Glaucoma [2 ed.] 0702051934, 9780702051937

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GLAUCOMA

Content Strategist: Russell Gabbedy Content Development Specialist: Alexandra Mortimer Content Coordinator: Humayra Rahman Khan Project Manager: Umarani Natarajan Designer: Christian Bilbow Illustration Managers: Jennifer Rose and Deena Burgess Illustrator: Ethan Danielson Marketing Manager: Brian McAllister

GLAUCOMA Medical Diagnosis & Therapy SECOND EDITION VOLUME ONE

Tarek M Shaarawy PD MD MSc Privat Docent University of Geneva Consultant Ophthalmologist and Head Glaucoma Sector Ophthalmology Service Department of Clinical Neurosciences Geneva University Hospitals Geneva, Switzerland

Mark B Sherwood FRCP FRCS FRCOphth Daniels Professor Departments of Ophthalmology and Cell Biology Director of Vision Research Center University of Florida Gainesville, FL, USA

Roger A Hitchings FRCS FRCOphth Emeritus Professor Glaucoma and Allied Studies University of London Consultant Surgeon (rtd) Moorfields Eye Hospital London, UK

Jonathan G Crowston PhD FRCOphth FRANZCO Ringland Anderson Professor Head of Ophthalmology Melbourne University Director, Centre for Eye Research Australia Melbourne, Australia

For additional online content visit expertconsult.com

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© 2015, Elsevier Limited. All rights reserved. Chapter 36 Uveitic Glaucoma © Keith Barton Chapter 110 Aqueous Shunts: Choice of Implant © Keith Barton Chapter 118 Aqueous Shunts after Retinal Surgery © Keith Barton Chapter 128 Devices in Development and New Procedures © Tarek M Shaarawy. Video spotlight 88-2 Diagnosis and Management of the Cyclodialysis Cleft © Moorfields Eye Hospital, 2006 Video 113-1 Surgical Technique for the Ahmed Implant © University of Tennessee, Memphis, 1998 Video spotlight 116-2 Blocked Tube and Ahmed Extender © Moorfields Eye Hospital Video 128-1 Ex-Press Aqueous Flow © Tarek M Shaarawy Video 128-2 C02 Laser-Assisted Sclerectomy Surgery © Tarek M Shaarawy Video spotlight 128-3 The InnFocus MicroShunt Surgical Technique © Isabelle Riss Video 128-4 Xen Implant Surgical Technique © Tarek M Shaarawy Video 128-5 Stegmann Canal Expander © Tarek M Shaarawy Video 128-8 High Frequency Deep Sclerotomy © Tarek M Shaarawy Video 128-9 Hydrus Implant © Tarek M Shaarawy Video 128-10 CyPass Implant © Tarek M Shaarawy First edition 2009 The right of Tarek M Shaarawy, Mark B Sherwood, Roger A Hitchings and Jonathan G Crowston to be identified as authors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-7020-5193-7 e-book ISBN: 978-0-7020-5541-6

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

Video Table of Contents Videos available at www.expertconsult.com More than 3 hours of footage available.

8

Mechanical Strain and Restructuring of the Optic Nerve Head

8-1

Laminar Microstructure Deformation  J CRAWFORD DOWNS

15

Gonioscopy

15-1

Video spotlight: Pseudoexfoliation  TAREK M SHAARAWY

16

Ultrasound Biomicroscopy

16-1

UBM Accomodation  GIORGIO MARCHINI

17

Angle Imaging: Ultrasound Biomicroscopy and Anterior Segment Optical Coherence Tomography

17-1

360° Angle Evaluation with Anterior Segment Optical Coherence Tomography  GUS GAZZARD

88-1

Video spotlight: Palmberg Compression Sutures and Autologous Blood  TAREK M SHAARAWY

88-2

Video spotlight: Diagnosis and Management of the Cyclodialysis Cleft  SONYA L BENNETT, ALAN LACEY and KEITH BARTON

97

Deep Sclerectomy

97-1

Deep Sclerectomy  ANDRÉ MERMOUD

97-2

Video spotlight: Removal of the Juxtacanalicular Trabeculum  TAREK M SHAARAWY

97-3

Video spotlight: Collagen Implant in Deep Sclerectomy  TAREK M SHAARAWY

97-4

Video spotlight: Aqueous Percolating after Full Dissection  TAREK M SHAARAWY

99

Complications of Nonpenetrating Glaucoma Surgery

99-1

Video spotlight: Deep Sclerectomy-Conversion to Trabeculectomy  JUAN ROBERTO SAMPAOLESI

77

Trabeculectomy

77-1

Trabeculectomy with Fornix-based Conjunctival Flap – Clip One  DAVINDER S GROVER AND RONALD L FELLMAN

