nonperfusion (Figure 6-2E) at 10-week follow-up. This corresponded with complete resolution of intraretinal/subretinal fluid on OCT (Figure 6-2F). At final followup, BCVA had improved to 20/30 with recovery of external limiting membrane and outer segment/inner segment lines on OCT without further injections.

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Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  155 110. Ma J, Yao K, Zhang Z, Tang X. 25-gauge vitrectomy and triamcinolone acetonide-assisted internal limiting membrane peeling for chronic cystoid macular edema associated with branch retinal vein occlusion. Retina. 2008;28(7):947-956. 111. Farah ME, Maia M, Rodrigues EB. Dyes in ocular surgery: principles for use in chromovitrectomy. Am J Ophthalmol. 2009;148(3):332-340. 112. Tsujikawa A, Fujihara M, Iwawaki T, Yamamoto K, Kurimoto Y. Triamcinolone acetonide with vitrectomy for treatment of macular edema associated with branch retinal vein occlusion. Retina. 2005;25(7):861-867. 113. Hirano Y, Sakurai E, Yoshida M, Ogura Y. Comparative study on efficacy of a combination therapy of triamcinolone acetonide administration with and without vitrectomy for macular edema associated with branch retinal vein occlusion. Ophthalmic Res. 2007;39(4):207-212. 114. Uemura A, Yamamoto S, Sato E, Sugawara T, Mitamura Y, Mizunoya S. Vitrectomy alone versus vitrectomy with simultaneous intravitreal injection of triamcinolone for macular edema associated with branch retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2009;40(1):6-12. 115. Weiss JN, Bynoe LA. Injection of tissue plasminogen activator into a branch retinal vein in eyes with central retinal vein occlusion. Ophthalmology. 2001;108(12):2249-2257. 116. Bynoe LA, Hutchins RK, Lazarus HS, Friedberg MA. Retinal endovascular surgery for central retinal vein occlusion: initial experience of four surgeons. Retina. 2005;25(5):625-632. 117. Feltgen N, Junker B, Agostini H, Hansen LL. Retinal endovascular lysis in ischemic central retinal vein occlusion: one-year results of a pilot study. Ophthalmology. 2007;114(4):716-723. 118. Hayreh SS. t-PA in CRVO. Ophthalmology. 2002;109(10):1758-1761. 119. Weinberg D, Dodwell DG, Fern SA. Anatomy of arteriovenous crossings in branch retinal vein occlusion. Am J Ophthalmol. 1990;109(3):298-302. 120. Frangieh GT, Green WR, Barraquer-Somers E, Finkelstein D. Histopathologic study of nine branch retinal vein occlusions. Arch Ophthalmol. 1982;100(7):1132-1140. 121. Kumar B, Yu DY, Morgan WH, Barry CJ, Constable IJ, McAllister IL. The distribution of angioarchitectural changes within the vicinity of the arteriovenous crossing in branch retinal vein occlusion. Ophthalmology. 1998;105(3):424-427. 122. Opremcak EM, Bruce RA, Lomeo MD, Ridenour CD, Letson AD, Rehmar AJ. Radial optic neurotomy for central retinal vein occlusion: a retrospective pilot study of 11 consecutive cases. Retina. 2001;21(5):408-415. 123. Mason J III, Feist R, White M Jr, Swanner J, McGwin G Jr, Emond T. Sheathotomy to decompress branch retinal vein occlusion: a matched control study. Ophthalmology. 2004;111(3):540-545. 124. Opremcak EM, Bruce RA. Surgical decompression of branch retinal vein occlusion via arteriovenous crossing sheathotomy: a prospective review of 15 cases. Retina. 1999;19(1):1-5. 125. Mester U, Dillinger P. Vitrectomy with arteriovenous decompression and internal limiting membrane dissection in branch retinal vein occlusion. Retina. 2002;22(6):740-746. 126. García-Arumí J, Martinez-Castillo V, Boixadera A, Blasco H, Corcostegui B. Management of macular edema in branch retinal vein occlusion with sheathotomy and recombinant tissue plasminogen activator. Retina. 2004;24(4):530-540. 127. Le Rouic JF, Bejjani RA, Rumen F, et al. Adventitial sheathotomy for decompression of recent onset branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2001;239(10):747-751. 128. Cahill MT, Kaiser PK, Sears JE, Fekrat S. The effect of arteriovenous sheathotomy on cystoid macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol. 2003;87(11):1329-1332.

