The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care

The Glaucoma Book

Paul N. Schacknow    John R. Samples ●

Editors

The Glaucoma Book A Practical, Evidence-Based Approach to Patient Care

Editors Dr. Paul N. Schacknow Visual Health Center 2889 10th Avenue, N. Palm Springs, FL 33461 USA

Dr. John R. Samples Oregon Health & Sciences University Casey Eye Institute Department of Ophthalmology 3375 SW, Terwilliger Blvd. Portland OR 97201-4197 USA

ISBN 978-0-387-76699-7 e-ISBN 978-0-387-76700-0 DOI 10.1007/978-0-387-76700-0 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010921595 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Custom illustrations by Alice Y. Chen, aliceychen.com Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

The gestational period for The Glaucoma Book has exceeded that of the African elephant (Loxodonta africana) whose pregnancy lasts an average of 660 days. The 2-year period from its conception to parturition has been filled with both pain and joy, similar to the human birth process. When two friends and colleagues decide to create a major textbook on glaucoma, it places a great strain not only upon them, but upon the ones that they love. Our wives, Sharma Schacknow and Griffen Samples, and our children Wesley Samples, Laura Samples, and Jeffrey Schacknow have shared with us our ups and downs, our late night phone calls, our unavailability for normal social functions, our thousands of e-mails to parts unknown and our happiness that this project has finally come to a wonderfully successful conclusion. No marriages were lost, no children abandoned. We dedicate this book with love to all of these family members who helped us maintain our mental equilibrium. We are back more fully in your lives. Hopefully, the copy of The Glaucoma Book that each family will have on the living room coffee table, will daily serve to remind each family that Paul and John have worked very hard to better the lives of our patients for whom they took an oath to serve and cure. Paul Schacknow and John Samples

Foreword

Putting together a comprehensive, multiauthored text is a daunting task. However, the benefits may justify the effort. Such is the case with regards to the present Glaucoma Book. It is not likely that many ophthalmologists (or others) will decide, at the end of a busy day, to pour themselves a cocktail, and settle into a comfortable chair with this large tome in hand, with the intent of reading it from start to finish. A pity. It would make several enjoyable and profitable days of good reading. The text starts with comments by an individual who is strongly grounded in the fundamentals of being a good physician. Ivan Goldberg has used his brilliance, his wide international experiences and knowledge, and his commitment to assuring that physicians know their craft, to provide a penetrating perspective on ophthalmology today and tomorrow. The Glaucoma Book ends with commentaries by the editors, John Samples, a true physician/scientist, and Paul Schacknow, an experienced community-based clinician. Samples’ essay “What Really Causes Glaucoma?” nicely describes the leading theories underlying the cell biology of glaucoma. In “What Do We Know Now, What Do We Need to Know About Glaucoma?,” Schacknow offers an essay on some of the controversial ideas raised within the book and speculates on future research. The stage is set for comments by the world’s leading experts in the field of glaucoma, and their trainees, to deal with the issues raised by Goldberg: the final curtain closes with the difficult but valid idea that while we know a lot, and are knowing more, there is no substitute for observing clearly and pondering thoughtfully. It is disturbing that half (or more) of the world’s people who have glaucoma never even get diagnosed; it is tragic that glaucoma is the leading cause of irreversible blindness in the world, when the overwhelming bulk of that misery could have been prevented by proper diagnosis and treatment. We are not clearly doing our job well; there is clearly much to learn and lots to do. While it is not the traditional way physicians use large texts, ophthalmologists would do well to spend several hours by the fire with The Glaucoma Book. The people who would really benefit would be patients. George L. Spaeth Esposito Research Professor Wills Eye Institute Philadelphia, PA USA

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Preface

Do we really need another book about glaucoma diagnosis and management? There are probably several classic, fairly up-to-date, texts about glaucoma sitting on your bookshelf. Who would have the audacity to write a new text entitled “The” Glaucoma Book, as though it would be the one you would turn to first for definitive, pragmatic answers to questions about diagnosis and management of your patients? Not just a comprehensive academic work with evidencebased science and exhaustive bibliographies, but also an everyday, pragmatic guide for comprehensive ophthalmologists, optometrists, and resident physicians, who would look to it for answers to clinical questions while patients are being examined in their offices. The Glaucoma Book has been written by physicians. Many of them are members of the American Glaucoma Society; all are either fellowship-trained glaucoma specialists, their current glaucoma fellows, and exceptional residents, optometric physicians, or experts on some special topics. These colleagues have large clinical practices and years of experience dealing with the everyday issues that confront eye physicians who manage glaucoma patients. Our goal was to create both a clinically based book and an academic reference that would serve to bring the explosion of new glaucoma diagnostic techniques and therapeutic interventions to those doctors in the trenches who see the great majority of glaucoma patients. We invited not only “the usual suspects” from well-known academic institutions, whose names you are familiar with from the literature and international scientific congresses, but also community-based, real world ophthalmologists, who both know the latest science and also how to see 50 patients in a day while still delivering state-of-the-art care. This book is nontraditional in several ways. We do not include a great deal of discussion on eye anatomy. We do have sidebar essays, inside of major chapters, that discuss important subtopics in greater detail. We have allowed the style to vary among manuscripts, some are more formal, with a large number of references, and some are more informal with a reflective or philosophical bent and few or no references. Photos, illustrations, and tables are sprinkled liberally throughout the book where most appropriate. The topic choices range from the conventional (e.g., open angle glaucoma, pigmentary dispersion syndrome) to those that have not previously appeared in a glaucoma textbook (e.g., medical-legal aspects of glaucoma care, doing community-based glaucoma research). The Glaucoma Book is intentionally idiosyncratic in its design. We have allowed each author the space needed to discuss their assigned topic, so some chapters are longer than others. There is considerable overlap and redundancy in this multiauthored text. This repetition of ideas and facts, from different perspectives, adds strength to the volume. While some topics may be explored to different depths within different chapters, each chapter stands on its own and may be read without having a need to build upon a previous chapter. Cross-referencing of similar topics between chapters and sidebars is done within chapters. The Glaucoma Book is divided into six sections, containing 92 chapters and 38 sidebar essays. Topics are presented in what seemed like a logical order. The book can be read from front to back or sampled intermittently as interesting patients present themselves in your practice. We did not censor our authors from expressing unconventional scientific ideas, as long as ix

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they could present convincing arguments for their opinions. This book is not meant for glaucoma subspecialists who are surely familiar with most of the information it contains. (Of course, we hope that a few of them too will buy a copy!) Rather, the editors feel that we have created an informative, useful tool for the working ophthalmologists and the ophthalmologists in training on current thinking in glaucoma circles. This should ultimately benefit our glaucoma patients who place their trust in us for proper diagnosis and treatment. Lake Worth, FL Portland, OR

Paul Schacknow John Samples

Contents

Part I  The Basics   1 Glaucoma in the Twenty-First Century................................................................. Ridia Lim and Ivan Goldberg

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  2 An Evidence-Based Approach to Glaucoma Care................................................ Louis R. Pasquale

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  3 Glaucoma Risk Factors: Intraocular Pressure...................................................... Nils A. Loewen and Angelo P. Tanna

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  4 Glaucoma Risk Factors: Fluctuations in Intraocular Pressure........................... Felipe A. Medeiros

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  5 Glaucoma is a 24/7 Disease...................................................................................... Amish B. Doshi, John H.K. Liu, and Robert N. Weinreb

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  6 Continuous Monitoring of Intraocular Pressure.................................................. Ron E.P. Frenkel, Max P.C. Frenkel, and Shamim A. Haji

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  7 Aqueous Veins and Open Angle Glaucoma........................................................... Murray Johnstone, Annisa Jamil, and Elizabeth Martin

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  8 Glaucoma Risk Factors: The Cornea..................................................................... Lionel Marzette and Leon Herndon

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  9 Glaucoma Risk Factors: Family History – The Genetics of Glaucoma.............. John R. Samples

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10 Glaucoma Risk Factors: Ethnicity and Glaucoma............................................... 101 M. Roy Wilson and Mark Gallardo 11 Glaucoma Risk Factors: Ocular Blood Flow......................................................... 111 Brent Siesky, Alon Harris, Rita Ehrlich, Nisha Kheradiya, and Carlos Rospigliosi Lopez 12 Glaucoma Risk Factors: Sleep Apnea and Glaucoma.......................................... 135 Rick E. Bendel and Janet A. Betchkal 13 Evaluating Ophthalmic Literature......................................................................... 139 Dan Eisenberg and Paul N. Schacknow

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14 Indications for Therapy........................................................................................... 155 George L. Spaeth Part II  The Examination 15 Clinical Examination of the Optic Nerve............................................................... 169 Scott J. Fudemberg, Yuanjun Zhao, Jonathan S. Myers, and L. Jay Katz 16 Clinical Cupping: Laminar and Prelaminar Components.................................. 185 Claude F. Burgoyne, Hongli Yang, and J. Crawford Downs 17 Disc Hemorrhages and Glaucoma.......................................................................... 195 David J. Palmer 18 Some Lessons from the Disc Appearance in the Open Angle Glaucomas..................................................................................................... 199 Stephen M. Drance 19 Evaluating the Optic Nerve for Glaucomatous Progression................................ 203 Felipe A. Medeiros 20 Digital Imaging of the Optic Nerve........................................................................ 209 Shan Lin and George Tanaka 21 Clinical Utility of Computerized Optic Nerve Analysis....................................... 219 Neil T. Choplin 22 Photography of the Optic Nerve............................................................................. 223 Roy Whitaker Jr. and Von Best Whitaker 23 Detecting Functional Changes in the Patient’s Vision: Visual Field Analysis................................................................................................ 229 Chris A. Johnson 24 Using Electroretinography for Glaucoma Diagnosis............................................ 265 Kevin C. Leonard and Cindy M. L. Hutnik 25 Glaucomatous Versus Nonglaucomatous Visual Loss: The Neuro-Ophthalmic Perspective....................................................................... 269 Matthew D. Kay, Mark L. Moster, and Paul N. Schacknow 26 Gonioscopy............................................................................................................... 283 Reid Longmuir 27 Beyond Gonioscopy: Digital Imaging of the Anterior Segment.......................... 293 Robert J. Noecker 28 Office Examination of the Glaucoma Patient........................................................ 301 Paul N. Schacknow 29 Glaucoma and Driving............................................................................................ 339 Odette Callender 30 Electronic Medical Records in the Glaucoma Practice........................................ 343 Mildred M.G. Olivier and Linda Hay

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31 Advanced Glaucoma and Low Vision: Evaluation and Treatment..................... 351 Scott Robison 32 Glaucoma and Medical Insurance: Billing and Coding Issues............................ 383 Cynthia Mattox 33 Medical Legal Considerations When Treating Glaucoma Patients.................... 391 J. Wesley Samples and John R. Samples Part III  The Glaucomas 34 Primary Open Angle Glaucoma............................................................................. 399 Matthew G. McMenemy 35 Normal Pressure Glaucoma.................................................................................... 421 Bruce E. Prum 36 Primary and Secondary Angle-Closure Glaucomas............................................. 461 Marshall N. Cyrlin 37 Malignant Glaucoma (Posterior Aqueous Diversion Syndrome)........................ 489 Marshall N. Cyrlin 38 Pigmentary Dispersion Syndrome and Glaucoma................................................ 499 Celso Tello, Nathan Radcliffe, and Robert Ritch 39 Exfoliation Syndrome and Glaucoma.................................................................... 507 Anastasios G. P. Konstas, Gábor Holló, and Robert Ritch 40 Neovascular Glaucoma............................................................................................ 517 Donald Minckler 41 Inflammatory Disease and Glaucoma.................................................................... 527 Sunita Radhakrishnan, Emmett T. Cunningham Jr, and Andrew Iwach 42 Posner–Schlossman Syndrome............................................................................... 537 Raghu C. Mudumbai and Sarwat Salim 43 Fuchs’ Uveitis Syndrome and Glaucoma............................................................... 539 Edney R. Moura Filho and Thomas J. Liesegang 44 Herpes Simplex Related Glaucoma........................................................................ 545 Edney R. Moura Filho and Thomas J. Liesegang 45 Herpes Zoster Related Glaucoma........................................................................... 549 Edney R. Moura Filho and Thomas J. Liesegang 46 Iridocorneal Endothelial Syndrome and Glaucoma............................................. 553 Sarwat Salim and Peter A. Netland 47 Ghost Cell Glaucoma............................................................................................... 555 Dinorah P. Engel Castro and Cynthia Mattox 48 Fuchs’ Endothelial Dystrophy and Glaucoma...................................................... 557 Blair Boehmer and Clark Springs

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49 Ocular Trauma and Glaucoma............................................................................... 561 Helen Tseng and Kenneth Mitchell 50 Infantile, Childhood, and Juvenile Glaucomas..................................................... 567 David S. Walton Part IV  The Medical Treatment 51 Medications Used to Treat Glaucoma.................................................................... 583 Paul N. Schacknow and John R. Samples 52 Choosing Adjunctive Glaucoma Therapy............................................................. 629 Jess T. Whitson 53 Monocular Drug Trials for Glaucoma Therapy in the Community Setting....................................................................................... 643 Tony Realini 54 Neuroprotection of Retinal Ganglion Cells........................................................... 647 Alvaro P.C. Lupinacci, Howard Barnebey, and Peter A. Netland 55 Compliance and Adherence: Lifelong Therapy for Glaucoma........................... 651 Alan Robin, Betsy Sleath, and David Covert 56 Alternative and Non-traditional Treatments of Glaucoma.................................. 657 Joseph R. Zelefsky and Robert Ritch 57 Intravitreal Steroids and Glaucoma....................................................................... 671 Yousuf Khalifa and Sandra M. Johnson 58 Pregnancy and Glaucoma....................................................................................... 673 Jeff Martow 59 Systemic Side Effects of Glaucoma Medications................................................... 677 Paul Lama 60 Systemic Diseases and Glaucoma........................................................................... 689 Paul Lama Part V  The Surgical Treatment 61 Laser Therapies: Iridotomy, Iridoplasty, and Trabeculoplasty........................... 713 Douglas Gaasterland 62 Laser Iridoplasty Techniques for Narrow Angles and Plateau Iris Syndrome...................................................................................... 741 Baseer U. Khan 63 Laser Therapies: Cyclodestructive Procedures..................................................... 749 Christopher J. Russo and Malik Y. Kahook 64 Laser Therapies: Newer Technologies................................................................... 753 Michael S. Berlin and Kevin Taliaferro 65 Incisional Therapies: Trabeculectomy Surgery.................................................... 765 Shlomo Melamed and Daniel Cotlear

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66 Incisional Therapies: Trabeculotomy Surgery in Adults..................................... 789 Ronald L. Fellman 67 Incisional Therapies: Canaloplasty and New Implant Devices........................... 795 Diamond Y. Tam and Iqbal “Ike” K. Ahmed 68 Incisional Therapies: Shunts and Valved Implants.............................................. 813 John W. Boyle IV and Peter A. Netland 69 Incisional Therapies: What’s on the Horizon?...................................................... 831 Richard A. Hill and Don S. Minckler 70 Incisional Therapies: Complications of Glaucoma Surgery................................ 841 Marlene R. Moster and Augusto Azuara-Blanco 71 Amniotic Membrane Grafts for Glaucoma Surgery............................................ 861 Hosam Sheha, Lingyi Liang, and Scheffer C.G. Tseng 72 Treating Choroidal Effusions After Glaucoma Surgery...................................... 867 Jody Piltz-Seymour 73 Cyclodialysis Clefts: Surgical and Traumatic....................................................... 871 George R. Reiss 74 Epithelial Downgrowth............................................................................................ 877 Matthew C. Willett, Sami Al-Shahwan, and Deepak P. Edward 75 Penetrating Keratoplasty and Glaucoma.............................................................. 883 Michele L. Scott and Peter A. Netland 76 Descemet’s Stripping Endothelial Keratoplasty (DSEK) and Glaucoma.......................................................................................................... 885 Theodoros Filippopoulos, Kathryn A. Colby, and Cynthia L. Grosskreutz 77 Cataract and Glaucoma Surgery............................................................................ 889 Joseph R. Zelefsky and Stephen A. Obstbaum 78 Cataract Extraction as Treatment for Acute and Chronic Angle Closure Glaucomas....................................................................................... 905 Baseer U. Khan 79 Refractive Surgery and Glaucoma......................................................................... 913 Sarwat Salim and Peter A. Netland 80 Glaucoma after Retinal Surgery............................................................................. 917 Annisa L. Jamil, Scott D. Lawrence, David A. Saperstein, Elliott M. Kanner, Richard P. Mills, and Peter A. Netland Part VI  The Future 81 Immunology and Glaucoma.................................................................................... 925 Michal Schwartz and Anat London 82 How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers............................................................................................................... 933 Paul A. Knepper, Michael J. Nolan, and Beatrice Y. J. T. Yue

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83 CD44 and Primary Open Angle Glaucoma........................................................... 939 Paul A. Knepper, Michael J. Nolan, and Beatrice Y.J.T. Yue 84 Stem Cells and Glaucoma....................................................................................... 953 Shan Lin, Mary Kelley, and John Samples 85 Cytoskeletal Active Agents for Glaucoma Therapy.............................................. 955 Jennifer A. Faralli, Marie K. Schwinn, Donna M. Peters, and Paul L. Kaufman 86 The Drug Discovery Process: How Do New Glaucoma Medications Come to Market?............................................................................... 961 Michael Bergamini 87 Glaucoma Clinical Research in the Community Setting...................................... 977 Harvey DuBiner, Helen DuBiner, and Paul N. Schacknow 88 Future Glaucoma Medical Therapies: What’s in the Pipeline?.......................... 983 Abbot F. Clark 89 Anecortave Acetate: A New Approach for the Medical Treatment of Glaucoma........................................................................................... 989 Amy Lewis Hennessy and Alan L. Robin 90 Future Glaucoma Instrumentation: Diagnostic and Therapeutic....................... 995 Kelly A. Townsend, Gadi Wollstein, and Joel S. Schuman 91 What Really Causes Glaucoma?............................................................................. 1011 John R. Samples 92 The Glaucoma Book: What Do We Know Now, What Do We Need to Know About Glaucoma?.................................................... 1015 Paul N. Schacknow Index.................................................................................................................................. 1023

Contents

Sidebars

Sidebar 4.1 Rapid Oscillations in Intraocular Pressure W. Daniel Stamer and Renata F. Ramos Sidebar 8.1 Pachymeters for Measuring Central Corneal Thickness Odette Callender Sidebar 10.1 Glaucoma in Latinos Elizabeth Salinas-Van Orman Sidebar 11.1 Ocular Perfusion Pressure and Glaucoma: Another View Edney R. Moura Filho and Arthur J. Sit Sidebar 15.1 Alpha-beta Peripapillary Atrophy S. Fabian Lerner Sidebar 15.2 Relative Afferent Pupillary Defects in Glaucoma Patients Edney R. Moura Filho and Rajesh K. Shetty Sidebar 23.1 Lens Induced Artifacts During Visual Field Testing Andrew C. S. Crichton Sidebar 23.2 Another Perspective on the Need for Goldmann Visual Fields in the Era of Automated Visual Fields Andrew C. S. Crichton Sidebar 31.1 Contact Lenses and the Glaucoma Patient Jane Bachman Groth Sidebar 34.1 Glaucoma Suspects - When to Treat, When to Observe Sophio Liao and Alan Robin Sidebar 34.2. Proteoglycan Biosynthesis and Degradation: What Really Causes Glaucoma? Ted Acott, Kate Keller, Mary Kelley, and John Samples Sidebar 36.1 Topiramate, Uveal Effusion and Secondary Angle Closure Glaucoma Theodoros Filippopoulos and Cynthia L. Grosskreutz Sidebar 40.1 Open Angle Glaucoma and Central Retinal Vein Occlusion Meena Beri

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Sidebar 40.2 Central Retinal Vein Occlusion and Monitoring Risk of Neovascular Glaucoma John Hyatt, Sarwat Salim, and Peter A. Netland Sidebar 41.1 Laboratory Testing for Uveitis in the Glaucoma Patient Omar Chaudhary and Sandra M. Johnson Sidebar 51.1 Circadian Variation of Aqueous Humor Dynamics: Implications for Glaucoma Therapy Arthur J. Sit Sidebar 51.2 How to Use Eye Drops to Treat Glaucoma Odette Callender Sidebar 51.3 Preservatives and Glaucoma Medications Clark L. Springs Sidebar 51.4 Carbonic Anhydrase Inhibitors Sophio Liao and Alan Robin Sidebar 51.5 Hyperosmotic Agents for the Acute Management of Glaucoma Kayoung Yi and Teresa C. Chen Sidebar 52.1 Combination Medical Therapy for Glaucoma Todd D. Severin Sidebar 60.1 Antihypertensive Medications and Glaucoma Kevin C. Leonard and Cindy M. L. Hutnik Sidebar 60.2 Glaucoma, Diet, Exercise, and Life Style Janet Betchkal and Rick Bendel Sidebar 60.3 Statin Medications and Glaucoma Kevin C. Leonard and Cindy M. L. Hutnik Sidebar 61.1 Comparing Laser Instruments Yara Catoira-Boyle Sidebar 61.2 New Forms of Trabeculoplasty Giorgio Dorin and John Samples Sidebar 61.3 Corneal Edema Following Angle Closure - How to Perform Laser Iridotomy Peter T. Chang Sidebar 65.1 Incisional Glaucoma Surgery—Making the Decision to Operate Claudia U. Richter Sidebar 65.2 Anticoagulants and Glaucoma Surgery Siva S. Radhakrishnan Iyer, Sarwat Salim, and Peter A. Netland Sidebar 65.3 Fornix Versus Limbal Based Flaps Kenneth B. Mitchell

Sidebars

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Sidebars

Sidebar 65.4 Antimetabolites and Glaucoma Surgery Claudia U. Richter Sidebar 68.1 Trabeculectomy or Tube Shunt Surgery – Which to Perform? Daniel A. Jewelewicz Sidebar 68.2 Encapsulated Filtering Blebs after Glaucoma Shunt Surgery Sandra M . Johnson Sidebar 70.1 Postoperative Flat Anterior Chamber Janet Betchkal and Rick Bendel Sidebar 70.2 Hypotony Maculopathy After Glaucoma Surgery Raghu C. Mudumbai and Sarwat Salim Sidebar 70.3 Fibrin Glue and Glaucoma Surgery Andrew M. Hendrick and Malik Y. Kahook Sidebar 77.1 Flomax: Implications for Glaucoma and Cataract Surgery Maria Basile and John Danias Sidebar 77.2 Anterior Chamber Intraocular Lenses, Pupillary Block and Peripheral Iridectomy Christopher C. Shen, Sarwat Salim, and Peter A. Netland

Contributors

Ted S. Acott, PhD Professor, Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA Iqbal “Ike” K. Ahmed, MD, FRCSC Department of Ophthalmology, Credit Valley Eye Care, Mississauga, ON, Canada Sami Al-Shahwan, MD Senior Academic Consultant, Department of Glaucoma Services, King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia Augusto Azuara-Blanco, MD, PhD, FRCS(Ed) Consultant Ophthalmologist and Honorary Senior Lecturer, Department of Ophthalmology, Aberdeen Royal Infirmary, The Eye Clinic, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK Howard Barnebey, MD Glaucoma Director, Specialty Eyecare Centre, Bellevue, WA, USA Maria Basile, MD Assistant Professor, Department of Ophthalmology, New York Eye and Ear Infirmary, Beth Israel Hospital, New York, NY, USA Rick E. Bendel, MD Assistant Professor of Ophthalmology, Mayo Clinic Jacksonville, Mayo School of Medicine, Consultant, Department of Ophthalmology, Jacksonville, FL, USA Michael V. W. Bergamini, BS, PhD Adjunct Professor, Department of Pharmacology and Neuroscience, University of North Texas Health Services Center, Fort Worth, TX, USA Meena Beri, MD Beri Eye Care Associates, Portland, OR, USA Michael S. Berlin, MS, MD Director, Glaucoma Institute of Beverly Hills, Los Angeles, CA, USA Janet Betchkal, MD Chairman, Department of Ophthalmology, St. Vincent’s Medical Center, Jacksonville, FL, USA Blair Boehmer, MD Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA John W. Boyle IV, MD Instructor of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA

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Claude F. Burgoyne, MD Senior Scientist and Van Buskirk Chair for Ophthalmic Research, Research Director, Optic Nerve Head Research Laboratory, Discoveries in Sight Research Laboratories, Devers Eye Institute, Legacy Health System, Portland, OR, USA Odette V. Callender, MD Chief of Ophthalmology, Wilmington VA Medical Center, Wilmington, DE, USA Dinorah P. Engel Castro, MD New England Eye Center, Department of Ophthalmology/Glaucoma Service, Tufts Medical Center, Boston, MA, USA Yara Paula Catoira-Boyle, MD Assistant Professor of Clinical Ophthalmology, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA Peter T. Chang, MD Assistant Professor of Ophthalmology, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA Omar Chaudhary, MD Resident, Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT, USA Teresa C. Chen, MD Assistant Professor of Ophthalmology, Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Neil T. Choplin, MD Eye Care of San Diego, San Diego, CA, USA Abbot F. Clark, PhD Professor, Department of Cell Biology & Genetics, Director, The North Texas Eye Research Institute, University of North Texas Health Sciences Center, Fort Worth, TX, USA Kathryn Colby, MD, PhD Department of Ophthalmology, Cornea Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Anastasios P. Costarides, MD, PhD Firman Professor of Ophthalmology, Department of Emory Eye Center, Emory University School of Medicine, Atlanta, GA, USA Daniel Cotlear, MD Director, the Glaucoma Service-Barzilai Medical Center, Ashkelon, Tel – Hashomer, Israel Consultant, the Sam Rothberg Glaucoma Center, Sheba Medical Center, Tel – Hashomer, Israel Department of Ophthalmology, Goldschleger Eye Institute, Ashkelon, Tel – Hashomer, Israel David W. Covert, MBA Associate Director, Department of Health Economics, Alcon Research Limited, Fort Worth, TX, USA Andrew C. S. Crichton, MD, FRCS Clinical Professor of Surgery, Department of Ophthalmology, University of Calgary, Calgary, AB, Canada Emmett T. Cunningham Jr., MD, PhD, MPH Adjunct Clinical Professor, Stanford University School of Medicine, Stanford, CA, USA Director, Department of Ophthalmology, The Uveitis Service, California Pacific Medical Center, San Francisco, CA, USA

Contributors

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Contributors

Marshall N. Cyrlin, MD Clinical Professor of Ophthalmology, Oakland University William Beaumont School of Medicine, Rochester, MI, USA Emeritus Director, Glaucoma Services, William Beaumont Eye Institute, Royal Oak, MI, USA Associated Vision Consultants, Southfield, MI, USA John Danias, MD, PhD Associate Professor, Department of Ophthalmology, Mount Sinai Medical Center, New York, NY, USA Giorgio Dorin Nuclear Electronics Engineer, Director, Clinical Applications Development, IRIDEX Corporation Inc., Mountain View, CA, USA Amish B. Doshi, MD Director of Glaucoma Service, Kaiser Permanente, Department of Ophthalmology, Antioch, CA, USA J. Crawford Downs, PhD Associate Scientist and Director, Ocular Biomechanics Laboratory, Discoveries in Sight Research Laboratories, Devers Eye Institute, Legacy Health System, Portland, OR, USA Stephen M. Drance OC, MD Department of Ophthalmology, University of British Columbia, Vancouver, BC, Canada Harvey DuBiner, MD Glaucoma Director, Clayton Eye Center, Morrow, GA, USA Helen DuBiner, PharmD Clayton Eye Center, Clinical Study Coordinator, Morrow, GA, USA Deepak P. Edward, MD, FACS Professor, Chair, Program Director, Department of Ophthalmology, Northeastern Ohio Universities College of Medicine, Summa Health Systems, Akron, OH, USA Rita Ehrlich, MD Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA Dan Eisenberg, MD The Shepherd Eye Center, Las Vegas, NV, USA Jennifer A. Faralli, PhD Research Associate, Department of Pathology, University of Wisconsin, Madison, WI, USA Ronald L. Fellman, MD Associate Clinical Professor of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA Glaucoma Associates of Texas, Dallas, TX, USA Edney de Resende Moura Filho, MD Fellow, Mayo Clinic, Jacksonville, FL, USA Theodoros Filippopoulos, MD Glaucoma Fellow, Assistant in Ophthalmology, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA Athens Vision Eye Institute, Kallithea, Athens, Greece Max P. C. Frenkel Department of Ophthalmology, Eye Research Foundation, Stuart, FL, USA

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Ronald E. P. Frenkel, MD, FACS, FICS Voluntary Associate Professor, Department of Ophthalmology, University of Miami, Bascom Palmer Eye Institute, Miami, FL Scott J. Fudemberg, MD Instructor, Glaucoma Department, Wills Eye Institute, Jefferson Medical College, Philadelphia, PA, USA Douglas E. Gaasterland, MD Clinical Professor, Eye Doctors of Washington, Department of Ophthalmology, Georgetown University & George Washington University, Chevy Chase, MD, USA Mark Gallardo, MD Assistant Professor/Director of Ophthalmology Services, Department of Ophthalmology, Texas Tech Health Sciences Center – El Paso, El Paso, TX, USA Ivan Goldberg, MBBS, FRANZCO, FRACS Clinical Associate Professor, Department of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Floor 4, Sydney, NSW, Australia Cynthia L. Grosskreutz, MD, PhD Associate Professor of Ophthalmology, Co-Director, Glaucoma Service, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA Jane A. Bachman Groth, OD Attending Clinical Faculty, Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA Shamin A. Haji, MD Eye Research Foundation, East Florida Eye Institute, Stuart, FL, USA Alon Harris, PhD Lois Letzter Professor of Ophthalmology, Professor of Cellular and Integrative Physiology, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA Linda J. Hay, JD Alholm, Monahan, Klauke, Hay & Oldenburg, LLC, Chicago, IL, USA Andrew M. Hendrick, MD Resident Physician, Department of Ophthalmology, University of Colorado, Denver, CO, USA Amy Lewis Hennessy, MD, MPH Glaucoma Specialist, Associate, International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Glaucoma Specialists, PA, Department of Ophthalmology/Glaucoma, Greater Baltimore Medical Center, Baltimore, MA, USA Leon W. Herndon Jr, MD Associate Professor of Ophthalmology, Department of Glaucoma, Duke University Eye Center, Durham, NC, USA Richard A. Hill, MD Professor Emeritus, Founder Orange County Glaucoma and Glaukous Corporation, Department of Ophthalmology, Santa Ana, CA, USA Gábor Holló, MD, PhD 1st Department of Ophthalmology, Semmelweis University School of Medicine, Budapest, Hungary

Contributors

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Contributors

Cindy M. L. Hutnik, MD, PhD Associate Professor, Departments of Ophthalmology and Pathology, Ivey Eye Institute, St. Joseph’s Health Care, University of Western Ontario, London, ON, Canada John D. Hyatt, MD Resident, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA Andrew Iwach, MD Department of Ophthalmology, Glaucoma Center of San Francisco, University of California – San Francisco, San Francisco, CA, USA Annisa L. Jamil, MD Glaucoma Consultants Northwest, Swedish Medical Center, Seattle, WA, USA Daniel A. Jewelewicz, MD Delray Eye Associates, Delray Beach, FL, USA Chris A. Johnson, Ph.D Professor, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Sandra M. Johnson Associate Professor of Ophthalmology, Glaucoma Service, University of Virginia School of Medicine, Charlottesville, VA, USA Murray Johnstone, MD Consultant in Glaucoma, Department of Ophthalmology, Swedish Medical Center, Seattle, WA, USA Malik Kahook, MD Associate Professor, Department of Ophthalmology, University of Colorado, Denver, CO, USA Elliott M. Kanner, MD, PhD Assistant Professor, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA L. Jay Katz, MD Professor, Jefferson Medical College, Director of Glaucoma Service, Wills Eye Institute, Philadelphia, PA, USA Paul L. Kaufman, MD Professor and Chair, Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, Madison, WI, USA Matthew D. Kay, MD Neuro-ophthalmologist, Private Practice, West Palm Beach, FL, USA Kate E. Keller, PhD Assistant Professor, Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA Mary J. Kelley, PhD Assistant Professor, Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA Yusuf Khalifa, MD Cornea Fellow, Moran Eye Institute, University of Utah, Salt Lake City, UT, USA Baseer U. Khan, MD, FRCS(C) Lecturer, Department of Ophthalmology, University of Toronto, Toronto, ON, Canada

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Nisha Kheradiya, BS Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA Paul A. Knepper, MD, PhD Research Scientist, Department of Ophthalmology and Visual Science, University of Illinois, Chicago, IL, USA Anastasios G. P. Konstas, MD, PhD Associate Professor in Ophthalmology, Head Glaucoma Unit, 1st University Department of Ophthalmology, Ahepa Hospital, Thessaloniki, Greece Paul J. Lama, MD Associate Clinical Professor of Ophthalmology, Columbia University, New York, NY, USA Director, Glaucoma Division, Department of Ophthalmology, Saint Barnabas Health Care System, Hackensack, NJ, USA Scott D. Lawrence, MD Instructor, Department of Ophthalmology, The Hamilton Eye Institute, University of Tennessee, Memphis, TN, USA Kevin C. Leonard, MSC, MD Resident, Departments of Ophthalmology and Pathology, Ivey Eye Institute, St. Joseph’s Health Care, University of Western Ontario, London, ON, Canada S. Fabian Lerner, MD Director, Glaucoma Section, Postgraduate Department, University Favaloro, Buenos Aires, Argentina Lingyi Liang, MD, PhD Fellow, Ocular Surface Center, Miami, FL, USA Sophie D. Liao, MD House Staff, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA Thomas J. Liesegang, MD Professor, Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA Ridia Lim, MB BS, MPH, FRANZCO Doctor, Glaucoma Department, Sydney Eye Hospital, Sydney, NSW, Australia Shan Lin, MD Associate Professor, Department of Ophthalmology, University of California San Francisco, School of Medicine, San Francisco, CA, USA John H. K. Liu, PhD Professor, Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA Nils A. Loewen, MD Northwestern University, Department of Ophthalmology, Feinberg School of Medicine, Chicago, IL, USA Anat London Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel Reid Longmuir, MD Assistant Professor, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Carlos Rospigliosi Lopez, MD Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA

Contributors

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Contributors

Alvaro P.C. Lupinacci, MD Glaucoma Fellow, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA Elizabeth Martin, BA Medical student, University of Washington, School of Medicine, Seattle, WA, USA Jeff Martow, MDCM, FRCS(C) Clinical Instructor, Department of Ophthalmology, St. Michael’s Hospital, University of Toronto, ON, Canada Lionel Marzette, MD Research Associate, Department of Ophthalmology, Duke University Eye Center, Durham, NC, USA Cynthia Mattox, MD Director of Glaucoma and Cataract Service, Department of Ophthalmology, New England Eye Center, Tufts University School of Medicine, Boston, MA, USA Matthew G. McMenemy, MD Department of Ophthalmology, Lone Star Eye Care, PA, Sugar Land, TX, USA Felipe A. Medeiros, MD, PhD Associate Professor, Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA Shlomo Melamed Professor of Ophthalmology, Director, The Sam Rothberg Glaucoma Center, Goldschleger Eye Institute, Sheba Medical Center, Tel Aviv University Medical School, Hashomer, Israel Richard P. Mills, MD, MPH Glaucoma Consultants Northwest, Seattle, WA, USA Don S. Minckler, MD, MS Professor of Ophthalmology and Pathology, Department of Ophthalmology & Pathology, University of California, Irvine, CA, USA Kenneth B. Mitchell, MD Associate Professor, Department of Ophthalmology, West Virginia University School of Medicine, Morgantown, WV, USA Mark L. Moster MD Chairman, Neuro-Ophthalmology, Albert Einstein Medical Center, Professor of Neurology, Jefferson Medical College, Neuro-Ophthalmology Service, Wills Eye Institute, Elkins Park, PA, USA Marlene R. Moster, MD Professor of Ophthalmology, Department of Ophthalmology, Thomas Jefferson University Hospital, Philadelphia, PA, USA Raghu Chary Mudumbai, MD Residency Program Director, Associate Professor, Department of Ophthalmology, University of Washington Medical Center, Seattle, WA, USA Jonathan S. Myers, MD Spaeth/Katz/Myers, P.C., Wills Eye Institute, Philadelphia, PA, USA Peter A. Netland, MD, PhD Professor and Chair, Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA

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Robert J. Noecker, MD, MBA Vice Chair Clinical Affairs, Director Glaucoma Service, Associate Professor, Department of Ophthalmology, UPMC Eye Center, University of Pittsburgh School of Medicine Pittsburgh, PA, USA Michael J. Nolan, BS, MA Research Coordinator, Department of Ophthalmology and Visual Science, University of Illinois, Chicago, IL, USA Stephen A. Obstbaum, MD Professor of Ophthalmology, NYU School of Medicine, New York, NY, USA Chairman, Department of Ophthalmology, Lenox Hill Hospital, New York, NY, USA Mildred M. G. Olivier, MD Associate Clinical Professor, Department of Ophthalmology, Midwestern University, Rosalsind Franklin University of Medicine and Science, Hoffman Estates, IL, USA David J. Palmer, MD Clinical Assistant Professor, Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Louis R. Pasquale, MD Co-Director, Glaucoma Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Donna Peters, PhD Professor, Departments of Pathology and Laboratory Medicine and Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Jody Piltz-Seymour, MD Director, Glaucoma Care Center PC, Century Eye Care LLC, Bristol, PA, USA Bruce E. Prum, Jr., MD Associate Professor of Ophthalmology, Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA Nathan Radcliffe, MD Assistant Professor, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA Sunita Radhakrishnan, MD Glaucoma Center of San Francisco & Glaucoma Research .and Education Group, San Francisco, CA, USA Siva S. Radhakrishnan Iyer, MD Resident, Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA Renata Fortuna Ramos, PhD Postdoctoral Fellow, Department of Bioengineering, Rice University, Houston, TX, USA Tony Realini, MD Associate Professor of Ophthalmology, Department of Ophthalmology, West Virginia University, Morgantown, WV, USA George R. Reiss, MS, MD Instructor, Department of Ophthalmology, Maricopa Medical Center, Glendale, AZ, USA Claudia U. Richter, MD Clinical Instructor, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

Contributors

xxix

Contributors

Robert Ritch, MD Shelley and Steven Einhorn Distinguished Chair in Ophthalmology, Chief, Glaucoma Service, Surgeon Director, Department of Ophthalmology, The New York Eye and Ear Infirmary, New York, NY, USA Professor of Clinical Ophthalmology, Department of Ophthalmology, The New York Medical College, Valhalla, NY, USA Alan L. Robin, MD Associate Professor, International Health, Bloomberg School of Public Health, Wilmer Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA Scott Robison, OD Adjunct Assistant Professor, Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA Christopher J. Russo, MD Department of Ophthalmology, Rocky Mountain Lions Eye Institute, University of Colorado Denver, Aurora, CO, USA Sarwat Salim, MD Assistant Professor, Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA John R. Samples, MD Clinical Professor, Oregon Health and Sciences University, Portland, OR, USA Clinical Professor, Rocky Vista University, Parker, CO, USA Director, Western Glaucoma Foundation Executive Secretary, Pacific Coast Oto-Ophthalmology Society Specialty Eye Care, Parker CO John Wesley Samples, BS, BA .D. Candidate, Case Western Reserve University School of Law, Class of 2011Submissions Editor, Case Western Reserve Journal of Law, Technology & theInternet David A. Saperstein, MD Vitreoretinal Associates, Glaucoma Consultants Northwest, Seattle, WA, USA Paul N. Schacknow, MD, PhD Clinical Associate Professor, Division of Ophthalmology, Nova Southeastern University, Fort Lauderdale, FL, USA Chief of Glaucoma Services, Visual Health Center, Palm Springs, FL USA Joel S. Schuman, MD, FACS Eye and Ear Foundation Professor and Chairman, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Director, UPMC Eye Center, Pittsburgh, PA, USA Professor of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA Professor, Center for the Neural Basis of Cognition, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, PA, USA Michal Schwartz, PhD Professor of Neuroimmunology, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel Marie K. Schwinn, PhD Postdoctoral Fellow, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA

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Michele L. Scott, MD Instructor, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA Todd Severin, MD Director, Glaucoma Services, East Bay Eye and Glaucoma Diagnostic Centers, San Ramon, CA, USA Hosam Sheha, MD, PhD Director of Medical Education and Clinical Studies, Ocular Surface Center, Miami, FL, USA Christopher C. Shen, MD Resident, Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA Rajesh K. Shetty, MD Assistant Professor, Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA Brent Siesky, PhD Research Associate, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA Craig Simms, COMT, ROUB, CDOS Clinical Instructor, Program Director, Calgary Ophthalmic Medical Technology Program, Rockyview Hospital Eye Clinic, Calgary, AB, Canada Arthur J. Sit, SM, MD Assistant Professor, Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, MN, USA Betsy Lynn Sleath, PhD Professor of Pharmaceutical Outcomes and Policy, University of North Carolina, School of Pharmacy, Chapel Hill, NC, USA George L. Spaeth, BS, MD Esposito Research Professor, Department of Ophthalmology, Wills Eye Institute, Jefferson Medical College, Philadelphia, PA, USA Clark Springs, MD Assistant Professor, Department of Ophthalmology, Indiana University, Indianapolis, IN, USA W. Daniel Stamer, PhD Professor, Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ, USA Kevin Taliaferro, BA Glaucoma Institute of Beverly Hills, Los Angeles, CA, USA Diamond Y. Tam, MD Glaucoma and Advanced Anterior Segment Surgery Fellow, Department of Ophthalmology and Vision Sciences, Credit Valley Eye Care, University of Toronto, Mississauga, ON, Canada H. George Tanaka, BSE, MD Clinical Instructor, Department of Ophthalmology, California Pacific Medical Center, San Francisco, CA, USA

Contributors

Contributors

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Angelo P. Tanna, MD Assistant Professor, Department of Ophthalmology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Celso Tello, MD Associate Professor of Ophthalmology, Director, Glaucoma Clinic, Department of Ophthalmology, New York Eye and Ear Infirmary, New York, NY, USA Kelly A. Townsend, BS Research Specialist, Biomedical Engineer, UPMC Eye Center, Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Ophthalmology, Ophthalmology and Visual Science Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Helen Tseng, MD Clinical Instructor, Department of Ophthalmology, University of California, Irvine, CA, USA Scheffer C. G. Tseng, MD, PhD Director, Ocular Surface Center, Miami, FL, USA Elizabeth Salinas Van Orman, MD Director of the Research Department, Specialty Eye Care, Parker, CO, USA David S. Walton, MD Clinical Professor of Ophthalmology, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA Robert N. Weinreb, MD Distinguished Professor of Ophthalmology, Department of Ophthalmology, University of California, La Jolla, San Diego, CA, USA Roy Whitaker Jr., MD Medical Director, Eye Consultants of Greensboro, Greensboro, NC, USA Von Best Whitaker, RN, MS, MA, PhD Research Associate Professor, North Carolina Agricultural and Technical State University, School of Nursing, Greensboro, NC, USA Jess T. Whitson, MD Professor, Department of Ophthalmology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX, USA Matthew C. Willett, MD Department of Ophthalmology, Summa Health Systems, Akron, OH, USA M. Roy Wilson, MD, MS Chancellor and Professor, Department of Ophthalmology, University of Colorado Denver, Denver, CO, USA Gadi Wollstein, MD Assistant Professor of Ophthalmology, UPMC Eye Center, Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Ophthalmology and Visual Science Research Center, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Hongli Yang, MS Graduate Research Assistant, Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA

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Kayoung Yi, MD, PhD Associate Professor, Department of Ophthalmology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, South Korea Beatrice Y. J. T. Yue, PhD Thanis A. Field Professor of Ophthalmology, Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago, IL, USA Joseph R. Zelefsky, MD Clinical Instructor in Ophthalmology, Department of Ophthalmology, New York University, New York, NY, USA Yuanjun Zhao Wills Eye Institute, Philadelphia, PA, USA

Contributors

Part I The Basics

Chapter 1

Glaucoma in the Twenty-First Century Ridia Lim and Ivan Goldberg

1.1  W  hat is Glaucoma for the Twenty-First Century? Our concepts of the glaucomas evolve as our understanding of disease processes increases, technology advances, and our treatment strategies become more sophisticated. Technology has always corralled our definitions and our understanding of the glaucomas; the challenge of this new century is to focus our progress for the direct benefit of our patients. To understand and to modify where we are heading, we must know where we are now, and how we arrived here. Since the time of Hippocrates, the glaucomas have mystified physicians. In the mid-nineteenth century, the truth began to emerge.1 The link with disc cupping followed Hermann von Helmholtz’s 1860s invention of the ophthalmoscope and Albrecht von Graefe’s observations. Thus, there arose the structural nerve head-based definitions: Glaucoma was considered a neurological disease. The association with raised intraocular pressure (IOP) occurred over several centuries but was boosted by improvements in tonometers between 1880 and 1910 (Table  1.1). Improved functional assessment established the mid-twentieth century triad definition: raised IOP with characteristic optic disc and visual field changes. As tonometry, perimetry, and optic disc structural evaluation have each advanced, significant developments in one area have emphasized that aspect of glaucoma. The most recent technological improvements in objective optic disc and retinal nerve fiber layer (RNFL) assessment have moved our focus once again to the underlying neurological consequences of this group of diseases. We must remember: Technological capabilities drive our definitions and concepts of the glaucomas and their management. Most glaucomas are chronic and relatively slowly progressive; technological advances occur faster than we can evaluate them critically. In every area, there is continued exponential growth. This could lead us to lose sight of our first call

as clinicians: All these advances are ultimately for the benefits of individual patients, for whom management strategies need to balance potential benefits against possible risks of harm. Understanding of a patient’s quality of life (QOL), independence, and personal dignity must also advance, so that progress has a meaningful human application. Physical, emotional, and financial considerations are part of this. Currently, we define the glaucomas as an optic neuropathy (with multifactorial risk factors that include increased IOP, increasing age, and genetic predisposition) characterized by recognizable patterns of optic disc and retinal nerve fiber structural and visual field functional damage. Glaucomatous optic neuropathy is not the disease; it is the end-result of several as yet unidentified cellular disease processes. Unlike almost all other optic neuropathies, contour changes of the optic nerve head (“cupping”) with progressive loss of the retinal nerve fiber layer and associated functional deficits are features of the disease; this results from accelerated retinal ganglion cell apoptosis, initiated by damaging processes that target the axons of these cells as they leave the globe. Thus, the definition varies with the perspective of the definer: retinal ganglion cell apoptosis to a scientist, optic neuropathy to a clinician, and fear of blindness for a patient.

1.2  W  hat Are the Challenges We Face in the Twenty-First Century and Beyond? We have to meet the challenge to find those with glaucoma who are undiagnosed. Population studies have yielded a wealth of data about glaucoma prevalence, incidence, and risk factors in Caucasian, Latino, African-American, Afro-Caribbean, Indian sub-continental, and Oriental populations (see Fig. 1.1). Second only to cataract, globally the glaucomas are the

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_1, © Springer Science+Business Media, LLC 2010

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R. Lim and I. Goldberg

Table 1.1  History of Glaucoma 2-8 Understanding of glaucoma Between the time of Hippocrates and the middle of the nineteenth century, glaucoma was very poorly understood. Any disease that was not diagnosable externally may have been labeled “glaucoma.” Hippocrates is credited for the term “glaucosis,” which translates to “sea green eye,” but the differentiation of glaucoma from other diseases, especially cataract, took many centuries. The word “glaucoma” is derived from the word “glaukos” and this means blue hue in Greek. There were a few notable observations: during the middle ages, Arabian physicians gave some descriptions of glaucoma. • Tenth century – At Tabari in the “Hippocratic writings” described inflammation and raised eye pressure. • 1348 – Sams ad Din of Cairo described an eye condition with hardness of the eyeball, hemicrania, reduced vision, and dilated pupil. Thereafter, understanding of glaucoma did not progress much until the 1800s. • 1622 – Richard Banister, in the first ophthalmology textbook in English, Banister’s Breviary, noted that the eye was hard in some morbid eye conditions. He also translated William Guillemeau’s 1585 text, “A treatise of one hundred and thirteen diseases of the eyes, and eye-lids,” which had incorporated information from Arabic and Greek sources. • 1709 – Michel Brisseau differentiated glaucoma from lens disorders; he attributed glaucoma to the vitreous. This view prevailed until direct disc viewing was possible. • 1818 – Antoine-Pierre Demours gave a good description of glaucoma and first described colored rings around lights. • 1823 – George James Guthrie labeled the disease “glaucoma.” • 1830 – William Mackenzie, author of the first comprehensive English book on ophthalmology, A Practical Treatise on the Diseases of the Eye, noted “the eyeball always in glaucoma feels firmer than natural.” The role of IOP in glaucoma was now firmly established. • 1850s – Albrecht von Graefe differentiated acute, chronic, and secondary glaucoma. • 1866 – Donders labeled cases with no congestive symptoms, with raised IOP “simple glaucoma;” this misleading label persisted for a century. • 1938 – Jonas S. Freidenwald showed that aqueous was actively produced by the ciliary body and was not solely a dialysate of plasma. • 1941 – Aqueous veins connecting the canal of Schlemm and the episcleral veins were described for the first time by K. W. Ascher. • 1959 – A. E. Maumenee’s advanced insights into congenital glaucoma. • 1969 – Cup/disc ratio increase as a sign of the damaging effect of raised IOP, in eyes with normal visual fields, was reported in a paper by Mansour F. Armaly and Roger E. Sayegh. Armaly’s cup/disc ratio gained widespread use in glaucoma management. • 1970 – Stephen Drance associated disc hemorrhage with nerve fiber layer defects. • 1973 – William Hoyt described nerve fiber layer defects as the earliest sign of glaucoma. • 1982 – Harry Quigley reported that 40% of nerve fibers could be lost without visual field loss detected by quantitative kinetic perimetry. Investigations of glaucoma • Early 1800s – Ophthalmologists performed digital tonometry. • 1860s – Several scleral tonometers were introduced, but use was not widespread. • 1850 – Invention of ophthalmoscope by Hermann Ludwig Ferdinand (von) Helmholtz; disc cupping seen by Albrecht von Graefe, Mueller and the idea that glaucoma was a vitreous disorder was finally abandoned. • 1856 – Albrecht von Graefe used a primitive campimeter, a row of dots on a sheet of paper, to plot peripheral visual field defects. • 1889 – Quantitative perimetry. Jannik Petersen Bjerrum used his office door to plot field defects, thereby inventing the tangent screen. This became the dominant form of perimetry for 50 years. He described the arcuate scotoma, a hallmark of glaucoma. • 1905 – Hjalmar Schiőtz invented the first reliable indentation tonometer. Corneal tonometers were possible with the introduction of cocaine in 1884. • Early 1900s – Iridocorneal angle was directly visualized by Trantas (1900), Salzmann (1915), Troncosco (1921). • 1928 – Schmidt used the water-drinking test in glaucoma patients. • 1916 – Biomicroscopes were invented in the 1890s. Allvar Gullstrand was the first to use slit illumination. In 1916, Zeiss combined these two principles, thus giving rise to the first slit lamp biomicroscope. • 1935–1940 – Barkan popularized gonioscopy as an essential part of eye examination using the Koeppe direct gonioscopy lens. • 1950 – W. Morton Grant described the tonographic method of measuring facility of outflow and rate of aqueous outflow. • 1954 – Hans Goldmann invented his quantitative perimeter. • 1955 – Hans Goldmann invented his tonometer, an unsurpassed instrument, based on the Imbert-Fick law. For once, patients could have IOP measurements sitting up. It remains the gold standard today and despite its limitations, it is a widely available and most commonly used tool. • 1970s – Computerized perimeters are introduced and developed by Humphrey and Octopus. Drug treatment of glaucoma • 1862 – Calabar bean found to cause miosis by Sir Thomas Richard Fraser. The Calabar bean, native to West Africa, was growing in the Royal Botanic Gardens in Edinburgh from seeds brought back by missionaries. In 1864, physostigmine (eserine) was isolated from the Calabar bean. • 1875 – Ludwig Laquer described the use of physostigmine for his own glaucoma. (continued)

1  Glaucoma in the Twenty-First Century

5

Table 1.1  (continued) • 1873-6 – Symphronio Coutinho, a Brazilian doctor, took samples of Jaborandi (Pilocarpus pennatifolius, a shrubby tree native to America) leaf to Europe. Systemic effects were noted and by 1876, Adolf Weber was using the isolated alkaloid, pilocarpine, in the treatment of glaucoma. • 1925 – Epinephrine was reported by Gradle and Hambuger to reduce IOP, but after elevating IOP in some cases it was not used until the 1940s when gonioscopy identified narrow angles and thus patients who should not use it. R. Weekers reported on the use of epinephrine in 1954 and it was reintroduced. • 1950s – Hyperosmotics – mannitol and urea. • 1954 – Acetozolamide, initially used as a diuretic in congestive heart failure, was reported by Bernard Becker to reduce IOP very effectively when used orally. • 1967 – Phillips reported IOP lowering with oral propranolol; in 1977, Zimmerman used timolol for glaucoma. Surgical treatment of glaucoma • 1857 – Surgical iridectomy used “to reduce aqueous production” by Albrecht von Graefe. An amazing advance in the treatment of glaucoma, this operation cured many cases of angle closure, but not by reducing aqueous production! • 1859 – Iridectomy with iris inclusion-Coccius • 1876 – Scleral trephination-Argyll-Robertson • 1878 – Anterior sclerectomy-Louis De Wecker • 1903 – Iridosclerectomy-Bader and Lagrange • 1905 – Cyclodialysis-Heine • 1906 – Iridenclesis-Soren Holth. This procedure was associated later with sympathetic ophthalmia. • 1909 – Elliot published “Sclero-corneal Trephining in the Operative Treatment of Glaucoma,” describing his first 900 cases. Corneoscleral trephination became the preferred operation, but was associated with thin blebs. • 1920 – Curran and Banzinger (1922) described separately the use of iridectomy to relieve “congestive glaucoma,” but the concept was ignored for 20 years until gonioscopy reliably allowed detection of pupil block angle closure. • 1924 – Preziozi used electrocautery to create a full thickness fistula between the anterior chamber and the subconjunctival space. • 1936 – Otto Barkan described goniotomy for chronic glaucoma in adults. It remains the operation of choice in congenital glaucoma, but is not used in adults. • 1940s – Barkan rediscovered the mechanism of pupil block; keen gonioscopists (Kronfeldt, Chandler, and Shaffer) popularized iridectomy for pupil block. • 1956 – Meyer-Schwickerath reported on laser iridotomy with a xenon arc photocoagulator. • 1958 – Harold Scheie reported a full-thickness fistulizing procedure for glaucoma. He modified Preziozi’s procedure by entering the eye with a knife and then using cautery to extend the scleral wound and to keep it open. Most common problems were hypotony and cataract. • 1968 – Trabeculectomy. J. E. Cairns described a guarded procedure removing a rectangular section of trabecular meshwork and deep cornea. He aimed to remove a block of the canal of Schlemm to get aqueous to flow freely into its cut ends. A bleb formed in about a third of cases. • 1968 – Anthony Molteno invented a glaucoma drainage device that shunted aqueous from the anterior chamber into a maintained episcleral reservoir. • 1976 – Theodore Krupin invented the first valved glaucoma drainage tube, at first without a reservoir. • 1979 – James B. Wise and Stanton L. Witter treated the trabecular meshwork with Argon laser to increase facility of outflow: “trabeculoplasty.” • 1982 – Robert Ritch described iridoplasty for acute angle closure crisis unresponsive to medication. • 1983 – Chen Wu Chen used Mitomycin C as an adjunctive in trabeculectomy. Published in a minor journal, a decade passed before it became popular. • 1984 – 5-Fluorouracil was first reported in an animal model and in a pilot study in glaucoma filtering surgery.

leading cause of visual disability. As the damage caused is irreversible, but mostly avoidable by treatment, the glaucomas are the leading cause of preventable blindness. As prevalence increases exponentially with increasing age, the glaucomas are set to become increasingly and relentlessly a worldwide public health issue as populations gray. In all communities, glaucoma is under-diagnosed. In deve­ loped countries, such as Australia, half of all glaucoma cases are undiagnosed.9,10 The percentage undiagnosed is far greater in underprivileged communities: up to 90% of glaucoma

patients are not diagnosed.11,12 Access to eye care is not the only issue: In an Australian study, up to 50% of the undiagnosed patients had seen either an ophthalmologist or an optometrist (or both) in the previous 12  months.13 In the Melbourne Visual Impairment Project (VIP), 97% of undiagnosed glaucoma cases that had seen an eye professional within the last 12 months had a visual field defect on standard automated perimetry: these were not early, subtle cases. Professional education is an issue. The challenge to find undiagnosed cases is very real, and multiple strategies are needed to overcome this challenge.

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R. Lim and I. Goldberg

Fig.  1.1  The studies timeline – important population and interventional studies in glaucoma. (Dates are recruitment or start dates and “N” is number of people unless stated as eyes). AGIS Advanced Glaucoma Intervention Study, multicenter USA.20 BDES Beaver Dam Eye Study, Wisconsin, USA.21 BMES Blue Mountains Eye Study, Blue Mountains, Australia.9 CIGTS Collaborative Initial Glaucoma Study, multicenter USA.22 CNTGS Collaborative Normal Tension Glaucoma Study, multicenter USA.23 EGPS European Glaucoma Prevention Study, multicenter

Europe.24 EMGT Early Manifest Glaucoma Trial, Sweden.25 FFFS Fluorouracil Filtering Surgery Study, multicenter USA.26 GLT Glaucoma Laser Trial, multicenter USA.27 GLTFS Glaucoma Laser Trial Follow Up Study, multicenter USA.27 LALES Los Angeles Latino Eye Study, Los Angeles, USA.11 MVIP Melbourne Visual Impairment Project, Melbourne, Australia.10 OHTS Ocular Hypertension Treatment Study, multi-center USA.28 SEE Salisbury Eye Evaluation Project, Maryland, USA29

1.2.1  P  opulation-Based (“Universal”) Screening

1. The condition should be an important health problem. 2. There should be an accepted treatment for the patients with recognized disease. 3. Facilities for diagnosis and treatment should be available. 4. There should be a recognizable latent or early symptomatic stage. 5. There should be a suitable test or examination. 6. The test should be acceptable to the population.

Screening is the use of a test or tests on a target population to find cases of disease. There are different types of screening: targeted and mass population screening. Tools used for screening should fulfill certain criteria. There is no one good massscreening test for glaucoma. As stated by the World Health Organization in 1968, the principles of screening are 14:

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1  Glaucoma in the Twenty-First Century

7. The natural history of the condition, including development from latent to declared disease should be adequately understood. 8. There should be an agreed policy on whom to treat as patients. 9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. 10. Case-finding should be a continuing process and not a “once and for all” project. Population-based screening for glaucoma for long has been handicapped by an undue reliance on IOP levels. An IOP greater than 21 mmHg became so integral to the definition of glaucoma that this alone became synonymous with glaucoma. Another failing was the arbitrary cut-off of 21 mmHg to differentiate “high pressure from “low pressure” or “normal tension” glaucoma, as if they were two different diseases.15 The number 21 mmHg as the borderline between normal and abnormal began with Leydhecker’s groundbreaking study in 1958 when the IOP of 20,000 eyes was measured with Schiotz tonometry, and a mean of 15.5 mmHg with a standard deviation of 2.57 mmHg was found.16 By the time Hollows and Graham published their Welsh population data in 1966, the idea of 21 mmHg was so well established that a bias for not finding an IOP of 21  mmHg (the “decision effect”) was seen.17 In their population (40–75  years), the IOP was 15.9 (SD~3) mmHg in men and 16.6 (SD~3) mmHg in women. The distribution of IOP was non-Gaussian with a skew to the right (i.e., more individuals with higher IOP than predicted) in those older than 60 years. Elevated IOP is not glaucoma, and ocular hypertension does not lead invariably to glaucomatous optic neuropathy. This arbitrary differentiation is obsolete, although, because of its usefulness as a defined cut-off, it still remains part of ophthalmology outcome terminology. What is the current role of IOP in diagnosis and treatment of glaucoma? Although IOP is not part of the definition of glaucoma, its reduction remains the only proven and approved means of treatment, and is the single most important modifiable risk factor. To cause glaucomatous optic neuropathy, there is a complex interaction between IOP and other risk factors. IOP is not a useful screening test for glaucoma. A single office measurement does not reflect an individual’s pressure range; it cannot be the basis for diagnosis. Many cases of glaucoma have been missed or diagnosed late by reliance on IOP for screening. David Eddy recognized this.18 David Eddy and John Billings also challenged the glaucoma world with their 1987 report that found “not a single book, chapter or paper that systematically reviewed the evidence on the effectiveness of treatment” of glaucoma.19 While some clinicians

became “glaucoma treatment skeptics,” a larger group set out to obtain the best evidence for IOP reduction in glaucoma care. What resulted were a number of National Eye Institutefunded prospective, randomized, controlled, multicenter clinical trials of management of ocular hypertension and glaucoma (see Fig.  1.1): AGIS, CIGTS, CNTGS, EMGT, EPGS, and OHTS. Is there a test or a group of tests that is good enough to detect the disease and is it a cost-effective exercise? In general, the cost considered is economic and not emotional or societal. A recent review of glaucoma screening in the United Kingdom30 concluded that while population screening for glaucoma alone is not efficient or cost-effective generally, targeted screening of “at risk” groups is (such as family members of glaucoma patients), screening older populations for more than one eye disease simultaneously, or for systemic conditions as well, changes the economic parameters dramatically. The 2005 report by the US Agency for Healthcare Research & Quality, US Preventative Services Task Force31 stated that there is no good single test at present to conduct population screening. However, in 2008, the World Glaucoma Association (WGA) devoted their fifth Consensus meeting to glaucoma screening32 for open-angle and angle-closure glaucomas. Their findings are summarized in Table 1.2.

1.2.2  C  ase Detection (“Opportunistic Screening”) Case detection or opportunistic screening is the process of finding asymptomatic cases as they present to the eye professional for other reasons. Currently, this consistently fails to find all cases of glaucoma, as demonstrated repeatedly in population studies. The most likely reason we fail to find all of the cases is an incomplete “comprehensive” examination, in which the optic disc and angle configuration have not been assessed properly. In agreement with the Melbourne VIP, a mass screening study in Malmö, Sweden,33 found that of the cases of glaucoma newly diagnosed by the screening program, 62% had seen an ophthalmologist at some stage previously, with 17% having seen one in the preceding 2 years. Many more cases of glaucoma would be diagnosed if ophthalmologists and optometrists competently and conscientiously examined the optic nerve, performed gonioscopy (and if necessary, performed a visual field test) in all adult patients, regardless of the presenting problem. This is particularly so in older patients where the disease is more prevalent. Eye care professionals need to be skilled to perform these tasks better. Patients might wonder why the examiner is looking at their optic nerve when they came in with another problem.

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Table 1.2  WGA consensus on glaucoma screening (2008) Open-angle glaucoma 1. Is Open Angle Glaucoma an important health issue?  YES • Glaucoma is the leading cause of preventable and irreversible blindness. • The goal of glaucoma screening is to prevent visual impairment, and to preserve both quality of life and visual functioning. • Each society should determine its own criteria, including the stage of disease, for the allocation of an affordable proportion of its resources for glaucoma care and screening. • The prevalence of open-angle glaucoma has been determined for some populations of European, African, and Asian ancestry. • Long-term data shows substantial frequency of glaucoma blindness in some populations. 2. Is there an accepted and effective treatment?  YES • High quality randomized trials (treatment versus no treatment) and meta-analyses have shown that topical ocular hypotensive medication is effective in delaying both onset and progression of open-angle glaucoma. • Treatments are effective, easy to use, and well tolerated. • It is not known whether postponing ocular hypotensive therapy affects the rate of subsequent conversion from ocular hypertension to open-angle glaucoma, or the rate of progression of visual field loss once open-angle glaucoma has developed. • It is not known whether the reduction in progression rate from IOP lowering therapy varies according to disease stage. • Current evidence suggests that glaucoma therapy itself is not associated with a measurable reduction of quality of life. • Patients’ perceived vision-related quality of life (VRQOL) and visual function is correlated with visual field loss, especially binocular visual field loss, in open-angle glaucoma. 3. Are facilities for diagnosis and treatment available?  YES • The resources for diagnosis and treatment of glaucoma vary worldwide. • Fewer resources are required to diagnose glaucoma at moderate to advanced asymptomatic stages when compared with very early stages. • Treatment of glaucoma requires facilities for regular long-term monitoring. • There is a need to study barriers to access for glaucoma care so that available facilities can be used optimally. 4. Is there an appropriate screening test?  POTENTIALLY • The best single test or group of tests for open-angle glaucoma screening is yet to be determined. • Optimal screening test criteria are not yet known. • Diagnostic test accuracy may vary according to the severity of the disease. • The tests available and effective for case-finding are not necessarily the same as those for population-based glaucoma screening, which requires a very high specificity to be cost-effective. 5. Is the natural history adequately understood?  YES • Open-angle glaucoma incidence rates are known for untreated and treated patients with ocular hypertension. • Open-angle glaucoma progression rates vary greatly among patients. • Progression event rates for patients (in clinical trials, under clinical care or observation) in terms of percent of patients/eyes progressing per year are available both for open-angle glaucoma and ocular hypertension. • Progression data expressed as rate of disease progression, (i.e., expressed in dB/year or in % of full field/year) are very sparse. 6. Is the cost of case finding economically balanced?  POTENTIALLY • The best evidence to date, based on two modeling studies, suggests: 1. Screening of high-risk subgroups could be more cost-effective than screening the entire population. 2. Screening may be more cost-effective as glaucoma prevalence increases. 3. The optimal screening interval is not yet known. 4. Screening may be more cost-effective when initial assessment is a simple strategy that could be supervised by nonmedical technicians. • Population-based screening studies are required to determine optimal screening strategies and their cost-effectiveness. • Multi-eye disease screening needs to be evaluated as to whether it would be more cost-effective than glaucoma-only screening. Angle-closure glaucoma 1. Are angle-closure and angle-closure glaucoma important health problems?  YES • Primary angle-closure glaucoma (PACG) accounts for approximately 25% of all glaucomatous optic neuropathy worldwide, but 50% of bilateral glaucoma blindness. • Visual impairment from Primary Angle Closure (PAC) and PACG can result from ocular damage other than glaucomatous optic nerve damage (e.g., corneal decompensation, cataract, and ischemic optic neuropathy). • Some Asian populations have a high prevalence of advanced angle closure glaucoma. • PACG is predominantly asymptomatic. • PACG is a problem of sufficient magnitude that public health intervention should be evaluated. 2. Is there an accepted and effective treatment?  YES • Angle closure is a progressive condition that can lead to glaucoma. • Iridectomy/iridotomy is the preferred initial treatment for cases of PAC and PACG. (continued)

1  Glaucoma in the Twenty-First Century

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Table 1.2  (continued)

3.

4.

5.

6.

• There is no evidence to support medical treatment alone for ACG in the absence of iridectomy/iridotomy. • Medical treatment may be indicated for lowering IOP after iridectomy/iridotomy, following risk assessment. • Iridectomy/iridotomy will not always alleviate irido-trabecular apposition since mechanisms other than pupillary block may be present, such as plateau iris or phacomorphic angle closure. • There is good evidence that preventive iridectomy/iridotomy will eliminate the risk of acute angle closure when performed on the fellow eye of patients who have experienced unilateral acute angle closure. • There is insufficient evidence for deciding which PACG patients should undergo lens extraction alone (without trabeculectomy). • Although commonly performed, there is limited evidence about the effectiveness of combined cataract extraction and trabeculectomy in eyes with PACG. Are facilities for diagnosis and treatment available?  YES • There is a need for a systematic assessment of the clinical capacity to identify and treat angle closure. • Gonioscopy is essential for diagnosis and treatment. Is there an appropriate screening test?  POTENTIALLY • There is evidence that limbal anterior chamber depth (LCD) may be an appropriate screening test for angle closure. • Clinic-based case-detection should target established primary angle closure (PAC) and primary angle closure glaucoma (PACG) as blindness can still be prevented when interventions are implemented at these stages. • Gonioscopy is the current gold standard for angle examination and is the appropriate test for diagnosing angle closure. • For accuracy of clinic-based case detection of PAC and PACG to improve, there needs to be a significant increase in the level and use of gonioscopy and disc examination training for ophthalmologists. Is the natural history adequately understood?  YES • An episode of symptomatic (“acute”) angle closure places the unaffected fellow eye at high risk of a similar fate. • The current best estimate for progression from PACS to PAC, or from PAC to PACG is approximately 20–30% over 5 years. • Asymptomatic angle closure is associated with later presentation and more advanced loss of vision than symptomatic angle closure, where facilities for treatment are readily available. Is the cost of case finding economically balanced?  POTENTIALLY • In assessing the cost-effectiveness of a screening program for PAC and PACG, we must consider fully the costs and benefits of the program. • Evaluation must consider the perspective of the decision maker, the incremental cost of the proposed program versus current programs and how we measure effectiveness. • A thorough cost-effectiveness analysis is not possible at present.

We explain this by saying, “Now that I have assessed you for your problem, I want to do a full eye examination for you, so you can be confident there is nothing else wrong with your eyes.” This is an important public health message to reinforce to all our colleagues. As the Asia Pacific Glaucoma Guidelines stress: Use IOP levels, dilated optic disc examination, angle estimation by gonioscopy (and visual field testing as needed) on all adults over 35 years old presenting to eye specialists for any reason, to detect glaucoma (see Table 1.3.).34

1.2.3  C  ommunity Education and Awareness: Patient Support Groups General community awareness of glaucoma, and increased understanding of their disease and the goals of treatment amongst our glaucoma patients, desperately needs improvement around the world. This is a challenge for all eye health practitioners. Although glaucoma patients have more knowledge of

glaucoma than the general public, they also have significant misconceptions about glaucoma.35 One in three new glaucoma patients, one in four established glaucoma patients, and almost one in two of the general public have been reported to believe that most patients with glaucoma go blind from it. Not surprisingly, diagnosis of glaucoma drops quality of life immediately, even in asymptomatic patients.36 We must allay our patients’ fears, balancing this with knowledge to encourage adherence to therapy. As glaucoma patients obtain their knowledge primarily from their treating physician, we must inform and educate them appropriately. As this information and support may need to be given repeatedly over a prolonged period, lack of professional time can be a major challenge. Patient support organizations are vital. Community groups at national levels are foundation stones for the world glaucoma patient community. Lay glaucoma organizations, such as Glaucoma Australia, are our interface with the wider community. They celebrated their 20th birthday in 2008 (see Fig. 1.2a, b). Glaucoma Australia’s mission is to minimize visual disability from glaucoma. It accomplishes this by increasing community awareness

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Table 1.3  Case detection guidelines Test Tonometry

Ideal Applanation tonometry

Dilated evaluation of the optic disc Slit lamp biomicroscope and van herick

Dilated stereoscopic slit lamp biomicroscopy or fundus photography NA

Gonioscopy

Indentation gonioscopy using a Sussman, Zeiss or Posner lens

Acceptable Tonopen, ocular response analyser, rebound tonometers Direct ophthalmoscope NA

Goldmann or Magna View lens using “manipulation”

Less than ideal Pneumotonometer, Shiotz tonometer, Phosphene tonometers Optic disc or RNFL computerized analysis alone NA

Comments

New technologies complement and do not replace clinical assessment If flashlight (FL) or van Herick (VH) test is positive, confirmation with gonioscopy is necessary. FL and VH do not diagnose or exclude angle closure. If FL is negative (1/4 of peripheral cornea), occludable angle is unlikely. If VH is positive AND IOP is elevated, >99% likelihood of PAC Mandatory in all glaucoma suspects Should have both types of lenses available To increase accuracy, gonioscopy is a “dark” art – dim room illumination, thin, short slit lamp beam, avoid light in pupil A trained technician must perform Goldmann, Henson’s and Bjerrum’s screen

A full threshold test using Frequency Doubling Visual field (FDP), Henson’s a standard automated examination if perimetry or achromatic perimetry IOP>21 or disc Bjerrum’s screen is suspicious Modified from Asia Pacific Glaucoma Guidelines by SEAGIG (South East Asian Glaucoma Interest Group), 200334

Fig. 1.2  Glaucoma Australia – Australia’s patient support organization. (a) Glaucoma Australia’s 20th anniversary and (b) “be eye wise” logo. Courtesy of Glaucoma Australia Inc

and understanding of glaucoma and the need for regular eye checks (strategies include an annual National Glaucoma Week, regular articles in the popular press and magazines, and radio interviews with TV stories); by supporting glaucoma patients and their families, especially with information and dialogue; and by funding glaucoma research. It conducts information meetings for the public, supports a Web site, and produces glaucoma education pamphlets. Globally, the World Glaucoma Association (WGA) links glaucoma professional associations. The WGA has helped to

bring into being the World Glaucoma Patient Association (WGPA) to improve the lives of glaucoma patients by encouraging the establishment of and cooperation among glaucoma patient organizations worldwide. It was launched in October 2004. The first World Glaucoma Day, a worldwide joint initiative of the World Glaucoma Association and the World Glaucoma Patient Association, took place on March 6, 2008. The day aimed to increase worldwide awareness of glaucoma so that more individuals would have their eyes checked,

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1  Glaucoma in the Twenty-First Century

permitting earlier diagnosis and thus a chance for more effective therapy. Other initiatives such as the JULeye initiative in Australia strive to bring corporate and private sponsors, the public, eye professionals, and eye researchers together for a designated month to raise money for research, and to increase public awareness of eye diseases so that more are diagnosed (http://www.juleye.com.au/). Advocacy should also be encouraged at the government level. The first American Glaucoma Society Advocacy Day in March 2008 demonstrated how the profession could increase government awareness and, therefore, involvement in glaucoma care and blindness prevention. Ophthalmologists should be involved in these activities. When and if patients do lose significant vision from glaucoma, we as physicians should guide them to low vision and rehabilitation support groups such as Vision Australia. As a profession, our record in offering this guidance is poor.

1.2.4  P  atient Involvement to Spread Information to Their Families and Friends Family history is an important risk factor for glaucoma. One effective way of finding new cases of glaucoma is to discuss family history with our patients. While many patients are ignorant of a positive family history, by encouraging extended family dialogue, new information may emerge, as well as urging other family members to be tested regularly. Also, when relatives accompany your glaucoma patient, ask them if they have had a comprehensive eye examination and encourage them to do so. “Don’t lose sight of your family!” is an important message to all our glaucoma patients. Self-reported recall of family history is known to be inaccurate. Even with this inaccuracy, family history of glaucoma is associated with a threefold excess age-adjusted risk of OAG (RR 3.14, 95% CI 2.32–4.25).30 The Glaucoma Inheritance Study in Tasmania (GIST), Australia, has looked carefully at self-reporting of family history and compared this with true family history. About a third of people were unaware of their positive family history of glaucoma.37 Patients were more aware of their parents’ ophthalmic history than their siblings’. Cross-sectional studies report a positive family history of 10–50%. This emphasizes the need for us to engage in discussion of family history with our patients and the need to do this repeatedly. This starts the conversation with parents, children, siblings, and extended family to help detect other cases of glaucoma. To ask, ask, and ask again is the message for acquiring family history. In the GIST study, about 60% of glaucoma was familial.38

1.2.5  Genetic Testing Genetic testing may be appropriate. Some familial glaucoma is more aggressive and requires early surgery. Knowing what mutation affects a patient may help this decision. There are other implications to genetic testing; genetic counseling must be available. Tests may not yet be specific enough to be much more than a research tool. While a good screening test needs to be highly specific (to avoid many false-positives that would overwhelm available resources), a good diagnostic test needs to be extremely sensitive (to avoid missing established cases). Some of the genes available for testing are: • • • •

Myocilin (MYOC) Optineurin (OPTN) Cytochrome P450 1B1 (CYP1B1) LOXL1 for pseudoexfoliation syndrome39

While the discovery of genes associated with different glaucomas opens a new and exciting era, one must remain cautious. It is the predictive value that indicates the true worth of a test, and predictive value depends on the prevalence of the disease. Used indiscriminately, a test might yield many more false than true positives: with no way to disprove the imminence of disease apart from passage of time, this could reduce the quality of life and do more harm than good. Progress in genetic research, such as the recent association of LOXL1 mutations with pseudoexfoliation syndrome, will unravel the underlying cellular mechanisms of glaucoma.39 In known family pedigrees of aggressive glaucoma such as familial juvenile-onset open angle glaucoma, characterized by high IOP and a rapidly progressive clinical course, testing for a known mutation in the myocilin gene is beneficial; it facilitates the decision to early surgery. Using gene testing in known pedigrees increases the likelihood that a positive test is a true positive and therefore is more meaningful. Jamie Craig’s Australian and New Zealand Registry of Advanced Glaucoma has started to collect information on patients with advanced glaucoma (at least one blind eye from glaucoma). Current known genes will be sought and perhaps new genes for blinding glaucoma will be found.1

1.3  W  e Have to Find Ways of Better and More Accurate Methods of 24-h IOP Measurement IOP is the only truly modifiable risk factor in glaucoma. A precise measure of an individual’s range of IOP would guide management. This is particularly so in patients whose

Personal communication

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glaucoma continues to worsen when “control” has been achieved on the basis of “office hours” IOP measurements. Fluctuations in IOP remain an unknown risk factor for glaucoma onset and progression. What fluctuations are important? Inter-visit fluctuations over months? Short-term fluctuations over hours and days? Very short-term fluctuations in seconds or fractions of a second? Diurnal fluctuations in IOP may be a glaucoma progression risk, independent of average IOP.40 What parameters of IOP are important? Peak IOP? The area under the IOP curve? Mean IOP? Is ocular perfusion pressure (blood pressure – IOP) more important? If so, what aspects of perfusion pressure?

1.3.1  Phasing of IOP To try to obtain more information about a patient’s IOP levels, sometimes it is measured several times during the day; this is inconvenient for all. Although this diurnal curve is useful, it is only part of the information. “In office” tests may not detect peak IOP, and early morning and supine IOP levels are missing. Another way to estimate this range is to see a patient at different times of the day on successive office visits. This is easier and more practical. Admitting a patient to hospital to measure IOP through day and night yields a fuller picture, but is impractical and costly. Home tonometry is difficult to teach. Even though the Proview phosphene tonometer (Bausch & Lomb, Rochester, New York) allows for self-testing without local anesthesia, using an entopic phenomenon of the pressure-induced phosphene to measure IOP, it has poor correlation with Goldmann applanation tonometry (GAT), which does not improve with experience.41,42 The Rebound tonometer (ICare, Tiolat Oy, Helsinki, Finland) might have the potential: It is easy to use, requires no anesthetic, can be performed by relatively inexperienced tonometrists43, and correlates reasonably with GAT.43

1.3.2  The Water-Drinking Test Recently, interest has returned to the water-drinking test (WDT).44–46 Originally used as a tool to detect glaucoma,47,48 the WDT might estimate the diurnal IOP curve.44 Relatively easy to do and requiring no additional equipment, either a set volume of water (e.g., 1 L) or a bodyweight-related volume of water (e.g., 10 mL water per kg weight)46 is imbibed in a few minutes. IOP is measured every 15 min for 1 h or until IOP has returned to baseline. Peak WDT IOP and peak diurnal IOP correlate, as do the fluctuations in IOP diurnally and following the WDT.

R. Lim and I. Goldberg

IOP fluctuations were significantly less in glaucoma patients controlled following surgery when compared with those on medical treatment.45 If ongoing research shows WDT validity, reliability, and reproducibility to estimate the diurnal curve, this test could become an important clinical tool.

1.3.3  IOP Telemetry Several forms of IOP telemetry are in various stages of development. A contact lens telemetry system has been used successfully in a small group of people.49 Implantable IOP telemetry systems are in the stage of animal testing in rabbits and nonhuman primates. Sensors have been implanted on tube-shunts and intraocular lenses.50,51 Ultimately, biocompatibility and sustained reliability will determine their long-term use.

1.4  W  e Have to Find Ways to Measure Progression So We Can Determine Who is at Risk in Their Lifetime to Lose Vision-Related QOL For each patient, we need to determine as best we can who may lose quality of life from glaucoma. This entails three variables: the individual life expectancy, the extent of visual damage already, and the measured rate of visual decline. The glaucoma continuum (see Fig.  1.3) facilitates our concepts of the glaucomas as they progress from undetectable through asymptomatic to manifest glaucoma. There are a few provisos: • Sometimes patients can have asymptomatic disease at a later stage of damage, while others can be symptomatic very early on due to bilateral disease with overlapping damaged areas • Many people do not progress through the whole continuum • The speed of decline is very individual • Individual life expectancy is important • Most patients are in the left part of the continuum rather than in the right • Some people develop functional changes before structural. In the EMGT, changes were almost entirely functional25 whilst in OHTS, 50% of the incident glaucoma was on the basis of structural changes only.53 Their significant variability partly depends on the methods of assessment of structure and function.

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1  Glaucoma in the Twenty-First Century

Fig. 1.3  The glaucoma continuum. Reprinted from ref. 52 , with permission from Elsevier

1.4.1  Structural Tests

1.4.2  Functional Tests

Clinical examination detects structural progression. Objective testing with computerized nerve fiber layer and optic disc analyzers are supplementary to our clinical examination and does not replace it. Up-skilling eye care colleagues to recognize an abnormal optic disc and retinal nerve fiber layer and to detect changes clinically are vital. Repeated optic disc and RNFL stereophotography facilitates structural assessment and detection of progressive damage. Major technological advances have occurred in the computerized objective assessment and follow-up of disc and RNFL structure. The Heidelberg Retina Tomograph (HRT, Heidelberg Engineering GmbH, Heidelberg, Germany), GDX (Laser Diagnostic Technologies, San Diego, California, USA) and Optical Coherence Tomograph (OCT, Stratus and Cirrus OCT; Carl Zeiss Meditec, Dublin, California, USA) have all improved. Each technology has its strengths and weaknesses; ultimately, none is as good at detecting glaucoma as are a group of experts. However, each has a valuable place in glaucoma management. As they measure different aspects of structure, they are likely to be complementary to one another, rather than “one technology fits all.” Any objective information that is reliable, reproducible, and is quantitative is useful and adds to management. Every technology comes at a cost; even digital stereophotography is not affordable to all. It remains more important to document an optic disc clinically with a detailed, careful drawing than it is to own multiple expensive technologies.

Visual field analysis is not precise to detect progressive glaucoma damage. Because of individual variability, several tests are needed to be sure of real change. For example, to detect a true difference of 4  dB in mean deviation over 2 years, three visual field tests are needed per year.54 Most clinicians assess perimetric progression by simply “eye-balling” rather than applying scientific rigor. As more information is available than can be easily processed by “clinical judgment,” any formalization is a bonus. Clinicians managing glaucoma need to be familiar with methods to detect visual field progression. There are four main ways to do so: clinical judgment, defect classifications systems, and event or trend analyses (see Table 1.4.). The perimetric progression analyses have to be accessible and user-friendly to all ophthalmologists. The Guided Progression Analysis and the Visual Field Index are being bundled with Humphrey software and may facilitate this. The other visual field analyzer in regular use is the Octopus system. Some, but not all of the above, can be used with the Octopus analyzer.

1.4.3  E  ffects of Visual Loss on Societal Functionality (e.g., Driving) and Independence As most patients highly value their ability to drive, fear of losing independence by losing their driver’s license markedly reduces quality of life. The link between visual field

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Table 1.4  Visual field progression analysis55 Type of field progression analysis

Types

Description

Advantages

Disadvantages

Clinical observation

• All the parameters of a series of visual fields are studied by the observer and compared

• Easy to do • No extra cost • Can be used with all perimeters

• • • •

Overview printout

• Several fields are on the same printout page for comparison

Defect classification systems

1. Auhorn and Karmeyer56 2. Hodapp-ParrishAnderson (Bascom Palmer Grading System57 3. Glaucoma Staging System & GSS 258 4. Brusini’s GSS & GSS 259 5. AGIS Score60 6. CIGTS Score60

Trend analysis

• Mean deviation (defect) index (MDI)-change analysis (Humphrey), Peritrend (Interzaag) • Glaucoma progression index (GPI)61/Visual field index

1. Five descriptive stages for the kinetic perimeter 2. Three glaucoma stages: early, moderate, severe, based on MD, number of points affected and proximity to fixation 3. Six stage system based on MD, proximity to fixation and number of points affected 4. Six to seven stage system based on MD and PSD, can be used on Humphrey and Octopus visual fields; is provided on the printout of the Oculus visual field 5. Score 1–20, uses the total deviation plot of 24-2, threshold values 6. Score 1–20, uses the total deviation plot of 24-2, probability values • First index to be used for progression • Linear regression on mean deviation

• Easy to do • No extra cost • Faster than looking at individual fields • Better defined • Validated techniques • Good reproducibility • Correlates well to disease

Clinical judgment

• Part of GPA printout • Pattern deviation probability maps are used • Central weighting

• Peridata62

• Progression analysis with box plot curve • Trend Analysis with significance for every point

• Progressor

• Linear regression analysis of pointwise threshold data

Non-scientific Poor reliability Poor reproducibility Large inter-observer variation • Observer-dependant • Non-scientific

• Stages are not necessarily linear to disease • 2–6 do not provide spatial information about the defect • 5,6 score calculations are time consuming and not suitable for normal clinical practice • Not sensitive to small increments of progression

• Humphrey and octopus • Age-matched normative data

• Affected by cataract

• Reported as a % of age-corrected normal • More resistant to cataract formation • Automated and included in Statpac • Can be used with any perimeter • Also simulates binocular fields • Based on a statistical approach

• May underestimate generalized reduction in sensitivities from glaucoma

• Uses all of the threshold information • Represents the data at the point • Also simulates binocular fields • Based on a statistical approach

• Additional software • Data needs transferring to another computer • Additional cost & time • Additional software • Data needs transferring to another computer • Additional cost & time • Watch statistical significance versus clinical significance (continued)

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1  Glaucoma in the Twenty-First Century Table 1.4  (continued) Type of field progression analysis Event analysis

Types

Description

Advantages

Disadvantages

• Delta program • CNTGS

• Uses paired t test • Defined as reduction in threshold by 10 dB or three time short-term fluctuation • Uses two baseline tests and compares the current total deviation at a point to baseline • Flagged if outside the test-retest variation of a stable glaucoma patient (5–95%)

• Relatively simple • Relatively simple

• Octopus only • Relatively simple

• Gives spatial and progression information • Only three tests are needed to get a GCP result but this is not specific enough

• Similar to GCP but uses pattern deviation probability plots • Tested in EMGT

• More resistant to cataract • Flags “Possible Progression” and “Likely Progression”

• Needs reliable baseline • It does not use all of the data available from previous tests • Two confirming fields are required • Needs reliable baseline, baseline can be reset • It does not use all of the data available from previous tests • May miss some fields progressive general loss i.e., underestimate progression63

• Glaucoma change probability (GCP, Statpac 2)

• Guided progression analysis (GPA)

loss and driving capability is weak. Most countries have visual standards to be able to drive. In Australia, an unrestricted, noncommercial license holder must have a horizontal visual field of 120°, 10° above and below the horizontal axis. The Esterman visual field test (EVFT) has been the main way to estimate the visual field and suitability to drive. It has disadvantages: it involves further testing, and the central 7° of the visual field is not tested. Owen et al have looked at binocular integrated visual field (IVF) to predict which patients will lose visual function to a level below the legal standard for driving.64 With IVF produced by simulating monocular Humphrey visual fields with the Progressor program,65 they have described a method that simulates better than does the EVFT what patients see binocularly, using available threshold information. This can identify, even from initial diagnosis, which of our patients are at most risk to lose their driver’s license. With this information, we may be able to determine which patients need more aggressive treatment to prevent such an outcome. The Peridata program also merges uniocular visual fields to yield binocular field information.62 The benefit of a program such as the Progressor is that all the threshold information that is recorded in normal followup testing can be merged to get the binocular data. No additional testing is required, as binocular information can be accessed with uniocular tests. This saves time and encourages routine access of binocular fields information; patients at risk may be found earlier, allowing more aggressive treatment. Figure 1.4 shows an example of a case of a visual field that is “passed fit for driving” on the EVFT that failed on the Progressor IVF analysis.

Another method of assessing the vision used for driving is the UFOV® (Useful field of view).65 This is the amount of binocular visual field that is seen with both eyes open without moving the eyes or head. The UFOV has been shown to correlate with a history of car accidents in the previous 5 years, and a poor reading of four or five was shown in a prospective study to double the relative risk of involvement in a car accident in the following 3 years. The UFOV is influenced by other factors such as cognitive function and training can improve it.

1.4.4  A  xon “Screamometer”: Future Studies of Retinal Ganglion Cell and Optic Nerve Function Paul Palmberg coined the term “axon screamometer” to describe a theoretical clinical device that would allow the detection of a single axon dying, or under glaucomatous attack. Working with ocular hypertensive and early glaucoma patients, Ventura and Porciatti have used the pattern electroretinogram (PERG) response to stress retinal ganglion cells, thereby identifying those under reversible attack.66,67 Francesca Codeiro has developed a noninvasive real-time imaging technique using confocal laser-scanning ophthalmoscopy to visualize single nerve cell apoptosis in vivo.68 If an “axon screamometer” were shown to be accurate, decisions to initiate or to accelerate treatment would become far more scientific.

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1.5  W  e Need to Find Effective Ways of Treating Glaucoma that Are More Tolerable to Our Patients What is on the horizon for treatment for our patients?

1.5.1  M  edications with Minimal Side Effects with Which Adherence, Dyscompliance, and Perseverance Are Not Issues Over the past decade, new classes of IOP-lowering medications have reduced the frequency of instillation and increased potency. With more types of eye drops and fixed combinations, adherence to and perseverance with a medication regimen have become greater issues. With eye drops, physical barriers to instillation success remain a challenge. While newer drug classes with high potency and low side effect potential will be welcomed, improved drug delivery systems might enhance the therapeutic index. For example, punctual plug delivery system technology69 and anterior juxtascleral depot (AJD) injections70 could well enhance the treatment. Medications to arrest the disease by strategies other than IOP reduction would open new paradigms for treatment.

1.5.2  E  ffective Lasers with Minimal Side Effects Newer lasers that appear to cause little or no structural damage to trabecular connective tissue (e.g., selective laser trabeculoplasty [SLT]) seem to be effective and repeatable. SLT is being used increasingly in earlier treatment. Even though the Glaucoma Laser Trial showed the effectiveness of Argon laser trabeculoplasty, its uptake as primary treatment was not high.27 Now that we have an equally effective laser with very few side effects, the treatment paradigm is shifting (see Fig. 1.5).