77-2

Trabeculectomy with Fornix-based Conjunctival Flap – Clip Two  RONALD L FELLMAN

100 Postoperative Management of Nonpenetrating

77-3

Trabeculectomy Closure  DAVINDER S GROVER AND RONALD L FELLMAN

100-1

77-4

Video spotlight: Creating a Limbal-based Conjunctival Flap  MICHAEL A COOTE

101 Results of Nonpenetrating Glaucoma Surgery

78

Tenon’s Cyst Formation, Wound Healing, and Bleb Evaluation

78-1

Video spotlight: Needling Old Bleb with 5FU and Avastin  SERGEY PETROV

82

Choroidal Effusion

82-1

Video spotlight: Drainage of Choroidal Effusion  DAVID S GREENFIELD

83

Trabeculectomy Related Corneal Complications

83-1

Surgical Excision of Cornealized Bleb  FATHI F EL SAYYAD

101-1

Late Bleb Leaks

86-1

Video spotlight: Needling  TAREK M SHAARAWY

Late Hypotony

Goniopuncture and Complications  TAREK M SHAARAWY

Phacoviscocanalostomy and Sclerectomy  JORGE ACOSTA

105 One-site Combined Surgery/Two-site Combined Surgery

105-1

One-site Combined Surgery  YVONNE M BUYS

105-2

Two-site Combined Surgery  YVONNE M BUYS

106 Combined Cataract Extraction and Glaucoma Drainage Implant Surgery

106-1

86

88

Glaucoma Surgery

Video spotlight: Combined Ahmed Valve and Phacoemulsification  OSCAR ALBIS-DONADO AND RICARDO DE LIMA

107 Combined Cataract and Nonpenetrating Glaucoma Surgery

xi

xii 107-1

Video Table of Contents Combined Phacoemulsification Nonpenetrating Glaucoma Surgery  GEMA REBOLLEDA, FRANCISCO J MUÑOZ-NEGRETE, and JAVIER MORENO-MONTAÑES

111 Surgical Technique 1 (Molteno Glaucoma Implant)

111-1

Surgical Technique for the Molteno Glaucoma Implant  ANTHONY CB MOLTENO

112 Surgical Technique 2 (Baerveldt Glaucoma Implant)

112-1

Video spotlight: Baerveldt Implantion without Ligation  CATHERINE J HEATLEY, K SHENG LIM and KEITH BARTON

112-2

Video spotlight: Early Control of Intraocular Pressure in Nonvalved Drainage Implant  MARK B SHERWOOD

113 Surgical Technique 3 (Ahmed Glaucoma Valve Drainage Implant)

113-1

Surgical Technique for the Ahmed Implant  PETER A NETLAND

113-2

Video spotlight: Ahmed Surgical Pearls  REMO SUSANNA

113-3

Video spotlight: Envelope and Trench Technique to Prevent Tube Erosion  TAREK M SHAARAWY

113-4

Video spotlight: Needling Old Ahmed Valve Bleb with 5FU and Avastin  SERGEY PETROV

116 Postoperative Complications

122 Cyclodestructive Techniques 122-1

Transcleral Cycloblation with Diode Laser  LAURA CRAWLEY and PHILIP A BLOOM

123 Endophotocoagulation 123-1

The Combined Procedure Phaco and ECP  STANLEY J BERKE

125 Trabectome 125-1

Video spotlight: Trabectome  DON MINCKLER

126 The Ex-PRESS™ Miniature Glaucoma Implant 126-1

Ex-Press 200 Glaucoma Implant Under a Scleral Flap  ELIE DAHAN, ANDRÉ MERMOUD and TAREK M SHAARAWY

126-2

Video spotlight: EX-Press Shunt  ALEXANDER V KUROYEDOV

126-3

Laser Treatment for Blocked Ex-Press Implant  TAREK M SHAARAWY

127 Canaloplasty 127-1

Video spotlight: Canaloplasty: Circumferential Viscodilation and Suture Tensioning of Schlemm’s Canal  RONALD L FELLMAN

128 Devices in Development and New Procedures 128-1

Ex-Press Aqueous Flow  TAREK M SHAARAWY

128-2

C02 Laser-Assisted Sclerectomy Surgery  TAREK M SHAARAWY

128-3

Video spotlight: The InnFocus MicroShunt Surgical Technique  ISABELLE RISS

116-1

Video spotlight: Managing a Tube Erosion  TAREK M SHAARAWY

116-2

Video spotlight: Blocked Tube and Ahmed Extender  CATHERINE J HEATLEY, K SHENG LIM and KEITH BARTON

128-4

Xen Implant Surgical Technique  TAREK M SHAARAWY

116-3

Video spotlight: Removal of Ahmed Drainage Implant Plate  TAREK M SHAARAWY

128-5

Stegmann Canal Expander  TAREK M SHAARAWY

128-6

Video spotlight: GATT: Gonioscopy Assisted Transluminal Trabeculotomy  RONALD L FELLMAN and DAVINDER S GROVER

128-7

Video spotlight: iStent  THIERRY ZEYEN

128-8

High Frequency Deep Sclerotomy  TAREK M SHAARAWY

128-9

Hydrus Implant  TAREK M SHAARAWY

118 Aqueous Shunts after Retinal Surgery 118-1

Aqueous Shunts after Retinal Surgery  USMAN A SARODIA, AROSHA FERNANDO, ALAN LACEY and KEITH BARTON