156  Chapter 6 129. Charbonnel J, Glacet-Bernard A, Korobelnik JF, et al. Management of branch retinal vein occlusion with vitrectomy and arteriovenous adventitial sheathotomy, the possible role of surgical posterior vitreous detachment. Graefes Arch Clin Exp Ophthalmol. 2004;242(3):223-228. 130. Kumagai K, Furukawa M, Ogino N, Uemura A, Larson E. Long-term outcomes of vitrectomy with or without arteriovenous sheathotomy in branch retinal vein occlusion. Retina. 2007;27(1):49-54. 131. Figueroa MS, Torres R, Alvarez MT. Comparative study of vitrectomy with and without vein decompression for branch retinal vein occlusion: a pilot study. Eur J Ophthalmol. 2004;14(1):40-47. 132. Yamamoto S, Saito W, Yagi F, Takeuchi S, Sato E, Mizunoya S. Vitrectomy with or without arteriovenous adventitial sheathotomy for macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2004;138(6):907-914. 133. Shahid H, Hossain P, Amoaku WM. The management of retinal vein occlusion: is interventional ophthalmology the way forward? Br J Ophthalmol. 2006;90(5):627-639. 134. Hayreh SS. Radial optic neurotomy for central retinal vein occlusion. Retina. 2002;22(2):374-377. 135. Hayreh SS. Radial optic neurotomy for nonischemic central retinal vein occlusion. Arch Ophthalmol. 2004;122(10):1572-1573. 136. Vasco-Posada J. Modification of the circulation in the posterior pole of the eye. Ann Ophthalmol. 1972;4(1):48-59. 137. Arciniegas A. Treatment of the occlusion of the central retinal vein by section of the posterior ring. Ann Ophthalmol. 1984;16(11):1081-1086. 138. Dev S, Buckley EG. Optic nerve sheath decompression for progressive central retinal vein occlusion. Ophthalmic Surg Lasers. 1999;30(3):181-184. 139. Bynoe LA, Opremcak EM, Bruce RA, et al. Radial optic neurotomy for central retinal vein obstruction. Retina. 2002;22(3):379-380. 140. Opremcak EM, Rehmar AJ, Ridenour CD, Kurz DE. Radial optic neurotomy for central retinal vein occlusion: 117 consecutive cases. Retina. 2006;26(3):297-305. 141. Kaderli B, Avci R, Gelisken O. Radial optic neurotomy in central retinal vein occlusion: preliminary results. Int Ophthalmol. 2004;25(4):215-223. 142. Weizer JS, Stinnett SS, Fekrat S. Radial optic neurotomy as treatment for central retinal vein occlusion. Am J Ophthalmol. 2003;136(5):814-819. 143. Binder S, Aggermann T, Brunner S. Long-term effects of radial optic neurotomy for central retinal vein occlusion consecutive interventional case series. Graefes Arch Clin Exp Ophthalmol. 2007;245(10):1447-1452. 144. Garcia-Arumi J, Boixadera A, Martinez-Castillo V, Montolio M, Verdugo A, Corcóstegui B. Radial optic neurotomy in central retinal vein occlusion: comparison of outcome in younger vs older patients. Am J Ophthalmol. 2007;143(1):134-140. 145. Nomoto H, Shiraga F, Yamaji H, et al. Evaluation of radial optic neurotomy for central retinal vein occlusion by indocyanine green videoangiography and image analysis. Am J Ophthalmol. 2004;138(4):612-619. 146. Martínez-Jardón CS, Meza-de Regil A, Dalma-Weiszhausz J, et al. Radial optic neurotomy for ischaemic central vein occlusion. Br J Ophthalmol. 2005;89(5):558-561. 147. Zambarakji HJ, Ghazi-Nouri S, Schadt M, Bunce C, Hykin PG, Charteris DG. Vitrectomy and radial optic neurotomy for central retinal vein occlusion: effects on visual acuity and macular anatomy. Graefes Arch Clin Exp Ophthalmol. 2005;243(5):397-405. 148. Horio N, Horiguchi M. Retinal blood flow and macular edema after radial optic neurotomy for central retinal vein occlusion. Am J Ophthalmol. 2006;141(1):31-34.