1.5.3  S  urgical Techniques Without Long-Term Consequences Fig. 1.4  A comparison of the Esterman binocular visual field, individual Humphrey visual fields and the Progressor binocular visual field in a patient. While the patient satisfies the Esterman criteria for driving, the Progressor field indicates a significant defect and failure. Reprinted from ref.65 with permission of BMJ Publishing Group

Glaucoma surgery faces the challenges of overcoming surgical failure (short- and long-term) and complications related to the formation of a bleb, including blebitis and dysesthesia.

1  Glaucoma in the Twenty-First Century

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Fig. 1.5  The classical treatment paradigm versus possible future treatment paradigm. MTMT maximum tolerated medical therapy, SLT selective laser trabeculoplasty

Trabeculectomy techniques are improving to try to produce diffuse, slightly elevated, normal vascularity, normal thickness, and comfortable blebs that last a lifetime and do not create a lifetime risk of blebitis and endophthalmitis. Peng Khaw’s “Moorfields Safer Surgery System” with a fornix-based conjunctival flap, large area mitomycin C application, and adjustable releasable suture has improved safety. Many newer surgical strategies represent variations to make a bleb. This includes the Express shunt procedure and the nonpenetrating glaucoma surgeries (deep sclerectomy, viscocanalostomy, Aqua Flow collagen glaucoma drainage device). The character of the blebs might be lower in profile and more diffuse; further studies are warranted. Novel procedures that do not form a bleb are the Trabectome, I-stent micro bypass, Eye Pass procedure, and the SOL-X shunt. The Eye Pass, SOL-X shunt, and I-stent procedures involve the insertion of a device. The Eye Pass and the I-stent are shunts from the anterior chamber to Schlemm’s canal, while the SOL-X is from the anterior chamber to the suprachoroidal space. The Trabectome and I-stent procedures have no conjunctival or scleral incisions; if they fail, trabeculectomy could be performed on “virginal” conjunctiva. Glaucoma Drainage Devices (GDD) might be useful for earlier stages of glaucoma. Traditionally, they have been

reserved for very damaged eyes when several other procedures have failed; it might be easier to teach and to perform than trabeculectomy, and reduce bleb-related complications. An ongoing study of trabeculectomy versus tubes (TVT study) should yield valuable information.71 In the next few decades, we may see changes in our treatment paradigm (see Fig. 1.5) with lasers being offered earlier, angle procedures being included in the treatment armamentarium, and possibly tube shunt procedures being performed earlier.

1.6  W  e Have to Measure QOL More Reliably and Use it to Help Patients More Appropriately We have clinical endpoints to manage our patients. IOP, optic disc and retinal nerve fiber layer assessment, and visual field parameters have been our main outcomes. In the twenty-first century, we should focus on the patient as a whole, not only in research but also in clinical practice. To do this, we need to use quality of life measures in our day-to-day patient assessment and management.

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1.6.1  I ncrease Familiarity of Profession with QOL Measure (e.g., NEI-VFQ-25, GQL-15)

1.6.2  I ncreased Use & Application to Treatment

There are four types of tools for quality of life measuring tools (see Table 1.5.): general health measurements, visionspecific instruments, glaucoma-specific instruments, and utility assessments. Some of these measures are not specific to glaucoma and some are designed for use in a research study setting. The types of quality-of-life measurement tools that are the most useful, clinically short, self-administered, reliable, and validated. The NEI-VFQ-51 is a 51-question tool, which has been validated, as has a 25-question version: NEI-VFQ-25.

Quality-of-life measures in glaucoma suffer the same predicament as do other clinical outcome measures: There is no true gold standard. We do not know how our glaucoma patients really feel. Therefore, we validate our instruments to a surrogate outcome such as the degree of visual field defect. The GQL-15, for example, correlates well with the degree of visual field loss. The GQL-15 (see Table  1.6.) has all the characteristics of a quality-of-life tool that could be used routinely in clinical practice. A 15-question tool, it could be used at baseline and intermittently during the course of a patient’s disease to gain better understanding of how our patients are faring. There are five “seeing” questions, seven “walking or mobility” questions, and three “adjustment” questions in this validated questionnaire. It correlates well with visual field severity in glaucoma patients.

Table 1.5  Quality of life instruments used in glaucoma patients Instrument

Description

General health instruments SIP Modified to be more specific for glaucoma SF-36 36 items, eight subscales (general health, physical/ social functions, role limitations by physical/ mental disability, mental health, vitality, pain) MOS-20 20 items, six subscales (physical/role/social functioning, mental health, health perceptions, pain) Vision-specific instruments ADVS Developed to assess impact of cataract; 20 activities, subscales include day/night/far/near vision, glare impact, overall vision VF-14 Developed to assess impact of cataract; 14 visionrelated activities from reading various print sizes to driving VAQ Assesses ten areas of vision, including peripheral vision, contrast sensitivity, acuity, impact of glare and low illumination, light/dark adaptation NEI-VFQ 51 items; developed to assess the impact of a broad range of eye problems; similar 25-item instrument (NEI-VFQ-25) developed later IVI 32 items, five domains: leisure/work, consumer/social interaction, household/personal care, mobility, emotional reaction to vision loss Glaucoma-specific instruments GSS Symptom checklist, ten items, two subscales Viswanathan Ten queries related to decreased visual ability et al SIG 43 items, 4 subscales: visual ability (visual function), local eye, systemic, and psychological GHPI Six items, glaucoma impact on physical, emotional, social, and cognitive components of health, stress associated with glaucoma and blindness worries GQL-15 15-most glaucoma-specific queries selected from a starting list of 50 by factor analysis Utility assessments Time trade-off How much lifespan to trade for perfect vision? Thermometer Vision assessment of 0–100, transformed to death/ health scale of 0–100 Choice-based Choices between visual disability outcomes conjoint analysis Based on ref. 72 with permission of Elsevier

1.7  F  ind Safe and Appropriate Way to Share Care with Other Eye Care Professionals: Proper Use of Available Human Resources Screening, case detection, professional and community education, promulgation of information, liaison with our communities, and tackling global blindness and visual disability are some ways we could train and work with other eye care professionals. With more work needed than human power or skills available, a safe sharing of this burden is necessary for success. This interface must be dynamic and under the leadership of ophthalmologists. As populations age, so will the burden of glaucoma increase. Different sharing models include a system in some United Kingdom hospital centers, where medical practitioners not formally ophthalmically trained (associate specialists) and optometrists work side by side under the supervision of an ophthalmologist. This significantly reduces the manpower burden.74 While using nonmedical optometric staff could reduce the burden, it could also increase it if unnecessary return visits results. That this depends on training and on supervision was shown by a formal comparison of the clinical decision skills of assistant optometrists in a glaucoma clinic at Moorfields Eye Hospital, London, with associate specialists.74 There was no difference demonstrated. In a rigorous randomized study assessing patient outcomes, the Bristol shared care glaucoma project compared hospital eye care with that of community optometrists.75 At 2 years, while there was no difference to patient outcomes,

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1  Glaucoma in the Twenty-First Century

1.8  Conclusion

Table 1.6  The glaucoma quality of life – 15 questionnaire The glaucoma quality of life – 15 questionnaire: List of daily activities with the strongest relationship with visual field loss in glaucomaa Patient instruction: Please circle the correct answer on the scale ranging from 1 to 5 where [1] stands for no difficulty, [2] for a little bit of difficulty, [3] for some difficulty, [4] for quite a lot of difficulty, and [5] for severe difficulty. If you do not perform any of the activities for other than visual reasons, please circle [0]. Does your vision give you any difficulty, even with glasses, with the following activities?

None

Do not perform for nonvisual A little Quite a bit Some lot Severe reasons

Reading 1 2 3 4 5 newspapers Walking after 1 2 3 4 5 dark Seeing at night 1 2 3 4 5 1 2 3 4 5 Walking on uneven ground 1 2 3 4 5 Adjusting to bright lights Adjusting to dim 1 2 3 4 5 lights 2 3 4 5 Going from light 1 to dark room or vice versa Tripping over 1 2 3 4 5 objects 1 2 3 4 5 Seeing objects coming from the side Crossing the 1 2 3 4 5 road Walking on 1 2 3 4 5 steps/stairs Bumping into 1 2 3 4 5 objects 2 3 4 5 Judging distance 1 of foot to step/curb Finding dropped 1 2 3 4 5 objects Recognizing 1 2 3 4 5 faces Reprinted from ref. 73 with permission of Lippincott a Based on the results of this study

Glaucoma concepts and management are changing rapidly. In this new millennium, we need to find those with glaucoma as yet unidentified so that they can receive treatment; we need to focus on the therapeutic, emotional, and societal needs of the individual patient; we need to understand IOP levels and fluctuations better; we need to find effective strategies to protect individuals from visual disability beyond lowering IOP; we need to find more specific and more sensitive ways to diagnose glaucoma and to detect its progression; and we need to find safe, responsible ways of working collaboratively with other eye care workers, for the benefits of our patients and our communities.

0 0 0 0

0 0 0

0 0

0 0 0 0

0 0

community was more costly than hospital care. The optometrists involved were keen volunteers with specialized training; this group might not represent results in the general optometric community. The opportunities for collaboration are there. With appropriate training, supervision, and lines of responsibility, our patients and communities could be better served.

References 1. Shaffer RN. The centennial history of glaucoma (1896–1996), American Academy of Ophthalmology. Ophthalmology. 1996;103 (8 Suppl):S40–S50. 2. Shaffer RN. Fifty years in ophthalmology. Surv Ophthalmol. 1990;35(3):236–239. 3. Nathan J. Hippocrates to Duke-Elder: an overview of the history of glaucoma. Clin Exp Optom. 2000;83(3):116–118. 4. Frezzotti R. The glaucoma mystery from ancient times to the 21st century, The glaucoma mystery: ancient concepts. Acta Ophthalmol Scand Suppl 2000;(232):14–18 5. Keeler R. Antique ophthalmic instruments and books: the Royal College Museum. Br J Ophthalmol. 2002;86(7):712–714. 6. Andersen SR. The history of the Ophthalmological Society of Copenhagen 1900–1950. Acta Ophthalmol Scand Suppl. 2002;234:6–17. 7. Dellaporta A. Historical notes on gonioscopy. Surv Ophthalmol. 1975;20(2):137–149. 8. Ritch R, Caronia RM, eds, Classic Papers in Glaucoma, Kugler Publications, The Netherlands, 2000. 9. Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of openangle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology. 1996;103(10):1661–1669. 10. Wensor MD, McCarty CA, Stanislavsky YL, et al. The prevalence of glaucoma in the Melbourne Visual Impairment Project. Ophthalmology. 1998;105(4):733–739. 11. Varma R, Ying-Lai M, Francis BA, et al. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology. 2004;111(8):1439–1448. 12. Sakata K, Sakata LM, Sakata VM, et al. Prevalence of glaucoma in a South brazilian population: Projeto Glaucoma. Invest Ophthalmol Vis Sci. 2007;48(11):4974–4979. 13. Wong EY, Keeffe JE, Rait JL, et al. Detection of undiagnosed glaucoma by eye health professionals. Ophthalmology. 2004;111(8):1508–1514. 14. Wilson JMG, Jungner G. Principles and practice of screening for disease. WHO Chron. 1968;22:473. 15. Wilson MR. The myth of "21". J Glaucoma. 1997;6(2):75–77. 16. Leydhecker W, Akiyama K, Neumann HG. Intraocular pressure in normal human eyes. Klin Monatsblatter Augenheilkd Augenarztl Fortbild. 1958;133(5):662–670. 17. Hollows FC, Graham PA. Intra-ocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol. 1966;50(10):570–586.

20 18. Eddy DM, Sanders LE, Eddy JF. The value of screening for glaucoma with tonometry. Surv Ophthalmol. 1983;28(3):194–205. 19. Eddy DM, Billings J. The quality of medical evidence: implications for quality of care. Health Aff (Millwood). 1988;7(1): 19–32. 20. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000; 130(4):429–440 21. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology. 1992;99(10):1499–1504. 22. Feiner L, Piltz-Seymour JR. Collaborative Initial Glaucoma Treatment Study: a summary of results to date. Curr Opin Ophthalmol. 2003;14(2):106–111. 23. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 1998;126(4):487–497 24. Miglior S, Zeyen T, Pfeiffer N, et  al. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005;112(3): 366–375. 25. Heijl A, Leske MC, Bengtsson B, et  al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268–1279. 26. Five-year follow-up of the Fluorouracil Filtering Surgery Study. The Fluorouracil Filtering Surgery Study Group. Am J Ophthalmol 1996;121(4):349–366 27. The Glaucoma Laser Trial (GLT) and glaucoma laser trial followup study: 7. Results. Glaucoma Laser Trial Research Group. Am J Ophthalmol 1995;120(6):718–731 28. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120(6):714–720; discussion 829–830 29. Friedman DS, Jampel HD, Munoz B, West SK. The prevalence of open-angle glaucoma among blacks and whites 73 years and older: the Salisbury Eye Evaluation Glaucoma Study. Arch Ophthalmol. 2006;124(11):1625–1630. 30. Burr JM, Mowatt G, Hernandez R, et al. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation. Health Technol Assess 2007;11(41):iii–iv, ix–x, 1–190 31. Fleming C, Whitlock E, Biel T, Smit B. Primary care screening for ocular hypertension and primary open-angle glaucoma: Evidence Synthesis. No. 34. Agency for Healthcare Research & Quality, US Preventative Services Task Force; 2005. Available at: http://www.ahrq. gov/clinic/uspstf05/glaucoma/ glaucsyn.pdf. Accessed June 2008 32. Weinreb RN, Healey PR and Topouzis Glaucoma Screening, WGA consensus series 5, Kugler Publications, 2008 The Netherlands 33. Grodum K, Heijl A, Bengtsson B. A comparison of glaucoma patients identified through mass screening and in routine clinical practice. Acta Ophthalmol Scand. 2002;80(6):627–631. 34. South East Asia Glaucoma Interest Group Guidlines, published online at www.seagig.org 35. Danesh-Meyer HV, Deva NC, Slight C, et al. What do people with glaucoma know about their condition? A comparative crosssectional incidence and prevalence survey. Clin Experiment Ophthalmol. 2008;36(1):13–18. 36. Odberg T, Jakobsen JE, Hultgren SJ, Halseide R. The impact of glaucoma on the quality of life of patients in Norway. I. Results from a self-administered questionnaire. Acta Ophthalmol Scand. 2001;79(2):116–120. 37. McNaught AI, Allen JG, Healey DL, et al. Accuracy and implications of a reported family history of glaucoma: experience from the Glaucoma Inheritance Study in Tasmania. Arch Ophthalmol. 2000;118(7):900–904.

R. Lim and I. Goldberg 38. Green CM, Kearns LS, Wu J, et  al. How significant is a family history of glaucoma? Experience from the Glaucoma Inheritance Study in Tasmania. Clin Experiment Ophthalmol. 2007;35(9): 793–799. 39. Marx J. Genetics. High-risk glaucoma gene found in Nordic studies. Science. 2007;317(5839):735. 40. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9(2):134–142. 41. Danesh-Meyer HV, Niederer R, Gaskin BJ, Gamble G. Comparison of the Proview pressure phosphene tonometer performed by the patient and examiner with the Goldmann applanation tonometer. Clin Experiment Ophthalmol. 2004;32(1):29–32. 42. Gunvant P, Lievens CW, Newman JM 3rd, et al. Evaluation of some factors affecting the agreement between the Proview Eye Pressure Monitor and the Goldmann applanation tonometer measurements. Clin Exp Optom. 2007;90(4):290–295. 43. Abraham LM, Epasinghe NC, Selva D, Casson R. Comparison of the ICare rebound tonometer with the Goldmann applanation tonometer by experienced and inexperienced tonometrists. Eye. 2008;22(4):503–506. 44. Susanna R Jr, Vessani RM, Sakata L, et  al. The relation between intraocular pressure peak in the water drinking test and visual field progression in glaucoma. Br J Ophthalmol. 2005;89(10): 1298–1301. 45. Danesh-Meyer HV, Papchenko T, Tan YW, Gamble GD. Medically controlled glaucoma patients show greater increase in intraocular pressure than surgically controlled patients with the water drinking test. Ophthalmology. 2008;115(9):1566–1570. 46. Kumar RS, de Guzman MH, Ong PY, Goldberg I. Does peak intraocular pressure measured by water drinking test reflect peak circadian levels? A pilot study. Clin Experiment Ophthalmol. 2008;36(4):312–315. 47. Schmidt K. Untersuchungen über Kapillarendothelstörungen bei Glaukoma simplex. Arch Augenheilkd 1928(98):569–581 48. Leydhecker W. The water-drinking test. Br J Ophthalmol. 1950; 34(8):457–479. 49. Pitchon E, Leonardi M, Renaud P, et al. First in vivo human measure of the intraocular pressure fluctuation and ocular pulsation by a wireless soft contact lens sensor. Abstracts of the Association for Research in Vision and Ophthalmology 2008 Annual Meeting; April 27–May 1, 2008; Fort Lauderdale, Florida. Abstract 687, 2008. 50. Downs J, Burgoyne CF, Liang Y, Sallee VL. A new implantable system for telemetric IOP monitoring in nonhuman primates (NHP). Program and abstracts of the Association for Research in Vision and Ophthalmology 2008 Annual Meeting. Fort Lauderdale, Florida. Abstract 2043, 2008 51. Aebersold J, Jackson D, Crain M, et al. Development of an implantable, RFID-based intraocular pressure sensing system for glaucoma patients. Program and abstracts of the Association for Research in Vision and Ophthalmology 2008 Annual Meeting. Fort Lauderdale, Florida. Abstract 688, 2008 52. Weinreb RN, Friedman DS, Fechtner RD, et al. Risk assessment in the management of patients with ocular hypertension. Am J Ophthalmol. 2004;138(3):458–467. 53. Kass MA, Heuer DK, Higginbotham EJ, et  al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120(6):701–713; discussion 829–830 54. Chauhan BC, Garway-Heath DF, Goni FJ, et al. Practical recommendations for measuring rates of visual field change in glaucoma. Br J Ophthalmol. 2008;92(4):569–573. 55. Spry PG, Johnson CA. Identification of progressive glaucomatous visual field loss. Surv Ophthalmol. 2002;47(2):158–173.

1  Glaucoma in the Twenty-First Century 56. Aulhorn E, Karmeyer H. Frequency distribution in early glaucomatous visual field defects. Doc Ophthalmol Proc Ser. 1977;14:75–83. 57. Hodapp E, Parrish RI, Anderson D. Clinical decisions in glaucoma, 52–61 ed. St. Louis, MO: CV Mosby; 1993. 58. Mills RP, Budenz DL, Lee PP, et al. Categorizing the stage of glaucoma from pre-diagnosis to end-stage disease. Am J Ophthalmol. 2006;141(1):24–30. 59. Brusini P, Filacorda S. Enhanced glaucoma staging system (GSS 2) for classifying functional damage in glaucoma. J Glaucoma. 2006;15(1):40–46. 60. Katz J. Scoring systems for measuring progression of visual field loss in clinical trials of glaucoma treatment. Ophthalmology. 1999;106(2):391–395. 61. Bengtsson B, Heijl A. A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol. 2008;145(2): 343–353. 62. Peridata. Available at: http://www.peridata.org. Accessed September 4, 2008 63. Artes PH, Nicolela MT, LeBlanc RP, Chauhan BC. Visual field progression in glaucoma: total versus pattern deviation analyses. Invest Ophthalmol Vis Sci. 2005;46(12):4600–4606. 64. Owen VM, Crabb DP, White ET, et  al. Glaucoma and fitness to drive: using binocular visual fields to predict a milestone to blindness. Invest Ophthalmol Vis Sci. 2008;49(6):2449–2455. 65. Crabb DP, Fitzke FW, Hitchings RA, Viswanathan AC. A practical approach to measuring the visual field component of fitness to drive. Br J Ophthalmol. 2004;88(9):1191–1196.

21 66. Ventura LM, Sorokac N. De Los Santos R, et al. The relationship between retinal ganglion cell function and retinal nerve fiber thickness in early glaucoma. Invest Ophthalmol Vis Sci. 2006; 47(9):3904–3911. 67. Ventura LM, Porciatti V. Restoration of retinal ganglion cell function in early glaucoma after intraocular pressure reduction: a pilot study. Ophthalmology. 2005;112(1):20–27. 68. Cordeiro MF, Guo L, Luong V, et al. Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc Natl Acad Sci USA. 2004;101(36):13352–13356. 69. http://clinicaltrials.gov/ct2/show?term=xalatan&rank=35 2008. 70. http://clinicaltrials.gov/ct2/show/NCT00451152?term=anecortave &rank=18;2008 71. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J Ophthalmol. 2007;143(1):9–22. 72. Spaeth G, Walt J, Keener J. Evaluation of quality of life for patients with glaucoma. Am J Ophthalmol. 2006;141(1 Suppl): S3–S14. 73. Nelson P, Aspinall P, Papasouliotis O, et  al. Quality of life in glaucoma and its relationship with visual function. J Glaucoma. 2003;12(2):139–150. 74. Banes MJ, Culham LE, Bunce C, et al. Agreement between optometrists and ophthalmologists on clinical management decisions for patients with glaucoma. Br J Ophthalmol. 2006;90(5):579–585. 75. Gray SF, Spry PG, Brookes ST, et al. The Bristol shared care glaucoma study: outcome at follow up at 2 years. Br J Ophthalmol. 2000;84(5):456–463.

Chapter 2

An Evidence-Based Approach to Glaucoma Care Louis R. Pasquale

Put several glaucoma specialists in a room and solicit opinions on just about any clinical issue and you are bound to receive multiple opinions on how to manage the problem. For example, a patient presents with shallow angles on van Herrick screening. What gonioscopic features would prompt you to perform a laser iridotomy? Would you perform a dark room provocative test to confirm your impression that the angle was potentially occludable? Do you perform a pharmacological challenge test before proceeding to prophylactic laser iridotomy? Would you order an ultrasound biomicroscopic test to confirm your impression? If you do decide that prophylactic laser iridotomy is indicated, what is the best surgical technique for achieving patency? Is there evidence to support a “best approach” to the patient with the narrow angle? In this chapter, we discuss how evidence-based medicine (EBM) can be used to provide the very best answers to questions such as these. This approach can be applied not only to glaucoma problems, but also to any clinical problem in medicine.

2.1  A  n Introduction to Evidence-Based Medicine The era of evidence-based medicine is upon us. The Cochrane Collaboration (a large collection of volunteers who use a systematic approach to evaluate the efficacy and safety of medical interventions)1 has outmuscled the senior, distinguished, and experienced collection of dinner speakers (the so-called members of “eminence-based medicine”)2 whisked in from afar by pharmaceutical companies to tell us what is best for our patients. Today, even when “thought leaders” (a buzzword that finds its origin in the business world used to denote someone held in high regard because of his or her trendsetting ideas or the appearance of his or her names on mail-in surveys) are recruited to speak about a medical product by industry, continuing medical education guidelines dictate that they must provide a balanced and evidence-based presentation.

Yet there is considerable confusion regarding EBM. An article in Time magazine stated that EBM was “a hard, cold empirical look at what works, what doesn’t and how to distinguish between the two.”3 This statement about EBM suggests that all patient problems have straightforward solutions and EBM helps find those solutions fairly readily. Clearly, we commonly encounter glaucoma problems that are not straightforward at all. For instance, should we commit a European-derived Caucasian male patient with thin corneas, intraocular pressure (IOP) in the high-teens, glaucoma-like discs, and unreliable visual field findings to medical therapy for glaucoma? The Ocular Hypertension Treatment Study (OHTS), a randomized control trial (RCT) comparing IOPlowering therapy versus observation in the prevention of primary open-angle glaucoma (POAG) in patients with ocular hypertension (OHTN), found thinner central corneal thickness (CCT) to be a risk factor for conversion to POAG among patients with OHTN4; but while our patient has thin CCT, his IOP is normal. The Barbados Eye Study5 found that thinner CCT was an independent risk factor for POAG in a population of African descent, where subjects had a spectrum of IOP ranging from normal to high; however, this patient is Caucasian, which raises the question of whether the data are specifically applicable to his situation. Furthermore, there are absolutely no data to suggest that such treatment would be cost-effective at this time. Finally, there are patient-specific issues that may make the answer to this question even more difficult to arrive at. For example, if the patient is 80 years old and has a pill-rolling tremor secondary to Parkinson’s disease and is already taking eight other oral agents for other systemic illnesses, then the physician may opt to observe the patient. On the other hand, if the patient is 53 years old, expresses anxiety about glaucoma blindness, and has a strong family history for the disease, then the physician may be inclined to initiate treatment. Dr. David Sackett, often regarded as the father of EBM, defines EBM as “the conscientious, explicit and judicious use of current best evidence in making decisions about the

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_2, © Springer Science+Business Media, LLC 2010

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care of individual patients.”6 EBM is a process and there is nothing cold and calculating about it. The process starts with a patient in your exam lane. Typically that patient has a clinical problem that cannot be answered by consulting an ophthalmology textbook or a single paper in the literature, unless that paper happens to be an EBM review on the topic. For example, a 45-year-old African-American female with a positive family history of glaucoma blindness presents with intraocular pressure (IOP) of 24 mmHg OU, central corneal thicknesses of 545 mm OU, and CDR = 0.4, OU. A standard automated perimetry test is performed and is reliable and normal in both eyes. Do we treat this patient? If we do treat her, what would be the best initial approach? First, we assemble what is called the “evidence cart.” Admittedly, the cart may not be loaded with items (as it might be if we were dealing with breast cancer or myocardial infarction), but the items that are there may be quite appropriate for that patient sitting in your exam lane. Then, we need to examine the quality of the evidence in that cart. Finally, we apply that evidence to our patient as best as we can, given the medical and nonmedical circumstances related to her case. Later in this chapter, we will demonstrate the EBM process in detail.

patient comfortable, and theoretically it should enhance resurfacing of the cornea epithelial defect – it had to be the correct approach! That night, the glaucoma specialist did a literature search on the management of cornea abrasions, and to his amazement he found a meta-analysis published in 1998 synthesizing the results of five randomized clinical trials comparing the patch versus no patch approach to managing traumatic corneal abrasions. The meta-analysis concluded that there was no advantage to patching as long as the patient was treated with a topical antibiotic, topical cycloplegia, and topical nonsteroidal anti-inflammatory agent.7 In fact, two randomized clinical trials (RCTs) published after this systematic literature review reached similar conclusions.8,9 Of course, it did not mean patching corneal abrasions was akin to malpractice; but it did indicate that this glaucoma specialist who completed his ophthalmology residency in 1990 and was not treating corneal abrasions on a regular basis anymore did not stay up-to-date in the management of traumatic corneal abrasion. He was not aware that one could manage corneal abrasions without resorting to patching the eye prior to delivering a lecture of the subject in year 2000. Oh by the way, I was that glaucoma specialist and that was the “ah-hah” moment that sparked my interest in EBM.

2.2  E  vidence-Based Medicine: An Interesting Story

2.2.1  T  he Evolution of Evidence-Based Medicine

In the year 2000, a glaucoma specialist was asked to give a talk on basic eye emergencies directed to primary care physicians. For a glaucoma specialist with a tertiary level glaucoma referral practice, delivering a talk on this subject seemed like a relatively easy task. During the talk, the glaucoma specialist pointed out that the best way to manage a traumatic corneal abrasion was to instill an antibiotic ointment and Cyclogyl 1% drops topically, pressure patch the eye, and follow-up with the patient the next day. A very clear rationale for this approach was provided: The antibiotic provided coverage against microbial invasion of the corneal stroma during the time when there was a breach in the overlying epithelial barrier; the cycloplegic agent reduced uveal spasm induced by the highly innervated cornea; and the pressure patch immobilized the lid to allow corneal limbal stem cells to resurface the epithelial break and settle onto the underlying Bowman’s membrane. How could that possibly be the wrong way to manage garden-variety corneal abrasions? At the end of the lecture, one of the course attendees politely approached the glaucoma specialist and stated that he might not be practicing EBM and that most abrasions could be treated without patching. This sounded like heresy to the glaucoma specialist. After all, the patch made the

While the origin of EBM can be traced back to medieval times,10 the trends in medical care that resulted in the current embrace of EBM can be traced back to the American Revolution, starting with a physician-signer of the Declaration of Independence, Dr. Benjamin Rush. Dr. Rush’s approach to disease was to zealously attack and conquer it. After all, it was this philosophy that allowed the colonists to ultimately prevail over a seemingly formidable British adversary. Unfortunately, there were no real tools to address most of the medical problems encountered; and the attacks fervently employed by Dr. Rush (limited exsanguinations, the induction of emesis, blistering, etc.) typically took a “one-sizefits-all” approach, without evidence that they actually helped patients.11 Ultimately Dr. Rush’s ardent medical philosophy was supplanted by the realization that most medical therapies of the time were largely ineffective. The highly influential Sir William Osler popularized this latter philosophy. His approach to disease can be summed up in one of his more famous aphorisms: One of the first duties of the physician is to educate the masses not to take medicines.12 Sir Osler, regarded as the father of modern medicine, stated that the role of the physician was to provide accurate diagnoses, prognoses, and palliative care for most conditions. Beginning

2  An Evidence-Based Approach to Glaucoma Care

Fig. 2.1  The medical profession’s approach to treatment interventions over time

in the early 1940s, the field of medicine witnessed the antibiotic revolution, the introduction of chemotherapy agents, and the discovery of prednisone. These agents looked like miraculous substances compared to what treatments were available to address medical conditions in the early 1900s (see Morrris13 for a historical account of the impact of antibiotic therapy in the 1940s). Nonetheless, initial enthusiasm for these new tools led to their indiscriminate and often ill-advised use that did not necessarily translate into clinical benefit for our patients. In the mid 1990s, Dr. David Sackett introduced the idea that we should evaluate the literature with an eye toward finding the best evidence to guide clinical decision-making. The relation between the degrees of intervention for medical illness as a function of time dating from the late 1700s to present is illustrated in Fig. 2.1.

2.2.2  Evidence-Based Medicine: Why Bother? There are compelling reasons to use the EBM process in the delivery of health care. First, there is an increasing volume of evidence available to address clinical problems, and the EBM approach helps keep the clinician abreast of this evidence in a way that allows them to deliver the best care for patients. For example, a major innovation in managing patients with OHTN involves using risk calculators to assess the chance of developing POAG. An estimate of the risk can be an important factor in deciding whether an OHTN patient should be committed to medical therapy for glaucoma. Mansberger introduced a glaucoma risk calculator to estimate the probability of converting from OHTN to POAG in 2003 using data from OHTS.14 In 2005, Medeiros and colleagues confirmed the function of a similar calculator in an independent sample of patients with OHTN.15 In 2007, researchers from the United States and Europe introduced a revised calculator based on the combined results of OHTS and the European

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Glaucoma Prevention Study (EGPS).16 The EGPS, was a placebo-controlled RCT that compared dorzolamide (a topical carbonic anhydrase inhibitor) versus placebo in the prevention of POAG among patients with OHTN. The EGPS has similar characteristics to OHTS, allowing investigators to pool the data from both trials in estimating the risk of developing POAG. The latest calculator represents a significant revision from the earlier tools in that it does not use diabetes status in estimating the risk of converting from OHTN to POAG. The initial versions of the calculator assigned a reduced risk of conversion from OHTN to POAG among diabetic patients because the OHTS found that a self-report of diabetes mellitus was associated with a reduced risk of converting from OHTN to POAG. However, when data from OHTS were combined with the EGPS, diabetes was no longer related with conversion from OHTN to POAG. Hence, the latest calculator provides the most updated assessment of risk. Certainly, more refinements of the glaucoma risk calculator are forthcoming, such as adjustment for life expectancy, and if you practice EBM, you will be familiar with these refinements because EBM engages you in following new developments in managing disease. Another reason to practice EBM is that learning the principles of EBM will make you a perpetual student of medicine; and, after all, was not lifelong learning about disease one of the reasons we entered this noble profession in the first place? You can begin practicing EBM now. You can review the medical decision-making that you make during the course of a day in your office and follow the EBM process to see what the consensus of evidence suggests is the best way to arrive at a particular management decision. You will be surprised that more often than not, the literature does not address your particular patient problem. While one may view this as a shortcoming of the EBM approach, it may also represent an opportunity to perform research to advance clinical knowledge in a particular area. There are other benefits to practicing EBM. It gives you a sense of control because you decide what questions are important and relevant (because they involve your patients) and you can find out the answer to these questions (if there are any answers). It provides a way for you to question the status quo. Does lowering IOP really slow the progression of visual field loss when we critically review the evidence? What is the ideal second-line treatment for POAG? What is the best surgical approach for a patient with pseudophakia and uncontrolled IOP? Many of these questions will be addressed in the subsequent chapters of this textbook. Finally, practicing EBM allows you to challenge seemingly authoritative expert opinion. If a learned glaucoma expert comes to your town espousing a statement like, “Visual field progression from POAG can be completely halted with the addition of new agent X,” then you can use the EBM process to see if such a statement is justified.

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2.2.3  The Evolution of Glaucoma Care Since EBM centers on using published evidence to guide clinical decision-making, it is useful to review how ophthalmic advances influenced our managerial approach to the glaucoma patient. It is difficult to treat a disease if you do not even know what type of condition it is. It is somewhat ironic that the word glaucoma has its origins in the Greek language and it roughly means “grayish gleam” – hardly a term associated with an optic nerve disease. It originally was a term referring to elderly people with seemingly white and quiet eyes and a dull appearance on external inspection that was associated with visual disability from multiple causes including mature cataract. Thus, prior to the invention of the ophthalmoscope by Hemholtz17 (before 1851), visual disability from glaucoma was frequently confused with other conditions. The postophthalmoscope era afforded the clinician an ability to inspect the optic nerve and identify a group of visually disabled people who had white and quiet eyes, relatively clear media, and excavated optic nerve heads. Palpation of the globes of many (but not all) of these patients suggested that the IOP was elevated (the Schiotz tonometer had not been invented yet). These observations established that glaucoma was an optic nerve disease, but the frequent association with a firm globe to palpation suggested that glaucoma was a condition of elevated IOP that produced pathologic optic nerve changes; it is now known that glaucoma can occur across a spectrum of IOP values that include those in the statistically normal range. Nonetheless, the invention of the ophthalmoscope allowed clinicians to direct IOP-lowering treatment to patients with pathologically cupped optic nerves and elevated IOP. Intuitively it made sense to lower IOP in these patients with the limited therapies available to achieve such an effect. No one dared to question that an RCT might be needed to confirm that patients would benefit from such treatment. A clear understanding that glaucoma existed in an angle-closure form and an open-angle form was not apparent until after the gonioscope was embraced as an important diagnostic tool. The postgonioscopic era began around 1920 when Koeppe and others perfected the technique of evaluating the filtration apparatus with the patient in the seated position.18 Ultimately, this technique allowed physicians to more accurately identify patients with angle closure glaucoma who would benefit from iridectomy. Interestingly, despite the clear-cut importance of gonioscopy in a glaucoma work-up, available evidence suggests that gonioscopy is relatively underutilized in the management of glaucoma patients today.19,20 Prior to the launch of timolol, ophthalmologists had fairly limited tools to lower IOP in glaucoma patients. The treatments available had either undesirable side-effect profiles or poor efficacy. Pilocarpine, which has reasonable efficacy and has

L.R. Pasquale

been available for more than 130 years to treat glaucoma,21 requires frequent application and produces a constricted pupil. In younger patients, these drugs produced significant myopic shift because of induced accommodation of the lens, and in myopic patients, they would occasionally cause retinal breaks.22 Topical epinephrine had a slightly better ocular side-effect profile but limited efficacy. Systemic carbonic anhydrase inhibitors were available from 1954, but they exposed the patient to systemic side effects. The introduction of timolol in 1978 ushered in the golden age of the topical beta-blocker. Topical beta-blockers were welcomed with open arms because while they did have some systemic side effects, they were tolerable and these drugs provided accep­ table efficacy with once-daily or twice-daily dosing. With relatively few published placebo-controlled masked trials using IOP lowering and safety parameters as the outcomes,23 timolol’s superiority over epinephrine and pilocarpine became apparent and it instantly became the first-line treatment for glaucoma. In this era, no one questioned whether topical beta-blockers should be used as a first-line agent for glaucoma unless there was a contraindication to using a beta-blocker. The 1990s witnessed the polypharmacy era, characterized by a significant expansion of the pharmacological armamentarium in treating glaucoma. The drugs that were introduced (topical carbonic anhydrase inhibitors24, alpha agonists25, and prostaglandin analogs26) created more treatment options for glaucoma patients. In fact, prostaglandin analogs offered the possibility of once-daily dosing, the virtual absence of systemic side effects, and IOP-lowering superior to timolol. In the 1990s, the balance had shifted from having limited options for lowering IOP to having a confusing number of ways of dealing with glaucoma, especially when one considers that parallel advances in laser trabeculoplasty and guarded sclerostomy surgery threatened to rival medical therapy in the treatment of glaucoma. This time period shares some parallels to the 1940s in general medicine when multiple tools were available to address disease (see Fig. 2.1). A dark cloud was building over the entire field of glaucoma sometime after the golden age of beta-blockers and just before the polypharmacy era when a public policy official (Dr. David Eddy) questioned whether many medical treatments for many diseases (his article did not specifically single out glaucoma treatment) were really benefiting patients.27 The glaucoma field was particularly vulnerable to this criticism because it narrowly focused on IOP as an outcome with precious few studies focused on whether our treatments preserved optic nerve structure and function. This shift in emphasis from considering IOP outcomes to visionpreserving outcomes ushered in the randomized clinical trial era of the 1990s. These trials help establish that lowering IOP helped to prevent development of POAG among patients

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2  An Evidence-Based Approach to Glaucoma Care

with the OHTS28 and slow disease progression in those with early manifest open-angle glaucoma (the Early Manifest Glaucoma Trial).29 In order to refine which IOP-lowering modalities were best for our patients, other RCTs compared a medicine-first approach to laser-first (the Glaucoma Laser Trial)30 and medicine-first to surgery-first (the Collaborative Initial Glaucoma Treatment Study) in managing open-angle glaucoma.31 These trials will be the subject of later chapters, but they can be summarized by stating that overall there is currently no clear-cut advantage to using one modality to lower IOP when compared with another for glaucoma. Nonetheless, I will demonstrate that the EBM process can be used to inform clinicians about the management of individual glaucoma patients. What will the future hold for glaucoma care and how will EBM help shape it? To answer this question, it is important to hark back to the time before the “postophthalmoscope” era. Initially, we did not even know that glaucoma was a disease of the optic nerve. Today, POAG – the most common form of glaucoma in the Western world – is a condition that is described in terms of risk factors rather than pathoetiologic elements. Similarly, primary angle closure glaucoma (PACG) – a common form of glaucoma in the Eastern world – is also poorly understood at a fundamental level. Thus, the next wave in glaucoma management will stem from a more complete understanding of the combination of genetic and environmental factors that dictate the etiology of all forms of glaucoma. As the various combinations of genetic determinants and environmental influences that dictate disease are published and confirmed, they will become the basis for genotype-specific tailored therapies, which may presage the “individualized medicine era of glaucoma.” EBM will be useful to determine if novel genotype-specific strategies to treat glaucoma are superior to conventional approaches of managing the condition. Initially, genotype-specific strategies may not be embraced (initially, there was resistance to accept Schiotz tonometry as a replacement for finger palpation of the globe in the assessment of IOP), but RCTs will pressure physicians to adopt these approaches if they are truly superior to the way we practice currently. In the interim, we will see modifications of the current ocular hypertension risk calculator and the emergence of new risk calculators that estimate the risk of developing glaucoma and the risk of progressing to more severe forms of the disease. Such knowledge will be based on a more complete understanding of the natural history of disease and how it is modified by current treatment. Such knowledge will, of course, be evidence-based. We will also see an increase in the use of meta-analysis to synthesize the rapidly accumulating evidence regarding our current glaucoma treatments. Meta-analysis is really a formal statistical approach to review the literature on a subject. First, the quality of the evidence is assessed so that only worthwhile reports are included.

Then, statistical methods are applied to determine which studies from disparate centers can be combined. Models are then formulated to convert a series of small trials into a single large trial. The advantage of this approach is particularly apparent if some of the smaller trials actually contradict one another, or if the individual trials conclude that one treatment is similar to another, but each individual study is actually underpowered to detect any real difference between the treatments. For example, a meta-analysis of nine RCTs concluded that bimatoprost and travoprost are slightly more effective in lowering IOP than latanoprost.32 This finding is consistent with another meta-analysis of 13 RCTs that concluded that bimatoprost was superior to latanoprost in lowering IOP.33 Nevertheless, more work is needed as still another literature synthesis has pointed out that no individual medical agent has been shown to preserve optic nerve function as measured by automated perimetry, and only beta-blockers have been shown to slow disease progression.34 The absence of such evidence does not mean that our current therapies are not effective at preserving vision, but more clinical research is needed to optimize our treatments for glaucoma.

2.3  The Evidence-Based Medicine Process 2.3.1  Formulation of a Clinical Problem Assume a 70-year-old white female presented to your office today with difficulty driving at night. Your examination leads you to conclude that the patient’s symptoms are related to mild cataract formation, but an incidental finding was the presence of exfoliation precipitates in the anterior segment of both eyes, IOPs of 26 mmHg OD and 21 mmHg OS, and open angles on gonioscopy. Furthermore, the cup-disc ratio is 0.8 OD and 0.55 OS. On Humphrey visual field testing, there is a superior arcuate defect and inferior nasal step in the right eye and a shallow superior nasal step in the left eye. The Snellen acuity is 20/30 OU in both eyes. After you explain that cataracts were making it difficult to drive at night, the patient opts to defer cataract extraction because she was not critically disabled by her visual complaint. She was actually relieved to know the major source of her vision problem was potentially fixable. Nonetheless, she was not prepared to discover she had glaucoma. You inform the patient about the diagnosis of exfoliation glaucoma and, without much reflection on the matter, initiate treatment with travoprost 0.004% ophthalmic solution dosed one drop at bedtime in both eyes. The patient readily accepts this treatment; but in a quieter moment, you wonder whether such treatment was the optimized approach to her case. This moment of reflection represents the genesis of the EBM process: formulation of a

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clinical question. In this case, the question is what is the best first-line treatment for this elderly lady with new-onset exfoliation glaucoma?

2.3.2  A  ssembling the Evidence Cart: From Textbooks to Systematic Reviews After crystallizing a clinical problem based on a patient encounter, the next task is assembling the available evidence that addresses this particular issue. Your question really is: “If I am committing this patient to medical therapy, is travoprost really the best choice for her?” Stated another way: Is there a prostaglandin analog that is particularly effective for exfoliation glaucoma? The meta-analyses referenced in the last section indicating that travoprost and bimatoprost were superior to latanoprost did not stratify their results by openangle glaucoma subtype (i.e., exfoliation glaucoma versus other types of glaucoma).32,33 This reformulation of the question assumes that medical therapy, as opposed to laser trabeculoplasty or incisional surgery, represents the best initial approach to managing her condition – an issue we will return to later. Furthermore, in thinking about the answer to this question, we must also consider the ocular side-effect profile of each agent. In general, there are many potential resources available to potentially address your patients’ problems, and oftentimes, these sources contain conflicting information. They include textbooks, “blue ribbon panels” convened by cost-conscious third-party payers, consensus panels handpicked by pharmaceutical companies, journal articles, online search engines such as PubMed, or online databases that search multiple articles and synthesize the literature on a particular subject. Where would you go first to find the answer to your question? Thomas Kuhn in his highly influential treatise entitled, The Structure of Scientific Revolutions,35 points out that, “Textbooks aim to communicate the vocabulary and syntax of a contemporary scientific language.” For example, a typical glaucoma textbook is useful to learn the basics about exfoliation glaucoma and will address disease management in general terms, but it is unlikely to guide you on the specifics of optimum management of your 70-year-old lady with newly diagnosed exfoliation glaucoma. You may seek the assistance of the personal library of journal articles that you subscribe to and read faithfully every month, but it will become obvious very quickly that scouring them will not be a terribly efficient way to find the answer to your question. The logical way to address this problem is to use a general online search engine like PubMed to find studies that address your particular question. In order to use PubMed, your patient encounter, which has been transformed to a relevant

L.R. Pasquale

clinical question, must be transformed again into “keywords” that can be searched. If we had used the keywords therapy and exfoliation glaucoma (other synonyms such pseudoexfoliation glaucoma should also be tried) on June 21, 2008, there would be 319 references and most of these would not be relevant to this patient’s individual clinical situation. In reviewing this list of publications, we find five articles36–40 that are relevant to our clinical problem. While we were able to find relevant information about our patient problem on PubMed, this is a somewhat time-consuming process. Is there a better way? The short answer is: not at the current time. Theoretically, the Cochrane Collaboration,1 an organization that provides up-to-date reviews on healthcare interventions in all areas of medicine, would be the ideal shortcut to get the answer to our patientrelated question. Essentially, the Cochrane Collaboration searches for articles that perform the kind of literature search outlined above and summarizes the results in one article. At this time, a search using keywords therapy and exfoliation glaucoma or exfoliation glaucoma alone did not yield any relevant results since no one has written an evidence-based review on the subject of optimum medical therapy for exfoliation glaucoma. In fact, the keyword glaucoma will yield a list of 86 meta-analytical articles on glaucoma in all.

2.3.3  Evaluating the Quality of the Evidence Once the evidence cart for our clinical question has been assembled, we must examine the quality of that evidence. Certainly, if the five articles we found related to our patient were of poorly designed studies, then they would not be useful in guiding our decision-making process with respect to our patient. Cochrane reviews would ordinarily do the quality analysis for us, but again there are no such reviews related to our patient. It is recommended that when the evidence cart is assembled that one looks for the RCTs first, as they represent a gold standard level of evidence for any particular intervention. Then one needs to ask the following questions about these RCTs: • Is the allocation to treatment arms random and, if possible, are the investigators masked to the interventions employed in the study? • Are the baseline attributes of each treatment arm clearly stated? A particularly useful study design incorporates a crossover paradigm. In crossover studies, each patient serves as his or her own control and is exposed to each treatment after an adequate washout period. This addresses any difference in baseline attributes between groups and also serves to increase the power of the study. • Is the study adequately powered to find a difference between treatment groups? Look for a mention of an

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2  An Evidence-Based Approach to Glaucoma Care

a priori power calculation in the methods section of the paper. • Do the authors present an intention-to-treat (ITT) analysis? There is an important dictum in clinical trials: once randomized, always analyzed. Patients who switch treatment arms or who drop out are always analyzed in the groups they were allocated to at the time of randomization. • Are withdrawals adequately reported and is the dropout rate reasonable (below 10%)? • Is there industry sponsorship for the study? Industry sponsorship does not mean the study is tainted but it is important to take note of such sponsorship. It is almost certain that industry sponsorship creates a certain publication bias, whereby results that do not show a product in a favorable light are suppressed. New rules about registering clinical trials with the Food and Drug Administration (FDA) are trying to minimize such publication bias. Let us look at the evidence we have accrued for our particular clinical question. All five studies are randomized clinical trials. The majority of studies involve Greek nationals, raising some concerns about the generalizability of the data to other populations. A summary of the quality of each article is provided in Table  2.1. Each article gets a point each if the masking is judged to be adequate, power calculations are provided, an intent-to-treat analysis is performed, the withdrawal rate is less than 10% (somewhat arbitrary), and industry support is declared. If the study is free from industry sponsorship, then a score of two points is given. More formal grading systems of papers can be performed, but since the purpose is not to perform a metaanalysis but to get a rough idea that the data in the paper are believable, a simplified grading system looking for these particular attributes is recommended. For the evidence, we have accumulated for our question, we have five studies with quality scores ranging from 1 to 6 on a scale of 0 to 6, with most studies having scores of 4 or more. Therefore, the quality of the evidence that we have accumulated is generally quite good.

2.3.4  Applying the Evidence to Our Case After assessing the overall quality of the evidence assembled, it is important to ascertain the outcome of these studies. All of these studies looked at either diurnal IOP or IOP at one time point as the main efficacy outcome. There are no data regarding whether any of the treatment options available to treat our particular patient are more effective in preserving vision. In looking at the IOP outcomes, it is also important to distinguish between statistical significance and clinical significance. Regulatory agencies state that differences in IOP of 1.5  mmHg or more constitute clinical significance, although there is no evidence to refute the notion that smaller differences in IOP that are statistically significant may also be clinically significant. The side-effect profile of the various treatment options should also be considered in making a decision about our patient. In summary, the evidence (summarized in Table 2.2) indicates that for exfoliation glaucoma, both travoprost and bimatoprost produce statistically significant lowering of diurnal IOP versus latanoprost, but the differences in IOP lowering are less than 1.5 mmHg. Latanoprost produced significant reduction in diurnal IOP versus timolol that was greater than 1.5  mmHg. Two studies indicated that fixed combination timolol 0.5%–dorzolamide 2% was superior to travoprost and latanoprost in terms of IOP lowering, but the difference was Latanoprost Latanoprost>Timolol Dorzolamide-Timolol fixed combination>Latanoprost

>1.5 mmHg difference No

Favors industry-sponsored product

a

(performed with either the argon or selective laser unit) in exfoliation glaucoma. Nonetheless, one can refer to the Glaucoma Laser Trial, which showed that argon laser trabeculoplasty was as effective as medical therapy (during the golden age of beta-blockers) in the treatment of open-angle glaucoma.30 Thus, if there are unusual circumstances that prevent adherence or if the patient and the physician simply prefer a laser-first approach after an appropriate informed consent process, it is reasonable to proceed with laser trabeculoplasty to manage the case. With respect to surgery, the Collaborative Initial Glaucoma Study evaluated whether glaucoma filtration surgery or medicine is the optimal initial approach to manage newly diagnosed OAG.31 The interim study results showed that visual acuity and visual field outcomes were similar in both groups after 4 years of follow-up, prompting the study investigators to conclude that physicians should not change their practice patterns of routinely not offering patients surgery as the first option to manage OAG.

2.3.5  T  he Basic Calculus of Evidence-Based Medicine A typical RCT will report the main outcomes of a study and discuss the side effects associated with one intervention versus another. For example, in the OHTS, which assessed whether prophylactic treatment of OHTN prevented people from developing POAG, it was reported that the rate of conversion from OHTN to POAG was reduced from 9.5 to 4.5% with ocular hypotensive therapy after 5 years.28 These data suggest that lowering IOP in OHTN helps people generally, but can we get a deeper understanding of the trial results? Furthermore, how do we use these data to guide treatment decisions for individual glaucoma patients? The terms absolute risk reduction, relative risk reduction, and the number needed to treat 41 help us assess exactly how effective ocular hypotensive therapy is in reducing conversion from OHTN to POAG. The absolute risk reduction (ARR) is the difference in outcome rate between treatment option 1 and treatment option 2 in a clinical trial. In the OHTS, 9.5% of patients

with OHTN who were observed converted to a diagnosis of POAG, while only 4.5% of those under treatment converted to the same diagnosis. The ARR is 9.5–4.5 or 5%. The relative risk reduction (RRR) is the proportional reduction in event rates (failure to respond to treatment) between treatment option 1 and treatment option 2 in a clinical trial. In the OHTS, treatment did not completely prevent patients with OHTN from developing glaucoma. In fact, treatment resulted in a 4.5/9.5 or 50% RRR. Most diseases have low rates of occurrence; therefore, RRR tends to inflate the apparent benefit of any given treatment and ARR tends to underestimate it. Thus, another term has been introduced into the calculus of EBM to put the relative effectiveness of treatment into perspective, and that term is the number needed to treat (NNT). The NNT is the number of patients who need to be treated in order for one patient to receive benefit (such as the prevention of one case of POAG from developing among a group of patients with OHTN). The NNT is calculated as 1/ ARR, rounded to the next highest whole number. For the OHTS, the NNT is 20 – that means one would have to treat 20 patients with OHTN to prevent one case of POAG from developing. A lower value for the NNT is desirable for any treatment intervention and an NNT in the range of 2–5 is generally regarded as indicative of an effective treatment (the NNT for the Early Manifest Glaucoma Trial where newly diagnosed OAG patients were randomized to treatment versus observation was 6),29 but a higher NNT may be acceptable for prophylactic treatments. The OHTS can be considered a prophylactic or preventive trial. Interestingly, if the RRR stays constant, but the number of people reaching an endpoint increases, then the NNT goes down. A case in point regards the subset of AfricanAmericans enrolled in the OHTS. The 5-year risk of converting from OHTN to POAG for African-Americans in the OHTS was 8.4% in the medical therapy arm and 16.1% in the observation arm.42 Thus, the ARR is 16.1–8.4 or 7.7% and the RRR is 8.4/16.1 or 48%. Overall, the NNT is 1/0.077 or 13. So among African-Americans, one would have to treat 13 patients with OHTN to prevent one case of POAG. The ARR, RRR, and NNT provide quantitative insights into the results of RCTs yielding a global estimate of treatment effectiveness, but they do not tell us which

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2  An Evidence-Based Approach to Glaucoma Care

individual patient requires treatment. The reader should be cautioned from concluding that all African-Americans with OHTN should be treated because the NNT is 13 when compared with an NNT of 20 overall. The decision to treat individual OHTN patients is better guided by the glaucoma risk calculator. The calculator, which has been validated in patients outside the OHTS15, accounts for important risk factors that predict conversion from OHTN to POAG and provides a 5-year risk estimate of converting from OHTN to POAG. The parameters that go into the calculation are age, mean IOP, central corneal thickness, vertical cup-disc ratio, and mean defect on the Humphrey visual field. Race is not entered into the calculator because multivariable analysis indicated that race was not an independent risk factor for conversion from OHTN to POAG. So a 48-year-old patient with mean IOP of 24  mmHg, OU; CCT of 520  mm OU; CDR = 0.4 OU; and PSD of 1.5 dB OD and 1.7 dB OS has a 5-year risk of converting to POAG of 15%. If one uses the calculator to stratify patients into low (£5% in 5 years), medium (5–15% risk in 5 years) or high (>15% risk in 5 years) risk of converting to POAG, then this person, regardless of race, would have a moderate-to-high increased risk of converting to POAG. As it turns out, African-Americans will tend to fall into the high-risk category by virtue of the fact that they tend to have thinner corneas than their Caucasian counterparts. Nonetheless, an African-American subject with thick corneas does not necessarily have to go on treatment because the NNT for African-Americans overall is 13. Ultimately, the risk calculator should not be viewed as the instrument that rigidly guides treatment decisions, as that is an individual decision between the patient and doctor. All treatment interventions have side effects relative to observation without therapy or an alternative treatment. Thus, it is useful to place an adverse effect profile in quantitative perspective as well when considering treatment for the individual patient. The term number needed to harm (NNH) is the number of patients that need to be treated to harm one patient. In the Collaborative Initial Glaucoma Treatment Study (CIGTS), patients with newly diagnosed OAG were randomized to treatment with medical therapy or surgery to lower IOP. Both treatments were equally effective in stabilizing vision and the visual field over a 5-year period. In fact, both treatments seem to have equivalent impact on qualityof-life measures. Nevertheless, 9% of patients in the medical therapy arm developed cataracts requiring surgical intervention, while 20% of patients in the surgical arm required cataract extraction.31 Thus, the NNH is calculated as 1/0.2–0.09 or 9. Thus in treating nine newly diagnosed patients with surgery first, the clinician would induce one extra cataract requiring surgical removal. A low NNH is not desirable, especially when the treatment inducing harm is not better than the alternative therapy (in this case medicine first). With that said, the “harm” in this case was a cataract that produces

vision loss that is reversible with cataract extraction. In fact, CIGTS researchers show that cataract surgery in patients with prior filtration surgery is quite successful.43 While the NNT and NNH provide quantitative interpretation of RCT results in terms of how they benefit patients, they do not tell us if treatment is cost-effective. Costeffectiveness is a somewhat controversial term because it indicates there is a cost above which society cannot bear the burden of treating a specific condition. We like to think that ideally we should spare no cost in preventing glaucoma, but in reality, resources are limited and must be distributed judiciously such that the most treatable conditions are addressed on a societal level. Certainly, we would not want to spend so much money on treating OHTN that there are no resources available to care for patients with cataract or progressive POAG. The costs of healthcare have risen by about 20% per year from 1998 to 2004, and society needs to allocate finite resources for the most cost-effective treatments.44 The National Institute for Clinical Excellence has set a ceiling for annual costs associated with treating any disease, which reflects the resources available in an affluent country. Basically, if the incremental cost-effectiveness ratio (ICER) is greater than a societal cutoff for willingness to pay, the treatment is regarded as not cost-effective. The upper limit for ICER may be much lower in countries of more limited means. The ICER is calculated using RCT data, the actual costs of treating or observing the condition in question, and accounting for the number of years of life people would be willing to swap in order to remain free of the condition in question. The ICER for treating all OHTN patients is approximately $89,000.45 That means the incremental cost of treating all OHTN patients to prevent one case of POAG is $89,000, a value that is of borderline cost-effectiveness even for a highly developed country like the United States. If we limit treatment, for example, to those patients with CCT 40 mm below the norm (550 mm), then the ICER is close to $37,000. Similarly, it is cost-effective to treat OHTN patients over the age of 76 (two decades above the age of 56), IOP >29 mmHg (4 mmHg above the IOP of 25 mmHg), and with vertical CDR of 0.6 or more (0.2 units above 0.4) because in each case the ICER is less than $50,000.

2.3.6  W  hat Do We Do When There Is Little or no Evidence? You are a busy glaucoma specialist and you are emotionally shaken because in the past 2 months you have performed two combined cataract extractions with trabeculectomy procedures that resulted in suprachoroidal hemorrhage – one occurred intraoperatively and one occurred postoperatively.

L.R. Pasquale

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In both instances, the patients developed excruciating pain, and in one instance, the vision went to light perception (LP) and did not improve. You are trying to decide whether there are preoperative measures to consider to prevent this from ever happening to you again. The experience has been devastating for the patients and for you. Your question is quite simple: What can be done to prevent suprachoroidal hemorrhage from developing? Very quickly you discover that there are no trials designed to answer this question. In fact, it is likely that there will never be a trial to answer this question because suprachoroidal hemorrhage is a relatively rare event and a trial would have to include a large number of patients in order to be adequately powered to determine if a particular intervention reduced the rate of suprachoroidal hemorrhage. While suprachoroidal hemorrhage is rare, it seems like a common event when it happens to one of your patients. So you hope to find some evidence that can help you. In this instance, the best source of evidence that can provide the answer to your question is observational studies. Observational studies may point to risk factors for the development of suprachoroidal hemorrhages. Those risk factors may lead you to adopt some strategies to minimize the development of suprachoroidal hemorrhage. The source of bleeding in suprachoroidal hemorrhages is the posterior ciliary arteries that bridge the sclera and enter the choroidal tissue. The literature review indicates that the risk factors for suprachoroidal hemorrhage can be divided into systemic and ocular risk factors. Systemic risk factors include older age, hypertension, atherosclerosis, and intraoperative tachycardia.46–48 The insight that you gain from this list is that patients need to have their cardiovascular status maximized at the time of surgery. If a patient is running a very high blood pressure on the day of surgery, it might be better to defer the operation to another day. Ocular risk factors include longer axial length, aphakia, intraoperative vitrectomy, and multiple prior surgeries. In reviewing this list of ocular risk factors, you realize that low IOP, lack of lens support, and absence of ocular turgor provided by the vitreous gel may tug on the bridging posterior ciliary vessels causing them to rupture. Thus, you decide that in future you will be careful to maintain control over the anterior chamber depth intraoperatively during all anterior segment procedures. You will avoid outflow procedures in aphakic patients unless they are absolutely necessary and even then perform them in a guarded fashion. Finally, for your trabeculectomies, whether they are combined with cataract surgery or not, you will use laser suture lysis and releasable sutures in a judicious fashion avoiding extreme hypotony, which could trigger a postoperative suprachoroidal hemorrhage. These maneuvers intuitively make sense and while they may not completely prevent a suprachoroidal hemorrhage, they may reduce the chance of encountering one.

2.4  Conclusion One of the wonderful things about the study of medicine is that the learning process continues for a lifetime. Adhering to EBM is like maintaining your continuing medical education. Physicians will benefit from engaging in the EBM process throughout their career. It allows one to track emerging practice trends (such as the intraocular injection of anti-angiogenic agents in the management of neovascular glaucoma49) and make rational decisions about adopting new management schema. One shortcoming is bringing EBM to the exam lane. The EBM process is not an exercise that can be performed when the patient is in our exam chair; however, once we have gone through the EBM process, it will certainly be absorbed into our practice patterns and help the next patients who present with similar problems. Furthermore, most of the searches for evidence are manual ones because ophthalmic meta-analytic topic reviews are just beginning to appear in the Cochrane database. At the current time, many glaucoma management issues cannot be resolved with the EBM process. The emergence of the electronic medical record, which requires a computer hooked up to the Internet in every exam lane, certainly helps us perform real-time calculations of risk for developing POAG in OHTN patients. In the end, the EBM process is about delivering the very best care for our patients.

Clinical Pearls • EBM is a process whereby the best medical evidence in the literature is applied to patients with specific clinical problems. • The EBM process involves four steps: (1) formulation of a clinical question, (2) assembly of the evidence that addresses that question, (3) an assessment of the quality of available evidence, and (4) application of the evidence to a particular patient. • The absolute risk reduction, relative risk reduction, and number needed to treat represent quantitative measures to assess efficacy of an intervention in a RCT. The number needed to harm represents a quantitative measure to assess the adverse effects of an intervention in a randomized clinical trial. • Most clinical challenges in glaucoma do not have a directly applicable randomized trial that addresses the problem.

2  An Evidence-Based Approach to Glaucoma Care

References 1. The reliable source of evidence in health care. In: Julian PT, Higgins, Sally, eds. The Cochrane Handbook for Systematic Reviews of Interventions. Wiley, Interscience, Sussex England; 2008. 2. Bhandari M, Zlowodzki M, Cole PA. From eminence-based practice to evidence-based practice: a paradigm shift. Minn Med. 2004;87:51–54. 3. Gorman C. Are doctors just playing hunches? Time. 2007;169(9): 52–54. 4. Gordon MO, Beiser JA, Brandt JD, et al. The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714–720. discussion 829–830. 5. Leske MC, Wu SY, Hennis A, Honkanen R, Nemesure B. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology. 2008;115:85–93. 6. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312:71–72. 7. Flynn CA, D’Amico F, Smith G. Should we patch corneal abrasions? A meta-analysis. J Fam Pract. 1998;47:264–270. 8. Michael JG, Hug D, Dowd MD. Management of corneal abrasion in children: a randomized clinical trial. Ann Emerg Med. 2002;40:67–72. 9. Le Sage N, Verreault R, Rochette L. Efficacy of eye patching for traumatic corneal abrasions: a controlled clinical trial. Ann Emerg Med. 2001;38:129–134. 10. Daly WJ, Brater DC. Medieval contributions to the search for truth in clinical medicine. Perspect Biol Med. 2000;43:530–540. 11. North R. Benjamin Rush, MD: assassin or beloved healer? Proc (Bayl Univ Med Cent). 2000;13:45–49. 12. Bean RB. Sir William Osler. Aphorisms. Springfield: Blackwell; 1961:164 13. Morris JN. Recalling the miracle that was penicillin: two memorable patients. J R Soc Med. 2004;97:189–190. 14. Mansberger SL. A risk calculator to determine the probability of glaucoma. J Glaucoma. 2004;13:345–347. 15. Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol. 2005;123:1351–1360. 16. Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. 2007;114:10–19. 17. von Helmholtz HLF. Beschreibung eines Augen-Spiegels. Berlin, Germany: A Förstner'sche Verlagsbuchhandlung; 1851. 18. Dellaporta A. Historical notes on gonioscopy. Surv Ophthalmol. 1975;20:137–149. 19. Hertzog LH, Albrecht KG, LaBree L, Lee PP. Glaucoma care and conformance with preferred practice patterns. Examination of the private, community-based ophthalmologist. Ophthalmology. 1996; 103:1009–1013. 20. Coleman AL, Yu F, Evans SJ. Use of gonioscopy in medicare beneficiaries before glaucoma surgery. J Glaucoma. 2006;15:486–493. 21. Kronfeld P. Eserine and pilocarpine: our 100-year-old allies. Surv Ophthalmol. 1970;14:479. 22. Beasley H, Fraunfelder FT. Retinal detachments and topical ocular miotics. Ophthalmology. 1979;86:95–98. 23. Zimmerman TJ, Kass MA, Yablonski ME, Becker B. Timolol maleate: efficacy and safety. Arch Ophthalmol. 1979;97:656–658. 24. Lippa EA, Carlson LE, Ehinger B, et al. Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1992;110:495–499. 25. Derick RJ, Robin AL, Walters TR, et  al. Brimonidine tartrate: a one-month dose response study. Ophthalmology. 1997;104: 131–136.

33 26. Camras CB, Schumer RA, Marsk A, et  al. Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension. Arch Ophthalmol. 1992; 110:1733–1738. 27. Eddy DM, Billings J. The quality of medical evidence: implications for quality of care. Health Aff (Millwood). 1988;7:19–32. 28. Kass MA, Heuer DK, Higginbotham EJ, et al. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–713. discussion 829–830. 29. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–1279. 30. The Glaucoma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. The Glaucoma Laser Trial Research Group. Ophthalmology 1990;97:1403–1413 31. Lichter PR, Musch DC, Gillespie BW, et  al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943–1953. 32. Denis P, Lafuma A, Khoshnood B, Mimaud V, Berdeaux G. A meta-analysis of topical prostaglandin analogues intra-ocular pressure lowering in glaucoma therapy. Curr Med Res Opin. 2007;23:601–608. 33. Cheng JW, Wei RL. Meta-analysis of 13 randomized controlled trials comparing bimatoprost with latanoprost in patients with elevated intraocular pressure. Clin Ther. 2008;30:622–632. 34. Vass C, Hirn C, Sycha T, Findl O, Bauer P, and Schmetterer L. Medical interventions for primary open angle glaucoma and ocular hypertension. Cochrane Database Syst Rev 2007: CD003167 35. Kuhn TS. The structure of scientific revoluations, 3rd ed. Chicago: The University of Chicago Press; 1996:212 36. Konstas AG, Kozobolis VP, Katsimpris IE, et al. Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients. Ophthalmology. 2007;114:653–657. 37. Konstas AG, Hollo G, Irkec M, et  al. Diurnal IOP control with bimatoprost versus latanoprost in exfoliative glaucoma: a crossover, observer-masked, three-centre study. Br J Ophthalmol. 2007;91: 757–760. 38. Parmaksiz S, Yuksel N, Karabas VL, Ozkan B, Demirci G, Caglar Y. A comparison of travoprost, latanoprost, and the fixed combination of dorzolamide and timolol in patients with pseudoexfoliation glaucoma. Eur J Ophthalmol. 2006;16:73–80. 39. Konstas AG, Mylopoulos N, Karabatsas CH, et al. Diurnal intraocular pressure reduction with latanoprost 0.005% compared to timolol maleate 0.5% as monotherapy in subjects with exfoliation glaucoma. Eye 2004;18:893–899 40. Konstas AG, Kozobolis VP, Tersis I, Leech J, Stewart WC. The efficacy and safety of the timolol/dorzolamide fixed combination vs latanoprost in exfoliation glaucoma. Eye. 2003; 17:41–46. 41. Barratt A, Wyer PC, Hatala R, et al. Tips for learners of evidencebased medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat. CMAJ. 2004;171:353–358. 42. Higginbotham EJ, Gordon MO, Beiser JA, et  al. The Ocular Hypertension Treatment Study: topical medication delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004;122:813–820. 43. Musch DC, Gillespie BW, Niziol LM, et al. Cataract extraction in the collaborative initial glaucoma treatment study: incidence, risk factors, and the effect of cataract progression and extraction on clinical and quality-of-life outcomes. Arch Ophthalmol. 2006; 124:1694–1700.

34 44. Pasquale LR, Dolgitser M, Wentzloff JN, et al. Health care charges for patients with ocular hypertension or primary open-angle glaucoma. Ophthalmology. 2008;115(4):633–638. 45. Kymes SM, Kass MA, Anderson DR, Miller JP, Gordon MO. Management of ocular hypertension: a cost-effectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2006;141:997–1008. 46. Speaker MG, Guerriero PN, Met JA, Coad CT, Berger A, Marmor M. A case-control study of risk factors for intraoperative suprachoroidal expulsive hemorrhage. Ophthalmology. 1991;98:202–209. discussion 210.

L.R. Pasquale 47. Obuchowska I, Mariak Z. Risk factors of massive suprachoroidal hemorrhage during extracapsular cataract extraction surgery. Eur J Ophthalmol. 2005;15:712–717. 48. Moshfeghi DM, Kim BY, Kaiser PK, Sears JE, Smith SD. Appositional suprachoroidal hemorrhage: a case-control study. Am J Ophthalmol. 2004;138:959–963. 49. Ehlers JP, Spirn MJ, Lam A, Sivalingam A, Samuel MA, Tasman W. Combination intravitreal bevacizumab/panretinal photocoagulation versus panretinal photocoagulation alone in the treatment of neovascular glaucoma. Retina. 2008;28: 696–702.

Chapter 3

Glaucoma Risk Factors: Intraocular Pressure Nils A. Loewen and Angelo P. Tanna

3.1  I ntraocular Pressure is Causatively Linked to Glaucoma: A Brief History For the first time, glaucoma was described as a blinding disease associated with high intraocular pressure (IOP) by the Persian physician Ali ibn Rabban at-Tabari (810–861 C.E.) in the writings Firdaws al hikma (Paradise of Wisdom).1 This association was later pointed out by Richard Banister of England in his 1622 A treatise of one hundred and thirteen diseases of eye: “If one feele the Eye by rubbing upon the Eie-lids, that the Eye be growne more solid and hard than naturally it should be...the humour settled in the hollow nerves be growne to any solid or hard substance, it is not possible to be cured.”2 In the 1800s, the Dutch ophthalmologist Franciscus C. Donders coined the expression “simple glaucoma” for increased IOP occurring without any inflammatory symptoms. In population-based surveys, intraocular pressure (IOP) has been consistently shown to be a continuous, positive risk factor for the prevalence of glaucoma, even through the normal range of IOP. The association of IOP and open angle glaucoma was first confirmed in studies in the 1990s, although still not in the form of a cause-effect relationship. In the Baltimore Eye Survey3 and the Barbados Eye Study4, IOP was found to be an important factor in glaucoma that correlated with increased prevalence and incidence.5 Statistically, elevated IOP does not equate with the diagnosis of glaucoma, and conversely, normal IOP does not exclude the diagnosis of glaucoma. From the standpoint of the management of individual patients, the significance of this is that the diagnosis of glaucoma must be based primarily on the examination of the optic discs and retinal nerve fiber layer and the evaluation of visual function. This often differs from the diagnosis of an individual at risk of converting to glaucoma, which includes other factors as reflected in glaucoma risk calculators (see Clinical Pearl: Predicting Glaucoma Risk).

Although IOP has been causatively linked to glaucoma development and progression, the value of IOP reduction in the treatment of glaucoma was passionately disputed until recently when the results of large randomized clinical trials of the late 1990s became available6,7 (Fig. 3.1). These studies demonstrated beyond correlation that a true causal relationship existed, by showing that lowering IOP can slow or prevent POAG progression. The two most noteworthy trials in this regard are the Ocular Hypertension Treatment Study (OHTS),8 which demonstrated that IOP reduction reduces the risk of conversion to glaucoma among ocular hypertensives, and the Early Manifest Glaucoma Trial (EMGT),9 which demonstrated that IOP reduction lowers the risk of glaucoma progression. Today, these studies have direct practical implications for daily patient care and are summarized in the following. While there are other risk factors for glaucoma, IOP remains the only modifiable variable used to prevent or delay progression. Other strategies, such as vascular,10,11 neuroprotective,11–14 or metabolic management15 appeared promising in animal experimentation or were recognized as risk factors (reviewed in10,16), but their influence on the course of glaucoma has not been established in randomized clinical trials.

3.2  I OP as a Function of Aqueous Humor Production and Outflow Intraocular pressure can be expressed using the modified Goldmann equation,17 which consists of four elements:

IOP = F/C + Pv – U

whereas F is the aqueous humor formation rate in microliters per minute, C is the facility of outflow in microliters per minute per millimeter of mercury, Pv is the episcleral venous pressure in millimeters of mercury, and U is the rate of outflow of

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_3, © Springer Science+Business Media, LLC 2010

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36

Fig.  3.1  Graph showing the incidence of open-angle glaucoma by intraocular pressure (IOP)7

aqueous humor via all channels that are intraocular pressure independent. Aqueous humor is produced by the ciliary body.18 The ciliary processes contain a fibrovascular core and are covered by a bi-layered epithelium. This double layer is the result of the optic cup invagination during embryogenesis. As it is joined apically, the basement membrane of the inner, nonpigmented epithelium is facing the posterior chamber. The vasculature is connected to the major circle of the iris.19 Blood flows toward the network of choroidal veins and exits through the vortex veins. A sphincter-like system regulates blood flow that allows adjustment of filtration pressure and, consequentially, aqueous humor production to some extent.20–22 The capillaries from the anterior arteriole in the stromal core of the ciliary processes are lined by fenestrated endothelial cells, allowing the passage of macromolecules, ions, and water. The ciliary nonpigmented epithelium in contrast has zonulae occludentes, adherentes, and desmosomes23,24 constituting the blood-aqueous barrier of the ciliary body.25 It is primarily the epithelium at the tip of the ciliary processes that contains carbonic anhydrase and Na-KATPase to actively produce aqueous humor. Aqueous humor leaves the eye via two routes: (1) the conventional outflow tract by passing through trabecular meshwork (TM) into Schlemm’s canal and subsequently following circuitous channels toward the surface of the sclera into the episcleral vasculature, and (2) the uveoscleral outflow tract by absorption into uveal tissues.26,27 Most regard the juxtacanalicular meshwork or the inner wall of Schlemm’s canal as the primary source of outflow resistance.28 Past suggestions that increase in outflow resistance in primary open angle glaucoma (POAG) derive from the accumulation of extracellular matrix material in the open spaces of the uveal and corneoscleral trabecular meshwork have recently been shown to be problematic as these decrease with age and in POAG.29,30 Aqueous humor passes through the juxtacanalicular trabecular meshwork and the inner wall of Schlemm’s canal through micropores and unique giant vacuoles that form in a pressure-dependent and energy-independent

N.A. Loewen and A.P. Tanna

fashion.31,32 Around 30 external collector channels drain from the outer wall of Schlemm’s canal toward the scleral surface into a deep scleral plexus that leads to the deep scleral veins and eventually to the episcleral veins. Despite this small caliber vascular network and its ability to regulate flow,33 this effect is relatively insignificant. Several unique vessels, termed the aqueous veins of Ascher, bypass the deep scleral plexus directly into the episcleral veins.34 Under physiological conditions, 70–95% of outflow occurs through the trabecular meshwork and is pressure dependent.35–38 The pressure independent uveoscleral outflow can increase significantly during inflammation to 60%.26,27 Pharmacologic enhancement of uveoscleral outflow into the supraciliary space was first demonstrated in humans with prostaglandin acid prodrugs39 and prostamides.40 Despite increased leakiness of the ciliary body vasculature, intraocular pressure is usually decreased during intraocular inflammation because of increased uveoscleral outflow and disappearance of gap junctions that serve intercellular metabolic and electronic coupling of ciliary epithelial, resulting in decreased aqueous humor production.41,42 IOP can be decreased through carbonic anhydrase inhibitor mediated reduction of aqueous humor production,43 betaadrenergic antagonists,44 and alpha-adrenergic agonists.45 The only medication class that addresses the primary pathology of reduced conventional outflow, the parasympathomimetics,46 has been all but abandoned because of its side effects and potential to reduce uveoscleral outflow.26 Trabeculoplasty has been employed to lower intraocular pressure by inducing remodeling of the TM and extracellular matrix.47 However, the extent of pressure reduction is much smaller than can be achieved with filtering procedures. Complete disruption of the TM and wall of Schlemm’s canal has recently been achieved with the trabectome,48 but this disruption is irreversible, creating a permanently open connection to the downstream drainage system. Therapies for advanced glaucoma traditionally attempt to lower intraocular pressure surgically by circumventing the outflow resistance of the TM by shunting aqueous humor to the sub-Tenon space (e.g., trabeculectomy, aqueous drainage device).49 These filtering procedures have a high rate of complication and failure50 despite the introduction of antifibrotics and improvement of drainage device design, respectively.

3.3  Important Randomized Clinical Trials 3.3.1  C  ollaborative Normal Tension Glaucoma Study Before the Collaborative Normal Tension Glaucoma Study (CNTGS),51 it was not known whether IOP that was in the

3  Glaucoma Risk Factors: Intraocular Pressure

normal statistical range was at all involved in glaucomatous optic nerve damage and visual field loss. During the study it became apparent that – similar to simple POAG – participating patients had a slower glaucoma progression (no progression in 5 years) when IOP was lowered by 30%. The most treatment benefits were observed in patients of female gender, with family history of glaucoma, without family history of stroke, without personal history of cardiovascular disease, and with mild disk excavation.52 Risk factors were female gender, migraine headaches, and optic disc hemorrhages.51,52 The natural course as well as the response to treatment can be highly variable, and treatment has to be individualized according to the stage of disease and rate of progression if the mentioned risk factors are not present.52,53

3.3.2  Advanced Glaucoma Intervention Study The Advanced Glaucoma Intervention Study (AGIS)54 has to be seen in its historical context. The goal of AGIS was to compare trabeculectomy with argon laser trabeculoplasty (ALT) in eyes that had failed medical management at a time when it was not established that ALT was less effective than trabeculectomy. Before 1980, trabeculectomy was the usual intervention for medically failing advanced glaucoma. AGIS established a benefit from lowering IOP in glaucoma by trabeculectomy55: Eyes with early average intraocular pressure greater than 17.5  mmHg had more progression than eyes with average intraocular pressure less than 14 mmHg. When IOP was less than 18 mmHg during all visits over 6 years in a separate analysis, mean changes from baseline in visual field defect scores were close to zero. A shortcoming is that AGIS was not originally designed to detect prevention of glaucoma progression but that preventative effects noted were detected in an after analysis.

3.3.3  C  ollaborative Initial Glaucoma Treatment Study The Collaborative Initial Glaucoma Treatment Study (CIGTS)56 compared treatment of newly diagnosed POAG with standard medical treatment (typically initial beta-blocker) versus filtration surgery. In the medication treatment arm, additional topical medications could be added, followed by ALT and filtration surgery if needed. In the surgical treatment arm, failed trabeculectomy could be followed by ALT. The surgical group had IOPs that were 2–3 points lower than the medical group. Surprisingly, despite the lower IOP, the surgical group had more visual field and more visual acuity loss

37

than the medical group in the first 3 years, but this difference disappeared in the follow-up.57 There were 3.8-fold more cataract extractions in the surgical group58 in the initial 5 years after trabeculectomy but not thereafter. While the surgical group complained about foreign body sensation at the bleb site, the medical group experienced more systemic symptoms. Results from CIGTS did not support altering treatment practices of initial medical management of patients with primary open-angle glaucoma.59

3.3.4  O  cular Hypertension Treatment Study and the European Glaucoma Prevention Study The purpose of the Ocular Hypertension Treatment Study (OHTS)8 was to determine whether the pharmacological reduction of elevated IOP can prevent glaucoma and to define risk factors for glaucoma development. Topical ocular hypotensive medication was effective in delaying or preventing onset of POAG in individuals with elevated IOP by about 50%. Results to date have shown an approximate 50% reduction in conversion from OHT to POAG, with a 20% reduction in intraocular pressure.60 OHTS demonstrated that medical treatment of people with intraocular pressure of ³24 mmHg reduces the risk of the development of primary open-angle glaucoma (POAG) by 60%.61 Factors that predicted the development of POAG included older age, race (African-American), sex (male), larger vertical cup–disc ratio, larger horizontal cup–disc ratio, higher intraocular pressure, greater Humphrey visual field (VF) pattern standard deviation, heart disease, and thin central corneal thickness.62 Reduction in IOP in the medication group was 22.5 ± 9.9% versus 4.0 ± 11.6% in the observation group. At 60 months, the overall probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group.60 Of African-American participants, 8.4% developed POAG in the medication group when compared with 16.1% in the observation group.63 The occurrence of an optic disc hemorrhage was associated with an increased risk of developing a POAG end point in participants in the OHTS. However, most eyes (86.7%) in which a disc hemorrhage developed have not developed POAG to date. The 96-month cumulative incidence of POAG in the eyes without optic disc hemorrhage was 5.2%, when compared with 13.6% in the eyes with optic disc hemorrhage.64 The same predictors for the development of POAG were identified independently in both the OHTS observation group and the European Glaucoma Prevention Study (EGPS)65: placebo group-baseline age, intraocular pressure, central corneal thickness, vertical cup-to-disc ratio, and Humphrey VF pattern standard deviation.66 There was no

38

evidence for a general effect of topical ocular hypotensive medication on lens opacification or visual function.67 Results of EGPS have to be interpreted with caution as several design problems might have caused the odd finding that IOP was lowered in the placebo-control group as well: (1) a high patient drop-out rate, especially in the dorzolamide arm; (2) commitment to dorzolamide treatment regardless of therapeutic effect; and (3) determination of baseline pressure with just two readings that could have been merely 2  h apart.68

3.3.5  Early Manifest Glaucoma Trial The Early Manifest Glaucoma Trial (EMGT)9 compared how glaucoma progression was affected by immediate combined medical (betaxolol) and laser therapy for newly diagnosed OAG with normal or moderately elevated IOP versus late or no treatment. Treatment caused an average reduction of IOP of about 5 mmHg (25%), which reduced glaucoma progression to 45% when compared with 62% in the control group and occurred later. These benefits were preserved after stratifying for age, ethnicity, and POAG stage and type. The percent of patient follow-up visits with disc hemorrhages was also related to progression (hazard ratio = 1.02 per percent higher).69 Progression risk decreased by about 10% with each millimeter of mercury of IOP reduction from baseline to the first follow-up visit (HR = 0.90 per millimeter of mercury decrease).69,70 Elevated IOP was a strong factor for glaucoma progression, but intraocular pressure fluctuation was not.70 Higher IOP, exfoliation, bilateral disease, and older age were progression factors previously known.71 New baseline predictors were lower ocular systolic perfusion pressure (£160 mmHg; HR 1.42), cardiovascular disease history (HR 2.75) in patients with higher baseline IOP, and lower systolic blood pressure (BP) (£125 mmHg; HR 0.46; 95% CI 0.21–1.02) in patients with lower baseline IOP. Thinner central corneal thickness (CCT) (HR 1.25 per 40 micrometer lower) was a new significant factor, a result observed in patients with higher baseline IOP.

3.3.6  Conclusion from Randomized Trials Lower intraocular pressure does delay or prevent progression of POAG as evidenced by delay or prevention of development of optic nerve damage from ocular hypertension, visual field defects from existing optic nerve changes,

N.A. Loewen and A.P. Tanna

and reduced progression of existing visual field defects. However, another conclusion is that despite good IOP control in many actively treated patients, POAG can still progress and can result in blindness in an unacceptably large number of patients.72,73

3.4  I OP as Risk Factor for Glaucoma Development The role of IOP in the diagnosis of glaucoma is different from its role in treatment. Because of the wide range of IOP that can be found inter-individually as well as intra-individually (as will be discussed), a single IOP measurement above the expected average has little merit. Glaucoma risk calculators reflect the complexity of multiple other glaucoma risk factors that bear equal or greater significance. At least one variable – central corneal thickness (CCT) – influences IOP measurements directly and must be taken into account when judging IOP that was measured clinically with the most common technique: Goldmann applanation tonometry. In addition, CCT may be an independent risk factor reflecting overall ocular rigidity, including that of the lamina cribrosa. One recent histological study questioned this theory when no correlation was found in nonglaucomatous human globes between CCT and lamina cribrosa and peripapillary scleral thickness.74 Histologic artifact and sectioning methods could partially account for the lack of a predicted association. CCT instead inversely correlates to optic disc size in Caucasians75 suggesting that – following Laplace’s law – a disc with a larger radius would be more deformable and vulnerable than a small one.

3.4.1  C  linical Pearl 3.1: Predicting Glaucoma Risk Ophthalmologists can show a high range of estimates for the probability of developing glaucoma in the same ocular hypertensive patients. In comparison to OHTS glaucoma risk calculations, treating physicians underestimated the risk of developing glaucoma by almost twofold on average.76 This can lead to either under- or over-treatment of patients. Clinicians need a more exact method to determine the probability of glaucoma from ocular hypertension. Gordon et al have recently developed a point system (Table 3.1) that can be more easily used than risk calculators for estimating the 5-year risk of developing POAG.66

39

3  Glaucoma Risk Factors: Intraocular Pressure Table 3.1  Glaucoma risk calculator Baseline predictor

Points for baseline predictor

0 1 2 3 Age (years)  21 mmHg) indicates the limited usefulness of IOP for the screening and diagnosis of glaucoma. According to the data obtained in Proyecto VER, screening results with an intraocular pressure higher than 22 mmHg (in the eye with a higher pressure) would miss 80% of the OAG cases. Among the participants with OAG in the LALES, the mean IOP was 17.3 mmHg, with 82% having an IOP of £21 mmHg. Higher systolic blood pressure, higher central corneal thickness, and diabetes mellitus were the major factors associated with elevated IOP in this study. The prevalence of OAG was 40% higher in participants with type 2 diabetes mellitus (T2DM) than in those without T2DM in the LALES. Trend analysis revealed that a longer duration of T2DM was associated with a higher prevalence of OAG. Proyecto VER found no association between primary OAG and a history of T2DM. The relatively high prevalence of DM and OAG in this group presents significant public health implications. While OAG is generally a disease that occurs bilaterally, over half (53%) of all persons with OAG in the LALES had only unilateral glaucomatous optic nerve damage at the time of examination, and 58% had OHT in one eye and no OAG or OHT in the other eye. The central corneal thickness (CCT) among persons with OAG was less than that of those with ocular hypertension (OAG, 545 mm; ocular hypertension, 568 mm). Prevalences of visual impairment in persons with and without OAG were 6.6 and 1.07%, respectively. Prevalences of legal blindness in persons with and without OAG were 1.04 and 0.37%, respectively. Overall, findings from the LALES regarding the causes of low vision are similar to those from Proyecto VER despite known demographic differences such as the LALES population being slightly younger, having fewer female participants (58% vs. 65%), and lesser Native American ancestry (5.3% vs. 40%). In addition to demographic differences, other factors may contribute to differences, including environmental exposure, accessibility and use of eye care services, and patterns of surgical practice in the two communities. The LALES results, as compared with those from the Proyecto VER study, show a striking similar percentage of vision loss from cataract (49.% vs. 46.7%), diabetic retinopathy (17.3% vs. 13%), and age-related macular degeneration (14.8% vs. 14.1%) together accounting for 82% of the low vision cases identified in the LALES. Contrary to the Proyecto VER study, LALES did not find glaucoma to be a major cause of blindness in Latinos, instead found age-related macular degeneration, diabetic

10  Glaucoma Risk Factors: Ethnicity and Glaucoma

retinopathy, and myopic degeneration to be more of a concern in this population, accounting for 62.5% of the cases of blindness. This may suggest that the severity of glaucomatous damage is less advanced or that the diagnosis was made at an earlier stage of the disease. In addition, this population of Latinos on average is younger than those in other population-based studies, and the course of their glaucoma over time remains to be determined. Even though the LALES data are applicable to the largest ethnic subgroup of Latinos who live in the United States, Latino persons of Mexican origin, they do not necessarily apply to other Latino subgroups such as Cubans, Puerto Ricans, or Dominicans. The data reported by the LALES suggest that Latinos with a predominantly Mexican ancestry have rates of OAG comparable to those of US blacks and significantly higher than those seen in non-Hispanic whites, and a high prevalence of ocular hypertension. Due to the fact that Latinos are the fastest-growing segment of the US population and vision loss from glaucoma can be prevented with early diagnosis and timely treatment, there is a need for directing additional resources toward preventing and treating glaucoma in the Latino population.

Bibliography Chopra V, Varma R, Francis BA, et al. Type 2 diabetes mellitus and the risk of open-angle glaucoma. The Los Angeles Latino Eye Study. Ophthalmology. 2008;115:227–232.