120 Goniotomy and Trabeculotomy 120-1 120-2 120-3

Goniotomy  PENG TEE KHAW Video spotlight: Classical Trabeculotomy  FRANZ GREHN Video spotlight: 360° Trabeculotomy Using an Illuminated Catheter  FRANZ GREHN

128-10 CyPass Implant  TAREK M SHAARAWY

First Edition Foreword In spite of the widespread use of the internet, there seems to be a need for a book that reports on the current philosophy of glaucoma and explores the boundaries of its many subjects. The Editors, who are among the leaders in glaucoma field, have demonstrated their competence by choosing some of the best people to write the chapters for both volumes. This first volume deals with the non-surgical aspects of glaucoma. Reading some of the chapters, I was not surprised by the advances that have occurred since the last book of this kind was compiled. The chapter on the molecular biology of our genetic knowledge is a good example of the explosion of our knowledge, but we are not anywhere near the time when the genetics of the elevated intraocular pressure are known and we are quite in the dark of the genetics of the many other risk factors at play in this multifactorial disease. Quoting from the book ‘It is now clear that glaucoma has wide genetic heterogeneity with no single gene accounting for all cases of any single glaucoma phenotype. In other words, alterations in different genes can lead to the same phenotype while in other cases variants in the same gene may lead to different phenotypes.’ We are still far away ‘from the time when it will be possible to predict at birth what ailments we are prone to and whether glaucoma is on the cards for the individual.’ We are also much more aware of geographical differences in the disease and of the economic imperatives which affect many aspects of the disease. The philosophy of screening, the pathogenesis of the diseases, the role of the vascular factors, the definition of the disease and its diagnosis, the ever more sophisticated diagnostic tools available, the many types of glaucoma and their managements as well as the medical agents are all included. The recognition that there are risk factors, in addition to intraocular pressure, for the development of glaucoma and its progression have not yet fully found their way into clinical practice. We remain surprised when patients with major reduction of their IOP either continue to progress or start to progress again later

in their lives. I know that under these circumstances the further reduction of the pressure in the eye is usually contemplated before considering whether there are other risk factors responsible for the progression. It is often stated, that nothing can be done about these other, non pressure, risk factors. Some of these other risk factors can be controlled or treated at present providing they are looked for and recognized. We do not have evidence-based knowledge that their control and treatment favorably affects the disease. If we channeled a fraction of our effort and resources to the entire disease, instead of channeling them almost entirely to IOP and its control, rapid progress would be made. Both of the controlled clinical trials, CNTGS and EMGT, which followed, for the first time, untreated glaucoma patients over fairly long periods of time make it clear that the course of untreated glaucoma is variable. Half of the untreated newly diagnosed patients with NTG showed no progression over a 5- to 8-year period. In the EMGT in patients with IOPs between 21 and 30 mmHg the number of untreated patients who did not progress was still 20%. It is not difficult to identify those patients in whom the disease progresses rapidly which would endanger their future visual well being. They clearly require appropriate treatment. On the other hand those in whom we can not identify current progression or find progression which is so slow as not to endanger their visual competence in their predicted life span probably require a different management. This is not currently widely practiced even though the information from the CNTGS and the EMGT have been in the public domain for quite a long time. One of my former fellows often said ‘everybody writes but nobody reads’. While this is an amusing exaggeration I know that this comprehensive book will deserve to be read widely. Stephen M Drance, OC MD Vancouver

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Preface The first edition of “Glaucoma” was published 5 years ago and almost instantly found its place as a comprehensive tool for glaucoma surgeons and general ophthalmologists alike. It has been praised by our peers and has received excellent reviews. Five years on we are both thankful to our colleagues and humbled by their kind words. Never the less, we continually aspire to build on feedback received and commit to keeping current and comprehensive. It is evident that the last 5 years have seen important strides in the accumulated knowledge about glaucoma, and, in this day and age, it is imperative to keep up-to-date. We are proud to present a second edition that is more encompassing and that expands on novel features, namely the spotlights, which make it both appealing and user friendly. In these concise cameos, not only do we aim to present the point of view of a chapter author but, whenever there is room for controversy, evidence-based counterpoints are proposed as well. We were able to draw in many experts in the field offering a podium to ponder specific points of view and challenging ideas.

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As skill transfer becomes more accessible with the convenience of the Internet, a significant update of the book’s video content was particularly important to our readers. We are confident that doubling the number of video clips in the second edition will be valuable. As with the first edition, our efforts have been intelligently channelled by Russell Gabbedy, and joined, for the second edition by Alexandra Mortimer, Humayra Rahman Khan and Umarani Natarajan of Elsevier who, through a lot of time and energy, have guided and positively encouraged the whole process. We are forever in their debt.