Combination Therapy, Management of Recalcitrant Cases, and Surgical Approaches  157 149. Arevalo JF, Garcia RA, Wu L, et al. Radial optic neurotomy for central retinal vein occlusion: results of the Pan-American Collaborative Retina Study Group (PACORES). Retina. 2008;28(8):1044-1052. 150. Furino C, Ferrari TM, Boscia F, et al. Combined radial optic neurotomy, internal limiting membrane peeling, and intravitreal triamcinolone acetonide for central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36(5):422-425. 151. Hasselbach HC, Ruefer F, Feltgen N, et al. Treatment of central retinal vein occlusion by radial optic neurotomy in 107 cases. Graefes Arch Clin Exp Ophthalmol. 2007;245(8):1145-1156. 152. Callizo J, Kroll P, Mennel S, Schmidt JC, Meyer CH. Radial optic neurotomy for central retinal vein occlusion: long-term retinal perfusion outcome. Ophthalmologica. 2009;223(5):313-319. 153. Opremcak EM, Rehmar AJ, Ridenour CD, Kurz DE, Borkowski LM. Radial optic neurotomy with adjunctive intraocular triamcinolone for central retinal vein occlusion: 63 consecutive cases. Retina. 2006;26(3):306-313. 154. Fortunato P, Pollazzi L, Baroni M, Evangelisti A, La Torre A. Venous retinal flow reperfusion mechanisms following radial optic neurotomy with adjunctive intraocular triamcinolone in central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2010;248(2):167-173. 155. Skevas C, Wagenfeld L, Feucht M, Galambos P, Richard G, Zeitz O. Radial optic neurotomy in central retinal vein occlusion does not influence ocular hemodynamics. Ophthalmologica. 2011;225(1):41-46. 156. García-Arumíi J, Boixadera A, Martinez-Castillo V, Castillo R, Dou A, Corcostegui B. Chorioretinal anastomosis after radial optic neurotomy for central retinal vein occlusion. Arch Ophthalmol. 2003;121(10):1385-1391. 157. Quinlan PM, Elman MJ, Bhatt AK, Mardesich P, Enger C. The natural course of central retinal vein occlusion. Am J Ophthalmol. 1990;110(2):118-123. 158. Fuller JJ, Mason JO III, White MF Jr, McGwin G Jr, Emond TL, Feist RM. Retinochoroidal collateral veins protect against anterior segment neovascularization after central retinal vein occlusion. Arch Ophthalmol. 2003;121(3):332-336. 159. Aggermann T, Brunner S, Krebs I, et al. A prospective, randomised, multicenter trial for surgical treatment of central retinal vein occlusion: results of the Radial Optic Neurotomy for Central Vein Occlusion (ROVO) study group. Graefes Arch Clin Exp Ophthalmol. 2013;251(4):1065-1072. 160. Bakri SJ, Beer PM. Choroidal neovascularization after radial optic neurotomy for central retinal vein occlusion. Retina. 2004;24(4):610-611. 161. Barak A, Kesler A, Gold D, Loewenstein A. Visual field defects after radial optic neurotomy for central retinal vein occlusion. Retina. 2006;26(5):549-554. 162. Yamamoto T, Kamei M, Sakaguchi H, et al. Comparison of surgical treatments for central retinal vein occlusion; RON vs. cannulation of tissue plasminogen activator into the retinal vein. Retina. 2009;29(8):1167-1174. 163. Noma H, Mimura T, Eguchi S. Association of inflammatory factors with macular edema in branch retinal vein occlusion. JAMA Ophthalmol. 2013;131(2):160-165.

Financial Disclosures Dr. Sophie J. Bakri has served on advisory boards for Genentech, Regeneron, Allergan, and Valeant Dr. Yewlin E. Chee has no financial or proprietary interest in the materials presented herein. Dr. Dean Eliott has no financial or proprietary interest in the materials presented herein. Dr. Seenu M. Hariprasad is a consultant or on the speaker’s bureau for Genentech, OD-OS, Ocular-Therapeutix, Alcon, Allergan, Optos, Regeneron, Clearside Biomedical, and Bayer. Dr. Nancy M. Holekamp is a consultant for Genentech, Regeneron, and Allergan. She is also on the speakers bureau for Genentech and Regeneron. Dr. Michael S. Ip is a consultant for Allergan, Genentech, Regeneron, and Thrombogenics. Dr. Shaun T. Ittiara has no financial or proprietary interest in the materials presented herein. Dr. Kapil G. Kapoor has no financial or proprietary interest in the materials presented herein. Dr. Pearse A. Keane has received travel grants from the Allergan European Retina Panel and served as a consultant for Novartis. He has received a proportion of his funding from the Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the author and not necessarily those of the Department of Health. - 159 -

160  Financial Disclosures

Dr. Amol Kulkarni has no financial or proprietary interest in the materials presented herein. Dr. Tamer H. Mahmoud is a consultant for Alcon, Alimera, Allergan, and the FDA, and he receives research support from Thrombogenics. Dr. SriniVas R. Sadda is a consultant for and receives research support from Carl Zeiss Meditec and Optos. Dr. Eric W. Schneider has no financial or proprietary interest in the materials presented herein. Dr. Michael A. Singer is a speaker for Allergan, Genentech, and Regeneron. He is also on the research advisory board for Allergan and Genentech and receives research support from Regeneron and Optos. Dr. Colin S. Tan receives research funding from the Clinician Scientist Career Scheme (CSCS/12005) awarded by the National Healthcare Group, Singapore. He has also served as a consultant for and receives travel support from Bayer (South East Asia).