Likewise, Asians comprise many ethnicities, and findings in one group of Asians do not necessarily generalize to another group of Asians. For example, a nationwide Japanese glaucoma survey reported a prevalence of POAG that is intermediate between that of black-Americans and white-Americans, and a POAG to primary angle-closure glaucoma (PACG) proportion that is similar to that in western populations.7 In contrast, PACG is the predominant type of glaucoma in some Asian populations such as the Chinese.8 The Japanese have also been found to have a higher prevalence of POAG with lower intraocular pressures compared to other populations.7 The average intraocular pressure for patients with untreated POAG in this population was calculated to be approximately 15  mmHg. A population-based study of descendents of Japanese living in the United States

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Cotter SA, Varma R, Ying-Lai M, et  al. Causes of low vision and blindness in adult latinos. The Los Angeles Latino Eye Study. Ophthalmology. 2006;113:1574–1582. www.nei.nih.gov/ latinoeyestudy/. Doshi V, Ying-Lai M, Azen SP, et  al. Sociodemographic, family history, and lifestyle risk factors for open-angle glaucoma and ocular hypertension. The Los Angeles Latino Eye Study. Ophthalmology. 2008;115:639–647. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol. 1983;118:166–191. Memarzadeh F, Ying-Lai M, Azen SP, et  al. Associations with intraocular pressure in Latinos: The Los Angeles Latino Eye Study. Am J Ophthalmol. 2008;146:69–76. Quigley HA, West S, Rodriquez J, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects (Proyecto VER). Arch Ophthalmol. 2001;119:1819–1826. Rodriguez J, Sanchez R, Munoz B, et al. Causes of blindness and visual impairment in a population-based sample of U.S. Hispanics. Ophthalmology. 2002;109:737–743. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA. 1991;266:369–374. U.S. Census Bureau. (NP-T4-F) Projections of the total resident population by 5-year age groups, race and Hispanic origin with special age categories: middle series, 2025 to 2045. Available at: http://www.census.gov/population/projections/nation/summary/np-t4-f.pdf. Accessed February 4, 2004. U.S. Census Bureau. Current population reports. Population projections of the United States by age, sex, race and Hispanic origin: 1995 to 2050. P25-1130. 1996. Available at: http://www. census.gov/prod/1/pop/p25-1130/p251130.pdf. Accessed February 4, 2004. Varma R, Ying-Lai M, Francis BA, et al. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: The Los Angeles Latino Eye Study. Ophthalmology. 2004;111: 1439–1448. West SK, Munoz B, Klein R, et al. Risk factors for type II diabetes and diabetic retinopathy in a Mexican-American population; Proyecto VER. Am J Ophthalmol. 2002;134:390–398.

has not been conducted to confirm that this finding also applies to the Japanese-American population. However, clinical impression supports a similarity with the native Japanese population, at least among first-generation JapaneseAmericans. Aside from giving us clues as to which populations are at greater risk for developing glaucoma, prevalence studies have provided insight into the differences between and within various ethnicities/races.1–15 Table  10.1 illustrates the variability in POAG prevalence among various races/ ethnicities. Whenever possible, we use the more restricted nomenclature of “black-American” when the data have been derived from studies performed only in this specific population. When the data are fairly consistent over several different black populations, the more general designation of

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“black” is used. Likewise, “Mexican-American” is used rather than the more general term “Hispanic.” Either “whiteAmericans” or “non-Hispanic whites” are used rather than the more general designation of “white.” Studies in Asia may look at very specific regional or ethnic groups with very well-defined populations.15

10.2  R  ace/Ethnicity and Incidence of Glaucoma As has been noted, a number of population-based studies of prevalence in relation to glaucoma have been conducted. Incidence studies, however, have been few in number and of variable quality. Furthermore, direct comparison of the various population groups studied in the available incidence studies is difficult as study design, patient selection, duration of study, and definitions of disease differed. What we can gather from these published studies is that like prevalence the incidence of glaucoma is higher in blacks.16–19

10.3  Race/Ethnicity, Age, and Glaucoma Race/ethnicity is only one of many factors to take into account when evaluating a patient for a possible diagnosis of glaucoma. As people age, the prevalence and incidence of glaucoma increases in all races and ethnicities (refer to Tables 10.1 and 10.2). This finding is consistent among all major population-based epidemiologic studies evaluating age as a risk factor for glaucoma. It is important to note that the finding of higher POAG prevalence with advancing age is more pronounced in blacks and Mexican-Americans compared to non-Hispanic whites. In the Baltimore Eye Study, as an example, the prevalence of POAG in black-Americans between the ages of 40–49 was 1.2% and increased to 11.3% in those above 80 years of age.1 The same study estimated a prevalence of 0.9% and only 2.2% in the same age groups for white-Americans. This accelerated prevalence with age was also seen, yet more pronounced, in Caribbean blacks in Barbados and St. Lucia.2,3 The prevalence studies conducted on MexicanAmericans living in both Southern California5 and Arizona6 revealed a similar pattern of increased prevalence compared

Table 10.1  Age-specific prevalence of definite primary open-angle glaucoma Black

Age (years) 30–39 40–49 50–59 60–69 70–79 70+ 80–89 80+ 90+ All

White

Hispanic

Asian

Baltimore1

Barbados2

St. Lucia3

Baltimore1

Melbourne9 Thessa-loniki4

Proyecto6

American

Caribbean

Caribbean

American

Australian

Mexican- MexicanAmerican American

1.23 4.05 5.51 9.15

 4 7.3 8.7 15.2

1.4 4.1 6.7 14.8

0.92 0.41 0.88 2.89

0.1 0.6 1.9 5.2

Greek

LALES5

Tajimi7

Liwan District15

Japanese

Chinese

2.6 4.9

0.5 0.59 1.73 5.66

1.32 2.92 7.36 14.72

2 2.7 4.7 8.2

  1.1   2.9   5.5

4.3

12.02 20

21.76

6

12

3.8

2

3.9

  3.9

9.5 5.5 11.26

23.2

4.74

2.16

6.8

8.76

1.29

11.8 1.7

4.74

Table 10.2  Age-specific incidence of definite primary open-angle glaucoma White

Black Barbados Eye Study

Melbourne VIP Project

Age (years)

(4-year incidence)

(9-year incidence)

Age (years)

(5-year incidence)

40–49 50–59 60–69 70+

1.2 1.5 3.2 4.2

2.2 3.6 6.6 7.9

40–49 50–59 60–69 70–79 80+

0 0.1 0.6 1.4 4.1

Total Annual incidence

2.2 0.55

4.4 0.489

Total

0.5 0.1

Rotterdam Eye Study Age (years) 55–59 60–64 65–69 70–74 75–79 80+ Total

(5-year incidence) 1.4 0.6 1.8 2.4 2.6 2.6 1.8 0.36

Blue Mountain Eye Study Age (years)

(10-year incidence)

70

 2 3.7 10.3

Total

4.5 0.45

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to white-Americans. The Los Angeles Latino Eye Study estimated a prevalence of 1.32% in Latinos of Mexican descent in the 40- to 49-year-old age group and 21.76% in those who were 80 years old or older – the most pronounced increase of prevalence in any population group studied thus far. We have clear evidence that the probability and risk of developing POAG increases with age through both prevalence and incidence studies. This information is useful in evaluating patients with suspected glaucoma as it can influence treatment patterns for patients. As glaucoma in all races/ ethnicities is rare prior to the age of 40, a patient’s age should be considered a risk factor for open-angle glaucoma. Simply stated, the older the patient is, the higher the risk. Further, the risk profile as a function of age is accentuated in blacks and Mexican-Americans.

10.4  Race/Ethnicity and Ocular Risk Factors 10.4.1  Intraocular Pressure We know from various studies that intraocular pressure (IOP) is a major risk factor for the development of and the progression of glaucoma.1,20–22 However, there is no magical value of intraocular pressure at which patients are either absolutely protected from or absolutely certain to developing glaucoma. Historically, there was a range of intraocular pressures of 10–21  mmHg that was considered “normal.” Being within this “normal” range, however, does not protect one from developing or having glaucoma, or from having an individual patient’s disease progress. Also, being above this IOP range does not necessarily mean that one will develop glaucoma or have glaucoma. So how does intraocular pressure matter in relation to glaucoma? Lowering the intraocular pressure in those patients suffering from POAG definitively reduces the incidence of disease progression.23–26 And lowering the intraocular pressure in certain patients with ocular hypertension also reduces the risk of progression to POAG.23 When comparing blacks and whites, there are conflicting reports in the medical literature, discussing differences in baseline IOPs in nonglaucomatous,1,20,27,28 ocular hypertensive,29,30 or POAG31–33 eyes. But there may be a racial difference in patient susceptibility to developing optic nerve head damage for a given intraocular pressure. In one study, optic nerve head and visual field progression were more prevalent in untreated black-Americans than in untreated white-Americans with POAG despite having identical IOP levels.32 Additionally, a study in South Africa reported that while only 5.4% of whites with ocular hypertension progress to POAG, 18.1% of blacks with ocular hypertension progress to POAG.29

Given this information, we may be more prone to initiate treatment earlier in black patients with ocular hypertension and may even be more aggressive in our degree of IOP reduction compared to our non-Hispanic white patients. The role of central corneal thickness and race in the measurement of IOP will be discussed more fully, but it may be that most clinical studies done before the turn-of-the-century failed to account for IOP measurement errors that might vary systematically (on average) in different racial/ethnic populations. As previously mentioned, the Japanese have been found to have a much higher prevalence of POAG, with intraocular pressures 21 mmHg or lower compared to other populations.7 In addition, the population sample in this study had a higher prevalence of POAG with pressures 21  mmHg or lower (3.6%) compared to that of POAG with an intraocular pressure greater than 21 mmHg (0.3%). This higher prevalence of POAG with lower intraocular pressures might be accounted for by the known thinner central corneal thickness in the Japanese population. This information, however, does not automatically translate into an increased prevalence of “low-tension” glaucoma among other Asian populations. Further prevalence studies are required in different Asian populations to determine if other Asian populations are at greater risk for developing glaucoma in the face of lower intraocular pressures.

10.4.2  Central Corneal Thickness For decades, Goldmann applanation has been considered the gold standard for measuring intraocular pressure. We do know, however, that the measurement of intraocular pressure can be influenced by the thickness of the central cornea. It is thought that thinner corneas may underestimate and thicker corneas may overestimate the actual intraocular pressure.34–36 The importance of this phenomena is not clearly understood and there are differing opinions on the necessity to correct the intraocular pressure based on the thickness of the central cornea. Central corneal thickness (CCT) does become important when dealing with patients suffering from ocular hypertension because those with thinner CCT measurements (5%) should be rejected. There is no meaning to phrases such as “sort of,” “almost,” and “maybe-a-little” significant. Without a hard delineation for statistical significance, the concept becomes useless and statistical analysis itself becomes meaningless. When performing analysis of a paper, subtle omission of data by arbitrary “cutoffs” is another common problem that occurs when results are presented. Surgical studies commonly use arbitrary definitions of success and only present results for those patients that yield data meeting these arbitrary values. Glaucoma drug studies commonly present graphs with a limited range of values that exaggerate small differences in pressure – this makes small changes seem to be of great clinical importance. Scientific truth requires that all data associated with an investigation are presented without regard to the success or failure of the underlying hypotheses. Finally, the Results section should not introduce new experimental variables. Only variables described in the introduction and defined critically in the Methods section should be presented in the Results section. Ex post facto introduction of interesting variables is forbidden in the Results section. If the data analysis discovers interesting new variables for study, they should be described in the “Discussion” section and considered for future experiments.

There is a distinction between the way significance is used in the biological sciences and the use in engineering. In the biological sciences, experiments are typically done once and only once. Even when repeated, there are usually modifications. Therefore the 5% cutoff for significance is usually considered an absolute. This is the Neyman–Pearson model7 and how we will use the term “significance” throughout this chapter. It should be noted that in engineering and other physical sciences, experiments can be very short and repeated many times. Under these circumstances, the concept of “almost significant” does take on meaning. If an experiment is performed ten times and the p value is 0.08, and then after another ten replicates the p value is 0.07, and so on, at some point in the series the direction toward significance will be clear. In this situation, the concept of almost significant can take on meaning. The replication now becomes an important variable and allows significance to be predicted. In fact, the ability to predict the outcome of an experiment, with less than 5% uncertainty, was Fisher’s original concept of statistical significance.8 The engineers’ version of significance is much closer to Fisher’s original description of significance than is the biologic sciences. For our purposes, we will restrict significance to the 5% cutoff as an absolute delineation.

13.4  The Discussion Section The “Discussion” is where authors are allowed to show their creativity in interpreting the meaning of the data. If they favor certain outcomes, it is here in this section where it is permitted for them to say why the data did or did not support the experimental hypotheses. How do the results relate to other similar work? This is the place for intellectual interpretation of the data. What were the unique strengths and weaknesses of this study? What went right? What went wrong? Would the results have been different if the methods were changed in some ways? Were there any surprising findings? What do these results mean for scientific advancement (e.g., better patient outcomes)? Do these results suggest the design of future studies? The Discussion section should not just repeat the data presented in the Results section. Also, new data not found in the Results section should not be introduced. Although some of the relevant past literature can be presented in the introduction, the discussion should contain a review of the obtained data and analysis as compared to other studies. Do these data extend or contradict the current knowledge base on this topic?

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After reading the Discussion section, the reader should understand the study findings and be able to integrate them into the body of scientific literature on this topic. What did the study show? What caveats must be remembered? What advancement was achieved?

when listing references and bibliography. Secondary sources (a reference that discusses another reference that contains the issue under discussion) may propagate errors contained in the secondary source. The ideal citation is to find the very first presentation of a concept.

13.5  Figures, Tables, and Graphs

13.7  Statistic Essentials

While raw data are critical for the statistical analysis done in the study (and for future generations to mine as well), tables and lists of numbers can be difficult to interpret. Well-designed graphics engage the readers and allow them to see comparisons between groups and summary statistics (measures of central tendency and variability) that are not immediately obvious from the raw data tables or text descriptions. Graphics can highlight important findings in the data, but they can also be used to mislead the interpretation of the facts. Selection bias is common in graphics that appear in scientific papers. Including only those patients with an IOP of less than 21  mmHg may leave out a large number of patients for whom the experimental drug did not reduce IOP very much at all. The reader must have access to all the data – positive and negative. This last item is especially important as it is very easy to mislead with clever choices for the graph parameters or data exclusion. The concept also applies to choice of graph scale. It is easy to compress a difference not wanted, or expand the apparent difference if wanted, by choice of scale. Imagine a 1.5  mmHg difference in IOP between two groups, 17.5 mmHg vs. 16 mmHg. If graphed on a scale from 0 through 30 mmHg, this difference would appear trivial, but change the scale to 15–18 mmHg and the difference appears very large. By constraining the Y axis far from zero the reader is misled by the graphic into thinking that the small numerical difference in mean IOP between the two groups of patients is “large” and important.

Our scientific methodology assumes that there is a truth, a reality, that there really is an “answer.” Our job, as scientists, is to find this truth. To do so we must remove our own biases as much as possible and we must attempt to observe nature in its purest, most undistorted form possible. Random sampling of data is the method that best achieves these goals.

13.6  Citations Scientific publications that are evidenced-based need to contain references for all the statements found throughout each of the formal sections of the paper. It is very common for authors to assume that information that is generally well known by scientists in the specific field does not need to be referenced. Nonetheless, although not strictly required, it is helpful to have references to all the things we have learned by interacting with our colleagues and our teachers, which we just assume are “given” in our special field. It is best to find primary sources rather than secondary sources such as textbooks and discussions from literature

13.7.1  The Box of Truth Think of the reality we seek to discover by research as a something inside a box. We may reach into the box of truth and grab something, pull it out and examine it, but we cannot directly see into the box. We do not know if what we have grabbed is representative or unusual of the items contained in the box. We do not even know if we have altered or damaged the item by our grabbing it for examination. We do not know the size of the box or how many pieces it may contain. All we have is what we grab, a sample from the total population (or universe) of items within the box. We may grab again, but it yields nothing more than another piece of the something inside. Should we grab again? If so, how many more times? What do we do with what we grab? The art and science of statistics is our guide to understanding samples and populations and also gives us guidance for understanding the truth of our research data. The building blocks of statistics are samples. Sampling is the act of taking a measurement. It is well known, from fields as disparate as quantum mechanics (Heisenberg’s uncertainty principle9) to factory production (Hawthorne effect10), that the act of measurement may itself change what is being measured. Using sampling methods we can determine the number of grabs that are likely needed to characterize the population accurately and evaluate the resulting pieces that have been grabbed (samples). Two critical concepts result from this idea. The first is that the act of sampling must be regulated. This process of sampling in a regulated fashion is called randomization. Randomization is done to reduce our selection bias when choosing samples (see section titled “Bias”). Second is that we may plot the results of sampling to see what sort of grouping or a shape may be formed to summarize the data. Such a graph is called a sampling distribution.

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The distribution obtained from a regulated (randomized) sampling process is the foundation of all statistical tests. Mathematicians have developed different statistical tests for each of many different kinds (shapes) of sampling distributions. It is imperative to have some idea of the type of distribution exhibited by our research data so that we can select the appropriate statistical tests for analysis. Also note that unregulated sampling, not randomized, yields what is formally called anecdotal data and has little value for scientific enquiry designed to determine “truth.” The exception is when the anecdote negates the generalization. If we declare all bacteria susceptible to antibiotic X, and someone presents a bacterium that is not, then this anecdote provides great value. The reverse, presenting a positive finding and declaring it as generalized, is completely inappropriate and will lead to dangerously wrong solutions. The example would be presenting a single bacterium sensitive to antibiotic X and then declaring all bacteria susceptible to X.

Bias Bias, in the statistical sense, is not a pejorative term. It is the acknowledgment that we cannot possibly perform an experiment without outside influence. Selection bias is a necessity. We do not randomly enter peoples’ homes to begin a research study. Rather, patients who we wish to enroll in a study present to us in a medical setting. We do not hijack people off the street and randomize them into having one of two different kinds of glaucoma surgery. We enroll those who present to us, meet explicit criteria, and agree to enter the study. There is very little randomness about this selection process. Yet once a patent qualifies for surgery and is willing to enter the study, we may then randomize them to either of the two treatments and we can thereby reduce some of the unnaturalness, or bias, of the selected group. Opinion bias of the researcher is also mandatory. If a researcher were to have zero bias regarding a research interest, then there would be no stimulus for the physician to perform the research. The researcher would not care enough about the result to justify the effort of doing the study. The entire reason a study is done is because someone believes in something strongly enough, is biased enough, to perform all the work required of a study. Researcher bias is the driving force of research. It is just that while the scientist may hope for a certain outcome, he/she must do everything to ensure that such bias has the least influence humanly possible on the design of the experiment, the choice of statistical analyses used, and the interpretation of the data obtained.

13.8  Randomization Why is randomization so important? The long answer lies deep within probability theory and has its ancient roots in gambling.11 If we return to our “box of truth,” we would not want to grab all the samples from only one corner of the box. We want to know the truth, a representation of the entire contents of the box. Therefore, we would want to grab samples from all over the entire volume of the box. The “all over” part describes randomization. The more randomly we can place our grabs, the better our samples will represent what is really in the box. This is the reason randomization is so important, and why it is critical to inspect the Methods section of an article very carefully. Salsburg discussed R.A. Fisher’s analysis of 90 years of nonrandomized fertilizer crop data. It was found completely useless because it was collected in a nonrandomized way.7 This demonstrates the concept that randomization is more important than sample size when searching for the truth. A small (number of subjects), well-randomized study is much more likely to yield quality results than a large, poorly randomized study. It is often assumed that large is good, small is not, but this is incorrect. The randomization is the primary determinant of study quality. One should evaluate the methods carefully to understand the care used in the randomization process. Many studies fail at this step. If randomization is not done appropriately, the rest of the paper will describe worthless observations. Poor randomization might lead to good results by chance alone, but more often will produce poor results with limited value. Key elements found in strong randomization methods include: (1) study designs purposely biased against the hypothesis, (2) masking, (3) independent analysis, and (4) post hoc evaluation of randomness. As noted, all studies have a research hypothesis or bias. If the hypothesis is that drug A works better than drug B, then the study design should purposely aid drug B. Imagine two glaucoma drugs, each given to a different group of patients. If the mean starting IOP of group 1 is 26.7 mmHg, and the mean starting IOP of group 2 is 26.3 mmHg then drug B should be assigned to group 2, assuming final mean IOP was the endpoint. The very small, 0.4 mmHg, IOP advantage should go to drug B, because this is appropriately biased against the researcher’s hypothesis. Doing this helps balance the presumed natural advantage of the favored drug A. Because both subjects and scientists are biased, both consciously and unconsciously by what they observe, it is key to design research with double-masked experimental treatments and outcomes wherever possible. For example, using drugs in identical masked containers (labeled drug A and drug B) or having one investigator manipulate the dial on a Goldmann Tonometer but another observer reading

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and recording the measurement without announcing values helps protect against such bias. Although a luxury, having the statistical analysis performed by an independent entity (e.g., a centralized reading center in a multicenter study for optic nerve head photos or visual fields) also helps reduce bias if the data sets (i.e., treatment groups for photos and fields) are masked to the analysts. This is not always possible for both economic and other pragmatic reasons. Alternatively, it would be best if separate members of the research team analyze the data, distinct from those who conduct the project and examine patients and administer treatments. At the very least, the statistical database should be encoded to mask the data identity. Finally, because even the best randomization plans may end up with nonrandom results, post hoc analysis of the randomization plan is useful and easy to do. If two experimental groups of patients are created from one large group, it is a simple task to determine if the variance of the sample is the same as the variances of the randomized groups. If not, then the study analysis must be changed to accept this situation. This will be explained later. It is important to realize that even the best randomization methods do not guarantee randomized results. Probability theory dictates that a nonrandomappearing result will occur in a small percentage of trials. This result alone does not imply poor randomization.

13.9  Scales of Measurement: Data Types Data resulting from observations made in research studies fall along four kinds of measurement scales called nominal, ordinal, interval, and ratio. Each succeeding scale represents a higher degree of measurement (as described in this section), with more powerful statistical tests being available as we progress from nominal to ratio data. Nominal data is named data – data that may be classified into categories. Examples of nominal classification include color (values: red, yellow, green, etc.), gender (values: male, female), and musical genre (values: classical, rock-and-roll, hip-hop, etc.). Nominal data are commonly found in the ophthalmology literature. We classify subjects in glaucoma experiments by race, gender, and presence or absence of a disease. Even pre-op and post-op classifications are nominal categories. Beware of tortured nominal data, artificial categories such as “less than 21 mmHg” vs. “greater than 21 mmHg,” that are arbitrary and easily manipulated. Intraocular pressure is measured along an interval scale (discussed below) and such data should not be arbitrarily divided into coerced nominal categories and then treated statistically as if it were nominal data. There is a difference between what we measure and what we describe. A description is a nominal or categorical result. A measurement is a continuous result.

D. Eisenberg and P.N. Schacknow

Ordinal data produce a ranking such as: A > B > C, but the magnitude between entries is not regular or not even known: A − B ¹ B − C. Example: 20/20 > 20/40 > 20/100 is a ranked result of visual acuity with unequal differences between the items. We often need ranked data when trying to evaluate subjective findings such as hyperemia, irritation, pain, or the degree of cataract. Anything that cannot be precisely measured, but can be graded or ranked, yields ordinal data. These forms of data are very common in ophthalmic research. Most of the symptoms patients describe as symptoms or the signs we see during examining them are graded as ordinal data. The patient is asked to describe pain on a scale of 1–10, but nuclear sclerotic cataracts are graded 1–4+. Interval data are numbered (and thus able to be ranked) with the numbers evenly spaced, but there is no natural zero. Here A > B > C, and A − B = B − C. The majority of our studies use interval data. Eye pressure and blood pressure in mmHg and the Fahrenheit and Celsius temperature scales measured in degree units are examples of interval scale data. Wait, you say, all four of these scales have a zero. They do, but it is not a natural, physical zero, representing “none” of the quantity being measured. All of these examples have possible measurements that are less than the scale zero, that is, negative values are possible. For the pressure scales, both eye pressure and blood pressure measurements are relative to earth’s atmospheric pressure, not the vacuum of outer space (true zero pressure). The two temperature scales have arbitrary zero values, different for each scale. Ratio data are interval scale data but with a natural, physical, zero. Temperature in Kelvin degrees is a ratio scale measurement. It represents true zero because it is the temperature at which molecular motion stops. Time measured from start is on a ratio scale of measurement, but timeline data are interval scale because the numbers relate to each other but not a true zero. Very few biological metrics are ratio scale. The good news is that the distinction between interval and ratio measurement is mostly unimportant for us as data analysts performing research. That’s because all major statistical tests are designed for interval scale measurements and remain statistically valid for ratio scale measurements as well. A special note about data that are “counted items.” It is tempting to consider counted data as interval data, but this is not correct and leads to bizarre and unclear outcomes. For example, we commonly see studies that report that the patients used 2.6 drops per day, or the typical family has 2.5 children. Clearly neither the drops nor the children are likely to be partial, non-integer, entities. Counted data are special and require special handling or else impossible findings occur. Think of counted data as groups of nominal data. We first name what we find and then count how many of each type is found. This is clearly not the same as taking a continuous measurement.

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Assuming data on the wrong scale of measurement may lead to the use of inappropriate statistical tests and yield invalid conclusions. Unfortunately this is more commonplace than might be expected. Some tests, however, are mathematically robust enough to handle data that they were not designed to evaluate. Note that the term “robust” in statistics means essentially “flexibility.” A robust test is able to tolerate deviations from the ideal and still produce valid results. It is valid, but not always desirable, to use statistical tests designed for lower scales on higher scale data, but not the reverse. Higher scale tests cannot be used with lower scale data. For example, it is possible and valid to use an ordinal scale test, such as the Mann–Whitney U-test, on interval scale data, like intraocular pressure. Discrimination ability (statistical power) will be lost, and this might make it an unwise choice, but still technically correct. The problem here is not that it is wrong to use the lower form of statistical test. It is just that the chances of finding meaningful (statistically significant) differences are lessened when the lesspowerful test is applied to higher-scale data. But let us emphasize that a test developed for a higher scale of measurement uses underlying assumptions that render it useless for analysis of lower scale data. For example, the very commonly used “Student’s t-test” should not be used to compare the mean Snellen visual acuity between two groups of subjects, because it assumes interval or ratio scale of measurements, while Snellen data are ordinal scale metrics. Using the t-test on these data is wrong and any results will be incorrect. (Interestingly, this popular test was developed in 1908 by William Gossett to aid in evaluating the Guinness brewing process. His employer forbid publishing and so he used the pseudonym “Student” to protect his identity.) It is mathematically possible to analyze counted data with a t-test, but the results are undefined and likely to be misleading. You can do various statistical tests on any set of numbers, but if the assumptions underlying the test are violated, the results are not valid.

13.10  Distributions: Part I Distributions are the way we visualize and organize the results of our grabs (samples). Say we grab ten samples and all ten items come out red. Our nominal distribution, sorted by color, would have a single column labeled red, ten units high. We could be very comfortable declaring that the stuff in the box was very likely red and our next grab would most likely be red. If we then examine a blue item we could declare that it was unlikely to have come from our box. However, if we grabbed ten items from another box and we obtained two red, two blue, two yellow, two green, and two pink items,

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then our distribution, sorted by color, would be flat. We would have no good way to predict the color obtained by the next grab. Another blue item could likely come from this box. Statistical testing is the method of comparing one distribution to another, and estimating the likelihood or probability that they are one and the same set of data. All statistical tests that sample data produce results that are expressed as probabilities. This is not to be vague or indecisive, but to illustrate that we never really know the contents of the box. Some boxes have a very large, unknowable or even infinite content. We can only sample a small portion of the contents, hopefully in a representative fashion. Everything we do in statistics, and life, is but a sampling of the total possibilities of the universe (population) of data. The term “likely” is a reminder that we are only making estimates of the truth based on our sampled data. Statistical testing is usually stated in terms of the “null hypothesis (H0),” although it may seem like a counterintuitive way to go about comparing alternatives. This concept was first developed by the legendary geneticist and mathematician Sir Ronald Fisher in 1925.8 The null hypothesis assumes that any kind of difference you see in the data between (among) two or more groups is due to chance and chance alone. This “chance and chance alone” is the presumed source of the findings until a statistical test rejects it, thus the double negative “reject the null hypothesis.” The confusing triple negative “fail to reject the null hypothesis” indicates the inability to reject and therefore a passive “acceptance” of chance as the main actor. We never accept the null hypothesis, or any other hypothesis, because we can never know the truth. This philosophical view is our scientific methodology. Mathematicians Jerzy Neyman and Egon Pearson, developed an alternate hypothesis (H1) model that is used in comparative study designs where one treatment is placed against another treatment, instead of against placebo.7 This alternate hypothesis model allows statistical power calculations. The term statistical power is an important term also related to distributions. The formal meaning of power is the degree of ability to correctly reject the null hypothesis, that is, to find a true positive result. For example, if a study has 80% power to find a true difference of 2 mmHg IOP between two samples, then a found difference of 2 mmHg will be correctly declared significant 80% of the time, and incorrectly declared not significant 20% of the time. We will not discuss the calculation of statistical power here, but it is important to note that it is heavily dependent on sample size and sample variability. Therefore, an otherwise excellently designed, masked, randomized controlled clinical trial may fail to show the desired outcome if the sample size (number of patients enrolled in the study) is too small and thus the power of the statistical testing is low relative to the degree of treatment effect. Put another way, if two drugs that truly have great differences in their ability to lower IOP were tested in two

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small groups of patients, you would likely find this large difference a “true” effect. But in order to find a statistical difference between two glaucoma medications with only slight differences in their ability to lower IOP, you would need much larger numbers of patients in each treatment group than in the first example. Large treatment effects are easier to demonstrate with smaller samples, while small treatment effects usually require larger samples. See Table 13.2 for an example of the interrelationship of power, statistical significance, and sample size. Power is especially important for negative studies because a low power test will have a large false-negative percentage finding “not significant” when in truth significance was correct. The obtained results in the low-powered test are then either truly negative, or, the study was underpowered and not able to discriminate the true difference that really exists between the groups. Power estimates, even post hoc, are therefore mandatory on all negative findings; otherwise the reader is unable to interpret the result. Overpowered studies, too large a sample size, are likely to declare trivial differences as “significant.” Correct study power balances false positive (Type I error) and false negative (Type II error) with respect to treatment effect and variability of the sample measurements as shown in Table 13.3. Table 13.2  Interrelationship of power, statistical significance, and sample size Original Neyman–Pearson model N

p

Power

Significant

90 0.001 0.92 Yes 80 0.002 0.88 Yes 70 0.004 0.84 Yes 60 0.007 0.78 Yes 50 0.01 0.70 Yes 40 0.03 0.60 Yes 30 0.06 0.48 No 20 0.12 0.34 No Difference of 1.5  mmHg, SD = 3.0, 2-tailed z t distribution.

Sample size Over (Error I) Over (Error I) Correct Correct Borderline Borderline Under (Error II) Under (Error II) test, power from

Table 13.3  Correct study power balances false positive (Error I) and false negative (Error II) with respect to treatment effect and variability of the sample measurements Significance and power Choice If null hypoth TRUE If null hypoth FALSE Not significant (same) Correct Error II false negative 1-Alpha% 1-Power% Significant (different) Error I false positive Correct Alpha (5%) Power (80%) Error I = declare significant when not: false positive (alpha%). Error II = declare not significant when it is: false negative (1-power%). Without power nothing can be said about case where null is false. We never really know the actual value of the null hypothesis. Adapted from Mandel J. Statistical Analysis of Experimental Data. Mineola, NY: Dover; 1984.

13.11  Distributions: Part II The shapes of the population and sampling distributions are the keys to understanding the data. To describe the shape of a distribution there are a number of key metrics. Most distributions have a density function that describes all aspects of the curve exactly. These density functions are very complex. For our purpose it is enough to know that they exist and that they are used to generate probabilities. Density functions themselves are never used in biologic reporting. Instead we more commonly see certain descriptive statistics to describe the data. Distributions of data are first described by measures of central tendency, various kinds of “averages.” You are most familiar with the arithmetic mean, hereafter called the mean unless otherwise indicated. (There are also a geometric and a harmonic mean, but these will not be described here.) It is calculated by adding up all the interval or ratio measurements and dividing the sum by the number of measurements. But the mean may not be the centermost point in the distribution, as it will be distorted if the distribution is not 100% symmetrical. Data points that are skewed to the right or left of the center will influence the calculation and shift the calculation of the mean toward the side of the distribution with the most and/or largest value measurements. For example, if 85 out of the 100 patients in a sample have IOPs between 18 and 22 mmHg, but 15 of the patients have IOPs of 50 mmHg, the mean will be 24.5 and not a good descriptor of the majority of the population. Outlying data influence the value of the mean. The mean tells us where the center of gravity lies for all of the values in the distribution, but it does not tell anything about the shape of the curve (symmetrical or nonsymmetrical). The median is defined as the measure of central tendency that is the point on an interval or ratio scale above and below exactly half of the data – truly the middle point. It is not influenced by large-value outlying measurements, only the rank order. More powerful statistical tests are possible on the mean as compared to the median. The mode is a meager descriptor of central tendency, defined as the most common value in the distribution. It is not used directly in statistical analysis but is a descriptive statistic used with nominal data, e.g., the most common name in a group of 150 middle school girls might be Brittany – the modal value. Measures of variability describe the shape of the distribution. The range is a simple statistic taken as the difference between the largest and smallest measurements. It is rarely used to describe the data in ophthalmic research except for very small size pilot studies and the presentation of patient ages. Similarly the mean deviation, which is the sum of the absolute (without regard to sign) differences of each

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measurement from the arithmetic mean of the distribution, divided by the number of measurements, is rarely used in statistical testing on higher-order data. The two most commonly used measures of variability used in statistical tests are the variance (V) and the standard deviation (SD), which is calculated as the square root of the variance. The variance is calculated by taking the sum of squares of deviations about the mean divided by the number of observations. (This eliminates the sign of each deviation from the mean.) The variance is a statistical value in squared units. The standard deviation is not in squared units and is more useful as a descriptive statistic while the variance is more useful in statistical calculations. The SD helps to describe the spread of the distribution relative to its mean. Is it tight and tall or wide and low? If we see one group has IOP of 24 mmHg with an SD of 4, compared to another group mean of 24 mmHg and SD of 7, we can know that the first group was a tighter set of measurements. The variance of data sets can and should directly be compared to determine if the two (or more) data sets are similar or have different variances. It is important to realize that many statistical tests are invalid if the variances of the groups to be compared are significantly different! It is unreasonable to simply assume that all sets of measurements result in equivalent variances. Of course there are methods designed to handle unequal variances (heteroscedastic in statistical speak). Also note that the SD, by itself, must be interpreted only with reference to the shape (type) of the underlying distribution. The SD only has meaning with respect to a specific kind of distribution. Fortunately, most biologic data are “t-shaped” or “normally (Gaussian)” distributed. Realize that by declaring the statistical tests you will use in the Methods section, you have by definition indicated that you know the distribution shape of the underlying experimental data. Some data sets that occur under less common experimental designs may not be normally or t-shaped in distribution. Examples include the Poisson and the related binomial distributions. These are discrete probability distributions that are useful for analysis of rare events. Using the Poisson distribution for statistical testing will be described later in this chapter.

13.12  Statistical Testing In scientific research, we formulate a hypothesis and conduct a randomized, double-masked clinical trial in an attempt to see if it is “true.” The data are interpreted by subjecting them to one or more appropriate statistical tests. These tests all state their conclusions in probabilistic terms. The results are described by the investigator not as certainties, but associated with some degree of doubt, even if the degree of doubt is small. We propose a null hypothesis that treatment one is

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no better than treatment two, or placebo. We then estimate the likelihood of finding a difference equal to or larger than the one that was found. If this probability is small, say less than 5%, we “reject” the null hypothesis of no difference in treatment outcomes and assert that the alternative hypothesis of differences in outcome for the two treatment conditions is true (significant). If the probability of the null hypothesis is not very small (>5%), we say that the treatment groups probably do not differ in response to the two medications (not significant, or formally, we “fail to reject” the null hypothesis). Results and interpretation of experimental findings are described in probabilistic terms. The degree of probability for rejecting the null hypothesis is described as the level of statistical significance (5% in the example above). Statistical testing, as used in clinical studies, is usually of the inferential type. This was the type of testing described earlier, where the goal was to predict the outcome of the next grab (sample). An inference is a statistical prediction of the population (the contents of the box) made on the basis of the characteristics of the sample. The way all statistical tests work is to compare the actual outcome to an estimated, theoretical outcome. The actual outcome is exactly what we have grabbed or sampled. The estimated outcome is our expected contents of the box (population) under investigation. In clinical terms, we hope that the limited observations made on the patients in the experimental groups reflect the true situation in the much larger population of all glaucoma patients, or at least those glaucoma patients with demographic characteristics similar to those patients in the study. These calculations for different kinds of distributions have been extensively worked out by mathematicians specializing in probability theory. You do not have to understand the details of the calculations to work with and interpret statistical tests. The concept of “statistically significantly different” means that the grabs (samples) obtained in one group is unlikely to have come from the same box as the other group, and that there are at least two different boxes. Formally we say there is less than a 5% chance that these distributions are really the same. Note that the exact nature of the measurement is not important. We do not care if the samples are intraocular pressure, phacoemulsification time, or any other defined parameter of interest. All measurements are converted into distributions, and then the distributions are compared to each other. (Of course this is the foundation of parametric statistics. Nonparametric or distribution free tests use alternate methods.) The final probability only declares the relationship of the distributions to each other. The exact method (i.e., the appropriate and most powerful statistical test) used to compare distributions does depend on the type of measurement in use. The statistician decides among the different tests available based on the characteristics of the (sampled) data set. As was mentioned when discussing measurement scales,

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each scale has an appropriate set of distributions and these distributions have appropriate sets of tests. There is some flexibility in which tests are chosen to analyze a specific set of data, but one must not “shop” for the test that gives the desired experimental outcome as statistically significant. The appropriate tests are determined a priori, before the data are analyzed, not a posteriori or “selected” after trying out several of them and seeing which gives the “best” results consistent with the researchers’ hypothesis. In short, looking for the test that gives the best statistical results is cheating! Let us explore the concept of “degrees of statistical significance” in some more detail. Some physicians and textbooks promote the idea that lower probabilities for the level of significance are associated with more important or stronger (more true) outcomes. For example, a probability (p) interpretation for the level of significance, like p 3 mmHg and ³20% reduction without additional drops at 1, 3, and 5 years were 58, 38, and 31% for SLT and 46,

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23, and 13% for ALT, but not statistically different. Another study showed success of SLT at 1, 2, 3, and 4 years at 60, 53, 44, and 44% with failure defined as need for any additional therapy, including another drop. Longterm evaluation of SLT as primary therapy is currently under way. The rate of responders who achieved at least 20% IOP reduction at 12 months was 59.7% for SLT and 60.3% for ALT. Those patients were on maximal medical therapy. When receiving SLT as primary therapy, responder rates with IOP lowering of ³20 and ³30% at 12 months were 83 and 55%. In the same study, patients who had been washed out of medications prior to SLT did not obtain as good results as primary SLT patients. In conclusion, SLT and ALT are the most common modalities of laser trabeculoplasty currently used. Most of the time, the choice of laser will be dictated by what machine is available to the treating physician. The studies show that both lasers are probably good primary therapy modalities with the potential to reduce cost, side effects, and noncompliance with medications. Nevertheless, due to lack of scarring of the trabecular meshwork, SLT has a theoretical potential to be repeated several times on patients who had prior ALT or SLT and it is also technically easier to perform treatment with this device. LTP should be considered in patients who are not good candidates for surgical therapy. The effects of both laser treatments have been shown to last with decreasing effect after 1 year.

Bibliography Chung PY, Schuman JS, Netland PA, et al. Five-year results of a randomized, prospective, clinical trial of diode vs Argon laser trabeculoplasty for open-angle glaucoma. Am J Ophthalmol. 1998;126(2):185–190. Damji KF, Bovell AM, Hodge WG, et al. Selective laser trabeculoplasty versus argon laser trabeculoplasty: results from a 1-year randomized clinical trial. Br J Ophthalmol. 2006;90:1490–1494. Damji KF, Shah KC, Rock WJ, et al. Selective laser trabeculoplasty vs argon laser trabeculoplasty: a prospective randomized clinical trial. Br J Ophthalmol. 1999;83:718–722. Fea AM, Bosone A, Rolle T, Brogliatti B, Grignolo FM. Micropulse diode laser trabeculoplasty (MDLT): A phase II clinical

study with 12 months follow-up. Clin Ophthalmol 2008;2(2): 247–252. Francis BA, Ianchulev T, Schofield JK, et al. Selective Laser trabeculoplasty as a replacement for medical therapy in open-angle glaucoma. Am J Ophthalmol. 2004;140(3):524–525. Fudemberg SJ, Myers JS, Katz LJ. Trabecular meshwork tissue examination with scanning electron microscopy: a comparison of Micropulse diode Laser (MLT), Selective Laser (SLT), and Argon Laser (ALT) Trabeculoplasty in human cadaver tissue. Invest Ophthal Vis Sci. 2008;49:ARVO E-Abstract 1236. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. Ophthalmology. 1990;97(11):1403–1413. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study: 7. Results. Am J Ophthalmol. 1995;120(6):718–731. Hodge WG, Damji KF, Rock W, et al. Baseline IOP predicts selective laser trabeculoplasty success at 1 year post-treatment: results of a randomized clinical trial. Br J Ophthalmol. 2005;89:1157–1160. Ingvoldstad DD, Krishna R, Willoughby L. Micropulse diode laser trabeculoplasty. Invest Ophthal Vis Sci. 2005;46:ARVO E-Abstract 123. Juzych MS, Chopra V, Banitt MR, et al. Comparison of long-term outcomes of selective laser trabeculoplasty versus argon laser trabeculoplasty in open-angle glaucoma. Ophthalmology. 2004;111(10):1853–1859. Latina MA, Sibayan SA, Shin DH, et  al. Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology. 1998;105(11):2082–2088. Lunde M. Argon laser trabeculoplasty in pigmentary dispersion syndrome with glaucoma. Am J Ophthalmol. 1983;96:721–725. McHugh D, Marshall J, Jffytche T, et  al. Diode laser trabeculoplasty (DLT) for primary open-angle glaucoma and ocular hypertension. Br J Ophthalmol. 1990;74:743–747. McIlraith I, Strasfeld M, Colev G, et al. Selective laser trabeculoplasty as initial and adjunctive treatment for open-angle glaucoma. J Glaucoma. 2006;15(2):124–130. Melamed S, Simon GJB, Levkovitch-Verbin H. Selective laser trabeculoplasty as primary treatment for open-angle glaucoma. Arch Ophthal. 2003;121:957–960. Ritch R, Liebermann J, Robin A, et al. Argon laser trabeculoplasty in pigmentary glaucoma. Ophthalmology. 1993;100:909. Robin AL, Pollack IP. Argon laser trabeculoplasty in secondary forms of open angle glaucoma. Arch Ophthalmol. 1983;101:382–384. Rubin B, Taglienti A, Rothman RF, et  al. The effect of selective laser trabeculoplasty on intraocular pressure in patients with intravitreal steroid-induced elevated intraocular pressure. J Glaucoma. 2008;17(4):287–292. Vishnu S, Catoira-Boyle Y, WuDunn D, et al. Efficacy of selective laser trabeculoplasty after argon laser trabeculoplasty in open angle glaucoma. Indianapolis, IN: Indiana University; 2007:ARVO poster 3971/B951. Weinand FS, Althen F. Long-term clinical results of selective laser trabeculoplasty in the treatment of primary open angle glaucoma. Eur J Ophthalmol. 2006;16(1):100–104.

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Sidebar 61.2.  New forms of trabeculoplasty Giorgio Dorin and John Samples In addition to the present modalities of laser trabeculoplasty (ALT, SLT, and MDLT), laser iridoplasty, laser iridotomy, laser iridectomy, and transscleral or endoscopic laser cyclophotocoagulation, there are a number of new potential laser applications for the treatment of glaucoma. These include transscleral application of infrared laser energy (a) to the pars plana to create a lowering of pressure, which we speculate may be due to increased uveoscleral outflow, and (b) to the Schlemm’s canal and nearby regions, a sort of trabeculoplasty ab-externo, which would work in angle closure or narrow angle situations. Finally, a deeper form of laser trabeculoplasty capable to interact with the deepest juxtacanalicular trabecular meshwork layers is considered.

Pars Plana Application of 810-nm Diode Laser in the Micropulse Emission Mode Application of laser to the pars plana to lower the intraocular pressure is not a new idea and, in fact, may be unknowingly performed by default with many transscleral laser cyclophotocoagulation procedures. In an animal study performed on monkey eyes, Liu and coworkers demonstrated that contact transscleral cyclophotocoagulation with the 1,064-nm Nd:YAG laser directed at the pars plana decreased IOP and resulted in tracer particles detectable in the suprachoroidal space. The same treatment over the pars plicata also resulted in IOP reduction, but without tracer particles detectable in the suprachoroidal space, suggesting two mechanisms of IOP reduction: lowering the production of aqueous humor with the treatment over the pars plicata and increasing the uveoscleral outflow with the treatment over the pars plana. Studies done with transscleral applications of infrared laser energy at the pars plana showed that coagulative necrosis can occur with these treatments. A study presented at the World Glaucoma Congress 2007 in Singapore suggested that micropulse diode laser applications over the pars plana can produce significant and long-lasting reduction of IOP without causing the destruction of any ocular structure. As a result, clinical trials are presently underway to study the lowering of pressure through the nondestructive micropulse laser application over the pars plana, whose mechanism of action remains to be elucidated.

External Laser Trabeculoplasty Laser trabeculoplasty delivered ab-externo through the sclera has the potential of overcoming some anatomic and physical disadvantages common to all present laser trabeculoplasty techniques with ab-interno gonioscopic laser delivery. A first obvious disadvantage is the prerequisite of an open angle to be applied. Another disadvantage, from an anatomic viewpoint, is that trabecular beams and less dense filtrating meshwork obstruct the delivery and the interaction of the laser energy with the deeper layers of the trabecular meshwork involved in the obstruction of the outflow. It has been suggested, though perhaps it is counterintuitive, that the application of infrared laser energy through the sclera could actually more effectively reach and interact with the walls of the Schlemm’s canal and perhaps with the juxtacanalicular meshwork, which are hypothesized as the site of origin of outflow resistance.

A Deeper Laser Trabeculoplasty From a gonioscopic approach, it seems intuitive that the deeper one is able to treat tissue the more likely the trabeculoplasty can produce a more pronounced hypotensive effect. At present the lasers most likely to have a deep interaction are those with infrared emission such as the 790-nm Titanium-Sapphire used for TLT and the 810-nm diode laser used in continuous wave emission for diode laser trabeculoplasty (DLT) and in micropulse emission for micropulse diode laser trabeculoplasty (MDLT). It could well be that these infrared lasers will be effective when conventional more superficial trabeculoplasty with visible emitting lasers (488/514 nm Argon laser, 532-nm CW frequency-doubled Nd:YAG laser and with 532-nm Q-switched frequency-doubled Nd:YAG laser) fails.

Staging of Treatment Laser treatments offer unique advantages in glaucoma management including flattening of the diurnal curve, elimination of compliance-related issues, decrease cost on a long-term basis, and difference in whether or not insurances will reimburse a treatment, usually favoring the laser. It is possible to visualize a time when the first treatment for glaucoma might be SLT followed by MDLT or TLT, followed by either nondestructive micropulse transscleral applications of trabeculoplasty ­ab-externo or pars plana cyclophotocoagulation or even both. This would occur in a stepwise fashion, and would have considerable advantage in terms of compliance and overall cost.

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However, much more clinical information is needed before this type of protocol is implemented. It is undeniably costeffective.

Conclusion Newer laser applications may reposition laser treatments with respect to invasive surgical treatments and medications in the management of glaucoma. The evolution of a laser-only protocol for treatment in select instances is anticipated.

Bibliography Aquino MCD, Tan A, Chew PTK. The initial experience with micropulse diode laser transscleral cyclophotocoagulation for severe glaucoma. World Glaucoma Congress 2007: Abstract P428. Ho Ching Lin, Wong EYM, Chew PTK. Effect of diode laser contact transscleral pars plana photocoagulation on intraocular pressure in glaucoma. Clin Experiment Ophthalmol. 2002;30:343–347. Liu GJ, Mizukawa A, Okisaka S. Mechanism of intraocular pressure decrease after contact transscleral continuous wave Nd:YAG laser cyclophotocoagulation. Ophthalmic Res. 1994;26:65–79.

61.3.1  I ridotomy Indications and Contraindications

61.3  The Iris Early in the 1960s some of the first-tested applications of laser for the eye were iris treatment to create an iridotomy.3 Iridotomy and iridoplasty are now among the more frequent laser treatments for glaucoma. These interventions are usually done for eyes with elevated IOP and angle closure, or for eyes with high-risk anatomic narrow angle. As with laser treatment for open-angle glaucoma, here again gonioscopic skill is important. The surgeon has to recognize that the angle is closed, partly or completely, and whether the closure is appositional or due to formation of peripheral anterior synechiae (PAS), or a mix of the two. If PAS are present it is important to determine the extent of the angle circumference involved. In addition to iridotomy and iridoplasty as iris treatments, the occasional patient with miosis benefits from laser photomydriasis or laser sphincterotomy. These two laser treatments are usually justified by a need to improve vision or fundus visualization rather than a need to improve glaucoma status.

Sidebar 61.3. Corneal edema following angle closure: how to perform laser iridotomy Peter T. Chang Corneal edema is a common sign in an acute angle-closure attack. The sudden and severe elevation of intraocular pressure (IOP) forces fluid into the cornea, overwhelming the capability of the endothelial pumps. While the edema

Angle closure may be acute, subacute, or chronic. Patients with angle closure often present with a chronic, indolent condition, suspected based on the van Herrick sign during slit lamp examination.33 Often, yet not always, these patients are hyperopic. They can be of any age, although the condition is more frequent among older individuals. The IOP is usually elevated, though it may be normal. Gonioscopy clarifies the extent of the anterior chamber angle blockage. Occasionally the presentation is acute and dramatic. In the event of acute, marked IOP elevation, the cornea may have stromal or epithelial edema, and be hazy. The patient may have disabling pain and nausea. This interferes with gonioscopy and laser iridotomy (see Sidebar 61.3). Breaking the acute attack medically becomes important, as this relieves the pressure elevation and allows the cornea to clear. The patient may need systemic hyperosmotic agents in addition to topical agents to break the acute attack. In subacute presentations, the patient may have undergone repeated episodes of angle closure, and have sector iris atrophy and numerous, small subcapsular lens opacities (glaucomflecken).

may provide helpful information regarding the acute nature of IOP elevation, further ophthalmic examination may be impeded by the corneal opacity. Visualization of the anterior segment structures is often critical to an accurate, prompt diagnosis because other entities, such as neovascular glaucoma and other secondary angle-closure glaucomas, may also present with elevated IOP and corneal edema yet require different management modalities than pupillary-block glaucomas. Inappropriate peripheral

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iridotomy could potentially exacerbate these other conditions. And of course significant corneal edema in the case of angle closure secondary to pupillary block, may preclude the ability to perform a laser peripheral iridotomy and necessitate incisional surgical intervention. Any attempt to improve corneal edema should include antiglaucoma medications to lower the IOP. Aqueous suppressants and parasympathomimetics are preferred due to their quicker onset and mechanisms of action. Additionally, corneal edema can be reduced with the use of topical hypertonic agents, such as glycerin, as they draw water from the cornea by osmosis. Instillation of topical glycerin causes significant burning or stinging, and it should, therefore, be preceded by use of a topical anesthetic agent. If glycerin is not readily available or if the use of glycerin does not yield significant reduction of corneal edema, anterior chamber paracentesis may be performed to lower IOP and to reduce corneal edema. Both the use of topical hyperosmotic agents and anterior chamber paracentesis may only temporarily clear the cornea, but they may do so for a sufficient amount of time to allow laser iridotomy to be performed My preferred technique for anterior chamber paracentesis was taught to me by my mentor, Dr. Paul Palmberg, at the Bascom Palmer Eye Institute. A half-inch, 30-gage needle is attached to a tuberculin syringe with the plunger removed. Following instillation of a topical anesthetic agent and a prep of the conjunctival sac and lashes with a povidone–iodine solution, the patient is positioned at the slit lamp with the lids held open either manually or with a wire speculum. A long entry path through the corneal stroma with this size needle almost eliminates the risk of wound leak. Entry into the anterior chamber through the limbus near 6-o’clock reduces the possibility of inadvertent injury to the crystalline lens in a phakic

61.4   Mechanism of Angle Closure Angle closure is usually the result of block of flow of aqueous humor from the posterior chamber through the pupil to the anterior chamber-pupillary block. This is more likely when the pupil is in a middilated state, as occurs when the patient is in a location with dim illumination (the theater or driving an automobile at night come to mind). The midperipheral iris balloons due to the slightly higher pressure in the posterior chamber; then the ballooned iris may come into contact with the trabecular meshwork. The IOP becomes elevated when there is sufficient trabecular blockage by this “flap valve” effect. Creation of a small hole through the iris relieves the

eye. The needle is withdrawn from the anterior chamber after approximately 20 s with the resultant IOP around 10  mmHg, as the small lumen of the 30-gage needle apparently prohibits flow against the atmospheric pressure at a lower IOP. Paracentesis should be performed with caution as these patients often have severe pain and nausea. Overtly short entry through the cornea may result in a leaky wound and, consequently, hypotony and increased risk for intraocular infection. Inadvertent trauma to the crystalline lens is also possible. Moreover, paracentesis in an eye with rubeosis irides may result in a significant hyphema and further elevation of IOP and worsening of visualization of anterior and posterior segment structures. Alternatively to peripheral iridotomy, which requires reasonably clear cornea, laser gonioplasty or iridoplasty can be performed even through a relative hazy cornea. Laser iridoplasty may resolve the acute angle-closure attack in addition to facilitating a subsequent laser iridotomy by reducing corneal edema, and should therefore be a part of an armamentarium of any glaucomatologist.

Bibliography Arnavielle S, Creuzot-Garcher C, Bron AM. Anterior chamber paracentesis in patients with acute elevation of intraocular pressure. Graefes Arch Clin Exp Ophthalmol. 2007;245:345–350. Lai JS, Tham CC, Lam DS. Limited argon laser peripheral iridoplasty as immediate treatment for an acute attack of primary angleclosure glaucoma: a preliminary study. Eye. 1999;13:26–30. Lam DS, Lai JS, Tham CC. Immediate argon laser peripheral iridoplasty as treatment for acute attack of primary angle-closure glaucoma: a preliminary study. Ophthalmology. 1998;105:2231–2236. Luxenberg MN, Green K. Reduction of corneal edema with topical hypertonic agents. Am J Ophthalmol. 1971;71:847–853.

pressure inequality, and allows the ballooned iris to return to a more normal location. Other patients have a normal IOP associated with a narrow, yet slit open, crowded anterior chamber recess. Iridotomy will often relieve the high risk status for these patients. Despite a successful iridotomy, some patients have a persistent appositional angle closure due to plateau iris with forward rotation of the ciliary body. These patients are often hyperopic. The condition is discovered during gonioscopy after iridotomy and can be definitively diagnosed with ultrasonic biomicroscopy. In this situation, iridoplasty is often helpful (see Chap. 62). Iridoplasty seldom relieves synechial angle closure.

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61.4.1  Iridectomy and Iridotomy  61.4.1.1  History Iridectomy as an effective treatment for glaucoma dates to 1857, when Albrecht von Graefe made the initial report.34 Not all glaucomatous eyes responded. Understanding the mechanism of pupillary block as the principal cause of angle closure was delayed until the publication of an explanation by Curran in 1920.35 Meyer-Schwickerath developed the xenon arc photocoagulator in the early 1950s, and reported creating iridotomies with this noninvasive instrument in 1956.36 The instrument was cumbersome and the focused spot size large; it burned through the iris tissue in some patients, yet often caused burns of the nearby cornea and lens. With the availability of ophthalmic laser systems starting in the late 1960s there followed a plethora of publications reporting iridotomy methods, success rates, long-term success, and complications with both continuous wave and high-power pulsed laser systems. These early studies are summarized.37 Focusing treatment contact lenses, developed with high dioptric power and antireflective coating, facilitated the procedure.38-40 After the original designs, eye surgeons developed lenses with features to enhance the iridotomy procedure, and many surgeons have readily adopted use of these special lenses. The Abraham lens has a 63-diopter treatment button. The Wise–Munnerlyn–Erickson lens has a 103-diopter treatment button. Lenses are available from commercial sources (Fig.  61.5). By the 1990s, techniques for iridotomy, iridoplasty, and pupilloplasty using these lenses were in wide use. Goins et  al furthered the laser iridotomy procedure in 1990 with description of a method for iridotomy using argon laser pretreatment followed by high-power pulsed laser applications. This reduced the occurrence of bleeding that accompanied iridotomies done with pulsed laser systems alone, and the complication of frequent late closure that followed argon laser iridotomy as it was done at that time.41 The surgeon should be familiar with the guidance provided by the American Academy of Ophthalmology in the Preferred Practice Pattern for Primary Angle Closure, available online at http://one.aao.org/CE/PracticeGuidelines/ default.aspx under Glaucoma in the Subspecialty Browser.42 61.4.1.2  Methods of Iridotomy

Fig. 61.5  Lenses for iridotomy. Abraham lens (upper left) has eccentric 66-diopter treatm ent button providing 1.5× image magnification and 0.67× treatment spot diameter reduction. Wise lens (lower left) has an eccentric 103-diopter treatment button providing 2.6× image magnification and 0.38× treatment spot diameter reduction. Pollack lens (upper right) combines a treatment button similar to the Abraham lens with a gonioscopic mirror to allow intraoperative anterior chamber angle viewing. Mandelkorn lens (lower right) has a large diameter viewing surface providing 1.2× image magnification and 0.83× laser treatment spot diameter reduction for iris periphery or lens capsule. (Photographs courtesy of Ocular Instruments, Inc., Bellevue, WA)

• Informed consent for the type laser surgery planned. • Obtain a presurgery measurement of IOP. • Pretreatment with a miotic – typically pilocarpine 1 or 2% – drops to the eye to be treated about one-quarter to onehalf hour before laser treatment. • Topical anesthesia (e.g., tetracaine or proparacaine). • Appropriate antireflective-coated, iridotomy treatment contact lens of choice with methylcellulose 1% solution for coupling with the eye surface. • Slit lamp biomicroscope delivery system adjusted with aiming beam centered in the on-axis slit beam and with laser confocal with microscope focus. • Anticipating posttreatment pressure spikes, some surgeons pretreat with Iopidine (apraclonidine) or brimonidine.

61.4.1.2.1  Preparation • A hazy cornea, as in an acute angle closure attack, precludes laser iridotomy. Topical or systemic medical glaucoma treatment, including hyperosmotic agents, to break the acute attack and lower the elevated IOP often clears the cornea allowing treatment to proceed.

61.4.1.2.2  T reatment and Suggested Laser System Settings The surgeon may find it advantageous to vary laser settings based on observation of tissue response during treatment.

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61.4.1.2.3  Continuous Wave Laser Systems Continuous Wave (CW) systems include argon lasers and frequency-doubled green Nd:YAG systems The “chipping” technique provides better results with CW systems than slower, burning techniques. • Power 1,200 mW (1.2 W) • Duration 0.05 s • Spot size 50 mm

61.4.1.2.4  Q  -switched, High-Power, Nd:YAG Laser Systems The “blasting” (disruptive) technique is better for lightly pigmented irides with noncompact stroma than for dense light-colored or deeply pigmented irides. • Energy per pulse usually 4.0–6.0  mJ (may be higher, though this approaches levels potentially causing crystalline lens damage). • Single pulses or bursts of three pulses. • Duration and spot size are an automatic characteristic of the system. • With the Q-switched pulsed system (prepared as indicated previously) ready to treat and the treatment site selected, make an initial tissue-disrupting application and observe the effect. • Make additional applications to exactly the same site, drilling deeper into the tissue. • Oozing of blood from disrupted small vessels will stop spontaneously or faster when pressure is applied to the eye with the treatment contact lens. Wait until the treatment site is again clearly visible. Subsequent applications may start the ooze again. • If brisk bleeding develops, stop it with pressure on the treatment contact lens and either choose another site or discontinue and postpone treatment to another day. The patient who has been forewarned about this rare possibility is not surprised if this situation develops during treatment.

61.4.1.2.5  T he Combined CW and Pulsed Laser Technique This is reliable and nearly always successful in one treatment session. • Start with the CW system (prepared as indicated previously) ready to treat. • Make two or three “chipping” applications close together on the tissue in a row parallel to the limbus to start a linear incision. Subsequent applications aimed at pigmented

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tissue in exactly the same site carry the opening into the iris stroma, deepening the cut. • About 30–50 applications will usually create small perforations to the posterior chamber, and puffs of pigmented debris enter the laser-created crypt. This often leaves devitalized, depigmented, or lightly pigmented strands across the base of the opening. • Next, move the patient to the Q-switched laser system, or move the system to the patient, with the system prepared as indicated previously and ready to treat. Reapply the treatment contact lens if it has come off the eye. Warn the patient that the laser makes a “snapping” sound when it comes to focus. • Provided the initial chipping burns have opened the tissue nearly to the posterior chamber, one laser Q-switched laser pulse, aimed carefully upon devitalized strands bridging the base of the treatment site, often suffices to open the iridotomy widely; if so, treatment is complete. Sometimes more than one application is required. Successful applications often cause a large cloud of pigment particles and pigmented cellular debris to migrate from the posterior chamber to the anterior chamber, which usually deepens.

61.4.1.2.6  Treatment Site • The far peripheral, upper nasal iris, under the lid is first choice – approximately the 12:30–1:30 meridian for the right eye and the 10:30–11:30 meridian for the left eye. Avoid the 12 o’clock meridian as bubbles formed during treatment will not move out of the way. • The far peripheral upper temporal iris is an attractive alternative. • Treatment should not be so far peripheral that arcus senilis or the peripheral corneal vascular arcade interfere with the view of the treatment site. • Treat in an iris crypt if one is available; alternatively treat in another, thin location. When treating with a continuous wave laser, seek a site that contains some pigment (to absorb the laser energy) – nevi are nice in this regard.

61.4.1.2.7  Postoperative Care • Rinse methylcellulose remnant from the tear film. • Apply an anti-inflammatory agent (e.g., prednisolone 1%). Do not dilate the pupil. • Consider doing repeat gonioscopy with a four-mirror lens (Zeiss or Sussman) to assess effect of treatment on the anterior chamber angle recess. • Record the lens type used, laser settings, treatment site(s), and number of laser applications in note in medical record.

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• Check IOP 1–2 h after treatment to assess for a pressure spike.43 A rise of IOP 5–10  mmHg above pretreatment level may justify supplemental topical glaucoma eyedrops immediately and for several postoperative days. Continue to monitor the patient until worrisome spikes are resolving with the additional medical treatment. • Discharge the stable patient on continued, unchanged use of preoperative medications supplemented with 4 days of topical anti-inflammatory drops t.i.d. or q.i.d. Plan to check status within a week to 10 days. • During the follow-up visit check IOP and do postoperative gonioscopy. When there is a need for the second eye to have iridotomy, this can be accomplished on the same day as the follow-up visit for the first eye iridotomy. • Adjust medical treatment as justified by findings. • The second follow-up visit can be 1–4 weeks later. Dilate the pupil during this visit to reduce the chance of formation of posterior synechiae and to allow thorough fundus examination.

61.4.1.2.8  Complications and Problems These are infrequent, yet important, and those amenable to altered treatment should be managed promptly. • Blurred vision – this is almost always transient and arises from the after image due to retinal pigment epithelial bleaching from the bright, visible laser beam, from pigment dispersion in the aqueous, or inflammation. There is a single report of loss of central vision from “snuffing.” • Pupil distortion – from peaking toward the treatment site – usually transient, occasionally persistent, yet is usually minor. • Monocular diplopia or glare from light entering the eye through the small iridotomy opening – this symptom usually decreases with time. • Inflammation – this usually responds to the anti-inflammatory agent, though persistent inflammation may cause posterior synechiae formation; pupil dilation within several weeks of laser surgery usually averts this. • Corneal epithelial or endothelial burns – these are the result of absorption of light energy at the corneal interface and may worsen if treatment is continued after they appear. Select a different site and restart the procedure. • Bleeding has already been mentioned and is more likely after pulsed laser iridotomy. • IOP spiking has also been mentioned – early postoperative monitoring reveals its occurrence. It usually responds to more aggressive antiglaucoma medication. • “Malignant” glaucoma due to unrelieved angle closure occurs rarely after laser iridotomy – it is the result of ciliolenticular block. Management, including cycloplegia

and additional laser and invasive surgical procedures, is presented elsewhere in this book. • Closure of the treatment site happens occasionally – if it occurs early postoperative it is usually from debris occluding the opening. Or, if it is delayed or late, it is usually from newly formed cellular structures that bridge the depth of the opening. These closures respond to application of one or two Q-switched laser pulses. • Local lens opacities – may follow energy deposition and tissue heating next to the lens surface. These persist yet do not progress. • Retinal burns – can arise from a focused laser beam encountering the retinal pigment epithelium. During treatment the path of the laser light should not point through the treatment lens directly toward the macula and the focus should be held tightly on the target iris tissue, ensuring divergence of the laser beam should it get past the target.

61.4.2  I ridoplasty Indications and Contraindications After patent iridotomy is achieved, the postoperative indentation, four-mirror, gonioscopy may show persistent appositional angle closure without PAS. This justifies a probable diagnosis of plateau iris. The diagnosis can be confirmed with ultrasound biomicroscopy, if available, which shows forward rotation of the ciliary body. Untreated persistent appositional angle closure has the potential to cause sustained elevation of IOP, trabecular meshwork damage, PAS formation, and secondary glaucomatous optic neuropathy. While medical treatment of IOP often helps, it does not solve this problem.

61.4.2.1  History The approach advocated years ago by Robert Ritch has proven effective and is widely accepted.44 It has proven effective to open the appositionally closed angle in plateau iris, and helpful to open the angle sufficiently to relieve an acute attack of angle closure.

61.4.2.2  Surgery and Postoperative Care 61.4.2.2.1  Preparation • While a treatment contact lens will stabilize the eye during the procedure, it is not required. • Otherwise, preparation including pretreatment with a miotic is as outlined for iridotomy.

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61.4.2.2.2  Suggested Laser System Settings Treatment is done with a continuous wave laser system (argon laser system or frequency-doubled green neody­ mium:YAG system). A low-power, slow application technique provides better results. • Power 150–500 mW (0.15–0.5 W) • Duration 0.2–0.5  • Spot size 200–500 mm The surgeon may find it advantageous to vary settings based on observation of tissue response during treatment – for example, a higher power and smaller diameter for lightly pigmented irides. The goal is to produce contraction of the iris stroma at and surrounding each application site.

61.4.2.2.3  Treatment • Make 30 or more evenly spaced applications to the far peripheral iris, leaving 1–2 application diameters between burns. • Postoperative monitoring and care. • Gonioscopy assures that there has occurred successful opening of the anterior chamber angle recess. • Topical anti-inflammatory agent immediately, and then t.i.d. to q.i.d. for 4 days.

61.4.2.2.4  Complications and Problems • Transient or, rarely, permanent blurred vision. • Transient iritis (treat with anti-inflammatory medications). • Spike of IOP (treat with increased antiglaucoma medications). • Transient or permanent change of pupil shape or diameter (rare and usually self-healing). • Need for retreatment in the event of persistent or recurrent crowding of the anterior chamber angle recess.

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relatively young aphakic glaucoma patients after surgery for congenital cataract who have small, poorly dilating pupils. Other patients have formed hammock pupil after lens surgery, with the iris covering the visual axis. The small or misplaced pupil in these eyes inhibits vision, especially in reduced light, and inhibits examination of the ocular fundus, handicapping glaucoma, or diabetes mellitus monitoring. Pupilloplasty and sphincterotomy are procedures that address this problem, and provide relief.

61.4.3.2  History Soon after xenon and argon systems were available, surgeons who applied photocoagulation to the retina noted side effects on the pupil in some cases. Eye movements during treatment resulted in light energy applications on the iris near the pupil border, with focal areas of stromal atrophy and subsequent irregular or enlarged pupil.45,46 The name photomydriasis and a description of a method first appeared in a publication by James et al in 1976.47 These investigators developed a method involving a double row of contiguous coagulative laser burns around the pupil margin, applied over the iris sphincter muscle. Clinically, the treatment doubled the diameter of the miotic pupil from 1.5 to 3.1 mm on average. This treatment also proved helpful for pseudophakic pupillary block.47 The method developed by L’Esperance and associates47 is still used occasionally. Wise in 1985 reported a method to make linear cuts in iris with multiple short-duration, relatively high-power argon laser burns delivered through an iridotomy lens.48 He illustrated cuts across the pupillary sphincter for treatment of miosis. Clinicians have subsequently used a combined continuous wave laser pretreatment followed by high-power, Q-switched pulsed laser to open a cut across the pupillary sphincter in several meridians, yielding a permanently enlarged, dilatable pupil and relief from miosis.

61.4.3.3  M  ethods of Pupilloplasty and Pupillary Sphincterotomy

61.4.3  O  ther Iris Laser Procedures: Pupilloplasty and Pupillary Sphincterotomy 61.4.3.1  Indications and Contraindications The usual cause of mydriatic-resistant miosis is previous long-term use of cholinergic medications as medical treatment for glaucoma. Surgical after effects causing pupillary sphincter fibrosis explain other cases. In this regard there are

61.4.3.3.1  Preparation • Warn the patient that several treatment sessions may be needed to achieve the desired endpoint. • Apply dilating medications (for example, a combination of Neo-Synephrine and tropicamide). • An iridotomy treatment contact lens stabilizes the eye for pupilloplasty. The laser energy is applied through the 63.0-diopter (Abraham lens) or 103.0-diopter (Wise– Munnerlyn–Erickson lens) focusing button of the lens.

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61.4.3.4  Pupilloplasty 61.4.3.4.1  Treatment and Suggested Settings • Continuous wave argon or frequency-double neodymium: YAG laser system with 200–500 mm spot size and 0.2  s duration. The required power is 200–600  mW, selected according to iris pigmentation and observed tissue reaction. • Apply multiple, contiguous, solitary laser burns to encircle the pupil margin in two concentric circles. The first circle, at the pupil margin is with the 200-mm spot size, and the outer circle is with the 500-mm spot size. The outer circle applications require the higher power setting to achieve the desired tissue reaction. • After healing, a second step of applications may be needed to combat recurrent miosis.

61.4.3.5  Sphincterotomy 61.4.3.5.1  Treatment and Suggested Settings • Initial steps of treatment are with continuous wave argon or green frequency-doubled Nd:YAG laser system with 50-mm spot size and 0.05 s duration. The required power is 1.2–1.4 W, selected according to iris pigmentation and observed tissue reaction. • Completion of treatment is with a Q-switched high-power pulsed neodymium:YAG laser system with one, two, or three pulses per burst at energy of 3.0–7.0 mJ per pulse. Lower energy settings in the range are for phakic eyes with miosis. • Select the meridian for a cut across the sphincter. • Apply multiple chipping continuous wave laser burns to the iris tissue in a line starting about 1 mm distal to the margin and extending toward the edge of the pupil, creating a cut line deep into the pupil margin tissue. • Make similar preparatory cuts in one, two, or three more evenly spaced meridians around the pupil. • Switch to the Q-switched laser system and apply disruptive pulses to the strands bridging the base of the meridional cuts. Avoid applications that hit the lens surface.

 ostoperative Monitoring and Care 61.4.3.6  P for Both Procedures • Apply anti-inflammatory steroids and a strong cycloplegic (e.g., atropine 1%). • Monitor for 1–2 h to identify and treat any posttreatment IOP spikes.

• Discontinue miotics; continue other antiglaucoma ­medications; supplement as needed for spikes of IOP. • Topical cycloplegic once daily for 1 week and antiinflammatory steroids t.i.d. to q.i.d. for 1 week, then taper to b.i.d. for another week; can then restart miotic, if needed.

61.4.3.7  Complications and Problems The occasional lightly pigmented, yet thick, iris is difficult to penetrate with either chipping CW laser burns or high-power pulsed laser applications. The surgeon may find it useful to move to an alternative treatment site, preferably one with some iris stromal pigment. Bleeding may follow disruptive laser applications to the iris. This is usually minor and transient, and stops spontaneously. It stops faster if the surgeon applies light pressure to the treatment contact lens on the eye. If the iris is close to the corneal inner surface during CW or pulsed laser iridotomy the laser applications may cause corneal endothelial damage. The damaged corneal site can interfere with the view of the iris treatment site. This can be sufficient to make it needed to move to a new site to do the treatment. Postoperative treatment-induced iritis may occur. Prophylactic topical steroids for 3–5 postoperative days are usually sufficient to suppress this problem. It may be sufficient to induce formation of posterior synechiae. This is also averted by postoperative pupil dilation about 1–3 weeks after iridotomy and pupilloplasty treatment. Dilation with a longlasting mydriatic is indicated after pupillary sphincterotomy; this averts posterior synechiae formation. Closure of an iridotomy by liberated tissue debris or proliferated iris pigment epithelium occurs rarely. An iridotomy may be discovered to be imperforate during an early postoperative follow-up examination. Both these respond to one or two disruptive high-power laser pulses applied through a treatment contact lens.

61.4.3.8  Expected Outcomes Once established, laser iridotomies persist. The iris will settle back from the anterior chamber angle recess after successful iridotomy in cases of pupillary block, except in sites where there are peripheral anterior synechiae. Peripheral anterior synechiae are detected during postoperative indentation gonioscopy. If there is plateau iris, the angle may not open spontaneously after iridotomy. It will open with indentation gonioscopy, which is an indication to consider iridoplasty.

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61.5  Ciliary Body Effective laser treatment of the ciliary processes and ciliary body reduces aqueous humor inflow, and secondarily reduces intraocular pressure – similar to the effect of beta blockers, carbonic anhydrase inhibitors, or alpha adrenergic agents. The laser treatment can be accomplished transsclerally with CW red and near-infrared lasers, or by invasive, direct application of infrared CW laser energy.

61.5.1  Indications and Contraindications These procedures are indicated to reduce aqueous inflow in glaucomatous eyes. The laser energy can be applied to an intact eye through the anterior sclera or can be applied directly to the ciliary processes during an invasive procedure. The goal is to reduce the formation of aqueous humor, bringing inflow into better balance with outflow resistance in eyes with a severe outflow handicap. Transscleral laser treatment of the ciliary body – transscleral cyclophotocoagulation (TSCPC) – is usually reserved for eyes with some vision potential and refractory glaucoma after failure of previous trabeculectomies or tube-shunt procedures; for eyes with limited vision and highly elevated IOP despite maximum acceptable medical treatment; for painful glaucomatous eyes with highly elevated IOP and little or no vision potential; for eyes with severe surface scarring precluding additional filtration procedures; and for eyes with recent onset of neovascular glaucoma, preferably prior to formation of circumferential occlusive peripheral anterior synechiae. Attractive success rates have been reported in small series of eyes with refractory glaucoma after penetrating keratoplasty,49 uveitic glaucoma,50 glaucoma after intravitreal silicone oil,51 refractory pediatric glaucoma,52,53 after failure of a previous tube-shunt procedure,54 and as a primary treatment in challenging situations.55 Transscleral cyclophotocoagulation may also be helpful for patients with a debilitated general medical condition that precludes invasive surgery, or those who refuse invasive surgery. Eyes with good vision are not excluded, though patients with these seriously affected eyes at any level of vision should be warned that in about 25% of cases – depending upon the preoperative vision and the diagnosis – postoperative vision will be somewhat worse than the pretreatment level and only rarely improved after surgery.56,57 Often, these eyes are at risk of imminent loss of vision from glaucoma. Treatment is less likely to be helpful for eyes with total occlusion of outflow, because these eyes would need near total stoppage of inflow in order for IOP to come to acceptable levels. While this treatment is often done in an office setting, it requires profound local, usually retrobulbar, anesthesia, or

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general anesthesia in an operating room setting; the patient must be cooperative and medically fit for this. Endoscopic photocoagulation (ECP) is for eyes with refractory glaucoma and some eyes with neovascular glaucoma. It has also been used widely for eyes with medically controlled glaucoma undergoing phacoemulsification. In the last group, the goal is to reduce dependence on medical glaucoma treatment. ECP is an invasive procedure. As with TSCPC it requires profound local, usually peribulbar, anesthesia, or general anesthesia in an operating room setting, with the usual associated requirements for patient cooperation and medial clearance.

61.5.2  History Ciliary ablation for glaucoma dates to the early twentieth century. Ciliary ablation has been done with nearly every imaginable method of energy delivery to the eye, including coagulation with chemicals, diathermy, freezing, xenon light, laser light delivered directly to the ciliary processes or across the sclera, and ultrasound.58 In the 1970s, cyclocryotherapy had largely replaced the earlier methods of ciliary ablation for recalcitrant glaucoma. The many postoperative problems associated with cyclocryotherapy59 led to interest in laser methods of ciliary ablation. In 1972, Beckman and coworkers were first to report using a laser method for transscleral cyclophotocoagulation.60 By the mid-1980s, commercial free-running neodymium:YAG laser systems had become available and were employed successfully for transscleral procedures.61–63 Success with ruby and neodymium:YAG systems was based on the high transmission through sclera of longer wavelength ruby (red) and neodymium:YAG (infrared) light coupled with relatively high absorbance of these wavelengths by pigment in ciliary tissue.64,65 Diode laser systems for eye treatment were commercially available starting in the late 1980s. These small, portable systems provided continuous output in the near-infrared part of the spectrum, thus meeting the requirement for good scleral transmission and melanin absorption. The energy could be delivered through fiber optics to a treatment handpiece. The fiber-optic tip compressed both surface vasculature over the sclera and the sclera itself, enhancing transmission of the treatment beam. Gaasterland, working with Buzawa of Iridex Corporation (Mountain View, CA) developed the G-Probe fiber-optic delivery device and methods for this diode laser treatment in the late 1980s; Gaasterland and Pollack reported on the method and initial results of treatments in 1992.58 The method has come into use for both early and late glaucoma of all varieties throughout the world. While there are some intraoperative and postoperative problems related to this approach to ciliary ablation, they are less than after cyclocryotherapy and somewhat less than

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after the neodymium:YAG method, both of which are now less frequently done.58 Endophotocoagulation of the ciliary processes, though an invasive procedure, offers direct visualization of location and effect on target tissue, adjustment of treatment parameters to optimize tissue response, and relative sparing of underlying pigmented tissue.66–68 Uram, in the early 1990s, developed a clinical method and commercial system for this treatment.69 This procedure has been adopted for eyes with glaucoma undergoing phacoemulsification as an alternative to combined cataract and glaucoma-filtering surgery.

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61.5.3  Surgery and Postoperative Care As with all surgical procedures, the patient should understand the plan, requirements, benefits, risks, and alternatives, and give informed consent for the proposed procedure. For TSCPC, warn the patient about the potential for postoperative pain and some reduction of vision. The patient should also understand that more than one step of TSCPC treatment may be needed to achieve the desired control of glaucoma.

61.5.4  Preparation For TSCPC, local peribulbar and retrobulbar anesthesia is needed. In the treatment room, using an Atkinson needle and 10-mL syringe, administer 2 mL of a 50% mix of Marcaine 0.5% and plain lidocaine 2% (without epinephrine) in the peribulbar space in the lateral half of the lower lid, followed by 3–4 mL in the retrobulbar space. Lesser amounts of anesthesia are seldom sufficient. • For ECP, standard operating room preparation is used with peribulbar or retrobulbar anesthesia. • Allow sufficient time before starting treatment for the local anesthetic agent to spread. Test gently for adequate numbing with forceps before starting TSCPC.

61.5.5  TSCPC 61.5.5.1  Treatment and Suggested Settings Set up the IRIS Medical Instruments OcuLight® SLx system or the IRIDEX IQ 810 system with G-Probe™ delivery; there are two treatment approaches for energy delivery: • “Slow Coagulation Technique” for eyes with dark and light brown iris color – 1.25  W and 4.0–4.5  s duration (5.0–5.6  J per application); and for eyes with all other

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•

degrees of iris pigmentation – 1.5 W and 3.5–4.0-s duration (5.25–6.0 J per application). “Standard Technique” uses a starting power of 1.75  W and 2.0-s duration (3.5  J per application); power is adjusted upward or downward in 0.25-W increments according to whether there are excessive tissue “pops” during applications; eyes with darker pigmentation require slightly lower energies to obtain equivalent results. Clean the delivery probe and fiber optic scrupulously with alcohol wipes before and after treatment. With slit lamp biomicroscope or another form of magnified observation, treat three quadrants, with about seven applications per quadrant. For the first step of treatment, omit the temporal quadrant; and for a second step of treatment on a later date, if needed, omit either the upper temporal or lower temporal quadrant. The location of each laser application is guided by the footplate of the G-Probe, which is positioned with the curved anterior edge of the footplate on the anterior border of the limbus and with each subsequent application spaced onehalf the width of the footplate. The fiber-optic protrudes 0.7 mm from the footplate, causing a slight indentation at the treatment site in the paralimbal tissue, which serves as a mark for the sequential applications (during the next application the trailing edge of the footplate bisects the indentation of the fiber optic at the site of the previous application). Observe for “pops” or surface burns and adjust power and technique accordingly. The probe tip must be clean throughout treatment, as charred debris on the tip can heat and burn into or through the sclera.

61.5.6  Endoscopic Photocoagulation 61.5.6.1  Treatment and Suggested Settings Set up the Medtronic Ophthalmics Endo Optiks system with the 20-gage endoscopic probe containing the fiber-optic light source, helium–neon aiming beam, and the 810-nm diode laser treatment source; power is from 0.5 to 0.9 W and duration is surgeon controlled: • Laser applications to the ciliary processes are typically from 0.5 to 2.0-s duration, depending upon observed tissue reaction of whitening and shrinkage. • This is an invasive procedure and is carried out in operative suite. Patients should be informed of risk and benefits, and indicate understanding of the alternatives of filtration surgery or transscleral cyclophotocoagulation. • Uram has described the method.69 The pupil is dilated widely. • The 20-gage fiber-optic probe – inserted through a limbal 2.5 mm paracentesis, after extra deepening of the anterior

732

•

•

•

• •

chamber and elevation of the iris to expand the ciliary sulcus of the posterior chamber of the phakic, aphakic, or pseudophakic eye with viscoelastic – rovides an endoscopic view to a monitor. In addition to the viewing function, the probe contains a light source, a helium–neon aiming beam, and the 810-nm diode laser treatment laser beam. Alternatively, in aphakic or pseudophakic eyes the probe may be introduced through the pars plana after a limited anterior vitrectomy. Long duration, about 0.5–2.0  s, laser applications are directed onto individual ciliary processes to produce whitening and shrinkage of the entire anterioposterior extent of the ciliary process, omitting scar or disrupted tissue. Power, duration, or both are adjusted downward if, due to boiling of tissue water, bubble formation is seen or “popping” occurs. From 180° to 360° of the ciliary body circumference is treated, usually requiring two or three paracentesis sites. The viscoelastic is removed from the anterior segment of the eye and, if needed, the paracentesis wounds closed with a single suture.

61.5.7  Postoperative Care • For both procedures, apply a strong, long-lasting cycloplegic (e.g., atropine) and a topical steroid at the conclusion of the procedure. Give a topical antibiotic for eyes after ECP; a soft eye patch protects the eye until the local anesthesia wears off. • The cycloplegic b.i.d. and steroid drops q.i.d. are continued for at least 2 weeks, and may be required for a longer time. Severe postoperative inflammation may require more aggressive use of steroids. The antibiotic given t.i.d. to q.i.d. may be discontinued after a week. • Acetaminophen (Tylenol) may be taken for pain; stronger analgesics are seldom needed. Some patients may benefit from short-term use of an ice pack. • As with all surgical procedures, patients are monitored at a decreasing frequency to assure safe healing during several months after the procedure.

D. Gaasterland

• “Pops” during TSCPC or ECP. Occasional popping sounds will occur normally. Repeated pops, with every application, indicate power is too high, which brings cellular water to a boil during the application; reduce the power. Consider lengthening duration of applications at the lower power. • Laser energy transmission to the posterior retina during diode TSCPC treatment appears to be well within safety guidelines.70

61.5.8.2  Postoperative • Pain – found in one-third to one-half of eyes undergoing TSCPC, this is usually mild, yet may be severe. Treatment is with topical cycloplegics, topical nonsteroidal antiinflammatory medications, icepacks, and systemic analgesics, as needed. • Inflammation – this is to be expected and should be treated appropriately. Severe inflammation with formation of a protein clot occurs occasionally after TSCPC, particularly in eyes with neovascular glaucoma, and requires more aggressive anti-inflammatory management. • Bleeding – this is rare, more often in eyes with neovascular glaucoma. It usually is sufficiently mild to resolve spontaneously with passage of time. • Change of visual acuity56,57 – decrease of two Snellen lines or more has been reported in various studies in anywhere from 12 to 40% (mean about 25%) of eyes treated with TSCPC. It appears more likely in eyes with preexisting poor vision. Improved vision has also occurred (though it is seldom discussed). The falloff, which sometimes improves with healing, has to be considered in comparison with the expected deterioration that would occur in the absence of intervention. • Sympathetic ophthalmia – has occurred in a small number of eyes after ciliary destructive procedures, including penetrating cyclodiathermy,71–s75 though none are reported yet after diode laser TSCPC. • Malignant glaucoma – was found in an eye after diode laser cyclophotocoagulation.76 By way of contrast, there are reports of successful treatment for malignant glaucoma with laser cyclotherapy,77 including treatment for malignant glaucoma with TSCPC.78

61.5.8  Problems and Complications 61.5.8.1  Intraoperative

61.5.9  Expected Outcomes

• Surface burns during TSCPC. These may occur if the fiber-optic tip is contaminated with charred debris58; clean the tip.

The goal of TSCPC is to reduce IOP by reducing aqueous humor inflow. When treatment ablates a large portion of the ciliary processes, less aqueous humor is formed thereafter.

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61  Laser Therapies: Iridotomy, Iridoplasty, and Trabeculoplasty

More extensive damage is followed by more reduction in aqueous production. Provided there is no increase of resistance to aqueous outflow through the trabecular meshwork and the uveoscleral route, the IOP will fall. The reported rates of lack of failure of the TSCPC intervention vary from about 50 to >90% after 1–2 years.79,80 Failure is more likely in eyes with zero or minimal outflow before treatment. The rates are dependent upon diagnosis and ethnic background of the patients. For example, patients with neovascular glaucoma often require a second step of treatment during the first 3 months after the initial step; with this they have about a 50–60% rate of long-term success. Often after TSCPC, patients are able to reduce topical and systemic medical glaucoma treatment slightly, yet most still need some continued medical treatment for satisfactory IOP control. A second step of TSCPC treatment for eyes with insufficient response to a first step is often helpful, though the rates of success are not established and appear to be lower than after the initial step of intervention (see Chap. 63).

61.6  Other Laser Procedures for Glaucoma 61.6.1  Laser Suture Lysis

ostium seen during gonioscopy. If no adjunctive antifibrotic was used during trabeculectomy, this procedure should be done during the first few postoperative days; after that the fibrosis during healing reduces the likelihood of improvement with suture lysis. For trabeculectomy performed with 5-fluorouracil, the time to expect benefit from suture lysis is extended to several postoperative weeks; when it was done with adjunctive mitomycin-C postoperative suture lysis may be beneficial for up to 2 months. After these intervals there is a decreasing likelihood of enhancement of bleb function. Suture lysis is done with topical anesthesia, usually with a treatment lens to enhance visualization of the sutures to be cut.82 Several lenses have been designed for this purpose. The lens compresses the bleb tissue over the suture. The lens for this can be the flat between mirrors of a four-mirror gonioscopy lens or one of several lenses specially designed to enhance suture visibility and a tight focus of the laser beam (Fig. 61.6). Occasionally the sutures cannot be located through thick overlying conjunctiva and Tenon’s tissues, in which case an invasive procedure may be justified. Most surgeons use an argon or frequency-doubled continuous wave neodymium-YAG laser for this procedure. Krypton red laser systems are an alternative. Diode systems at 810 nm are less likely to be successful because the dye of black nylon sutures is poorly absorbent at this wavelength.

This laser intervention allows the surgeon to divide one or more scleral flap sutures, with the goal to enhance insufficient aqueous bleb formation and filtration after trabeculectomy. This procedure and trabeculectomy with releasable scleral flap sutures have a similar efficacy.81 Eligible eyes have had recent trabeculectomy yet have elevated IOP and a low or flat filtration bleb with a deep anterior chamber and a patent inner

The power setting for blue–green (argon) or green (frequencydoubled neodymium:YAG) systems is 200–1,000 mW with duration of 0.05–0.2 s (usually 0.1 s) and a spot size of 50 or 100 mm.

Fig. 61.6  Lenses for lysis of nylon sutures. All provide compression of conjunctiva and blanching of blood vessels overlying buried sutures. Hoskins lens (left) has 3.0  mm diameter glass button centered in a flange designed to retract lids; button yields 1.2× image magnification and 0.83× laser treatment spot diameter reduction. Ritch lens (center) is cone shaped with a 5.94  mm diameter convex contact surface and a

frosted, nonreflective external surface; flange and lens cone enhance lid retraction; lens does not alter image magnification or laser treatment spot size. Mandelkorn lens (right) has 5.6  mm diameter base; lens yields 1.32× image magnification and 0.76× laser treatment spot diameter reduction; wide handpiece provides lid separation. (Photographs courtesy of Ocular Instruments, Inc., Bellevue, WA)

61.6.1.1  L  aser System Settings and Laser Applications

734

Slightly lower power is sufficient during treatment with red (krypton) continuous wave laser systems. One or two precisely placed applications to a clearly visible suture usually suffices to divide the suture; the surgeon can see the successfully cut ends of the suture separate. Formation or elevation of the bleb usually follows. Sometimes local pressure on the flap or massage of the eye is needed to initiate flow into the bleb through the site of the cut suture. If this is not successful, cutting another suture may help. Problems that may arise after suture lysis include lack of success to enhance filtration, overfiltration with hypotony or even a shallow or flat anterior chamber, burns or perforation of the bleb wall with potential for a local leak, bleeding, iris incarceration, malignant glaucoma, and dellen formation adjacent to a high bleb.

61.6.2  S  ealing Hypotonous Cyclodialysis Clefts This condition usually follows ocular trauma. A small cleft can cause excessive hypotony, choroidal effusion, shallowing of the anterior chamber, cataract, retinal and choroidal folds, optic disk edema, and secondary decline of vision.83 Such clefts, when located with gonioscopy, are amenable to laser photocoagulation of the inner surface of the cleft at its entrance in the anterior chamber recess. Large clefts are not eligible because laser treatment of this type is almost never successful; other management is indicated. For small clefts, noninvasive laser treatment with the continuous wave argon or frequency-doubled neodymium:YAG laser energy can be done using a gonioscopic lens, or invasive laser treatment can be done using an endoscopic diode laser system. Both approaches require that the entrance to the cleft be surgically visible, which may require adjunctive intracameral viscoelastic to deepen a shallow anterior chamber. Treatment must be aggressive, which is potentially painful. Peribulbar or retrobulbar anesthesia may be required. 61.6.2.1  L  aser System Settings and Laser Applications Recommended treatment starts with blue–green (argon) or green (frequency-doubled neodymium:YAG) continuous wave laser system set at 2–3  W (2,000–3,000  mW) power using a spot size of 50–100 mm with 0.1-s duration. Laser applications are in contiguous rows parallel to the limbus onto the visible outer scleral surface of the cleft starting at the scleral spur. The entire visible inner scleral surface of the cleft is treated. Next the spot size is increased to 100–200 mm and power reduced to 1 W, while duration is unchanged at 0.1 s.

D. Gaasterland

Overlapping rows of laser applications are made to the choroid and ciliary body inner surface of the cleft; these rows are made parallel to the limbus starting at the visible depth of the cleft and moving anteriorly toward the base of the iris. Postoperative treatment is with topical atropine BID to enhance apposition of the walls of the cleft; topical corticosteroids are avoided in order to enhance healing with fibrosis. Because the trabecular drainage pathways may have collapsed during hypotony, there is a possibility that several days following cleft closure the IOP will become elevated due to cleft healing with resumption of aqueous production. The elevation is usually transient, resolving as the outflow pathways resume function; the transient rise of IOP is managed with standard glaucoma medications. Failure of a first session of treatment to provoke closure can be approached with a second session of laser treatment. Thereafter alternative surgical management becomes justified.

61.6.3  T  reatment to Reopen an Occluded Inner Ostium of a Filtering Site Occasionally, early in the postoperative period, a filtering operation fails to function adequately due to occlusion of the inner ostium of the filtering tract by iris incarceration, PAS formation, or a membrane across the inner opening. An early iris occlusion may be opened with coagulative, followed by high-power pulsed disruptive laser applications onto the juncture of the occluding iris tissue and the endothelial surface of the cornea at the border of the inner ostium.84 Thin membranes occluding the inner ostium can be opened with disruptive laser applications.85 Early laser treatments preceded availability of high-power pulsed laser systems, which have enhanced the ease and success of these procedures. Apply topical anesthesia for the gonioscopic laser treatment contact lens.