Tarek M Shaarawy Mark B Sherwood Roger A Hitchings Jonathan G Crowston

List of Contributors Leslie Abrams-Tobe, MD

Clinical Research Fellow, Glick Eye Institute, Department of Ophthalmology, Indiana University Medical Center, Indianapolis, IN, USA Ch 24 Spotlight: Value of Blood Flow in Studies

Samer A Abuswider, MBBCh FRCS(Glasg)

Clinical Glaucoma Fellow, Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada Ch 71 Selective Laser Trabeculoplasty

Jorge Acosta, MD

Consultant Professor of Ophthalmology, CEMIC University, Buenos Aires, Argentina Ch 101 Results of Nonpenetrating Glaucoma Surgery Video 101-1 Phacoviscocanalostomy and Sclerectomy

Pavi Agrawal, BSc MBBChir(cantab) FRCOPhth

Consultant Ophthalmic Surgeon, Nottingham University Hospital, Nottingham, UK Ch 17 Angle Imaging: Ultrasound Biomicroscopy and Anterior Segment Optical Coherence Tomography

Nitin Anand, MBBS MD(Ophth) FRCSEd FRCOphth

Consultant Ophthalmology and Glaucoma Specialist, Calderdale and Huddersfield NHS Trust, Lindley, Huddersfield, UK Ch 45 Target Intraocular Pressure Ch 97 Spotlight: Enhancing Deep Sclerectomy Result with Antimetabolites

Florent Aptel, MD PhD

Professor, Joseph Fourier University; Hospital Practitioner, Department of Ophthalmology, University Hospital, Grenoble, France Ch 89 Cataract Following Trabeculectomy

Makoto Araie, MD PhD

Director, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers; Professor Emeritus, The University of Tokyo, Visiting Professor, Ophthalmology, Saitama Medical University, Kamiyoga, Setagaya-ku, Tokyo, Japan Ch 43 Management of Normal Tension Glaucoma

Enyr S Arcieri, MD

Glaucoma Assistant Professor, Instituto Mexicano de Oftalmología, Queretaro, Mexico Ch 117 Glaucoma Implants: Results Video spotlight 106-1 Combined Ahmed Valve and Phacoemulsification

Professor of Ophthalmology, Presidente Antônio Carlos University (UNIPAC), Araguari, Minas Gerais; Medical Assistant, Glaucoma Service, University of Campinas (UNICAMP), Campinas, São Paulo; Medical Assistant, Glaucoma Service, Federal University of Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil Ch 106 Combined Cataract Extraction and Glaucoma Drainage Implant Surgery

Luciana M Alencar, MD PhD

Ehud I Assia, MD

Oscar Albis-Donado, MD

Assistant Physician in Ophthalmology, University of São Paulo, São Paulo; Director, Glaucoma Department, Hospital Oftalmológico de Brasília, Brasília, Brazil Ch 13 Function Specific Perimetry

R Rand Allingham, MD

Richard and Kit Barkhouser Professor of Ophthalmology, Director, Division of Glaucoma, Duke Department of Ophthalmology, Associate Faculty, Center of Human Genetics, Durham NC, USA Ch 25 Genetics of Glaucoma Ch 31 Exfoliation Syndrome and Exfoliative Glaucoma

Annahita Amireskandari, MD

Clinical Research Fellow, Glick Eye Institute, Department of Ophthalmology, Indiana University Medical Center, Indianapolis, IN, USA Ch 24 Spotlight: Value of Blood Flow in Studies

Director, Department of Ophthalmology, Meir Medical Center, Kfar-Saba; Medical Director, Ein-Tal Eye Center, Tel-Aviv; Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel Ch 97 Spotlight: CO2 Laser Assisted Sclerectomy Surgery (CLASS) for Open-Angle Glaucoma Treatment

Tin Aung, FRCS(Ed) PhD

Professor, Senior Consultant and Head, Glaucoma Service, Singapore Eye Research Institute and Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Ch 30 Spotlight: Angle-Closure

George Baerveldt, MD

Ophthalmologist, NVision Centers, Newport Beach, CA, USA Ch 112 Surgical Technique 2 (Baerveldt Glaucoma Implant)

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xvi

List of Contributors

Nafees Baig, FCOphthHK FHKAM

Clinical Assistant Professor (Honorary), Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong; Associate Consultant, Hong Kong Eye Hospital, Hong Kong SAR, People’s Republic of China Ch 72 Peripheral Iridotomy for Angle-Closure Glaucoma Ch 103 The Role of Lens Extraction in Primary Angle Closure Glaucoma

Annie K Baik, MD

Assistant Clinical Professor of Ophthalmology, UC Davis Eye Center, Sacramento, CA, USA Ch 124 Spotlight: Sympathetic Ophthalmia

Allen Beck, MD

Professor, Department of Ophthalmology, Emory University, Atlanta, GA, USA Ch 34 Childhood Glaucomas

Sonya L Bennett, MBChB FRANZCO

Consultant Ophthalmologist City Eye Specialists; Ophthalmology Clinic, Greenlane Clinical Centre, Auckland District Health Board; Senior Clinical Lecturer, Ophthalmology Department, University of Auckland, Auckland, New Zealand Video spotlight 88-2 Diagnosis and Management of the Cyclodialysis Cleft

Stanley J Berke, MD FACS

Associate Clinical Professor of Ophthalmology, Department of Ophthalmology, Columbia University Medical Center, New York, NY, USA Ch 79 Intraoperative Complications of Trabeculectomy

Associate Clinical Professor of Ophthalmology, Hofstra North Shore-LIJ School of Medicine, Chief, Glaucoma Service, Nassau University Medical Center, East Meadow, NY, USA Ch 123 Endophotocoagulation Video 123-1 The Combined Procedure Phaco and ECP

Mirko Babic

Tui H Bevin, MPH

Rajendra K Bansal, MD

Assistant of Ophthalmology, University of São Paulo, São Paulo, Brazil Ch 114 Other Glaucoma Implants

Anita Barikian, MD

Research Fellow, Ophthalmology Department, American University of Beirut, Beirut, Lebanon Ch 60 Glaucoma Secondary to Trauma

Howard Barnebey, MD

Glaucoma Specialist, Specialty Eyecare Centre, Seattle, WA, USA Ch 21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis

Keith Barton, MD FRCP FRCS

Glaucoma Service and NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, and Department of Genetics and Epidemiology, UCL Institute of Ophthalmology, London, UK Ch 36 Uveitic Glaucoma Video spotlight 88-2 Diagnosis and Management of the Cyclodialysis Cleft Ch 110 Aqueous Shunts: Choice of Implant Video spotlight 112-1 Baerveldt Implantion without Ligation Video spotlight 116-2 Blocked Tube and Ahmed Extender Ch 118 Aqueous Shunts after Retinal Surgery Video 118-1 Aqueous Shunts after Retinal Surgery

Christophe Baudouin, MD PhD

Professor and Chair of Ophthalmology, Department of Ophthalmology, Quinze-Vingts National Ophthalmology Hospital, Paris; University of Versailles Saint-Quentinen-Yvelines, Versailles; Institut de la Vision, Paris, France Ch 91 Modulation of Wound Healing: Choice of Antifibrosis Therapies

Research Fellow in Ophthalmology, Department of Medicine, University of Otago Dunedin School of Medicine, Dunedin, New Zealand Ch 111 Surgical Technique 1 (Molteno Glaucoma Implant)

Shibal Bhartiya, MS

Consultant, Glaucoma Services, Fortis Memorial Research Institute, Haryana, India Ch 96 Principle and Mechanism of Function Ch 97 Spotlight: If Primary Deep Sclerectomy Fails Ch 100 Postoperative Management of Nonpenetrating Glaucoma Surgery

Philip A Bloom, FRCS FRCOphth

Consultant Ophthalmologist, Western Eye Hospital, Marylebone Road, London, UK Ch 122 Cyclodestructive Techniques Video 122-1 Transcleral Cycloblation with Diode Laser

Dana M Blumberg, MD MPH

Assistant Professor of Ophthalmology, Columbia University College of Physicians and Surgeons; New York-Presbyterian Hospital and Columbia University Medical Center, New York, NY, USA Ch 67 When to Perform Glaucoma Surgery

Kathryn Bollinger, MD

Assistant Professor in Ophthalmology, Department of Ophthalmology, Georgia Health Sciences Health System, Medical College of Georgia, Augusta, GA, USA Ch 40 Glaucoma and Intraocular Tumors

Christopher Bowd, PhD

Research Scientist of Ophthalmology, Director of the Hamilton Glaucoma, Center-based Visual Field Assessment Center, UC San Diego Shiley Eye Center, La Jolla, CA, USA Ch 20 Optic Disc Imaging

List of Contributors

John W Boyle IV, MD

Partner, Gulf South Eye Associates, Metairie, LA, USA Ch 113 Surgical Technique 3 (Ahmed Glaucoma Valve Drainage Implant)

James D Brandt, MD

Professor of Ophthalmology & Vision Science, University of California, Davis, CA, USA Ch 18 The Impact of Central Corneal Thickness and Corneal Biomechanics on Tonometry Ch 124 Spotlight: Sympathetic Ophthalmia

David C Broadway, MD FRCOphth

Consultant and Honorary Professor, Department of Ophthalmology, Norfolk and Norwich University Hospital and Schools of Biological Science & Pharmacy, University Of East Anglia, Norwich, UK Ch 75 Preoperative Conjunctival Health and Trabeculectomy Outcome Ch 122 Spotlight: Operative Techniques Ch 122 Spotlight: Postoperative Management and Interventions

Stephen Brocchini, PhD

Professor of Chemical Pharmaceutics, UCL School of Pharmacy and National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 95 Future Strategies

Alain M Bron, MD

Professor of Ophthalmology, Department of Ophthalmology, University Hospital Dijon, University of Burgundy, Dijon, France Ch 19 Optic Disc Photography in the Diagnosis of Glaucoma Ch 89 Cataract Following Trabeculectomy

Donald L Budenz, MD MPH

Jennifer Burr, MD

Reader, Population and Behavioural Health Sciences, School of Medicine, University of St Andrews, St Andrews, Fife, UK Ch 47 Medical Management of Glaucoma: Cost-effectiveness