61.6.3.1  L  aser System Settings and Laser Applications For iris occluding the inner ostium, begin with a blue–green (argon) or green (frequency-doubled neodymium:YAG) continuous wave laser system with power of 400–1,000  mW, spot diameter of 50–100 mm, and duration of 0.1–0.2 s. The laser applications cause local shrinkage when applied to the iris tissue at the edge of the adhesion to the cornea. During treatment, adjust spot size, power, or duration to achieve a blanching tissue reaction. Apply a double row of treatment

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61  Laser Therapies: Iridotomy, Iridoplasty, and Trabeculoplasty

spots to the adhesion site. This will ensure against bleeding during the next step. Next, with the gonioscopic lens in place, switch to a Q-switched neodymium:YAG system set to deliver single pulses at 3.0–6.0 mJ. Direct sufficient applications to disrupt the coagulated tissue at the edge of the inner ostium and separate the adhesion. For thin membranes occluding the inner ostium, use settings as in the second step of iris occlusions and make laser applications directly to the center of the membrane with the Q-switched neodymium:YAG laser system. In successful cases, with local massage, the filtering bleb inflates and the IOP falls. For several days treat with increased frequency of topical steroid medication. If the bleb does not inflate after successful clearing of the inner ostium and massage, another, nonlaser, management option is justified.

61.6.4  C  oagulation of Bleeders Located in the Internal Aspect of Surgical Wounds Small, pesky bleeders occasionally follow trabeculectomy or other surgeries that are completed with full thickness limbal wounds.86 Sometimes the bleeder is located in the iris at the site of the iridectomy or behind the iris from a damaged ciliary process. Wherever located, these bleeders often leak intermittently and cause a postoperative hyphema. The bleeding site in the anterior chamber angle is found with gonioscopy and with the slit lamp when in the iris. When found, provided the optical pathway to the site is clear, the bleeder can be coagulated with a continuous wave argon or frequency-doubled neodymium:YAG laser system. It is helpful for localization when there is a small clot of blood at the site of origin of the bleeding, which occurs when there has been recent leakage.

61.6.4.1  L  aser System Settings and Laser Applications Make single applications of blue–green (argon) or green (frequency-doubled neodymium:YAG) continuous wave laser energy onto and adjacent to the bleeding site using power of 600–1,000 mW, a spot size of 50 or 100 mm, and 0.1–0.2-s duration. Make sufficient applications to blanch the bleeding site thoroughly. Occasionally, on another day, a second session of treatment may be required – warn the patient about this during the preoperative discussion before the first treatment session. Usually no escalation of the postoperative medication regimen is needed. If successful, the recurrent bleeding stops.

61.6.5  D  irect Treatment of New Vessels on Trabecular Meshwork in Neovascular Glaucoma The early pathophysiology in neovascular glaucoma is formation of fine, new vessels on the inner surface of the open trabecular meshwork. The retraction of the fibrosis that follows pulls the base of the iris onto the trabecular tissue, forming PAS. Although contemporary management of this condition rests upon panretinal photocoagulation and, more recently, intravitreal administration of an anti-VEGF agent, the ophthalmologist encounters an occasional case of early rubeosis after ischemic retinal vein occlusion or diabetic retinopathy that would benefit from immediate inhibition of fibrovascular tissue proliferating in the anterior chamber angle recess. The goal is to coagulate the small new vessels traversing the angle recess and thus interrupt formation of PAS. More than one session of treatment is often required as new vessels form after the first session.87 Apply topical anesthesia for the gonioscopic laser treatment contact lens.

61.6.5.1  Laser System Settings and Applications Make applications of blue–green (argon) or green (frequencydoubled neodymium:YAG) continuous wave laser energy directly onto the small vessels in the anterior chamber angle recess using power of 600–1,000  mW, a spot size of 50 or 100 mm, and 0.1–0.2 s duration. Adjust power and duration to cause observable blanching of the vessels. Use sufficient applications to blanch vessels in at least one-third to one-half the circumference of the angle, treat even more if the neovascularization is circumferential. Most treated eyes do not require a modified medication regimen. Long-term, persistent avoidance of angle closure with normalization of IOP are reported for about three-quarters of treated eyes, in reports from the days before panretinal photocoagulation and anti-VEGF agents.87 Nowadays, this procedure should be considered adjunctive to these newer modalities of management and applied in early cases of rubeosis when the clinical course justifies it.

61.7  Conclusion Table 61.1 compares the five types of laser trabeculoplasty that are presently approved. Two of these are continuous wave (CW) using argon laser (ALT) or diode laser (DLT). Three of the present trabeculoplasties are pulsed treatments. These include selective laser trabeculoplasty (SLT) using a

Table 61.1  Comparison of laser trabeculoplasty techniques and treatment parameters

40–70 × 10−3 2.0–3.6 × 103 50 (or 100) spaced over 180° (or 360°) 6.5–13% 2.0–7.0

# (s) J J/cm2 #

J

−/−

Treated fraction (%) of the TM circumference Total energy per eye

Expected endpoint

Blanching (mild) to bubbles (intense)

1 (0.1s – 100%)

µm W W/cm2 s

−/−

(50) 54 0.4–0.7 20–36 × 103 0.1

nm

Laser wavelength (Spot diameter in air) spot diameter at tissue Laser power Laser irradiance Laser pulse length Pulses/application site (time – % duty factor) Laser energy per pulse (per application site) Laser fluence per pulse (per application site) Number of applications and placement over the TM

3.0–20.0 Blanching to no visible reaction (in lightly pigmented TM)

6.5–13%

3.0–10 × 103 50 (100) spaced over 180° (360°)

60–200 × 10−3

1 (0.1–0.2s – 100%)

(75) 53 0.6–1.0 30–50 × 103 0.1–0.2

Laser trabeculoplasty Laser trabeculoplasty Goldmann 3-mirror Ritch trabeculoplasty lens (1.08×) (0.71×) 488/514 (or 532) 810

−/− −/−

Indication(s) for use (IFU) Contact gonio lens (laser magnification)

DLT

Units

ALT 88–90

Characteristics and parameter 88–90

CW-laser trabeculoplasty

0.6 × 10−3(60 × 10−3)

100 (0.2s at 15%)

(200–300) 200–300 2 2.83–6.37 × 103 300 × 10−6

Laser trabeculoplasty Latina laser gonio lens (1.0×) 810

MLT91–ww93

3.96–12.0

No visible tissue reaction

30–120 × 10−3 No visible tissue reaction to small bubbles

0.5–1.0 0.85–1.91 (85–191) 50 (or 100) confluent over 180° 66–100 (132–200) (or 360°) confluent over 180° (360°) 50% (or 100%) 50% (or 100%)

0.6–1.2 × 10−3

1 (3 × 10−9s – 100%)

(400) 400 200–400 × 03 160–320 × 106 3 × 10−9

532

Laser trabeculoplasty Latina laser gonio lens (1.0×)

SLT89,90

Pulsed-laser trabeculoplasty

Comparison of various laser trabeculoplasty techniques and treatment parameters within the range considered typical for average patients

2.0–4.0 Visible TM tissue reaction with microbubbles

25%

4.1–16.3 × 103 50 spaced over the inferior 180°

40–80 × 10−3

1 (7 × 10−6s – 100%)

(200) 216 4.3–17.1 × 103 13.7–54.5 × 106 7 × 10−6

Laser trabeculoplasty Goldmann 3-mirror lens (1.08×) 790

TLT94

736 D. Gaasterland

61  Laser Therapies: Iridotomy, Iridoplasty, and Trabeculoplasty

frequency-doubled laser and based upon the notion that the laser selectively affects pigmented cells in the meshwork; microdiode laser trabeculoplasty (MLT); and Titanium laser trabeculoplasty (TLT), which was approved in the Fall of 2008. Both MLT and TLT use frequencies that would be expected to reach into the deeper aspects of the trabecular meshwork, and could, theoretically have more effect upon the juxtacanalicular meshwork. In terms of treatment applications, the table describes what has appeared in the literature to date. Generally all of the treatments have involved 50–66 treatments in 180°. Some clinicians favor treating 360° at once while others favor treating only 180° at a time. One of the most valuable aspects of this table is that it compares what one sees as an endpoint. Traditionally ALT treatment has resulted in blanching or bubbles. Virtually no tissue reaction is seen with MLT. With the other treatments, some type of tissue reaction is usually seen.

References 1. Maiman TH (1960) Stimulated optical radiation in ruby. Nature 187:493–497 2. Steinert RF, Puliafito CA. The Nd-YAG Laser in Ophthalmology. Principles and Clinical Applications of Photodisruption. 1985. W.B. Saunders Company, Philadelphia, chapters 1, 2. 3. Zaret MM, Breinin GM, Schmidt H et al (1961) Ocular lesions produced by an optical maser (laser). Science 134:1525–1528 4. Campbell CJ, Rittler MC, Koestler CJ (1963) The optical maser as retinal photocoagulator: an evaluation. Trans Am Acad Ophthalmol Otolaryngol 67:58–67 5. Kapany NS, Peppers NA, Zweng HC et al (1963) Retinal photocoagulation by lasers. Nature 199:146–149 6. Mainster MA, Sliney DH, Belcher CD et al (1983) Laser photodisruptors. Damage mechanisms, instrument design and safety. Ophthalmology 90:973–991 7. Trokel SL, Srinivasan R, Braren B (1983) Eximer laser surgery of the cornea. Am J Ophthalmology 96:710–715 8. Kass MA, Heuer DK, Higginbotham EJ, et al, Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–713 9. Collaborative Normal-Tension Glaucoma Study Group (1998) Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 126:487–497 10. Leske MC, Heijl A, Husssein M, et al, Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment. The Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121:48–56. 11. Lichter PR, Musch DC, Gillespie BW, et al, CIGTS Study Group. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943–1953 12. The AGIS Investigators (2000) The Advanced Glaucoma Intervention Study (AGIS): The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429–440

737 13. Robin AL, Pollack IR (1983) Argon laser trabeculoplasty in secondary forms of open-angle glaucoma. Arch Ophthalmol 101:382–384 14. Wise JB, Witter SL (1979) Argon laser therapy for open-angle glaucoma. A pilot study. Arch Ophthalmol 97:319–322 15. Hager H. [Special microsurgical interventions. 2. First experiences with the argon laser apparatus 800] Klin Monatsbl Augenheilkd. 1973;162:437–450 [in German]. 16. Krasnov MM (1973) Laseropuncture of anterior chamber angle in glaucoma. Am J Ophthalmol 75:674–678 17. Wickham MG, Worthen DM (1979) Argon laser trabeculotomy: long-term follow-up. Ophthalmology 86:495–503 18. Schwartz AL, Del Priore LV (1991) The evolving role of argon laser trabeculoplasty in glaucoma. Ophthalmol Clin North Am 4:827–838 19. Weinreb RN, Ruderman J, Juster R et  al (1983) Influence of the num ber of laser burns administered on the early results of argon laser trabeculoplasty. Am J Ophthalmol 95:287–292 20. Weinreb RN, Ruderman J, Juster R et al (1983) Immediate intraocular pressure response to argon laser trabeculoplasty. Am J Ophthalmol 95:279–286 21. Gaasterland DE, Kupfer C (1974) Experimental glaucoma in the rhesus monkey. Invest Ophthalmol 13:455–457 22. Wise JB (1981) Long-term control of adult open angle glaucoma by Argon laser treatment. Ophthalmology 88:197–202 23. Rodriques MM, Spaeth GL, Donohoo P (1982) Electron microscopy of argon laser therapy in phakic open-angle glaucoma. Ophthalmology 89:198–210 24. Acott TS, Kingley PD, Samples JR et al (1988) Human trabecular meshwork organ culture: morphology and glycoaminoglycan synthesis. Invest Ophthalmol Vis Sci 29:90–100 25. Bylsma SS, Samples JR, Acott TS et al (1988) Trabecular cell division after argon laser trabeculoplasty. Arch Ophthalmol 106:545–547 26. Anderson RR, Parish JA (1983) Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 29(220):524–527 27. Latina MA, Park C (1995) Selective targeting of trabecular meshwork cells: in vitro studies of pulsed and CW laser interactions. Exp Eye Res 60:359–371 28. Latina MA, Sibayan SA, Shin DH et al (1998) Q-switched 532-nm Nd:YAG laser trabeculoplasty (Selective Laser Trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology 105:2082–2090 29. Latina MA, de Leon JM (2005) Selective laser trabeculoplasty. Ophthalmol Clin North Am 18:409–419 30. Barkana Y, Belkin M (2007) Selective laser trabeculoplasty. Diagnostic and surgical techniques. Surv Ophthalmol 52:634–654 31. Glaucoma Laser Trial Research Group (1995) The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study: 7. Results. Am J Ophthalmol 120:718–731 32. The AGIS Investigators (2004) The Advanced Glaucoma Intervention Study (AGIS) 13. Comparison of treatment outcomes within race: 10-year results. Ophthalmology 111:651–664 33. Van Herrick W, Shaffer RN, Schwartz A. Estimation of width of angle of anterior chamber. Incidence and significance of the narrow angle. Am J Ophthalmol. 1969 Oct;68(4):626–9 34. Von Graefe A (1857) Ueber die Iridectomie die Glaucom; und uber den glaucomatosen process. Graefes Arch Clin Exp Ophthalmol 3(pt 2):456–555 35. Curran EJ (1920) A new operation for glaucoma involving a new principle in the etiology and treatment of chronic primary glaucoma. Arch Ophthalmol 49:695–716 36. Meyer-Schwickerath G (1956) Erfahrungen mit der Lichtkoagulation der Netzhuat und der Iris. Doc Ophthalmol 10:91–131 37. American Academy of Ophthalmology (1994) Laser peripheral iridotomy for pupillary-block glaucoma. Arch Ophthalmol 101:1749–1758 38. Abraham RK (1981) Protocol for single-session argon laser iridectomy for angle closure glaucoma. Int Ophthalmol Clin 21:145–166

738 39. Schirmer KE (1983) Argon laser surgery of the iris, optimized by contact lenses. Arch Ophthalmol 101:1130–1132 40. Wise JB, Munnerlyn CR, Erickson PJ (1986) A high effeciency laser iridotomy-sphincterotomy lens. Am J Ophthalmol 101:546–553 41. Goins K, Schmeisser E, Smith T (1990) Argon laser pretreatment in Nd:YAG iridotomy. Ophthalmic Surg 21:497–500 42. American Academy of Ophthalmology (2005) Preferred Practice Pattern. Primary Angle Closure. American Academy of Ophthalmology, San Francisco, CA 43. Krupin T, Stone RA, Cohen BH et al (1985) Acute intraocular pressure response to argon laser iridotomy. Ophthalmology 92:922–926 44. Ritch R (1982) Argon laser treatment fo medically unresponsive attacks of angle-closure glaucoma. Am J Ophthalmol 94:197–204 45. Zweng HC, Little HL, Hammond AH (1974) Complications of argon laser photocoagulation. Trans Am Acad Ophthalmol Otolaryngol 78:195–204 46. Thomas NE, Morse PH (1976) Anterior segment complications of argon laser therapy. Ann Ophthalmol 8:299–301 47. James WA Jr, deRoetth A Jr, Forbes M, et al. Argon laser photomydriasis. Am J Ophthalmol. 1976;81:62–70 48. Wise JB (1985) Iris sphincterotomy, iridotomy, and synechiotomy by linear incision with the argon laser. Ophthalmology 92:641–645 49. Shah P, Lee GA, Kirwan JK et al (2001) Cyclodiode photocoagulation for refractory glaucoma after penetrating keratoplasty. Ophthalmology 108:1986–1991 50. Schlote T, Derse M, Zierhut M (2000) Transscleral diode laser cyclophotocoagulation for the treatment of refractory glaucoma secondary to inflammatory eye diseases. Br J Ophthalmol 84:999–1003 51. Kan SK, Park KH, Kim DM et al (1999) Effect of diode laser transscleral cyclophotocoagulation in the management of glaucoma after intravitreal silicone oil injection for complicated retinal detachments. Br J Ophthalmol 83:713–717 52. Izgi B, Demirci H, Ysim F et al (2001) Diode laser cyclophotocoagulation in refractory glaucoma. Comparison between pediatric and adult glaucomas. Ophthalmic Surg Lasers 32:100–107 53. Kirwan JF, Shah P, Khaw PT (2002) Diode laser cyclophothocoagulation. Role in the management of refractory pediatric glaucomas. Ophthalmology 109:316–323 54. Semchyshyn TM, Tsai JC, Joos KM (2002) Supplemental transscleral diode laser cyclophtotcoagulation after aqueous shunt placement in refractory glaucoma. Ophthalmology 109:1078–1084 55. Egbert PR, Fiadoyor S, Budenz DL et al (2001) Diode laser transscleral cyclophotocoagulation as a primary surgical treatment for primary open-angle glaucoma. Arch Ophthalmol 119:345–350 56. Wilensky JT, Kammer J (2004) Long-term visual outcome of transscleral laser cyclotherapy in eyes with ambulatory vision. Ophthalmology 111:1389–1392 57. Pokroy R, Greenwald Y, Pollack A et  al (2008) Visual loss after transscleral diode laser cyclophotocoagulation for primary openangle and neovascular glaucoma. Ophthalmic Surg Lasers Imaging 39:22–29 58. Gaasterland D, Pollack I (1992) Initial experience with a new method of laser transscleral cyclophotocoagulation for ciliary ablation in severe glaucoma. Trans Am Ophthalmol Soc 90:225–246 59. Caprioli J, Strang SL, Spaeth GL (1985) Cyclocryotherapy in the treatment of advanced glaucoma. Ophthalmology 92:947–954 60. Beckman H, Kinsshita A, Rota AN et al (1972) Transscleral ruby laser irradiation of the ciliary body in the treatment of intractable glaucoma. Trans Am Acad Ophthalmol Otolaryngol 76:423–435 61. Wilensky JT, Welch D, Mirolovich M (1985) Transscleral cyclocoagulation using a neodymium:YAG laser. Ophthalmic Surg 16:95–98 62. Fankhauser F, van der Zypen E, Kwasniewska S et  al (1986) Transscleral cyclophtocoagulation using a neodymium:YAG laser. Ophthalmic Surg 17:94–100

D. Gaasterland 63. Federman JL, Ando F, Schubert HD et al (1987) Contact laser for transscleral photocoagulation. Ophthalmic Surg 18:182–184 64. Smith RS, Stein MN (1968) Ocular hazards of transscleral laser radiation: I. Spectral reflection and transmission of the sclera, choroid and retina. Am J Ophthalmol 66:21–31 65. Rol P, Niederer P, Dürr U et al (1990) Experimental investigations on the light scattering properties of the; human sclera. Lasers Light Ophthalmol 3:201–202 66. Charles S (1981) Endophotocoagulation. Retina 1:117–120 67. Patel A, Thompson JT, Michels RG et  al (1986) Endolaser treatment of the ciliary body for uncontrolled glaucoma. Ophthalmology 93:825–830 68. Zarbin MA, Michels RG, de Bustros S et al (1988) Endolaser treatment of the ciliary body for severe glaucoma. Ophthalmology 95:1639–1647 69. Uram M (1995) Endoscopic cyclophotocoagulation in glaucoma management. Curr Opin Ophthalmol 6:19–29 70. Myers JS, Trevisani MG, Imami N et al (1998) Laser energy reaching the posterior pole during transscleral cyclophotocoagulation. Arch Ophthalmol 116:488–491 71. Bodian M (1953) Sympathetic ophthalmia following cyclodiathermy. Am J Ophthalmol 36:217–225 72. Harrison TJ (1993) Sympathetic ophthalmia after cyclocryotherapy of neovascular glaucoma without ocular penetration. Ophthalmic Surg 24:44–46 73. Edward DP, Brown SVL, Higginbotham E et al (1969) Sympathetic ophthalmic following Neodymium:YAG cyclotherapy. Ophthalmic Surg 20:644–646 74. Lam S, Tessler HH, Lam BL et al (1992) High incidence of sympathetic ophthalmia after contact and noncontact Neodymium:YAG cyclotherapy. Ophthalmology 99:1818–1822 75. Bechrakis NE, Müller-Stolzenburg NW, Helbig H et  al (1994) Sympathetic ophthalmia following laser cyclocoagulation. Arch Ophthalmol 112:80–84 76. Azuara-Blanco A, Dua HS (1999) Malignant glaucoma after diode laser cyclophotocoagulation. Am J Ophthalmol 127:467–469 77. Herschler J (1980) Laser shrinkage of the ciliary processes: a treatment for malignant (ciliary block) glaucoma. Ophthalmology 87:1155–1159 78. Carassa RG, Bettin P, Fiori M et al (1999) Treatment of malignant glaucoma with contact transscleral cyclophotocoagulation. Arch Ophthalmol 117:688–690 79. Pastor SA, Singh K, Lee DA et al (2001) Cyclophotocoagulation. A report by the American Academy of Ophthalmology. Ophthalmology 108:2130–2138 80. Kaushik S, Pandav SS, Jain R et al (2008) Lower energy levels adequate for effecdtive transscleral diode laser cyclophotocoagulation in Asian eyes with refractory glaucoma. Eye 22: 398–405 81. Aykan U, Bilge AH, Akin T et al (2007) Laser suture lysis or releasable sutures after trabeculectomy. J Glaucoma 16:240–245 82. Hoskins HD Jr, Migliazzo C (1984) Management of failing filtering blebs with the argon laser. Ophthalmic Surg 15:731–733 83. Ormerod LD, Baerveldt G, Sunalp MA et al (1991) Management of the hypotonous cyclodialysis cleft. Ophthalmology 98: 1384–1393 84. Ticho U, Ivry M (1977) Reopening of occluded filtering blebs by argon laser photocoagulation. Am J Ophthalmol 84:413–418 85. Van Buskirk EM (1982) Reopening filtration fistulas with the argon laser. Am J Ophthalmol 94:1–3 86. Sharpe ED, Simmons RJ (1986) Argon laser therapy of occult recurrent hyphema from anterior segment wound neovascularization. Ophthalmic Surg 17:283–285 87. Simmons RJ, Dueker DK, Kimbrough RL et  al (1977) Goniophotocoagulation for neovascular glaucoma. Trans Am Acad Ophthalmol Otolaryngol 83:80–89

61  Laser Therapies: Iridotomy, Iridoplasty, and Trabeculoplasty 88. American Academy of Ophthalmology. Committee on Ophthalmic Procedures Assessment. Laser trabeculoplasty for primary openangle glaucoma. Ophthalmology. 1996;103(10):1706–1712. 89. Park CH, Latina MA, Schuman JS (2000) Developments in laser trabeculoplasty. Ophthalmic Surgery and Lasers 30(4):315–322 90. Olivier MMG (2004) Glaucoma laser treatment: where are we now? Techniques in Ophthalmology 2(3):118–123 91. Fea AM, Bosone A, Rolle T, Brogliatti B, Grignolo FM (2008) Micropulse diode laser trabeculoplasty (MDLT): a phase II clinical study with 12 months follow-up. Clin Ophthalmol 2(2):247–252

739 92. Ingvoldstad DD, Krishna R, Willoughby L. Micropulse diode laser trabeculoplasty versus argon laser trabeculoplasty in the treatment of open angle glaucoma [abstract]. Invest Ophthal Vis Sci. 2005;46:ARVO E-Abstract 123. 93. Fea AM, Dorin G (2008) Laser treatment of glaucoma: evolution of laser trabeculoplasty techniques. Tech Ophthalmol 6(2):45–52 94. Garcia-Sanchez j, Garcia-Fiejoo J, Saenz-Frances F et  al. Titanium sapphire laser trabeculoplasty: hypotensive efficacy and anterior chamber inflammation. Invest Ophthal Vis Sci. 2007;48:E-Abstract 3975.

Chapter 62

Laser Iridoplasty Techniques for Narrow Angles and Plateau Iris Syndrome Baseer U. Khan

The apparent mechanism of intraocular pressure (IOP) elevation in primary angle closure (PAC) is straightforward: the obstruction of aqueous to the trabecular meshwork (TM) by the peripheral iris, usually interacting with the lens, which is therefore termed papillary block. With age, the crystalline lens increases in diameter, moving the peripheral iris forward and/or increasing pupil block, thus narrowing the angle.1–4 The conundrum that arises is determining when the threshold of occludability has been reached. Most epidemiological studies have chosen to define this point as when 270° or more of the posterior (pigmented) trabecular meshwork is not visible on gonioscopy; however, this threshold is arbitrary and has not been validated.5 The issue of angle compression has not been addressed. Nevertheless, at this time, the literature does not purport any other definition to be of greater accuracy and thus this is the operational definition used in this chapter. Laser peripheral iridotomy (LPI) is almost universally accepted as the first-line management of PAC (Fig. 62.1). However, performing an LPI does not guarantee resolution of occludability. In a study of PAC suspects (eyes deemed occludable without signs of increased IOP), 20% of eyes demonstrated persistent occludability following LPI.6 There are two significant implications of these findings: It is imperative to reexamine the angle following LPI, and that PAC can be multifactorial in a significant number of patients. Persistent occludability may be managed with medication, surgery, or further laser therapy. Chronic miotic therapy may adequately open the angle; however, this is not generally tolerated well by the prepresbyopic patient. Brow ache, cataract formation, posterior synechiae formation, and retinal detachment are all possible undesirable side effects. Crystalline lens removal with or without adjunctive procedures will be very effective in increasing angle width. Concomitant presence of a cataract makes this approach highly desirable, but the removal of a lens without cataractous changes remains controversial. Argon laser peripheral iridoplasty (ALPI) is the final option and is discussed in further detail in this chapter.

62.1  P  athophysiology and Mechanism of Action In 1995, Ritch et al described four anatomic levels of force causing the iris to obstruct the trabecular meshwork: (1) the iris (pupil block), (2) the ciliary body (plateau iris), (3) the lens (phacomorphic glaucoma), and (4) posterior to the lens (malignant glaucoma).7 Pupil block results when the pupil margin abuts another structure 360°, thereby limiting the flow of aqueous from the posterior to anterior chamber.8 In the phakic eye, the interacting structure is the anterior lens capsule, but pupil block can also be seen in aphakic and pseudophakic eyes (the discussion of which is beyond the scope of this chapter). In the absence of an alternative communication between the two chambers, the pressure in the posterior chamber rises relative to the anterior chamber causing the midperipheral iris to bow anteriorly (iris bombe). The arching of the iris can significantly narrow the angle, obstructing the TM and resulting in an increase in IOP. LPI creates an alternative pathway for aqueous to flow from the posterior to anterior chamber, thereby equalizing pressure and allowing the iris to move posteriorly to its natural position, resulting in widening of the angle.6,9,10 LPI effectively manages pupil block but does not alter the lens position or anterior chamber depth6; therefore, persistent occludability indicates a secondary or alternate mechanism. Plateau iris is secondary to large or anteriorly positioned pars plicata11,12 that push the peripheral iris anteriorly against the TM. Phacomorphic glaucoma is secondary to a large or subluxed crystalline lens that moves the entire iris diaphragm forward.13,14 Malignant glaucoma, resulting from posteriorly directed aqueous flow, is rare in previously unoperated eyes. Originally described by Kimbrough et  al in 197915 to treat angle closure in nanophthalmos, ALPI has been primarily described in the management of persistent appositional closure following LPI,16–18 be it secondary to plateau iris19 or phacomorphic glaucoma.20,21 More recently, ALPI has been used in the setting of acute angle closure.16,22–28

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_62, © Springer Science+Business Media, LLC 2010

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Fig.  62.1  Management algorithm for primary angle closure (PAC) glaucoma. LPI laser peripheral iridotomy; ALPI argon laser peripheral iridoplasty

ALPI contracts the peripheral iris stroma, which physically opens the angle.16–18 Histopathology suggests that the initial effect is due to heat-induced collagen shrinkage and that the long-term effect is secondary to contraction of a fibroblastic membrane in the region of laser application.29

plateau iris configuration in the pseudophakic eye. ALPI has also successfully been used in eyes with iridociliary cysts that resulted in a pseudoplateau iris configuration.33

62.2.2  Acute Angle Closure 62.2  Indications 62.2.1  Plateau Iris Syndrome Plateau iris configuration is a result of large or anteriorly positioned pars plicata.11,12 Clinically, this is manifest by a relatively normal central anterior chamber depth, but a narrow angle peripherally. Plateau iris syndrome is defined as PAC in the presence of a patient LPI.30 In a long-term study of 23 eyes with appositional PAC following LPI (mean follow-up of 79 months), 20 eyes remained open over the course of follow-up. Three patients required retreatment due to gradual reclosure, 5–9 years after initial treatment.19 None of these eyes required filtration surgery. Antiglaucoma medications were reduced from 1.2 to 0.6 after treatment. Lens extraction will remove any pupil block and phacomorphic contribution to angle closure but will not relieve the plateau iris configuration31,32; ALPI is thus also indicated in

ALPI has been used to break attacks of acute angle closure primarily22–28 or in cases that were recalcitrant to medical therapy and/or LPI.16 In a randomized trial, 77 eyes in acute angle closure with IOPs over 40 mmHg in which an LPI could not be performed due to corneal edema, received topical pilocarpine and timolol.28 They were then randomized to receive either ALPI or systemic acetazolamide (and intravenous mannitol if the IOP was greater than 60 mmHg). There were no significant differences in IOP between the two groups at the initiation of therapy and at 2 and 24 h posttherapy. However, there was a significantly lower IOP in the ALPI group at 15  min, 30  min, and 1  h after initiation of therapy. As the underlying pupil block had not been corrected, all patients underwent an LPI within 48  h of initial therapy. Long-term follow-up (mean 15.7 months) failed to show any significant differences between groups with respect to IOP, PAS formation, or antiglaucoma medication requirement.25 ALPI appears to be a safe alternative in the management of acute angle

62  Laser Iridoplasty Techniques for Narrow Angles and Plateau Iris Syndrome

closure and should be given particular consideration when systemic therapy may adversely affect a patient.

62.2.3  Phacomorphic Glaucoma A large or anteriorly subluxed crystalline lens, particularly in a smaller eye, can cause significant narrowing of the angle, leading to occlusion. Definitive management is lens removal; however, these eyes can present in acute angle closure and are often not amenable to LPI. ALPI has been suggested as a fast and safe alternative to medical management to lower IOP and functions as a temporizing modality until cataract surgery can be performed under more favorable circumstances.20,21 A prospective series of 10 patients presenting with acute phacomorphic induced angle closure, with IOPs greater than 40  mmHg, underwent ALPI.21 The IOP was reduced to a mean of 25.5 mmHg by 2 h and 13.6 mmHg by 24 h. Uneventful cataract surgery was then performed within 4 days of presentation.

62.2.4  Other Indications Lens extraction has been described as an effective modality in managing PAC. When concomitant PAS are present, especially when greater than 270°, goniosynechiolysis has been proven to augment the IOP lowering effect34–36 (Fig. 62.2a, b). Due to the phenomenon of “iris memory,” the unabated iris has a propensity to reform PAS. To reduce the incidence of PAS reformation, postoperative miotics are prescribed to patients to draw the peripheral iris away from the TM. Performing ALPI following cataract surgery combined with goniosynechiolysis further increases angle width.36 Malignant or ciliary block glaucoma occurs due to posterior misdirection of aqueous flow. In a previously unoperated eye, this is usually associated with a choroidal effusion that

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may occur secondary to nanophthalmos,15 panretinal photocoagulation, sulfa-based agents, etc. ALPI can also be useful in managing angle-closure in these cases.37 Though described in one study,38 ALPI is generally thought to not lyse PAS and is therefore not helpful or indicated in chronic angle closure glaucoma (CACG).37

62.3  Clinical Assessment 62.3.1  History Symptoms consistent with PAC after undergoing an LPI should alert the examiner to assessing the eye for persistent occludability.

62.3.2  Clinical Examination The examiner should be careful to note any anomalies that may suggest secondary angle closure issues such as neovascularization of the iris, prior panretinal photocoagulation, iris abnormalities, etc. Acutely, the cornea will often be edematous upon an acutely high rise in IOP, requiring topical glycerin to adequately examine and possibly initiate laser therapy. The presence (and patency) or absence of an LPI should be determined. Gonioscopy is then performed to assess for occludability. Dynamic gonioscopy, using a handheld Posner or similar lens, with indentation is critical to determine the presence of PAS, which has implications on the utilization of ALPI and the necessity of goniosynechiolysis if cataract surgery is to be performed. Dynamic gonioscopy will also assess for the presence of the “double hump” sign created by the anterior ciliary body processes in plateau iris configuration.39 A light touch is useful in performing routine gonioscopy; putting pressure on the lens to create indentation is very useful, but the examiner needs to be cognizant of how the lens is being held.

Fig. 62.2  (a) Visante image of chronic angle closure with PAS formation before goniosynechiolysis. (b) Postoperative imagine demonstrates a deeper chamber and open angles. The red circle identifies a trace amount of residual iris tissue following goniosynechiolysis

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Central anterior chamber depth will be relatively normal in plateau iris configuration. Conversely, a shallow central anterior chamber depth, increased lens thickness, and advanced maturity of the lens indicate a lenticular contribution to occludability. The relative health of the optic nerve and the IOP will determine the urgency and aggressiveness of any intervention that is required.

62.3.3  Ancillary Testing As indicated earlier, the definition of occludability is arbitrary and has been suggested by some to be not sensitive enough. Furthermore, clinical exam is hindered by variable amounts of ambient light that can constrict the pupil, making an occludable angle appear open. Ancillary testing may be useful in cases that are deemed suspect or borderline on clinical examination.

62.3.3.1  Provocative Testing Physiologic or pharmacologic dilation of the pupil will cause crowding of the angle and result in an increase in IOP if occludability is present. Dark room prone provocative testing involves having a patient sitting in a chair in a dark room with their head down for a duration of 1 h. An IOP elevation at the end of this time greater than 8 mmHg indicates a positive result.39,40 The sensitivity and specificity of dark room testing, however, has not been validated in the literature; one consideration being the lability of IOP can be a function of POAG and unrelated to angle closure.41 Pharmacologic testing utilizes a weak mydriatic such as cyclopentolate or phenylepineprhine. This dilation, however, is nonphysiologic and results in low sensitivity. Furthermore, patients can suffer an acute attack hours after instillation after being discharged home. Overall, provocative testing has not been validated and poses a potential safety concern for patients.41

62.3.3.2  Imaging The advantage of imaging is the ability to view and objectively quantify anatomical structures under virtually no ambient light – minimizing angle opening by pupil constriction. Ultrasound biomicroscopy (UBM) is the gold standard in anterior segment imaging and was instrumental in understanding and describing pupil block and plateau iris configuration.40 While providing excellent resolution of the iris and ciliary body, UBM is a contact modality and requires an experienced technician (usually a physician) to perform. Anterior segment optical coherence tomography (AS-OCT)

B.U. Khan

is an optical diagnostic device operating at 1,310 nm, which provides good penetration into the anterior segment – angle imaging is excellent while ciliary body visualization is variable. This is a result of absorption of the imaging light by pigmented uveal tissue, thereby attenuating the image signal beyond these structures. The AS-OCT has the advantage of being a noncontact modality and requires little training to perform. Two studies have demonstrated UBM and AS-OCT to yield comparable results in quantifying angle anatomy and width42,43 (Figs. 62.3a, b and 62.4a, b), though there has been no standardization of what quantitatively constitutes an occludable angle or an angle at risk. No doubt this will be an area of research in the years to come. Schleimpflug photography has also been described, but its relatively low resolution inadequately visualizes angle anatomy.2,44

62.4  Technique Like most techniques, the parameters vary from clinician to clinician. Those that are presented here are those of the author’s but are within the reported variance of the stated parameters.

62.4.1  Pretreatment The eye is pretreated with pilocarpine 1% and then 15 min later again with pilocarpine 1% and brimonidine 0.2%. Others have described the use of pilocarpine 4%37; however, in the author’s experience, the degree of pupil constriction is equivalent with the lower concentration, which yields a lower incidence and severity of brow ache and nausea. Higher doses of pilocarpine may shift the lens–iris diaphragm forward so the author advises that they be avoided. If any corneal edema exists, the eye is also instilled with other IOP lowering medication and topical glycerin.

62.4.2  Treatment Treatment is conducted at least 15 min after the second instillation of pretreatment drops. Patients should be advised that they may feel discomfort, but they should avoid movement during laser application. Either an Abraham37 iridotomy lens or an SLT gonio laser lens can be used to place the laser burns. A gonioscopy lens results in a tangential application of energy, resulting in a more diffuse delivery, leading to less peripheral stromal contraction and thinning,37 which then requires more injury. There is also a risk of inadvertent

62  Laser Iridoplasty Techniques for Narrow Angles and Plateau Iris Syndrome

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Fig. 62.3  Visante optical coherence tomography image of the anterior segment (a) precataract surgery and (b) postcataract surgery. Figures courtesy of Robert J. Noecker, MD, University of Pittsburgh School of Medicine

Fig. 62.4  Laser peripheral iridotomy (LPI). (a) Scan of angle before LPI and (b) post LPI. Figures courtesy of Robert J. Noecker, MD, University of Pittsburgh School of Medicine

damage to the TM. However, a gonioscopy lens provides better access to the peripheral angle and allows the clinician to see the efficacy of the contraction burns as they are applied – unlike the Abraham lens, which requires the clinician to examine the patient immediately after with a goniolens to assess the effect of the treatment. Furthermore, a goniolens provides access to areas of the angle that might be obstructed by peripheral corneal pathology when viewed through an Abraham lens such as marked arcus senilis or a pterygium. The author’s preference is to use a goniolens. The laser is set for a spot size of 500 mm and a duration of 0.5 s. The power is set at 200 mJ to start with and titrated up until the iris stroma begins to contract approximately halfway through duration of the burn. Bubble formation or pigment release indicates a suprathreshold power that should be

reduced. Lighter irides may fail to demonstrate an effect up to 500 mJ, at which point the spot size is reduced – increasing the power delivery per unit area.37 It is important to depress the laser pedal or trigger for the full duration of the burn; there is a propensity to simply depress and release, which will result in a subtherapeutic and variable application of energy. The contraction burns should be placed as peripheral as possible, being careful not to apply energy to the TM if using the SLT lens. The space between burns should be approximately 2 spot diameters – closer burns may result in iris tissue necrosis.37 This results in approximately 12–14 burns per 180°. Care should be taken to avoid placing burns over large vessels, which may bleed, as well as on the horizontal axis where the long ciliary nerves enter the iris and contribute to

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pupil constriction. Ablation of the nerves may result in Urrets-Zavalia syndrome (a fixed and dilated pupil).45 If the angle approach is extremely narrow, a staged approach can be planned; applying burns slightly more centrally first, permitting better visualization for a second treatment directed more peripherally at another time.37 The author treats 180° at a time beginning with the inferior half, which is usually narrower. At the follow-up appointment, the angle is reassessed and the second half is treated if necessary.

62.4.3  Posttreatment One hour posttreatment, the IOP is checked to ensure no IOP spike has occurred. Patients are given pilocarpine 1% qid for 2 weeks and steroid drops qid for 4 days. Patients are then examined in 4–6 weeks to reassess the angle.

62.4.4  Complications Complications from ALPI are almost always mild and selflimited. Patients almost always develop a mild iritis that subsides within a few days. Rarely, patients may demonstrate a protracted anterior chamber inflammation that is amenable to steroid therapy. Endothelial burns can occur, especially when using the Abraham iridotomy lens, and resolve within several days with no sequelae.28 Pigmented scars often develop at the site of burn placement but are of no consequence. Finally, an enlarged or atonic pupil can sometimes result4,37 – the theory being that ciliary nerves are damaged during laser application; however, this likely is also selflimited but may take months to resolve.

62.5  Conclusion Although the mechanism is well understood, the quantitative definition of occludability continues to challenge the clinician in the management of angle closure. Quantitative imaging techniques show promise in being able to properly define these parameters, but thorough and evidence-based research is required before adopting these as the gold standards for evaluation and diagnosis. These measures will also be cost prohibitive in many parts of the world. Until that time, the clinician needs to continue to rely heavily on clinical examination and acumen to determine which eyes require treatment for what is generally a curable condition when identified early. ALPI is a safe and effective procedure that can be used primarily or adjunctively to manage angle closure.

B.U. Khan

References 1. Foster PJ. The epidemiology of primary angle closure and associated glaucomatous optic neuropathy. Semin Ophthalmol. 2002;17(2): 50–58. Review. 2. Friedman DS, Gazzard G, Foster P, et al. Ultrasonographic biomicroscopy, Scheimpflug photography, and novel provocative tests in contralateral eyes of Chinese patients initially seen with acute angle closure. Arch Ophthalmol. 2003;121(5):633–642. 3. Markowitz SN, Morin JD. The clinical course in primary angleclosure glaucoma: a reassessment. Can J Ophthalmol. 1986;21(4): 130–133. 4. Wojciechowski R, Congdon N, Anninger W, Teo Broman A. Age, gender, biometry, refractive error, and the anterior chamber angle among Alaskan Eskimos. Ophthalmology. 2003;110(2):365–375. 5. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86(2):238–242, Review. 6. He M, Friedman DS, Ge J, et al. Laser peripheral iridotomy in primary angle-closure suspects: biometric and gonioscopic outcomes: the Liwan Eye Study. Ophthalmology. 2007;114(3):494–500. 7. Ritch R, Liebmann JM, Tellow C. A construct for understanding angle closure glaucoma: the role of ultrasound biomicroscopy. Ophthalmol Clin North Am. 1995;8:281–293. 8. Pavlin CJ, Harasiewicz K, Foster FS. An ultrasound biomicroscopic dark-room provocative test. Ophthalmic Surg. 1995;26(3):253–255. 9. American Academy of Ophthalmology. Laser peripheral iridotomy for pupillary-block glaucoma. Ophthalmology. 1994;101(10):1749– 1758, Review, No abstract available. 10. Fleck BW, Dhillon B, Khanna V, Fairley E, McGlynn C. A randomised, prospective comparison of Nd:YAG laser iridotomy and operative peripheral iridectomy in fellow eyes. Eye. 1991;5(Pt 3): 315–321. 11. Pavlin CJ, Ritch R, Foster FS. Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol. 1992;113(4):390–395. 12. Ritch R. Plateau Iris is caused by abnormally positioned ciliary processes. J Glaucoma. 1992;1:23–26. 13. Jain IS, Gupta A, Dogra MR, Gangwar DN, Dhir SP. Phacomorphic glaucoma – management and visual prognosis. Indian J Ophthalmol. 1983;31(5):648–653. 14. Epstein DL. Diagnosis and management of lens-induced glaucoma. Ophthalmology. 1982;89(3):227–230. 15. Kimbrough RL, Trempe CS, Brockhurst RJ, Simmons RJ. Angleclosure glaucoma in nanophthalmos. Am J Ophthalmol. 1979;88(3 Pt 2):572–579. 16. Ritch R. Argon laser treatment for medically unresponsive attacks of angle-closure glaucoma. Am J Ophthalmol. 1982;94(2):197–204. 17. Ritch R. Argon laser peripherl iridoplasty: an overview. J Glaucoma. 1992;1:206–213. 18. York K, Ritch R, Szmyd LJ. Argon laser peripheral iridotoplasty: indications, techniques and results. Invest Ophthalmol Vis Sci. 1984;25(suppl):94. 19. Ritch R, Tham CC, Lam DS. Long-term success of argon laser peripheral iridoplasty in the management of plateau iris syndrome. Ophthalmology. 2004;111(1):104–108. 20. Yip PP, Leung WY, Hon CY, Ho CK. Argon laser peripheral iridoplasty in the management of phacomorphic glaucoma. Ophthalmic Surg Lasers Imaging. 2005;36(4):286–291 21. Tham CC, Lai JS, Poon AS, et al. Immediate argon laser peripheral iridoplasty (ALPI) as initial treatment for acute phacomorphic angle-closure (phacomorphic glaucoma) before cataract extraction: a preliminary study. Eye. 2005;19(7):778–783. 22. Chew P, Chee C, Lim A, et  al. Laser treatment of severe acute angle-closure glaucoma in dark Asian irides: the role of iridoplasty. Lasers Light Ophthalmol. 1991;4:41–42.

62  Laser Iridoplasty Techniques for Narrow Angles and Plateau Iris Syndrome 23. Lim AS, Tan A, Chew P, et al. Laser iridoplasty in the treatment of severe acute angle closure glaucoma. Int Ophthalmol. 1993;17:33–36. 24. Matai A, Consul S. Argon laser iridoplasty. Indian J Ophthalmol. 1987;35(5–6):290–292. 25. Lai JS, Tham CC, Chua JK, et al. To compare argon laser peripheral iridoplasty (ALPI) against systemic medications in treatment of acute primary angle-closure: mid-term results. Eye. 2006;20(3):309–314. 26. Lai JS, Tham CC, Chua JK, Lam DS. Immediate diode laser peripheral iridoplasty as treatment of acute attack of primary angle closure glaucoma: a preliminary study. J Glaucoma. 2001;10(2):89–94. 27. Lai JS, Tham CC, Chua JK, Poon AS, Lam DS. Laser peripheral iridoplasty as initial treatment of acute attack of primary angle-closure: a long-term follow-up study. J Glaucoma. 2002;11(6):484–487. 28. Lam DS, Lai JS, Tham CC, Chua JK, Poon AS. Argon laser peripheral iridoplasty versus conventional systemic medical therapy in treatment of acute primary angle-closure glaucoma: a prospective, randomized, controlled trial. Ophthalmology. 2002;109(9):1591–1596. 29. Sassani JW, Ritch R, McCormick S, et al. Histopathology of argon laser peripheral iridoplasty. Ophthalmic Surg. 1993;24(11):740–745. 30. Wand M, Grant WM, Simmons RJ, Hutchinson BT. Plateau iris syndrome. Trans Sect Ophthalmol Am Acad Ophthalmol Otola­ ryngol. 1977;83(1):122–130. 31. Tran HV, Liebmann JM, Ritch R. Iridociliary apposition in plateau iris syndrome persists after cataract extraction. Am J Ophthalmol. 2003;135(1):40–43. 32. Azuara-Blanco A. Iridociliary apposition in plateau iris syndrome persists after cataract extraction. Am J Ophthalmol. 2003;136(2): 395. 33. Crowston JG, Medeiros FA, Mosaed S, Weinreb RN. Argon laser iridoplasty in the treatment of plateau-like iris configuration as result of numerous ciliary body cysts. Am J Ophthalmol. 2005;139(2): 381–383. 34. Teekhasaenee C, Ritch R. Combined phacoemulsification and goniosynechialysis for uncontrolled chronic angle-closure glaucoma after acute angle-closure glaucoma. Ophthalmology. 1999;106(4):669–674.

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35. Harasymowycz PJ, Papamatheakis DG, Ahmed I, et  al. Phacoemulsification and goniosynechialysis in the management of unresponsive primary angle closure. J Glaucoma. 2005;14(3): 186–189. 36. Lai JS, Tham CC, Lam DS. The efficacy and safety of combined phacoemulsification, intraocular lens implantation, and limited goniosynechialysis, followed by diode laser peripheral iridoplasty, in the treatment of cataract and chronic angle-closure glaucoma. J Glaucoma. 2001;10(4):309–315. 37. Ritch R, Tham CC, Lam DS. Argon laser peripheral iridoplasty (ALPI): an update. Surv Ophthalmol. 2007;52(3):279–288, Review. 38. Wand M. Argon laser gonioplasty for synechial angle closure. Arch Ophthalmol. 1992;110(3):363–367. 39. Kiuchi Y, Kanamoto T, Nakamura T. Double hump sign in indentation gonioscopy is correlated with presence of plateau iris configuration regardless of patent iridotomy. J Glaucoma. 2009;18(2): 161–164. 40. Friedman Z, Neumann E. Comparison of prone-position, darkroom, and mydriatic tests for angle-closure glaucoma before and after peripheral iridectomy. Am J Ophthalmol. 1972;74(1):24–27. 41. Epstein DL, Allingham RR, Schuman JS, eds. In: Chandler and Grant’s Glaucoma. 4th ed. Baltimore: Lippincott Williams & Wilkins, 1997;279–280. 42. Dada T, Sihota R, Gadia R, Aggarwal A, Mandal S, Gupta V. Comparison of anterior segment optical coherence tomography and ultrasound biomicroscopy for assessment of the anterior segment. J Cataract Refract Surg. 2007;33(5):837–840. 43. Radhakrishnan S, Goldsmith J, Huang D, et al. Comparison of optical coherence tomography and ultrasound biomicroscopy for detection of narrow anterior chamber angles. Arch Ophthalmol. 2005;123(8):1053–1059. 44. Böker T, Sheqem J, Rauwolf M, Wegener A. Anterior chamber angle biometry: a comparison of Scheimpflug photography and ultrasound biomicroscopy. Ophthalmic Res. 1995;27(Suppl 1):104–109. 45. Espana EM, Ioannidis A, Tello C, Liebmann JM, Foster P, Ritch R. Urrets-Zavalia syndrome as a complication of argon laser peripheral iridoplasty. Br J Ophthalmol. 2007;91(4):427–429.

Chapter 63

Laser Therapies: Cyclodestructive Procedures Christopher J. Russo and Malik Y. Kahook

63.1  Introduction

63.2  Indications

Early attempts to reduce intraocular pressure (IOP) through treating the ciliary body utilized the process of diathermy to destroy aqueous-producing cells.1 This method quickly fell out of favor due to a high rate of hypotony as well as lack of efficacy. Cryotherapy was another early method of ciliary body ablation, and, while the results were more successful and repeatable than diathermy, freezing of the ciliary body never achieved widespread acceptance.2–4 The use of cyclophotocoagulation (CPC) was first reported in the early 1960s using a xenon arc photocoagulator for ciliary body destruction. A decade later, the arc photocoagulator was replaced by a laser and development of the present form of cycloablation began its evolution.5 There were several shortcomings with early CPC methodologies, particularly the transpupillary method. Due to minimal visualization of the ciliary processes through a dilated pupil, treatment was limited to a fraction of the total ciliary body with subsequent suboptimal IOP reduction.6 A solution to this problem was found when the ciliary body was targeted via a transscleral route. While the ciliary body was not directly visualized, treatment of a much larger area was achieved while remaining a noninvasive procedure. In the 1970s, the Nd:YAG laser with a sapphire-tipped contact probe was used via a transscleral approach and found a place in the armamentarium for treatment of refractory glaucoma.7,8 The procedure continued to evolve when the solid-state diode laser replaced the Nd:YAG laser and a disposable probe was introduced. Today a new form of cycloablation utilizing the solid-state diode laser in combination with an endoscope has greatly enhanced the precision of the procedure while minimizing the destructive forces applied to adjacent structures. This procedure, known as endoscopic cyclophotocoagulation (ECP), provides the ophthalmologist better control of laser application to the targeted tissue and may represent a more viable option for earlier treatment of glaucoma refractory to standard medical or laser trabeculoplasty therapy.

The goal of all cycloablative procedures is to lower IOP by reducing aqueous production via destruction of the nonpigmented ciliary epithelium. In the past, CPC was often considered only in cases of refractory glaucoma. Patients on maximum medical therapy showing continued progression of disease were often considered as appropriate candidates. Other indications were in patients who had failed filtration surgery or were considered at high risk for failure or complications post-traditional filtration procedures. Commonly treated glaucomas included neovascular glaucoma, glaucoma associated with penetrating keratoplasty, and aphakic glaucoma. Reasons that CPC remained one of the last lines of treatment in these cases often centered on the complications of the procedure. These included the expected collateral damages associated with transscleral ablation: chronic inflammation, pain, and hemorrhage, as well as a relative or perceived higher incidence of hypotony. Additionally, the lack of ability to titrate or target treatment through the transscleral route often resulted in incomplete ablation and suboptimal reduction in IOP. Several of these concerns have been addressed with the development of ECP, and, as such, the indications for ECP have evolved compared to CPC. Visualization of the area undergoing treatment has been a breakthrough in the emergence of cycloablative procedures. The endoscopic approach allows both a precise titration of treatment and a decrease in collateral damage. While great advances have been made since the beginning days of CPC, both CPC and ECP are certainly not risk-free. Complications for both include pain, chronic inflammation, vitreous hemorrhage, hypotony, macular edema, serous choroidal detachments, development of phthisis bulbi, and ineffectiveness. ECP is an invasive procedure carrying the risk of postoperative leak from surgical wounds as well as the possibility of endophthalmitis. Thus, it is imperative that the patient population is selected with great care and undergoes thorough preoperative counseling.

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_63, © Springer Science+Business Media, LLC 2010

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63.3  Cyclophotocoagulation

63.3.2  Endoscopic Cyclophotocoagulation

63.3.1  Techniques/Features

With visualization of the tissue being treated and a less destructive method of applying the laser, ECP has achieved successful outcomes while minimizing some of the complications associated with a transscleral approach. ECP employs the same 810-nm diode laser as CPC, but allows the surgeon to precisely aim and deploy the laser to cause effective cycloablation while avoiding damage to adjacent structures. Pantcheva examined histopathological changes in human autopsy eyes after ECP and CPC.17 Light and electron microscopy were used to examine autopsy eyes that underwent either procedure and untreated control eyes. Changes were found at the histological level in both treatment groups, with the CPC group exhibiting disruption of the ciliary body muscle and stroma as well as changes in the ciliary processes (both the pigmented and nonpigmented ciliary epithelium). In the ECP group, extensive contraction of the ciliary processes was observed as well as changes to the ciliary body epithelium. There was much less destruction (if any) to the ciliary body muscle and deformation of structures in the ECP group. It was concluded that the higher degree of selectivity implicit in ECP results in less photocoagulative damage to structures adjacent to the targeted tissues. The technique utilized in ECP is critical to successful outcomes. Good exposure facilitates better treatment, and this can be achieved with injection of a cohesive viscoelastic between the iris and anterior lens capsule. A curved probe is employed allowing for better access to the ciliary body. Most of the early reports on use of ECP were performed through a single clear corneal wound; however, a study by Kahook and Noecker has shown that two-site treatment allows for better exposure and treatment under the initial subincisional site allowing for 360° ablation.18 A distance of 2 mm between the probe and ciliary processes is ideal as shown by Yu and colleagues who examined the effectiveness of the diode laser used in ECP at different distances and with different viscoelastics.19 While results with the various viscoelastics were not statistically significant, it was shown that 2 mm was the optimal treatment distance between the target tissue and laser probe. This corresponds to six ciliary processes in view on the endoscope monitor. Initial power is 0.25 W titratable to 1.2 W. Pulse mode is possible but continuous laser is preferable, utilizing a painting technique. Evidence of appropriate treatment delivery is tissue whitening and contraction. ECP has been performed with both pars plana and clear cornea approaches. The pars plana approach works adequately in pseudophakic or aphakic eyes that have been vitrectomized. However, the pars plana approach becomes technically difficult in phakic eyes or eyes that have not previously undergone vitrectomy. Viscoelastic has often been used with ECP to help elevate the iris for increased exposure of ciliary epithelium.

Transscleral laser CPC comprises treatment with both the Nd:YAG laser and the diode laser. The mechanism of action is ciliary body destruction by absorption of the wavelengths of the corresponding lasers. While the ciliary epithelium is ablated, it is important to realize that the underlying ciliary body muscle and blood vessels are also destroyed. At this point, the diode laser offers several advantages over the Nd:YAG laser including smaller size (portability) and balance of emitted energy to absorbed energy; thus the diode laser has found wider use. Noncontact Nd:YAG laser cyclophotocoagulation (NCYC) is no longer in use in most centers. Historically, it was performed at the slit lamp with a LASAG Microruptor laser. Contact Nd:YAG laser cyclophotocoagulation (CYC) employs a 2.2-mm sapphire tip coupled with a fiber-optic probe. Both methods carry the risks and complications previously discussed including chronic inflammation, pain, and hypotony. Despite its drawbacks, several studies have confirmed some success with NCYC and CYC. Several investigators independently found success rates from 45 to 86% in the intermediate term (6–22 months) among recipients of NCYC.9–12 Schuman found similar results with CYC with success rates of 56–72% in the intermediate term (12–36 months).13 Long-term results of CYC were reported by Lin.14 Mean pretreatment IOP was 36.3 mmHg and mean posttreatment IOP was 18.9 mmHg at 10 years. However, 62.5% of eyes with initial visual acuity better than 20/200 on the Snellen chart lost at least two lines at the end of follow-up. Additional findings included need for retreatment in approximately 44% and a failure rate above 50%. Transscleral diode laser CPC utilizing the contact method has been shown to have similar results to CYC. At a wavelength of 810  nm, the light emitted from the diode laser enables a better coupling of emitted energy and absorbed energy due to the intrinsic physical properties of the ciliary epithelium and surrounding pigmentation. This allows for less application time and a decreased energy per application spot. Long-term data from Kosoko et al showed an average 44% decrease in IOP after 270° treatment with average follow-up of 19 months.15 Success rates dropped from an average of 80% at 1 year to approximately 57% at 2 years. Carassa on the other hand, increased treatment to 360° and achieved an average 50% lowering of IOP in all 12 eyes reported.16 Such encouraging results led to greater acceptance of cycloablation as a modality of treatment for glaucoma, especially in refractory cases.

63  Laser Therapies: Cyclodestructive Procedures

There have been reported cases of postoperative IOP spikes secondary to retained viscoelastics. Iris hooks may be an effective alternative, especially in cases of aphakia or compromised posterior capsule where viscoelastic removal is more complicated.20 The current standard approach is through a clear cornea incision. It is, thus, easy to understand why ECP is increasingly being paired with cataract surgery in glaucoma patients. Indications for ECP currently include cases of glaucoma where filtering surgery is contraindicated, patients maintained on multiple topical therapies who are scheduled for cataract extraction, and pediatric glaucoma refractory to other modalities of treatment. Long-term data for ECP performed concurrently with phacoemulsification has been reported by Berke.21 This study included both a large amount of patients and an extended follow-up period. The phaco/ECP group was compared to a group of glaucoma patients that had phaco alone. Over a mean follow-up period of 3.2 years, the ECP group was found to have an average decrease in IOP of 3.4  mmHg – from 19.1 to 15.7 mmHg. The phaco group actually had an IOP rise from 18.2 to 18.9 mmHg. The ECP group was also found to have a decrease in the number of glaucoma medications needed while the phaco group was unchanged. The postoperative rate of CME was unchanged. This data is particularly valuable because it examines the usefulness of ECP in the setting of medically controlled glaucoma. Lima et  al examined the results of ECP versus Ahmed valve glaucoma drainage devices in cases of advanced glaucoma. Sixty-eight eyes of patients with refractory glaucoma were randomized to either arm of treatment.22 The procedures were all performed by a single surgeon. None of the eyes had previously undergone cycloablation or glaucoma drainage device implantation. Preoperative IOP was approximately 41 mmHg in both groups. Results showed significant IOP reductions in both groups to around 14 mmHg with the ECP group being slightly lower. Overall, complications were higher in the Ahmed valve arm of the study. Chen et  al evaluated the IOP lowering effects of ECP. Successful treatment was defined as posttreatment IOP of less than 21  mmHg. Treatment was successful for 94% of patients at 1 year and 82% at 2 years.23 Average IOP reduction of all study participants was 34% from pretreatment levels. Only 6% of patients lost two or more lines on the Snellen chart during the average 12.9 months of follow-up. Neely and Plager have reported on the use of ECP in children. One study details the results of ECP on 34 aphakic or pseudophakic eyes with pediatric glaucoma.24 Success was defined as postoperative IOP of less than 24  mmHg with associated decrease in IOP of at least 15% from pretreatment levels. The pretreatment mean IOP was 32.6 mmHg. Success was achieved in a total of 18 out of 34 eyes, or 53%. Patients were followed an average of 44 months. Of note, retinal detachment occurred in two eyes within 1 month of treatment.

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They used 360° treatment in 23.5% of eyes and no cases of hypotony were noted. Another study by Neely and Plager included 36 eyes of 29 pediatric glaucoma patients who received ECP. Treatment success was defined as IOP less than 21 mmHg with or without glaucoma medications. Pretreatment IOP was 35.06  mmHg with a posttreatment IOP of 23.63. An average 30% decrease in IOP was appreciated. Several eyes required multiple treatments for an average of 1.42 treatments per eye. Overall success was 43% of eyes. Retinal detachment was reported in two eyes with complications of hypotony and vision loss from hand motion to no light perception in one patient each.25 All complications were seen in aphakic eyes. Gayton et al examined the increasingly popular combination of ECP with cataract extraction. It was compared against combined trabeculectomy and cataract extraction. Success was defined as posttreatment IOP less than 19  mmHg and was achieved in 30% of ECP eyes and 40% of trabeculectomy eyes. When patients were also treated with topical glaucoma medications in addition to their respective surgeries, the ECP arm showed a success rate of 65% compared to 52% in the trabeculectomy arm.26 ECP in combination with cataract extraction was found to be a viable option for lowering IOP to a similar degree as filtering surgery while avoiding some of the complications associated with trabeculectomy. The advantages of ECP over previous methods of cycloablation seem obvious, but head-to-head, well-controlled trials comparing the endoscopic versus the transscleral route have not been performed. Such studies are needed to better delineate the advantages and disadvantages of both modalities.

63.4  Conclusion Cycloablative procedures have evolved from their first introduction and will continue to improve with the introduction of new technologies and laser capabilities. CPC and the transscleral approach involved targeting the ciliary epithelium without direct visualization, an increased amount of energy delivered to the intraocular structures, and inability to titrate treatment. While ECP does have several benefits over CPC, including less damage to adjacent structures, direct visualization of targeted tissue, and lower frequency of complications, it is still an intraocular procedure with all of the associated risks (Table 63.1). Cycloablative therapies have not been utilized as first-line or even second-line treatments in glaucoma. However, with the advancements in ECP and the recent published results revealing substantial efficacy and safety, it is possible that ECP will become an increasingly appealing option earlier and in more instances than previously accepted. One limitation is the lack of stand-alone data for ECP since most reports

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Table 63.1  Advantages and disadvantages of CPC and ECP CPC ECP

Advantages

Disadvantages

Avoid intraocular surgery Can be performed in clinic Easy to perform Less collateral damage

Destruction of adjacent tissues Higher amount of energy delivered Higher complication rate Risk factors associated with intraocular surgery Spikes in IOP postoperatively Requires expensive equipment

Titratable Direct visualization

detailing efficacy of ECP often combine cataract extraction at the time of surgery. Long-term studies of ECP are ongoing and will help in better understanding where it fits in our treatment algorithm of glaucoma.

References 1. Weve H. Die Zyklodiatermie das Corpus ciliare bei Glaukorm. Zentralbl Ophthalmol. 1933;29:562–569. 2. deRoetth A. Cryosurgery for the treatment of glaucoma. Trans Am Ophthalmol Soc. 1964;63:189–204. 3. deRoetth A. Cryosurgery for the treatment of advanced simple glaucoma. Am J Ophthalmol. 1968;66:1034–1041. 4. Bellows AR, Grant WM. Cyclocryotherapy in advanced inadequately controlled glaucoma. Am J Ophthalmol. 1973;75:679–684. 5. Weekers R, Lavergne G, Watillion M, et al. Effects of photocoagulation of ciliary body upon ocular tension. Am J Ophthalmol. 1961;52:156–163. 6. Lee P-F, Pomerantzeff O. Transpupillary cyclophotocoagulation of rabbit eyes; an experimental approach to glaucoma surgery. Am J Ophthalmol. 1971;71:911–920. 7. Beckman H, Kinoshita A, Rona AN, et al. Transscleral ruby laser irradiation of the ciliary body in the treatment of intactable glaucoma. Trans Am Acad Ophthalmol Otolatnygol. 1972;76:423–436. 8. Schuman JS. Nd:YAG laser transscleral cyclophotocaogulation. In: Thomas JV, Belcher CD, Simmons RJ, eds. Glaucoma Surgery. St Louis: Mosby-Yearbook; 1992. 9. Hampton C, Shields MB, Miller KN, Blasin M. Evaluation of a protocol fro transscleral neodymium: YAG cyclophotocoagulation in one hundered consecutive patients. Ophthalmology. 1990;97:910–917. 10. Devenyi RG, Trope GE, Hunter WH, et al. Neodymium-YAG transscleral cyclophotocaulation in human eyes. Ophthalmology. 1987;94:1519–1522.

11. Trope GE, Ma S. Mid term effects of neodymium:YAG thermal cyclophotocoagulation in glaucoma. Ophthalmology. 1990;97:73–75. 12. Klapper RM, Wandel T, Donnenfeld E, et  al. Transscleral neodymium:YAG thermal cyclophotocoagulation in refractory glaucoma, a preliminary report. Ophthalmology. 1988;95:719–722. 13. Schuman JS, Belows AR, Shingleton BJ, et  al. Contact transscleral Nd:YAG laser cyclophotocaogulation: midterm results. Ophthalmology. 1992;99;1089–1094, discussion 1095. 14. Gaasterland D, Abrams D, Belcher C, et al. A multicenter study of contact diode laser transscleral cyclophotocoagulation in glaucoma patients. Invest Ophthalmol Vis Sci. 1992;33(Suppl):1019 15. Kosoko O, Gaasterland DE, Pollack IP, et al. Long term outcome of initial ciliary ablation with contact diode laser transscleral cyclophotocoagulation for severe glaucoma. Ophthalmology. 1996;103: 1924–1302. 16. Carassa RG Trabucchi G, Bettin P, et al. Contact transscleral cyclophotocagulation (CTCP) with diode laser: a pilot clinical study. Invest Ophthalmol Vis Sci. 1992;33(Suppl):1019. 17. Pantcheva MB, Kahook MY, Schuman JS, et  al. Comparison of acute structural and histopathological changes in human autopsy eyes after endoscopic cyclophotocoagulation and trans-scleral cyclophotocoagulation. Br J Ophthalmol. 2007;91:248–252. 18. Kahook MY, Lathrop KL, Noecker RJ. One-site versus two-site endoscopic cyclophotocoagulation. J Glaucoma. 2007;16:527–530. 19. Yu JY, Kahook MY, Lathrop KL Noecker RJ. The effect of probe placement and type of viscoelastic material on endoscopic cyclophotocoagulation laser energy transmission. Ophthalmic Surg Lasers Imaging. 2008;39:133–136. 20. Kahook MY, Schuman JS, Noecker RJ. Endoscopic cyclophotocaogulation using iris hooks versus viscoelastic devices. Ophthalmic Surg Lasers Imaging. 2007;38:170–172. 21. Berke SJ, Sturm RT, Caronia RM, et al. Phacoemulsification combined with endoscopic cyclophotocoagulation (ECP) in the management of cataract and medically controlled glaucoma: a large, long term study. Presented at the AGS Annual Meeting; March 2006; Charleston, SC. 22. Lima FE, Magacho L, Carvalho DM, et al. A prospective, comparative study between endoscopic cyclophotocoagulation and the Ahmed drainage implant in refractory glaucoma. J Glaucoma. 2004;13:233–237. 23. Chen J, Cohn RA, Lin SC, et al. Endoscopic photocoagulation of the ciliary body for treatment of refractory glaucoma. Am J Ophthalmol. 1997;124:787–796. 24. Carter BC, Plager DA, Neely DE, et  al. Endoscopic diode laser cyclophotocoagulation in the management of aphakic and pseudophakic glaucoma in children. J AAPOS. 2007;11:34–40. 25. Neely DE, Plager DA. Endocyclophotocoagulation for management of difficult pediatric glaucomas. J AAPOS. 2001;5:221–229. 26. Gayton JL, Van Der Karr M, Sanders V. Combined cataract and glaucoma surgery; trabeculectomy versus endoscopic laser cycloablation. J Cataract Refract Surg. 1999;25:1214–1219.

Chapter 64

Laser Therapies: Newer Technologies Michael S. Berlin and Kevin Taliaferro

The treatment of glaucoma with lasers has been one of the earliest applications of laser technology in medicine. Progress in laser technology has led to the development of several new glaucoma therapies. This chapter reviews basic laser light properties, current laser applications, and the latest developments in the use of lasers to treat glaucoma: Excimer Laser Trabeculostomy (ELT), an alternative to trabeculectomy; Titanium:Sapphire Laser Trabeculoplasty (TLT) and Micropulse Diode Laser Trabeculoplasty (MDLT), alternatives to Selective Laser Trabeculoplasty (SLT); Diode Laser Cyclophotocoagulation (DCPC) and Endoscopic Cyclophotocoagulation (ECP), alternatives to cyclocryotherapy.

64.1  Laser Light Properties and Parameters Lasers are devices that concentrate electromagnetic energy and radiate light as a monochromatic beam. Laser light is comprised of photons that propagate as coherent, minimally divergent electromagnetic waves through space. Its interaction with tissue varies depending on the parameters of the light – such as wavelength, pulse duration and fluence (Fig. 64.1) – and the properties of the tissue. The characteristics of the laser and the various components of the target tissue determine the relative amounts of absorbance, scattering, transmission, and reflection of incident laser radiation (Fig. 64.2). The absorption path length, or the distance into the target tissue in which photon absorption occurs, is also essential in determining the laser–tissue interaction. Photons with higher energy levels are generally absorbed at a much deeper plane than those with lower energy levels. Also affecting the absorption path length is the molecular composition of the target tissue. When photons possess a similar wavelength to the absorption profile of the tissue’s components they are absorbed at a higher rate. This causes the photons to have a shorter penetration depth. Another important component of laser–tissue interaction is irradiance, or the number of photons delivered to the target area per unit time (Fig.  64.3). When irradiance is increased, more energy is delivered. Under certain conditions,

when laser energy is applied to tissue, heat may be generated at the local target site from increased molecular vibrations. This heat is then conducted away from the local site to cooler regions of the tissue. If the diffusion rate of heat in the target tissue is slower than the rate at which heat is being generated by laser radiation, thermal events will occur in local sites of the target tissue.1 When parameters are carefully chosen, laser–tissue interactions can also occur without thermal change to the target tissue. These situations enable surgical procedures that are unique to specific lasers, such as the nonthermal, nonscar-producing tissue ablation with excimer lasers for refractive corneal surgery and ELT. Understanding these laser–tissue interaction parameters determines if the tissue phase change will occur through (1) photovaporization: thermal molecular fragmentation; (2) photodisruption: plasma expansion leading to mechanical molecular fragmentation; or (3) photodissociation: direct, nonthermal, molecular decomposition. Photovaporization occurs when high energy laser light is delivered to the target tissue resulting in carbonization of tissue. Carbonization occurs when the target tissue has been converted to carbon from the heat of laser energy absorption. Photodisruption describes the optical breakdown of molecules. Molecules are fragmented into ionic components creating rapidly expanding ionic “plasma.” The fragmentation, expanding plasma, along with subsequent shock-wave effects, cause the mechanical disruption of the adjacent tissue.2 Photodissociation is the process in which chemical bonds are broken nonthermally through the absorption of photons. The energy absorbed by the tissue is sufficient to dissociate carbon–carbon and carbon–nitrogen bonds directly. The resultant fragments expand and are rapidly expelled, dissipating heat.3

64.2  Lasers for Outflow One of the primary factors causing elevated intraocular pressure (IOP) in open-angle glaucoma is the obstruction of outflow at the juxtacanalicular trabecular meshwork and inner

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_64, © Springer Science+Business Media, LLC 2010

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754 Fig. 64.1  Wavelength, pulse duration, and fluence

Fig. 64.2  Light absorption, transmission, scattering, and reflection

Fig. 64.3  Irradiance

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wall of Schlemm’s canal. Many attempts have been made to bypass this outflow obstruction through the utilization of lasers. Early work by Krasnov et al showed only moderate success using a ruby laser (943  nm) to perform trabeculopuncture.4 Other laser trabeculopuncture attempts, including Hager’s study using an argon laser (488 + 514 nm) and Fankhauser’s study using an Nd:YAG laser (1,064 nm), have also been unsuccessful.5 Following these initial attempts, Wise et  al determined that a continuous wave, essentially long pulsed argon laser (488 + 514  nm) could successfully modify the trabecular meshwork to increase outflow without perforation.6 However, this argon laser trabeculoplasty (ALT) causes thermal damage to the trabecular meshwork and repetition of the procedure is not effective in lowering pressure. The next generation of laser trabeculoplasty was the development of the short pulse length SLT (see chap. 27). The SLT procedure has shown to be as effective as ALT with less thermal damage. This allows SLT to be clinically appropriate as initial therapy. However, like ALT, SLT is limited in both the extent of IOP lowering and the duration of efficacy. Generally, when SLT is repeated, clinical effectiveness is noticeably decreased. Alternatives to SLT include TLT and MDLT. The subsequent generation of laser therapy targets the site of the identified anatomic pathology, the juxtacanalicular trabecular meshwork, and inner wall of Schlemm’s canal, rather than the trabecular meshwork to increase outflow. The goals are to normalize IOP and to increase the duration of effectiveness while minimizing invasiveness and eliminating the patient compliance issues of medication therapies.

64.2.1  Excimer Laser Trabeculostomy During the development of nonthermal, short-pulsed excimer 193 nm ArF lasers for corneal refractive surgery, it was discovered that these lasers could also remove angle tissue, trabecular meshwork, and sclera with almost no thermal damage – unlike all prior lasers used to treat angle tissue – thereby minimizing inflammation and scar tissue formation. To treat the angle tissue and to be clinically useful, the lasers needed a delivery system into the eye since the ultraviolet (UV) wavelengths are readily absorbed by the cornea. Since 193 nm ArF cannot be transmitted through fiber optics, 308  nm XeCl UV excimer lasers were used in preclinical trials, which began in the 1980s, initially designed for nonthermal, full-thickness, ab interno sclerectomy. Histology confirmed that this laser caused minimal thermal damage when compared to visible or infrared lasers. Unlike ALT, SLT, and other lasers in which the laser– tissue interaction is thermal and “treats” the tissue, ELT, like LASIK, precisely excises tissue without thermal injury or scarring of the surrounding tissue, enabling the creation of an anatomic opening connecting the anterior chamber directly to Schlemm’s canal (Fig. 64.4a–f). With this advantage in mind

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and the exquisite accuracy of depth of tissue removal, early developers saw that it was possible to use this 308 nm XeCl laser to precisely excise the juxtacanalicular trabecular meshwork and inner wall of Schlemm’s canal to increase internal outflow by creating ostia into Schlemm’s canal instead of creating a full thickness sclerectomy. The first human clinical trial for ELT was performed by Vogel et al in Germany in 1997.7 In 22 eyes with open-angle glaucoma, the median IOP reduction was 7 mmHg. Furthermore, the minimal trauma to the eye from this procedure left all other options of surgery open. Another advantage of ELT is that this procedure enables pneumatic canaloplasty. As ELT is performed, both coaxial endoscopic views and gonioscopic views reveal gas bubble expansion at the previous ostium created as Schlemm’s canal is entered at each subsequent ELT site, confirming patency and continuity of flow into Schlemm’s canal (Fig. 64.5a–c). As a result of ELT converting trabecular meshwork tissue into gas by photoablation, the pressure of this gas is proposed to dilate Schlemm’s canal and collector channels to improve aqueous outflow. Numerous clinical studies have demonstrated ELT’s ability to achieve the long-term reduction of IOP and the elimination of glaucoma medications in patients with open-angle glaucoma or ocular hypertension. In a study by Giers et al, ELT was performed on 33 patients with phakic eyes.8 After 3 years, there was a mean IOP reduction of 36% among the subjects in addition to a mean medications reduction of 91%. In the same study, 15 patients with pseudophakic eyes underwent ELT. After 3 years, the mean IOP reduction among this group was 47%, and the mean medications reduction was 77%. In another study, Babighian et al followed 21 patients who underwent ELT for a 2-year period.9 Patients had a mean preoperative IOP of 24.8 ± 2.0 mmHg. Two years later, they had a mean IOP of 16.9 ± 2.1 mmHg, a reduction of 32%. When ELT is combined with cataract surgery, the same corneal incision is used. After phacoemulsification is performed, ELT sites (current protocol = 10 sites) are created in the inferior quadrants. In a study by Pache et al, in which this combined procedure was performed on 60 patients by Georgaras, at the postoperative 1-year visit, 91% of patients continued to have a ³20% reduction in IOP from baseline levels.10 Giers et al also conducted a study in which 33 patients underwent combined ELT and phacoemulsification/IOL implantation procedures.11 At the 3-year follow-up visit, there was a 39% IOP reduction and a 70% medications reduction. ELT has been approved for use in the European Union since 1998. Thousands of ELT procedures have been successful in lowering and maintaining lower IOP for years in Europe. Currently, clinical studies are pending in both Canada and the United States, and the next generation of ELT devices is under development.1

EyeLight, Inc.

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Fig. 64.4  Schematic and photos of Excimer Laser Trabeculostomy (ELT) procedure. (a) Paracentesis, viscoelastic, and probe across chamber. (b) Probe across chamber. (c) Probe contacts trabecular meshwork, laser pulses ablate tissue into gas. (d) Second opening

created into Schlemm’s canal. (e) Laser pulses excising the trabecular meshwork. (f) Patent trabeculostomies enable outflow into Schlemm’s canal. (Animation stills courtesy of Rudolf G. Peschke)

64.3  A  lternatives to Argon Laser Trabeculoplasty

length and therefore the same tissue absorption and penetration depth.12  2 With SLT, the target chromophore, the region responsible for light absorption, is intracellular pigment that

Several newer alternatives to ALT have a common goal of achieving equivalent IOP lowering with less damage to the trabecular meshwork. With the development of SLT (q-switched, 532  nm), thermal damage is minimized by decreasing the pulse duration to 3  ns vs. 100,000,000  ns (0.1  s) for ALT while maintaining almost the same wave-

 Note: the terminology “Argon” Laser Trabeculoplasty is commonly used, although most lasers used for this procedure are no longer Argon (l = 488 + 514 nm), but solid state, frequency doubled Nd:YAG (532 nm). The laser-tissue effects are similar in spite of the difference in wavelength.

2

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Fig. 64.5  Photos of ELT procedure. (a) Coaxial endoscopic view of the trabecular meshwork. (b) As second ostium is created into Schlemm’s canal,

(c) bubble expansion is observed at the adjacent ELT site confirming flow and patency into Schlemm’s canal. (Photos courtesy of Professor J. Funk)

limits the spread of laser-induced thermal damage resulting in much less structural damage to the trabecular meshwork. This short pulse duration ensures that the heat diffusion is limited. SLT has proven as successful as ALT in decreasing IOP for several years, but, like ALT, both the extent of IOP lowering and the duration of efficacy are limited.

groups. Both had a mean IOP reduction of approximately 25% after 12 months.15 TLT was approved for use in the European Union in November 2003, and approved in Canada in January 2006. It is currently considered an investigational device in the United States and is undergoing a multicenter clinical trial to evaluate its safety and efficacy.

64.3.1  T  itanium:Sapphire Laser Trabeculoplasty Another alternative to ALT is the 790 nm Titanium:Sapphire laser (SOLX, Inc., Waltham, Massachusetts) with a pulse duration of 7,000 ns. This laser was originally developed in the 1990s for ab interno laser sclerostomy; however, it was noted that IOP decreased when the laser energy was focused on the trabecular meshwork.13 Similar to 532 nm SLT, histologic analysis has shown that the laser is selective for targeting pigmented trabecular meshwork cells causing less thermal damage and scarring to surrounding tissue than ALT, but slightly more than SLT due to the deeper absorption depth of this 790 nm wavelength (Fig. 64.6 a–c). In the pilot clinical trial, 206 eyes underwent TLT and were followed for 12 months.14 3 All of the eyes were treated with approximately 50 pulses at 30–80 mJ using a 200 mm diameter spot over 180° of the meshwork. Results showed a reduction from a mean preoperative IOP of 22.5 ± 5.1 to 17.0 ± 3.3 mmHg at 12 months. This represents a 24% reduction in IOP. Harasymowycz et  al randomized 181 patients with primary open-angle glaucoma to receive either TLT or ALT. They found an insignificant difference between the two

3

 Gabriel Simon Ophthalmic Institute, Madrid, Spain.

64.3.2  M  icropulse Diode Laser Trabeculoplasty Yet another alternative to ALT is MDLT. Unlike other trabeculoplasty procedures that utilize continuous wave lasers, MDLT uses an 810  nm diode laser to deliver a repetitive series of short, subthreshold pulses (Fig. 64.7a, b; see also, Chap. 61: Figs. 61.1 and 61.4). In a typical MDLT procedure, a series of 100 pulses are delivered to the eye with 300 ns of “on” time and 1,700 ns of “off” time. Due to the short “on” time pulse, and the low irradiance, less heat disperses to adjacent tissue, and the thermal event is restricted to the chromophore.16 MDLT has shown to be effective in reducing IOP with less of the side effects associated with ALT. Several studies have shown insignificant differences in IOP reduction between MDLT and ALT, but intraoperative and postoperative discomfort was significantly reduced with MDLT.17 A limited study by Ingvoldstad et al randomized 21 patients with primary open-angle glaucoma to receive either MDLT or ALT and found that MDLT was equally as effective in reducing IOP as ALT after three months, with a reduction of 4.5  mmHg in the MDLT group and 4.6  mmHg in the ALT group.18 In another study, conducted by Fea et  al,

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Fig. 64.6  (a) Titanium:Sapphire Laser Trabeculoplasty (TLT) being performed for primary open angle glaucoma. (b) Slit lamp view of trabecular meshwork during TLT. (c) Slit lamp view of trabecular meshwork immediately post-TLT. (Photos courtesy of Solx, Inc., Waltham, Massachusetts)

Fig. 64.7  (a) Micropulse Diode Laser (OcuLight SLX 810 nm Laser) attached to a Haag Streit slit lamp prior to insertion of goniolens (Photo courtesy of IRIDEX Corp., Mountain View, California). (b) Diagram of goniolens optics

MDLT was found to be effective in reducing IOP in 75% of eyes with open-angle glaucoma after 12 months of follow-up.17 MDLT has been proven to reduce IOP with limited complications and side effects. In addition, this same laser can be

used for retinal photocoagulation and transscleral cyclophotocoagulation by altering the pulse duration and thereby modifying the thermal laser–tissue interactions. Additional clinical studies are currently being conducted to determine the long-term efficacy of MDLT.

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64.3.3  I OPtima CO2 Laser Assisted Nonpenetrating Deep Sclerectomy Trabeculectomy, the standard surgical procedure for filtration surgery, is known to be associated with numerous postoperative complications. Nonpenetrating deep sclerectomy (NPDS) procedures have gained much attention in efforts to achieve filtration without penetration into the anterior chamber to reduce the risk profile. In NPDS procedures, a scleral flap is created and most of the underlying sclera is removed until only the trabecular meshwork remains, without actually entering the anterior chamber (Fig. 64.8). This technique entails a steep learning curve for the surgeon to become accustomed to both the anatomy and the precision needed. If an insufficient amount of sclera is removed, filtration will not occur. Conversely, if the surgeon removes too much, the thin trabecular membrane may be punctured, requiring conversion of the procedure to a standard trabeculectomy. This intraoperative complication occurs in as many as 30–50% of cases. Because of this high rate of complications, researchers have explored several

Fig. 64.8  Nonpenetrating deep sclerectomy procedure performed under direct observation with CO2 laser and scanner attached to a micromanipulator mounted on the surgical microscope. (Photo courtesy of Dr. Ehud Assia)

Fig. 64.9  IOPtima CO2 laser assisted nonpenetrating deep sclerectomy. Percolation of aqueous in the area treated by the CO2 laser. (Photo courtesy of Dr. Ehud Assia)

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methods to achieve repeatable and satisfactory results while shortening the procedure’s learning curve. A variety of lasers, including 193 nm excimer, 2,100 nm holmium, and 2,940 nm erbium:YAG lasers have been used in NPDS trials; however, none of these lasers was clinically practical for this application. In 2006, Assia et al evaluated the use of a CO2 laser (10,600  nm) for performing a deep sclerectomy in a manner identical to that described by Seiler et al in 1989.19 In his partial external trabeculectomy (PET) procedure, Seiler used the 193 nm excimer laser under flap ab externo to excise scleral tissue until aqueous percolating through the base of the treatment site absorbed the energy and prevented perforation.20 Assia chose the CO2 laser because of its controlled penetration depth and because its radiation is also absorbed and dissipated rapidly in water. These characteristics are useful in NPDS because the laser energy would be absorbed by percolating fluid flowing through the trabecular membrane and prevent the perforation of the trabecular membrane (Fig. 64.9). Additional clinical studies are currently being conducted to determine the long-term efficacy of this CO2 laser in performing NPDS.

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64.4  Lasers for Inflow 64.4.1  Cyclophotocoagulation The goal of cyclophotocoagulation is to reduce the inflow of aqueous humor through the destruction of the ciliary body. However, titration is critical and very difficult to estimate to achieve control without hypotony. In addition, short-term postoperative pressure spikes may occur and the blood aqueous barrier is often compromised with resultant chronic uveitis. Insufficient destruction of ciliary processes results in inadequate reduction in IOP. Therefore, the therapeutic window is a narrow one. Using laser light for ciliary body destruction was found to be as effective as cyclocryotherapy, more easily titrated, and less painful. The continuous wave, long pulse duration (20 mm) photocoagulative Nd:YAG laser (1,064 nm), is used in the majority of cyclophotocoagulation procedures in contrast to the short pulse duration, q-switched photodisruptive Nd:YAG laser used for posterior capsulotomy. This wavelength is able to deeply penetrate the sclera due to its minimal absorption and backscatter. In addition, the Nd:YAG laser can be used via both a contact, fiber optic probe or noncontact slit-lamp delivery system. Subsequently, the use of the infrared diode laser (810 nm) to perform transscleral cyclophotocoagulation has gained popularity. This diode laser has practically replaced cyclocryotherapy and Nd:YAG lasers for cyclodestruction. One of the most common diode laser systems is the continuous-wave 810  nm semiconductor diode laser with a fiber-optic G-Probe (OcuLight SLx, IRIS Medical Instruments, Mountain View, California). The G-Probe is a 400-mm diameter fiber optic delivery device specifically designed to facilitate transscleral cyclophotocoagulation (Fig. 64.10a–d). DCPC, like other cyclodestructive procedures is reserved for glaucomas resistant to other treatments and is indicated

Fig.  64.10  (a) Cyclophotocoagulation via noncontact slit lamp delivery. (b) G-Probe fiberoptic delivery device (Photo courtesy of IRIDEX Corp., Mountain View, California). Diagram (c) and

M.S. Berlin and K. Taliaferro

for late stage glaucoma patients who experience pain and discomfort because of their elevated IOP. Studies have shown that DCPC is successful in controlling IOP in eyes with refractory glaucoma. Iliev et  al found a 55% reduction in IOP and a 65% reduction in glaucoma medications over a 3-year follow-up period.21 However, similar to Nd:YAG laser therapy, clinical studies have shown that the effectiveness of diode cyclophotocoagulation may decrease over time, requiring additional treatments. In seven recent clinical studies, additional treatments were necessary in 25–45% of patients who underwent cyclophotocoagulation.21 Complications of diode laser transscleral cyclophotocoagulation commonly observed are chronic uveitis, ocular discomfort, headache, hyphema, vitreous hemorrhage, hypotony, and phthisis. According to the study conducted by Iliev et al, hypotony occurred in 17.6% of cases and was not correlated to increased laser energy, repeat treatments, or type of glaucoma. Staging photocoagulation with fewer initial treatment sites and lower laser power may reduce this risk of hypotony.21

64.4.2  Endoscopic Cyclophotocoagulation ECP follows the same concepts for the reduction of inflow as transscleral cyclophotocoagulation, but the laser energy delivery to the ciliary process is ab interno under direct observation via an endoscope, rather than transscleral (Fig. 64.11a–c). The advantage is the direct observation of the cyclodestruction process. The disadvantage is the requirement of incisional surgery. Therefore, ECP is usually performed concurrent with cataract surgery. Similar to transscleral cyclophotocoagulation, ECP uses an 810-nm semiconductor diode laser. In addition to this laser, the ECP unit includes a video camera, a xenon light source, and a helium–neon laser aiming beam (Endo Optiks,

(d) photograph of G-Probe delivery device applied to an eye (Illustration and photograph courtesy of IRIDEX Corp., Mountain View, California)

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Fig. 64.11  (a) Endoscopic cyclophotocoagulation of the ciliary body. Coaxial probe crosses anterior chamber into posterior chamber to view and treat ciliary processes. (b) Endoscopic view of ciliary body during

ECP. (c) Endoscopic cyclophotocoagulation procedure being performed on patient. (Diagram and photos courtesy of Endo Optiks, Little Silver, New Jersey)

Little Silver, New Jersey). These elements are combined in a 20-gauge fiber optic cable and endoscope probe. The endoscope allows for a 70° field of vision for the surgeon. The laser is focused 0.75 mm beyond the tip of the probe. Titration of the directly observed photocoagulative thermal cyclodestruction is controlled by modulating the duration of the laser pulse, switched by a foot pedal. There are two approaches for performing ECP: a limbal approach and a pars plana entry. More common is the limbal approach since an anterior vitrectomy is required for a pars plana entry. Also, risks of choroidal and retinal detachment are associated with a pars plana entry.