Yvonne M Buys, MD FRCSC

Professor, Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto Western Hospital, Toronto, ON, Canada Ch 105 One-site Combined Surgery/Two-site Combined Surgery Video 105-1 One-site Combined Surgery Video 105-2 Two-site Combined Surgery

Louis B Cantor, MD

Chair and Professor of Ophthalmology, Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA Ch 116 Postoperative Complications

Joseph Caprioli, MD

David May II Professor of Ophthalmology, UCLA David Geffen School of Medicine, Chief, Glaucoma Division, Jules Stein Eye Institute, Los Angeles, CA, USA Ch 23 Measuring Glaucoma Progression in Clinical Practice

Roberto G Carassa, MD

Director, Italian Glaucoma Center, Milano, Italy Ch 98 Viscocanalostomy

Daniel S Casper, MD PhD

Associate Clinical Professor of Ophthalmology, Department of Ophthalmology, Columbia University Medical Center, New York, NY, USA Ch 79 Intraoperative Complications of Trabeculectomy

Kittner Family Distinguished Professor and Chairman, Department of Ophthalmology, UNC School of Medicine, Chapel Hill, NC, USA Ch 4 Practical Application of Glaucoma Care in Different Societies

Yara Paula Catoira-Boyle, MD

Catey Bunce, BSc(Hons) MSc DSc

Piero Ceruti, MD

Senior Statistician, Moorfields Eye Hospital, NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 26 Genetic Epidemiology

Claude F Burgoyne, MD

Senior Scientist, Van Buskirk Chair for Ophthalmic Research, and Research Director, Optic Nerve Head Research Laboratory, Devers Eye Institute, Legacy Health, Portland, OR, USA Ch 8 Mechanical Strain and Restructuring of the Optic Nerve Head

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Associate Clinical Professor of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA Ch 116 Postoperative Complications Head of Vitreo-retinal Service, Coordinator of Glaucoma Research Activity, University Eye Clinic Department of Neurological and Movement Sciences, University of Verona, Borgo Trento Hospital, Verona, Italy Ch 16 Ultrasound Biomicroscopy

Debasis Chakrabarti, MS

Consultant, Glaucoma Services, Suryodaya Eye Centre, The Calcutta Medical and Research Institute (CMRI), Kolkata, West Bengal, India Ch 81 Postoperative Shallow Anterior Chamber

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List of Contributors

Raka Chakrabarti, MS

Etsuo Chihara, MD

Pratap Challa, MD

Neil T Choplin, MD

Errol Chan, MBBS MMed FRCOphth

George A Cioffi, MD

Consultant Ophthalmologist, Susrut Eye Foundation and Research Centre, Salt Lake, Kolkata, India Ch 81 Postoperative Shallow Anterior Chamber Associate Professor of Ophthalmology, Director, Residency Training Program, Duke University, Durham, NC, USA Ch 80 Early Postoperative Increase in Intraocular Pressure Registrar, Department of Ophthalmology, National University Health System, Singapore Ch 3 Spotlight: Economics of Glaucoma Care in Asian Countries: An Overview

Peter T Chang, MD

Associate Professor of Ophthalmology, Director, Glaucoma Fellowship, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, USA Ch 115 Intraoperative Complications

Robert T Chang, MD

Assistant Professor, Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Stanford, CA, USA Ch 92 Technique

Balwantray C Chauhan, PhD

Mathers Professor, Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada Ch 12 Long-term Follow-Up of Visual Fields

Aiyin Chen, MD

Clinical Glaucoma Fellow, Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA Ch 85 Late Failure of Filtering Bleb

Jason Cheng, MBBS FRCOphth FEBO

Associate Consultant, Ophthalmologist, Khoo Teck Puat Hospital, Singapore Ch 105 One-site Combined Surgery/Two-site Combined Surgery

Paul TK Chew, FRCSEd FRCOphth

Head, Glaucoma Division, Department of Ophthalmology, National University Health System, Singapore Ch 3 Spotlight: Economics of Glaucoma Care in Asian Countries: An Overview Ch 44 Spotlight: An Overview of Angle-Closure Management

Mark Chiang, MBBS(Qld) MPhil FRANZCO

Consultant Ophthalmologist, Queensland Eye Institute, City Eye Centre, Royal Children’s Hospital, Brisbane, QLD, Australia Ch 87 Blebitis and Endophthalmitis

Director, Sensho-kai Eye Institute, Kyoto, Japan Ch 119 Spotlight: Endothelial Cell Count PostDrainage Implant Surgery Adjunct Clinical Professor of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD; Private Practice, Eye Care of San Diego, San Diego, CA, USA Ch 21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis Jean and Richard Deems Professor, Edward S. Harkness Professor and Chairman, Columbia University, College of Physicians and Surgeons; Ophthalmologist-in-Chief, New York-Presbyterian Hospital, New York, NY, USA Ch 67 When to Perform Glaucoma Surgery

Colin I Clement, BSc(Hon) MBBS PhD FRANZCO

Clinical Senior Lecturer, The University of Sydney; Glaucoma Unit, Sydney Eye Hospital; Eye Associates, Sydney, NSW, Australia Ch 50 Outcomes

Anne L Coleman, MD PhD

Fran and Ray Stark Professor of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA; Professor of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles, CA, USA Ch 62 Interpreting Clinical Studies on Glaucoma Neuroprotection

Nathan G Congdon, MD MPH

Professor of Ophthalmology and Public Health, Chinese University of Hong Kong; Joint Professor, Shantou International Eye Center, Shantou, People’s Republic of China Ch 4 Practical Application of Glaucoma Care in Different Societies Ch 72 Peripheral Iridotomy for Angle-Closure Glaucoma

Michael A Coote, MB BS FRANZCO GAICD

Associate Professor, Centre for Eye Research Australia and Clinical Director of Ophthalmology, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia Ch 19 Spotlight: Benchmarking Optic Disc Examination Ch 102 Cataract Surgery in Open-Angle Glaucoma Video spotlight 77-4 Creating a Limbal-based Conjunctival Flap

Vital P Costa, MD

Director, Glaucoma Service and Professor of Ophthalmology, University of Campinas, São Paulo, Brazil Ch 56 Parasympathomimetics Ch 106 Combined Cataract Extraction and Glaucoma Drainage Implant Surgery

List of Contributors

David P Crabb, PhD

Professor of Statistics and Vision Research, Department of Optometry and Visual Science, City University, London, UK Ch 11 Visual Fields

Alan S Crandall, MD

John A. Moran Presidential Professor of Ophthalmology and Visual Sciences, Senior Vice Chair, Director of Glaucoma and Cataract; Co-Director of Moran International Division, University of Utah School of Medicine, Salt Lake City, UT, USA Ch 104 Spotlight: Bleb Management

E Randy Craven, MD

Chief of Glaucoma, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Associate Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA Ch 21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis

Laura Crawley, BSc(Hons)MB ChB(Hons) MRCP FRCOphth

Fellow of Ophthalmology, Imperial College Healthcare NHS Trust, London, UK Ch 122 Cyclodestructive Techniques Video 122-1 Transcleral Cycloblation with Diode Laser

Jonathan G Crowston, PhD FRCOphth FRANZCO

Ringland Anderson Professor, Head of Ophthalmology, Melbourne University; Director, Centre for Eye Research Australia, Melbourne, Australia Ch 19 Spotlight: Benchmarking Optic Disc Examination Ch 78 Tenon’s Cyst Formation, Wound Healing, and Bleb Evaluation

Emmett T Cunningham, Jr., MD PhD MPH

Director, The Uveitis Service, California Pacific Medical Center, San Francisco; Adjunct Clinical Professor of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA Ch 36 Spotlight: Uveitic Glaucoma

The late Elie Dahan, MD

Formerly Senior Consultant, Glaucoma and Pediatric Ophthalmology, Ein Tal Eye Hospital, Tel Aviv; Honorary Senior Consultant, Tel Aviv University; Head of the Glaucoma Service, Jerusalem University Hospital, Jerusalem, Israel Ch 77 Spotlight: Anterior Chamber Maintainer Ch 126 The Ex-PRESS™ Miniature Glaucoma Implant Video 126-1 Ex-Press 200 Glaucoma Implant Under a Scleral Flap

Annegret H Dahlmann-Noor, MD PhD

Consultant Ophthalmologist, National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 95 Future Strategies

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Karim F Damji, MD FRCSC MBA

Professor, Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada Ch 71 Selective Laser Trabeculoplasty

Alexander Day, PhD MRCOphth

NIHR Clinical Lecturer, NIHR Biomedical Research Centre, Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, UK Ch 30 Primary Angle-Closure Glaucoma

Me’Ja Day, BS

Medical Student, Morehouse School of Medicine, Atlanta, GA, USA Ch 71 Spotlight: Laser Trabeculoplasty: A PatientCentred View

Philippe Denis, MD PhD

Professor of Ophthalmology, Department of Ophthalmology, Croix-Rousse Hospital, University Hospitals of Lyon, France Ch 122 Spotlight: UC3 Novel Ultrasound Circular Cyclo-Coagulation

Syril Dorairaj, MD

Assistant Professor of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA Ch 35 Secondary Angle-Closure Glaucoma Ch 41 Glaucoma in the Phakomatoses and Related Conditions

J Crawford Downs, PhD

Professor and Vice Chair of Basic Science Research, Department of Ophthalmology; Director, Center for Ocular Biomechanics and Biotransport, The University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA Ch 8 Mechanical Strain and Restructuring of the Optic Nerve Head Video 8-1 Laminar Microstructure Deformation

Gordon N Dutton, FRCS FRCOphth MD

Professor, Department of Visual Science, Glasgow Caledonian University, Glasgow, Scotland, UK Ch 57 Fixed Combination Therapies in Glaucoma