Multiple studies have shown ECP to have comparable results to DCPC in reducing IOP and glaucoma medications. In one study, 68 eyes with refractory glaucoma underwent ECP. Over a 1-year period, IOP was reduced 34% and glaucoma medications were decreased by 33%.22 However, even with this significant pressure reduction, there were a considerable number of complications associated with this procedure. These complications included fibrin exudates (24%), hyphema (12%), cystoid macular edema (10%), vision loss (6%), and choroidal detachment (4%). Most ECP procedures are performed concurrent with phacoemulsification cataract surgery. The same limbal

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incisions used for the phacoemulsification surgery are used for the ECP. After phacoemulsification is performed, 180– 270° of the ciliary processes are treated. Then, an intraocular lens is implanted and the operation is concluded in a typical fashion. In a study conducted by Berke et  al, 626 eyes underwent combined ECP and phacoemulsification surgery.23 There was a significant 18% reduction in IOP and 53% reduction in antiglaucoma medication over the 3-year study period. In patients who have refractory glaucoma associated with a penetrating keratoplasty, ECP may offer an advantage over transscleral cyclophotocoagulation. Studies have shown that transscleral cyclophotocoagulation is associated with a higher rate of corneal graft failures. In a small pilot study, ten patients who had penetrating keratoplasties underwent ECP. At 30 months postprocedure, 80% of the patients maintained an IOP less than 22 mmHg with an average reduction of 1.4 medications and none of the corneal grafts failed as a result.22

Sidebars Excimer laser trabeculostomy procedure ELT is performed as an outpatient procedure under topical anesthesia. Since 308 nm laser radiation is absorbed by the cornea, an optical fiber must be used to deliver the energy intracamerally. A paracentesis is created, followed by the stabilization of the anterior chamber with viscoelastic. The fiber optic probe is then advanced through the paracentesis across the anterior chamber to contact the trabecular meshwork. This placement is visualized through gonioscopy or via an endoscope. Pulsed photoablative energy is then applied. In most protocols, 10 sites are created in an inferior quadrant. A small amount of blood reflux from Schlemm’s canal is commonly observed and confirms each opening’s patency. The probe is then removed from the eye, and the viscoelastic is exchanged for balanced salt solution. Postoperatively, topical antibiotics and steroid drops are generally continued for 1–2 weeks. Following ELT, IOP decreases immediately. Additionally, pressure lowering medications are rarely needed.24

Micropulse diode laser trabeculoplasty The IRIDEX OcuLight SLx 810 diode is the most commonly used device for MDLT procedures. Preoperatively,

64.5  Conclusions With the goal of controlling IOP and reducing the need for patient compliance, the continuing progress in clinical laser therapies holds a promising future for less invasive, more effective treatments for glaucoma. These newer laser therapies are appropriate as first-line, initial treatment having resolved concerns that arose in earlier laser therapies without compromising IOP lowering efficacy. Although many of the laser procedures under development, particularly those involving endoscopic or ab interno laser delivery, are difficult and offer challenges to even experienced surgeons, their surgical counterparts, including such procedures as trabeculectomy and goniotomy, are difficult as well. We anticipate that the demonstrated effectiveness of these procedures will accelerate their inclusion into the ophthalmic surgery armamentaria and continue to make a significant impact on the treatment of the glaucomas.

topical anesthesia is applied to the operative eye, and the patient is seated at the laser delivery slit lamp. A gonio lens is then coupled to the eye with Goniosol and an aiming beam is focused on the anterior trabecular meshwork. The laser is set at a power of 2 W with 2 ms duration and 60–65 spots are applied over the inferior 180° or 120–130 applications are made over 360°. Postoperatively, 0.1% indomethacin eye drops are administered immediately after the treatment and are continued throughout the first day. In some cases topical steroid drops may be indicated.16

Titanium:sapphire laser trabeculoplasty procedure Preoperatively, topical anesthesia is applied to the operative eye and the patient is seated at a slit-lamp. A gonio lens is then coupled to the eye with Goniosol. Following visualization of the trabecular meshwork, an He–Ne aiming laser is focused on the pigmented region. Initial laser settings should start at a power of 25 mJ and duration of 8 mm. If this is insufficient in producing slight movements of the trabecular meshwork and depigmentation, or “micro-bubbles” in the meshwork, the power may be increased in 25  mJ steps. In most protocols, initial treatment should include 180° of the trabecular meshwork. Postoperatively, topical steroid eye drops are continued for 1–2 weeks.15

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Diode laser cyclophotocoagulation procedure This procedure is performed under retrobulbar or, occasionally, topical anesthesia. The anterior ciliary body is approximated to be 1.5–3.0 mm posterior to the corneoscleral limbus. However, in cases where the ciliary body’s location is assumed to be abnormal, transillumination may be used to localize the ciliary body. Once its location is determined or approximated, the surgeon applies a slight amount of pressure to the sclera via the G-probe over the ciliary body. The number of treatment sites should range from 15 to 30 spots. The laser’s pulse power ranges from 1,500 to 2,000 mW. These power levels should be adjusted to prevent excessive damage. Pulse duration is fixed at 2 s. No more than 270° of the ciliary body’s circumference is treated, leaving the superior sector (the common site of most filtration surgeries) intact. The immediate postoperative care for DCPC is the instillation of antibiotic/steroid ointment with an overnight eye patch. For patients with severe glaucomatous optic neuropathy, use of an oral carbonic anhydrase inhibitor overnight may decrease the risk of postoperative pressure spikes. Oral analgesics are also prescribed. On postoperative day 1, the patient is started on topical antibiotics and steroid drops. In addition, all glaucoma medications are restarted except for miotics and prostaglandin analogues, which may worsen inflammation. In cases of moderate inflammation, cycloplegics, such as 1% atropine sulfate, are used. Glaucoma medications may be discontinued when deemed appropriate.21

IOPtima CO2 laser-assisted nonpenetrating deep sclerectomy procedure Preoperatively the patient is prepared in a similar fashion to trabeculectomy surgery. The procedure is performed under retrobulbar anesthesia. A local peritomy is followed by the creation of a 4 × 5-mm partial thickness scleral flap. The sclera under the flap is then ablated with the carbon dioxide laser. Initially, the laser power is set to 10 W. After every 5–10 laser shots, a noticeable amount of charred tissue may accumulate. This charred tissue is removed with a damp surgical sponge. At the initial sign of fluid percolation, the laser power should be decreased to 5 W. Once fluid is seen, there should be delays between each laser pulse to ensure that only dry tissue continues to be ablated. If the tissue appears to be ablated unevenly, the fluid should be allowed to percolate until it fills the deeper troughs, revealing only the elevated tissue regions.

Once clinically adequate filtration is observed, the surgeon closes the scleral flap with 10–0 nylon sutures.19

Endoscopic cyclophotocoagulation procedure: limbal approach In the limbal approach, the pupil is dilated with topical 2% cyclopentolate. Under retrobulbar anesthesia with bupivacaine, a limbal paracentesis is made at the 3 o’clock position for a right eye and at 9 o’clock for a left eye. Viscoelastic is used to stabilize the anterior chamber. The surgeon also injects enough viscoelastic into the posterior chamber to sufficiently inflate the ciliary sulcus and break any posterior synechiae that would preclude access from an anterior approach. The probe is then advanced through the paracentesis, across the anterior chamber and into the posterior chamber. Once the ciliary processes are visualized the treatment is initiated. The laser power is set according to the surgeon’s preference, usually in the 60–90 mW range. The beam is focused on the raised processes rather than the valleys between them. The photocoagulative laser energy is applied to each ciliary process. The thermal effect causes the tissue to shrink and turn white. This transformation signals the endpoint of the treatment. If excessive energy is used, the ciliary process will visibly rupture with an audible “pop.” This rupture can cause the blood aqueous barrier to be further compromised leading to an increased risk of inflammation and hyphema. Depending on the level of IOP reduction required, 180–270° of the ciliary process are treated. The probe is then removed and the viscoelastic is exchanged for balanced salt solution.19 Following ECP, antibiotic/steroid ointment is applied and the eye is patched. For patients with severe glaucomatous optic neuropathy, use of an oral carbonic anhydrase inhibitor overnight may decrease the risk of postoperative pressure spikes. Oral analgesics are also prescribed. On postoperative day 1, the patient is started on topical antibiotics and steroid drops. In addition, all glaucoma medications are restarted except for miotics and prostaglandin analogues, which may worsen inflammation. In cases of moderate inflammation, cycloplegics, such as 1% atropine sulfate, are used. Glaucoma medications may be discontinued when deemed appropriate.22

Endoscopic cyclophotocoagulation procedure: pars plana approach In the pars plana approach, three ports are created: one for infusion in the inferior pars plana and two superior ports for illumination and vitrectomy. An anterior vitrectomy

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is initially performed to allow access to the ciliary processes. Then, the endoscope is inserted and the same end point of treatment is observed as with the limbal approach. Following ECP, antibiotic/steroid ointment is applied and the eye is patched. For patients with severe glaucomatous optic neuropathy, use of an oral carbonic anhydrase inhibitor overnight may decrease the risk of postoperative pressure spikes. Oral analgesics are also

References 1. Sliney DH, Mainster MA. Opthalmic laser safety: tissue interactions, hazards, and protection. In: Stamper RL, Berlin MS, eds. Lasers in Ophthamology. Philadelphia, PA: W.B. Saunders Company; 1998:157-164. 2. Berlin MS. General aspects of laser therapy. In: Stamper RL, Lieberman MF MF, Drake MV, eds. Becker-Shaffers’s Diagnosis and Therapy of the Glaucomas. St. Louis, MO: Mosby, Inc.; 1999:522-524. 3. Berlin MS. Current options in laser sclerotomy. In: Ritch R, Shields MB, Krupin T, eds.The Glaucomas: Glaucoma Therapy. St. Louis, Missouri: Mosby, Inc. 1996; 1591-1604. 4. Krasnov MM. Laseropuncture of anterior chamber angle in glaucoma. Am J Ophthalmol. 1973;75:674. 5. Berlin MS. Re-thinking glaucoma surgery: ELT present and future. Lecture for ALCON vs. Irvine. Irvine, California. May, 2008. 6. Wise JB. Long-term control of adult open angle glaucoma by argon laser treatment. Ophthalmology. 1981;88:197. 7. Vogel M, Lauritzen K. Selective excimer laser ablation of the trabecular meshwork. Clinical results. Der Ophthalmologe. 1997; 94(9):665-667. 8. Giers et al. Personal communication. 9. Babighian S, Rapizzi E, Galan A. Efficacy and safety of ab interno excimer laser trabeculotomy in primary open-angle glaucoma: two years of follow-up. Ophthalmologica. 2006;220(5):285-290. 10. Pache M, Wilmsmeyer S, Funk J. Laser surgery for glaucoma: excimer-laser trabeculotomy. Klin Monatsbl Augenheilkd. 2006; 223(4):303-307. 11. Giers et al. Personal communication. 12. Kramer TR, Noecker RJ. Comparison of the morphologic changes after selective laser trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology. 2001;108:773-779. 13. Lewandowski JT. Exploring uveoscleral outflow: a new treatment system seeks to take the bleb out of glaucoma surgery. Glaucoma

prescribed. On postoperative day 1, the patient is started on topical antibiotics and steroid drops. In addition, all glaucoma medications are restarted except for miotics and prostaglandin analogues, which may worsen inflammation. In cases of moderate inflammation, cycloplegics, such as 1% atropine sulfate, are used. Glaucoma medications may be discontinued when deemed appropriate.22

Today. http://glaucomatoday.com/pages/current/innovators.html Accessed April 5, 2007. 14. Groves N. Investigational device in United States: titanium-sapphire laser procedure reduces IOP by 25%. Ophthalmology Times. http:// www.solx.com/pdf/254200.pdf Accessed April 7, 2007 15. Harasymowycz P, Ahmed I, Perez B. Initial results from a multicenter, randomized clinical trial comparing argon laser and Titanium:Sapphire laser trabeculoplasty in primary open-angle glaucoma. Paper presented at: The 2008 ASCRS Symposium on Cataract, IOL and Refractive Surgery; April 7, 2008; Chicago, IL. 16. Fea AM, Dorin G. Laser treatment of glaucoma: evolution of laser trabeculoplasty techniques. Tech Ophthalmol. 2008; 6(2):45-52. 17. Fea AM, Bosone A, Rolle T, Brogliatti B, Grignolo FM. Micropulse diode laser trabeculoplasty (MDLT): A phase II clinical study with 12 months follow-up. Clin Ophthalmol. 2008; 2(2):247-252 18. Ingvoldstad DD, Krishna R, Willoughby L. MicroPulse diode laser trabeculoplasty versus argon laser trabeculoplasty in the treatment of open angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46. E-Abstract 123. 19. Assia EI, Rotenstreich Y, Barequet IS, Apple DJ, Rosner M, Belkin M. Experimental studies on nonpenetrating filtration surgery using the CO2 laser. Graefes Arch Clin Exp Ophthalmol. 2007;245(6):847-854. 20. Seiler T, Kriegerowski M, Bende T, Wollensak J. Partial external trabeculectomy. Klin Monatsbl Augenheilkd. 1989;195(4):216-220. 21. Iliev ME, Gerber S. Long-term outcome of trans-scleral diode laser cyclophotocoagulation in refractory glaucoma. Br J Ophthalmol. 2007;91:1631-1635. 22. Lin S. Endoscopic cyclophotocoagulation. Br J Ophthalmol. 2002; 86:1434-1438. 23. Boyle, E.L. Combined phaco-ECP procedure lowers IOP, number of medications. Ocular Surgery News. http://www.endooptiks.com/ articles/berke_ecp_phaco_4.pdf Accessed April 22, 2007. 24. Berlin MS, Giers U, Kleineberg L, Taliaferro K. ELT: excimer laser trabeculostomy: clinical update, 2008. American Glaucoma Society Annual Meeting; March 2008.

Chapter 65

Incisional Therapies: Trabeculectomy Surgery Shlomo Melamed and Daniel Cotlear

Trabeculectomy with an antimetabolite is considered the “gold standard” for the surgical management of glaucoma. Surgical management for glaucoma was first described in 1857 by Von Graefe, who reported that by removing a large piece of the iris he could help many patients with glaucoma. In 1909, Elliot described a full-thickness filtering procedure by using a trephine to make an anterior sclerectomy under a conjunctival flap, coupled with a peripheral iridectomy. Uncontrolled transclerostomy flow with resulting hypotony was the trigger for most surgeons to switch from full-thickness sclerostomy to a partial-thickness fistula. The guarded fistula was first suggested in 1961 by Sugar but was only published in 1968 by Cairns. The obstruction of the aqueous humor was assumed to be at the juxtacanalicular portion of the trabecular meshwork, and the outflow system distal to the juxtacanalicular meshwork (primarily Schlemm’s canal and the distal collector channels) was thought to be normal in patients with glaucoma. Therefore, the primary goal of the trabeculectomy was to eliminate the obstruction to aqueous humor outflow at the inner aspect of Shlemm’s canal1 (Figs. 65.1 and 65.2). Although Cairns intention was to avoid “unnecessary and a non physiologic bypass” of the collector channels by excising a portion of the trabecular meshwork and adjusted Schlemm’s canal, we know today that the mechanism responsible for lowering intraocular pressure (IOP) after guarded filtration procedure is a through-and-through fistula, through the scleral flap borders, connecting the anterior chamber with the subconjunctival space. Possible alternative routes of filtration after trabeculectomy surgery (Fig. 65.3) are through: 1 . The cut ends of Schlemm’s canal 2. Suprachoroidal space 3. Scleral vessels 4. Thin scleral flap 5. The scleral flap borders Since then, many surgical and wound-healing modifications were added to the procedure. In order to keep the fistula open and functional, these modifications mainly address the

wound-healing process in order to minimize the fibroblast proliferation and secondary scar tissue formation. At this point, it is necessary to define that all the trabeculectomy modifications still use a common concept to lower the IOP by creation of a fistula between the anterior chamber of the eye and the sub-Tenon and subconjunctival space. The aqueous humor is diverted by this fistula from the anterior chamber outside of the eye into the sub-Tenon and subconjunctival space, and finally collected into the episcleral and conjunctival veins. In order to guide the reader systematically through the trabeculectomy procedure and all controversial aspects of this procedure (see Sidebar 65.1), we will explain the procedure step by step, in chronological order.

65.1  Anesthesia General anesthesia is reserved for noncooperative patients. Topical anesthesia with eye drops – Localin (oxybu­ procaine hydrochloride 0.4%), tetracaine/amethocaine (2-(dimethylamino) ethyl p-(butylamino) benzoate monohy­ drochloride 0.5%), lidocaine 2% (lignocaine hydrochloride 2%) – and jelly (Xylocaine – lidocaine 2%) should be preferred in most cases. When compared to peribulbar or retrobulbar anesthesia, there was no difference regarding pain control or surgical complication.2,3 Another option is to inject nonpreserved lidocaine 1% into the anterior chamber. In addition to the anesthetic effect, intracameral lidocaine dilates the pupil. Although there is an advantage in combined surgery (cataract extraction combined with trabeculectomy), this effect is unwanted in trabeculectomy alone. The main disadvantage of the topical anesthesia is the lack of akinesia, which can be achieved with retrobulbar injections, or partial akinesia with peribulbar or sub-Tenon injections. Subconjunctival injection at the bleb site is to be avoided because it delivers poorer surgical outcomes.4 For retrobulbar or peribulbar injections, a mixture of 50% lidocaine and 50% bupivacaine 0.75% is used in order to

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_65, © Springer Science+Business Media, LLC 2010

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Fig. 65.1  Line of incision into anterior chamber. Reprinted with permission from Cairns JE1; Elsevier

Fig. 65.3  Possible alternative routes of filtration after trabeculectomy surgery

Fig. 65.2  Elevation of the corneoscleral flap. Reprinted with permission from Cairns JE1; Elsevier

prolong the anesthetic effect up to 6 h from 15 to 30 min with lidocaine only. It is recommended not to inject more than 5 ml of anesthetic volume around or behind the globe in order to avoid a “positive” pressure on the globe, which may add to the ischemic damage of the already compromised optic nerve. Complications of injections are

globe perforation, optic nerve damage, and peri/retrobulbar hemorrhage.

65.2  Eye Exposure A good exposure of the surgical field is mandatory, and is achieved with a lid speculum, which opens the eye, preferably without creating pressure on the globe.

65  Incisional Therapies: Trabeculectomy Surgery

Sidebar 65.1  Incisional glaucoma surgery: making the decision to operate Claudia U. Richter Glaucoma is a group of diseases with patients who present with varying degrees of optic nerve damage and visual field loss as well as individually varied general medical, ophthalmic, and social issues. All of these factors combine to make the risk/benefit ratio and the decision to do glaucoma surgery different for each patient. Incisional glaucoma surgery, whether by filtering surgery, aqueous tube shunt, or nonpenetrating procedures, lowers intrao­ cular pressure (IOP) by providing an alternative path for aqueous humor outflow, and often stops or limits progression of the disease. The decision to perform incisional glaucoma surgery is based upon our knowledge of the natural history of glaucoma progression correlated with a particular patient’s history and status, the patient’s response to medical and laser therapy, the benefits of surgery, and contraindications to and risks of surgery. Glaucoma is frequently a slowly progressive illness with a long disease period before optic nerve damage and visual loss are detectable. However, once glaucoma damage is present, progression of damage may occur at lower IOPs and more rapidly than earlier in the disease course. Glaucoma progression may occur more rapidly with greater IOP elevation above the targeted pressure. Additionally, the greater the degree of glaucoma damage, the lower is the pressure required to minimize future vision loss. Patients with advanced glaucoma may require IOPs approximating 12 mmHg to minimize the risk of further glaucomatous damage, a level difficult to reach and maintain with only medical and laser therapy. Conversely, patients with little glaucomatous damage and few risk factors may tolerate higher pressures. Patients with advanced glaucoma who have not reached a targeted low IOP are appropriately managed surgically in order to reach the clinically indicated low target IOP. Incisional glaucoma surgery is typically recommended only when medical and laser therapies have failed to prevent optic nerve damage or visual field loss, or lower IOP to a level that will prevent such loss. Initial glaucoma surgery without prior medical or laser therapy is rarely appropriate or performed in the USA, but may be for a patient presenting with advanced glaucoma damage and high IOP for whom urgent IOP control is the best hope to salvage vision. Most patients are tried on multiple topical antiglaucomatous medications, often in combination, including a prostaglandin analog, a beta-adrenergic blocker, an alphaagonist, and a topical carbonic anhydrase inhibitor.

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Pilocarpine, phospholine iodide and oral carbonic anhydrase inhibitors may be tried, but their side effects frequently preclude long-term use. All the topical antiglaucomatous medications may cause side effects that limit their use: allergic reactions, precipitation of asthma, keratitis, and decreased vision, for example. Some patients may experience annoying side effects such as increased skin pigmentation, hyperemia, and ocular irritation. Should these patients have glaucoma surgery to relieve their symptoms? That question can be answered only after an extensive discussion of the possible benefits and complications of surgery. The complex medication schedule and the cost of chronic medical therapy may prevent a patient’s persistence with an otherwise successful medication plan. If these barriers to chronic successful management of glaucoma cannot be overcome, glaucoma surgery may be necessary to provide long-term control of the disease. Laser trabeculoplasty (LTP) often lowers IOP for a number of years, reportedly as often as 75% after initial laser treatment, and is indicated prior to incisional glaucoma surgery in those patients with a type of glaucoma that may respond. LTP may be performed prior to initiating topical glaucoma medications or after a trial of one to several medications. There is currently no consensus as to the best time in the disease course for laser intervention, with some ophthalmologists using it as first-line therapy. The efficacy of LTP in controlling glaucoma fades with time, and 30–50% of eyes require additional surgical therapy within 5 years of treatment. Additional sessions of LTP are less successful than initial therapy. However, even considering the limitations of this procedure, LTP does lower IOP for an extended time in many patients with fewer complications than incisional surgery and should be considered prior to incisional surgery. However, LTP is not indicated prior to incisional glaucoma surgery in those patients with advanced glaucoma and high IOP because it is not always successful, takes time to be effective, and may cause IOP elevations – these patients require urgent glaucoma control to prevent progression. Incisional glaucoma surgery is successful in 70–80% of patients in reducing IOP and preserving vision. It also frequently eliminates or reduces the need for antiglaucomatous medications, reducing ocular side effects, compliance problems, and the ongoing cost of disease management for the patient. However, glaucoma surgery may fail 20–30% of the time and carries risks of significant complications. Therefore, the recommendation for surgery should include an extensive discussion with the patient of the proposed procedure, the postoperative management necessary to maximize success, and the potential complications. For

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most patients with uncontrolled IOP or progressive optic nerve damage and visual field loss, surgery will be the correct decision. Some patients with compliance difficulties or medication side effects will choose to improve their compliance or endure side effects and therefore delay or avoid surgery. The physician and patient must carefully weigh the risks of vision loss in the patient’s lifetime without surgery, which is often difficult and always imprecise. If a patient appears to have a life-threatening disease or a limited life expectancy, consultation with the patient’s other physicians may be helpful in the decision-making process. In summary, incisional glaucoma surgery is usually required when the IOP in uncontrolled or optic nerve cupping is progressing or visual field loss is progressing despite a comprehensive medication trial and LTP. The greater degree of glaucoma damage and the more elevated the IOP, the more urgent the surgery. While frequently successful, glaucoma surgery may also have vision threatening complications, both in the early postoperative period and later, and requires careful counseling of the prospective surgical patient of the potential risks as well as benefits and the postoperative care necessary.

It is important not to drag the conjunctiva with the speculum arms because this may tighten the conjunctiva and create an unnecessary surgical difficulty.

65.3  Traction Suture This step is useful since it helps to keep the eye in the desired inferior position throughout the surgery. The suture can be placed in clear cornea or underneath the superior rectus muscle. For the clear corneal traction suture, a 7/0 spatulated Vicryl or silk corneal traction suture is placed half thickness and 2 mm anterior to the limbus. The eye is rotated inferiorly, and the suture is affixed to the drape inferior to the eye (Fig. 65.4a–c). In the superior rectus muscle traction suture technique, a 4/0 silk suture is passed approximately 12  mm behind the superior limbus, underneath the superior rectus muscle, and attached to the drape over the patient’s forehead. The clear corneal traction suture is preferred because it provides better exposure (more firmly attached), no risk for subconjunctival hemorrhage or conjunctival damage, no risk of postoperative proptosis due to the superior rectus damage, and has been found to provide a better surgical outcome by the UK National Survey of Trabeculectomy.5

Bibliography Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compare with laser and medicine in open-angle glaucoma. Ophthalmology. 1994;101:1651–1656. Richter CU, Shingleton BJ, Bellows AR, et  al. Retreatment with argon laser trabeculoplasty. Ophthalmology. 1987;94: 1085–1089. Shingleton BJ, Richter CU, Dharma SK, et al. Long-term efficacy of argon laser trabeculoplasty. A 10-year follow-up study. Ophthalmology. 1993;100:1324–1329. Spaeth GL, Baez KA. Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years. Arch Ophthalmol. 1992;110:491–494. The Advanced Glaucoma Intervention Study (AGIS): 13. Comparison of treatment outcomes within race: 10-year results. Ophthalmology. 2004;111:651–664. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429–440. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial follow-up study: 7. Results. Glaucoma Laser Trial Research Group. Am J Ophthalmol. 1995;120:718–731. Weber PA, Burton GD, Epitropoulos AT. Laser trabeculoplasty retreatment. Ophthalmic Surg. 1989;20:702–706.

65.4  Conjunctival Incision The bleb surgical site is in the upper globe, preferably under the upper eyelid in order to reduce infections or bleb leakage.6 It is advised to use a topical vasoconstrictive agent, like adrenaline 0.01%. Efrin 10% can also be used but provides less vasoconstriction. The vasoconstrictive agent is used before conjunctival dissection in order to minimize conjunctival bleeding. The conjunctival incision can be performed in a limbal base or fornix base fashion.7,8 In general, the limbal base technique first described by Cairns was abandoned due to higher rate of postoperative complications (Table  65.1). The higher rates of complications are probably related to the differences in bleb morphology, with limbus-based flap cases more likely to develop cystic blebs.7 Limbal base bleb creation is more time-consuming, has more risk of buttonhole formation, and allows poorer surgical exposure, which prevents diffuse antibiotic application. A large and diffuse antibiotic treated area results in a Table  65.1  Postoperative complications of limbal-base versus fornix-base techniques Complication Cystic bleb Blebitis Leakage

Limbal base 90% 20% 24%

Fornix base 20% None 65%

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Sidebar 65.2  Anticoagulants and glaucoma surgery Siva S. Radhakrishnan Iyer, Sarwat Salim, and Peter A. Netland Many patients requiring glaucoma surgery are concomitantly receiving anticoagulation therapy for other comorbidities, including arrhythmia, cardiac prosthetic valve, or thromboembolic disease resulting from various etiologies. The alternative of complete discontinuation of anticoagulation therapy before surgical intervention has raised concerns about the risk of serious thromboembolic events in the perioperative period in these patients. Glaucoma surgeons are usually concerned about hemorrhagic complications of anticoagulation that can ultimately affect surgical success. Anticoagulation therapy is commonly categorized in two groups: those undergoing therapy with warfarin, and those undergoing therapy with an antiplatelet agent (clopidogrel and aspirin [acetylsalicylic acid]). The antiplatelet agents, which inhibit activation of the lipid peroxidation system in the platelet wall, are usually regarded as less severe drugs for blood thinning. Warfarin and aspirin should usually not be mixed. The common intraoperative and postoperative surgical complications associated with blood thinning medications include retrobulbar hemorrhage, hyphema, vitreous hemorrhage, and suprachoroidal hemorrhage. A few retrospective studies have analyzed hemorrhagic complications of glaucoma surgery in patients using anticoagulation therapy. Law and colleagues reported a higher incidence of complications following glaucoma surgery in patients who were on either warfarin or antiplatelet therapy compared to controls, with the highest rate of complication noted in patients who continued warfarin therapy through surgery. In this study, there were less hemorrhagic complications in patients who discontinued Coumadin compared with those who continued anticoagulation; however, the difference failed to reach statistical significance. Similarly, in a retrospective examination of 367 trabeculectomies, Cobb et  al observed that continuation of either warfarin or aspirin therapy in those undergoing surgery had approximately twice the risk of hyphema. However, the use of aspirin did not adversely affect the eventual surgical outcomes, whereas warfarin’s use ultimately resulted in poor surgical outcomes and intraocular pressure (IOP) control. Alwitry and colleagues reported that most glaucoma surgeons in the United Kingdom do not routinely stop anticoagulation therapy prior to glaucoma surgery. A smaller percentage of these surgeons chose to discontinue longterm anticoagulation therapy and initiate heparin therapy.

Bleeding complications secondary to anticoagulation therapy are not limited to the glaucoma surgical patient, as there have been concerns among surgeons in other subspecialties including vitreoretinal surgery and oculoplastic surgery. However, a unique aspect of glaucoma surgery is the risk of hypotony and hypotony-related complications, including suprachoroidal hemorrhage, during the early postoperative period. In high-risk eyes, glaucoma surgeons may choose to discontinue anticoagulation during the perioperative period or use other techniques to reduce the risks of hemorrhagic complications during and after surgery. When surgeons choose to discontinue anticoagulant therapy, the approaches vary and can be individualized to each patient. In patients treated with warfarin, the drug can be discontinued for a minimum of 3 days prior to surgery to improve coagulation intraoperatively and postoperatively. The patient’s primary care practitioner may allow withholding warfarin for an additional several days after surgery, which may avoid postoperative complications in high-risk eyes. It is worth noting that warfarin cessation may lead to a rise in clotting factors that put the patient in a hypercoagulable state, shown to peak at 1 week afterwards. Because aspirin has a prolonged antiplatelet aggregation effect, some surgeons recommend cessation of aspirin therapy 1 or 2 weeks prior to surgery, with approval by the patient’s primary care provider. Discontinuation of aspirin on the day of surgery probably has little or no influence on the antiplatelet effect of the drug during the perioperative and immediate postoperative period. There are risks associated with discontinuation of long-term anticoagulation therapy in patients undergoing surgery. The risk of thromboembolic events is probably low (less than 1%). However, some of these problems such as pulmonary embolus or stroke can be life-threatening. In each patient, the ocular risk of continuation of anticoagulant therapy should be weighed against the systemic risk of life-threatening hemorrhagic complications. Communication and coordination with the physician who is managing the long-term anticoagulant therapy is strongly recommended, along with a frank discussion with the patient of the risks and benefits of altering anticoagulation therapy in the perioperative period. Alternatives to discontinuation of anticoagulation therapy may be tried in order to reduce the risk of bleeding complications. Modifying anesthetic methods may be helpful, including use of topical and local anesthesia in order to minimize the risk of retrobulbar hemorrhage associated with retrobulbar injection of anesthetic. Surgical techniques, also, may be modified to avoid

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hemorrhagic complications. Meticulous use of hemostasis during flap dissection, anterior placement of sclerotomy to avoid the ciliary body, and omitting surgical iridectomy have been shown to avoid bleeding. Tightly securing the scleral flap to prevent bleeding and postoperative hypotony has been advocated. Postoperative hypotony increases the risk of bleeding complications, specifically suprachoroidal hemorrhage. In glaucoma drainage implant surgery, use of suture ligatures around the tube or two-stage surgery can reduce the rate of postoperative hypotony. Intraoperative and postoperative use of viscoelastics may avoid or mitigate problems associated with hypotony. Gradual reduction of the IOP during surgery may avoid dramatic fluctuations in IOP, which increase the risk of bleeding complications. In summary, the current literature suggests that patients receiving anticoagulation therapy with warfarin and/or antiplatelet agents who are candidates for glaucoma surgery are at increased risk for serious hemorrhagic complications. Many glaucoma subspecialists continue anticoagulation through surgery, although surgeons may modify their anesthetic and surgical techniques to minimize complications. In patients at high risk for ocular hemorrhagic complications, the surgeon may recommend withholding anticoagulant therapy during the perioperative period. In all instances, ophthalmologists should collaborate with the patient’s physician and other medical specialists in assessing the patient’s risk of hemorrhagic ocular complications, the systemic risk of discontinuing anticoagulant therapy, and the perioperative plan for use of anticoagulant drugs.

Bibliography Alwitry A, King AJ, Vernon SA. Anticoagulation in glaucoma surgery. Graefes Arch Clin Exp Ophthalmol. 2008;246(6):891–896. Baudo F, de Cataldo F, Mostarda G, et al. Management of patients on long-term oral anticoagulant therapy undergoing elective surgery: survey of the clinical practice in the Italian anticoagulation clinics. Intern Emerg Med. 2007;2:280–284. Cobb CJ, Chakrabarti S, Chadha V, Sanders R. The effect of aspirin and warfarin therapy in trabeculectomy. Eye.2007;21(5):598–603. Grip L, Blomback M, Schulman S. Hypercoaguable state and thromboembolism following warfarin withdrawal in post-myocardialinfarction patients. Eur Heart J. 1991;12(11):1225–1233. Jampel H. Glaucoma surgery in the patient undergoing anticoagulation. J Glaucoma. 1998;7(4):278–281. Jeganathan VS, Ghosh S, Ruddle JB, Gupta V, Coote MA, Crowston JG. Risk factors for delayed suprachoroidal hemorrhage following glaucoma surgery. Br J Ophthalmol. 2008;92(10):1393–1396. Konstas AGP, Jay JL. Modification of trabeculectomy to avoid postoperative hyphema. The ‘guarded anterior fistula’ operation. Br J Ophthalmol. 1992;76:353–357. Law SK, Song BJ, Yu F, Kurbanyan K, Yang TA, Caprioli J. Hemorrhagic complications from glaucoma surgery in patients on anticoagulation therapy or antiplatelet therapy. Am J Opthalmol. 2008;145(4):736–746. McCormack P, Simcock PR, Tullo AB. Management of the anticoagulated patient for ophthalmic surgery. Eye. 1993;7:749–750. Narendran N, Williamson TH. The effects of aspirin and warfarin therapy on haemorrhage in vitreoretinal surgery. Acta Ophthalmol Scand. 2003;81:38–40. Parkin B, Manners R. Aspirin and warfarin therapy in oculoplastic surgery. Br J Ophthalmol. 2000;84:1426–1427. The Flurouracil Filtering Surgery Study Group. Risk factors for suprachoroidal hemorrhage after filtering surgery. Am J Ophthalmol. 1992;113:501–507. Tuli SS, WuDunn D, Ciulla TA, Cantor LB. Delayed suprachoroidal hemorrhage after glaucoma filtration procedures. Ophthalmology. 2001;108(10):1808–1811.

Fig. 65.4  Clear corneal traction suture. (a, b) a corneal traction suture is placed half thickness and 2 mm anterior to the limbus. (c) The eye is rotated inferiorly, and the suture is affixed to the drape inferior to the eye

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Fig. 65.5  Tight suture techniques. (a) The conjunctiva is grasped close to the limbus. (b) The conjunctiva is then lifted and an initial small incision parallel to the limbus is made with Vannas or Westcott scissors. (c) The incision is extended parallel to the limbus

postoperative diffuse posterior filtering bleb and an increase in bleb survival.7,9 One of the risks with fornix base opposed to limbal base may be a higher rate of early leakage, but this was not found to be a risk factor of bleb failure.10 This leakage can be minimized with new surgical methods of tight suture techniques11-13 (Fig. 65.5a–c). The conjunctiva is grasped close to the limbus at the selected superior nasal or temporal quadrant, with a nontraumatic fine forceps. Toothed forceps that can cut the conjunctiva should not be used. The conjunctiva is then lifted and an initial small incision parallel to the limbus is made with Vannas or Westcott scissors (preferable blunt tip instruments). The incision is extended parallel to the limbus up to two clock hours. The 12 o’clock or superior nasal quadrant is preferred unless the conjunctiva is scarred from previous surgery. The first reason for selecting these positions is to reserve the nearby areas, mainly the temporal or superotemporal quadrant for subsequent cataract surgery. Another reason is that these sites provide lower IOPs at long-term follow-up compared to the superior or superotemporal positions.14 The Tenon’s capsule can be separated together with the conjunctiva or in two steps. Performing a separate incision and separation of the Tenon’s capsule improves the ability to enter the sub-Tenon space. A blunt and, as much as possible, nontraumatic undermining of the Tenon is carried out with Westcott scissors, in order to minimize inflammatory mediator release and to reduce the post scar formation.15 The subTenon’s space should be dissected at least 8  mm posterior from the limbus. Meticulous care must be made to prevent conjunctiva buttonhole formation, and it is advised to grasp just the Tenon layer as this may result in a button-hole. An area of approximately 5.5 mm exposed sclera is desired. Bleeding episcleral blood vessels should be gently diathermized, in order to minimize clot and fibrin formation and to reduce the postop inflammation. Wet field cautery with or

Fig. 65.6  Wet field cautery

without the use of a Weck-cell sponge is the preferred technique (Fig. 65.6). Care must be taken not to cauterize the conjunctiva. Smaller tipped cautery units are preferable. This can be achieved by pushing the conjunctiva away from the cautery tip with the Weck-cell sponge. Cautery of deep scleral blood vessels is not necessary and may also just increase inflammatory mediators in the field. Excessive and loose episcleral tissue should be removed with a sharp blade to minimize postop scar tissue formation. Small incision trabeculectomy (SIT)16 avoids Tenon dissection. A limbal parallel conjunctival incision of 2.5 mm is performed and then a scleral pocket extending posteriorly is carried out and the subconjunctival space is entered (see Sidebar 65.3). There are still not enough published reports of success rates or prevalence of cystic bleb or scar tissue development around these small blebs.

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Sidebar 65.3. Fornix versus limbal based flaps Kenneth B. Mitchell Surgeons become comfortable with either limbal or fornix-based flaps and it becomes their “fastball.” That being said, it is useful to note the advantages and disadvantages of both incisions for trabeculectomy. The fornix-based flap

from the limbal zone and visualization is excellent. Closure may be quicker. The surgeon may be less in need of an experienced assistant. A fornix-based flap is easily combined with a single site phaco-trabeculectomy. Disadvantages

The fornix-based incision can be quickly made (Fig. 65.3-1a–d). Conjunctiva and Tenon’s are fused at the limbus and Tenon’s is thinnest anteriorly. There is much less manipulation of the conjunctiva and Tenon’s after the initial incision and dissection. Vessel transection is anterior where the vessel diameter is smallest. This relates to less bleeding, which may be controlled by application of brimonidine with or without light wet-field cautery. There is usually no need for dissecting Tenon’s

Any posterior hemorrhage from tissue plane dissection with scissors is more difficult to visualize and treat with fornix-based flaps. Closure of the flap is less routine than with a limbalbased flap. If no relaxing incisions were made, there is some judgment call as to where to approximate the flap to the corneal periphery. Is one suture enough? Is a running suture necessary? Any tightness on reapproximating the flap to the cornea may result in a button-hole or tear from the suture needle. These holes are anterior and must be closed with interrupted sutures. Their anterior location may interfere with filtration in that region.

Fig. 65.3-1  Steps in creating a fornix-based flap. (a) Beginning the fornix-based flap with nontoothed forceps and scissors tenting the fused conjunctiva and Tenon’s up at the limbus. (b) Ending the

curvilinear limbal incision. (c) Exposing the scleral bed. (d) Blunt dissection posteriorly for antimetabolite or tube shunt plate insertion

Advantages

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Fig. 65.3-2  Creating a limbal-based flap. (a) Starting the limbal based flap in a patient with thin conjunctiva and scant Tenon’s. (b) Reflecting the limbal-based flap onto the cornea

At the end of the case, when these flaps are challenged with a balanced salt solution infusion into the anterior chamber, slight leakage is often seen. Is that significant? Does it always translate into a positive Seidel the next day? No, but early bleb leaks are more common with fornix-based flaps. Fortunately, they tend to be small and resolve, or can be treated with bandage soft lenses, fibrin sealant, or suture reinforcement, and IOP control is usually not compromised. If suture knots are not buried or if buried knots come to the surface, they may cause irritation, which tempts their removal perhaps a bit earlier than the surgeon would like. Limbal-based flaps Advantages Closure of a limbal-based flap is usually straightforward (Fig.  65.3-2a, b). Whether Tenon’s and conjunctiva are closed separately or together, a snug running suture with locking bites usually balloons up nicely after infusion challenge and are water-tight. Any gape can usually be closed with additional interrupted bites. These gapes are located posteriorly and may not interfere with filtration elsewhere. The suture closure located posteriorly is not associated with irritative symptoms as much as an anterior suture closure. Disadvantages The creation of the flap or its extension may bring the surgeon into the neighborhood of the superior rectus. Bleeding, an inadvertent tenotomy, or disinsertion may result. Even without tendon injury, bleeding is encountered as the vascular diameter of the conjunctival vessels is greatest posteriorly. Tenon’s capsule is thickest posteriorly

and a decision to excise Tenon’s may be made. This can result in thinner flaps posteriorly; particularly with antimetabolite use. The dissection anteriorly to clear the limbal region requires sharp dissection or scraping Tenon’s off the corneal-scleral surface, both in the region of the flap’s insertion. The more the manipulation, the greater is the risk of pressure compression from forceps, inadvertent cautery burn, and button-holes. A surgeon usually needs an experienced assistant to elevate the conjunctiva and Tenon’s flap for the scleral dissection and the intracameral steps. A limbal-based flap requires more manipulation during one-site phaco-trabeculectomy surgery. A “ring of steel” appearance with the use of antimetabolites occurs occasionally in limbal-based flaps and is rare after fornix-based flaps. Thin-walled blebs are more often seen after limbal based flaps with antimetabolite use. In association, blebitis has been described more often with limbal-based flaps.

Conclusion Both flaps have their champions, advantages, and disadvantages. With care, either can result in acceptable, diffuse, posterior blebs and acceptable IOP control.

Bibliography Kohl D, Walton D. Limbus-based versus fornix-based conjunctival flaps in trabeculectomy: 2005 Update. Int Ophthalmol Clin. 2005;45(4):107–113.

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65.5  Anterior Chamber Paracentesis A paracentesis is performed – prior to the fistula creation in order to manage intraoperative complications – mainly to prevent anterior chamber collapse. The secondary goal is to check if the fistula is functional and the bleb is without leakage at the end of the surgery by injecting a small amount of fluid into the anterior chamber. This is performed by injecting balanced salt solution (BSS) through a 30-gauge blunt-tipped needle into the anterior chamber, which should cause an elevation of the bleb without conjunctival leak along the limbal border or from a conjunctival buttonhole (Fig. 65.7). The most preferred paracentesis sites are at 11 or 1 o’clock vertically down or horizontally at 3 or 9 o’clock and parallel over the iris to minimize possible lens damage. The paracentesis is made either with a disposable 25or 27-gauge needle, or a 15° or a stiletto knife. If an anterior chamber maintainer is used, then the desired position is at 6 o’clock and the paracentesis is performed with a 25-gauge stiletto knife. The anterior chamber system provides many advantages during the operation, mainly keeping a deep anterior chamber and lowering the chance for IOP fluctuations. The advantage of the 3, 6, and 9 o’clock positions is that hypotony with a flat anterior chamber postoperatively can be managed at the slit lamp by injecting a viscoelastic material.

65.6  Scleral Flap Size and Shape There are two popular scleral flap shapes: triangle or rectangular. Some prefer trapezoids, and even other shapes are not unknown, although some investigators suggest that from

Fig. 65.7  Anterior chamber paracentesis

S. Melamed and D. Cotlear

clinical observation more posterior large flaps are associated with thicker (noncystic) and more diffuse blebs then anterior small flaps.17 No scleral flap size or shape has been proven to be superior. The pitfalls with more posterior large flaps are ciliary body damage – mainly ciliary body hemorrhage.

65.6.1  Rectangular Scleral Flap Technique A straight, partial thickness, scleral cut is made 4 mm behind and tangential to the limbus to create the posterior border of the scleral flap (Fig. 65.8a–g). The initial cut is dissected anterior toward the limbus with an angled crescent blade. The knife should be advanced as parallel to the sclera while carefully monitoring the flap thickness, and then converted by cutting down the sides to a 4  mm to 4  mm half-thickness scleral flap with a diamond blade or straight Vannas scissors. In order to minimize leakage and to maximize posterior flow, it is recommended to leave a 1 mm border between the scleral flap edges and the limbus.

65.6.2  Triangular Scleral Flap Technique An isosceles triangle partial thickness scleral cut is made (Fig. 65.9a–g). The triangle base is positioned 1 mm posterior to the limbus with the triangle apex pointed toward the fornix. The triangle dimensions are: 3 mm base length and each side length of 3–4  mm. The flap edge is lifted at the apex with a nontoothed forceps, and slight traction is applied in order to cut the collagen scleral fibers and to create a smooth flap bed. The flap is dissected best by a beaver, diamond, or crescent blade. Throughout the dissection, the flap can be adjusted to the proper thickness. The desired scleral flap thickness is one-half to two-thirds to prevent flap dehiscence or suture cheese wiring. Throughout the flap creation, it is best to keep the surgical area dry, because it allows better visualization of the flap details. Only if bleeding, which obscures the surgical site, occurs at this stage must irrigation with BSS be carried out. The flap is extended 1–2 mm and anterior to the anatomical limbus. The next steps apply for both scleral flap shapes. A circumferential cut is made at the scleral bed – underneath the partial thickness scleral flap at the most anterior border – with a sharp instrument like a diamond, 15°, or stiletto knife, and the anterior chamber is entered. Another cutting technique is to make a parallel incision into the anterior chamber with a keratome to create a corneal tunnel; this should reduce injury to the structures underneath, which could be damaged using a perpendicular cut. The incision is made anterior or at the corneolimbal junction and extended

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Fig. 65.8  (a–g) Rectangular scleral flap technique

posterior toward the sclerolimbal junction (Fig. 65.10). This junction is also known as the surgical limbus and is visible as the transfer zone from the translucent bluish-gray cornea and the white sclera (Fig. 65.11). This junction is an important anatomical landmark because failure to perform a welllocalized trabeculectomy by excessive posterior extension may result in ciliary body damage with subsequent hemorrhage or ostium blockage by uveal tissue. The fistula is created by removing a portion of the scleral bed underneath the flap. It can be performed by hand cut or with the use of a punch like the Kelly-Descemet’s punch.

The desired size of the ostium should be more then 40–50 mm in diameter, because below that size, significant resistance to the physiological aqueous outflow18 can still remain. Since each punch bite removes tissue sections of approximately 0.25 × 0.30  mm, one punch bite is enough. Proper technique is vital to create a functional ostium. The punch must be rotated vertically so that it is perpendicular to the bed of the flap, in order to avoid a tunnel-like ostium that might close. Another important consideration is to make sharp cuts and to remove the excised tissue to prevent secondary blockage of the ostium. The scleral flap is sutured

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Fig. 65.9  (a–g) Triangular scleral flap technique

tight to allow a minimal desired fluid flow rate through the flap borders. The control of the resistance to outflow is determined by flap construction, suture position, and tension.19

65.7  Flap Suturing Techniques There are many flap closure suturing variations. A large survey in the United Kingdom reported that scleral flap shape is most often rectangular and most commonly secured with two interrupted 10–0 nylon sutures at the upper two corners5 (Fig. 65.12).

Nylon suture is preferred because of its low tendency to create an inflammatory response. It is better to create a tight wound closure that can be reopened with similar results, by suture lysis20 or removal of a releasable suture in the postoperative period, rather than a loose overfiltrating bleb with hypotony.21 The releasable suture is released simply by pulling the exteriorized corneal loop with a suture-holding forceps under topical anesthesia with the patient seated at the slit lamp. The use of releasable sutures in filtration surgery originated by Schaffer et al22, and since then, many technique modifications have been reported.23,24 There are several releasable suture techniques. All have in common an exterior suture end (exterior loop or buried

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Fig.  65.12  Flap suturing technique. In this picture, two interrupted 10–0 nylon sutures were placed at the each corner and one halfway between them

Fig. 65.10  Creating a corneal tunnel

requires specially designed forceps (Khaw Transconjunctival Adjustable Suture Forceps No 2-502, manufactured by Duckworth and Kent) to allow transconjunctival suture tension release.19 This maneuver, although reported as safe, may have the potential complications of conjunctival buttonhole formation, especially through thin conjunctiva encountered after antimetabolite use. In patients with thick or scarred conjunctivae, suture lysis or adjustable suture maneuvers may not be possible, and releasable sutures are preferred. A formed anterior chamber must be established and results of collapsed anterior chamber and hypotony must be avoided. Additional sutures are placed until a well-formed anterior chamber is achieved.

65.8  Antimetabolites

Fig. 65.11  The surgical limbus. Reprinted with permission from Salmon JF, Kanski J. Textbook of Glaucoma. 3rd ed. Elsevier ButterworthHeinemann; 2004

in the corneal stroma) that can be pulled at the slit lamp (Fig. 65.13a–f). When the wound and the anterior chamber are believed to be stabilized, the sutures can be removed serially to increase filtration. Peng Khaw’s adjustable suture technique allows a titrated outflow compared to the releasable or suture lysis technique but

The most commonly used antimetabolites are mitomycin C (MMC) and 5-fluorouracil (5-FU). Both were introduced as adjuncts to trabeculectomy in the early 1980s.25,26 Their main action is inhibition of the fibroblast proliferation and activity. MMC is an alkaloid synthesized by Streptomyces caespitosus that affects fibroblast proliferation by crosslinking their DNA. 5-FU is a phase-specific pyrimidine analog that blocks DNA synthesis by inhibiting thymidylate synthesis. The drug produces a direct cell-cycle nonspecific cytotoxic effect by reducing fibroblast collagen synthesis. The use of antimetabolites provides lower postop IOP and better longterm success rates of filtrating surgery. In the hand of experts, the success rate of filtering surgery – alone or with adjunctive

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Fig. 65.13  (a) A spatulate needle enters the sclera at point A and is advanced trough the episclaral/scleral tissue into clear cornea, and exit at point B. (b) The tip of the needle is then rotated towards the limbus and advanced through the corneal stoma into the scleral flap. (c) The needle exits near the scleral flap border at point C. The suture is pulled so that the loop is tightened against the cornea. (d) The needle is passed through the scleral flap edge and across the cut scleral flap into the adjustant sclera at 45° to the flap edges and

(e) comes out at point D, leaving a small loop above the scleral flap. (f) The releasable knot is tied by placing three or four throws around a tying forceps of the suture end that extends from point D. The suture loop lying on the surface of the scleral flap was grasped with a forcep. End D is then pulled towards the cornea, and loop B is pulled posteriorly away from the cornea, creating a hemibow slipknot. The end of the suture knot tied over the incision is gently cut with the Vannas scissors

Fig. 65.14  Avascular cystic bleb

medical therapy – in a previously unoperated eye is up to 90% at 2 years.27 But as with any potential antifibrotic substance, their mutilation of the wound healing process is associated with serious complications, which are related to the duration of exposure and concentration of the antimetabolite. Those agents cause thin avascular cystic blebs (Fig. 65.14) with early and late complications like leakage, hypotony, blebitis, and endophthalmitis.28 Additional antimetabolite complications include corneal toxicity, uveitis, and suprachoroidal hemorrhage. An isolated bleb leak must be carefully observed. Fortunately, the majority of them resolve with antibiotic prophylaxis alone, and do not develop into blebitis or endophthalmitis.29 Blebitis and endophthalmitis are hazardous complications of glaucoma filtering surgery frequently associated with bleb failure and loss of functional vision. In a retrospective study using MMC, a 1.3% annual risk of endophthalmitis was

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Fig. 65.16  Antimetabolite should be applied over a large scleral area

Fig. 65.15  Tenon’s cyst or encapsulated bleb

found along with a 4.4% risk of at least one of the following complications: bleb leakage, blebitis, or endophthalmitis.30 Although intraoperative MMC is more effective than 5-FU in reducing IOP, and prevention of Tenon’s cyst or encapsulated bleb31 (Fig.  65.15), both agents are effective and equally safe adjuvants intraoperatively if used by an expert glaucoma specialist. The success or complication rates after 1 year were not found to be statistically significant in a recent study.32 Longterm result studies have shown a decline of IOP control over time. One study found success rates of 61% at 5 years, 44% at 10 years, and 41% at 14 years in eyes treated with 5-FU.33 Concentration and exposure time varies among surgeons, depending on the desired postoperative IOP and the patient’s risk profile of bleb failure.34 MMC concentration of 0.2– 0.5  mg/ml and exposure time of up to 5  min have been advocated. Regarding 5-FU, the recommended concentration is 50 mg/ml for 5 min. The antimetabolite is soaked in pieces made from a Weck-cell sponge preferably made from polyvinyl alcohol and not from methylcellulose, which tends to fragment. 35 Those soaked pieces are placed underneath the Tenon and some surgeons also apply the antimetabolites under the scleral flap, since this appears to be advantageous.36 To do so, the scleral flap needs to be created before applying the antimetabolite. The main disadvantage is that if the anterior chamber is entered prematurely, the antimetabolite should not be used.

In order to achieve diffuse posterior blebs, it is advocated to apply the antimetabolite over a large scleral area (Fig.  65.16). The conjunctival edges should be lifted and kept away from the antimetabolite to minimize postop leakage and late cystic limbal bleb formation. Special conjunctival forceps (No2-686, Duckworth and Kent) have been produced for this step. After their usage, the soaked antimetabolite pieces are removed and disposed of as any other antimetabolite substance. The eye is irrigated thoroughly with 20–60 ml of BSS and the irrigation fluid is absorbed by preplaced surgical pads. After the irrigation, those pads are discarded in the toxic waste container, and some surgeons also change their gloves too for the next steps of the operation. Other antiscarring agents were tested: mushroom lectins,37 methylxanthines,38 matrix metalloproteinases,39,40 and an antibody that neutralizes transforming growth factor-beta 2 (TGF-ß2). Regarding Trabio (lerdelimumab CAT-152 – human monoclonal antibody to TGF-ß2, which is believed to be responsible for the formulation of excessive scar tissue), Cambridge Antibody Technology UK announced that it has terminated further development since Trabio failed to meet the primary endpoint of improving the outcome of surgery for glaucoma in its second pivotal (“International” Phase III) clinical trial. See Sidebar 65.4 for further discussion of antimetabolites.

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Sidebar 65.4  Antimetabolites and glaucoma surgery Claudia U. Richter Glaucoma filtration surgery is performed when the surgeon judges that vision preservation is more likely with better glaucoma control than the risks of vision loss with surgery. The outcome of filtration surgery is improved by the use of the antimetabolites 5-fluorouracil and mitomycin-C with higher success rates, lower IOP, and fewer glaucoma medications. Unfortunately, these adjunctive agents increase the risk of vision threatening complications including hypotony maculopathy, bleb leaks, and bleb infections and endophthalmitis. How does the surgeon weigh the risks of complications – some of which may not occur for years – with the chance for improved success? There are two observations that make the case for the use of antimetabolites in primary filters: the better outcomes of primary filters compared to those performed after previous conjunctival-scarring surgery and the lower IOPs obtained by filtering surgery performed with antimetabolites. Numerous studies show that primary glaucoma filtering surgery has higher success rates than surgery that follows conjunctival scarring surgery, and great effort is made to maximize successful results with filtration surgery. Meticulous surgical procedure to minimize tissue handling and obtain adequate subconjunctival aqueous humor flow is essential but not sufficient for surgical success. Postoperative steroid therapy results in better outcomes and is nearly universally used. Despite these efforts, some glaucoma filtering operations are not successful, usually because fibrosis and vascularization develop between the conjunctiva and sclera, preventing subconjunctival flow of aqueous humor and reduction of IOP. 5-Fluorouracil inhibits fibroblast growth because it antagonizes pyrimidine metabolism, inhibits DNA synthesis, and results in cell death. Mitomycin-C inhibits the proliferative phase of wound healing by its inhibition of DNA replication, mitosis, and protein synthesis. Both agents reduce subconjunctival fibrosis and vascularization, improving the development of filtering blebs and the successful outcome of filtering surgery, both for primary and secondary filters. The importance of setting and achieving a low-target IOP, rather than just reaching an IOP at or below 21 mmHg to minimize the risk of further glaucoma damage, is one of the important advances in glaucoma management. The Advanced Glaucoma Intervention Study demonstrated that those patients whose IOPs were always below 18 mmHg, and averaged 12 mmHg, had minimal visual field progression compared with patients who had higher IOPs. Antimetabolite therapy in glaucoma filtering

surgery results in lower IOPs. Lower long-term IOP is expected to result in better long-term preservation of vision and is a powerful argument for the use of antimetabolites in primary filtering surgery. Unfortunately, antimetabolite therapy in filtering surgery has both short-term and long-term risks. 5-FU frequently causes corneal toxicity including punctate keratopathy, filamentary keratopathy, frank epithelial defects, and whorl-like or striate melanokeratosis. These toxic corneal effects frequently resolve without reducing vision but may lead to bacterial corneal ulceration and corneal melting. Both 5-FU and mitomycin-C can cause thin-walled, avascular blebs. These types of blebs may develop focal bleb leaks, often years after glaucoma surgery, and are more common with the use of mitomycinC. The thin-walled avascular blebs are also associated with an increased risk of developing endophthalmitis. The lower IOPs achieved with antimetabolite therapy can result in hypotony, which may lead to choroidal effusions, suprachoroidal hemorrhage, shallowing of the anterior chamber, and hypotony maculopathy. Hypotony maculopathy is characterized by folds in Bruch’s membrane and retina secondary to choroidal thickening and may persist after normalization of IOP. It has been reported sporadically following 5-FU use and more commonly, but at variable rates, following mitomycin-C. Young myopic individuals are more prone to the development of maculopathy, and the incidence appears to be affected by trabeculectomy flap design. Dealing with the difficult complications of hypotony maculopathy, bleb leaks, and bleb infections and endophthalmitis is arduous and difficult for both the glaucoma surgical patient and surgeon. Undoubtedly, these complications can be catastrophic and life-changing for the patient. However, these complications are significantly less common than the overall success rate of filtering surgery enhanced by antimetabolite therapy. The greater risk for patients facing primary filtering surgery is failure of the surgery or partial success with still inadequate IOP control, continuing glaucoma damage, and vision loss throughout their lifetime. Antimetabolite therapy with 5-fluoruracil or mitomycin-C significantly enhances the chance for successful glaucoma control and is appropriately used in primary filtering surgery.

Bibliography Andreanos D, Georgopoulos GT, Vergados J, et al. Clinical evaluation of the effect of mitomycin-C in re-operation for primary open angle glaucoma. Eur J Ophthalmol. 1997;7:49–54.

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Costa VP, Comegno PE, Vasconcelos JP, et al. Low-dose mitomycin C trabeculectomy in patients with advanced glaucoma. J Glaucoma. 1996;5:193–199. Greenfield DS, Liebmann JM, Jee J, Ritch R. Late-onset bleb leaks after glaucoma filtering surgery. Arch Ophthalmol. 1998;116: 443–447. Gross RL, Feldman RM, Spaeth GL, et  al. Surgical therapy of chronic glaucoma in aphakia and pseudophakia. Ophthalmology. 1988;95:1195–1201. Heuer DK, Gressel MG, Parrish RK II, et  al. Trabeculectomy in aphakic eyes. Ophthalmology. 1984;91:1045–1051. Jacobi PC, Dietlein TS, Krieglstein GK. Adjunctive mitomycin C in primary trabeculectomy in young adults: a long-term study of case-matched young patients. Graefes Arch Clin Exp Ophthalmol. 1998;236:652–657. Martini E, Laffi GL, Sprovieri C, Scorolli L. Low-dosage mitomycin C as an adjunct to trabeculectomy. A prospective controlled study. Eur J Ophthalmol. 1997;7:40–48. Rasheed el-S. Initial trabeculectomy with intraoperative mitomycin-C application in primary glaucomas. Ophthalmic Surg Lasers. 1999;30:360–366. Robin AL, Ramakrishnan R, Krishnadas R, et  al. A long-term dose-response study of mitomycin in glaucoma filtration surgery. Arch Ophthalmol. 1997;115:969–974. Roth SM, Spaeth GL, Starita RJ, et al. The effects of postoperative corticosteroids on trabeculectomy and the clinical course of glaucoma: five-year follow-up study. Ophthalmic Surg. 1991;22:724–729. Shirato S, Kitazawa Y, Mishima S. A critical analysis of the trabeculectomy results by a prospective follow-up design. Jpn J Ophthalmol. 1982;26:468–480.

65.9  Peripheral Iridectomy A peripheral iridectomy (PI) (Fig. 65.17) is performed with Vannas scissors to prevent iris incarceration and ostium

Singh K, Mehta K, Shaikh N, et al. Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil. Prospective randomized clinical trial. Ophthalmology. 2000;107:2305–2309. Soltau JB, Rothman, RF, Budenz DL, et al. Risk factors for glaucoma filtering bleb infections. Arch Ophthalmol. 2000;118:338–342. Stamper RL, McMenemy MG, Lieberman MF: Hypotonous maculopathy after trabeculectomy with subconjunctival 5-fluorouracil. Am J Ophthalmol. 1992;114:544–553. Starita RJ, Fellman RL, Spaeth GL, et  al. Short- and long-term effects of postoperative corticosteroids on trabeculectomy. Ophthalmology. 1985;92:938–946. Suner IJ, Greenfield DS, Miller MP, et al. Hypotony maculopathy after filtering surgery with mitomycin C. Incidence and treatment. Ophthalmology. 1997;104:207-14;discussion 214–215. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130:429–440. The advanced glaucoma intervention study (AGIS);13. Comparison of treatment outcomes within race: 10-year results. Ophthalmology. 2004;111:651–64. Wilkins M, Indar A, Wormald R. Intra-operative mitomycin C for glaucoma surgery. Cochrane Database Syst Rev. 2001;(1): CD002897. WuDunn D, Cantor LB Palanca-Capistrano AM, et al. A prospective randomized trial comparing intraoperative 5-fluorouracil vs mitomycin C in primary trabeculectomy. Am J Ophthalmol. 2002;134:521–528. Zacharia PT, Deppermann SR, Schuman JS. Ocular hypotony after trabeculectomy with mitomycin C. Am J Ophthalmol. 1993;116:314–326.

blockage, which may lead to bleb failure. In pseudophakic patients, the PI may not be mandatory.41 Intracameral Miochol (acetylcholine chloride) can be used to constrict the pupil before the iridectomy, in order to achieve a well-sized peripheral iridectomy. Encroaching the pupillary borders must be prevented to eliminate visual complaints like monocular diplopia, halos, and photophobia, which are associated with a large iridectomy. Peripheral iridectomy complications include iris bleeding with secondary hyphema, increased postoperative intracameral inflammation, damage to the underlying zonules, and possible vitreous loss through the peripheral iridectomy from excessive intrusion of a surgical instrument.

65.10  Conjunctival Closure

Fig. 65.17  A peripheral iridectomy is performed with Vannas scissors, to prevent iris incarceration and ostium blockage, which may lead to bleb failure

Meticulous closure of the conjunctival flap is mandatory to reduce the risk of leakage. Nylon or absorbable 10 to 9/0 sutures like Vicryl may be used for this task (Fig. 65.18a–f). Various techniques including horizontal mattress sutures or tight wing sutures are practiced to achieve this goal by creation of a water-tight border at the limbus. Another tip is to precauterize or scrape the epithelium adjacent to the

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Fig. 65.18  (a–f) Conjunctival closure

and posterior filtering diffuse bleb without signs of leakage (Fig. 65.20b). At the end of the surgery, a subconjunctival injection containing steroid and antibiotics is injected into the inferior fornix (Fig. 65.21). The eye is patched and an eye shield applied until first dressing. The eye shield is recommended for the first 24 h and then at bedtime for another 2–4 weeks.

65.11  Postoperative Follow-up

Fig.  65.19  Precauterizing the epithelium adjacent to the limbus to promote wound healing at the conjunctival corneal border

limbus in order to promote wound healing at the conjunctival corneal border (Fig. 65.19). For conjunctival closure, only tapered noncutting needles are preferred, but if corneoscleral anchoring sutures are performed, a spatulated needle is preferred. Leakage can be best tested with the Seidel Technique. The conjunctiva is painted with fluorescein drops and examined under a blue light to determine whether there is any leakage. The bleb potency is checked by injecting BCC through the paracentesis (Fig. 65.20a). An ideal result is a well-formed

Thorough postop treatment and follow-up are mandatory to a successful outcome. Weekly visits, and clinical and treatment evaluations are not less important than a successful and uncomplicated operation. Rigorous antifibrotic treatment with topical steroid drops, subconjunctival antimetabolite injection, and additional procedures like suture removal/ adjustment or laser lysis, and bleb needling are vital to keep the fistula open and to prevent the formation of the conjunctival “ring of steel.”11,34 Hourly topical steroid (prednisolone acetate 1%) eye drops are given for the first week and then tapered down according to the clinical weekly evaluation of the bleb morphology. Usually their use is discontinued 1–3 months postop. Nonpreservative drops are preferred to reduce the inflammatory response.42 Systemic steroid treatment carries systemic side effects and should not be adopted routinely.43

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Fig. 65.20  (a) Bleb potency is checked by injecting BCC through the paracentasis. (b) A well-formed and posterior filtering diffuse bleb without signs of leakage

Fig. 65.21  A subconjunctival injection containing steroid and antibiotics is injected into the inferior fornix

Broad-spectrum antibiotic eye drops are usually prescribed for the first postoperative week. Topical cycloplegic (1% cyclopentolate hydrochloride) drops may be given for 2–4 weeks.44

65.11.1  Complications Complications and bleb failure are described in detail in Chap. 70. This section is intended to guide the reader to a few important points in postoperative management. Complications are secondary to improper surgical technique or usage of the antimetabolites. Overfiltration may produce a flat anterior chamber, choroidal detachment, persistent hypotony, hypotony maculopathy, aqueous misdirection, cataract, and suprachoroidal hemorrhage.

Antimetabolite complications (described in detail in the antimetabolite paragraph) are mainly hypotony, bleb leak, blebitis, and endophthalmitis. A large population survey from the UK of first-time trabeculectomies performed on chronic open angle glaucoma patients revealed the following complications (listed in Fig. 65.22a, b)5 at 1 year from the trabeculectomy. The complications were divided into early (less than 2 weeks from the operation) and late. In this survey, flat anterior chamber refers only to corneolenticular touch, and hypotony was defined as an intraocular pressure (IOP) equal to or less than 6 mmHg. Hyphema was the most frequent complication in the early period, and the majority resolved within a week (Fig. 65.23). Cataract was the most frequent complication in the late period and the most common cause of visual loss cases. Other complications encountered in various reports include: conjunctival buttonholes and tears [3%], scleral flap disinsertion, vitreous loss, and acute visual loss known as “wipe out syndrome,” with a prevalence of 5% in advanced glaucoma optic neuropathy patients.

65.11.2  Postoperative Bleb Evaluation The desired bleb appearance has been described previously. Important signs to look for are: extension, elevation, conjunctival vessel appearance, microcysts, and leakage. Diffuse elevation is associated with a functional filtering bleb, whereas corkscrew conjunctival vessels and flat blebs are signs of early bleb failure. The anatomical sites of bleb failure are: 1. Extraocular, due to fibrosis and subsequent scarring of the subconjunctival and Tenon’s tissue. This is the most common cause of filter failure, with the typical “ring of steel” appearance. In order to reduce this complication rate and

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Fig. 65.22  (a) Early and (b) late complications following first-time trabeculectomies for chronic open angle glaucoma as reported in a large population survey from the UK5

to improve the surgical outcome, the following tips are suggested17 (Fig. 65.24): • Good exposure and antimetabolite application over a large area. • Tight adjustable sutures. • Large scleral flaps, not cut to the limbus. • Single scleral punch sclerostomy.

2. Scleral, due to tight flap sutures, or pronounced fibrosis along the flap edges. 3. Sclerostomy. The ostium is blocked by one of the following: uveal tissue, blood clot, vitreous, fibrosis, or remnant corneoscleral membrane left from an incomplete tissue removal. Following are a few points concerning early bleb failure examples and possible treatment regimens.

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gush of aqueous and increase of bleb area and depth. This may be a transient lowering of the IOP unless there is loosening of the sutures at the same time. Excessive pressure could lead to occlusion of the internal ostium, for example, by iris tissue or vitreous, which would lead to secondary raised IOP.19 This can be solved surgically by release of the incarcerated iris tissue (Fig. 65.26). Suture release or lysis is an effective method of decreasing scleral resistance to flow and lowering IOP.46 This suture maneuver can be performed successfully before the healing of the tissues – within a week from the operation if no antimetabolite was used and months if MMC was used.47 Fig. 65.23  Hyphema was the most frequent complication in the early period following trabeculectomy

65.11.2.1  Flat Blebs In the immediate postoperative period, suture lysis – removal of a releasable suture or local digital or cotton tip pressure adjacent to the scleral flap borders (Carlo Traverso maneuver)45 – is performed to encourage refiltration. These maneuvers may be coupled with subconjunctival 5 mg 5-FU antimetabolite injection near the bleb border (Fig. 65.25a, b). High IOP may result in worsening of the glaucomatous optic neuropathy. Massage of the flap borders results in a

Fig. 65.24  Techniques that reduce complications

65.11.2.2  Bleb Leakage Prophylactic antibiotic treatment is sufficient if there is a well-established anterior chamber without further complications. But if there is hypotony with a shallow anterior chamber or hypotony maculopathy, supplementary measures (tissue adhesive, cryotherapy, therapeutic bandage contact lens, or autologous blood injection) with or without ophthalmic viscoelastic device (OVD) injection into the anterior chamber are advised to close the conjunctival leak. Injection of a dense viscoelastic – such as Healon 5 (sodium hyaluronate 2.3%) – into a hypotonous flat anterior chamber can be used as a temporary step in keeping a deep anterior chamber with elevation of the IOP.48

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Fig. 65.25  (a) Flat bleb. (b) Bleb elevation after a successful traverse maneuver

Fig. 65.26  Iris incarcerated in the ostium after Traverso maneuver. Iris tissue is visible through the conjunctiva flap border (black arrow)

References 1. Cairns JE. Trabeculectomy. preliminary report of a new method. Am J Ophthalmol. 1968;66(4):673–679. 2. Pablo LE, Perez-Olivan S, Ferreras A, et al. Contact versus peribulbar anaesthesia in trabeculectomy: a prospective randomized clinical study. Acta Ophthalmol Scand. 2003;81:486–490. 3. Carrillo MM, Buys YM, Faingold D, Trope GE. Prospective study comparing lidocaine 2% jelly versus sub-Tenon’s anaesthesia for trabeculectomy surgery. Br J Ophthalmol. 2004;88:1004–1007. 4. Edmunds B, Bunce CV, Thompson JR, et  al. Factors associated with success in first-time trabeculectomy for patients at low risk of failure with chronic open angle glaucoma. Ophthalmology. 2004;111:97–103.

5. Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National Survey of Trabeculectomy. III. Early and late complications. Eye. 2002;16:297–303. 6. Hu CY, Matsuo H, Tomita G, et al. Clinical characteristics and leakage of functioning blebs after trabeculectomy with mitomycin-C in primary glaucoma patients. Ophthalmology. 2003;110:345–352. 7. Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C. Ophthalmology. 2003;110:2192–2197. 8. Kohl DA, Walton DS. Limbus-based versus fornix-based conjunctival flaps in trabeculectomy: 2005 update. Int Ophthalmol Clin. 2005;45(4):107–113. 9. Agbeja AM, Dutton GN. Conjunctival incisions for trabeculectomy and their relationship to the type of bleb formation: a preliminary study. Eye. 1987;1:738–743. 10. Henderson HW, Ezra E, Murdoch IE. Early postoperative trabeculectomy leakage: incidence, time course, severity, and impact on surgical outcome. Br J Ophthalmol. 2004;88:626–629. 11. Jones E, Clarke J, Khaw PT. Recent advances in trabeculectomy technique. Curr Opin Ophthalmol. 2005;16(2):107–113. 12. Ng PW, Yeung BY, Yick DW, Tsang CW, Lam DS. Fornix-based trabeculectomy using the 'anchoring' corneal suture technique. Clin Experiment Ophthalmol. 2003;31(2):133–137. 13. Levkovitch-verbin H, Goldenfeld M, Melamed S. Fornix-based trabeculectomy with mitomycin-C. Ophthalmic Surg Lasers. 1997;28(10):818–822. 14. Negi AK, Kiel AW, Vernon SA. Does the site of filtration influence the medium to long term intraocular pressure control following microtrabeculectomy in low risk eyes? Br J Ophthalmol. 2004;88: 1008–1011. 15. Chang L, Crowston JG, Cordeiro MF, et al. The role of the immune system in conjunctival wound healing after glaucoma surgery. Surv Ophthalmol. 2000;45:49–68. 16. Das J, Sharma P, Chaudhuri Z. A comparative study of small incision trabeculectomy avoiding Tenon’s capsule vis-a-vis trabeculectomy with mitomycin-C. Indian J Ophthalmol. 2004;52:23–27. 17. Jones E, Clarke J, Khaw PT. Recent advances in trabeculectomy technique. Curr Opin Ophthalmol. 2005;16:107–113. 18. AGFID Project Team. Experimental flow studies in glaucoma drainage device development. Br J Ophthalmol. 2001;85:1231–1236. 19. Wells AP, Bunce C, Khaw PT. Flap and suture manipulation after trabeculectomy with adjustable sutures: titration of flow and intraocular pressure in guarded filtration surgery. J Glaucoma. 2004;13:400–406.

65  Incisional Therapies: Trabeculectomy Surgery 20. Melamed S, Ashkenagi I, Glorinski J, Blumenthal M. Tight scleral flap trabeculectomy with post operative laser suture lysis. Am J Ophthalmol. 1990;109:303–309. 21. Aykan U, Bilge AH, Akin T, Certel I, Bayer A. Laser suture lysis or releasable sutures after trabeculectomy. J Glaucoma. 2007;16(2): 240–245. 22. Schaffer RN, Hetherington J, Hoskins HD. Guarded thermal sclerostomy. Am J Ophthalmol. 1971;72:769–772. 23. Kolker AE, Kass MA, Rait JL. Trabeculectomy with releasable sutures. Arch Ophthalmol. 1994;112:62–66. 24. Raina UK, Tuli D. Trabeculectomy With releasable sutures a prospective, randomized pilot study. Arch Ophthalmol. 1998;116: 1288–1293. 25. Heuer DK, Parrish RK II, Gressel MG, Hodapp E, et  al. 5-Fluorouracil and glaucoma filtering surgery, II: a pilot study. Ophthalmology. 1984;91:384–394. 26. Chen CW. Enhanced intraocular pressure controlling effectiveness of trabeculectomy by local application of mitomycin C. Trans Asia Pac Acad Ophthalmol. 1983;9:172. 27. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 2nd ed. Savona, Italy: DOGMA; 2003. 28. Rothman RF, Liebmann JM, Ritch R. Low-dose 5-fluorouracil trabeculectomy as initial surgery in uncomplicated glaucoma: longterm followup. Ophthalmology. 2000;107:1184–1190. 29. DeBry PW, Perkins TW, Heatley G, Kaufman P, Brumback LC. Incidence of late-onset bleb-related complications following trabeculectomy with mitomycin. Arch Ophthalmol. 2002;120(3):297–300. 30. Debry PW, Perkins TW, Heatley G, et  al. Incidence of late-onset bleb-related complications following trabeculectomy with mitomycin. Arch Ophthalmol. 2002;120:297–300. 31. Membrey WL, Poinoosawmy DP, Bunce C, Hitchings RA. Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 intraocular pressure control and complications. Br J Ophthalmol. 2000;84:586–590. 32. Singh K. Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil prospective randomized clinical trial Ophthalmology. 2000;107(12):2305–2309. 33. Suzuki R, Dickens CJ, Iwach AG, et  al. Long-term follow-up of initially successful trabeculectomy with 5-fluorouracil injections. Ophthalmology. 2002;109:1921–1924. 34. Khaw PT, Jones E, Mireskandari K, et  al. Modulating wound healing after glaucoma surgery. Glaucoma Today. July/August: 12–19, 2004.

787 35. Khaw PT. Advances in glaucoma surgery: evolution of antimetabolite adjunctive therapy. J Glaucoma. 2001;10(5 Suppl 1):S81–S84. 36. El Sayyad F, Belmekki M, Helal M, et  al. Simultaneous subconjunctival and subscleral mitomycin C application in trabeculectomy. Ophthalmology. 2000;107:298–301. 37. Batterbury M, Tebbs CA, Rhodes JM, Grierson I. Agaricus bisporus (edible mushroom lectin) inhibits ocular fibroblast proliferation and collagen lattice contraction. Exp Eye Res. 2002;74:361–370. 38. Saika S, Yamanaka O, Okada Y, et al. Pentoxifylline and pentifylline inhibit proliferation of human Tenon’s capsule fibroblasts and production of type-I collagen and laminin in vitro. Ophthalmic Res. 1996;28:165–170. 39. Mead AL, Wong TT, Cordeiro MF, et al. Evaluation of anti-TGFbeta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci. 2003;44:3394–3401. 40. Wong TT, Mead AL, Khaw PT. Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 2003;44: 1097–1103. 41. Shingleton BJ, Chaudhry IM, O'Donoghue MW. Phacotrabeculectomy: peripheral iridectomy or no peripheral iridectomy? J Cataract Refract Surg. 2002;28(6):998–1002. 42. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106:556–563. 43. Vote B, Fuller JR, Bevin TH, Molteno AC. Systemic anti-inflammatory fibrosis suppression in threatened trabeculectomy failure. Clin Exp Ophthalmol. 2004;32:81–86. 44. Raina UK, Tuli D. Trabeculectomy with releasable sutures a prospective, randomized pilot study. Arch Ophthalmol. 1998;116:1288–1293. 45. Traverso CE, Greenidge KC, Spaeth GL, et al. Focal pressure: A new method to encourage filtration after trabeculectomy. Ophthalmic Surg. 1984;15:62. 46. Khaw PT, Sherwood MB, Doyle JW, et al. Intraoperative and post operative treatment with 5-fluorouracil and mitomycin-c: long term effects in  vivo on subconjunctival and scleral fibroblasts. Int Ophthalmol. 1992;16:381–385. 47. Hoffman RS, Fine IH, Packer M. Stabilization of flat anterior chamber after trabeculectomy with Healon5. J Cataract Refract Surg. 2002;28(4):712–714. 48. Savage JA, Condon GP, Lytle RA, et  al. Laser suture lysis after trabeculectomy. Ophthalmology. 1988;95:1631–1638.

Chapter 66

Incisional Therapies: Trabeculotomy Surgery in Adults Ronald L. Fellman

Glaucoma patients who require incisional glaucoma surgery and who neither are optimal candidates for filtering surgery nor need an intraocular pressure (IOP) as low as 10  mmHg may be candidates for trabeculotomy. Trabeculotomy ab externo is an anterior chamber angle procedure designed to increase conventional trabecular outflow. IOP is lowered without creating a filtering bleb. Patients with only mild to moderate disc damage and with uncontrolled IOPs greater than 21 mmHg may do well with postoperative IOPs in the mid- to late teens and perhaps just one antiglaucoma medication – the typical scenario post-trabeculotomy surgery (Fig. 66.1a, b). It is well known that trabeculotomy is effective for congenital glaucoma, but it is also useful for select cases of juvenile and adult glaucomas,1 as well as steroid-induced glaucoma. It also works well when combined with phacoemulsification.2,3 In Europe and Asia, where angle and canal surgery are popular, trabeculotomy remains an option to filtration surgery for adult and juvenile glaucomas.4 In many parts of the world, angle and/or canal surgery is carried out earlier in the disease process than in the USA. Surgeons in these locales believe that surgery that addresses the collector system has a better chance of long-term function than does more conventional glaucoma surgery. Decades of topical medications, as seen typically with the US treatment paradigm, along with continued collapse of the collector system with progressive disease, probably create a more unfavorable environment for procedures that theoretically reestablish normal outflow, such as trabeculotomy, and other nonpenetrating novel canal procedures, such as canaloplasty. Intervening earlier may increase the success with these alternative surgeries. Trabeculotomy is a more difficult and complicated operation than trabeculectomy and does not lower IOP as much. Most US eye surgeons prefer an easier surgical procedure that also achieves lower IOPs. Trabeculotomy is technically more demanding because the surgeon must find, cannulate, and manipulate the canal compared to just removing a block of corneoscleral tissue as done with a glaucoma filtering surgery. Because there is no bleb formation, the trabeculotomy site may be selected anywhere at the limbus but is typically placed slightly off the 12 o’clock position.

Because no bleb is formed, future superiorly placed conjunctival surgery is usually not a problem. However, postoperative day 1 hyphema is common, and treatment to blunt postoperative IOP spike is often necessary. Adult patients with primary open angle glaucoma (POAG) who are not optimal candidates for filtration surgery, and who require incisional glaucoma surgery, may be reasonable candidates for trabeculotomy, especially if they require combined cataract and glaucoma surgery (Table 66.1).

66.1  S  urgical Technique for Trabeculotomy Ab Externo The following describes trabeculotomy from an external approach (ab externo) as this is the most common approach worldwide. The ultimate success of trabeculotomy is highly dependent on the following: 1 . Intraoperative localization of Schlemm’s canal 2. Accurate identification of Schlemm’s canal 3. The successful cannulation of Schlemm’s canal 4. Opening of the canal either by a metal trabeculotome or suture technique 5. Adequate closure of the scleral flap and wound to prevent bleb formation 6. A permanent cleft into Schlemm’s canal with minimal peripheral anterior synechiae (PAS) formation

66.1.1  Exposing Schlemm’s Canal There are currently two popular techniques to expose the canal. The classic T-shaped cut-down in the scleral bed remains a steadfast method of exposing the canal (Fig. 66.2a, b). Another technique gaining in popularity is the exposure of the canal similar to that used with other nonpenetrating surgical techniques such as viscocanalostomy, deep sclerectomy, and canaloplasty.

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_66, © Springer Science+Business Media, LLC 2010

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Fig.  66.1  Goniophotograph and high-resolution ultrasound of Schlemm’s canal post-trabeculotomy in a 72-year-old patient with pseudophakic glaucoma. (a) Goniophotograph of chamber angle post trabeculotomy. The green arrow designates the opening into Schlemm’s canal. The inner wall of the canal is cleaved open during trabeculotomy exposing its posterior wall. The black arrow designates anterior trabecular pigment. Preoperative IOP on two medications was 26 mmHg and postoperative IOP control at 2 years was excellent at 14  mmHg on one medication. This 72-year-old pseudophake had

moderate disc damage and mild field loss. (b) High frequency ultrasound of trabeculotomy site in (a). The opening into Schlemm’s canal can easily be seen with this 100  MHz high frequency ultrasound system from iScience Interventional (Menlo Park, California). The site of greatest resistance in glaucoma, the trabecular meshwork and juxtacanalicular tissue, is cleaved open allowing flow to the downstream collector system. This trabeculotomy was successful because the cleaved anterior leaflets remained open and did not fuse back together, a likely cause of failure

Table 66.1  Potential candidates for trabeculotomy

and cornea (Fig. 66.3a, b). The scleral spur lies underneath this zone and is a circumferential ring of white scleral fibers identified in stark contrast to the juxtaposed longitudinal fibers of the scleral bed. The difference in the direction of the fibers is easy to appreciate under the microscope.

  1. Severe ocular surface disease (blepharitis, ocular rosacea, cicatrizing diseases)   2. Juvenile glaucoma with classis trabeculodysgenesis   3. Steroid-induced glaucoma   4. Failed filter under optimal circumstances in fellow eye   5. Symptomatic filtering bleb in fellow eye   6. Poor candidate for a filter; e.g., uveitic disease   7. History of suprachoroidal hemorrhage in the fellow eye   8. History of blebitis in the fellow eye   9. History of chronic hypotony with visual loss in the fellow eye 10. Patients with post scleral buckle with severe conjunctival scarring 11. Need for combined cataract glaucoma surgery with mild to moderate glaucoma damage 12. Congenital glaucoma with trabeculodysgenesis (classic example)

The T-shaped cut-down is the classic technique used to expose the canal and is the same for pediatric, juvenile, and adult cases. The absolute essential landmark for all ab externo glaucoma surgery is the accurate identification of the scleral spur. The scleral spur is the location where the ciliary body attaches to the sclera. Limbal anatomy is highly variable from patient to patient and the location of the canal varies considerably. Due to this variability, a nylon suture, as seen in Fig. 66.2a, may be used to help verify the exact location. The limbal zone is a 1.5 mm transition area between sclera

66.1.2  S  ingle Scleral Flap with T Cut Technique 1. Create a fornix-based conjunctival flap in the desired location and follow with very light wet-field cautery. 2. Create a 2/3 thickness scleral flap, dimensions approximately 4–5  mm at its base and 5  mm posterior extent (Fig.  66.4). Make sure the flap extends anteriorly into clear cornea in order to adequately uncover an anterior displaced canal and posteriorly to uncover a posteriorly displaced canal. The most common error is to make the scleral flap too superficial, leaving a great deal of tissue to dissect through to reach the canal, or failure to make the flap large enough to gain access to the canal. In other words, do not make a wimpy scleral flap! 3. In a very meticulous and deliberate manner, make a radial cut 1  mm anterior to the proposed site of the spur and extend one millimeter posteriorly (Fig. 66.5a).

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Fig. 66.2  Alternate approaches to expose Schlemm’s canal for trabeculotomy. (a) Classic T cut approach with single flap. A single scleral flap is fashioned to expose the canal. Several meticulous radial cuts are made through the layers of sclera over the proposed site of the canal. Once the canal is exposed, a lateral cut is made on each side to gain better access to the canal. A 5-0 nylon suture is used to probe the canal and verify its identity and location. (b) Nonpenetrating surgery dual flap approach. Nonpenetrating surgery typically calls for a two flap technique to unroof the canal. The first flap is 300 mm thick and the second deep flap is generally 600 mm thick. Careful forward dissection of the deep flap usually

unroofs the canal. Note the smooth transition of endothelium as seen on the back side of the deep flap. Note (a). Thermally blunt the tip of a 5-0 clear nylon suture to use as a canal probe. This will prevent a sharp edge from perforating the floor of the canal. Insert the tip of the blunted suture into the proposed canal site for 2–3 mm. Flex the suture anteriorly over the cornea and release it, it should spring back to its original position if in the canal. If not, it will stay over the cornea indicating the suture is likely in the suprachoroidal space. Now flex it posteriorly, over the sclera. Again, it should spring back to its original position if in the canal. If not, the suture is likely in the anterior chamber

Fig. 66.3  Variable location of Schlemm’s canal. (a) Anteriorly located Schlemm’s canal. The location of Schlemm’s canal is highly variable as limbal anatomy is quite different based on genetics, refractive error, developmental abnormalities, and other factors. The key is to always

make the scleral flap large enough so that the posterior border will still cover a posteriorly located canal. (b) Posteriorly located Schlemm’s canal. Prior to dissection, the location of the canal is a guess. The proper construction of the flap is critical in order to successfully find the canal

4. Deepen the cut, fiber by fiber, as you approach the roof of the canal (Figs. 66.5b, c). 5. Once in the canal, the texture of the floor of the canal is very different than the prior dissection. Pigment may be seen in the floor of the canal; the tissue is slightly darker as well. If in the wrong location, which may happen, these landmarks will not present themselves, and the case

becomes exponentially more difficult. The chamber may be perforated and collapse. 6. No matter how convinced one is that one has found the canal, it behooves you to verify the exact location with a suture technique. Initially, avoid using a metal trabeculotome at this stage to probe the canal until you are convinced you have located the canal.

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  7. Thermally blunt the tip of a 5-0 nylon clear suture.   8. Insert the blunted tip about 2–3 mm into the suspected canal (Fig. 66.2a).   9. Flex the suture in an anterior direction over the cornea and release. It should spring back into position. If not, the suture may stay over the cornea, indicating the suture is not in the canal but is probably in the suprachoroidal space. 10. Flex the suture in a posterior direction over the sclera and let it go. It should spring back; if it does not, the

R.L. Fellman

suture is probably somewhere in the anterior chamber and not in the canal. These very simple maneuvers may help identify the canal. 11. Another simple method is to place a blue 6-0 Prolene blunted suture in the canal, and if the cornea is clear, the blue suture may be seen gonioscopically.

66.1.3  Opening the Canal (Trabeculotomy)

Fig. 66.4  Fashion scleral flap. After making a fornix-based conjunctival flap, dissect a 2/3 thickness uniform scleral flap – this is not the time to be skimpy on your flap. The anterior extent of the flap is into clear cornea and the posterior extent of the flap should be posterior enough to allow an adequate dissection of the flap prior to discovering the canal

  1. There are several methods to open the canal from an ab externo approach: filamentary technique with a suture, standard metal trabeculotome, microcatheter rupture of canal wall, and viscodilation and canal rupture.   2. The filamentary suture technique is widely used in the pediatric glaucomas and is popular because the entire angle or 360° can be opened at one sitting. Occasionally, less of the angle is opened due to altered anatomy. This same technique, either a 180 or 360° filamentary trabeculotomy, can be used in the pediatric, juvenile, or adult open angle glaucomas (Fig. 66.6a–e).   3. The classic method of using a metal trabeculotome is still very popular throughout the world, especially in Japan and Germany. The metal probe is inserted into the canal (Fig.  66.7a–c) and the canal walls are ruptured with a single rotating movement into the anterior chamber, and the process may be repeated in the opposite direction.   4. The iTrack 250A canaloplasty microcatheter (iScience Interventional, Menlo Park, California) may be used as a “suture,” with a similar technique (Fig. 66.8a, b). The microcatheter advantage is that viscoelastic may be inserted throughout the entire angle prior to rupture. This may cut down on bleeding and hyphema formation.

Fig. 66.5  Scleral bed radial cut down technique. (a) Initiate radial cut down. Estimate the position of the scleral spur, and the length of the cut should be approximately 1 mm anterior and 1 mm posterior to the proposed site of the scleral spur and canal. (b) Radial cut down progress. A careful fiber by fiber cut down seeking the

canal will eventually expose it. This part of the procedure is very meticulous and methodical. (c) Full radial cut down to canal. The scleral spur is finally exposed and is noted by its circumferential nature and compactness. There is blood noted in the canal, which is directly anterior to the spur

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66  Incisional Therapies: Trabeculotomy Surgery in Adults

Fig. 66.6  Filamentary trabeculotomy with Prolene suture. (a)Thermally blunt a 6-0 Prolene suture in order to produce a small bulb on the end of the suture so it will not be sharp. (b) Note the blunt end of the suture. The arc of the suture is utilized to the surgeon’s advantage by placing the suture on the globe prior to inserting into the canal. This allows a less traumatic insertion of the suture into the canal. (c) Cannulate the canal for 360° and pull the opposite end of the suture out of the canal.

(d) If possible, follow the position of the suture by gonioscopy to note its progress. Note the blue Prolene suture in Schlemm’s canal verified by gonioscopy. (e) The trabeculotomy is performed by grasping both ends of the Prolene suture. Pull in opposite directions to bow-string the suture into the anterior chamber creating the trabeculotomy (yellow arrow). This method allows opening the entire angle at one sitting. If the suture does not go all the way around, a 180° may also be accomplished

Fig. 66.7  Trabeculotomy performed with traditional metal trabeculotome. (a) Trabeculotomy probe positioned over limbus to visualize the surgical maneuver necessary to open the canal. (b) Trabeculotomy probe gently inserted into the canal and carefully threaded several

millimeters until the majority of the probe is in the canal. (c) Rotation of probe into the anterior chamber by breaking through the inner wall of the canal creating the trabeculotomy

The opening is larger with the microcatheter with the potential advantage that the anterior leaflets of the trabecular meshwork are less likely to close back up, months later. 5. Close the scleral flap in a water-tight fashion. If the iris prolapses at any stage, perform a small basal iridotomy (Fig. 66.9).

6 . Close the conjunctiva in standard fashion. 7. Patch and shield the eye. Obviously, the technique varies depending on surgeon training and preference.5–7 The results combined with phacoemulsification work well with either a one- or two-site technique.8 Postoperative IOP control with phacotrabeculotomy is superior

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Fig.  66.8  (a) Verification of Schlemm’s canal with either a 5-0 nylon suture or microcatheter. (b) An advanced method of canal verification. A special microcatheter (iScience Interventional, Menlo Park, California) with an illuminated tip acts as a beacon to help

R.L. Fellman

identify the canal. The microcatheter is able to travel the entire circumference of the canal and the illuminated tip verifies the catheters position at all times. Viscoelastic may also be administered through the microcatheter

gives us a new method to remove a small piece of trabecular tissue to create the trabeculotomy. This may easily be carried out in conjunction with phacoemulsification for cataract surgery.11

References

Fig.  66.9  Closure of scleral flap. The scleral flap is always closed tightly following a trabeculotomy because excess filtration may shallow the chamber and lead to peripheral anterior synechiae

to phacoemulsification alone9 and appears to be most effective in patients over age 70.9 Phacotrabeculotomy lowers IOP to £21°mmHg in 84% of patients with medications and in 36% of patients without at 3 years.10 Postoperative IOP spikes up to 40 mmHg may occur due to postoperative hyphema.10 The postoperative care for trabeculotomy is simple. The main theme is to blunt the IOP rise usually associated with postoperative day 1 hyphema. Miotics may be useful for the first two postoperative months, but not mandatory, to help keep open the drainage area and probably keep the anterior leaflets from reapproximating. Inflammation is usually minimal. Try to use as little postoperative steroids as possible for a steroid IOP response may occur. A novel way of performing a trabeculotomy using a goniotomy transchamber-like approach with a Trabectome

1. Chihara E, Nishida A, Kodo M, et al. Trabeculotomy ab externo: an alternative treatment in adult patients with primary open-angle glaucoma. Ophthalmic Surg. 1993;24:746–749. 2. Tanito M, Ohira A, Chihara E. Factors leading to reduced intraocular pressure after combined trabeculotomy and cataract surgery. J Glaucoma. 2002;11:3–9. 3. Honjo M, Tanihara T, Inatani M, et al. Phacoemulsification, intraocular lens implantation, and trabeculotomy to treat pseudoexfoliation syndrome. J Cataract Refract Surg. 1998;24:781–786. 4. Abdelrahman AM. Trabeculotome-guided deep sclerectomy. A pilot study. Am J Ophthalmol. 2005;140:152–154. 5. Fellman RL. Trabeculotomy. In: Spaeth George L, ed. Ophthalmic Surgery: Principles and Practice. 3rd ed. Philadelphia: Saunders; 2003. 6. Lynn JR, Fellman RL, Starita RJ. Full circumference trabeculotomy: an improved procedure for primary congenital glaucoma (Abstr). Ophthalmology. 1988;95(Suppl):168. 7. Beck AD, Lynch MG. 360 degress trabeculotomy for primary congenital glaucoma. Arch Ophthalmol. 1995;113: 1200–1202. 8. Tanihara H, Honjo M, Inatani M, et al. Trabeculotomy combined with phacoemulsification and implantation of an intraocular lens for the treatment of primary open angle glaucoma and coexisting cataract. Ophthalmic Surg Lasers. 1997;28:810–817. 9. Tanito M, Ohira A, Chihara E. Surgical outcome of combined trabeculotomy and cataract surgery. J Glaucoma. 2001;10: 302–308. 10. Park M, Hayashi K, Takahashi H, Tanito M, Chichara E. Phacoviscanalostomy versus phacotrabeculotomy: a middle term study. J Glaucoma. 2006;15:456–461. 11. Minckler DS, Baerveldt G, Alfaro MR, Francis BA. Clinical results with the Trabectome for treatment of open-angle glaucoma. Ophthalmology. 2005;112:962–967.

Chapter 67

Incisional Therapies: Canaloplasty and New Implant Devices Diamond Y. Tam and Iqbal “Ike” K. Ahmed

Incisional surgery for the treatment of glaucoma was first described in 1896 with surgical iridectomy,1 followed by corneo–scleral trephination in the 1920s2 and full thickness procedures in the 1950s.3 In 1968, Cairns described the technique of trabeculectomy,4 still considered by many today to be the gold standard of glaucoma surgery. Techniques have been modified and the addition of adjunctive antimetabolites has perhaps improved the original procedure to enhance long-term success and survival, as measured by intraocular pressure reduction and control, but the common final goal remains to create and maintain a nonphysiologic fistula from the anterior chamber to the subconjunctival space. Although lowering of intraocular pressure (IOP) is undisputable and well established, the generous complication profile of these procedures is well known. Both short-term and long-term risks of blebitis, endophthalmitis, hypotony, overfiltration, bleb leaks, dysesthesia, overhang, encapsulation, corneal dellen, endo­ thelial cell loss, episcleral fibrosis, aqueous misdirection, and accelerated cataract formation are some of the many potential complications, most of which are lifetime risks for patients undergoing trabeculectomy.5 Prior to the advent of trabeculectomy, the first glaucoma drainage device emerged in 1906 with the implantation of a horse hair through a corneal paracentesis in a patient with a blind painful hypertensive eye.6 While this had fairly obvious limitations and risks, the first tube and plate device was introduced in the late 1960s by Molteno.7,8 This was followed by several variations including the Krupin eye disc,9 Baerveldt tube and plate shunt,10 and the Ahmed valve.11 These long tube shunt devices are designed to allow a conduit for aqueous humor to flow from the anterior chamber to a reservoir in the posterior subconjunctival space, usually 10–12  mm posterior to the limbus. Like trabeculectomy, these procedures, while effective, have a significant risk of hypotony and suprachoroidal hemorrhage. Tube shunts, although filtering aqueous posteriorly, share some similar postoperative challenges with trabeculectomy, such as bleb encapsulation and fibrosis. While posterior

filtration may be less likely to encounter these issues, as the bleb is further from the metabolically active limbal zone, tube shunts have their own unique set of postoperative risks, such as tube or plate exposure, tube lumen occlusion, corneal endothelial loss even with proper tube positioning, tube migration, ptosis, and diplopia. Because of the unpredictability of wound healing modulation, flow control, the nonphysiologic nature of subconjunctival filtration, the significant risk of hypotony and other visually devastating complications, new glaucoma surgical approaches have emerged toward the enhancement of physiologic mechanisms of aqueous outflow. In 1893, De Vicentiis first described surgery of the iridocorneal angle in patients with congenital glaucoma. Goniotomy followed in the 1940s, described by Barkan.12,13 Since then procedures involving the iridocorneal angle have continued to emerge, from laser trabeculopuncture, to goniocurretage, to the Trabectome microelectrocautery device (NeoMedix Corp. San Juan Capistrano, California) and the trabecular microbypass stent (Glaukos Corp., Laguna Hills, California). Ab externo approaches to Schlemm’s canal have also been developed such as the nonpenetrating canaloplasty using the iScience microcatheter device (iScience Interventional Inc., Menlo Park, California). Aqueous humor alternatively exits the anterior chamber via the uveoscleral outflow pathway, consisting of the interstitium of the ciliary body, the suprachoroidal space, and choroidal and scleral vasculature. While this pathway, reportedly comprising anywhere from 20 to 54% of total aqueous outflow,14,15 is commonly augmented medically by prostaglandin analogs, surgical approaches to enhance suprachoroidal draining have also been attempted first with cyclodialysis, followed by suprachoroidal seton devices and implants. Recently, a gold micro-shunt has been developed to act as a conduit between the anterior chamber and the suprachoroidal space (SOLX Inc., Waltham, Massachusetts). This chapter reviews the various new surgical devices except for the trabecular micro-bypass stent (Glaukos Corp., Laguna Hills, California), which is discussed in another chapter.

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67.1  B  asic Review of Anatomy and Physiology of Aqueous Outflow Aqueous humor production begins with the epithelium of the ciliary body behind the iris, travels forward through the pupillary aperture into the anterior chamber, and exits the eye through the anterior chamber angle. The delicate regulation of this pathway is responsible for the control of IOP. Overproduction or decrease in egress or filtration results in elevated IOP, commonly leading to optic neuropathy. While surgical approaches directed at decreasing aqueous production involve cyclodestruction via transscleral diode laser, transscleral cryoablation, or more recently endoscopic diode laser cycloablation, many novel techniques and devices have emerged to enhance outflow. The two physiologic outflow pathways in the normal human eye are the conventional pathway and the uveoscleral outflow pathway. The conventional pathway consists of the trabecular meshwork, Schlemm’s canal, and distal intrascleral and episcleral venous plexi. The uveoscleral outflow pathway consists of the interstitium of the ciliary body, the suprachoroidal space, and ultimately scleral or choroidal vasculature. Alternatively, while subconjunctival filtration is nonphysiologic, it still remains the most widely utilized means of surgical IOP reduction via trabeculectomy and tube shunt procedures.

67.1.1  Subconjunctival Filtration 67.1.1.1  Anterior Subconjunctival Filtration Filtration of aqueous humor into the anterior subconjunctival space is achieved by the procedure of trabeculectomy, where a fistula is created from the anterior chamber under a scleral flap, to the subconjunctival space to form what is commonly known as a bleb. Once entering this space, aqueous humor is absorbed by episcleral and scleral vasculature to eventually enter the orbital circulation. This procedure thus bypasses both the conventional and uveoscleral outflow pathways and results in a nonphysiologic means of IOP lowering. The success of anterior subconjunctival filtration depends upon both intra- and postoperative factors. During surgery, ostium size and scleral flap suture tension determine the amount of aqueous egress, while postoperatively, episcleral fibrosis and wound healing ultimately determine bleb survival. Although surgical techniques have improved and postoperative care has evolved with the use of adjustable sutures, postoperative laser suture lysis, the advent of antimetabolites such as mitomycin-C and 5-fluorouracil, achieving a therapeutically low IOP whilst avoiding hypotony, remains a major challenge. In a recent 5-year follow-up report of

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trabeculectomy with adjunctive mitomycin-C, a surprising 42% rate of hypotony, defined as an IOP lower than 6 mmHg at 6 months postoperatively, was reported.16 Additionally, antimetabolite-related complications must also be considered, including endothelial cell toxicity; delayed conjunctival wound healing; avascular encapsulated limbal blebs, which are at risk of leaking, especially with small intraoperative application zones; and perhaps most significantly, persistent long-term hypotony.17-20 Despite these potentially visually devastating early and late complications of trabeculectomy, its technical ease of performance, familiarity to all glaucoma surgeons, and welldocumented efficacy in IOP lowering cause it to remain arguably the most commonly performed glaucoma surgical procedure today.

67.1.1.2  Posterior Subconjunctival Filtration The Molteno, Krupin, Ahmed, Baerveldt, and OptiMed glaucoma drainage devices share the tube and plate design whereby a tube is placed into the anterior chamber connecting to a plate reservoir fixated to the postequatorial sclera. This design allows aqueous humor to egress from the anterior chamber to the posterior subconjunctival space away from the active limbal zone with the potential advantages of less extensive subconjunctival fibrosis, a potentially larger reservoir for aqueous fluid, and lower incidence of bleb dysesthesia. Although traditionally reserved for patients who have failed primary trabeculectomy or who have conjunctival pathology, which makes such a procedure less likely to succeed, recent reports have shown that the long nonvalved tube shunt devices have a lower incidence of postoperative complications, avoid persistent hypotony, and maintain good IOP control over a 1-year period when compared to a repeat trabeculectomy with adjunctive mitomycin-C.21,22 Current studies are ongoing comparing primary trabeculectomy versus primary tube shunt procedures as well as comparing valved versus nonvalved long tube shunt devices.

67.1.2  Schlemm’s Canal Outflow 67.1.2.1  Proximal Outflow System The conventional outflow system can be thought of as consisting of a proximal and a distal component. The proximal outflow system includes the uveosclera, corneoscleral and juxtacanalicular trabecular meshwork, Schlemm’s canal and its collector channels. The distal outflow system includes aqueous veins and the episcleral and scleral venous plexi. Early work by Grant in the 1950s yielded strong evidence

67  Incisional Therapies: Canaloplasty and New Implant Devices

that the juxtacanalicular trabecular meshwork (JTM) and the extracellular matrix accounted for 75% of aqueous outflow resistance with elevation of IOP in glaucoma due to resistance at the JTM and/or collapse of Schlemm’s canal.23-25 Because of the nonphysiologic nature of subconjunctival filtration surgery and the significant risk profile in both the short- and long-term, the quest for a safer alternative has been ongoing since the 1950s. Ab externo Schlemm’s canal surgery and nonpenetrating glaucoma surgery first emerged in the 1960s as “sinusotomy,”26-29 followed by guarded deep scleral flaps in the 1980s,30-32 viscodilation of Schlemm’s canal in the 1990s,33 and then various implants and drainage devices under a scleral flap in the late 1990s and early 2000s.34-38 While early nonpenetrating procedures have been able to avoid some of the risks of fistulizing surgery, success of these early procedures still relied on the formation of a bleb. More recently, viscocanalostomy attempted to reexpand a segment of Schlemm’s canal, but expansion of the entire circumference was not possible until recently with the development of a microcatheter to cannulate the entire 360° (iScience Interventional Inc., Menlo Park, California). The 200 mm microcatheter allows for 360° viscodilation of Schlemm’s canal as well as suture passage to maintain mechanical expansion of the canal. Recent studies have revealed effectiveness in IOP reduction as well as proportional decrease in IOP in relation to the degree of distension of Schlemm’s canal.39 In addition, data released by iScience has shown an increase in trans-trabecular aqueous flow with increased centripetal tension of the canal suture (Fig. 67.1).

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Ab interno Schlemm’s canal surgery has also emerged with the premise that if the major resistance point in aqueous outflow is the JTM, devices which result in bypass of this point of resistance should result in lowering of IOP. Although goniotomy in adults and laser trabeculopuncture have been largely unsuccessful as a result of scarring in the surgical area,40-44 new devices such as the trabecular microbypass stent (Glaukos Corp., Laguna Hills, California) and the Trabectome microelectrocautery device (NeoMedix Corp., San Juan Capistrano, California) have been designed to allow aqueous humor to bypass the resistance of the JTM and enter Schlemm’s canal directly. The trabecular microbypass stent is a titanium L-shaped half pipe designed to rest in Schlemm’s canal with a snorkel into the anterior chamber.45 The Trabectome microelectrocautery device is designed with the purpose of removing trabecular meshwork to allow aqueous to directly contact Schlemm’s canal. Initial studies and clinical data have shown these devices to be effective in IOP reduction and in decreasing the number of glaucoma medications required for IOP control.46-49

67.1.2.2  Distal Outflow System After entrance into Schlemm’s canal and its collector channels, aqueous humor enters the surrounding circulation through aqueous veins and ultimately episcleral and intrascleral venous plexi. The relationship between episcleral venous pressure (EVP) and IOP has been established since the 1950s.50 As further evidence that elevated IOP was indeed correlated to raised EVP, patients in an inverted posture were found to have an elevated IOP.51 While the normal EVP varies between individuals, it may range from 8 to 13 mmHg, theoretically being the lowest possible attainable IOP from Schlemm’s canal surgery. Patients with conditions predisposing to elevated EVP such as Sturge–Weber syndrome, venous obstructive disease, arteriovenous malformations in the orbit, head, neck, or mediastinum are prone to elevated IOP resulting in glaucomatous optic atrophy.52,53 Surgical approaches and attempts at reducing EVP have yet to be described or reported.

67.1.3  Suprachoroidal Outflow

Fig. 67.1  A graph comparing the aqueous flow across the trabecular meshwork and the inner wall of Schlemm’s canal with and without tension on a Prolene suture in the canal. Reprinted from Tam DY, Ahmed IK. New glaucoma surgical devices. In: Franz Grehn F, Stamper R, eds. Glaucoma [Essentials in Ophthalmology series]. Berlin: Springer; 2009 with permission from Springer

Aqueous humor exits the anterior chamber also via the uveoscleral pathway, consisting of the interstitium of the ciliary body, the suprachoroidal space, and ultimately choroidal and scleral vasculature. Augmentation of outflow via this pathway is achieved using prostaglandin analogues medically, and, historically, by creation of a cyclodialysis cleft separation of the ciliary body from the sclera via both ab externo

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and ab interno approaches.54-58 Although this often resulted in early successful lowering of IOP, these procedures had several limitations and risks including possible prolonged irreversible hypotony, intraoperative and postoperative hemorrhage due to the vascular nature of uveal tissue, and late closure with scarring of the cleft leading to rapid onset of IOP spikes. One study reported that 75% of patients undergoing ab interno cyclodialysis cleft creation required further surgical intervention at just 60 days postoperatively.55 Yet others have attempted to prevent closure and fibrosis of a created cyclodialysis cleft with use of implants such as high molecular weight hyaluronic acid, Teflon tube implants, hydroxyethyl methacrylate capillary strip, and a scleral strip.59-62 However, these implants have yet to demonstrate successful long-term control of IOP in human eyes with glaucoma. Suprachoroidal seton device implantation has also been reported but likewise without successful long-term control of IOP. Furthermore, implantation of sizeable devices in the suprachoroidal space carries risks of suprachoroidal hemorrhage, choroidal detachment and atrophy, and exudative retinal detachment.63,64 The gold suprachoroidal shunt (SOLX Inc., Waltham, Massachusetts) is a new ab externo device designed to provide a pathway for aqueous to travel through and around the shunt from the anterior chamber into the suprachoroidal space to augment uveoscleral outflow.

67.2  T  he EX-PRESS Shunt: A Subconjunctival Filtration Device While trabeculectomy has been well established as a potent IOP lowering procedure, late hypotony, defined as an IOP of less than 6 mmHg at 6 months, has been reported in 42% of patients.16

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Although a well established procedure and technically familiar to all glaucoma surgeons, inconsistency even between cases of the same surgeon may yield differing ostium sizes and thus, differing amounts of flow. Because of these challenges, as well as the unacceptably high rate of hypotony, the Ex-PRESS Mini Glaucoma Shunt (Optonol Ltd., Neve Ilan, Israel) has been developed to attempt to improve performance and consistency in trabeculectomy. Four designs of this stainless steel device exist (R-50, X-50, T-50, X-200) with the same functional design, but differing in dimensions and lumen size with the X-200 shunt having a 200 mm wide lumen while the others with 50 mm lumens (Fig.  67.2). The tip of the shunt consists of one or multiple orifices, which sit in the anterior chamber and allow aqueous to drain through the 27-gauge shaft, designed to approximate the thickness of human sclera. On the underside of the shaft, a spur is present to prevent extrusion of the device out of the anterior chamber, while the scleral side of the shunt consists of an external plate, which prevents the shunt from migrating into the anterior chamber. While the original intent of the shunt was for placement directly under the conjunctiva into the anterior chamber, the high incidence of resultant hypotony, conjunctival erosion and shunt migration required placement of the shunt under a trabeculectomy style scleral flap.66,67 The device appears to be safe in patients undergoing magnetic resonance imaging (MRI) as well as biocompatible to human ocular tissue.70 The surgical placement of the shunt begins as if one were to perform a trabeculectomy, with a conjunctival peritomy, gentle cautery, and creation of a scleral flap. Because of the size of the external footplate of the shunt, the scleral flap may have to be slightly larger in dimension than that performed during standard trabeculectomy in order to attain full coverage of the footplate. After the scleral flap has been constructed, the anterior chamber is inflated with viscoelastic or air, particularly in the

Fig. 67.2  A schematic diagram of the different models of the Ex-PRESS shunt with specifications listed below each

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area where the shunt will be placed. Identification of the scleral spur is critical to the correct placement of the shunt. At the base of the scleral flap, this anatomical landmark should be readily identifiable, and intraoperative gonioscopy can be used to confirm this. At this point, an entry is made into the anterior chamber exactly at the level of the scleral spur with a 27-gauge needle or sapphire blade (manufactured by Optonol) (Fig. 67.3). The angle of entry must be parallel to the iris in order to ensure proper shunt positioning. An entry that is angled toward the iris results in the shunt embedded in the iris, risking incarceration; and likewise an entry toward the cornea may result in shunt-to-cornea touch and endothelial trauma. The shunt is preloaded on an injector system and is released by the surgeon using the index finger once it has been successfully placed in the previously created needle track entry (Figs. 67.4 and 67.5). Flow through the shunt is then assessed by dry removal of viscoelastic from the anterior chamber using a blunt

cannula and irrigation of balanced saline solution (BSS) through the anterior chamber. A peripheral surgical iridectomy is not required. Scleral flap and conjunctival flap closure is then performed in the same manner as standard trabeculectomy. Although the shunt itself is designed to restrict flow, diligent assessment of scleral flap tension must still be performed as excess flow may still occur in the presence of the shunt (Figs. 67.6 and 67.7). Once satisfactory flow has been achieved, watertight conjunctival closure must also be achieved. As the Ex-PRESS shunt relies on a subconjunctival bleb for IOP control, it too may require similar postoperative adjunctive procedures as trabeculectomy such as laser suture lysis and bleb needling with or without anti-metabolites. While similar to standard trabeculectomy in the mode of filtration and reliance on a bleb, the Ex-PRESS shunt has the advantages of providing a constant orifice size for filtration, requiring a smaller entry into the anterior chamber, obviating the need for

Fig. 67.3  The sapphire blade specifically manufactured for creating the entrance into the anterior chamber for the Ex-PRESS shunt

Fig. 67.5  The Ex-PRESS shunt is inserted into the opening at the level of the scleral spur. Turning the shunt 90° may facilitate its entry

Fig.  67.4  The handle of the Ex-PRESS shunt injector showing the metal wire under the plastic apparatus that is to be depressed by the surgeon’s index finger when the shunt is to be released from the tip

Fig.  67.6  Two interrupted 10–0 nylon sutures are placed into the scleral flap. Tension is adjusted via a slipknot technique. The Ex-PRESS shunt footplate can be seen through the scleral flap with the tip of the shunt visible in the anterior chamber

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Fig. 67.7  A gonioscopic view of the Ex-PRESS shunt in the anterior chamber

a surgical iridectomy, and providing two-tiered control of IOP via the shunt lumen size and scleral flap tension. It is possible to inject the device in a highly controlled manner.65 However, despite the design of the shunt to regulate flow, hypotony and overfiltration remain ­postoperative risks; although when compared to trabeculectomy, some studies have shown that the complication profile, hypotony, and related complications are less frequent in the early ­postoperative period.66 Although exclusion criteria advised for the use of the Ex-PRESS shunt includes narrow and closed angle glaucoma, it has been our anecdotal experience that it is as well suited for this angle morphology as it is for the open angle glaucomas. The Ex-PRESS Mini Glaucoma Shunt is a new device designed to improve the control of IOP and reduce the complication profile of subconjunctival filtration surgery. However, the shunt still relies on a nonphysiologic bleb as the mechanism of IOP lowering, much like trabeculectomy, and therefore the same short-term and long-term complications associated with blebs apply also to the Ex-PRESS shunt. Advantages of the shunt over trabeculectomy include a possibly lowered early postoperative incidence of hypotony, the elimination of the need for a surgical iridectomy, and ease of learning the procedure due to its similarity to performing a standard trabeculectomy. Although it was initially implanted without a scleral flap, the use of a “trabeculectomy-like” flap has made the insertion of this device more appealing.68 Furthermore, the efficacy of the device has been demonstrated when combined with phacoemulsification.69

67.3  Schlemm’s Canal Devices 67.3.1  N  onpenetrating Ab Externo Schlemm’s Canaloplasty Canaloplasty is the procedure by which catheterization of Schlemm’s canal is achieved via an ab externo approach

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in order to restore and enhance physiologic aqueous outflow through the conventional pathway thus avoiding a subconjunctival bleb. Expansion of Schlemm’s canal was first described by Stegmann as viscocanalostomy, a nonpenetrating procedure, wherein two cut ends of the canal were inflated with viscoelastic spanning a few clock hours.33 Various implants were used in an attempt to enhance the success of nonpenetrating surgery in the early 2000s, but these procedures continued to rely on a bleb for IOP control.34-36 Recently, a device has been developed to allow 360° cannulation of Schlemm’s canal to expand the entire circumference with viscoelastic and also to allow a suture to be delivered within the canal to exert centripetal force maintaining expansion of the canal. This procedure, termed canaloplasty, aims to restore physiologic outflow via the conventional pathway with suture-assisted canal distension, foregoing the need for a bleb or fistula. Although in theory Schlemm’s canal can be accessed from any location, the usual chosen surgery site is the superior sclera, for eyelid coverage, in the possible event of bleb formation, as well as for patient comfort. This requires the patient to maintain a downgaze position for the majority of the procedure. While, in the authors’ experience, topical anesthesia and patient cooperation usually is sufficient for successful performance of the surgery, a traction suture may be utilized to assist in globe positioning, and retrobulbar or peribulbar block as well. In some cases, general anesthesia may be required. If a corneal traction suture is utilized, careful site selection is required to ensure the suture is placed several clock hours away from the intended surgical site. A fornix-based conjunctival peritomy is created leaving an anterior skirt of conjunctiva attached to the limbus. Blunt dissection is carried out posteriorly to ensure that the posterior edge is relaxed sufficiently to allow for creation of a 5 mm × 5 mm parabolic scleral flap. The posterior conjunctiva should also be easily brought forward to appose to the anterior lip to allow for easy closure at the conclusion of surgery. Light cautery is then applied to the sclera, being careful to avoid aqueous and ciliary veins. Observation of the location of such vessels should also affect the initial selection of where to perform the dissection. A superficial parabolic scleral flap of approximately 5  mm anterior–posterior length by 5 mm width is then outlined on the scleral surface (Fig. 67.8). Although this scleral flap may be any shape, it is the authors’ preference to create a parabolic flap to facilitate watertight closure at the end of surgery. A crescent knife is then used to fashion the superficial flap of approximately one-third scleral thickness (typically 200–300 mm) forward into clear cornea. A deep inner scleral flap is then outlined approximately 1 mm inside from the edge of the superficial scleral flap. Once again, the crescent knife is used to fashion the deep flap and carry it forward directly into Schlemm’s canal. An approximately 100 mm thick layer of sclera should be left covering the choroid at the base of the deep dissection (Fig. 67.9).

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Fig. 67.8  The scleral flap for canaloplasty is outlined in a parabolic shape

Fig. 67.10  Schlemm’s canal is exposed with a crescent blade

Fig. 67.9  After a superficial flap has been fashioned, a deeper scleral flap is created with slightly smaller dimensions than that of the superficial flap

Fig. 67.11  The radial edges of the deep scleral flap are then released being careful not to penetrate into the globe

It is not uncommon to be left with a full thickness dissection at some points of the dissection of the deep flap. Care must then be taken to reestablish a tissue plane leaving a thin layer of sclera in the bed of the dissection. It is of utmost importance that the surgeon maintains an adequate depth during the deep flap dissection in order to unroof Schlemm’s canal (Figs. 67.10 and 67.11). If the dissection is too deep, then penetration into the globe occurs, while if the dissection is too superficial, which is more common, it is possible to dissect and pass right over Schlemm’s canal into clear cornea without exposing the canal itself. This results in a difficult situation where a deeper plane of dissection needs to be established with only a thin layer of residual sclera in the bed. Identification of the proper anatomical landmarks is often challenging in these situations and there is a resultant higher likelihood of penetration into the anterior chamber unintentionally.

Once the white limbus-parallel fibers of the scleral spur are visible at the deep dissection, fibers of the outer wall of Schlemm’s canal should be visible by lifting of the deep flap with a toothed forceps. Aqueous humor may be observed to percolate through the Schlemm’s canal and blood regurgitation may be encountered from the cut ends of the canal (Fig.  67.12). A paracentesis incision should be made in the clear cornea away from the surgical site to lower the IOP to single digits levels to prevent outward bulging of Descemet’s membrane and the inner wall of Schlemm’s canal, lowering the likelihood of penetration into the anterior chamber during the ensuing delicate dissection. The deep flap is now advanced forward approximately another 1 mm to expose Descemet’s membrane. Aqueous humor may again be observed to percolate through Descemet’s membrane in the anterior bed of the deep dissection commonly known as the trabeculodescemet window (TDW). In some instances, to increase aqueous

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Fig. 67.12  Once the deep flap has been excised, the trabeculodescemet window (TDW) can be seen. Note than heme is emerging from the two cut ends of Schlemm’s canal

Fig.  67.13  Once the entire circumference of the canal has been cannulated with the iScience microcatheter, the device is primed with ophthalmic viscosurgical device, which can be seen emerging from the tip of the device on the right

percolation through the TDW, a Mermoud forceps can be used to delicately strip the inner wall of Schlemm’s canal away. The corneal stroma should be separated from Descemet’s window with surgical sponges such as Merocel (Merocel Corp., North Mystic, Connecticut) and Weck-cel (Medtronic, Jacksonville, Florida) sponges carefully and gently pushing down on Schwalbe’s line and Descemet’s membrane. Excessive downward pressure, sudden movements, or a dry sponge may easily perforate the TDW and enter the anterior chamber. For this reason, it is the authors’ recommendation that the very tip of the surgical sponges be moistened with a minute amount of balanced saline solution prior to use on the surgical field. Once the TDW has been satisfactorily fashioned, the underside of the deep flap is scored with a sharp tip blade at the very anterior aspect and cut off with Vannas scissors. Each cut end of Schlemm’s canal is then intubated with a 150-mm outer bore viscocanalostomy cannula, and a very small amount of high viscosity sodium hyaluronate, such as Healon GV (Advanced Medical Optics Inc., Santa Ana, California), is injected into each end to dilate the ostia and facilitate entrance of the iScience device into the canal. In the normal human eye, Schlemm’s canal is known to be of 300 mm in diameter. Studies have shown evidence to suggest that the canal, however, collapses in glaucoma as a result of increased trabecular meshwork and inner wall resistance.71 A vicious cycle may then be set up, wherein the elevated IOP further compresses Schlemm’s canal because of the reduced circumferential flow of aqueous from the canal into its collector channels. The iScience device aims to restore the patency and re-expand the canal using a 45-mm working length flexible polymer microcatheter of 200-mm shaft diameter with a rounded 250-mm tip diameter designed to be atraumatic to, and to guide the 360° passage and catheterization of, Schlemm’s canal (iScience Interventional Inc., Menlo

Park, California). The catheter consists of a central support wire designed to provide a backbone for guidance during advancement and to add resistance to potential kinking of the microcatheter. The optical fibers in the microcatheter allow for transmission of a red blinking light from a laser-based micro-illumination system to the tip to assist in visualization and localization of the tip during passage. Thirdly, the microcatheter possesses a true lumen for the delivery of substances such as viscoelastic to expand the canal during passage or retraction (Fig. 67.13). The proximal end of the device connects to the nonsterile laser-based micro-illumination light source on a mayo stand from one arm, with another arm connected to a sterile screw-mechanism syringe designed to assist in controlled injection of viscoelastic into Schlemm’s canal. The microcatheter is then secured to the surgical drape with surgical tape such as Steri-strips (3M, St. Paul, Minnesota). Two nontoothed forceps are then used to introduce the microcatheter into one of the cut ends of Schlemm’s canal and advanced 360° until the tip emerges from the other cut end of the canal. Although in the vast majority of patients, this passage is possible, a minority of patients will not allow successful catheter passage through the entirety of the canal. In addition, the authors have observed the microcatheter pass into the suprachoroidal space posterior to Schlemm’s canal. In these cases, early recognition of unusual location of the blinking red light is of utmost importance and the catheter retracted to attempt passage again with scleral depression or removal of the entire microcatheter and passage attempted in the opposite direction. Once the microcatheter has been passed 360° and the tip has emerged, a 10–0 Prolene suture with the needles cut off is tied around the shaft of the device near the tip with the two loose ends tied to the loop (Fig. 67.14). The device is then withdrawn carefully in the reverse direction to which it was

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Fig. 67.14  A 10–0 Prolene suture is tied around the end of the device prior to its retraction

Fig. 67.15  Once the suture has been delivered and cut away from the microcatheter, the two cut ends must be matched and tied together

passed, with controlled injection of viscoelastic into the canal by a surgical assistant. Care must be taken not to inject an excessive amount of viscoelastic into Schlemm’s canal as a Descemet’s detachment can occur. Regurgitation of heme into the anterior chamber is also commonly seen during passage or withdrawal of the microcatheter. Once the catheter has been removed, the 10–0 Prolene is cut from the tip, essentially leaving two single 10–0 Prolene sutures in the canal with two loose ends emerging from each cut end of Schlemm’s canal. The surgeon must then identify the corresponding ends and each suture is tied to itself in a slipknot fashion with some back and forth movement in the canal, known as “flossing,” to ensure that the suture sits anteriorly in Schlemm’s canal. Suture tension is then assessed by observing the amount of indentation of the TDW, as well as by pulling the suture knot posteriorly, until it is only barely able to reach the scleral spur (Figs.  67.15 and 67.16). The suture is postulated to produce a surgical pilocarpine-like effect by putting the trabecular meshwork on tension and

Fig. 67.16  The two suture knots can be seen resting on the TDW

thus enhancing flow through Schlemm’s canal and its collector channels. Suture tension is felt to play an important role in canaloplasty, where a greater suture tension results in more distension of Schlemm’s canal with resultant greater IOP reduction and increased flow.39 The superficial scleral flap is then placed back into position and sutured in a watertight fashion with five interrupted 10–0 nylon sutures. High viscosity sodium hyaluronate is then injected under the superficial scleral flap using the viscocanalostomy cannula in order to maintain the scleral lake – the space where aqueous humor that has percolated through the TDW accumulates and is then absorbed into episcleral, scleral, and choroidal circulation. The conjunctiva is then closed over the surgical site in a watertight fashion with a 10–0 Vicryl suture in a running horizontal mattress fashion. Canaloplasty seeks to restore aqueous outflow through the conventional outflow pathway into Schlemm’s canal and its collector channels to control IOP. However, the potential space under the superficial scleral flap, or the scleral lake, also allows for aqueous humor to drain into multiple pathways such as the cut ends of Schlemm’s canal, the surrounding scleral and episcleral vasculature, the suprachoroidal space, and even subconjunctivally in some patients, resulting in a bleb despite a watertight closure. It has been the authors’ experience that fibrosis of the TDW can occur postoperatively with a resultant elevated IOP that requires YAG (yttrium–aluminum–garnet) laser to puncture the TDW, restoring aqueous flow to the scleral lake and resulting in IOP control (Figs. 67.17 and 67.18). A recent study demonstrated that 94 patients who underwent canaloplasty had an IOP reduction from 24.6 to 14.9 mmHg with a decrease in medication usage from 1.9 to 0.6 medications.39 A similar efficacy was observed in patients undergoing combined phacoemulsification and intraocular lens implantation surgery with canaloplasty.72 Complications reported were elevated IOP and hyphema, most commonly, with

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Descemet’s detachment, hypotony, and choroidal effusion also being reported. Careful patient selection must occur for successful canaloplasty. As the suture in Schlemm’s canal places centripetal tension on the inner wall, it draws the trabecular meshwork in toward the pupil (Figure 67-19). Although this is a minute distance, in narrow angle patients or those with crowded anterior segments, this may result in constant or intermittent iridotrabecular touch, peripheral anterior synechiae, and angle closure. As a result, it is advisable to exclude patients with narrow angles or crowded anterior segments from being phacoemulsification and intraocular lens implantation surgery with canaloplasty.72 Complications Fig.  67.17  Postoperative gonioscopic photograph of the TDW with the two suture knots

Fig.  67.18  Postoperatively, Nd:YAG laser goniopuncture may be required to break the TDW membrane to augment aqueous egress from the anterior chamber. Note the scrolled edges of the Descemet’s membrane around the suture knots revealing the puncture sites. Reprinted from Tam DY, Ahmed IK. New glaucoma surgical devices. In: Franz Grehn F, Stamper R, eds. Glaucoma [Essentials in Ophthalmology series]. Berlin: Springer; 2009 with permission from Springer

reported were elevated IOP and hyphema, most commonly, with Descemet’s detachment, hypotony, and choroidal effusion also being reported. Careful patient selection must occur for successful canaloplasty. As the suture in Schlemm’s canal places centripetal tension on the inner wall, it draws the trabecular meshwork in toward the pupil (Fig. 67.19). Although this is a minute distance, in narrow angle patients or those with crowded anterior segments, this may result in constant or intermittent iridotrabecular touch, peripheral anterior synechiae, and angle closure. As a result, it is advisable to exclude patients with narrow angles or crowded anterior segments from being potential candidates for canaloplasty. Preoperative gonioscopy

Fig. 67.19  An anterior segment OCT image showing the anterior distension and expansion of Schlemm’s canal induced by the intracanalicular suture. Reprinted from Tam DY, Ahmed IK. New glaucoma surgical devices. In: Franz Grehn F, Stamper R (eds). Glaucoma [Essentials in Ophthalmology series]. Berlin: Springer; 2009 with permission from Springer

and in some cases adjunctive anterior segment imaging is of great importance in assessing the angle and iris profile when a patient is being considered for this procedure. It has been the authors’ experience that postoperatively even the patient who had an unequivocally open angle may develop peripheral anterior synechiae and iris incarceration into microperforations in the TDW. An intact Schlemm’s canal is also a prerequisite to successful canaloplasty; thus, patients with prior surgery such as a trabeculectomy or patients with obvious scarring in Schlemm’s canal due to prior medication use, laser, surgery, corneoscleral trauma at the limbus may not be good candidates for canaloplasty. In summary, canaloplasty is the procedure of catheterizing and distending Schlemm’s canal with an ab externo nonpenetrating dissection and using a microcatheter to deliver viscoelastic and sutures to restore aqueous outflow through the conventional pathway and into a scleral lake created at the surgical site. The aim is to lower IOP in glaucomatous eyes without the reliance on a subconjunctival bleb, thus avoiding both short- and long-term complications of subconjunctival filtration surgery. Studies have shown efficacy at 1 year in terms of IOP reduction and dependence on glaucoma medications with a low complication profile and minimal postoperative management. However, canaloplasty remains technically challenging and other issues remain to be studied such as the optimal tension of the suture in Schlemm’s canal, the yet-undetermined long-term implications of a suture in the canal, fibrosis of the TDW resulting in the need for postoperative YAG laser, closure and contraction of the intrascleral lake, and its implications are yet poorly understood. Finally, because of episcleral venous pressure, it would seem that in theory, a ceiling to the maximal amount of physiologic outflow should exist, and thus a limit in the lowest IOP attainable by this procedure. This too, is yet to be well understood and requires further investigation.

67  Incisional Therapies: Canaloplasty and New Implant Devices

67.4  A  b Interno Devices: The Trabecular Micro-bypass Stent and the Trabectome While canaloplasty seeks to access Schlemm’s canal from an ab externo approach, devices have also emerged for access to Schlemm’s canal via an ab interno approach. Because studies have shown the juxtacanalicular tissue and inner wall of Schlemm’s canal to be the site of greatest resistance to aqueous outflow,71,73 it follows that bypassing this point of resistance allowing aqueous humor to access Schlemm’s canal directly should produce IOP lowering with the resultant resistance point being episcleral venous pressure (EVP). One device that seeks to provide a direct passage from the anterior chamber to the lumen of Schlemm’s canal is the trabecular micro-bypass iStent (Glaukos Corp., Laguna Hilla, California). This 1-mm long titanium stent is an L-shaped stent designed to partially sit inside Schlemm’s canal and has a “snorkel,” which sits in the anterior chamber.74,75 This Glaukos device is reviewed in detail in another chapter of this textbook. Traditionally, goniotomy has been a procedure that has been attempted to remove the resistance point of the trabecular meshwork and inner wall of Schlemm’s canal. A blade is used to create an incision in the angle along several clock hours to, in theory, allow aqueous humor direct access to collector channels. Success has been attainable, however, only in the pediatric population77 and similar results seemingly unattainable in the adult population.40,76,79 Although proce-

Fig. 67.20  The Trabectome handpiece and footplate

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dures such as goniotomy and trabeculotomy, used when the view to the angle is poor,78 have not found success in IOP control in adults, these procedures have led to innovative advances such as laser trabecular ablation, laser goniopuncture, and goniocurretage.44,80,81 The Trabectome (NeoMedix Corp., San Juan Capistrano, California) is a new device that is a microelectrocautery handpiece designed to ablate trabecular meshwork and Schlemm’s canal inner wall tissue over an area of several clock hours. The device is a disposable handpiece that is activated by foot pedal control connected to a console that allows the surgeon to adjust infusion, aspiration, and dissipated electrosurgical energy. A 19-gauge infusion sleeve, 25-gauge aspiration port, and bipolar electrocautery unit located 150 mm away from an insulated footplate make up the components of the handpiece. The length of the footplate is 800 mm from heel to tip with a maximum width of 230 mm and maximum thickness of 110 mm (Fig.  67.20). The tapered design of the footplate leads to a pointed tip to aid penetration through trabecular meshwork tissue. Cross-sectional view of the footplate reveals an elliptical shape with an anterior–posterior dimension of 5 mm at the tip, widening to 50 mm at the heel with a meridional diameter from 350 mm at the tip to 500 mm at the bend, designed to fit into Schlemm’s canal. Once the tip of the footplate is inserted into the canal, trabecular tissue is guided into the electrocautery unit by the footplate, while the insulated smooth design, along with continuous irrigation, protect the outer wall of Schlemm’s canal and the collector channel ostia from trauma and injury.

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Fig. 67.21  Under direct gonioscopic view, the meshwork is incised by the tip of the Trabectome handpiece. Photo courtesy of Douglas J. Rhee, MD

Fig.  67.22  Heme reflux is seen once the canal has been entered. Photo courtesy of Douglas J. Rhee, MD

Surgery is typically carried out with a temporal approach through a clear corneal incision of 1.6 mm to accommodate the electrocautery unit. Alternatively, when combined with clear cornea coaxial phacoemulsification, the main incision may be used for the Trabectome handpiece. Ophthalmic visco-devices are used to inflate and stabilize the anterior chamber and a gonioprism used for direct visualization of the angle. Once the instrument has been inserted into Schlemm’s canal, the foot pedal is depressed to begin electrocautery. The surgeon’s hand simultaneously moves in one direction to ablate the tissue until the tip of the handpiece has reached the limit of visibility. The handpiece may then be turned to achieve ablation in the opposite direction again, to the limits of view. Typically, the total arc length amenable to treatment through a single incision is 60–90°. Although tissue debris is released during electrocautery, aspiration and continuous irrigation assist in maintaining a clear view to the angle (Figs.  67.21–67.23). With irrigation maintaining

D.Y. Tam and I.''Ike''.K. Ahmed

Fig.  67.23  The Trabectome actively ablating angle tissue. Photo courtesy of Douglas J. Rhee, MD

pressure in the eye, reflux of heme is not typically seen during ablation, but commonly seen when the handpiece is withdrawn from the anterior chamber and the IOP drops. It is advisable to place a clear corneal suture and intracameral air at the conclusion of Trabectome ablation as these maneuvers seemed to correlate with less postoperative hyphema.49 A recent study reported 101 patients undergoing the procedure with an IOP reduction from 27.6  mmHg preoperatively to a maximum follow-up of 30 months in ten patients with a mean postoperative IOP of 16.3 mmHg.47 The same group also reported a decrease in medication usage from 1.2 to 0.4 at 6 months follow-up.49 Despite the excellent outcome in some patients, a 16% failure rate, defined as an IOP of 21 mmHg or greater on topical medical therapy or the need for trabeculectomy, was reported. The most significant complication reported from the procedure was partial peripheral anterior synechiae and goniosynechiae (14%), followed by transient corneal injury (6%) such as epithelial defect (3%), Descemet’s hemorrhage (1%), Descemet’s scrolling/ detachment (1%), persistent Descemet’s injury (1%), and, finally, hypotony (1%). As mentioned previously with canaloplasty, patients must be chosen carefully for this procedure as those with narrow angles or crowded anterior segments may be more likely to develop peripheral anterior synechiae at the surgical site due in part to tissue proximity compounded by postoperative inflammation. In summary, the ab interno Schlemm’s canal devices such as the iStent and the Trabectome seek to bypass the known point of most resistance in aqueous outflow in the conventional pathway in glaucoma patients, the juxtacanalicular meshwork and inner wall of Schlemm’s canal. The trabecular micro-bypass stent is designed to rest in the canal itself, allowing aqueous to enter the canal through a snorkel that sits in the anterior chamber, while the Trabectome ablates the trabecular tissue and inner wall of Schlemm’s canal to allow

67  Incisional Therapies: Canaloplasty and New Implant Devices

aqueous to access collector channels directly in a treated arc length of the iridocorneal angle. These procedures are advantageous in their use of a small incision, the avoidance of a subconjunctival bleb, minimal postoperative management, and preservation of conjunctival tissues in the event that a filter is indeed required for IOP control in the long term. Although these devices resemble other prior innovations in goniosurgery in their aim to provide direct access of aqueous humor to Schlemm’s canal and its collector channels, they differ in that there is preservation of the outer wall and the collector channel ostia, which are critical to aqueous egress and filtration. Previous procedures have been more likely to damage and cause fibrosis of these structures, ultimately resulting in failure to control IOP and creating a distal resistance point to aqueous egress. Histopathologic studies appear to support the notion that the insulated footplate on the Trabectome protects the outer wall and collector channels.48 While the studies to date seem to show promising IOP control and decreased medication usage in some patients, longer follow-up for a larger number of patients is required, the formation of peripheral anterior goniosynechiae postoperatively is of concern, and histochemical work to assess the role and implications of inflammatory mediators in Schlemm’s canal and the collector channels following electrocautery remains to be done. As with canaloplasty and ab externo Schlemm’s canal approaches, a similar question remains about the lowest attainable IOP with these procedures because of downstream factors such as EVP.

67.5  T  he Gold Microshunt: A Suprachoroidal Device The gold microshunt (SOLX Inc., Occulogix, Waltham, Massachusetts) is a 24-karat gold device designed to be surgically placed in an ab externo fashion with the anterior aspect

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of the device situated in the anterior chamber, the body to sit intrascleral, and the posterior aspect to rest in the suprachoroidal space (Fig. 67.24a, b). The device is composed of two leaflets fused together vertically concealing nine channels within the body that connect the anterior openings to the posterior ones (Fig. 67.25). Two different models of the device exist, the GMS (XGS-5) and the GMS Plus (XGS-10), both measuring 5.2 mm long, 2.4 mm wide anteriorly and 3.2 mm wide posteriorly, but differing in weight and channel size. The XGS-5 model weighs 6.2 mg and is 60 mm in thickness with the channels measuring 25 mm in width and 44 mm in height while the XGS-10 model weighs 9.2  mg and the channels measure 25 mm in width by 68 mm in height. Aqueous humor from the anterior chamber exiting through the uveoscleral pathway to the suprachoroidal space is enhanced by this device by allowing fluid to travel both through the channels in the shunt and also around the body of the shunt (Fig. 67.26). Gold has been chosen because it is an inert, noncorrosive metal, and because of its known biocompatibility, especially as a intraocular foreign body, even after many years.82,83 Implantation of the gold shunt, in theory, can be in any location around the circumference of the globe. However, due to ease of access and technical performance of the surgery, superotemporal and inferotemporal are the most commonly chosen locations. Angle anatomy should be relatively preserved in the location of choice and thus, preoperative gonioscopy is imperative. One must also use caution in highly myopic eyes and with large anterior segments as the scleral spur may be further posterior on the sclera than usual, mandating a more posteriorly placed shunt. Intraoperative gonioscopy is also an important tool in implantation of the gold microshunt. A fornix-based conjunctival peritomy is fashioned to approximately 4 mm in length leaving a short 1 mm skirt of conjunctiva attached to the limbus. Then, typically 2  mm posterior to the limbus, a perpendicular 3.5  mm scleral incision is created to near full thickness leaving only a thin layer of sclera visible covering the blue hue of the choroid

Fig. 67.24  (a, b) The SOLX suprachoroidal gold microshunt on fingertip. The shown is a different model from the one discussed in this chapter. Illustrations courtesy of SOLX Inc., Waltham, Massachusetts

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Fig. 67.25  An interior view of the gold shunt revealing the channels connecting the anterior openings with the posterior ones. The shunt shown is a different model from the one discussed in this chapter. Illustration courtesy of SOLX Inc., Waltham, Massachusetts

Fig. 67.26  A schematic diagram of the intended position of the gold shunt. Reprinted from Tam DY, Ahmed IK. New glaucoma surgical devices. In: Franz Grehn F, Stamper R, eds. Glaucoma [Essentials in Ophthalmology Series]. Berlin: Springer; 2009 with permission from Springer

Fig. 67.27  A scleral cutdown is initiated to near full thickness with the blue choroidal hue seen at the base of the dissection

D.Y. Tam and I.''Ike''.K. Ahmed

Fig. 67.28  The toothed forceps reveals the layers of scleral dissection including a full thickness cutdown with a near full thickness scleral tunnel

(Fig.  67.27). A scleral tunnel incision is then fashioned toward the clear cornea at this 95% plane created by the perpendicular incision. Once the tip of the crescent blade is visible at the limbus and has clearly passed the scleral spur, the tunnel is adequately anterior. The original perpendicular incision is then completed to full thickness revealing choroidal tissue (Fig. 67.28). A paracentesis incision may be required at this point to lower the IOP and lessen bulging of the choroidal tissue through the full thickness incision. A blunt cannula is then used to administer nonpreserved xylocaine very gently into the suprachoroidal space posterior to the incision. The cannula need not be advanced very far into the highly vascular suprachoroidal space. A small amount of viscoelastic should also be injected gently into the suprachoroidal space to provide space for the posterior edge of the shunt. The anterior chamber at this point should be filled with viscoelastic in the area of anticipated shunt placement. An entry wound should then be created into the anterior chamber at the level of the scleral spur to allow for the anterior edge of the shunt to be placed. Note that this may be slightly posterior to the anterior aspect of the scleral tunnel. Intraoperative gonioscopy is at this step, very useful in determining the position of the entry into the anterior chamber. The shunt is then brought onto the field and very gently removed from its housing. A nontoothed forceps is recommended as well as avoidance of grasping the shunt body as the delicate channels in the body are easily crushed (Fig. 67.29). A 27-gauge needle on the body of the shunt can then be used to guide the posterior aspect of the shunt into the suprachoroidal space. Alternatively, two positioning holes on the posterior edge of the shunt are available for use by a Sinskey hook (Figs. 67.30 and 67.31). The posterior openings of the shunt should not be visible and should be wholly in the suprachoroidal space. The anterior aspect of the shunt is then placed into the anterior chamber through the previously created entry at the level of the scleral spur. A positioning hole

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67  Incisional Therapies: Canaloplasty and New Implant Devices

Fig.  67.29  The gold shunt is gently inserted into the scleral tunnel with a non-toothed forceps

Fig. 67.32  Postoperative goniophotograph of the gold shunt

Fig. 67.30  A 27-gauge needle is gently used on the body of the shunt to encourage it into the proper position

Fig. 67.33  The posterior openings of the shunt are fully located in the suprachoroidal space and not visible

Fig. 67.31  A gonioscopic view intraoperatively with a Sinskey hook assisting the gold shunt into position

is present at the head of the shunt to allow for positioning assistance again by a Sinskey hook through the anterior chamber. The shunt is in satisfactory position when all of the anterior drainage openings can be seen on intraoperative gonioscopy just anterior to or at the scleral spur while all of the posterior openings are fully in the suprachoroidal space (Figs. 67.32 and 67.33). The scleral incision is then closed in a watertight fashion using four to five interrupted 10–0 nylon sutures (Fig. 67.34). A 10–0 Vicryl suture is then used to close the overlying conjunctiva in a running horizontal mattress fashion to ensure watertight closure as well. Postoperative imaging of the shunt by anterior segment optical coherence tomography has indeed shown a suprachoroidal reservoir of fluid surrounding the body of the shunt (Fig. 67.35). Nonrandomized clinical data released by SOLX, in patients with at least one prior failed incisional glaucoma procedure,

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Fig. 67.35  Anterior segment OCT image showing the gold shunt in position with a small amount of fluid around the shunt body

for the XGS-5 model of the shunt showed an IOP reduction from 27.4 ± 4.7 preoperatively to 18.1 ± 4.7 postoperatively at a 1-year follow-up, accounting for a 33% reduction in 39 patients who received the GMS. The XGS-10 model showed a reduction from 25.5 ± 6.0 to 18.0 ± 2.5 also at a 1-year follow-up in a group of 40 patients. Medication usage decreased from 1.97 ± 0.74 to 1.50 ± 0.94 in the XGS-5 group while the decrease was from 2.25 ± 0.84 to 0.85 ± 0.90 in the XGS-10 group at 1 year. With the definition of success as an IOP between 5 and 21 mmHg, ten out of the final 36 patients in the XGS-5 group and three out of the final 13 patients in the XGS-10 were classified as failures. Reported complications of shunt placement include cataract formation, choroidal detachment, shunt-cornea touch, shunt-iris touch, shunt exposure, shunt migration, peripheral anterior synechiae formation around the shunt, anterior chamber inflammation, hyphema, hypotony, vitreous hemorrhage, infection, pain, and blurred vision. Fibrosis and membrane growth over the anterior shunt orifices has also been observed and may prevent aqueous from entering the channels of the shunt. The gold microshunt is a new ab externo suprachoroidal glaucoma drainage device designed to provide aqueous a pathway through and around the shunt into the suprachoroidal space, thus lowering IOP. While early results are promising, current US Food and Drug Administration (FDA) trials are further investigating the device. Certain questions remain to be studied such as the optimal size of the shunt orifices and channels to maintain IOP control without significant risk for

Fig.  67.36  Current treatment landscape comparing glaucoma treatment modalities in terms of efficacy in IOP lowering versus risk. Reprinted from Tam DY, Ahmed IK. New glaucoma surgical

devices. In: Franz Grehn F, Stamper R, eds. Glaucoma [Essentials in Ophthalmology series]. Berlin: Springer; 2009 with permission from Springer

Fig. 67.34  Interrupted nylon sutures are used to close the scleral incision in a watertight fashion

67  Incisional Therapies: Canaloplasty and New Implant Devices

hypotony. It is also unknown whether flow around the shunt into the suprachoroidal space plays a significant role in IOP reduction and if, as such, fibrosis and scarring in this effect cyclodialysis cleft plays a role in long-term success of this procedure.

67.6  Conclusion Trabeculectomy was first described 40 years ago, and to this day, this nonphysiologic bleb-forming procedure is still considered widely to be the gold standard of glaucoma surgery. Although potent in IOP lowering, and relatively simple to learn and perform, this procedure is fraught with short-term and potential lifetime risks with visually devastating consequences. Combined with the task of attempting to modulate wound healing both intraoperatively and postoperatively, glaucoma surgeons have begun to search for alternative procedures to achieve IOP control. Several new devices have emerged, attempting to make trabeculectomy safer (the Ex-PRESS shunt), to augment physiologic conventional outflow (canaloplasty, trabecular micro-bypass stent, Trabectome), and suprachoroidal outflow (gold microshunt). Although studies are ongoing and long-term successes still have yet to be demonstrated from these procedures, early results are promising in the quest for a safe, reliable, and predictable glaucoma surgical procedure Fig. 67.36.

References 1. Richey SO. Management of glaucoma. Trans Am Ophthalmol Soc. 1896;7:723–730. 2. Davenport RC. The after results of corneo-scleral trephining for glaucoma. Br J Ophthalmol. 1926;10(9):478–484. 3. Scheie HG. Retraction of scleral wound edges; as a fistulizing procedure for glaucoma. Am J Ophthalmol. 1958;45(4, Part 2):220–229. 4. Cairns JE. Trabeculectomy. Preliminary report of a new method. Am J Ophthalmol. 1968;66(4):673–679. 5. Borisuth NS, Phillips B, Krupin T. The risk profile of glaucoma filtration surgery. Curr Opin Ophthalmol. 1999;10(2):112–116. 6. Rollett M, Moreau M. Le drainage au crin de la chambre anterieure contre l’hypertonie et la douleur. Rev Gen Ophtalmol. 1907;26: 289–292. 7. Molteno ACB. New implant for drainage in glaucoma: animal trial. Br J Ophthalmol. 1969;53:161–168. 8. Molteno ACB. New implant for drainage in glaucoma: clinical trial. Br J Ophthalmol. 1969;53:606–615. 9. Krupin T, Podos SM, Becker B, Newkirk JB. Valve implants in filtering surgery. Am J Ophthalmol. 1976;81(2):232–235. 10. Lloyd MA, Baerveldt G, Heuer DK, Minckler DS, Martone JF. Initial clinical experience with the Baerveldt implant in complicated glaucomas. Ophthalmology. 1994;101(4):640–650. 11. Coleman AL, Hill R, Wilson MR, et al. Initial clinical experience with the Ahmed Glaucoma Valve implant. Am J Ophthalmol. 1995;120(1):23–31.

811 12. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol. 1948;32(9):701–728. 13. Scheie HG. Goniotomy in the treatment of congenital glaucoma. Trans Am Ophthalmol Soc. 1949;47:115–137. 14. Bill A, Phillips CI. Uveoscleral drainage of aqueous humor in human eyes. Exp Eye Res. 1971;12:275–281. 15. Toris CB, Yablonski ME, Wang YL, et al. Aqueous humor dynamics in the aging human eye. Am J Ophthalmol. 1999;127:407–412. 16. Bindlish R, Condon GP, Schlosser JD, D’Antonio J, Lauer KB, Lehrer R. Efficacy and safety of mitomycin-C in primary trabeculectomy: five-year follow-up. Ophthalmology. 2002;109(7):1336–1341. 17. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology. 1991;98(3):317–321. 18. Fluorouracil Filtering Surgery Study one-year follow-up. The Fluorouracil Filtering Surgery Study Group. Am J Ophthalmol. 1989;108(6):625–635. 19. Kupin TH, Juzych MS, Shin DH, Khatana AK, Olivier MM. Adjunctive mitomycin C in primary trabeculectomy in phakic eyes. Am J Ophthalmol. 1995;119(1):30–39. 20. Ticho U, Ophir A. Late complications after glaucoma filtering surgery with adjunctive 5-fluorouracil. Am J Ophthalmol. 1993; 115(4):506–510. 21. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL. Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J Ophthalmol. 2007;143(1):9–22. 22. Gedde SJ, Herndon LW, Brandt JD, Budenz DL, Feuer WJ, Schiffman JC. Surgical complications in the Tube Versus Trabeculectomy Study during the first year of follow-up. Am J Ophthalmol. 2007;143(1):23–31. 23. Grant WM. Further studies on facility of flow through the trabecular meshwork. AMA Arch Ophthalmol. 1958;60(4 part 1):523–533. 24. Rosenquist R, Epstein D, Melamed S, Johnson M, Grant WM. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res. 1989;8(12):1233–1240. 25. Ethier CR, Kamm RD, Palaszewski BA, Johnson MC, Richardson TM. Calculations of flow resistance in the juxtacanalicular meshwork. Invest Ophthalmol Vis Sci. 1986;27(12):1741–1750. 26. Epstein E. Fibrosing response to aqueous; its relation to glaucoma. Br J Ophthalmol. 1959;43:641–647. 27. Krasnov MM. Externalization of Schlemm’s canal (sinusotomy) in glaucoma. Br J Ophthalmol. 1968;52:157–161. 28. Ellingsen BA, Grant WM. Trabeculotomy and sinusotomy in enucleated human eyes. Invest Ophthalmol. 1972;11:21–28. 29. Johnstone MA, Grant WM. Microsurgery of Schlemm’s canal and the human aqueous outflow system. Am J Ophthalmol. 1973;76: 906–917. 30. Koslov VI, Bagrov SN, Anisimova SY, et al. [Nonpenetrating deep sclerectomy with collagen] [Russian]. Oftalmokhirurgiia. 1990;3: 44–46. 31. Fyodorov SN, Ioffe DI, Ronkina TI. Deep sclerectomy: technique and mechanism of a new antiglaucomatous procedure. Glaucoma. 1984;6:281–283. 32. Zimmerman TJ, Kooner KS, Ford VJ, et  al. Trabeculectomy vs. nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg. 1984;15: 734–740. 33. Stegmann R, Pienaar A, Miller D. Viscocanalostomy for open angle glaucoma in black African patients. J Cataract Refract Surg. 1999;25:316–322. 34. Sourdille P, Santiago P-Y, Villain F, et  al. Reticulated hyaluronic acid implant in nonperforating trabecular surgery. J Cataract Refract Surg. 1999;25:332–339. 35. Ambresin A, Shaarawy T, Mermoud A. Deep sclerectomy with collagen implant in one eye compared with trabeculectomy in the other eye of the same patient. J Glaucoma. 2002;11:214–220.

812 36. Sanchez E, Schnyder CC, Sickenberg M, Chiou AG, Hédiguer SE, Mermoud A. Deep sclerectomy: results with and without collagen implant. Int Ophthalmol. 1996/97;20:157–162. 37. Spiegel D, Kobuch K. Trabecular meshwork bypass tube shunt: initial case series. Br J Ophthalmol. 2002;86:1228–1231. 38. Yablonski ME. Trabeculectomy with internal tube shunt: a novel glaucoma surgery. J Glaucoma. 2005;14:91–97. 39. Lewis RA, von Wolff K, Tetz M, et al. Canaloplasty: circumferential viscodilation and tensioning of Schlemm’s canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults: interim clinical study analysis. J Cataract Refract Surg. 2007;33(7): 1217–1226. 40. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol. 1977;83:174–179. 41. Tanihara H, Negi A, Akimoto M, et  al. Surgical effects of trabeculectomy ab externo on adult eyes with primary open angle glaucoma and pseudoexfoliation syndrome. Arch Ophthalmol. 1993;111: 1653–1661. 42. Krasnov MM. Q-switched laser goniopuncture. Arch Ophthalmol. 1974;92:37–41. 43. Wickham MG, Worthen DM. Argon laser trabeculotomy: long-term follow-up. Ophthalmology. 1970;86:495–503. 44. Epstein DL, Melamed S, Puliatio CA, Steinert RF. Neodymium: YAG laser trabeculopuncture in open-angle glaucoma. Ophthalmology. 1985;92:931–937. 45. Bahler CK, Smedley GT, Zhou J, Johnson DH. Trabecular bypass stents decrease intraocular pressure in cultured human anterior segments. Am J Ophthalmol. 2004;138(6):988–994. 46. Spiegel D, Wetzel W, Haffner DS, Hill RA. Initial clinical experience with the trabecular micro-bypass stent in patients with glaucoma. Adv Ther. 2007;24(1):161–170. 47. Minckler D, Baerveldt G, Ramirez MA, et al. Clinical results with the Trabectome, a novel surgical device for treatment of open-angle glaucoma. Trans Am Ophthalmol Soc. 2006;104:40–50. 48. Francis BA, See RF, Rao NA, Minckler DS, Baerveldt G. Ab interno trabeculectomy: development of a novel device (TrabectomeTM) and surgery for open-angle glaucoma. J Glaucoma. 2006;15:68–73. 49. Minckler DS, Baerveldt G, Alfaro MR, Francis BA. Clinical results with the Trabectome for treatment of open-angle glaucoma. Ophthalmology. 2005;112:962–967. 50. Bain WE. Variations in the episcleral venous pressure in relation to glaucoma. Br J Ophthalmol. 1954;38(3):129–135. 51. Friberg TR, Sanborn G, Weinreb RN. Intraocular and episcleral venous pressure increase during inverted posture. Am J Ophthalmol. 1987;103(4):523–526. 52. Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Ophthalmology. 1978;85(3):276–286. 53. Bigger JF. Glaucoma with elevated episcleral venous pressure. South Med J. 1975;68(11):1444–1448. 54. Suguro K, Toris CB, Pederson JE. Uveoscleral outflow following cyclodialysis in the monkey eye using a fluorescent tracer. Invest Ophthalmol Vis Sci. 1985;26:810–813. 55. Jordan JF, Dietlein TS, Dinslage S, et al. Cyclodialysis ab interno as a surgical approach to intractable glaucoma. Graefes Arch Clin Exp Ophthalmol. 2007;245:1071–1076. 56. Shields MB, Simmons RJ. Combined cyclodialysis and cataract extraction. Ophthalmic Surg. 1976;7(2):62–73. 57. Galin MA, Baras I. Combined cyclodialysis cataract extraction: a review. Ann Ophthalmol. 1975;7(2):271–275. 58. Gills JP Jr, Paterson CA, Paterson ME. Action of cyclodialysis utilizing an implant studied by manometry in a human eye. Exp Eye Res. 1967;6:75–78. 59. Klemm M, Balazs A, Draeger J, Wiezorrek R. Experimental use of space-retaining substances with extended duration: functional and morphological results. Graefes Arch Clin Exp Ophthalmol. 1995;233(9):592–597.

D.Y. Tam and I.''Ike''.K. Ahmed 60. Nesterov AP, Batmanov YE, Cherkasova IN, Egorov EA. Surgical stimulation of the uveoscleral outflow: experimental studies on enucleated human eyes. Acta Ophthalmol (Copenh). 1979;57(3):409–417. 61. Pinnas G, Boniuk M. Cyclodialysis with teflon tube implants. Am J Ophthalmol. 1969;68(5):879–883. 62. Krejci L. Cyclodialysis with hydroxyethyl methacrylate capillary strip. Ophthalmologica. 1972;164:113–121. 63. Ozdamar A, Aras C, Karacorlu M. Suprachoroidal seton implantation in refractory glaucoma: a novel surgical technique. J Glaucoma. 2003;12:354–359. 64. Jordan JF, Engels BF, Dinslage S, et al. A novel approach to suprachoroidal drainage for the surgical treatment of intractable glaucoma. J Glaucoma. 2006;15:200–205. 65. Sarkisian SR. Use of an Injector for the Ex-PRESS™ Mini Glaucoma Shunt. Ophthalmic Surg Lasers Imaging. 2007;38(5):434–436. 66. Coupin A, Li Q, Riss I. Ex-PRESS miniature glaucoma implant inserted under a scleral flap in open-angle glaucoma surgery: a retrospective study. Fr J Glaucoma. 2007;30(1):18–23. 67. Maris PJG, Ishida K, Netland PA. Comparison of trabeculectomy with Ex-PRESS miniature glaucoma device implanted under scleral flap. J Glaucoma. 2007;16:14–19. 68. Dahan E, Carmichael TR. Implantation of a miniature glaucoma device under a scleral flap. J Glaucoma. 2005;14(2):98–102. 69. Traverso CE, De Feo F, Messas-Kaplan A, et al. Long term effect on IOP of a stainless steel glaucoma drainage implant (Ex-PRESS) in combined surgery with phacoemulsification. Br J Ophthalmol. 2005;89(4):425–429. 70. Nyska A, Glovinsky Y, Belkin M, Epstein Y. Biocompatibility of the Ex-PRESS miniature glaucoma drainage implant. J Glaucoma. 2003;12(3):275–280. 71. Moses RA, Grodzki WJ Jr, Etheridge EL, Wilson CD. Schlemm’s canal: the effect of intraocular pressure. Invest Ophthalmol Vis Sci. 1981;20(1):61–68. 72. Shingleton B, Tetz M, Korber N. Circumferential viscodilation and tensioning of Schlemm’s canal (canaloplasty) combined with temporal clear corneal phacoemulsification cataract surgery for the treatment of open angle glaucoma and visually significant cataract – one year results. J Cataract Refract Surg. 2008;34(3):433–440. 73. Grant WM. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol. 1963;69:783–801. 74. Zhou J, Smedley GT. A trabecular bypass flow hypothesis. J Glaucoma. 2005;14(1):74–83. 75. Zhou J, Smedley GT. Trabecular bypass: effect of Schlemm canal and collector channel dilation. J Glaucoma. 2006;15(5):446–455. 76. Herschler J, Davis EB. Modified goniotomy for inflammatory glaucoma. Histologic evidence for the mechanism of pressure reduction. Arch Ophthalmol. 1980;98:684–687. 77. Gramer E, Tausch M, Kraemer C. Time of diagnosis, reoperations and long-term results of goniotomy in the treatment of primary congenital glaucoma: a clinical study. Int Ophthalmol. 1996;20: 117–123. 78. Mendicino ME, Lynch MG, Drack A, et al. Long-term surgical and visual outcomes in primary congenital glaucoma: 360 degrees trabeculotomy versus goniotomy. J AAPOS. 2000;4:205–210. 79. Dickens CS, Hoskins HD Jr. Epidemiology and pathophysiology of congenital glaucoma. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas, vol. 2. 2nd ed. St. Louis: Mosby; 1996:729–738. 80. Hill RA, Baerveldt G, Ozler SA, et  al. Laser trabecular ablation (LTA). Lasers Surg Med. 1991;11:341–346. 81. Jacobi PC, Dietlein TS, Krieglstein GK. Technique of goniocurettage: a potential treatment for advanced chronic open angle glaucoma. Br J Ophthalmol. 1997;81:302–307. 82. Eisler R. Mammalian sensitivity to elemental gold (Au). Biol Trace Elem Res. 2004;100:1–17. 83. Sen SC, Ghosh A. Gold as an intraocular foreign body. Br J Ophthalmol. 1983;67:398–399.

Chapter 68

Incisional Therapies: Shunts and Valved Implants John W. Boyle IV and Peter A. Netland

The earliest attempts to drain fluid out of the anterior chamber into the subconjunctival space consisted of implanting a variety of foreign objects into the eye extending from the anterior chamber to the subconjunctival space. These early operations failed because of excessive fibrosis over the subconjunctival portion of the implant at the limbus, seton migration, or conjunctival erosion. Dr. Anthony Molteno introduced the concept of draining fluid away from the anterior chamber to a plate posterior to the limbus.1 The Molteno implant had an episcleral plate positioned in the equatorial region, which was connected to the anterior chamber by means of an elongated silicone tube. Additional modifications of glaucoma drainage implants have improved the safety and efficacy of the devices. Dr. Theodore Krupin developed a pressure-sensitive, slit valve that provided resistance to the flow of aqueous, reducing the occurrence of early postoperative hypotony.2 Dr. Mateen Ahmed introduced the Ahmed Glaucoma Valve, which is a pressuresensitive glaucoma drainage device with a valve designed to open when the intraocular pressure is approximately 8 mmHg.3 Implants with increased surface area have been intended to increase the surface area of the end-plate and possibly lower the intraocular pressure. Thus, double-plate versions of the Molteno implant4 and the Ahmed Glaucoma Valve5 have been introduced. Also, Dr. George Baerveldt introduced a nonvalved silicone tube attached to a large barium-impregnated silicone plate.6 Essential steps of glaucoma drainage implant surgery include suturing an episcleral plate with an attached tube posterior to the limbus and placing the other end of a tube in the anterior chamber. The tube is covered with allograft or autograft material to prevent erosion of the tube through the conjunctiva. Drainage implants have been useful in treating patients who have failed or are at high risk for failure of other glaucoma surgical procedures, including trabeculectomy. There is increasing interest in use of these devices for primary glaucoma surgery (Sidebar 68.1).

68.1  Current Glaucoma Drainage Devices Current glaucoma drainage devices can be classified into two broad categories, valved or nonvalved (Table  68.1). Valved implants or flow-restrictive drainage devices provide resistance to aqueous flow and prevent hypotony during the early postoperative period. Nonvalved implants or open tube drainage devices provide little resistance to aqueous flow during the early postoperative period until a fibrous capsule forms around the plate. Various techniques have been devised for use during the early postoperative period to prevent hypotony associated with open tube implants. The Ahmed Glaucoma Valve and the Eagle Vision implant with a modified Krupin slit valve are examples of flow-restrictive drainage devices. The nonvalved implants or open tube drainage devices include the Baerveldt glaucoma implant and the Molteno implant.

68.1.1  Ahmed Glaucoma Valve The Ahmed Glaucoma Valve (New World Medical, Inc., Rancho Cucamonga, California) consists of a silicone tube attached to a valve mechanism on an end plate, comprised of either polypropylene or silicone. The valve consists of two thin silicone elastomer membranes (8 mm long × 7 mm wide) positioned in a venturi-shaped chamber. The elastic membranes of the valve restrict flow up to a pressure of approximately 8–12  mmHg, which is intended to reduce the incidence of early postoperative hypotony. Early results suggested that the Ahmed Glaucoma Valve restricts aqueous flow,7 while subsequent studies have demonstrated true valve function of the device.8,9

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_68, © Springer Science+Business Media, LLC 2010

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Sidebar 68.1  Trabeculectomy or tube shunt surgery – which to perform? Daniel A. Jewelewicz Until fairly recently, tube shunt surgery was considered a “surgical last resort” in patients who had failed prior trabeculectomy. This has changed recently, with tube shunt surgery gaining in popularity and even becoming the primary glaucoma surgery of choice for some surgeons. The Tube Versus Trabeculectomy Study (TVT) is the first study to prospectively compare the results of trabeculectomy to tube shunt surgery. The investigators followed up 212 patients aged 18–85 with intraocular pressure (IOP) ranging from 18 to 40 mmHg who were on maximally tolerated medical therapy. One half received a trabeculectomy with 4 min of 0.4-mg/cc mitomycin C (MMC). The other half received a Baerveldt 350 implant (BGI). IOP, visual acuity, complications, and need for reoperation were compared for both groups over the course of 1 year. The three most salient points to be gleaned from the treatment outcomes in the Tube Versus Trabeculectomy Study After 1 Year of Follow-Up are: 1. Tube shunt surgery was more likely to maintain IOP control at 1 year. The cumulative probability of failure was 3.9% in the tube group and 13.5% in the trabeculectomy group, indicating that a trabeculectomy was more than four times as likely to fail at 1 year. Failure was defined as: (a) IOP > 21  mmHg or not reduced by 20% below baseline on two consecutive visits after 3 months (b) IOP < or equal to 5  mmHg on two consecutive visits after 3 months (c) Reoperation for glaucoma (d) Loss of light perception 2. Tube shunt surgery is more likely to require supplemental medication at 1 year. The number of medications in the tube group was 1.3, and 0.5 in the trabeculectomy group. 3. Tube shunt surgery is more likely to avoid hypotony. Three trabeculectomy patients failed because of hypotony; none did in the tube group. The authors then examined more closely the nature of the complications in a second paper, the Surgical Complications in the Tube Versus Trabeculectomy Study During the First Year of Follow Up. They noted: 1. Postoperative complications were higher in the trabeculectomy group – 57% in the trabeculectomy group and 34% in the tube group.

2. The rates of intraoperative surgical complications and re-operation were similar between the two groups. It is tempting to conclude that tube shunt surgery is a superior form of surgical reduction of IOP – it is reported as more likely to work and it has fewer complications, albeit with the possible need for continued medication. It is also worth noting that the single case of endophthalmitis in the entire study occurred in the trabeculectomy group. As with all studies, though, data must be interpreted cautiously. Other studies offer differing results. In October 2007, Stein et  al published the Longitudinal Rates of Postoperative Adverse Outcomes After Glaucoma Surgery Among Medicare Beneficiaries 1994 to 2005. This was an excellent retrospective study that examined a nationally representative longitudinal sample by examining Medicare claims. They compared Medicare beneficiaries older than or equal to 68 years who underwent primary trabeculectomy, trabeculectomy with excision of scar tissue, or tube shunt surgery. In contradistinction to the TVT study they noted that: 1. Rates of severe adverse outcomes, less severe adverse outcomes, corneal edema and low vision/blindness were higher in the tube shunt group – 2% in the tube shunt group experienced severe adverse outcomes, versus 0.6% in the trabeculectomy group, and 1.3% in the trabeculectomy with scarring group. 2. Rates of re-operation were highest in the trabeculectomy scarring group. It is somewhat alarming to note that within 6 years of undergoing tube shunt surgery, more than 40% experienced an adverse outcome, and nearly 30% received a code indicating low vision or blindness. However, these data must be taken in context. This was a retrospective study, and as such there were no screening criteria. Patients in the tube shunt group may very well have had prior trabeculectomy surgery, possibly even more than once. Furthermore, this study examined charts from 1990 onward, when tube shunt surgery was not nearly as commonplace as now (and was therefore often reserved for complicated cases that had failed prior surgical intervention). Lastly, this study examined Medicare claims; the codes used may have been appropriate for billing but not necessarily for accurate diagnosis. Nonetheless, this study does suggest that tube shunt surgery may not be as safe as the TVT study leads us to believe. We must also exercise similar caution when interpreting the results from the TVT Study. The TVT study looked only at BGI 350 implants compared with trabeculectomy using 0.4 mg/cc MMC for 4 min. Glaucoma surgery is an

68  Incisional Therapies: Shunts and Valved Implants

art, and an experienced glaucoma surgeon will choose not only which procedure to perform, but also modify the procedure in order to achieve the best result for an individual patient. One might use only 30 s for MMC if the conjunctiva is thin, or as long as 5 min if there is scarring from prior failed surgeries. One may choose to use a valved implant if there is concern about hypotony, or if one does not need an especially low target IOP. Some surgeons use MMC with tube shunts to prevent encapsulation. Some might place the implant inferonasally rather than superotemporally. These are excellent studies that offer clinically relevant information – but how should they be applied to your practice? Should you favor one procedure over the other? As with any study, careful consideration should be given to individual cases, using the study results as one potential piece of information in the decision-making process. The following issues should be considered when deciding on the most appropriate surgical approach. Factors that may favor trabeculectomy Does the patient have a history of intolerance to many glaucoma medications? Does the patient have difficulty administering eyedrops? Is he or she arthritic? If so, a trabeculectomy may be a better option, as there is less likelihood of requiring supplemental medication. Does the surgeon have access to a surgical assistant? Most glaucoma surgeons place a BGI beneath the superior and lateral rectus muscles, requiring extensive dissection that is greatly facilitated by an assistant. If no assistant is available, trabeculectomy may be a better option. (Note that Ahmed and Molteno implants require less dissection, as they are placed between the muscles and may be an alternative.) Does the patient have endothelial disease that may be potentially worsened by placing a tube near the corneal endothelium? Has the patient had a Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK), or will he or she need one in the future? Having a tube in the anterior chamber makes this significantly more difficult. If so, a trabeculectomy would be a better choice. Does the patient have a scleral buckle or other hardware in the eye? This may make placement of the plate difficult with tube shunt surgery. Is the eye unusually short with a crowded anterior chamber? In a short, crowded, phakic eye it may be difficult to place a tube without jeopardizing the cornea or lens. Factors that may favor tube shunt surgery

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Does the patient have extensive scarring from prior superior surgery such as extracapsular cataract extraction (ECCE)? If so, the necessary conjunctival dissection for a trabeculectomy could be difficult. Does the patient have an inflammatory or uveitic glaucoma that would induce scarring and render a trabeculectomy more likely to fail? Does the patient intend to wear contact lenses? An avascular bleb is a contraindication to contact lens wear due to the increased risk of infection, and a tube shunt may be a better option. Is the patient at risk for hypotony (high myope, scleral disorder, etc.)? If so, a ligated, nonfenestrated tub shunt may be a better option. Does the patient have difficulty returning to the office for regular postop visits? Is he or she elderly, frail, or live far away? Trabeculectomy generally requires more postop visits in the first 3 months, and so tube shunt surgery may be a better option. Is the patient exposed to dirty conditions due to occupation or recreation that might increase the risk of infection through a thin bleb? Above and beyond all these considerations is each individual surgeon’s expertise and level of comfort performing these procedures. We do what we feel would be best for our patients in our hands. But the TVT study has certainly demonstrated that tubes should no longer be relegated to last resort status in eyes that have had multiple prior surgeries. They deserve a place in our surgical armamentarium as a viable alternative to trabeculectomy in the correct patient.

Bibliography Gedde SJ, Herndon LW, Brandt JD, Budenz DL, Feuer WJ, Schiffman JC. Surgical complications in the tube versus trabeculectomy study during the first year of follow-up. Am J Ophthalmol. 2007;143(1):23–31. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL and the Tube Versus Trabeculectomy Study Group. Treatment outcomes in the tube vs trabeculectomy study. Am J Ophthalmol. 2007;143(1):9–22. Jamil A, Mills R. Glaucoma tube or trabeculectomy? That is the question. Am J Ophthalmol. 2007;143(1):141–142 Stein JD, Ruiz D Jr, Belsky D, Lee PP, Sloan FA. Longitudinal rates of postoperative adverse outcomes after glaucoma surgery among medicare beneficiaries 1994 to 2005. Ophthalmology. 2008;115(7):1109–1116.e7.

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Table 68.1  Design features of current glaucoma drainage implants Implant type Ahmed Glaucoma Valve

Size

184 mm2 364 mm2a 96 mm2 184 mm2 364 mm2a 96 mm2 Eagle Vision implant 209 mm2 Baerveldt implant 250 mm2 350 mm2 Molteno implant 134 mm2 268 mm2a a Indicates double-plate model.

Material

Valved/ nonvalved

Polypropylene Polypropylene Polypropylene Silicone Silicone Silicone Silicone Silicone Silicone Polypropylene Polypropylene

Valved Valved Valved Valved Valved Valved Valved Nonvalved Nonvalved Nonvalved Nonvalved

The plate of the Ahmed Glaucoma Valve varies in size and composition, depending on the model. A hard, polypropylene plate is used in the single-plate (S2 model) and the double-plate (B1 model). Both models have a surface area of 184 mm2 (16 × 13 mm) and are 1.9 mm thick. A soft, silicone plate is used in the flexible single-plate (FP7 model) and the flexible double-plate (FX1 model). Advantages of the flexible silicone model include ease of implantation and likely improved biocompatibility compared with polypropylene.10,11 The double-plate (Bi-Plate) Ahmed Glaucoma Valve allows for greater surface area (364 mm2) for aqueous drainage, and may be implanted on either the right or left side of the eye.5 Both single-plated models (S2 and FP7) exist in smaller sizes (S3 and FP8) intended for pediatric patients, although many clinicians use the larger-sized plates for children.

the preferred size because it appears safer and slightly more effective than the 500  mm2 implant.12,13 Unlike the Ahmed and Krupin valves, which fit between the rectus muscles, the Baerveldt implant must be positioned under two adjacent rectus muscles.

68.1.4  Molteno Implant The single plate Molteno Implant (IOP, Inc., Costa Mesa, California, and Molteno Ophthalmic Limited, Dunedin, New Zealand) consists of a nonrestrictive silicone tube attached to a 13-mm polypropylene end-plate with a surface area of 134 mm2. The double-plate Molteno Implant consists of two plates connected by a 10-mm silicone tube, providing an increased surface area of 270 mm2. The double plate Molteno Implant can be implanted on the right or left side of the eye. A pediatric-size plate (8  mm diameter) is available. The Molteno dual ridge device incorporates a modification that attempts to minimize overfiltration and early hypotony without tube occlusion. The upper surface of the plate is divided into two separate spaces by a V-shaped ridge that encases an area of 10.5  mm2 around the opening of the silicone tube. Theoretically, aqueous must overcome the conjunctival resistance to flow across the ridge into the bleb. While one earlier study supported the benefit of this modification, a more recent study found unpredictable results.14,15

68.2  Indications 68.1.2  Eagle Vision Glaucoma Valve The Eagle Vision glaucoma valve (Eagle Vision, Inc., Memphis, Tennessee) consists of a silicone tube attached to a valve mechanism on a silicone disc with a surface area of 209 mm2. The valve is a pressure-sensitive slit valve that is calibrated to close at approximately 8–10 mmHg.

The indications for glaucoma drainage device implantation include the following: previous failure of primary surgery (usually trabeculectomy), extensive conjunctival scarring, and likely failure of trabeculectomy (Table 68.2). Glaucoma drainage implants can be considered for use in primary glaucoma surgery.

Table 68.2  Indications for glaucoma drainage implants

68.1.3  Baerveldt Glaucoma Implant The Baerveldt Glaucoma Implant (Advanced Medical Optics, Inc., Santa Ana, California) consists of a nonrestrictive silicone tube attached to a soft barium-impregnated silicone plate with a surface area of 250 mm2 (20 × 13 mm), 350 mm2 (32 × 14 mm), or 500 mm2 (36 × 17.5 mm). The plate has fenestrations that allow growth of fibrous tissue through the plate to reduce the height of the bleb, which may reduce the incidence of postoperative diplopia. The 350 mm2 implant is

Failed trabeculectomy Extensive conjunctival scarring Likely failure of trabeculectomy, including   Neovascular glaucoma   Uveitic glaucoma   Glaucoma associated with penetrating keratoplasty   ICE syndrome   Epithelial downgrowth   Refractory pediatric glaucoma   Glaucoma following retinal detachment surgery Primary surgerya a Currently under investigation.

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68.2.1  Failed Trabeculectomy Glaucoma drainage implants may be considered in eyes that have failed to achieve control of intraocular pressure after trabeculectomy, with or without mitomycin C. Some patients may be candidates for a second trabeculectomy, but conjunctival scarring or rapid failure of trabeculectomy may hasten the decision to proceed to a drainage implant.

68.2.2  Extensive Conjunctival Scarring Drainage implant surgery may be warranted in cases with inadequate conjunctiva because of scarring from previous surgical procedures. Conjunctival scarring near the limbus may preclude the trabeculectomy procedure. In contrast, glaucoma drainage implants may be performed despite extensive conjunctival scarring posterior to the limbus. In some patients, such as those with severe ocular surface disease, it is not possible to perform trabeculectomy, whereas glaucoma drainage implants may be effective.16 Patients who have undergone multiple previous ocular surgeries may have extensive conjunctival scarring that may preclude trabeculectomy.

68.2.3  Poor Prognosis for Trabeculectomy In some instances, primary surgical treatment with trabeculectomy has a poor prognosis for success. In patients with neovascular glaucoma and uveitic glaucoma, filtration surgery has a high failure rate. In these settings, surgeons may choose to implant a drainage device rather than to perform a trabeculectomy, in order to improve the likelihood of longterm success. Other glaucomas that may be associated with poor long-term success for trabeculectomy include iridocorneal endothelial (ICE) syndrome, epithelial downgrowth, and refractory pediatric glaucomas.

68.2.4  Primary Surgery Glaucoma drainage implants are indicated for primary surgery when trabeculectomy is judged likely to fail by the surgeon. In addition, drainage devices can be considered for broader use for primary surgery, rather than trabeculectomy. One-year results from a randomized, prospective trial comparing trabeculectomy versus Baerveldt implant in patients who have undergone previous trabeculectomy and/or cataract extraction with intraocular lens implantation showed similar

success rates.17 The trabeculectomy group required fewer glaucoma medications but had a higher rate of postoperative complications.18 A randomized, prospective trial comparing trabeculectomy to the Ahmed Glaucoma Valve for primary surgery has also been reported.19,20 In this trial, despite lower intraocular pressures for the trabeculectomy group during the first year, longer follow-up showed similar intraocular pressure control and success rates in comparisons between the two groups. Contact lens wearers who require glaucoma surgery should also be considered for primary drainage implant surgery. Although clinicians are concerned about the long-term complications associated with filtration blebs – such as bleb leaks, hypotony, and endophthalmitis – it is not known whether long-term complication rates would be improved after drainage implant surgery compared with trabeculectomy.

68.2.5  Contraindications There are no known absolute contraindications for glaucoma drainage implants. Glaucoma drainage implant surgery and other glaucoma surgical procedures are relatively contraindicated in patients who are noncompliant with self-care in the postoperative period. Borderline corneal endothelial function may worsen after glaucoma drainage implant surgery or other types of glaucoma surgery.21

68.3  Surgical Techniques 68.3.1  Basic Techniques Retrobulbar anesthesia is administered in most cases. In order to achieve adequate exposure, a 6-0 silk or polyglactin traction suture on a spatula (side-cutting) needle is placed through the cornea near the limbus. Maximal exposure for suturing the plate is achieved by placing the bridle suture adjacent to the quadrant chosen for implantation. The basic techniques for drainage implant surgery are similar for different types of devices (Fig. 68.1a–c). In most instances, the device is placed in a superior quadrant, usually the superotemporal quadrant. In the quadrant chosen for implantation of the device, a fornix-based incision is made through the conjunctiva and Tenon’s capsule. Radial relaxing incisions on one or both sides of the conjunctival flap are frequently required to improve surgical exposure. For implantation of the double-plate devices, a 180° superior conjunctival flap is created. Blunt Westcott scissors are used to dissect between the episclera and Tenon’s capsule. The closed blades

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Fig. 68.1  Glaucoma drainage implant surgical procedure. (a) The plate (arrow) is sutured to the sclera in the equatorial region. (b) The tube is inserted into the anterior chamber through a needle tract. (c) The tube is covered with patch material

of Stevens tenotomy scissors (curved or straight) are inserted posteriorly and spread, creating a pocket between the rectus muscles. Wet-field cautery is used sparingly, usually around the site of the tube insertion at the limbus. In the unusual instance when bleeding seems to persist, a Weck-cell sponge soaked in epinephrine-containing solution can provide hemostasis and facilitate posterior dissection. Prior to implantation, valved implants should be examined and primed. During the sterilization process, the membranes in the valve may adhere to each other. Intraoperative priming of the valve is performed by using a 27- or 30-gauge cannula to irrigate balanced salt solution (BSS) through the tube, ensuring that the valve is functioning properly. In the open tube implants, it is advisable to flush the tubes to confirm that the tube is open. The Ahmed Glaucoma Valve, Eagle Vision implant, and single-plate Molteno Implant are placed into the pocket between the muscles. For the Baerveldt Glaucoma Implant, the superior and lateral or medial rectus muscles are identified with muscle hooks, and the plate is placed between and beneath the muscles. The valve mechanisms of the Ahmed and Eagle Vision valves should not be grasped with toothed forceps when inserting the plates into the sub-Tenon pocket, because this may damage the devices.22 The valve is positioned 8–9 mm posterior to the limbus, and the plate is anchored to the sclera with 8-0 or 9-0 nylon suture on a spatula needle though the openings on the anterior edge of the plate. Other permanent suture material with similar or greater tensile strength may be substituted for 8-0 or 9-0 nylon. Care should be taken to avoid scleral perforation, especially in buphthalmic eyes with thin sclera. Implants placed in the superonasal quadrant should not be positioned further than 8 mm posterior to the limbus. Evaluation of postmortem eyes implanted with the Ahmed valve in the superonasal quadrant have shown that the posterior edge of the plate may be close to the optic nerve with further posterior placement of the plate.23

The drainage tube is then cut bevel up to permit the tube tip to extend approximately 3 mm into the anterior chamber. The anterior chamber is entered with a 23-gauge needle approximately 0.5  mm posterior to the limbus, parallel or angling slightly forward to the iris plane. The 23-gauge needle provides an adequate size track for tube insertion while minimizing leakage of aqueous around the tube postoperatively. Entry into the anterior chamber posterior to Schwalbe’s line and anterior to the iris plane will minimize the risk of contact with the cornea or iris, respectively. The drainage tube is inserted into the anterior chamber through the needle track using nontoothed forceps. An instrument designed for tube insertion (Tube Inserter, New World Medical, Inc., Rancho Cucamonga, California) facilitates this step. The tube is then loosely secured to the sclera using a single 9-0 or 10-0 nylon suture, avoiding constriction of the tube. To prevent erosion of the tube through the conjunctiva near the limbus, a rectangular flap of processed pericardium (Tutoplast, New World Medical, Inc., Rancho Cucamonga, California; or IOP, Inc., Costa Mesa, California) or preserved donor sclera is sutured over the tube. Other suitable patch graft materials may be used, such as fascia lata, dura, or cornea. Both autograft and allograft patch materials have been used successfully for this application. Although some surgeons use up to four sutures to anchor the patch graft, only two interrupted 9-0 or 10-0 nylon sutures placed on either side of the graft are required to secure the patch graft to the sclera. Fibrin glue may also be used to secure the patch graft, which reduces the need for suturing.24 As an alternative to the use of patch materials, a partialthickness limbal-based scleral flap can be made. A needle tract can be made under the flap through which the tube is placed. The flap is sutured over the flap using 10-0 nylon sutures. Alternatively, a long needle tract may be created with the 23-gauge needle, which minimizes the risk of postoperative erosion of the conjunctiva over the tube.

68  Incisional Therapies: Shunts and Valved Implants

The conjunctiva is closed using 9-0 or 8-0 polyglactin suture on a tapered needle. The monofilament 9-0 polyglactin suture is preferred because it has a smaller diameter but a higher tensile strength compared with 8-0 braided polyglactin suture. Relaxing incisions are also closed using interrupted or continuous 9-0 polyglactin sutures. Fibrin glue is an alternative to sutures for conjunctival closure, especially when the conjunctiva can be re-approximated with minimal tension. Subconjunctival steroids and antibiotics are injected, preferably 180° away from the plate. Topical steroid and antibiotics are started on postoperative day 1 and tapered over the next 6–8 weeks.

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Following implantation of a glaucoma drainage device, aqueous humor flows from the anterior chamber through a tube connected to a posterior episcleral plate reservoir in the subconjunctival space. Unless a flow-restrictive or valved device is used, no resistance to aqueous humor outflow exists during the early postoperative period, until the formation of a capsule around the plate that resists aqueous flow. To avoid overfiltration and hypotony in the early postoperative period, a two-stage implantation25-27 or temporary ligation of the tube15,28-30 may be utilized. In the first stage of a two-stage implantation, the plate is secured to the episclera without inserting the tube into the anterior chamber. The tube is folded back and placed under the patch

graft or beneath an adjacent rectus muscle and can be attached to the episclera with a nylon or silk suture to facilitate identification during the second stage. In the second stage, the tube is inserted 4–6 weeks later after a fibrous capsule (pseudocyst) has formed around the plate. This technique minimizes the risk of postoperative hypotony, but disadvantages include transient postoperative intraocular pressure elevation requiring antiglaucoma medication and a second surgical procedure and its attendant inconvenience and risk. In routine cases, most clinicians implant open tube devices with transient flow restriction techniques (Fig.  68.2a–c). Aqueous flow can be limited in the early postoperative period by internal and external occlusion techniques. In the “rip-cord” technique, a 5-0 nylon or Prolene suture can be placed into the tube lumen at the plate end, providing additional restriction of flow with an absorbable 6-0 or 7-0 Vicryl suture around the tube. The end of the rip-cord suture is placed subconjunctivally near the inferior limbus for subsequent removal. Alternatively, a 6-0 or 7-0 Vicryl suture can be tied tightly approximately 2 mm from the junction of the plate and the tube. This technique prevents any aqueous flow until 4–6 weeks later, when the suture loses tensile strength and the fibrous capsule has formed. Some surgeons also choose to create a slit anterior to the Vicryl suture so that some fluid can escape – maintaining a low IOP during the early postoperative period.31 A 10-0 Prolene suture can be placed around the tube tip prior to tube insertion into the anterior chamber to restrict flow during the postoperative period. This suture can be opened with a laser, providing additional control of the intraocular pressure during the postoperative period.

Fig.  68.2  Flow-restriction techniques for open-tube implants. (a) Rip-cord suture. A Prolene suture in the lumen of the tube, and a polyglactin suture around the outside of the tube (arrow) reduces or eliminates aqueous flow. (b) Rip-cord suture in a patient with a Baerveldt implant. The suture can be visualized under the inferior bulbar conjunctiva at the slit lamp. The 4-0 Prolene suture can be removed at the slit

lamp after making a small conjunctival incision with topical anesthesia. (c) Prolene suture ligature at tip of tube. The 8-0 to 10-0 Prolene suture is tied tightly near the tip of the tube (arrow) and loosely at another proximal position on the tube. The suture at the tip of the tube can be cut with a laser during the postoperative period, thereby allowing aqueous flow through the tube

68.3.2  Modifications

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Fig. 68.3  Pars plana tube insertion devices. (a) Pars Plana Clip (New World Medical, Inc., Rancho Cucamonga, California). (b) Hoffman elbow (Advanced Medical Optics, Inc., Santa Ana, California)

Viscoelastic is not required for routine cases. However, in certain patients, surgeons may make a self-sealing stab incision (paracentesis) into the anterior chamber near the limbus, usually temporally, and inject viscoelastic into the anterior chamber. Prior to tube insertion, the viscoelastic may help avoid shallowing of the anterior chamber, which can occur when the anterior chamber is later entered with a 23-gauge needle. After tube placement, viscoelastic may help minimize the risk of hypotony in eyes the surgeon considers to be at risk for this problem. In eyes that contain silicone oil, viscoelastic may avoid intraoperative loss of oil through the tube.32 Also, placement of the plate in an inferior quadrant (usually inferotemporal) may minimize the loss of silicone oil through the tube during the postoperative period. In certain patients who are pseudophakic or aphakic and who have had a vitrectomy performed previously, it may be preferable to place the tube into the vitreous cavity rather than the anterior chamber (Fig.  68.3a, b). The Pars Plana Clip (Model PC, New World Medical, Inc., Rancho Cucamonga, California) provides for tube insertion through the pars plana, and can be used with any glaucoma drainage implant. The Pars Plana Clip is easily sutured to the sclera and eliminates kinking of the tube.33 Pars plana insertion also eliminates the possibility of tube-cornea touch, which may be a consideration in patients with preexisting corneal grafts. The Hoffman Elbow (Advanced Medical Optics, Inc., Santa Ana, California) has been designed for pars plana insertion of the Baerveldt Implant through the pars plana.34 Repositioning of the Baerveldt implant tube from the anterior chamber into the vitreous cavity may avoid tube-related anterior segment complications.35 Some surgeons apply mitomycin C to the area around the plate during surgery, in an attempt to improve the success of the procedure. However, a randomized, prospective, multicenter trial showed no benefit of intraoperative mitomycin C during Ahmed Glaucoma Valve implantation compared with

Fig.  68.4  Mitomycin C and Ahmed Glaucoma Valve implantation. Cumulative probability of success (Kaplan–Meier analysis) from a randomized, controlled, multicenter clinical trial (Reprinted from Costa et al.,36 with permission from Elsevier)

controls in various clinical outcome measures, including postoperative intraocular pressure, number of postoperative medications, and postoperative success rates (Fig.  68.4).36 Similarly, the use of mitomycin C during Baerveldt implant surgery failed to show an improvement in postoperative intraocular pressure compared to controls.37

68.4  Clinical Outcomes Multiple studies have reported the short- and long-term results of the more commonly implanted drainage implants, such as the Ahmed Glaucoma Valve (Fig.  68.5a, b), the Baerveldt Implant (Fig.  68.6a, b), and the Molteno Implant. In these studies, success was typically characterized as an intraocular pressure less than 21 or 22  mmHg and greater than 4 or

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Fig. 68.5  Clinical outcomes after the Ahmed Glaucoma Valve. (a) Mean intraocular pressure after the Ahmed Glaucoma Valve. (b) Cumulative probability of success after the Ahmed Glaucoma Valve (Figures reprinted from Huang et al.,40 with permission from Elsevier)

Fig. 68.6  Clinical outcomes after the Baerveldt implant. (a) Mean intraocular pressure. (b) Cumulative probability of success after the Baerveldt implant (Figures reprinted from Siegner et al.,42 with permission from Elsevier)

5  mmHg, with or without medicines, and without further glaucoma surgery or loss of light perception. These studies usually reported outcomes based on the cumulative probability of success. Most of these studies are retrospective, noncomparative case series; and direct comparison of surgical outcomes between different drainage implants is difficult because of the lack of uniformity in the studies. In long-term follow-up of patients after drainage implant surgery for refractory glaucoma, the intraocular pressure usually ranges in the mid-teens, occasionally reaching the low-teens.38-46 The intraocular pressure may vary before stabilizing in this range. Initially, the intraocular pressure is low, often less than 10 mmHg, before the formation of a capsule around the implant plate. This hypotensive phase may be followed by a rise of the intraocular pressure, typically at 3–6 weeks after surgery. When the increased intraocular pressure is transient, improving after nonsurgical therapy, it has been

described as a “hypertensive phase.” When the increased intraocular pressure persists, it can be described as “failure” of the drainage implant surgery. The hypertensive phase is presumably due to the formation of a thickened capsule around the plate of the implant. The increased intraocular pressure may be severe in rare instances, requiring surgical treatment. The incidence of the hypertensive phase has varied in different reports, occurring in 30–82% of patients following polypropylene (Model S2) Ahmed Glaucoma Valve implantation.40,41,47-49 The incidence of the hypertensive phase may be lower after silicone plate (Model FP7) compared with polypropylene plate (Model S2) implantation.48 A hypertensive phase has not been commonly observed after treatment with the Baerveldt or double-plate Molteno implants.42,50 Patients often require adjunctive medical therapy for IOP control after surgery, and most studies allow additional medical therapy in their success criteria. The average number

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of postoperative glaucoma medications required is usually around one.40,42 In studies with the Ahmed Glaucoma Valve, success rates of IOP control ranged from 76 to 87% at 1 year and from 68 to 77% at 2 years.38-41 One study with long-term follow-up found success rates at 4 years of 76%.41 Similar success and complication rates were observed after implantation of the silicone plate compared with the polypropylene plate of Ahmed valve. For the Baerveldt implant, the cumulative probability of success reported in studies ranges from 73 to 92% at 6 months and from 60 to 79% at 24 months.42,51 In trials with the Molteno implant, success rates of 74% with a mean follow-up of 33 months and 57% with a mean follow-up of 44 months were found.43,44 Reported success rates with the Krupin valve have ranged from 66 to 80% at 1–2 years.45,46 Multiple studies have shown that African-American race is a risk factor for surgical failure of trabeculectomy with adjunctive mitomycin C. In a retrospective, comparative study, AfricanAmerican race was also shown to be a risk factor for failure of glaucoma drainage device implantation.47 Success for white patients and African-American patients was 100% and 91% at 1 year and 96 and 79% at 3 years, respectively. In a study of Molteno implants in African-American patients, success rates of 72% at a mean follow-up of 30 months were found.52 Reported success rates after double-plate implants compared with single-plate implants have varied, depending on the implant type. Postoperative intraocular pressure tended to be lower after double-plate Molteno implant than after single-plate implantation.53 In a noncomparative series of 50 eyes treated with the double-plate Ahmed Glaucoma Valve, surgical success rates, mean intraocular pressure, and mean number of medicines were comparable to previous studies reported after implantation of the single-plate Ahmed Glaucoma Valve.5 The 350  mm2 and 500-mm2 Baerveldt implants also have had similar surgical success rates in studies that compared the different models.13

J.W. Boyle and P.A. Netland

68.4.2  Uveitic Glaucoma Glaucoma drainage implants have effectively lowered intraocular pressure in patients with controlled and uncontrolled uveitic glaucoma. In a study of 21 eyes with average follow-up of 24.5 months following Ahmed Glaucoma Valve implantation, the average postoperative IOP was 11.6 mmHg compared with 35.1  mmHg preoperatively, with an overall success rate of 94% at 4 years.61 In a retrospective study of 24 patients treated with the Baerveldt implant, success rates of 96% at 3 months and 92% at 6, 12, and 24 months were reported.62 The intraocular pressure was reduced from a preoperative mean of 30 mmHg on three antiglaucoma medications to a postoperative mean at 1 year of 13 mmHg on one medication. In patients with uveitis and uncontrolled glaucoma, the success rates are usually improved in patients treated with intensive antiuveitis therapy, including the use of immunomodulatory medications.61,63,64

68.4.3  Neovascular Glaucoma Neovascular glaucoma frequently fails to respond to medical therapy, and trabeculectomy has a high likelihood for failure. Reported success rates with drainage implants for neovascular glaucoma are generally lower compared to other types of glaucoma. Success rates were 79 and 56% at 12 and 18 months, respectively, in patients receiving different models of the Baerveldt Glaucoma Implant, with loss of light perception in nearly one-third of patients.65 In a study of the Ahmed Glaucoma Valve, the success rate was 68% at an average follow-up of 13 months.40 Studies are pending showing the potential benefit of antivascular endothelial growth factor (VEGF) medicines prior to glaucoma drainage implantation.

68.4.1  Pediatric Glaucoma In patients with congenital or aphakic glaucoma, cumulative probabilities of success have ranged from 70 to 94% at year 1 and from 56 to 86% at year 2.54-60 Children may be treated with trabeculectomy with mitomycin C or glaucoma drainage implant, depending on surgeon preference. In some patients judged to be at high risk for complications, such as those with advanced buphthalmos or Sturge–Weber syndrome associated with glaucoma, two-stage implantation over a 4- to 6-week period is probably safer than one-stage implantation, even when valved devices are implanted.59,60 This approach allows capsule formation around the plate, thereby providing additional protection against postoperative hypotony, and its associated complications.

68.4.4  G  laucoma Associated with Penetrating Keratoplasty Eyes that undergo corneal transplantation frequently develop elevated intraocular pressure, and conventional filtration surgery may have an increased likelihood for failure.66-68 In 31 eyes treated with the Ahmed Glaucoma Valve, the success rate at 12 and 20 months was 75 and 52%, respectively.69 Eyes with a history of infectious keratitis or keratouveitis had 5.8 times the risk of graft failure after placement of the Ahmed Glaucoma Valve. In some instances, the risk of graft failure may be increased after glaucoma drainage device implantation because of mechanical endothelial trauma or

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inflammation associated with multiple surgeries. Other glaucoma surgical treatments besides glaucoma drainage implants have been associated with increased risk of graft failure. In patients with corneal grafts, there was no significant difference in graft failure rate after glaucoma drainage implant surgery, trabeculectomy, or cyclophotocoagulation.21

68.4.5  G  laucoma Associated with Severe Ocular Surface Disease A keratoprosthesis is an alternative for visual rehabilitation in patients with severe ocular surface disease, including ocular cicatricial pemphigoid, Stevens–Johnson syndrome, severe dry eye disease, severe chemical burns, and repeated failure of penetrating keratoplasty. These patients have a high incidence of both open-angle and closed-angle glaucoma before surgery, and many without glaucoma preoperatively develop elevated intraocular pressure after keratoprosthesis surgery. In a study of 55 eyes with severe ocular surface disease treated with keratoprostheses, there was an incidence of glaucoma of 64%.16 These patients then underwent Ahmed Glaucoma Valve implantation at the same time as the keratoprosthesis if they were previously diagnosed with glaucoma (20 of 35 eyes) or underwent Ahmed Glaucoma Valve implantation at a later time if a diagnosis of postkeratoprosthesis glaucoma was made (15 of 35 eyes). Intraocular pressure was controlled in 81% of patients with 25% requiring additional medications. Vision was improved in 63%, worse in 20%, and unchanged in 17% of eyes.

68.4.6  G  laucoma Following Retinal Detachment Elevated intraocular pressure can occur after pars plana vitrectomy and silicone oil injection for complicated retinal detachments. Most of these cases can be managed with antiglaucoma medicines. Trabeculectomy has a poor prognosis in this clinical situation due to significant conjunctival scarring, possible blockage of sclerostomy by silicone oil, and other adverse effects. In a study including eyes that failed medical therapy, elevated intraocular pressure was managed with the Ahmed Glaucoma Valve.32 Viscoelastic was injected into the anterior chamber, and the implants were placed in an inferior quadrant to prevent loss of silicone oil. Of 450 eyes treated with pars plana vitrectomy and silicone oil, 51 (11%) developed elevated intraocular pressure. Of these eyes, the majority were treated medically, while the remaining eyes that failed medical therapy were treated surgically with the Ahmed Glaucoma Valve. The intraocular pressure was

reduced from a mean of 44  mmHg preoperatively to 14 mmHg postoperatively, with a reduction of antiglaucoma medicines from 3.5 to 1.2. A need for prolonged steroid therapy in eyes containing silicone oil was observed. Silicone oil, observed at the tip of the tube in the anterior chamber in approximately 20% of cases, did not cause obstruction or loss of function of the tube.

68.5  Complications Complications may occur after glaucoma drainage implant surgery (Table 68.3), although most problems occurring with drainage implants can be treated effectively.

68.5.1  Hypotony Hypotony and complications associated with hypotony may occur during the immediate postoperative period after glaucoma drainage implant surgery. Options to restrict aqueous flow include two-stage implantation technique, suture ligature around the tube, and temporary occlusion of the tube lumen with a stent. In a study of 103 eyes treated with the Baerveldt implant, hypotony and choroidal effusions occurred in 32% and 20% of eyes, respectively.42 Similarly, hypotony-induced choroidal detachments and shallow anterior chamber occurred in 20% of eyes after placement of the Molteno implant.70 In eyes treated with the Ahmed Glaucoma Valve, hypotony occurred less frequently compared with nonvalved implants, presumably because of the flow-restrictive device on the Ahmed Glaucoma Valve.38,40 Hypotony and choroidal effusions may resolve without surgical treatment. When hypotony occurs with a flat chamber and lens-corneal touch, the anterior chamber may be reformed with viscoelastic injected into the anterior chamber in the clinic or may be treated in the operating room. Choroidal effusions may be treated with topical corticosteroid and cycloplegic medications, while large or persistent choroidal Table 68.3  Complications of drainage implants Hypotony Choroidal effusion Obstruction of tube by fibrin, blood, iris, vitreous Tube retraction and erosion Tube kink Motility disturbance Corneal decompensation and graft failure Endophthalmitis Retinal detachment Valve malfunction (rare)a a Associated with Ahmed Glaucoma Valve.

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effusions may be drained surgically. Removal of the tube can be considered in severe cases.

68.5.2  E  levated Intraocular Pressure Due to Other Causes Elevated intraocular pressure in the postoperative period may occur due to thickening of the capsule or “encapsulation” of the bleb around the drainage implant plate (see Sidebar 68.2).

Sidebar 68.2. Encapsulated filtering blebs after glaucoma shunt surgery Sandra M. Johnson The hypertensive phase (HP) is a well-known clinical entity that has been associated with glaucoma filtration surgery such as trabeculectomy, the Ahmed Valve (New World Medical, Rancho Cucamonga, California) as well as other glaucoma tube implants. Like many clinical entities, this one lacks a well-accepted, specific definition and criteria for diagnosis. Hypertensive phase, encapsulated bleb, or Tenon’s cyst (Fig. 68.2-1) following trabeculectomy has been described as a thick-walled bleb with prominent vascularity that is localized with associated elevated intraocular pressure (IOP). The thick wall causes the bleb to become more of an extension of the anterior

Fig. 68.2-1  Case of Tenon’s cyst. This patient had IOP of 23 mmHg pre-op on four topical medications. He had an Ahmed placed, and 12 days postoperative his IOP was 37  mmHg with a congested thick-walled bleb that deviated his eye nasally. An area of corneal dellen developed adjacent to this elevated thick-walled bleb. Aqueous suppression was instituted and IOP gradually stabilized in the teens over the next 6 weeks

In one study, encapsulated blebs were observed in 23% of patients, occurring at a median of 32 days after surgery, with a mean intraocular pressure of 34.4  mmHg.47 Initial treatment of elevated intraocular pressure due to encapsulated bleb consists of adjunctive medical therapy. Other methods to lower persistent elevated intraocular pressure include digital ocular compression, needling with or without 5-fluorouracil (5-FU) injection, or surgical excision of the capsule around the implant plate. Laser cyclophotocoagulation or a second glaucoma drainage device can also be considered.

chamber rather than a filtration site. It generally occurs 1–6 weeks following surgery and lasts up to 3 months. The intraocular pressure becomes elevated and some have defined the elevation in general terms such as an IOP over 21  mmHg, but we would benefit from better definitions. Patient risk factors have been sought for Tenon’s cysts following trabeculectomy and have included male gender, prior laser trabeculoplasty, prior conjunctival surgery, type of conjunctival incision, and prior beta-blocker usage. There is a suggestion that longterm IOP control is not as good in eyes that have experienced the HP. In a series of 62 patients who underwent a polypropylene Ahmed glaucoma tube shunt surgery, 23% developed Tenon’s cysts over a median time of 32 days postoperative and the IOP rose to the preop level for a duration up to 108 days. In a series of 85 patients, reported by Ayyala, 82% of patients developed an HP. Caprioli sought to characterize the HP following the insertion of polypropylene Ahmed valves. In his series of 156 surgical cases, 56.4% developed HP. He reported that 40.9% of eyes had IOP reach 30 mmHg or higher, which is the preoperative level for his series. Etiology The etiology of the hypertensive phase may be related to the flow and/or characteristics of the aqueous itself, because it develops in both eyes having had trabeculectomies or those with implanted glaucoma drainage devices. There also are likely patient factors, as suggested previously, that have yet to be exactly determined. It is known that there is greater bleb failure in eyes with disrupted blood aqueous barrier such as uveitic and neovascular glaucoma. Molteno proposes that opposing “fibro proliferative” and “fibro degenerative” factors in aqueous determine the ultimate bleb histology. For example, Tripathi has described the finding of proinflammatory transforming

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growth factor-alpha 2 (TGF-a2) in the aqueous of glaucoma eyes, and Jampel has suggested that uric acid levels in aqueous influence the outcome of trabeculectomy. The successful blebs around a glaucoma tube implant are the ones that develop a collagen stroma that becomes less compact, as supported by rabbit studies. There is a mechanical theory that relates to compression of the Tenon’s layer from the flow of aqueous into a bleb. Of note, early flow restriction is commonly used with nonvalved implants like the Molteno (IOP, Inc., Costa Mesa, California) and Baerveldt (Advanced Medical Optics, Inc., Santa Ana, California) compared to a valved design like the Ahmed. This also supports a mechanical compression of the inner wall of the filtration bleb as a contributing factor to HP development. Support for restriction of flow is derived from reports on the Baerveldt implant by Siegner and one from Tsai. The case series of Siegner describes no HP following the use of the nonvalved Baerveldt implant and Tsai reported 27% for his Baerveldt group compared to 60% for his Ahmed group. Ayyala also reported 84% HP with Ahmed versus 44% with the implantation of doubleplate Molteno devices. As previously mentioned, the exposure of the developing capsule to aqueous and pressure of its flow is limited early on in the healing cascade following surgery when a nonvalved implant is used. Also, the healing of an eye following a tube implant has been thoroughly studied by Molteno on eyes with the Molteno device. The fibro degenerative layer is dependent of aqueous flow as is the fibro vascular layer. The early flow restriction used in the nonvalved implants may have a role in the interaction of the aqueous and the forming capsule layers. Additionally, the degress of surface area of an implant may play a role in the HP associated with the tube implants. Evidence related to surface area is also presented in the study by Ayyala who compared the HP in patients following implantation of a double-plate Molteno implant to those who received an Ahmed implant. Fewer patients in the Molteno group experienced an HP compared to those in the Ahmed cohort. Both of these implants are constructed of similar material: polypropylene. The surface area of a double-plate Molteno is 270 mm2 and that of the Ahmed is 185 mm2. The smaller surface area of the Ahmed implant may have a role in the HP noted. Support for surface area as a factor for HP development is also derived from the reports on the Baerveldt implant by Siegner and Tsai, where the Ahmed groups with smaller surface area for filtration had more HP reported than the Baerveldt groups. The Baerveldt has a surface area of 350 mm2. The Baerveldt implant is constructed of silicone. Thus, we need to consider the material of the implant as another

variable that may be a factor in the development of HP, as compared to the Ahmed implant. In fact, Baerveldt implants were less reactive in the subconjunctival space compared to polypropylene implant plates. Direct comparison of HP associated with the silicone Baerveldt and the polypropylene Molteno are not available. However, comparison of the silicone and the polypropylene Ahmed has shown no difference in the HP in a report by Ayyala. A report by Mackenzie defined HP as IOP over 21 mmHg and 48% of HP developed with the silicone Ahmed versus 51% in the polypropylene in the cohorts reported.

Treatment Some authors suggest intraoperative techniques to influence the development of HP. A report by Susanna, in his prospective study of 92 eyes with neovascular glaucoma, also suggests some modulation of the HP with posterior tenonectomy intraoperative when mitomycin C (MMC) was used as an adjunct in Ahmed placement. The HP was 40% versus 46.8%. Ellingham suggests that the use of MMC over the second Molteno plate at the time of surgery reduces the incidence of HP. Costa completed a prospective randomized study on management of Tenon’s cysts following trabeculectomy. He compared needling to medical management and found no difference in the outcomes of filtration surgery. This suggests that medical management should be first-line treatment, because it is simpler and noninvasive. Of course, in a nonvalved implant, the first-line treatment of the development of elevated IOP would be removal of stints or ligature sutures that are restricting flow, just as laser suture lysis is done with trabeculectomy patients who have rising intraocular pressure. In persistent HP in these eyes and in postoperative Ahmed cases, the medical management is utilized as described for Tenon’s cysts following trabeculectomy. Aqueous suppressants are the medical treatment of choice with additional digital massage a further option. As with other conditions, how aggressive one is with treatment depends upon the status of the optic nerve. Moroi and her coworkers described a cohort with a high incidence of failures with medical management, and they utilized needling in most of their cases with some success and excision of the capsule for failures of needling also with some success. Chen and Palmberg described a technique of needling the encapsulated glaucoma implant with the use of 5-fluorouracil. However, one patient in their series developed endophthalmitis, supporting the use of this as

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a second-line treatment. Freedman described serial tapping of the bleb to remove the reactive aqueous. Excision of the encapsulation can be undertaken, although this is likely not to be successful if the fibrosis is so extensive as to have a complete failure of filtration prior to excision.

Conclusions HP can occur after any filtration surgery and occurs frequently following the Ahmed glaucoma implant. This surgery is notable for a smaller surface area for the filtration reservoir versus other glaucoma tube implants. Although, polypropylene is more reactive than silicone, using a silicone Ahmed has not eliminated HP. The other factor in Ahmed surgery is unrestricted flow in patients who may have reactive aqueous and/or early high flow of aqueous. Mitomycin C has not had a great impact on the development of HP nor has surgical intervention once it occurs. Initial aggressive treatment of inflammation in the anterior chamber should theoretically create a less proinflammatory aqueous. Early use of aqueous suppressants in the postoperative period for a valved design, once the brief hypotensive period passes, is recommended. This can create a medical ligature or stent to decrease aqueous in the early bleb and contribute to the milieu created by the nonvalved implants and theoretically reduce HP in this procedure. Needling and surgical revision remain alternatives for failure to control the HP with medical therapy with some success reported.

Bibliography Ayyala RS, Harman LE, Michelini-Norris B, et al. Comparison of different biomaterials for glaucoma drainage devices. Arch Ophthalmol. 1999;117:233–236. Ayyala RS, Michelini-Norris B, Flores A, et al. Comparison of different biomaterials for glaucoma drainage devices: part 2. Arch Ophthalmol. 2000;118:1081–1084. Ayyala RS, Zurakowski D, Monshizadeh R, et al. Comparison of double plate Molteno and Ahmed glaucoma valve in patients with advanced uncontrolled glaucoma. Ophthalmic Surg Lasers. 2002;33:94–101. Ayyala RS, Zurakowski D, Smith JR, et al. A clinical study of the Ahmed Glaucoma valve implant in advanced glaucoma. Ophthalmology. 1998;105:1968–1976. Campagna JA, Munden PM, Alward WL. Tenon’s cyst formation after trabeculectomy with mitomycin C. Ophthalmic Surg. 1995;26:57–60. Chen PP, Palmberg PF. Needling revision of glaucoma drainage device filtering blebs. Ophthalmology. 1997;104:1004–1010. Costa VP, Correa MM, Kara-Jose N. Needling versus medical treatment in encapsulated blebs. A randomized prospective study. Ophthalmology. 1997;104:1215–1220.

Eibschitz-Tsimhoni M, Schertzer RM, Musch DC, Moroi SE. Incidence and management of encapsulated cysts following Ahmed glaucoma valve insertion. J Glaucoma. 2005;14: 276–279. Ellingham RB, Morgan WH, Westlake W, House PH. Mitomycin C eliminates the short-term intraocular pressure rise found following Molteno tube implantation. Clin Experiment Ophthalmol. 2003;31:191–198. Freedman J, Rubin B. Molteno implants as a treatment for refractory glaucoma in black patients. Arch Ophthalmol. 1991;109: 1417–1420. Hinkle DM, Zurakowski D, Ayyala RS. A comparison of the polypropylene plate Ahmed glaucoma valve to the silicone plate Ahmed glaucoma flexible valve. Eur J Ophthalmol. 2007; 17:696–701. Jampel HD, Moon J, Quigley HA, Barron Y, Lam K. Aqueous humor uric acid and ascorbic acid concentrations and the outcome of trabeculectomy. Arch Ophthalmol. 1998;116:281–285. Kouros N, Caprioli J. Evaluation of the hypertensive phase after insertion of the Ahmed Glaucoma Valve. Am J Ophthalmol. 2003;136:1001–1008. Lloyd MA, Baerveldt G, Nguyen QH, Minckler DS. Long-term histologic studies of the Baerveldt implant in a rabbit model. J Glaucoma. 1996;5:334–339. Mackenzie PJ, Schertzer RM, Isbister CM. Comparison of silicone and polypropylene Ahmed glaucoma valves: 2 year follow-up. Can J Ophthalmol. 2007;42:227–232. Molteno ACB, Fucik M, Dempster AG, Bevin TH. Otago Glaucoma Surgery Outcome Study. Facotrs controlling capsule fibrosis around Molteno implants with histopathologic correlation. Ophthalmology. 2003;110:2198–2206. Molteno ACB, Suter AJ, Fenwick M, Bevin TH, Dempster AG. Otago Glaucoma Surgery Outcome Study: cytology and immunohistochemical staining of bleb capsules around Molteno implants. Invest Ophthamol Vis Sci. 2006;47(5):1975–1981. Richter CU, Shingleton BJ, Bellows AR, Hutchinson BT, O’Connor T, Brill I. The development of encapsulated filtering blebs. Ophthalmology. 1988;95:1163–1168. Schwartz AL, Van Veldhuisen PC, Gaasterland DE, et al. The Advanced Glaucoma Intervention Study (AGIA): 5. Encapsulated bleb after initial trabeculectomy. Am J Ophthalmol. 199;127:8–19. Scott DR, Quigley HA. Medical management of a high bleb phase after trabeculectomy. Ophthalmology. 1988;95:1169–1173. Seigner SW, Netland PA, Urban RC, et al. Clinical experience with the Baerveldt glaucoma drainage implant. Ophthalmology. 1995;102:1298–1307. Shah AA, WuDunn D, Cantor LB. Shunt Revision versus additional tube shunt implantation after failed tube shunt surgery in refractory glaucoma. Am J Ophthalmol. 2000;129:455–460. Sherwood MB, Spaeth GL, Simmones ST, et al. Cysts of Tenon’s capsule following filtration surgery. Arch Ophthalmol. 1987;105:1517–1521. Susanna R, Latin America Glaucoma Society Investigators. Partial Tenon’s capsule resection with adjunctive mitomycin C in Ahmed glaucoma valve implant surgery. Br J Ophthalmol. 2003;87:994–998. Tripathi RC, Li J, Ghan WF, Tripathi BJ. Aqueous in glaucomatous eyes contains and increased level of TGF-beta 2. Exp Eye Res. 1994;59:723–729. Tsai JC, Johnson CC, Dietrich MS. The Ahmed shunt versus the Baerveldt shunt for refractory glaucoma. Ophthalmology. 2003;110:1814–1821. Yarangumeli A, Koz OG, Kural G. Encapsulated blebs following primary standard trabeculectomy: course and treatment. J Glaucoma. 2004:13:251–255.

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68  Incisional Therapies: Shunts and Valved Implants Fig. 68.7  Obstruction of drainage implant tube. (a) Patient with elevated intraocular pressure and blockage of drainage implant tube with fibrin during the immediate postoperative period. (b) Same eye as shown in (a), a short time after treatment with 10 µg tissue plasminogen activator (TPA) in 0.1 cc. The intraocular pressure remained in the normal range after injection of TPA. (c) Patient with shallow anterior chamber during the immediate postoperative period developed blockage of drainage implant tube with iris tissue. (d) Same eye as shown in (c), immediately after injection of viscoelastic in the anterior chamber

68.6  E  levated Pressure Following Implantation Failure to prime the Ahmed Glaucoma Valve with balanced salt solution intraoperatively can lead to increased intraocular pressure postoperatively. Fibrosis of the valve and postoperative valve failure is rare, but has been reported.71 Fibrovascular ingrowth into the Ahmed Glaucoma Valve is uncommon, but has been documented as a cause of late failure in adults and pediatric patients.72 Elevated intraocular pressure may be caused by obstruction of the tube by fibrin, blood, iris, vitreous, or other substances (Fig. 68.7a–d). This was found to occur in 11% of eyes, most frequently by blood in patients with neovascular glaucoma.40 Occlusion of the tube by the posterior capsule has also been reported after Ahmed Glaucoma Valve implantation.73 Intracameral injection of tissue plasminogen activator (0.1– 0.2  cc of 5–20 µg) may dissolve a fibrin or blood clot. Neodymium:yttrium aluminum garnet (Nd:YAG) laser can be used to ablate iris tissue or the posterior capsule occluding the tube. A vitrectomy may be required for vitreous in the tube. Tube obstruction may be due to kinking of the tube after pars plana insertion. This complication can be managed by reinserting the tube in a different scleral entry site or by using a Pars Plana Clip.32 The Pars Plana Clip has a smooth curvature that avoids kinking. Utilizing the clip during the initial insertion of the tube through the pars plana will avoid this potential complication.

Fig. 68.8  Tube extender (New World Medical, Inc., Rancho Cucamonga, California). The tube extender can be used for any type of glaucoma drainage device, and has been used for treatment of tube retraction. Arrow shows the direction of aqueous flow

68.6.1  T  ube Migration, Retraction, and Erosion Tube migration and retraction can occur after any type of glaucoma drainage implant surgery. Inadequate anchoring of the tube or plate may lead to tube-cornea touch, lens injury, obstruction of the tube, or tube retraction. If tube retraction occurs and the tube is too short to reposition, a new valve can be reinserted, the tube can be reinserted in the pars plana, or a tube extender can be utilized to lengthen the tube. The Tube Extender (New World Medical, Inc., Ranch Cucamonga, California) has been

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shown to be an effective device to lengthen the tube from either an Ahmed Glaucoma Valve, Baerveldt implant, or Molteno implant (Fig. 68.8).74 Erosion of the tube through the overlying conjunctiva is another recognized complication. As previously described, the tube should be covered with preserved pericardium or preserved donor sclera to prevent this complication. Melting or thinning of the patch graft can occur, potentially leading to an exposed tube. Erosion of the tube should be repaired immediately by surgical debridement, and by covering the area with patch graft and conjunctiva. Erosion of the implant plate may necessitate explantation of the device.

68.6.2  Motility Disturbances and Diplopia In the early postoperative period, transient motility disturbances, including diplopia and restriction of gaze, are attributed to periocular swelling and typically resolve in weeks. Permanent motility disorders may result from mechanical displacement (mass effect) by the implant and bleb, fat adherence syndrome, or posterior fixation suture (Faden) effect associated with scarring under the rectus muscles. This complication has been reported more frequently following implantation of larger drainage devices, such as the Baerveldt and double-plate Molteno implants, but may occur after any type of drainage implant.6,75-78 Common presentations include exotropia, hypertropia, limitation of rotations, muscle palsies, and acquired Brown’s syndrome.

68.6.3  Vision-Threatening Complications Complications that threaten vision are not common after glaucoma drainage implant surgery. Suprachoroidal hemorrhage, choroidal effusions, and retinal detachments are potential complications following surgery. They have been reported to occur in up to 2–5% of patients.40,41 Endophthalmitis is a rare complication of glaucoma drainage implant surgery that can be associated with any type of glaucoma drainage device. The incidence in one study, which examined 542 eyes with Ahmed Glaucoma Valves, was 1.7%, with Haemophilus influenzae and Streptococcus species as the most common isolated organisms.79 The majority of cases of endophthalmitis occurred at least 6 weeks after implantation. Conjunctival erosion overlying the Ahmed Glaucoma Valve tube was found to be the most important risk factor. Surgical revision with a patch graft is recommended in all cases with an exposed tube.

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68.4  Conclusion Glaucoma drainage implants are effective for the treatment of patients who have a variety of refractory or intractable glaucomas, including failure to respond to trabeculectomy, extensive conjunctival scarring, or poor prognosis of trabeculectomy for primary surgery. Broader use drainage implants, including use for primary surgery, can be considered. Glaucoma drainage implants can be classified as valved or nonvalved implants. The Ahmed Glaucoma Valve is a popular valved implant, while the Baerveldt and Molteno implants are representative open-tube devices. The valve mechanism of the Ahmed Glaucoma Valve may minimize the incidence of hypotony and its associated complications, while open-tube devices use adjunctive flow-restrictive techniques to minimize the risk of hypotony during the immediate postoperative period. Visionthreatening complications are uncommon after drainage implant surgery.

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830 58. Netland PA, Walton DS. Glaucoma drainage implants in pediatric patients. Ophthalmic Surg. 1993;24:723–729. 59. Ishida K, Mandal AK, Netland PA. Glaucoma drainage implants in pediatric patients. Ophthalmol Clin North Am. 2005;18:431–442. 60. Mandal AK, Netland PA. The Pediatric Glaucomas. Edinburgh: Elsevier; 2006. 61. Da Mata A, Burk SE, Netland PA, et  al. Management of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology. 1999;106:2168–2172. 62. Ceballos EM, Parrish RK, Schiffman JC. Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic glaucoma. Ophthalmology. 2002;109:2256–2260. 63. Netland PA, Denton NC. Uveitic glaucoma. Contemp Ophthalmol. 2006;5:1–8. 64. Papadaki TG, Zacharopoulos IP, Pasquale LR, et  al. Long-term results of Ahmed glaucoma valve implantation for uveitic glaucoma. Am J Ophthalmol. 2007;144:62–69. 65. Sidoti PA, Duphy TR, Baerveldt G, et  al. Experience with the Baerveldt glaucoma implant in treating neovascular glaucoma. Ophthalmology. 1995;102:1107–1118. 66. Foulks GN. Glaucoma associated with penetrating keratoplasty. Ophthalmology. 1987;94:871–874. 67. Franca ET, Arcieri ES, Arcieri RS, et al. A study of glaucoma after penetrating keratoplasty. Cornea. 2002;21:284–288. 68. Insler MS, Cooper HD, Kastl PR, et  al. Penetrating keratoplasty with trabeculectomy. Am J Ophthalmol. 1985;100:593–595. 69. Coleman AL, Mondino BJ, Wilson MR, et al. Clinical experience with the Ahmed glaucoma valve implant in eyes with prior or

J.W. Boyle and P.A. Netland concurrent penetrating keratoplasties. Am J Ophthalmol. 1997;123: 54–61. 70. Wilson RP, Cantor L, Katz LJ, et al. Aqueous shunts. Molteno versus Schocket. Ophthalmology. 1992;99:672–678. 71. Feldman RM, el-Harazi SM, Villanueva G. Valve membrane adhesion as a cause of Ahmed glaucoma valve failure. J Glaucoma. 1997;6:10–12. 72. Trigler L, Proia AD, Freedman SF. Fibrovascular ingrowth as a cause of Ahmed glaucoma valve failure in children. Am J Ophthalmol. 2006;141:388–389. 73. Tessler Z, Jluchoded S, Rosenthal G. Nd: YAG laser for Ahmed tube shunt occlusion by the posterior capsule. Ophthalmic Surg Lasers. 1997;28:69–70. 74. Sarkisian SR, Netland PA. Tube extender for revision of glaucoma drainage implants. J Glaucoma. 2007;16:637–639. 75. Munoz M, Parrish RK. Strabismus following implantation of Baerveldt drainage devices. Arch Ophthalmol. 1993;111:1096–1099. 76. Dobler-Dixon AA, Cantor LB, Sondhi N, et al. Prospective evaluation of extraocular motility following double-plate Molteno implantation. Arch Ophthalmol. 1999;117:1155–1160. 77. Christmann LM, Wilson ME. Motility disturbances after Molteno implants. J Pediatr Ophthalmol Strabismus. 1992;29:44–48. 78. Frank JW, Perkins TW, Kushner BJ. Ocular motility defects in patients with Krupin valve implant. Ophthalmic Surg. 1995;26: 228–232. 79. Al-Torbak AA, Al-Shahwan S, Al-Jadaan I, et al. Endophthalmitis associated with the Ahmed glaucoma valve implant. Br J Ophthalmol. 2005;89:454–458.

Chapter 69

Incisional Therapies: What’s on the Horizon? Richard A. Hill and Don S. Minckler

For decades, the primary resistance to aqueous outflow has been thought to reside in the outer one-third of the trabecular meshwork including the juxtacanalicular connective tissue in continuity with the inner wall of Schlemm’s canal. Dysfunction of this portion of the trabecular outflow system has been considered to be the main cause of open-angle glaucoma (COAG).1,2 Surgical therapies have either targeted this tissue directly or bypassed it via scleral fistulas such as trabeculectomy. Goniotomy and ab externo trabeculotomy, still considered the mainstay of surgeries for congenital glaucoma worldwide, have not been considered useful by North American surgeons in adult open-angle glaucoma, but have remained popular in Europe and especially Japan. Other types of microincisional surgery utilizing lasers, such as Q-switched neodymium:YAG, have also been attempted but not been found successful because of a posttreatment healing process described as tissue filling-in whether utilizing micropuncture or strip-ablations. The amount of tissue removed during laser ablation has been increased and thermal damage minimized through the application of erbium:YAG lasers still being clinically utilized in Europe. The ultimate goal of all nonaesthetic surgery is the restoration of physiologic function. Trabeculectomy and tube shunt surgery have not addressed the primary dysfunction involved in open-angle glaucoma. As an alternative to restoration of function, aqueous is shunted away from physiologic outflow structures into new reservoirs, which allows for passive diffusion. These reservoirs are associated with complications unique to their function and location. Limbal filtering blebs cause bleb-related dysesthesia, and wound leaks or overfiltration may be associated with hypotony maculopathy and bleb-related endophthalmitis. Aqueous drainage shunts produce equatorial filtering blebs, which pose little risk of infection unless the device extrudes, but they can create muscle interference with secondary diplopia. The capsule that forms around the equatorial explant may become over-collagenized with clinically inadequate diffusional capacity. In terms of the restoration of function of the filtering organ, respect must be shown to the tissues while treating the defect which is present. Healing responses must be

integrated into the surgical plan so that filling-in will not cause operative failure. Native tissue functions, such as pumping effects secondary to the ocular pulse (choroidal piston), should be preserved. Recently, there have been two additional novel surgical approaches to the trabecular portion of the outflow system. One involves trabecular stenting, (Glaukos, iStent, Fig. 69.1). Another technique removes an arc of trabecular meshwork and inner wall of Schlemm’s via electro-ablation with simultaneous infusion of fluid and aspiration of tissue debris (NeoMedics, Trabectome, Fig. 69.2).

69.1  Developing a Microstent The concept for the iStent was developed from the observation that trabecular tissues would fill in to apposition after injury or focal removal. The iStent is actually a family of devices to enhance the physiologic outflow of the eye. This device makes a bypass opening in the trabecular meshwork and allows trabecular meshwork to fill into the edge of the device inlet but prevents closure of the opening (Fig. 69.3). The development of the trabecular stent was not possible until recent engineering improvements in micro machining. The size of the device is based on the scale imposed by the trabecular meshwork and Schlemm’s canal. The iStent, which resides in the lumen of Schlemm’s canal, is 1,000 mm long and 250 mm in width. It has an open, arched body (Fig.  69.1). The iStent design is intended to perform two functions: providing direct access of aqueous into Schlemm’s from the anterior chamber (the snorkel effect) (Fig.  69.4), and pushing the anterior trabecular meshwork away from the posterior wall of Schlemm’s canal, where aqueous collector channel openings are located. The arch precludes occlusion of a collector channel opening should it lie behind the iStent (Fig. 69.5). The device is self-trephining with the aid of an angled tip and open in its tail portion to allow for bidirectional flow. The arch portion of the device also has elevated retention

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_69, © Springer Science+Business Media, LLC 2010

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features to limit movement or backing out (self-retaining) from its placement in Schlemm’s canal. The device is made out of medical grade titanium (6AL4V) and is heparin-coated (Duraflow). The weight is approximately 60 mg, and mirror image left and right eye devices are required because of anatomical considerations.

Fig. 69.1  Glaukos trabecular iStent. Courtesy of Glaukos Corp., Laguna Hills, California

R.A. Hill and D.S. Minckler

69.2  Surgical Techniques Both procedures (Glaukos iStent or Trabectome) can be performed either as a stand-alone surgery or in combination with cataract surgery. Trabecular surgery at the same time as cataract surgery may be performed before or after cataract

Fig.  69.3  In vivo goniophotograph of the first iStent implantation, 6 months postoperatively. Courtesy of Glaukos Corp., Laguna Hills, California

Fig. 69.2  Trabectome surgical unit and handpiece. Illustration courtesy of NeoMedix, Tustin, California

69  Incisional Therapies: What’s on the Horizon?

Fig. 69.4  In vivo goniophotograph 6 months postimplantation. Note trabecular meshwork has filled in to edge of snorkel and stopped. Courtesy of Dr. Jonathan Meyers, Wills Eye Hospital

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and loss of view when the iStent applicator or Trabectome instrument is placed through the cornea. Gonioscopes were designed (RAH) in conjunction with Ocular Instruments (Bellevue, Washington) for both procedures (Fig.  69.6), and provide excellent wide-angle views. Both lenses are modified Swan–Jacobs direct gonioscopes for comfortable right- or left-handed manipulation with an elongated handle moved to the side of the lens. On the side facing away from the surgeon, a metal flange facilitates stabilization of the eye and negates the need for traction sutures. After the creation of the corneal wound, viscoelastic is usually instilled into the anterior chamber to overdeepen it. This allows excellent access to the filtering angle and maximizes the safety in phakic adult and pediatric patients. Alternatively, the Trabectome hand piece includes an infusion sleeve for continual irrigation with balanced salt solution, which is usually adequate in pseudophakic eyes to maintain a deep anterior chamber. The Trabectome surgical pack includes a Simcoe irrigation cannula for use if necessary to ensure removal of all viscoelastic after angle surgery. For iStent, the applicator/hand piece tip is advanced through the wound up to the pupillary margin and the gonioscope placed on the eye. For both procedures, the patient’s head should be tilted away at approximately a 45° angle and the microscope body and oculars adjusted toward the operator as necessary to optimize the view. Taping the patient’s head is avoided to allow head adjustments intraoperatively. With the gonioscope on the eye, a light touch is used to view the filtering angle. Care should be taken not to indent the cornea as this distorts the view. The site for surgery is selected based

Fig. 69.5  An iStent implanted in eye bank tissue, showing stenting of Schlemm’s canal. Courtesy of Glaukos Corp., Laguna Hills, California

surgery and lens implantation. Potential advantages of angle surgery first before cataract surgery include greater clarity of the peripheral cornea for improved visualization of the filtering angle. In addition, reflux hemorrhage, highly likely, with either can be easily removed during the cataract removal. Both surgeries are started by making a small, temporal, clear corneal incision, with a 15° degree knife or appropriately sized keratome. This incision is made as close to the limbus as possible to prevent lifting of the gonioscope

Fig. 69.6  The trabecular bypass surgical gonioscope. Courtesy of Ocular Instruments, Bellevue, Washington

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on observed positions of external aqueous vein complexes (Fig.  69.7) and areas of increased trabecular pigmentation. Aqueous veins may originate with a “C” or “S” shape at the limbus, and their episcleral portion tends to be more linear in which tri-laminar flow often can be seen. The large aqueous

R.A. Hill and D.S. Minckler

vein complexes are usually found at 3:30 and 8:30, inferior nasally, in the right and left eyes respectively.3 The areas of increased trabecular pigmentation are a clinical sign that large collector channel ostia are in proximity.4 Finding these structures preoperatively will give an approximate position for surgery that will give maximal access to the outflow structures. Viscoelastic support of the anterior chamber at a hypotonous pressure leads to congestion of Schlemm’s Canal, aiding in identifying Schlemm’s Canal.

69.2.1  iStent Implantation

Fig.  69.7  A large aqueous vein at approximately 3:30 in a right eye. The origin is “C” or “S” shaped – they tend to be more linear and tri-laminar flow can be seen. Courtesy of Glaukos Corp., Laguna Hills, California

The iStent is held by the applicator (Fig. 69.8a, b) outer tubing, which is 26-gauge stainless steel, from which extends four micromachined fingers from a smaller tube securing the device by the inlet tube. This applicator can also be used to reposition a stent or to reacquire a stent during surgery. The distal, pointed end of the iStent is inserted through trabecular meshwork in a penetrate, lift, and slide insertion technique (Fig. 69.9). The angle of attack is approximately 30° and the stent is passed through trabecular meshwork at a

Fig. 69.8  The iStent is held by the applicator tubing, which is 26-gauge stainless steel from which extends (a) four micromachined fingers from a smaller tube (b) securing the device by the inlet tube. Courtesy of Glaukos Corp., Laguna Hills, California

Fig. 69.9  The pointed end of the iStent is inserted through trabecular meshwork in a penetrate, lift, and slide insertion technique

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69  Incisional Therapies: What’s on the Horizon?

position of about one-half of the way down the pigmented portion of the trabecular meshwork band (uveal-scleral meshwork). The initial penetration usually goes through trabecular meshwork and the inner wall of Schlemm’s canal lodging in the outer wall of Schlemm’s canal. At this point, there is a definite sticking sensation and the eye itself can be moved without the implant advancing. A small lifting or a small backing motion is utilized to disengage the posterior wall of Schlemm’s canal and a sliding motion is then used to

advance the device into Schlemm’s canal. Once this has occurred, the release button on the applicator is pushed and the applicator fingers holding the snorkel of the device are released. At this part of the implantation sequence, the heel of the device compresses trabecular meshwork focally and the implant is not locked into Schlemm’s canal. Using the applicator, the device must be advanced slightly further to allow the heel to pass beyond trabecular meshwork and the body of the device to sit entirely within Schlemm’s canal (Fig. 69.10a–e).

Fig. 69.10  (a–e) Implantation sequence of the Glaukos iStent. Illustrations courtesy of Glaukos Corp., Laguna Hills, California

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Fig. 69.11  Trabectome in use. The footplate acts as a guide within Schlemm’s canal as the hand piece is rotated. Simultaneous aspiration removes tissue debris and infusion both maintains the anterior chamber and provides cooling as additional protection from thermal injury to adjacent tissues. Illustration courtesy of NeoMedix, Tustin, California

This is accomplished by pushing on the snorkel of the device with the tip of the empty applicator. Reflux of blood may not occur at this point in time as it is tamponaded by viscoelastic in the anterior chamber. When the operator is sure that the device is in the correct position, the applicator is withdrawn from the eye and viscoelastic is removed by irrigation with balanced salt solution. If there is doubt on the correctness of the implantation, the device may be reacquired by the applicator and another site chosen for implantation. The gonioscope is then replaced and the device viewed.

as additional protection from thermal injury to adjacent tissues (Fig. 69.11). Most Trabectome surgeons are attempting to treat at least 3 clock hours (Fig. 69.12). After both surgeries, it is important to irrigate any viscoelastic used from the eye with balanced salt solution, and suture or hydrate the wound so that intraocular pressure remains reasonably normal and additional blood reflux is minimized to avoid temporary elevation of intraocular pressure.

69.2.2  Trabectome Trabecular Excision The Trabectome hand piece – currently cleared for singleuse only by the US Food and Drug Administration (FDA) – includes a foot-pedal controlled infusion sleeve and an aspiration function (Fig. 69.2). The tip of the hand piece is passed through trabecular meshwork in a compression and rotation maneuver, using primarily visual clues. Gentle compression of the mesh creates a fold into which the tip can be rotated. The Trabectome tip incorporates an electroablation function utilizing a spark between active and return electrodes, shielded from the posterior wall of Schlemm’s by the ceramic coated footplate. The footplate acts as a guide within Schlemm’s canal as the hand piece is rotated. Simultaneous aspiration removes tissue debris and infusion maintains both the anterior chamber and provides cooling

Fig. 69.12  Scanning electron micrograph; the Trabectome hand piece then utilizes an electric spark to ablate the meshwork and inner wall of Schlemm’s canal and aspirate tissue debris for approximately 3 clock hours. Courtesy of Doug Johnson

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69  Incisional Therapies: What’s on the Horizon?

69.3  Results 69.3.1  iStent Implantation The first Glaukos iStent currently has completed a multicenter randomized trial in the US comparing IOP outcomes after iStent and phacoemulsification to phacoemulsification alone; these results have been submitted to the FDA for approval for use in the United States. The Glaukos iStent is CE marked for use in Europe. Peer-reviewed published studies include basic science studies and initial clinical case series.5–10 The initial proof of concept study (N = 6) utilized a silicone transtrabecular tube.8 In cultured autopsy eye perfusion experiments, adding successive bypass shunts produced dramatic step-wise increases in outflow, an encouraging demonstration of the potential for titrating therapy and achieving lower pressures with multiple iStents. 6 A follow-up series, which actually used an early model titanium iStent (N = 6), established that both pressures and medications could be reduced with stent stability at a follow-up of 1 year.9 After the initial proof of principle studies, the device has been studied further as a stand-alone device, in combination with cataract surgery and with two or three iStent implants per eye. Studies of iStent implantation alone include De Feo et al,11 who studied 45 patients who had iStent implantation without cataract surgery. The authors found that IOP dropped from a mean preoperative level of 28.4 ± 6.39 to 17.9 ± 3.62 mmHg at 18 months, and medications decreased from 2.1 ± 0.94 to 1.2 ± 1.18. The most common adverse events were transient iStent lumen occlusion (seven eyes) and malpositioning (nine eyes). Transient occlusion or malpositioning did not always preclude function. The iStent was also studied in a multicenter open label refractory population by Simmons et al12 with a total of 45 patients whom had failed filtering surgery. Thirty of the 45 subjects had reached 18 months of a 24-month study. Preoperative mean IOP of 28.4 ± 6.39 was reduced to 17.9 ± 3.62  mmHg at month 18 (P 270° of the posterior trabecular meshwork (the part which is often pigmented) cannot be seen. This definition is arbitrary and its evaluation in longitudinal study is an important priority. Producing a more evidence based definition of this parameter is a major research priority.1 b Foster et al1 defined glaucoma by both structural and functional evidence. Eyes with a CDR or CDR asymmetry >97.5th percentile for the normal population, or a neuroretinal rim width reduced to  180°

+ Limited Par Plana Vitrectomy

• Very shallow anterior chamber • Excessive positive posterior pressure • History of malignant glaucoma in fellow eye

+ Endocyclophotocoagulation

• Prominent plateau iris configuration • Mild to moderate ACG • Advanced ACG

• Removal of a non-cataractous lens requires additional discussion with patient to explain rational for surgery. Hyperopic patients in this scenario are generally very happy patients post-operatively. • Increase post operative steroids • Requires post-operative miotics • Consider post-operative ALPI • Careful not to damage posterior capsule • Avoid over decompression • Must rule out choroidal hemorrhage if performing due to build up of posterior pressure during surgery • Titration of energy crucial • Increase post-operative steroids • Non-penetrating procedures should only be performed if appositional closure only • Err on side of suturing flap tightly to avoid hypotony and aqueous misdirection

+ Filtering procedures

These indications are based on the experience and practice of the author.

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78.4.1  Principles

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the anterior chamber would provide adequate dilation; non-preserved 0.5% phenylepinephrine can also be used.

78.4.1.1  Anterior Chamber Stability At all times the anterior chamber should remain pressurized. These eyes are particularly susceptible to choroidal hemorrhages and aqueous misdirection. Loss of anterior chamber pressure may result in either of these complications.

78.4.1.2  Manage Positive Posterior Pressure Due to high IOP and crowded anterior segments, these patients invariably demonstrated positive posterior pressure. Attention to proper wound construction and usage of ophthalmicviscoelastic devices is imperative. Occasionally, adjunctive procedures maybe required to further decompress the eye. Constant attention to the development of iris prolapse is also required as post-AAC irides are often atrophic and floppy.

78.4.1.3  Corneal Endothelium These eyes are at a greater risk of post-operative corneal decompensation. The anterior chambers are typically shallow and therefore endothelial cells are more susceptible to phacoinjury. Furthermore, if the eye has already suffered an AAC attack, the endothelium has already been traumatized.

78.4.1.4  Beware of Zonular Compromise Zonular incompetence is often present either as a cause or result of PAC. Zonular laxity can result in the anterior movement of the lens precipitating angle narrowing or AACG can result in compromise to the zonules. In the author’s opinion, a capsular tension ring should be placed prior to IOL insertion in any eye that has suffered a previous AAC.

78.4.2  Preoperative Considerations Preoperative treatment with IV mannitol or acetazolamide will reduce IOP and deturgess the vitreous minimizing the risk of choroidal hemorrhage and aqueous direction and reducing posterior pressure. Placing the patient in a slight reverse-Trendelenburg position on the operating table and using the minimal amount of tension on the lid speculum will also help to reduce posterior positive pressure. While useful in routine cases, preoperative dilation of the pupil should be avoided, because it could exacerbate angle closure. Instead intra-cameral, non-preserved, 1% lidocaine injected in

78.4.3  Incisions With the initial incision, care should be taken not to allow the chamber to shallow. Wound length should err on the side of being longer. Increased wound length will reduce OVD or irrigation solution loss when instruments are placed through the wound, also the anteriorization of the internal ostomy of the wound will reduce the incidence of iris prolapse. Consideration should be given to performing the capsulorhexis using intra-ocular microforceps, which can be inserted through a paracentesis prior to creating the main incision. This will further minimize loss of OVD during this step. Alternatively, the capsulorhexis can be performed using a cystotome through a paracentesis.

78.4.4  OVDs The viscoelastic soft-shell technique34 optimizes the various properties of cohesive and dispersive OVDs and is of particular utility in challenges that may present in phacoemulsification in a PAC eye. Briefly, the soft shell technique calls for the injection of a dispersive agent first and then the injection of a cohesive agent centrally and just anterior to the lens – pushing the dispersive against the cornea and peripherally. The cohesive OVD assists in deepening the anterior chamber and maintaining the space. The dispersive OVD coats the endothelium, protecting it from trauma from irrigating fluids and phacoemulsification energy. Coating iris with a dispersive agent will also reduce the risk of iris prolapse. Finally, dispersive agent will effectively trap the cohesive OVD centrally, reducing the risk of sudden expression of the cohesive agent through the main wound, thereby improving anterior chamber stability. Used instead of the cohesive agent, a super-cohesive OVD, such as Healon-5 (AMO) is particularly useful in these cases. During phacoemulsification, the dispersive agent should be injected intermittently toward the cornea especially if the anterior chamber is particularly shallow, the lens very dense or there is a history of an AACG episode. Upon completion of phacoemulsification, before withdrawing the hand-piece, the cohesive agent should be injected into the eye to maintain the anterior chamber and prevent collapse while the handpiece is exchanged for the irrigation and aspiration (IA) equipment. Finally, a cohesive agent should be injected at conclusion of irrigation and aspiration, to prevent collapse as well as to prepare for lens insertion. The use of a cohesive is

78  Cataract Extraction as Treatment for Acute and Chronic Angle Closure Glaucomas

especially important here as it mitigates the need to go posterior to the lens with the IA hand piece – a maneuver that requires a partial or complete collapse of the AC.

78.4.5  Capsulorhexis Due to the anterior vaulting and positive posterior pressure in PAC eyes, there is greater propensity of the capsulorhexis to run out. To reduce this risk, size of the capsulorhexis should err on the smaller side – the capsulorhexis can be enlarged after lens insertion more safely. The use of a super-cohesive OVD, aside for the advantages listed above, will also help to lower the risk of running out the capsulorhexis. If vision blue is to be used, it should be injected under the OVD and not prior to OVD injection as the later can result in instability of the anterior chamber.

78.4.6  Iris Chronic cholinergic usage may result in a phimotic pupil with posterior synechiae. Standard measures for managing small pupils may be under taken, but care should be made to minimize iris manipulation as much as possible as these eyes are at greater risk for post-operative inflammation, especially if there has been a recent history of AACG. Conversely, the pupil may be atrophic and enlarged, increasing the risk of iris prolapse. A single iris hook, placed through a paracentesis made just posterior to the main incision will alleviate iris prolapse through the main wound.

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routine cases and can be minimized by appropriate wound sizing, alternatively consideration should be given to bimanual phacoemulsification. This technique offers enhanced anterior chamber stability through minimizing leakage around instrumentation at the corneal wounds, especially at the second instrument site. While bimanual phacoemulsification is optional, bimanual IA is necessary. There is significant leakage around co-axial IA hand pieces. Bimanual IA significantly reduces leakage and improves anterior chamber stability. The creation of a second paracentesis to provide sub-paracentesis access to the primary site is often necessary and is inconsequential.

78.4.8  Postoperative Management Routine postoperative medical management with an antibiotic, NSAID and steroid is often adequate. However, if there has been a past history of AAC or intra-operative iris manipulation was required, the frequency of steroid dosing should be increased. Post-operative corneal edema, if present, may be ameliorated with topical hypertonic solution or ointment. If goniosynechialysis was performed (see below), postoperative pilocarpine should be administered until post-operative inflammation has subsided to prevent reformation of peripheral anterior synechiae. Postoperative laser peripheral iridoplasty has also been described. See Chap. 61 for indications and techniques.

78.5  Adjunctive Procedures 78.5.1  Goniosynechialysis

78.4.7  P  hacoemulsification and Irrigation and Aspiration The author is of the opinion that a surgeon should not change flow and power parameters for challenging cases as this adds increased variability in a case that presents with altered characteristics. Rather attention to meticulous surgical technique should be observed. Keeping the phaco tip within the pupil margin will minimize dispersive OVD removal – maintaining the seal at the main wound and reducing iris floppiness. Minimizing posterior forces induced by the phaco tip and second instrument during nuclear manipulation will minimize iatrogenic trauma to the zonular complex. Leakage through the main wound is usually minimal, however than can be considerable leakage through the paracentesis through which the second instrument is inserted in the eye. Though this leakage is usually inconsequential in

After insertion of IOL, a miosis-inducing agent such as Miochol is injected into the anterior chamber. Mechanical manipulation of the iris may be required if the pupil is atonic after an AAC. The chamber is then deepened using a cohesive viscoelastic – if the PAS are weak, this alone may result in GSL.35 Inspection and view of the angle require an intraoperative gonio lens. Classically, this was done with direct lenses such as the Swan-Jacob or Barkan lens. While these lenses provide good visualization of the angle, they require intraoperative tilting of the patient’s head and microscope to gain view to the entire angle. Alternatively, the author’s preference is to use an indirect intraoperative gonio lens such as the Maxfield AC Four Mirror or the Osher Surgical Gonio Posterior Pole Lenses. Once the PAS have been identified intraoperatively, a blunt instrument, such as a Swan knife, under visualization is pressed against the most peripheral iris adjacent to the point of adhesion, and then a posterior

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sweeping motion is made, lysing the PAS, until the trabecular meshwork is exposed.27 The technique requires precise placement of the tip of the knife; if the tip is too proximal, tissue may be left, if too distal the trabecular mesh work or cilary body may be damaged. The author’s preference is to use the intraocular Ahmed Micro-graspers (MST, Redmond, Washington). In this technique, peripheral iris is grasped with the forceps, and under visualization, a centripetal and slightly posterior force is applied to the iris, disinserting the iris, until the scleral spur is exposed.36 This is done up to 360°, as required, inserting the forceps through either the main wound or the side port incision. The most common complication in GSL is a localized hyphema usually a result of overly aggressive disinsertion of the iris. This is easily managed by tamponading the hemorrhage by pressuring the AC with a cohesive OVD. Overly aggressive manipulation of the iris can result in irido- or cyclo-dialysis; however, this is very uncommon. As mentioned, post-operative management should include increased steroid dosing, topical miotic therapy, and possible peripheral laser iridoplasty – all modalities directed to minimize recurrence of PAS formation.

B.U. Khan

was created – toward the optic nerve to avoid inadvertent damage to the lens. This can be minimized, in the author’s opinion, if the vitrector is positioned so that the cutter is facing posteriorly. Often the lip of the incision must be grasped by a 0.12 forceps to facilitate insertion of the vitrector. The vitrector should be inserted until the tip can be visualized posterior to the lens. The vitrectomy should then be performed in 5  s increments – every 5  s, the surgeon should reassess AC depth and IOP as described previously. This should be continued until a reasonable outcome has been achieved. Excessive debulking of vitreous will result in an undesirably deep AC, particularly if there is zonular instability, which presents a separate set of technical challenges. Once an acceptable end point has been reached, OVD should be injected in the AC to ensure adequate AC depth and pressurization. The sclerostomy should be checked to ensure it is free of vitreous. If vitreous is present, the vitrector can be used on the surface of the sclera to remove it. The sclerostomy should be closed with an 8–0 Vicryl in a shoe tie knot – this can be released and a further vitrectomy can be performed later in the case if required. Upon completion of the case, the suture is then permanently tied and the conjunctiva closed in a routine fashion. The newer 25 gauge systems do not require sutured closure.

78.5.2  Limited Pars Plana Vitrecomy The LPPV can be performed at any point of the procedure according to the indications discussed above. The optimal location to perform a LPPV is in the infero-temporal quadrant. Here access is optimized while preserving superior conjunctiva that will be important if a filtering procedure is required subsequently. Sub-conjunctival injection of anesthetic should provide adequate anesthesia, although patient may feel the MVR incision and should be advised as such. The MVR incision should be 4 mm posterior to the limbus and therefore the peritomy should be created accordingly. The MVR blade should be aimed toward the optic nerve and inserted until visualized posterior to the lens if the density of the cataract permits visualization. If there is significant liquification of the vitreous, fluid may be liberated – the surgeon should look for a flow of fluid out of the sclerostomy site. Digital assessment of the anterior chamber pressure and observed deepening of the AC are objective signs that will indicate to the surgeon if the posterior segment has been significantly decompressed. If minimal to no change has occurred, a LPPV is required. The cut rate should be at the highest frequency setting, the flow rate low (20  cc/min), and vacuum should be minimal (100 mmHg). Bottle height is irrelevant as there is no infusion of fluid into the eye in this procedure. The vitrectomy sequence should be set to ICA (Irrigation-Cut-Aspiration). The vitrector only (any irrigation sleeve should be removed) should be inserted carefully in the same direction as wound

78.5.3  Endocyclophotocoagulation After insertion of the endocapsular IOL insertion, a cohesive OVD is injected in the sulcus. The ECP probe is then inserted through the main wound and the tip is positioned in the sulcus. Through the endoscopic view, laser energy is applied to the ciliary processes, particularly anteriorly to shrink and rotate the processes away from the posterior iris. The energy applied to the ciliary process needs to be titrated to achieve the desired outcome: too little energy will induce little to no effect; too much energy will cause the ciliary process to burst and bleed. The titration of energy is achieved by establishing the correct distance from the tip of the probe to the ciliary process; the distance is inversely proportional to degree of burn. Complications from ECP are usually minimal and selflimiting; small hyphema and prolonged inflammation. Patients should receive a higher frequency of steroids in the immediate post-operative phase until inflammation subsides.

78.5.4  Filtration Procedures Any number of filtration procedures can be performed adjunctive to lens removal, the descriptions of which are beyond the scope of this chapter. One procedural consideration

78  Cataract Extraction as Treatment for Acute and Chronic Angle Closure Glaucomas

worth mentioning is to err on the side of suturing the scleral flap too tight (where applicable). This reduces the risk of post-operative hypotony, flat anterior chamber, and aqueous misdirection; adverse events to which PAC eye are more susceptible.

78.6  Conclusion Primary angle closure glaucoma is a subset of glaucoma that can be cured by the appropriate interventions. The earlier the risk of PAC and PACG are realized by the clinician, the lower the morbidity associated with required intervention, once again emphasizing the vigilance of both establishing better diagnostic criteria as well as performing routine gonioscopy. The aging changes that the crystalline undergoes are central to the pathophysiology of PAC. The age of the patient at the time of presentation often coincides with the development of visual deterioration and presbyopia. Replacement of the crystalline lens with an IOL offers patients a relatively safe and curative procedure that has the ancillary benefit of improving a patient’s vision.

References 1. Foster PJ. The epidemiology of primary angle closure and associated glaucomatous optic neuropathy. Semin Ophthalmol. 2002;17(2): 50–58. Review. 2. Saw SM, Gazzard G, Friedman DS. Interventions for angle-closure glaucoma: an evidence-based update. Ophthalmology. 2003;110(10): 1869–1878. quiz 1878–9, 1930. Review. 3. Aung T, Tow SL, Yap EY, Chan SP, Seah SK. Trabeculectomy for acute primary angle closure. Ophthalmology. 2000;107(7):1298–1302. 4. Lowe RF. Causes of shallow anterior chamber in primary angleclosure glaucoma. Ultrasonic biometry of normal and angle-closure glaucoma eyes. Am J Ophthalmol. 1969;67(1):87–93. 5. Lowe RF. Aetiology of the anatomical basis for primary angle-closure glaucoma. Biometrical comparisons between normal eyes and eyes with primary angle-closure glaucoma. Br J Ophthalmol. 1970;54(3): 161–169. 6. Friedman DS, Gazzard G, Foster P, et al. Ultrasonographic biomicroscopy, Scheimpflug photography, and novel provocative tests in contralateral eyes of Chinese patients initially seen with acute angle closure. Arch Ophthalmol. 2003;121(5):633–642. 7. Markowitz SN, Morin JD. The ratio of lens thickness to axial length for biometric standardization in angle-closure glaucoma. Am J Ophthalmol. 1985;99(4):400–402. 8. Markowitz SN, Morin JD. Angle-closure glaucoma: relation between lens thickness, anterior chamber depth and age. Can J Ophthalmol. 1984;19(7):300–302. 9. Wojciechowski R, Congdon N, Anninger W, Teo Broman A. Age, gender, biometry, refractive error, and the anterior chamber angle among Alaskan Eskimos. Ophthalmology. 2003;110(2):365–375. 10. Ritch R, Liebmann JM, Tellow C. A construct for understanding angle closure glaucoma: the role of ultrasound biomicroscopy. Ophthalmol Clin North Am. 1995;8:281–293.

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11. Campbell DG, Vela A. Modern goniosynechialysis for the treatment of synechial angle-closure glaucoma. Ophthalmology. 1984;91(9): 1052–1060. 12. Hayashi K, Hayashi H, Nakao F, Hayashi F. Changes in anterior chamber angle width and depth after intraocular lens implantation in eyes with glaucoma. Ophthalmology. 2000;107(4):698–703. 13. Kurimoto Y, Park M, Sakaue H, Kondo T. Changes in the anterior chamber configuration after small-incision cataract surgery with posterior chamber intraocular lens implantation. Am J Ophthalmol. 1997;124(6):775–780. 14. Meyer MA, Savitt ML, Kopitas E. The effect of phacoemulsification on aqueous outflow facility. Ophthalmology. 1997;104(8):1221–1227. 15. Kim DD, Doyle JW, Smith MF. Intraocular pressure reduction following phacoemulsification cataract extraction with posterior chamber lens implantation in glaucoma patients. Ophthalmic Surg Lasers. 1999;30(1):37–40. 16. Kooner KS, Cooksey JC, Perry P, Zimmerman TJ. Intraocular pressure following ECCE, phacoemulsification, and PC-IOL implantation. Ophthalmic Surg. 1988;19(9):643–646. 17. Steuhl KP, Marahrens P, Frohn C, Frohn A. Intraocular pressure and anterior chamber depth before and after extracapsular cataract extraction with posterior chamber lens implantation. Ophthalmic Surg. 1992;23(4):233–237. 18. Hansen TE, Naeser K, Rask KL. A prospective study of intraocular pressure four months after extracapsular cataract extraction with implantation of posterior chamber lenses. J Cataract Refract Surg. 1987;13(1):35–38. 19. Hansen TE, Naeser K. Nilsen NE Intraocular pressure 2 1/2 years after extracapsular cataract extraction and sulcus implantation of posterior chamber intraocular lens. Acta Ophthalmol (Copenh). 1991;69(2):225–228. 20. Miyake K, Asakura M, Kobayashi H. Effect of intraocular lens fixation on the blood-aqueous barrier. Am J Ophthalmol. 1984;98(4):451–455. 21. Lam DS, Leung DY, Tham CC, et  al. Randomized trial of early phacoemulsification versus peripheral iridotomy to prevent intraocular pressure rise after acute primary angle closure. Ophthalmology. 2008;115(7):1134–1140. 22. Hata H, Yamane S, Hata S, Shiota H. Preliminary outcomes of primary phacoemulsification plus intraocular lens implantation for primary angle-closure glaucoma. J Med Invest. 2008;55(3–4):287–291. 23. Liu CJ, Cheng CY, Wu CW, Lau LI, Chou JC, Hsu WM. Factors predicting intraocular pressure control after phacoemulsification in angle-closure glaucoma. Arch Ophthalmol. 2006;124(10):1390–1394. 24. Euswas A, Warrasak S. Intraocular pressure control following phacoemulsification in patients with chronic angle closure glaucoma. J Med Assoc Thai. 2005;88(suppl 9):S121–S125. 25. Lai JS, Tham CC, Chan JC. The clinical outcomes of cataract extraction by phacoemulsification in eyes with primary angle-closure glaucoma (PACG) and co-existing cataract: a prospective case series. J Glaucoma. 2006;15(1):47–52. 26. Kubota T, Toguri I, Onizuka N, Matsuura T. Phacoemulsification and intraocular lens implantation for angle closure glaucoma after the relief of pupillary block. Ophthalmologica. 2003;217(5):325–328. 27. Teekhasaenee C, Ritch R. Combined phacoemulsification and goniosynechialysis for uncontrolled chronic angle-closure glaucoma after acute angle-closure glaucoma. Ophthalmology. 1999;106(4):669–674. 28. Harasymowycz PJ, Papamatheakis DG, Ahmed I, et  al. Phacoemulsification and goniosynechialysis in the management of unresponsive primary angle closure. J Glaucoma. 2005;14(3): 186–189. 29. Lai JS, Tham CC, Lam DS. The efficacy and safety of combined phacoemulsification, intraocular lens implantation, and limited goniosynechialysis, followed by diode laser peripheral iridoplasty, in the treatment of cataract and chronic angle-closure glaucoma. J Glaucoma. 2001;10(4):309–315.

912 30. Dada T, Kumar S, Gadia R, Aggarwal A, Gupta V, Sihota R. Sutureless single-port transconjunctival pars plana limited vitrectomy combined with phacoemulsification for management of phacomorphic glaucoma. J Cataract Refract Surg. 2007;33(6): 951–954. 31. Chalam KV, Gupta SK, Agarwal S, Shah VA. Sutureless limited vitrectomy for positive vitreous pressure in cataract surgery. Ophthalmic Surg Lasers Imaging. 2005;36(6):518–522. 32. Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically controlled chronic angle closure glaucoma with cataract. Ophthalmology. 2008;115(12): 2167–2173.

B.U. Khan 33. Yuen NS, Chan OC, Hui SP, Ching RH. Combined phacoemulsification and nonpenetrating deep sclerectomy in the treatment of chronic angle-closure glaucoma with cataract. Eur J Ophthalmol. 2007;17(2): 208–215. 34. Arshinoff SA. Dispersive-cohesive viscoelastic soft shell technique. J Cataract Refract Surg. 1999;25(2):167–173. 35. Razeghinejad MR. Combined phacoemulsification and viscogoniosynechialysis in patients with refractory acute angle-closure glaucoma. J Cataract Refract Surg. 2008;34(5):827–830. 36. Khan B, Ahmed II. Phaco and Goniosynechiolysis using Microforceps for Synechial Angle Closure GlaucomaAmerican Glaucoma Society Meeting; 2006.

Chapter 79

Refractive Surgery and Glaucoma Sarwat Salim and Peter A. Netland

The demand for refractive surgery has escalated over the past decade, and surgical options have been developed for various refractive errors. Although secondary glaucoma is uncommon after refractive surgery, there are concerns related to patients who are glaucoma suspects or who have been diagnosed with glaucoma. This review will address preoperative, intraoperative, and postoperative considerations that clinicians need to be aware of in refractive surgery patients.

may be due to ischemia from compromised blood flow or direct trauma to the optic nerve head.5 Therefore, in patients with susceptible optic nerves, LASIK may not be the ideal procedure, and PRK may be a better alternative since there is no elevated IOP phase in this surgery. In patients presenting with a functional bleb after trabeculectomy, the microkeratome pass during LASIK may destroy the bleb integrity. In such cases, PRK may also be preferable.

79.1  Preoperative Considerations

79.2.1  Postoperative Considerations

Refractive surgery is most commonly performed in young myopes. In some population-based studies, myopia has been identified as a risk factor for the development of glaucoma. In the Blue Mountains Eye Study, glaucoma was almost three times more prevalent in myopes when compared with non-myopes.1 In addition, myopia is a risk factor for steroidinduced ocular hypertension and glaucoma.2 Topical steroids are routinely used in patients after refractive surgery. In photorefractive keratectomy (PRK), steroids may be required for an extended period of time to combat stromal haze and regression, further prolonging the risk – especially in glaucoma suspects and patients with glaucoma.

A significant challenge after refractive surgery relates to obtaining accurate IOP measurements for follow-up visits. It has been well established that corneal thickness has a major influence on IOP measurements.6,7 The Goldmann applanation tonometer (GAT) uses a prism of 3.06 mm in diameter with an estimated average corneal thickness of 520 microns to cancel the opposing forces of surface tension and corneal rigidity to allow indentation. It is now known that a wide variation exists in corneal thickness among individuals. In general, IOP is overestimated in thicker corneas and underestimated in thinner corneas with GAT, depending on the amount of force required to indent the cornea. Excimer laser ablation reshapes the central cornea and alters corneal thickness, curvature, and structure.8,9 The power change of central cornea depends on the degree of treatment, and the resultant thinning leads to underestimation of IOP by GAT. Because error results from both changes in corneal thickness and to a lesser degree, curvature, underestimation of IOP cannot be calculated from nomograms based on thickness alone.10 Although many formulas for IOP correction have been proposed, there is no general consensus on a particular algorithm. One reasonable recommendation is to record the difference between the preoperative IOP and that measured at 3 or 6 months after surgery – allowing adequate time interval for the cornea to heal and stabilize – and use this difference as a correction factor. Another way to overcome imprecise recordings is to use different modalities

79.2  Intraoperative Considerations During laser in situ keratomileusis (LASIK), intraocular pressure (IOP) is markedly elevated in the range of 60–90 mmHg to provide mechanical support and stability to the eye for the microkeratome to form a corneal flap. Although the duration of this dramatic IOP rise is transient, it can vary between surgeons and patients. Cases of optic neuropathy and visual field loss associated with LASIK have been attributed to the effect of markedly high IOP rise on the optic nerve.3,4 Although the exact mechanism of optic nerve damage is not clearly understood, some investigators have speculated that the damage

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for IOP measurements, which are less likely to be affected by surface properties of the cornea. The pneumotonometer, Tono-Pen, and dynamic contour tonometer have been shown to be less or not affected when compared with GAT readings in eyes after refractive surgery.11-13 Because of the difficulties in measuring IOP after procedures that thin the cornea, physicians should be attentive to other parameters of glaucoma evaluation, such as stereoscopic optic nerve assessment, nerve fiber analysis, and visual field testing. In certain patients, it may be helpful to include strategies designed to detect early visual loss, such as short wavelength automated perimetry and frequencydoubling technology perimetry. When ordering scanning laser polarimetry, physicians need to be mindful that corneal refractive surgery may alter the corneal birefringence, affecting the accuracy of this device, especially with the earlier models that lack the variable corneal compensator.14 Recent studies, using individualized corneal polarization compensation or alternative techniques such as optical coherence tomography (OCT), have shown that LASIK-induced corneal alterations did not affect mean nerve fiber layer thickness measurements.15-17 Other concerns in the postoperative period are steroidinduced ocular hypertension and flap-associated complications. Case reports of end stage glaucoma resulting from masking of steroid response due to inaccurate IOP measurement by standard methods have been reported both after PRK and LASIK.18,19 Another condition that may lead to underestimation of IOP after LASIK is the interface cyst.20 The accumulation of fluid under the LASIK flap renders the cornea softer and easily distensible. Lower IOP measurements due to flap interface fluid can mask steroid-induced IOP elevation, resulting in optic nerve damage. Davidson et al described a distinct entity called pressureinduced interlamellar stromal keratitis (PISK) in a patient after uncomplicated LASIK.21 Although the clinical presentation of this condition is similar to diffuse lamellar keratitis (DLK), it usually presents beyond the first postoperative week. Unlike DLK, which resolves with corticosteroid therapy, PISK results from steroid response. Elevated IOP in PISK does not respond to IOP lowering medications, while discontinuation of steroids leads to resolution of both keratitis and elevated IOP.

79.2.2  Other Considerations Glaucoma patients who have had refractive surgery may become candidates for combined cataract and glaucoma surgery at a later time. Availability of accurate lens power calculations is improving, which helps predict the correct intraocular lens (IOL) choice for an individual patient.

S. Salim and P.A. Netland

If unexpected refractive errors are found postoperatively after combined surgery, management choices will include intraocular lens exchange, contact lens, refractive corneal surgery, and piggy-back IOLs. Clear lens extraction may be performed for high myopia, but can be associated with vision loss during the postoperative period. In addition to other potential complications, including retinal detachment, endophthalmitis, and cystoid macular edema, elevated IOP and glaucoma can occur after clear lens extraction for high myopia. In a retrospective study of highly myopic eyes treated with clear lens extraction (without intraocular lens implantation), Rodriguez and coworkers22 reported treatment of 11 of 33 eyes (33%) with anti-glaucoma medications, with secondary glaucoma developing in 8 of 33 (24%) eyes. Severe vision loss with legal blindness due to glaucoma has been reported following clear lens extraction for high myopia.23 Patients treated with lens extraction for high myopia require continued monitoring for glaucoma after the refractive procedure.

79.3  Conclusion Refractive surgery is a rapidly growing sector of ophthalmology. In the average patient, there is probably little or no change of the nerve fiber layer or the optic nerve after the procedure. However, patients with preexisting glaucoma may be more sensitive to transient alterations of IOP during the refractive procedure. IOP should be monitored in patients requiring long-term treatment with steroid drops after refractive procedures. Measurement of IOP should take into account the decreased corneal thickness that occurs after certain refractive procedures, especially LASIK and PRK. Refractive surgery is not contraindicated for glaucoma suspects or glaucoma patients, although opinions vary among corneal and glaucoma specialists about the suitability of individual patients for certain procedures. With multiple choices now available for refractive correction, both patients and physicians have more options. With vigilant screening, detailed informed consent, and meticulous postoperative surveillance, adverse effects can be circumvented and patients are more likely to enjoy the benefits of this advancing technology.

References 1. Mitchell P, Hourihan F, Sandbach J, et al. The relationship between glaucoma and myopia: The Blue Mountains eye Study. Ophthalmology. 1999;106:2010–2015. 2. Podos SM, Becker B, Morton WR. High myopia and primary openangle glaucoma. Am J Ophthalmol. 1966;62:1038–1043.

79  Refractive Surgery and Glaucoma 3. Lee AG, Kohnen T, Ebner R, et  al. Optic neuropathy associated with laser in situ keratomileusis. J Cataract Refract Surg. 2000;26:1581–1584. 4. Bushley DM, Parmley VC, Paglen P. Visual field defect associated with laser in situ keratomileusis. Am J Ophthalmol. 2000;129: 668–671. 5. Lim MC. Refractive surgery and the glaucoma patient: caveat emptor. Int Ophthalmol Clin. 2004;44(2):137–150. 6. Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal thickness. Acta Ophthalmol (Copenh). 1975;53:34–43. 7. Whitacre MM, Stein RA, Hassanein K. The effect of corneal thickness on applanation tonometry. Am J Ophthalmol. 1993;115: 592–596. 8. Chatterjee A, Shah S, Bessant DA, et al. Reduction in intraocular pressure after excimer laser photorefractive keratectomy. Correlation with pretreatment myopia. Ophthalmology. 1997;104:355–359. 9. Fournier AV, Podtetenev M, Lemire J, et  al. Intraocular pressure change measured by Goldmann tonometry after lasik in situ keratomileusis. J Cataract Refract Surg. 1998;24:905–910. 10. Mark HH. Corneal curvature in applanation tonometry. Am J Ophthalmol. 1973;223–224. 11. Zadok D, Tran DB, Twa M, et  al. Pneumotonometry versus Goldmann tonometry after laser in situ keratomileusis for myopia. J Cataract Refract Surg. 1999;25:1344–1348. 12. Garzozi HJ, Chung HS, Lang Y, et al. Intraocular pressure and photorefractive keratectomy: a comparison of three different tonometers. Cornea. 2001;20:33–36. 13. Kaufman C, Bachmann LM, Thiel MA. Intraocular pressure measurements using dynamic contour tonometry after laser in situ keratomileusis. Invest Ophthalmol. 2003;44:3790–3794.

915 14. Gurses-Ozden R, Liebmann JM, Schuffner D, et al. Retinal nerve fiber layer thickness remains unchanged following laser-assisted in situ keratomileusis. Am J Ophthalmol. 2001;132:512–516. 15. Choplin NT, Schallhorn SC, Sinai M, et al. Retinal nerve fiber layer measurements do not change after LASIK for high myopia as measured by scanning laser polarimetry with custom compensation. Ophthalmology. 2005;112:92–97. 16. Zangwill LM, Abunto T, Bowd C, Angeles R, et al. Scanning laser polarimetry retinal nerve fiber layer thickness measurements after LASIK. Ophthalmology. 2005;112:200–207. 17. Halkiadakis I, Anglionto L, Ferensowicz M, et al. Assessment of nerve fiber layer thickness before and after laser in situ keratomileusis using scanning laser polarimetry with variable corneal compensation. J Cataract Refract Surg. 2005;31:1035–1041. 18. Shaikh NM, Shaikh S, Singh K, et al. Progression to end-stage glaucoma after laser in situ keratomileusis. J Cataract Refract Surg. 2002;28:356–359. 19. Kim JH, Sah WJ, Hahn TW, et al. Some problems after photorefractive keratectomy. J Refract Corneal Surg. 1994;10(2 suppl):226–230. 20. Hamilton DR, Manche EE, Rich LF, et  al. Steroid induced glaucoma after laser in situ keratomileusis associated with interface fluid. Ophthalmology. 2002;109:659–665. 21. Davidson RS, Brandt JD, Mannis MJ. Intraocular pressure-induced interlamellar keratitis after LASIK surgery. J Glaucoma. 2003;12: 23–26. 22. Rodriguez A, Guierrez E, Alvira G. Complications of clear lens extraction in axial myopia. Arch Ophthalmol. 1987;105:1522–1523. 23. King JS, Priester B, Netland PA. Pseudophakic glaucoma and vision loss after clear lens extraction for high myopia. Ann Ophthalmol. 2004;36:53–54.

Chapter 80

Glaucoma after Retinal Surgery Annisa L. Jamil, Scott D. Lawrence, David A. Saperstein, Elliott M. Kanner, Richard P. Mills, and Peter A. Netland

Following vitreoretinal surgery, patients may develop elevated intraocular pressure (IOP), which may be due to multiple different mechanisms. Preexisting glaucoma may be a potential cause of any postoperative IOP elevation in patients undergoing treatment for retinal disorders. Neovascularization of the anterior segment from underlying ischemic retinopathy may lead to neovascular glaucoma during the perioperative and postoperative periods. Also, prolonged treatment with topical or intravitreal steroids following retinal surgery can cause a steroid-induced glaucoma in susceptible patients. It is estimated that ocular hypertension occurs after vitreoretinal surgery in 19–28% of cases.1 The increased intraocular pressure may be acute or chronic depending on the underlying pathophysiologic mechanism. Additionally, multiple ocular surgeries increase the risk of temporary or sustained ocular hypertension.2 Frequently, this complication can be easily managed by medical therapy alone; however, some cases may go on to develop a secondary glaucoma requiring surgical intervention. Various vitreoretinal surgical techniques and their relation to elevated intraocular pressure will be examined to define their mechanisms and consider possible interventions for the establishment of intraocular pressure control.

80.1  Scleral Buckle The occurrence of primary open angle glaucoma (POAG) in patients with rhegmatogenous retinal detachments is higher than in the general population alone.3 The prevalence of POAG in patients with retinal detachments is 4.0–5.8% compared to that in the general population which is between 1.1 and 3.0%.4,5 In addition, the placement of a scleral buckle to repair a retinal detachment often results in an elevation of intraocular pressure or secondary glaucoma due to a closed angle mechanism. Postoperative narrowing of the angle has been found in 14.4% of patients after the use of a scleral buckle. In the same study, permanent abnormal intraocular pressure elevation and

narrowing of the angle was seen in 3.75% of cases.6 The incidence of acute angle-closure glaucoma was 1.4% over a 6-year period following scleral buckle.7 Patients with narrow angles or those treated with anteriorly placed buckles or encircling bands may be predisposed to develop angle-closure glaucoma.6 Ciliary body congestion has been postulated as one mechanism, with impaired venous drainage from direct pressure of the buckle, swelling and anterior rotation of the ciliary body, and choroidal effusions, leading to anterior movement of the lens–iris diaphragm, and narrowing of the anterior chamber angle.8 Angle closure in the late postoperative period may occur due to peripheral anterior synechiae. Sato et al. described three cases where there was development of glaucoma despite normal intraocular pressure and normal angle anatomy after scleral buckling surgery.9 Scanning laser Doppler flowmetry at the optic nerve head was measured in eyes with an encircling element and found to be significantly lower than that of the comparable area in fellow eyes. These patients demonstrated visual field defects and glaucomatous optic neuropathy. After the scleral buckle was removed, blood flow improved with no further progression of the disease. When the anterior chamber shallows following scleral buckle, most cases resolve spontaneously within a few days. Acute IOP elevations can be managed with topical or systemic anti-glaucoma medications. Cycloplegics are often employed to deepen the anterior chamber and rotate the ciliary body posteriorly. Adjunctive use of topical steroids may also help to decrease inflammation and prevent the formation of peripheral anterior synechiae. Miotics should be avoided due to the risk of increased inflammation and anterior movement of the lens–iris diaphragm. Surgical treatments include argon laser peripheral iridoplasty as well as drainage of large choroidal effusions. Laser peripheral iridotomy is usually not indicated, as pupillary block is uncommon following scleral buckling procedures. Persistent elevations in intraocular pressure may require revision of the buckle or loosening of the encircling band.

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80.2  Panretinal Photocoagulation Panretinal photocoagulation is routinely used to treat potential or active neovascularization of the anterior and posterior segments. Profound elevations of intraocular pressure at the time of photocoagulation were common with the xenon arc and ruby lasers. Argon laser is considered a safer modality, but the transfer of thermal energy causes an inflammatory cascade that can lead to ciliochoroidal effusions and detachments with anterior rotation of the ciliary body. Subsequent forward shifting of the lens–iris diaphragm may lead to narrowing of the anterior chamber angle with the potential for angle-closure glaucoma.10 The majority of cases of secondary glaucoma following panretinal photocoagulation resolve within several days to 2 weeks.11 However, IOP spikes during the acute postoperative period should be treated with cycloplegics as well as topical and systemic anti-glaucoma medications. Topical steroids may help to decrease the inflammatory stimulus of choroidal effusions.

80.3  Pars Plana Vitrectomy Simple pars plana vitrectomy may be associated with elevated intraocular pressures due to either open angle or closed angle mechanisms. In one study, 43.3% of patients undergoing pars plana vitrectomy had intraocular pressures above 30 mmHg in the acute postoperative period.12 Subjects who demonstrated early IOP spikes had a tendency to sustain high IOP 6 weeks or more after surgery. In another study examining the effects of simple pars plana vitrectomy on IOP in the early postoperative period, 92% of eyes experienced a rise in IOP 2 h after surgery. However, only 39% of them reached an IOP of at least 30 mmHg.13 These findings suggest that there are a significant number of patients with acute elevations in IOP in the first 24 h after surgery followed by normalization of the pressure curve in many patients. The underlying causes of these pressure elevations after vitrectomy may be, in part, related to the interventions performed at the time of surgery. In one series, among the open angle mechanisms, gas expansion without angle closure was the most common cause of acute postvitrectomy IOP elevation followed in descending order by inflammation, silicone oil related (without pupillary block), corticosteroid response, and erythroclastic glaucoma.12 For those who experienced closed angle glaucoma, ciliary body edema causing pupillary block was the most common mechanism followed in descending order by pupillary block secondary to fibrin, gas, and, lastly, silicone oil. Risk factors for IOP elevation delineated in this study include intraoperative or previous scleral buckling, intraoperative scatter endophotocoagulation, intraoperative lensectomy, and postoperative fibrin formation. Surprisingly, a

A.L. Jamil et al.

preexisting history of glaucoma did not increase the overall rate of IOP elevation after a vitrectomy.12 In contrast, Desai and coworkers had found that 60% of ocular hypertensives required pressure reducing medications postoperatively compared to 35% of normotensive patients.13 Medical management can help abate postoperative pressure elevation, and surgical intervention is infrequently required. Although Han et al reported the need for surgical treatment in 11.3% of subjects, no patients required any surgical intervention in the study conducted by Desai et al12,13 When required, surgical interventions included anterior chamber paracentesis, laser peripheral iridotomy, and laser iridoplasty or membranectomy.12

80.4  Intravitreal Gas Intravitreal gas tamponade for repair of retinal detachment can be associated with a significant intraocular pressure spike during the rapid phase of gas expansion. Patients with advanced glaucomatous optic nerve damage or compromised retinal vasculature may be particularly vulnerable to vision-threatening sequelae from increased IOP. Sulfur hexafluoride (SF6) and perfluoropropane (C3F8) achieve retinal tamponade by expanding within the vitreous cavity. Elevated IOP is directly related to the expansile property and final volume of the intraocular gas bubble. Perfluoropropane (C3F8) and sulfur hexafluoride (SF6) are commonly used high molecular weight gases in nonexpansile concentrations of 14% and 18%, respectively.14,15 However, despite these concentrations, pressure spikes are common in the early postoperative period.16,17 The incidence of high intraocular pressure after pars plana vitrectomy and long acting gas tamponade has been reported by Chen and Thompson who found a 43% incidence of pressures greater than 25 mmHg.16 These gases can remain in the eye for 10–14 days for sulfur hexafluoride and up to 55–65 days for perflouropropane.15 Mittra and coworkers found that 52% of their subjects experienced an elevation greater than 25 mmHg and 29% experienced an elevation over 30 mmHg in the first 4 to 6 h after surgery.18 Certain tonometers are preferred when monitoring the IOP after retinal gas tamponade. A gas-filled eye has altered rigidity, which can provide false readings if using the Schiotz tonometer. Also, pneumatic tonometry can underestimate the IOP. Recommended tonometers include the Perkins or Goldmann applanation tonometers. The Tono-Pen (Mentor Inc, Norwell, Massachusetts) is commonly used in practice because of its portability and facility of use in patients with corneal aberrations. It has demonstrated good correlation when compared with a monometer except for cases with pressures exceeding 30 mmHg where it falls short by underestimating the actual intraocular pressure.19

80  Glaucoma after Retinal Surgery

Elevated pressure after the use of intravitreal gas develops by both open and closed angle mechanisms. Angle closure with pupillary block occurs when the anterior displacement of the lens–iris diaphragm results in iris bombe and iridocorneal touch. This mechanism can occur despite the patient assuming a prone position. There are also cases of closed angle glaucoma with the enlarging gas bubble causing iridocorneal apposition without pupillary block. In addition, open angle glaucoma occurs when the rate of expansion of the gas exceeds the rate of egress of the aqueous humor through the trabecular meshwork. Anterior chamber fibrinous exudation has been reported in some patients following intravitreal gas injection. The incidence is increased in diabetics and may lead to pupillary block with angle closure.20 Risk factors for increased intraocular pressure after intravitreal gas tamponade include the concentration of gas used, older patient, postoperative fibrin in the anterior chamber, concurrent use of a scleral buckle, and intraoperative endophotocoagulation.12,16 Nitrous oxide inhaled anesthetics will elute from the blood stream into adjacent gas filled spaces and increase the volume of these spaces. Patients with intraocular gas who receive nitrous oxide during surgery can develop intraocular pressures in excess of 70 mmHg, which can result in artery occlusion, retinal ischemia, and/or infarction. The US Food and Drug Administration (FDA) mandates that all patients treated with intraocular gases wear a medic alert bracelet warning medical practitioners that the patient has gas in their eye and that inhaled nitrous oxide should be avoided during all anesthetic procedures. Patients with intraocular gas should be cautioned against travelling to places where the atmospheric pressure decreases significantly as this can result in dangerous IOP elevations. Generally, it is suggested that these patients do not increase their elevation by 2,500 feet or travel by air where changes in the cabin pressure can instantaneously cause severe elevation of intraocular pressure.21 Mittra and coworkers found that the use of topical aqueous suppressants immediately after surgery significantly reduced the intraocular pressure 4–6  h and one day after surgery when compared against a control group.18 In their study, 9.5% of the control group and none of those who had postoperative instillation of aqueous suppressants required an anterior chamber tap. All patients undergoing intravitreal gas injection should maintain a face-down position following surgery in order to augment the tamponade effect of the gas bubble as well as to decrease anterior displacement of the lens–iris diaphragm. IOP elevations in the initial postoperative period should be treated with topical and systemic anti-glaucoma agents. The treatment of high elevation of IOP is based on the underlying causative mechanisms. If pupillary block is present, an inferior laser peripheral iridotomy is necessary. Angle closure without pupillary block resulting in iridocorneal touch must be treated promptly to prevent the establishment of peripheral anterior

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synechiae. This can be accomplished by partial removal of the intravitreal gas and reformation of the anterior chamber with the help of a viscoelastic. In addition, a paracentesis can immediately lower pressures in the setting where topical medications are ineffective. Air travel in patients who have undergone intravitreal gas tamponade should be avoided until the gas bubble has been completely absorbed.22

80.5  Silicone Oil Silicone oil endotamponade for complex retinal detachments is a common cause of secondary glaucoma. The reported incidence of postoperative IOP elevation following silicone injection has varied, with one report exceeding 50%.23 The highly purified silicone oils that are now available have less toxicity with a presumed reduction in secondary glaucoma. A recent study found a lower incidence (11%) of glaucoma after pars plana vitrectomy with injection of highly purified silicone oil (5,000 centistokes).24 Postoperative IOP elevation was attributed to preexisting glaucoma in 31% of cases and neovascular glaucoma in 29% of patients. Twenty-five percent of patients with postoperative IOP elevation were determined to have silicone oil-related glaucoma due to the presence of silicone oil in the anterior chamber and/or anterior chamber angle. Notably, no eye developed pupillary block with angle closure due to silicone oil, all patients were aphakic or pseudophakic at the time of surgery, and all were exposed to steroids postoperatively.24 Thus, elevated IOP in patients with silicone oil endotamponade may be due to multiple mechanisms. In aphakic patients treated with pars plana vitrectomy and silicone oil injection, inferior peripheral iridectomy has become standard, and has greatly reduced pupillary block as a cause of secondary glaucoma.25 Removal of the entire lens capsule with forceps at the time of vitrectomy may help to eliminate late closure of the iridectomy. A prone position is advocated postoperatively to prevent forward movement of the lens–iris diaphragm. Since it has a lower density than water, the silicone oil tends to accumulate superiorly. Follow-up slit lamp exams should focus on the superior angle, looking for oil droplets. In eyes developing an increased IOP, the IOP increases during the first 3 months following surgery.23,24 Topical and systemic anti-glaucoma medications achieve effective control of intraocular pressure in a majority of patients, and topical steroids are often administered after surgery to control inflammation. Guarded filtration surgery (trabeculectomy) is generally not recommended due to the upward migration of silicone oil as well as conjunctival scarring following pars plana vitrectomy. However, a glaucoma drainage implant is useful for the treatment of elevated IOP in eyes that do not respond to medical therapy.24,26 Transscleral diode cycloablation is

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recommended for patients with a poor visual prognosis and can achieve a reduction in IOP of approximately 49% from baseline IOP with success rates of 44%.27 In patients with elevated IOP after silicone oil endotamponade, removal of the silicone oil may not be enough to resolve the underlying problem.28,29 In a study by Moisseiev and colleagues, removal of the emulsified oil did not change the intraocular pressure in 91% of subjects.29 Silicone oil removal and medications offered IOP control in only 25% of patients in another study.28 Budenz and coworkers found that patients who underwent silicone oil removal with or without glaucoma surgery and those with glaucoma surgery alone experienced satisfactory IOP control.30 Decisions to surgically manage glaucoma in these patients must be thoroughly discussed with the retinal specialist because removal of silicone oil prematurely is associated with a re-detachment rate in 11–33% of eyes.28 In eyes with intractable elevation of IOP after pars plana vitrectomy and silicone oil injection, glaucoma drainage implant surgery can control the IOP in the majority of eyes, when implanted in the inferonasal or inferotemporal quadrant.26 Viscoelastic is used intraoperatively to prevent the loss of silicone oil. This technique is especially helpful in eyes that cannot have the oil removed due to the risk of recurrent retinal detachment. Silicone oil may accumulate around the tube, which is a benign finding that occurs in approximately 40% of eyes (Fig.  80.1).26 Eyes containing silicone oil require prolonged treatment with topical corticosteroids during the postoperative period.

80.6  Conclusion Glaucoma after vitreoretinal surgery is a common reality in clinical practice. Understanding the underlying process helps to determine the required therapy. In most cases, intraocular

Fig.  80.1  Patients who are treated with silicone oil endotamponade and glaucoma drainage implant may accumulate silicone oil adjacent to the tube, which usually does not require treatment

A.L. Jamil et al.

pressure can be controlled medically with surgery as a secondary option. However, as illustrated previously, some chronic pressure elevations may need a surgical intervention. Regardless, these complicated cases necessitate judicious communication with the retina specialist to ensure that all therapeutic goals are achieved on a case-by-case basis.

References 1. Weinberg RS, Peyman GA, Huamonte FU. Elevation of intraocular pressure after pars plana vitrectomy. Arch Klin Exp Ophthalmol. 1976;200:157–161. 2. Tranos P, Asaria R, Aylward W, Sullivan P, Franks W. Long term outcome of secondary glaucoma following vitreoretinal surgery. Br J Ophthalmol. 2004;88:341–343. 3. Scott IU, Gedde SJ, Budenz DL, et al. Baerveldt drainage implants in eyes with a preexisting sclera buckle. Arch Ophthalmol. 2000;118: 1509–1513. 4. Becker B. In discussion of: Smith JL. Retinal detachment and glaucoma. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:731–732. 5. Phelps CD, Burton TC. Glaucoma and retinal detachment. Arch Ophthalmol. 1977;95:418–422. 6. Sebestyen JG, Schepens CL, Rosenthal ML. Retinal detachment and glaucoma. I Tonometric and gonioscopic study of 160 cases. Arch Ophthalmol. 1962;67:736–745. 7. Perez RN, Phelps CD, Burton TC. Angle closure glaucoma following sclera buckling procedures. Trans Am Acad Ophthalmol Otolaryngol. 1976;81:247–252. 8. Chandler PA, Grant WM. Lectures on glaucoma. Philadelphia: Lea and Febiger; 1965:204–207. 9. Sato EA, Shinoda K, Inoue M, Ohtake Y, Kimura I. Reduced choroidal blood flow can induce visual field defect in open angle glaucoma patients without intraocular pressure elevation following encircling scleral buckling. Retina. 2008;28:493–497. 10. Blondeau P, Pavan PR, Phelps CD. Acute pressure elevation following panretinal photocoagulation. Arch Ophthalmol. 1981;99: 1239–1241. 11. Liang JC, Huamonte FU. Reduction of immediate complications after panretinal photocoagulation. Retina. 1984;4:166–170. 12. Han DP, Lewis H, Lambrou FH, Mieler WF. Mechanisms of intraocular pressure elevation after pars plana vitrectomy. Ophthalmology. 1989;96:1357–1362. 13. Desai UR, Alhalel AA, Schiffman RM, Campen TJ, Sundar G, Muhich A. Intraocular pressure elevation after simple pars plana vitrectomy. Ophthalmology. 1997;104:781–785. 14. Peters MA, Abrams GW, Hamilton LH. The nonexpansile, equilibrated concentration of perfluoropropane gas in the eye. Am J Ophthalmol. 1985;100:831–839. 15. Chang S. Intraocular gases. In: Ryan SJ, ed. Retina, vol. 3. St. Louis: CV Mosby; 1989:245. 16. Chen PP, Thompson JT. Risk factors for elevated intraocular pressure after the use of intraocular gases in vitreoretinal surgery. Ophthalmic Surg Lasers. 1997;28:37–42. 17. Chen CJ. Glaucoma after macular hole surgery. Ophthalmology. 1998;105:94–9. 18. Mittra RA, Pollack JS, Dev S, et al. The use of topical aqueous suppressants in the prevention of postoperative intraocular pressure elevation after pars plana vitrectomy with long-acting gas tamponade. Ophthalmology. 2000;107:588–592. 19. Lim JI, Blair NP, Higginbotham EJ, Farber MD, Shaw WE, Garretson BR. Assessment of intraocular pressure in vitrectomized gas-containing eyes. A clinical and monometric comparison of the

80  Glaucoma after Retinal Surgery Tono-Pen to the pneumotonometer. Arch Ophthalmol. 1990;108: 684–688. 20. Abrams GW, Swanson DE, Sabates WI, Goldman AI. The results of sulfur hexafluoride gas in vitreous surgery. Am J Ophthalmol. 1982;94:165–171. 21. Mills MD, Devenyi RG, Lam WC, Berger AR, Beijer CD, Lam SR. An assessment of intraocular pressure rise in patients with gas-filled eyes during simulated air flight. Ophthalmology. 2001;108:40–44. 22. Diecket JP, O’Connor PS, Schacklett DE, et  al. Air travel and intraocular gas. Ophthalmology. 1986;93:642–645. 23. deCorral LR, Cohen SB, Peyman GA. Effect of intravitreal silicone oil on intraocular pressure. Ophthalmic Surg. 1987;18:446–449. 24. Al-Jazzaf AM, Netland PA, Charles S. Incidence and management of elevated intraocular pressure after silicone oil injection. J Glaucoma. 2005;14:40–46. 25. Ando F. Intraocular hypertension resulting from pupillary block by silicone oil. Am J Ophthalmol. 1985;99:87–88.

921 26. Ishida K, Ahmed IK, Netland PA. Ahmed glaucoma valve surgical outcomes in eyes with and without silicone oil endotamponade. J Glaucoma. 2009;18:325–330. 27. Sivagnanavel V, Ortiz-Hurtado A, Williamsom TH. Diode laser trans-scleral cyclophotocoagulation in the management of glaucoma in patients with long-term intravitreal silicone oil. Eye. 2005;19:253–257. 28. Honavar SG, Goyal M, Majji AB, Sen PK, Naduvilath T, Dandona L. Glaucoma after pars plana vitrectomy and silicone oil injection for complicated retinal detachments. Ophthalmology. 1999;106:169–177. 29. Moisseiev J, Barak A, Manaim T, Triester G. Removal of silicone oil in the management of glaucoma in eyes with emulsified silicone. Retina. 1993;13:290–295. 30. Budenz DL, Taba KE, Feuer WJ, et  al. Surgical management of secondary glaucoma after pars plana vitrectomy and silicone oil injection for complex retinal detachment. Ophthalmology. 2001;108: 1628–1632.

Part VI

The Future

Chapter 81

Immunology and Glaucoma Michal Schwartz and Anat London

Glaucoma, although once thought of as a single disease, is actually a group of diseases of the optic nerve involving loss of retinal ganglion cells. The process of cell death occurs in a characteristic pattern of optic neuropathy – a broad term for a certain pattern of damage to the optic nerve (the bundle of nerve fibers that carries information from the eye to the brain). Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss that can progress to permanent blindness.

81.1  G  laucoma as a Neurodegenerative Disease Traditionally, elevation in intraocular pressure (IOP) has been considered to be the main cause of glaucoma.1 IOP is determined by the balance between secretion and drainage of aqueous humor. In glaucoma, this balance is interrupted, as insufficient fluid drains out of the eye, leading to increased IOP. As a result, the retina and the optic nerve heads are subjected to mechanical,2,3 hypoxic,4 and oxidative tissue stress.5 Over the past decades, scientists have focused on elevated IOP as a primary therapeutic target, trying to diminish this major risk factor,6–10 while totally disregarding the process of damage that derives from it. Consequently, the currently approved glaucoma medications and surgical therapies are directed at lowering IOP; and, indeed, there is evidence from several clinical trials for a significant attenuation of progressive visual field loss among the treated patients.6–8,11 However, some patients continued to suffer from an ongoing visual field loss even after their IOP was effectively controlled.12–14 Even more confusing is the case of normal tension glaucoma (NTG), in which progressive retinal ganglion cell death and subsequent glaucomatous damage occurs in the absence of any elevated IOP. Moreover, some studies have reported a negligible relationship between mean IOP and vision loss in glaucoma.15–17 These observations indicate the possible contribution of IOP-independent mechanisms to disease progression.

It seems, therefore, that glaucoma is a complex multivariate disease, initiated by several risk factors (with elevated IOP as only one of them), whose individual contributions to glaucomatous destruction have not yet been fully elucidated. As a result, the efforts of researchers have shifted toward understanding and subsequently preventing the disease progression, regardless of the primary cause. Thus, the major goal of glaucoma treatment is moving to neuroprotection, preventing the spread of damage, and protection from the progressive loss of the nerve fiber layers.18,19 There are many molecular and cellular elements that contribute to the pathological progression and neuronal loss in glaucoma, even after the primary risk factor no longer exists. Following the initial insult, there is a progressive self-perpetuating secondary degeneration of neurons that were spared from the primary injury. This secondary damage is an outcome of the hostile environment produced by the degenerating neurons. The noxious extracellular environment includes mediators of oxidative stress and free radicals, excessive amounts of glutamate and excitotoxicity, increased calcium concentration, deprivation of neurotrophins and growth factors, abnormal accumulation of proteins, and apoptotic signals (Scheme 81.1), all of which are universal features of many neurodegenerative diseases.20 These characteristics place glaucoma among the common neurodegenerative disorders.

81.1.1  Oxidative Stress and Free Radicals Oxidative stress is involved in the pathogenesis of many neurodegenerative disorders.21–27 The central nervous system (CNS) has a unique sensitivity to oxidative stress. Its function requires electrical excitability, transsynaptic chemical connections, and a high metabolic rate, that involves the augmented use of oxygen and adenosine triphosphate (ATP) synthesis. In addition, the CNS lacks an appropriate defense system against the elevated levels of reactive oxygen species (ROS) produced in these tissues. These ROS, accumulating in cells that undergo oxidative stress, react with nitric oxide

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_81, © Springer Science+Business Media, LLC 2010

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Scheme 81.1  Immune protection in glaucoma Degenerating neurons create a noxious milieu, which consists of oxidative stress and free radicals, excessive amounts of glutamate and excitotoxicity, increased calcium concentration, deprivation of neurotrophins and growth factors, abnormal accumulation of proteins, and apoptotic signals. These features are characteristics of a hostile microenvironment to the remaining neurons that leads to secondary degeneration and further loss of neurons.

to produce free radicals, leading to a chain of reactions that result in mitochondrial dysfunction, DNA degradation, and eventually cell death. As in Alzheimer’s disease,24,27 Parkinson’s,23 and amyotrophic lateral sclerosis (ALS),21,22 the association of oxidative stress with neurodegeneration has been increasingly reported in glaucoma. Free radicals cause extensive damage to the retinal ganglion cells and their axons28–30; they contribute to the secondary degeneration by either a direct neurotoxic effect, or indirectly through the induction of glial dysfunction,31 oxidative modification of proteins,32 and activation of apoptotic pathways.33 Oxygenderived free radicals are therefore an important therapeutic target for treating glaucoma. A variety of antioxidants34,35 and nitric oxide synthase (NOS)-inhibitors36 are currently being investigated as potential therapeutic agents.

81.1.2  E  xcessive Glutamate, Increased Calcium Levels, and Excitotoxicity Glutamate is an essential neurotransmitter, participating in a variety of neurological processes in the CNS.37,38 It is also the main excitatory neurotransmitter in the retina and is involved in photo-transduction.39 Excessive levels of glutamate are toxic and detrimental to neurons; an excess of glutamate can hyperactivate the N-methyl-d-aspartate (NMDA) receptor, resulting in a poisonous influx of calcium40 – a phenomenon termed excitotoxicity.41,42 In glaucoma, the initially degenerating neurons expel their glutamate stores into the extracellular environment, thereby damaging their still healthy neighboring neurons. Moreover, Muller glial cells, which normally take up glutamate, fail to do so in glaucoma,43 and thus glutamate levels continue to escalate, leading to retinal ganglion cell death.44,45 Excitotoxicity is also common in other neurodegenerative diseases and neurological disorders including ALS,46 Alzheimer’s,47,48 Parkinson’s,49,50 stroke, and Huntington’s disease.38,51 Blocking NMDA receptors by a glutamate antagonist can prevent the glaucomatous excitatory damage.52

The immune system plays a key role in the ability of the optic nerve and the retina to withstand these threatening conditions, by recruiting both innate (resident and blood-borne macrophages) and adaptive (self-antigens specific T cells) cells that together create a protective niche and, thereby, halt disease progression. The spontaneous immune response might not be sufficient, and therefore boosting it by immunization (with the appropriate antigen, in specific timing and dosing) may be a suitable therapeutic vaccination to treat glaucoma.

However, because glutamate is a fundamental neurotransmitter vital for the normal maintenance of the retina and essential to many CNS functions,37 the blockage of its receptor is accompanied by many side effects. Another approach is to focus on the increased influx of calcium, caused by the excess of glutamate and the hyperstimulation of voltage-gated calcium channels.51,53 Indeed, some calcium channel blockers have been shown to reduce retinal damage.54,55

81.1.3  D  eprivation of Neurotrophins and Growth Factors Neurotrophins are crucial for the normal maintenance of the CNS. These factors are required by all types of neurons including retinal ganglion cells (RGCs). They are produced in the superior colliculus and lateral geniculate nucleus in the brain and delivered along the optic nerve to the RGCs. Any interference with this neurotrophin supply could lead to neuronal damage. Ganglion cells are supported by brain-derived neurotrophic factor (BDNF), which delays apoptosis and prevents secondary degeneration.56–60 Moreover, retinal cells respond to ciliary nerve trophic factor (CNTF) and fibroblast growth factor (FGF).61 In glaucoma, retrograde and anterograde axonal transport are defective, often resulting in an insufficient supply of neurotrophins and growth factors to the retinal ganglion cells, leading to their apoptotic breakdown. Administration of neurotrophins can protect the retinal ganglion cells and prevent their programmed cell death.56–60

81.1.4  Abnormal Accumulation of Proteins A shared feature among many of the neurodegenerative diseases is the abnormal increased accumulation of certain selfproteins during disease progression. The accumulation of beta-amyloid protein in the senile plaques in Alzheimer’s

81  Immunology and Glaucoma

and of alpha synuclein protein in Parkinson’s are among the main characteristics of each of these diseases.62 The abnormal processing of amyloid precursor protein has also been reported in glaucoma.63 This is in addition to the oxidatively modified proteins that are produced during glaucomatous neurodegeneration.32 Drug candidates that inhibit aggregation are now being tested in the clinic for the treatment of Alzheimer’s and Parkinson’s, and might also serve in the future as a therapy for glaucoma.62,64

81.1.5  Apoptotic Signals The final outcome of disease progression is the enhanced activation of programmed cell death pathways among retinal ganglion cells. In a normal cell, a balance is maintained between pro-apoptotic and anti-apoptotic proteins. During disease progression, this balance is interrupted and there is an increase in the proportion of pro-apoptotic signals. This is manifested by the upregulation of the expression of proapoptotic genes, such as bax,65 in parallel to the downregulation of the anti-apoptotic genes, such as bcl-xL.66 Following the initial death signal, there is a rapid cascade of caspase activation that eventually results in a noninflammatory cell death.67–69 The programmed cell death cycle of retinal cells is an interesting potential therapeutic target, though caution should be taken when considering this approach, since any anti-apoptotic agent can also serve as a potential carcinogen.

81.2  P  harmacological Neuroprotection for Glaucoma The features described previously, presenting the toxic environment that is one of the well-known characteristics of neurodegenerative diseases, are also associated with glaucoma. This hostile environment might explain the fact that in glaucoma, as in other neurodegenerative disorders, primary cell death is followed by the secondary degeneration of surrounding neurons that were affected by the toxic microenvironment caused by the initial dying cells. This spread of damage, as a part of disease progression, is one of the hallmarks of neurodegenerative diseases, and can be clearly seen in glaucoma. We, as well as others, have proposed that the factors contributing to this ongoing degeneration are physiological compounds emerging in toxic quantities from the injured fibers or their cell bodies. Studies along these lines have revealed that some of the compounds identified in the pathogenesis of glaucoma are already known to be active in other neurodegenerative diseases. The many common

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features between the neurodegenerative diseases and glaucoma have led to the recognition of glaucoma as a neurodegenerative disease, rather than simply a disease of elevated ocular pressure.70–72 This raises the possibility of utilizing similar therapeutic approaches for glaucoma that are currently being used in other neurodegenerative disorders.20 Indeed, treatments used for Alzheimer’s and Parkinson’s are becoming more relevant to glaucoma; for example, Memantine, an NMDA channel blocker, used as a therapy for Alzheimer’s and Parkinson’s diseases, was evaluated for glaucoma treatment but ultimately failed to meet critical endpoints. It is likely that as our recognition of glaucoma as a neurodegenerative disease increases, more of the newly developed therapies will be based on neuroprotection,73,74 fighting against the spread of damage and degeneration of retinal ganglion cells.

81.3  P  rotection of the Retinal Ganglion Cells Involves the Immune System The CNS was always viewed as an “immune privileged” site, in which any immune response was considered harmful, and was usually associated with a disease or other malfunction. Our own studies of acute and chronic injuries to the rodent optic nerve led us to the unexpected discovery that the immune system plays a key role in the ability of the optic nerve and the retina to withstand injurious conditions. Our first observations that the immune system (in the form of T cells directed to certain self-antigens) can protect injured neurons from death came from studies in rodents showing that passive transfer of T cells specific to myelin basic protein (MBP) reduces the loss of retinal ganglion cells (RGCs) after traumatic optic nerve injury.75 We found that these T cells are also effective when directed to either cryptic or pathogenic epitopes of MBP, as well as toward other myelin-derived antigens or their epitopes.76,77 These findings raised a number of critical questions. For example, are myelin antigens capable of protecting the visual system from all types of acute or chronic insults? Is the observed neuroprotective activity of immune cells merely an artifact of our experimental system, or does it indicate the critical participation of the immune system in fighting off injurious conditions in the visual system and in the CNS in general? If the latter is true, does that mean that glaucoma is a systemic disease? And if so, can this finding be translated into a systemic therapy that would protect the eye? In a series of experiments carried out over almost a decade, we have learned much about the role of the immune response in neuroprotection. We first learned that the injury-induced response of T cells reactive to specific self-antigens residing in the site of stress (eye or brain) is a spontaneous physiological

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response that protects the nerve against the degenerative effects of the hostile environment – a concept that was established in our lab and named “protective autoimmunity.”78 Unfortunately, this protective response might not always be sufficient or properly controlled, which might explain the minimal spontaneous recovery following many severe CNS insults, including the damage that occurs in glaucoma. Secondly, we discovered that the specificity of such protective T cells depends on the site of the insult and type of cells damaged. Thus, for example, the protective effect of vaccination with myelin-associated antigens is restricted to injuries of the white matter; i.e., to myelinated axons.77,79,80 If the insult is to the retina, which contains no myelin, myelin-related antigens have no effect. We also sought to identify the phenotype of the beneficial autoimmune T cells, and to understand what determines the balance between a beneficial (neuroprotective) outcome of the T cell-mediated response to a CNS injury and a destructive effect causing autoimmune disease. Finally, we examined ways of translating the beneficial response into a therapy for glaucoma. Some critical aspects of this approach had to be addressed along the way: (1) We verified that the loss of RGCs in a rat model of high intraocular pressure (IOP), simulating some types of glaucoma, is T cell-dependent81; (2) We attempted to determine whether the specific self-antigens that are harnessed by the protective autoimmune T cells in our rat model of chronic glaucoma, and which can be boosted for therapeutic purposes, reside in the retina or the optic nerve82; and, finally, (3) We searched for an antigen that would be able to safely boost the physiological response without causing autoimmune disease. Using a rat model of elevated intraocular pressure, we showed that a protective response could be obtained only with an antigen residing in the retina, suggesting that, at least in this model, the site of self-perpetuating degeneration, and therefore the site in need of protection, is not the optic nerve but the retina.79,82 We further determined that in immunedeficient animals, the number of surviving retinal ganglion cells following an insult of elevated IOP is significantly lower than in matched controls with an intact immune system. This suggests that the ability to withstand insult to the optic nerve or to the retina depends on the integrity of the immune system, and particularly on the specific cell population within the immune system that recognizes the site-specific self-antigens. Interestingly, treatment with steroids, which have an immunosuppressant effect, caused a significant loss of RGCs.82 Moreover, in a model of RGC loss induced by non-IOP conditions (for example uveitis), steroids, which alleviate the inflammatory manifestations of the uveitis, not only failed to protect RGCs but even caused further death. These results prompted us to suggest that the well-controlled boosting of the T cell response might protect RGCs, even under conditions of normal tension glaucoma as well as in uveitis.

M. Schwartz and A. London

81.3.1  T  cells Specific to Antigens Residing in the Site of Damage Help Clean and Heal To manifest their protective effects, anti-self T cells should home to the site of damage and be locally activated. This is why only those antigens that are present at the site of lesion can be used for the vaccination. Once activated, the T cells provide a source of cytokines and growth factors, which create the proper niche for microglia and infiltrating bloodborne monocytes, so as to make them active protective cells that the eye can tolerate (Scheme 81.1). Namely, such activated microglia/macrophages can take up glutamate, remove debris, and produce growth factors; additionally, they do not produce agents that are part of their cytotoxic mechanism, such as TNFa, which the eye, like the brain tolerates poorly.83–87 Such T cells are constitutively controlled by regulatory T cells that are part of the physiological immune network and are themselves amenable to control upon need.88,89

81.4  S  earching for an Antigen for Potential Glaucoma Therapy Among the many immunomodulatory compounds that we tested for therapy of glaucoma was glatiramer acetate (GA), also known as Copaxone, a synthetic 4-amino-acid copolymer, currently used as a treatment (administered according to a daily regimen) for multiple sclerosis. We chose to test this compound because of its low-affinity cross-reaction with a wide range of self-antigens residing in the CNS. In the rat model of chronically high IOP, vaccination with GA significantly reduces RGC loss even if the IOP remains high. Vaccination does not prevent disease onset, but rather slows down the progression of the RGC loss by controlling the milieu of the nerve and retina, making it less hostile to neuronal survival and allowing the RGCs to better withstand the stress.79,88,90–92 In our initial studies, we used GA emulsified in complete Freund’s adjuvant (CFA).79 We subsequently found that in models of optic nerve insults and in models of spinal cord injury, regardless of the choice of the antigens, the type of adjuvant (amount of mycobacteria), the timing of the vaccination, and the dosing critically affect the outcome.93–95 In subsequent studies in a model of IOP, we tested adjuvantfree GA, and found that GA is effective even without an adjuvant, but the onset of the treatment, the frequency, and the dosing are critical.94 Given that a self-perpetuating degeneration is a multiparameter disease in which numerous factors are participating, it seems that a therapy involving the well-controlled activation of the immune system can provide a multidimensional effectual treatment. For chronic

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81  Immunology and Glaucoma

Fig. 81.1  Factors contributing to glaucoma versus immune responses

treatment, daily, weekly, and monthly regimens were tested; no benefit was found in daily injection, while weekly and monthly treatments were effective.94

81.5  Conclusion During the past decade, scientists and clinicians began to accept that glaucoma should not be viewed as a distinct syndrome with its own peculiar features, but as one of the large group of neurodegenerative disorders of the central nervous system (CNS). Regardless of the primary source of tissue injury, degeneration may continue due to the loss of equilibrium that exists between the initial insult and the ability of the eye to withstand it. As described previously, this stage of equilibrium is generally managed by the immune system (Fig. 81.1). According to our view, rather than or in addition to fighting off the risk factor(s), there is a need to protect the tissue from the ongoing spread of damage, an approach collectively termed “Neuroprotection.”18 This view of glaucoma has led to major changes in the nature of glaucoma research, the way in which clinicians perceive the disease, and the approach to therapy. One comprehensive approach is to harness the immune system, which if properly controlled can be used to modulate the local milieu, so as to become protective rather than hostile to the RGCs (Scheme 81.1). Such selective

immune activation can address the multiple risk factors contributing to the glaucomatous degeneration process. Currently, more specific antigens are being tested as possible candidates for specific immune therapy of glaucoma.

References 1. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363:1711–1720. 2. Burgoyne CF, Downs JC, Bellezza AJ, et al. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res. 2005;24:39–73. 3. Sigal IA, Flanagan JG, Ethier CR. Factors influencing optic nerve head biomechanics. Invest Ophthalmol Vis Sci. 2005;46: 4189–4199. 4. Tezel G, Wax MB. Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol. 2004; 122:1348–1356. 5. Tezel G, Hernandez R, Wax MB. Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes. Arch Ophthalmol. 2000;118:511–518. 6. Quigley HA, Maumenee AE. Long-term follow-up of treated openangle glaucoma. Am J Ophthalmol. 1979;87:519–525. 7. Kass MA, Heuer DK, Higginbotham EJ, et  al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120: 701–713. discussion 829–730.

930 8. Leske MC, Heijl A, Hussein M, et  al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121:48–56. 9. Johnson EC, Cepurna WO, Jia L, et al. The use of cyclodialysis to limit exposure to elevated intraocular pressure in rat glaucoma models. Exp Eye Res. 2006;83:51–60. 10. Nickells RW, Schlamp CL, Li Y, et al. Surgical lowering of elevated intraocular pressure in monkeys prevents progression of glaucomatous disease. Exp Eye Res. 2007;84:729–736. 11. Heijl A, Leske MC, Bengtsson B, et  al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–1279. 12. Jay JL, Allan D. The benefit of early trabeculectomy versus conventional management in primary open angle glaucoma relative to severity of disease. Eye. 1989;3(Pt 5):528–535. 13. Nouri-Mahdavi K, Brigatti L, Weitzman M, et al. Outcomes of trabeculectomy for primary open-angle glaucoma. Ophthalmology. 1995;102:1760–1769. 14. Brubaker RF. Delayed functional loss in glaucoma. LII Edward Jackson Memorial Lecture. Am J Ophthalmol. 1996;121:473–483. 15. Richler M, Werner EB, Thomas D. Risk factors for progression of visual field defects in medically treated patients with glaucoma. Can J Ophthalmol. 1982;17:245–248. 16. Schulzer M, Drance SM, Carter CJ, et al. Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol. 1990;74:196–200. 17. Chauhan BC, Drance SM. The relationship between intraocular pressure and visual field progression in glaucoma. Graefes Arch Clin Exp Ophthalmol. 1992;230:521–526. 18. Schwartz M, Belkin M, Yoles E, et al. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. J Glaucoma. 1996;5:427–432. 19. Schwartz M. Neurodegeneration and neuroprotection in glaucoma: development of a therapeutic neuroprotective vaccine: the friedenwald lecture. Invest Ophthalmol Vis Sci. 2003;44:1407–1411. 20. Schwartz M. Lessons for glaucoma from other neurodegenerative diseases: can one treatment suit them all? J Glaucoma. 2005;14:321–323. 21. Beckman JS, Carson M, Smith CD, et al. ALS, SOD and peroxynitrite. Nature. 1993;364:584. 22. Abe K, Pan LH, Watanabe M, et al. Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neurosci Lett. 1995;199:152–154. 23. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–989. 24. Castegna A, Thongboonkerd V, Klein JB, et al. Proteomic identification of nitrated proteins in Alzheimer’s disease brain. J Neurochem. 2003;85:1394–1401. 25. Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med. 2004;10(Suppl):S18–S25. 26. Potashkin JA, Meredith GE. The role of oxidative stress in the dysregulation of gene expression and protein metabolism in neurodegenerative disease. Antioxid Redox Signal. 2006;8:144–151. 27. Sultana R, Poon HF, Cai J, et al. Identification of nitrated proteins in Alzheimer’s disease brain using a redox proteomics approach. Neurobiol Dis. 2006;22:76–87. 28. Oku H, Yamaguchi H, Sugiyama T, et al. Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit. Invest Ophthalmol Vis Sci. 1997;38:2540–2544. 29. Levkovitch-Verbin H, Harris-Cerruti C, Groner Y, et al. RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection. Invest Ophthalmol Vis Sci. 2000;41:4169–4174. 30. Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Retin Eye Res. 2006;25:490–513. 31. Tezel G, Wax MB. Glial modulation of retinal ganglion cell death in glaucoma. J Glaucoma. 2003;12:63–68.

M. Schwartz and A. London 32. Tezel G, Yang X, Cai J. Proteomic identification of oxidatively modified retinal proteins in a chronic pressure-induced rat model of glaucoma. Invest Ophthalmol Vis Sci. 2005;46:3177–3187. 33. Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002;192:1–15. 34. Ritch R. Potential role for Ginkgo biloba extract in the treatment of glaucoma. Med Hypotheses. 2000;54:221–235. 35. Siu AW, Maldonado M, Sanchez-Hidalgo M, et al. Protective effects of melatonin in experimental free radical-related ocular diseases. J Pineal Res. 2006;40:101–109. 36. Neufeld AH, Sawada A, Becker B. Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A. 1999;96:9944–9948. 37. Sahai S. Glutamate in the mammalian CNS. Eur Arch Psychiatry Clin Neurosci. 1990;240:121–133. 38. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994;330:613–622. 39. Tsacopoulos M, Poitry-Yamate CL, MacLeish PR, et al. Trafficking of molecules and metabolic signals in the retina. Prog Retin Eye Res. 1998;17:429–442. 40. Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res. 1997;37:3483–3493. 41. Siliprandi R, Canella R, Carmignoto G, et al. N-methyl-d-aspartateinduced neurotoxicity in the adult rat retina. Vis Neurosci. 1992; 8:567–573. 42. Dreyer EB. A proposed role for excitotoxicity in glaucoma. J Glaucoma. 1998;7:62–67. 43. Napper GA, Pianta MJ, Kalloniatis M. Reduced glutamate uptake by retinal glial cells under ischemic/hypoxic conditions. Vis Neurosci. 1999;16:149–158. 44. Olney JW. Glutaate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol. 1969;28:455–474. 45. Olney JW, Price MT, Samson L, et al. The role of specific ions in glutamate neurotoxicity. Neurosci Lett. 1986;65:65–71. 46. Van Den Bosch L, Van Damme P, Bogaert E, et al. The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762:1068–1082. 47. Riederer P, Hoyer S. From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain. J Neural Transm. 2006;113:1671–1677. 48. Lipton SA. Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation. Curr Drug Targets. 2007;8:621–632. 49. Beal MF. Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol. 1998;44:S110–114. 50. Lancelot E, Beal MF. Glutamate toxicity in chronic neurodegenerative disease. Prog Brain Res. 1998;116:331–347. 51. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–634. 52. Stuiver BT, Douma BR, Bakker R, et  al. In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine: combined therapy and temporal course of protection. Neurodegeneration. 1996;5:153–159. 53. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988;11:465–469. 54. Takahashi K, Lam TT, Edward DP, et  al. Protective effects of flunarizine on ischemic injury in the rat retina. Arch Ophthalmol. 1992;110:862–870. 55. Bath CP, Farrell LN, Gilmore J, et al. The effects of ifenprodil and eliprodil on voltage-dependent Ca2+ channels and in gerbil global cerebral ischaemia. Eur J Pharmacol. 1996;299:103–112. 56. Mansour-Robaey S, Clarke DB, Wang YC, et al. Effects of ocular injury and administration of brain-derived neurotrophic factor on

81  Immunology and Glaucoma survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994;91:1632–1636. 57. Peinado-Ramon P, Salvador M, Villegas-Perez MP, et al. Effects of axotomy and intraocular administration of NT-4, NT-3, and brainderived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Invest Ophthalmol Vis Sci. 1996;37:489–500. 58. Gao H, Qiao X, Hefti F, et al. Elevated mRNA expression of brainderived neurotrophic factor in retinal ganglion cell layer after optic nerve injury. Invest Ophthalmol Vis Sci. 1997;38:1840–1847. 59. Klocker N, Cellerino A, Bahr M. Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells in vivo. J Neurosci. 1998;18:1038–1046. 60. Rocha M, Martins RA, Linden R. Activation of NMDA receptors protects against glutamate neurotoxicity in the retina: evidence for the involvement of neurotrophins. Brain Res. 1999;827:79–92. 61. Unoki K, LaVail MM. Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor. Invest Ophthalmol Vis Sci. 1994;35:907–915. 62. Lansbury PT, Lashuel HA. A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature. 2006; 443:774–779. 63. McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA, et al. Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci. 2002;43:1077–1087. 64. Weydt P, La Spada AR. Targeting protein aggregation in neurodegeneration – lessons from polyglutamine disorders. Expert Opin Ther Targets. 2006;10:505–513. 65. Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell. 1994;79:189–192. 66. Levin LA, Schlamp CL, Spieldoch RL, et al. Identification of the bcl-2 family of genes in the rat retina. Invest Ophthalmol Vis Sci. 1997;38:2545–2553. 67. Thornberry NA. Caspases: key mediators of apoptosis. Chem Biol. 1998;5:R97–103. 68. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–1316. 69. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res. 1999;18:39–57. 70. Gupta N, Yucel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol. 2007;18:110–114. 71. Mozaffarieh M, Flammer J. Is there more to glaucoma treatment than lowering IOP? Surv Ophthalmol. 2007;52(Suppl 2):S174–179. 7 2. Nickells RW. From ocular hypertension to ganglion cell death: a heoretical sequence of events leading to glaucoma. Can J Ophthalmol. 2007;42:278–287. 73. Hartwick AT. Beyond intraocular pressure: neuroprotective strategies for future glaucoma therapy. Optom Vis Sci. 2001;78:85–94. 74. Chidlow G, Wood JP, Casson RJ. Pharmacological neuroprotection for glaucoma. Drugs. 2007;67:725–759. 75. Moalem G, Leibowitz-Amit R, Yoles E, et al. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med. 1999;5:49–55. 76. Fisher J, Levkovitch-Verbin H, Schori H, et  al. Vaccination for neuroprotection in the mouse optic nerve: implications for optic neuropathies. J Neurosci. 2001;21:136–142. 77. Mizrahi T, Hauben E, Schwartz M. The tissue-specific self-pathogen is the protective self-antigen: the case of uveitis. J Immunol. 2002; 169:5971–5977.

931 78. Yoles E, Hauben E, Palgi O, et al. Protective autoimmunity is a physiological response to CNS trauma. J Neurosci. 2001;21:3740–3748. 79. Schori H, Kipnis J, Yoles E, et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci U S A. 2001;98:3398–3403. 80. Avidan H, Kipnis J, Butovsky O, et al. Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells. Eur J Immunol. 2004;34:3434–3445. 81. Bakalash S, Kipnis J, Yoles E, et al. Resistance of retinal ganglion cells to an increase in intraocular pressure is immune-dependent. Invest Ophthalmol Vis Sci. 2002;43:2648–2653. 82. Bakalash S, Kessler A, Mizrahi T, et  al. Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma. Invest Ophthalmol Vis Sci. 2003;44:3374–3381. 83. Moalem G, Gdalyahu A, Shani Y, et al. Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J Autoimmun. 2000;15:331–345. 84. Butovsky O, Hauben E, Schwartz M. Morphological aspects of spinal cord autoimmune neuroprotection: colocalization of T cells with B7–2 (CD86) and prevention of cyst formation. FASEB J. 2001;15:1065–1067. 85. Barouch R, Schwartz M. Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J. 2002;16: 1304–1306. 86. Butovsky O, Talpalar AE, Ben-Yaakov K, et al. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFNgamma and IL-4 render them protective. Mol Cell Neurosci. 2005;29:381–393. 87. Shaked I, Tchroesh D, Gersner R, et  al. Protective autoimmunity: interferon-gamma enables microglia to remove glutamate without evoking inflammatory mediators. J Neurochem. 2005;92:997–1009. 88. Kipnis J, Mizrahi T, Hauben E, et al. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci USA. 2002;99:15620–15625. 89. Kipnis J, Cardon M, Avidan H, et  al. Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration. J Neurosci. 2004;24:6133–6143. 90. Kipnis J, Yoles E, Porat Z, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci U S A. 2000;97:7446–7451. 91. Benner EJ, Mosley RL, Destache CJ, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004;101:9435–9440. 92. Schwartz M. Modulating the immune system: a vaccine for glaucoma? Can J Ophthalmol. 2007;42:439–441. 93. Hauben E, Agranov E, Gothilf A, et al. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001; 108:591–599. 94. Bakalash S, Shlomo GB, Aloni E, et al. T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure. J Mol Med. 2005;83:904–916. 95. Blair M, Pease ME, Hammond J, et al. Effect of glatiramer acetate on primary and secondary degeneration of retinal ganglion cells in the rat. Invest Ophthalmol Vis Sci. 2005;46:884-890.

Chapter 82

How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers Paul A. Knepper, Michael J. Nolan, and Beatrice Y. J. T. Yue

Multiple biomarker panels of common, multifactorial diseases – such as cardiovascular1-3 and Alzheimer’s disease4,5 – have recently been described, facilitating the diagnosis and risk management of these diseases. In principle, a biomarker is an indicator of a biochemical feature or facet that can be used to diagnose or monitor the progress of a disease.6 Detection technology has been identified for possible types of biomarkers in primary open-angle glaucoma (POAG).7 We will summarize known biomarkers with the intent of cataloging the biomarkers in the aqueous humor, trabecular meshwork (TM), optic nerve, and blood in patients with POAG. To facilitate comparisons and to offer mechanistic clues, biochemical changes such as up- or downregulation of proteins that have been reported in POAG are organized into three categories: namely, extra­ cellular matrix (ECM) changes, cytokine/signaling molecules, and aging/stress (listed respectively in Tables 82.1,8–23 82.2,24–33 and 82.334–46). POAG is the most common type of glaucoma, particularly in populations with European and African ancestry. This disease is the leading cause of blindness in African-Americans. The major ocular risk factors for POAG include intraocular pressure (IOP) elevation and aging. The prevalence of POAG increases from 0.02% at ages 40 to 49 to 2% to 3% for persons over the age of 7047; and incidence of ocular hypertension increases from 2 to 9% over the same time span.48 Although the relationship between Alzheimer’s disease and POAG remains obscure, more than 20% of Alzheimer’s patients also have POAG.49 The plasma concentration of a variety of signaling proteins differs between patients with Alzheimer’s and normal control subjects,4 indicating that systemic plasma changes take place along with central nervous dysfunction. It is likely that cellular insults or molecular defects intersect, leading to neurodegeneration. Similar scenarios may also occur in POAG.

82.1  ECM Changes in POAG ECM components in the TM are essential for maintenance of the normal aqueous humor outflow.50-53 In the TM of POAG eyes, excessive, abnormal accumulations as well as

decreases of other ECM materials (Table  82.1) have been documented.8,50-53 The ECM produced by the cells is composed of multidomain macromolecules such as collagens, cell-binding glycoproteins, and proteoglycans that link together to form a structurally stable composite. Recent studies have revealed that ECM is a dynamic entity determining and controlling the behavior and biologic characteristics of the cells. One key component of the ECM in TM is proteoglycans, which are macromolecules consisting of a core protein to which glycosaminoglycan side chains are covalently attached. This class of molecules has been implicated in the maintenance of resistance to aqueous humor outflow ever since Barany,54 in the 1950s, demonstrated that perfusion of the anterior chamber with testicular hyaluronidase greatly reduced the outflow resistance in enucleated bovine eyes. In the TM tissue, proteoglycans form gel-like networks that may function as a gel filtration system. The major types identified include chondroitin, dermatan, and heparan sulfate proteoglycans that may represent decorin, biglycan, versican, perlecan, and syndecan.50-52 The relative amounts of each type of glycosaminoglycan in the TM tissue have been determined.10,50-52 Hyaluronic acid and chondroitin–dermatan sulfates are the major constituents, with heparan sulfate and keratan sulfate present in smaller amounts. A depletion in hyaluronic acid and an accumulation of chondroitin sulfates and undigestible glycosaminoglycan material have been associated with POAG conditions.10 Both chondroitin sulfate and hyaluronic acid have been shown to contribute to flow resistance and influence flow rate in vitro.55 The flow rate was decreased when hyaluronic acid and chondroitin sulfate were used at POAG concentrations.56 Disrupting glycosaminoglycan chain biosynthesis by sodium chlorate or b-xyloside increases outflow facility in perfusion culture.57 Of note, the level of an ectodomain fragment of hyaluronic acid receptor CD44 (sCD44) was found to be elevated (Table 82.2) in the aqueous humor of POAG patients,29 and the concentration was correlated with visual field loss.29 sCD44 is cytotoxic to TM cells, but the toxicity can be blocked by hyaluronic acid.58 The decreased hyaluronic acid may thus result in diminished protective capacity and further deterioration in POAG conditions.

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_82, © Springer Science+Business Media, LLC 2010

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Table 82.1  Extracellular matrix changes in POAG Aqueous humor

Trabecular meshwork

Optic nerve

Systemic (blood)

ECM Elements CD44 ↓8 Cochlin ↑9 Chondroitin sulfate ↑10 Collagen type IV nc11 Elastin ↑12 ↑13 Fibronectin nc14 nc11 Hyaluronic acid ↓↓15 ↓↓↓↓10 ↓16 10 GAGase-resistant material ↑↑↑↑ Tenascin ↑17 Thrombospondin-1 ↑18 ECM Remodeling Enzymes and Inhibitors MMP-1 ↑19 ↑20 21 19 MMP-3 nc ↑ ↑20 MT1-MMP ↑22 TIMP-1 nc21 ↑19 TIMP-2 ↑23 The increase or decrease in the reported biochemical changes in POAG are expressed as statistically significant ↑ or ↓. Whenever possible, a twofold change is denoted by two arrows, a threefold change by three arrows, and a fourfold change by four arrows, and nc indicates no change. GAGase – glycosaminoglycan-degrading enzyme; MMP – matrix metalloproteinase; MT1-MMP – membrane type 1-MMP; TIMP – tissue inhibitor for MMP

Fibronectin, laminin, vitronectin, and matricellular proteins that include tenascin and thrombospondin-1 have been localized in the TM.18,50,51 These glycoproteins are crucial in biologic processes such as cell attachment, spreading, and cell differentiation. Overexpression of fibronectin and laminin, as well as collagen type IV, results in a decrease in the TM cell monolayer permeability.50,59 The expression of throm­bospondin-1 has in addition been shown to be increased18 in the TM of POAG eyes (Table 82.1). Elastin is localized to the central core of sheath-derived plaques or elastic-like fibers in the TM.50 Fibrillin-1, a component of microfibrils, is found in both the core and the surrounding sheath of the elastic-like fibers. Fibrillin-1 and type VI collagen are also constituents of long-spacing collagens in the TM.50,53 It is believed that the collagen fibers and elastic-like fibers are organized in the TM to accommodate resilience and tensile strength, providing a mechanism for reversible deformation in response to cyclic hydrodynamic loading. In trabecular lamellae and in juxtacanalicular (JCT) regions, accumulation of long spacing collagens and sheathderived plaques has been documented in POAG and aged eyes.50,53 The ECM is constantly modified by the surrounding cells through enzymes such as matrix metalloproteinase (MMP) family members and inhibitors such as tissue inhibitors for matrix metalloproteinase (TIMPs) found in the TM.52 Ongoing ECM turnover, initiated by MMPs, appears to be essential for maintenance of the aqueous outflow homeostasis. MMP-3, and possibly also MMP-9, may be responsible for

the efficacy of laser trabeculoplasty, an alternative treatment to reduce IOP in patients with glaucoma.50,52 Addition or induction of MMP-3 in perfused human anterior segment organ cultures increases the aqueous humor outflow facility, whereas blocking the endogenous activity of the MMPs in the TM reduces it.52 The ECM in the TM may also be remodeled in response to exogenous stimuli such as glucocorticoids and oxidative stress.50,51 Mechanical stretch caused an increase in MMP-1 and MMP-3 activities and alteration of ECM molecules including proteoglycans and matricellular proteins.60 The ECM is modulated by cytokines. The most studied cytokine in the TM is transforming growth factor-beta (TGF-b). A higher than normal level30 of TGF-b2 was found in the aqueous humor of patients with POAG (Table 82.2). TGF-b2 upregulated ECM-related genes in TM cell cultures. In TGFb2-perfused organ cultures, focal accumulation of fine fibrillar extracellular material was observed in TM tissues. Furthermore, TGF-b2 perfusion reduced outflow facility and elevated IOP.61 These results suggest that the increased TGF-b2 level in the aqueous humor may be related to the pathogenesis of glaucoma. Other cytokines such as tumor necrosis factor-a (TNF-a) that is increased in the optic nerve head of POAG (Table 82.2) also modulate the ECM, probably via regulation of MMP and TIMP expressions.50,51,62 The cochlin deposits in the glaucomatous TM (Table 82.1) appear to increase with age and are associated with proteoglycans. Such deposits have been proposed to contribute to the increase of ECM resistance to outflow and the POAG pathology.9

82  How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers

82.2  Cytokine/Signaling Molecules in POAG The TM and optic nerve utilize local and probably systemic cell signaling pathways to maintain cell viability. Locally in the TM, the Rho family of small guanosine triphosphatase (GTPase) has been shown to be of vital importance in the outflow system.54,63,64 In the active GTP-bound state, Rho GTPases interact with and activate downstream effectors such as Rho kinase to modulate the assembly of actin structures. In TM cells, a decrease in actin stress fibers and focal adhesions has been shown to occur with treatment of Rho kinase inhibitors and gene transfer of dominant negative RhoA and dominant negative Rho-binding domain of Rho kinase.64 These cellular changes are associated with reduced myosin light chain (MLC) phosphorylation and/or enhanced outflow facility.53 Conversely, molecules including sphingosine-1-phosphate and endothelin-1 that activate Rho/Rho kinase signaling pathway through G-protein coupled receptors

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promote MLC phosphorylation, and in turn decrease the aqueous humor outflow facility.54,63,64 Endothelial-1 has been reported to be increased in the aqueous humor24 and blood25 of POAG patients (Table 82.2). The aqueous humor that also modulates TM cell signaling contains albumin as a major constituent. Other components encompass hydrogen peroxide (H2O2), ascorbic acid, cyto­ kines such as TGF-b, heptocyte growth factor, and vascular endothelial growth factor (VEGF), and molecules including MMPs, proteinase inhibitors, sCD44, and hyaluronic acid.50 A recent study has demonstrated that addition of normal aqueous humor rather than the standard fetal bovine serum to monolayers of TM cultures decreases cell proliferation and produces changes in cellular and molecular characteristics to mimic more closely the TM physiologic profiles in situ.65 Increased levels of TGF-b2, sCD44, interleukin-2, phospholipase 2, thymulin (Table  82.2), glutathione, ascorbic acid (Table 82.3), and a decreased level of hyaluronic acid

Table 82.2  Changes in cell signaling molecules in primary open angle glaucoma Aqueous humor Trabecular meshwork

Optic nerve

Systemic (blood)

Endothelin-1 ↑ ↑24,25 Hepatocyte growth factor ↑26 Interleukin 2 ↑27 28 Phospholipase A2 ↑ Soluble CD44 ↑↑29 Transforming growth factor-b2 ↑30 Thymulin ↑↑↑31 20 Tumor necrosis factor-a ↑ ↑33 Vascular endothelial growth factor ↑32 The increase or decrease in the reported changes in POAG are expressed as statistically significant ↑ or ↓. Whenever possible, a twofold change is denoted by two arrows, a threefold change by three arrows, and a fourfold change by four arrows. 24

Table 82.3  Changes related to stress and aging in POAG Aqueous humor

Trabecular meshwork

Optic nerve

Systemic (blood)

Acetylcholinesterase ↑34 35 aB-Crystallin ↑ 3-a-Hydroxysteroid dehydrogenase ↓36 Ascorbic acid ↑↑↑37 Cortisol ↑38 Fatty acid Eicosapentaenoic ↓39 Docosahexaenoic ↓39 Omega 3 ↓39 40 Glutathione ↑↑↑ ↓41 Hypoxia inducible factor-1a (HIF-1a) ↑42 Nuclear factor-kB (NF- kB) ↑43 44 Nitric oxide ↑ Senescence associated b-galactosidase ↑45 Serum amyloid A ↑↑46 The increase or decrease in the reported changes in POAG is expressed as statistically significant ↑ or ↓. Whenever possible, a twofold change is denoted by two arrows, a threefold change by three arrows, and a fourfold change by four arrows.

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(Table  82.1) have been reported in the aqueous humor of POAG eyes. Since TM cells are in constant contact with the aqueous humor, it is expected that altered levels and/or activities of aqueous humor components would have an impact on the behavior and activities of these cells. The sCD44 found in the POAG aqueous humor is hypophosphorylated.66 The hypophosphorylated form has high cytotoxicity and low hyaluronic acid-binding affinity and is suggested to represent a pathophysiologic feature of the disease process.66

cell vulnerability occurs as a result of dysfunctional pathways, stress, aging, or other insults, eventually leading to the disease process. Biochemical changes (listed in Tables  82.1, 82.2, and 82.3) indicate that diverse pathways/mechanisms/ molecules including pro-inflammatory cytokines may trigger dysregulation of normal defense mechanisms, faulty signaling, and/or progressive fibrosis, leading to the disease process. A deeper understanding of the various mechanisms is a prerequisite for designing novel gene therapies or treatment modalities for POAG.

82.3  Stress and Aging in POAG

References

TM cellularity is reduced with aging.67,68 Morphologic studies have also revealed thickened basement membranes and accumulation of sheath-derived plaques and long spacing collagens in the TM of aged eyes.52 The number of senescent cells that stain positive for senescence-associated b-galactosidase is increased (Table 82.3) in the TM of POAG eyes,45 supporting further that POAG is an age-related disease.51,69 Oxidative damage has been implicated to contribute to the morphologic and physiologic alterations in the aqueous outflow pathway in aging and glaucoma.70 The TM is known to be exposed to 20–30 mM H2O2 present in the aqueous humor and is subjected to chronic oxidative stress.50 Superoxide dismutase, an enzyme involved in the protection against oxidative damage, has been shown to decline with age in human TM tissues.69 TM cells also synthesized a specific set of proteins, such as aB-crystalline, that may act as molecular chaperones to prevent oxidative or heat shock damage.35 Markers of oxidative damage,70,71 abnormalities in mitochondrial DNA,72 and diminished blood levels of oxidant scavengers glutathione41 are found in POAG patients . It appears that oxidative stress that exceeds the capacity of TM cells for detoxification is involved in damaging the cells and alteration of the aqueous humor outflow. Upregulation of acute stress response protein amyloid in blood of POAG patients46 underscores the notion that POAG has ocular and systemic altered protein expression.

82.4  Conclusions and Perspectives This chapter summarizes the current knowledge of possible biomarkers in POAG. The exact role of each biomarker is sketchy at present, and a direct link to POAG remains to be established. While individual biomarkers are only indicative of POAG, combining multiple biomakers for the risk assessment in POAG is a goal for the future. The regulation of TGF-b, CD44, and Wnt73 signaling cascades is areas of active research. A theme applicable perhaps to both POAG and other neurodegenerative diseases is emerging that selective

1. de Lemos JA, Lloyd-Jones DM. Multiple biomarker panels for cardiovascular risk assessment. N Eng J Med. 2008;358:2172–4. 2. Parikh SV, de Lemos JA. Biomarkers in cardiovascular disease: integrating pathophysiology into clinical practice. Amer J Med Sci. 2006;332:186–97. 3. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Eng J Med. 2006;355:2631–9. 4. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nature Med. 2007;13:1359–62. 5. Simonsen AH, McGuire J, Hansson O, et al. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol. 2007;64:366–70. 6. Ross JS, Symmans WF, Pusztai L, Hortobagyi GN. Pharma­ cogenomics and clinical biomarkers in drug discovery and development. Amer J Clin Path. 2005;124(Suppl):S29–41. 7. Golubnitschaja O, Flammer J. What are the biomarkers for glaucoma? Surv Ophthalmol. 2007;52(Suppl 2):S155–61. 8. Knepper PA, Goossens W, Mayanil CS. CD44H localization in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1998;39: 673–680. 9. Picciani R, Desai K, Guduric-Fuchs J, et  al. Cochlin in the eye. Prog Retin Eye Res. 2007;26:453–469. 10. Knepper PA, Goossens W, Hvizd M, et al. Glycosaminoglycans of the human trabecular meshwork in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1360–1367. 11. Hann CR, Springett MJ, Wang X, et al. Ultrastructural localization of collagen IV, fibronectin, and laminin in the trabecular meshwork of normal and glaucomatous eyes. Ophthalmic Res. 2001;33:314–324. 12. Umihira J, Nagata S, Nohara M, et al. Localization of elastin in the normal and glaucomatous human trabecular meshwork. Invest Ophthalmol Vis Sci. 1994;35:486–494. 13. Pena JD, Netland PA, Vidal I, et al. Elastosis of the lamina cribrosa in glaucomatous optic neuropathy. Exp Eye Res. 1998;67:517–524. 14. Vesaluoma M, Mertaniemi P, Mannonen S, et al. Cellular and plasma fibronectin in the aqueous humour of primary open-angle glaucoma, exfoliative glaucoma and cataract patients. Eye. 1998;12:886–890. 15. Navajas EV, Martins JR, Melo LA Jr, et  al. Concentration of hyaluronic acid in primary open-angle glaucoma aqueous humor. Exp Eye Res. 2005;80:853–857. 16. Gong H, Ye W, Freddo TF, et al. Hyaluronic acid in the normal and glaucomatous optic nerve. Exp Eye Res. 1997;4:587–595. 17. Pena JD, Varela HJ, Ricard CS, et al. Enhanced tenascin expression associated with reactive astrocytes in human optic nerve heads with primary open angle glaucoma. Exp Eye Res. 1999;68:29–40. 18. Flugel-Koch C, Ohlmann A, Fuchshofer R, et al. Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous

82  How the Revolution in Cell Biology Will Affect Glaucoma: Biomarkers eyes, and induction by TGF-b1 and dexamethasone in  vitro. Exp Eye Res. 2004;79:649–663. 19. Ronkko S, Rekonen P, Kaarniranta K, et al. Matrix metalloproteinases and their inhibitors in the chamber angle of normal eyes and patients with primary open-angle glaucoma and exfoliation glaucoma. Graefes Arch Clin Exp Ophthalmol. 2007;245: 697–704. 20. Yan X, Tezel G, Wax MB, et  al. Matrix metalloproteinases and tumor necrosis factor-a in glaucomatous optic nerve head. Arch Ophthalmol. 2000;118:666–673. 21. Schlotzer-Schrehardt U, Lommatzsch J, Kuchle M, et  al. Matrix metalloproteinases and their inhibitors in aqueous humor of patients with pseudoexfoliation syndrome/glaucoma and primary openangle glaucoma. Invest Ophthalmol Vis Sci. 2003;44:1117–1125. 22. Golubnitschaja O, Yeghiazaryan K, Liu R, et al. Increased expression of matrix metalloproteinases in mononuclear blood cells of normal-tension glaucoma patients. J Glaucoma. 2004;13:66–72. 23. Maatta M, Tervahartiala T, Harju M, et  al. Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma. J Glaucoma. 2005;14:64–69. 24. Tezel G, Kass MA, Kolker AE, et al. Plasma and aqueous humor endothelin levels in primary open-angle glaucoma. J Glaucoma. 1997;6:83–89. 25. Emre M, Orgul S, Haufschild T, et al. Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma. Br J Ophthalmol. 2005;89:60–63. 26. Hu DN, Ritch R. Hepatocyte growth factor is increased in the aqueous humor of glaucomatous eyes. J Glaucoma. 2001;10:152–157. 27. Yang J, Patil RV, Yu H, et al. T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am J Ophthalmol. 2001;31:421–426. 28. Ronkko S, Rekonen P, Kaarniranta K, et al. Phospholipase A2 in chamber angle of normal eyes and patients with primary open angle glaucoma and exfoliation glaucoma. Mol Vis. 2007;13:408–417. 29. Nolan MJ, Giovingo MC, Miller AM, et al. Aqueous humor sCD44 concentration and visual field loss in primary open-angle glaucoma. J Glaucoma. 2007;16:419–429. 30. Picht G, Welge-Luessen U, Grehn F, et  al. Transforming growth factor b2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development. Graefes Arch Clin Exp Ophthalmol. 2001;239:199–207. 31. Noureddin BN, Al-Haddad CE, Bashshur Z, et al. Plasma thymulin and nerve growth factor levels in patients with primary open angle glaucoma and elevated intraocular pressure. Graefes Arch Clin Exp Ophthalmol. 2006;244:750–752. 32. Hu DN, Ritch R, Liebmann J, et  al. Vascular endothelial growth factor is increased in aqueous humor of glaucomatous eyes. J Glaucoma. 2002;1:406–410. 33. Lip PL, Felmeden DC, Blann AD, et al. Plasma vascular endothelial growth factor, soluble VEGF receptor FLT-1, and von Willebrand factor in glaucoma. Br J Ophthalmol. 2002;86:1299–1302. 34. Zabala L, Saldanha C, Martins e Silva J, et al. Red blood cell membrane integrity in primary open angle glaucoma: ex vivo and in vitro studies. Eye. 1999;13:101–103. 35. Lutjen-Drecoll E, May CA, Polansky JR, et al. Localization of the stress proteins aB-crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Invest Ophthalmol Vis Sci. 1998;39:517–525. 36. Weinstein BI, Iyer RB, Binstock JM, et al. Decreased 3a-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma. Exp Eye Res. 1996;62: 39–45. 37. Lee P, Lam KW, Lai M. Aqueous humor ascorbate concentration and open-angle glaucoma. Arch Ophthalmol. 1977;95:308–310. 38. McCarty GR, Schwartz B. Reduced plasma cortisol binding to albumin in ocular hypertension and primary open-angle glaucoma. Curr Eye Res. 1999;18:467–476.

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39. Ren H, Magulike N, Ghebremeskel K, et  al. Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids. Prostaglandins Leukot Essent Fatty Acids. 2006;74:157–163. 40. Ferreira SM, Lerner SF, Brunzini R, et al. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol. 2004;137:62–69. 41. Gherghel D, Griffiths HR, Hilton EJ, et al. Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:877–883. 42. Tezel G, Wax MB. Hypoxia-inducible factor-1a in the glaucomatous retina and optic nerve head. Arch Ophthalmol. 2004;122:1348–1356. 43. Tsai DC, Hsu WM, Chou CK, et  al. Significant variation of the elevated nitric oxide levels in aqueous humor from patients with different types of glaucoma. Ophthalmologica. 2002;216:346–350. 44. Wang N, Chintala SK, Fini ME, et al. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. Nature Med. 2001;7:304–309. 45. Liton PB, Challa P, Stinnett S, et al. Cellular senescence in the glaucomatous outflow pathway. Exp Geront. 2005;40:745–748. 46. Wang WH, McNatt LG, Pang IH, et  al. Increased expression of serum amyloid A in glaucoma and its effect on intraocular pressure. Invest Ophthalmol Vis Sci. 2008;49:1916–23. 47. Mukesh BN, McCarty CA, Rait JL, Taylor HR. Five-year incidence of open-angle glaucoma: the visual impairment project. Ophthalmology. 2002;109:1047–1051. 48. Quigley HA. Open-angle glaucoma. N Eng J Med. 1993;328:097–1106. 49. Tamura H, Kawakami H, Kanamoto T, et  al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer’s disease. J Neuro Sci. 2006;246:79–83. 50. Yue BYJT. Cellular mechanisms in the trabecular meshwork affecting the aqueous humor outflow pathway. In: Albert DM, Miller JW, eds. Albert and Jacobiec’s principles and practice of ophthalmology. Chap. 192. 3rd ed. Oxford, UK: Elsevier; 2007:2457–2474. 51. Knepper PA, Yue BYJT: Cellular mechanisms in the trabecular meshwork affecting the aqueous humor outflow pathway. In: Levine LA, Albert DM (eds) Ocular disease: mechanisms and management. Elsevier, Oxford, UK (In Press). 52. Acott TS, Kelley MJ. Extracellular matrix in the trabecular meshwork. Exp Eye Res. 2008;86:543–61. 53. Lutjen-Drecoll RJW. Morphology of aqueous outflow pathways in normal and glaucomatous eyes. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas, vol. 1. 2nd ed. CV Mosby: St. Louis; 1996:89–123. 54. Tan JCH, Peters DM, Kaufman PL. Recent developments in understanding the pathophysiology of elevated intraocular pressure. Curr Opin Ophthalmol. 2006;17:168–174. 55. Barany EH. The effect of different kinds of hyaluronidase on the resistance to flow through the angle of the anterior chamber. Acta Ophthalmol. 1956;33:397–403. 56. Knepper PA, Fadel JR, Miller AM, et al. Reconstitution of trabecular meshwork GAGs: influence of hyaluronic acid and chondroitin sulfate on flow rates. J Glaucoma. 2005;14:230–238. 57. Keller KE, Bradley JM, Kelley MJ, Acott TS. Effects of modifiers of glycosaminoglycan biosynthesis on outflow facility in perfusion culture. Invest Ophthalmol Vis Sci. 2008;49:2495–505. 58. Choi J, Miller AM, Nolan MJ, et al. Soluble CD44 is cytotoxic to trabecular meshwork and retinal ganglion cells in  vitro. Invest Ophthalmol Vis Sci. 2006;46:214–222. 59. Tane N, Dhar S, Roy S, et al. Effect of excess synthesis of extracellular matrix components by trabecular meshwork cells: Possible consequence on aqueous outflow. Exp Eye Res. 2007;84:832–842. 60. Vittal V, Rose A, Gregory KE, et al. Changes in gene expression by trabecular meshwork cells in response to mechanical stretching. Invest Ophthalmol Vis Sci. 2005;46:2857–2868. 61. Gottanka J, Chan D, Eichhorn M, Lutjen-Drecoll E, Ethier CR. Effects of TGF-b2 in perfused human eyes. Invest Ophthalmol Vis Sci. 2004;45:153–8.

938 62. Kelley MJ, Rose AY, Songg K, et al. Synergism of TNF and IL-1 in the induction of matrix metalloproteinases-3 in the trabecular meshwork. Invest Ophthalmol Vis Sci. 2007;48:2634–2643. 63. Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000;41:619–623. 64. Rao PV, Epstein DL. Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs. 2007;21:167–177. 65. Fautsch MP, Howell KG, Vrabel AM, et  al. Primary trabecular meshwork cells incubated in human aqueous humor differ from cells incubated in serum supplements. Invest Ophthalmol Vis Sci. 2005;46:2848–2856. 66. Knepper PA, Miller AM, Wertz CJ, et al. Hypophosphorylation of aqueous humor sCD44 and primary open angle glaucoma. Invest Ophthalmol Vis Sci. 2005;46:2829–2837. 67. Alvarado JA, Murphy CG, Polansky JR, Juster R. Age-related changes in trabecular meshwork cellularity. Invest Ophthalmol Vis Sci. 1981;21:714–727.

P.A. Knepper et al. 68. Alvarado J, Murphy C, Juster R. Trabecular meshwork cellularity in primary open-angle glaucoma and non-glaucomatous normals. Ophthalmology. 1984;91:564–579. 69. Gabelt BT, Kaufman PL. Changes in aqueous humor dynamics with age and glaucoma. Prog Retina Eye Res. 2005;24: 612–637. 70. Sacca SC, Izzotti A, Rossi P, Traverso C. Glaucomatous outflow pathway and oxidative stress. Exp Eye Res. 2007;84: 389–399. 71. De La Paz MA, Epstein DL. Effect of age on superoxide dismutase activity of human trabecular meshwork. Invest Ophthalmol Vis Sci. 1996;37:1849–1853. 72. Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2006;47:2533-2541. 73. Wang WH, McNatt LG, Pang IH, et al. Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. J Clin Invest. 2008;118:1056-64.

Chapter 83

CD44 and Primary Open Angle Glaucoma Paul A. Knepper, Michael J. Nolan, and Beatrice Y.J.T. Yue

In our view, primary open-angle glaucoma (POAG) is a common neurodegenerative disease caused by a variety of molecular defects and/or cellular insults that result in cell stress and death of the trabecular meshwork (TM) and retinal ganglion cells (RGC). One potential biological marker of POAG is CD44, which is one of the adhesion/homing molecules. Direct evidence for CD44’s very central role in POAG includes: (1) aqueous humor of patients with POAG contains an increased amount of the soluble extracellular 32-kDa fragment of CD44 (sCD44) in comparison with the aqueous humor of age-matched normal individuals1; (2) increased levels of sCD44 in the aqueous correlates with the extent of visual field loss in POAG patients2; (3) sCD44, particularly hypo-phosphorylated sCD44, is a potent and specific toxic protein to TM and RGC in vitro3; and (4) overexpression of both full-length CD44 and truncated sCD44 in transgenic mouse eyes is sufficient to cause ocular hypertension. The increase in intraocular pressure (IOP) lasted more than 90 days accompanied by optic nerve damage. The overexpression of CD44 may thus be the first documented animal model that closely mimics the human disease POAG.4 Other models have been cytodestructive and nonphysiologic. These data suggest that the elevated sCD44 levels documented in POAG compared with secondary glaucoma or normal aqueous is not just an epiphenomenon but plays a causal role in the POAG disease process. In this chapter, we will focus on CD44’s role in cell signaling pathways, immune status, response to cell stress, and their impact on cell viability. The question that is asked is: “Are CD44 and its ectodomain sCD44 life or death factors in POAG?”

83.1  CD44 Functions as a Receptor CD44 is a type 1 transmembrane glycoprotein expressed in many cell types of neuroectodermal and mesenchymal origin. CD44 is a receptor for hyaluronic acid (HA). Our biochemical studies of POAG TM have revealed a significant decrease in HA and an increase in chondroitin sulfate.5

In addition, computer-aided microscopy studies of the juxtacanicular tissue of POAG post-mortem eyes have also confirmed the loss of HA and the increase in the amount of chondroitin sulfate.6 The cell mechanisms causing the decrease of HA in aging5–10 or the further loss of HA in POAG are unknown. It is now recognized that HA, even at low concentrations, has important regulatory functions in cellular differentiation.8,11 Emerging evidence suggests that HA is a key factor in promoting cell motility, adhesion, and proliferation. These cell events are orchestrated by three HA cell receptors – CD44, RHAMM (receptor for HA-mediated motility), and intercellular adhesion molecule (ICAM-1) – all of which have been identified in the human TM.12

83.1.1  CD44 Interactions CD44, the principal receptor for HA, is well characterized and increases in aging.13–15 CD44 plays major roles in multiple physiological processes including autoimmunity,16–18 phagocytosis,19,20 and cell survival.21–23 CD44 vaccination has recently been reported to be useful in treating insulin-dependent diabetes mellitus24 and inflammatory central nervous system (CNS) diseases like multiple sclerosis.25 While there is no clinically available vaccination for POAG, the possibility is intriguing. CD44 is an 80–250  kDa transmembrane protein; its ectodomain is released as sCD4426–28 (see Fig. 83.1). The nucleotide sequence of CD44 cDNA predicts a 37-kDa protein with homology to cartilage link protein.29 CD44 is multifunctional due to sequence differences arising from alternate splicing of mRNA, as well as posttranslational modifications. CD44 (standard) is the most common form. CD44 proteins are differentially phosphorylated and glycosylated.30 The structure of CD44 is remarkable for its versatility32 and is a molecule with a thousand faces due to its surprising number of numerous functions, interactions, and isoforms.32 In addition to HA, CD44 has multiple ligands – chondroitin sulfate,33 collagen types I and IV, fibronectin,34 osteopontin,35

P.N. Schacknow and J.R. Samples (eds.), The Glaucoma Book: A Practical, Evidence-Based Approach to Patient Care, DOI 10.1007/978-0-387-76700-0_83, © Springer Science+Business Media, LLC 2010

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Fig.  83.1  Interactions and signal transduction pathways involving CD44. CD44 associates with HA, matrix metalloproteinase-9 (MMP-9), erbB2, erbB3, EGFR, and TGFb in the extracellular domain. CD44 is shed as soluble CD44 (sCD44), which does not have variable spliced inserts and is highly conserved. sCD44 may be internalized into mitochondria leading to apoptosis or disrupt membrane interactions, especially the CD44-mediated heterodimer that forms between erbB2 and erbB3 and also TGFb. sCD44 release causes decreased signal transduction through erbB2–erbB3 leading also to apoptosis. Signal transduction through the EGFR receptor family involves tyrosine kinase activation, Ras, Raf, Mek, and Map kinase (MAPK) activation, leading

to transcription. In addition to the MAPK cascade, the EGFR family is involved with the NF-kB signal transduction pathway. TNF-a receptor associated factor-2 (TRAF-2) is the link between the TNF-a pathway and EGFR. Both CD44 and EGFR function through Ras, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC), which leads through the inhibitor of NF-kB kinase (IKK) complex, which consists of IKK-1, IKK-2, and NEMO. TNF-a binds to the TNF-a receptor, which results in signal transduction through IKK, IkB, and NF-kB. Casein kinase II (CKII) activity is negatively regulated in part by TGFb1. Smaller molecular weight HA (smaller pinkish HA) is pro-inflammatory and has low affinity binding to sCD44

TGF-b receptor,36 and matrix metalloproteinases.37,38 CD44 undergoes a variety of activation-dependent, cell-type specific, posttranslational modifications that can affect its ligand specificity and affinity. CD44 plays a critical role in the cell survival of many cell types through its interaction with multiple signaling pathways, including Ras, PKC NF-kB, MAPK, and the PI3K–PKB/Akt pathways.3 In several cell types, CD44, HA, and androgen receptor stimulation enhance cell survival.3 Heparan sulfate side chains on CD44 bind and sequester growth factors and chemokines. Each ligand interaction is influenced by CD44 exons and by glycosylation patterns.39 sCD44 is the ectodomain fragment of CD44 and does not have variable spliced inserts typical of CD44, and

the N-terminus of sCD44 ectodomain is highly conserved. ERM (ezrin, radixin, moesin) family members are located just beneath the plasma membrane and act as molecular linkers between a cytoplasmic domain of CD44 and the actinbased cytoskeleton.40 CD44 participates in the uptake and degradation of HA.41 CD44 is expressed on a variety of ocular cells and tissues including RGC and axons.42 Aging leads to altered T cells, increases in CD44 expression, and the accumulation of cells with signal transduction defects.43 Functional analysis of CD44 as a receptor for the ECM and its role in signal transduction in cells depends on many factors including: matrix interaction,14 cell type,44 extracellular ligands,45

83  CD44 and Primary Open Angle Glaucoma

and cytoplasmic interaction of CD44. Emerging evidence indicates that the ectodomain fragment, sCD44, is functionally distinct from the membrane CD44.27 The expression and proteolytic release of sCD44 by cells allows the nascent membrane CD44 to bind and internalize HA as well as other HA binding proteins.46 CD44 and HA are also involved in the activity of adenosine triphosphate (ATP)-binding cassette (ABC) transporters that remove potentially toxic proteins from cells. A number of the genes implicated in glaucoma have a relationship to the ABC transporters. TM cells express functionally active ABC transporters.47 ATP-binding cassette transporter superfamily members respond to stressors such as hypoxia, cytokine signaling, increased pressure, mechanical stretch, and aging, which are collectively vital to the function of the TM. The ABCB1 transporter (multidrug resistance protein, p-glycoprotein) expression and function are controlled by HA and CD44, both of which are altered in POAG. Notably, ABC transporter genes ABCB1, ABCA6, ABCA8, ABCA2, ABCF2, and ABCA5 are all flagged as present in TM tissue by Affymetrix microarray analysis.47 ABCF2 maps to 7q36, a published glaucoma loci GLC1F (7q35-36). In a calcein– AM functional assay of MDR, TM cells incorporate calcein– AM, and MDR activity is inhibited by metabolic stress. These results support the hypothesis that MDR is expressed in cells relevant to the POAG disease process, and abnormal stress may lead to decreased MDR activity and TM cell dysfunction in POAG.

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Fig. 83.2  Western blot of micro-dissected normal and POAG ciliary body solubilized in 1% Triton X-100 and using CD44H antibody which recognizes all forms of CD44. Right: molecular weight (in kilodaltons). Bottom: individual specimen number, age, and clinical status. Note the marked increase in CD44H (~85 kDa) in POAG as compared to normal

to the hydrophobic domains of proteins without disrupting protein–protein interactions. POAG CD44H is increased on Western blots because it is extracted and quantitated, whereas POAG CD44 is decreased on histological sections because it is extracted and removed from the section. Thus, the immunocytochemical studies and Western blot analysis of CD44H1,48 support the notion that the expression and regulation of CD44 is changed in POAG.

83.1.2  CD44 Localization in POAG We have determined the CD44H profile in normal and in POAG anterior segments by Western blot analysis and computer-assisted densitometry.48 Western blot analysis of POAG eyes demonstrated a marked increase of CD44H (P > 0.001) in the ciliary body in all cases of POAG (Fig.  83.2). Immunocytochemical studies also showed a marked change in CD44 in POAG eyes. In normal eyes, the CD44 profile indicated that the highest concentration of CD44 was in the ciliary body stroma. When sections were pretreated with Triton X-100, all of the normal anterior segment regions exhibited a substantial increase in CD44 staining. In contrast, significant decreases in the amount of CD44 were present in POAG eyes compared with normal eyes. As evidenced by scattergram plots (Fig. 83.3), individual cases of normal and POAG eyes are clustered into distinctive patterns in ciliary body stroma and TM. Results of these studies indicate that the concentration of CD44H is increased in the anterior segment of POAG eyes.48 Triton X-100 is useful in solubilizing a number of integral membrane proteins,49 such as CD44,50 which are associated with lipid rafts.51 Triton X-100 binds

83.2  sCD44 and POAG 83.2.1  Ectodomain Shedding of sCD44 The 32-kDa ectodomain fragment of CD44 is released from the membrane CD44 by proteolytic cleavage as sCD44.27 sCD44 is shed from the cell surface in response to ligand binding. The ectodomain has been shown to be released from the cell surface by MT1-MMP, a membrane bound metalloprotease28 in junction with ADAMS 10 and 17.52-54

83.2.2  P  arallel in Processing of sCD44 and Alzheimer’s b-Amyloid An emerging concept in cell biology, applicable to neurodegenerative diseases such as POAG and Alzheimer’s disease is that a specific population of cells becomes vulnerable to a toxic protein. Often the protein is misfolded or aggregated

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Fig.  83.3   Scattergram plots of ciliary body and TM of the optical density of CD44H immunostaining without Triton X-100 pretreatment (x axis) versus the change in optical density of CD44 between pretreatment with Triton X-100 and without Triton

X-100 (y-axis). Individual cases of POAG eyes are indicated by solid, numbered circles ●, and individual cases of normal eyes are indicated by open, numbered circles ○. Note clear separation of normal from POAG

Fig. 83.4  Ectodomain shedding of CD44 and amyloid precursor protein by initial cleavage of the ectodomain and a second cleavage in the transmembrane domain. Potential ectodomain cleavage of CD44 is shown by

MT1-MMP and of amyloid precursor protein by b- and a-secretase. Putative phosphorylation sites are noted by CK II, PKC, APPK, and MAPK. The beta-amyloid like protein fragments are shown in red

with a change in its tertiary, three-dimensional structure. As a consequence, the target cells die. There is a marked parallel in the processing of CD44 and b-amyloid (Fig. 83.4). In both diseases, the intramembrane portion is cleaved by a presenilin g-secretase which occurs close to the cytoplasmic border to release an intracellular fragment that translocates to the nucleus and promotes transcription; A second cleavage occurs extracellularly to generate an amyloid-like peptide.55 b-amyloid in Alzheimer’s disease is phosphorylated on its ectodomain, analogous to sCD44, and aberrant phosphorylation of the b-amyloid precursor protein enhances the secretion of the b-peptide by g-secretase.56

Clinically, the prevalence of POAG is high in patients with Alzheimer’s disease.57,58 b-secretase is a second enzyme used in the processing of amyloid precursor protein. It is a transmembrane aspartyl protease,59 the rate-limiting step in the production of toxic b-amyloid, and is active within endosomal/lysosomal compartments. Significantly, b-secretase is up-regulated by cell stress.60 Whether CD44 is cleaved by b-secretase is not known, but it is an attractive unifying hypothesis that cell stress is a basic element in the pathogenesis of POAG. There are common mechanisms in ectodomain processing. First, the majority of shedding events of the ectodomain are inhibited by metalloproteinase inhibitors61,62

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83  CD44 and Primary Open Angle Glaucoma

that interfere with the maturation and the transport of the transmembrane proteins. Second, the ectodomains are shed in response to protein kinase C activators, a stress responder. Third, domain swap constructs of the extracellular domain adjacent to the transmembrane region result in shedding of transmembrane proteins that are normally not shed. Although the phosphorylation sites are yet to be identified in sCD44, phosphorylation is a key to stress response in several neurodegenerative diseases.63 We anticipate critical phosphorylation sites within the a-helix portion of sCD44. Regulation of phosphorylation may prove to be a key posttranslational modification. If phosphorylation is downregulated, the charge on sCD44 is changed to create a mitochondrial signaling domain. For example, the net charge on the a-helix portion of sCD44 is zero, but with reduced or

absent phosphorylation, the charge becomes basic and the sCD44 would be directed to the mitochondria and cause cell death (Table 83.1).

83.2.3  s CD44 Concentration in POAG Aqueous Humor We determined amounts of sCD44 in the aqueous humor of normal and glaucoma patients using microscale methods developed in our laboratory.1,2,64 In this ongoing study, we have excluded any patient with recent (6 months) intraocular surgery. As shown in Table 83.2, POAG aqueous without filtration surgery contained a highly significant increase in

Table 83.1  Putative phosphorylation and influence on theoretical isoelectric point of the HA binding sites in the ectodomain of sCD44 HA binding site

Example

Amino acid sequence and charge

Phosphorylation sites

Theoretical isoelectric point

1st helix sCD44

Normal Normal

+ . . + . - . - + + . . + . - . - +

3 2

4.02 5.03

POAG POAG

+ . . + . . . - + .

1 0

8.55 11.0

1

8.71

0

9.99

-

KN GRY SIS R T

2nd helix sCD44

Normal POAG

+ . . + . . . . + . .

+ -

. - + . . .

+

N R D G TR Y V Q K . + . . + . . . +

The amino acid sequence of the first helix of sCD44 is shown with positive charge (+) representing basic amino acids, the negative charge (-) representing acidic amino acids, and neutral (.) representing neutral amino acids. Phosphorylation of serine or threonine residues results in a negative charge (-) whereas lack of phosphorylation of serine or threonine results in a neutral charge. The theoretical isoelectric point was determined by www.nihilnovus.com. Table 83.2  Aqueous sCD44* concentration in normal and glaucoma patients Clinical status

Subset

n†

sCD44 concentration

Normal Ocular hypertension POAG

None None POAG, No filtration surgery POAG, With filtration surgery and medications ║ POAG, With filtration surgery and no medications Normal pressure

124 5 90 10 3 12

5.88(0.27) 9.82(2.82) 12.76(0.66) 5.86(1.26) 12.62(3.81) 9.19(1.75)

Myocilin mutation None Secondary glaucoma, no filtration surgery

2 7 36

4.77 (0.11) 6.79(1.67) 8.98(0.65)

Secondary glaucoma, with filtration surgery║

11

6.84(0.56)

JOAG Secondary glaucoma

Comparison

P value

vs. Normal vs. Normal vs. POAG, no filtration surgery vs. Normal vs. Normal vs. POAG, no filtration surgery vs. POAG, no filtration surgery vs. POAG, no filtration surgery vs. Normal vs. POAG, no filtration surgery vs. all secondary glaucoma, no filtration surgery

0.15‡  0.000001). Successful POAG filtration surgery decreased sCD44 concentration. The increased concentration of sCD44 was observed in POAG patients with or without a positive family history and was not influenced by glaucoma medications. Significantly, normal pressure glaucoma and ocular hypertension also contained increased sCD44, whereas juvenile open angle glaucoma patients did not have an increased concentration of sCD44. Interestingly, patients with diabetes and POAG with mild to moderate visual field loss have a significantly lower sCD44 aqueous concentration.65 We sought to determine if there was a relationship between known risk factors for POAG and aqueous sCD44 concentration. A review of the literature disclosed age, gender, hypertension, increased IOP, and race as risk factors for developing POAG. In the current analysis of the cohort, race was the only identifiable glaucoma risk factor that correlated with the extent of visual field loss and sCD44 concentration (see Fig. 83.5). sCD44 concentration was greater in AfricanAmericans than in white patients with mild and moderate visual field loss. In both subsets, sCD44 concentration correlated to the stage of visual field loss. In POAG aqueous of white patients, the sCD44 concentration increased as the visual field loss progressed from mild to moderate to severe. Of note, the sCD44 concentration significantly decreased in African-American patients with severe visual field loss in comparison with white patients. African-Americans with severe visual field loss also had a significantly shorter known duration of the disease and higher IOP. The decrease in sCD44 in the aqueous of African-American POAG patients could be the result of end-stage glaucomatous damage to the ciliary epithelium caused by an accelerated disease process.

We considered several factors that would influence sCD44 concentration and the POAG disease process and extensively explored phosphorylation as a key posttranslation control. In normal aqueous humor samples, the apparent isoelectric point (pI) of the 32-kDa sCD44 was 6.38 ± 0.08 with an isoelectric variance of 5.4–7.0 (see Fig.  83.6). In contrast, in POAG aqueous humor samples, the apparent pI of sCD44 was 6.96 ± 0.07 (P