Hassan Eldaly, MBBS MSc Ophth

Consultant Ophthalmologist, Glaucoma Specialist, Kom Ombo Ophthalmic Hospital, Aswan Eye and Laser Center, Aswan, Egypt Ch 10 Spotlight: Tonometry and Intraocular Fluctuation

Fathi F El Sayyad, FRCSEd FRCOphth

Professor of Ophthalmology, Director of El Sayyad Eye Center, Cairo, Egypt Ch 83 Trabeculectomy Related Corneal Complications Video 83-1 Surgical Excision of Cornealized Bleb

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List of Contributors

Benedetto Falsini, MD

Brad Fortune, OD PhD

The late Francisco Fantes, MD

Paul Foster, PhD FRCS(Ed) FRCOphth

Adjunct Investigator, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD, USA Ch 24 Spotlight: Practicalities Formerly Professor of Clinical Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA Ch 93 Complications Associated with Modulation of Wound Healing in Glaucoma Surgery

Herbert P Fechter III, MD PE

Associate Scientist and Director, Electrodiagnostics Service, Discoveries in Sight Research Laboratories, Devers Eye Institute, Legacy Health, Portland, OR, USA Ch 14 Electrophysiology in Glaucoma Assessment Professor of Glaucoma Studies and Ophthalmic Epidemiology, NIHR Biomedical Research Centre, Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, UK Ch 30 Primary Angle-Closure Glaucoma

Assistant Professor, Uniformed Services University; Private Practice, Eye Physicians and Surgeons of Augusta, Augusta, GA, USA Ch 93 Complications Associated with Modulation of Wound Healing in Glaucoma Surgery

Panayiota Founti, MD PhD

Robert D Fechtner, MD

Professor of Clinical Ophthalmology, Department of Ophthalmology, SUNY, New York, NY, USA Ch 109 Preoperative Evaluation of Patients Undergoing Drainage Implant Surgery

Professor of Ophthalmology, Institute of Ophthalmology and Visual Science, New Jersey Medical School, Newark, NJ, USA Ch 29 Primary Open-Angle Glaucoma

Ronald L Fellman, MD

Attending Surgeon and Clinician, Glaucoma Associates of Texas; Associate Clinical Professor Emeritus, University of Texas Southwestern Medical Center, Dallas, TX, USA Ch 77 Trabeculectomy Video 77-1 Trabeculectomy with Fornix-based Conjunctival Flap – Clip One Video 77-2 Trabeculectomy with Fornix-based Conjunctival Flap – Clip Two Video 77-3 Trabeculectomy Closure Video spotlight 127-1 Canaloplasty: Circumferential Viscodilation and Suture Tensioning of Schlemm’s Canal Video spotlight 128-6 GATT: Gonioscopy Assisted Transluminal Trabeculotomy

Eva Fenwick, PhD

Research Fellow, Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia Ch 46 Spotlight: Evaluation of Quality of Life

Arosha Fernando, MRCOphth

Specialist Registrar, Moorfields Eye Hospital, London, UK Video spotlight 118-1 Aqueous Shunts after Retinal Surgery

Ophthalmologist, Undergraduate Teaching Fellow, Moorfields Eye Hospital, London, UK Ch 46 Quality of Life

Jeffrey Freedman, MB BCh PhD FRCS(Edin) FCS(SA)

Stefano A Gandolfi, MD

Full Professor of Ophthalmology and Chairman, University Eye Clinic, University of Parma, Parma, Italy Ch 32 Pigmentary Glaucoma Ch 101 Spotlight: Nonpenetrating Surgery: When is this my Preferred Option?

Julián García-Feijoó, MD PhD

Professor and Chairman, Department of Ophthalmology, Instituto de Investigación, Hospital Clínico San Carlos, Universidad Complutense, Oftared, Madrid, Spain Ch 128 Spotlight: Combined Trabecular Micro-Bypass Stent Implantation and Phacoemulsification

David Garway-Heath, MD FRCOphth

IGA Professor of Ophthalmology, Glaucoma and Allied Studies, UCL Institute of Ophthalmology; Consultant Ophthalmic Surgeon, Moorfields Eye Hospital; Theme Leader for Visual Assessment and Imaging, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 10 Tonometry and Intraocular Pressure Fluctuation

Gus Gazzard, MD

Clinical Assistant Professor, Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Stanford, CA, USA Ch 92 Technique

Honorary Senior Lecturer and Consultant Ophthalmic Surgeon, Glaucoma Service, Moorfields Eye Hospital, London, UK Ch 17 Angle Imaging: Ultrasound Biomicroscopy and Anterior Segment Optical Coherence Tomography Video 17-1 360° Angle Evaluation with Anterior Segment Optical Coherence Tomography

Frederick W Fitzke, PhD

Steven J Gedde, MD

Ann Caroline Fisher, MD

Professor of Visual Optics and Psychophysics, Division of Visual Science, UCL Institute of Ophthalmology, University College London, London, UK Ch 65 Ultrastructural Imaging

Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA Ch 84 Aqueous Misdirection Ch 117 Spotlight: TVT Study

List of Contributors

Noa Geffen, MD

Ophthalmologist, Department of Ophthalmology, Meir Medical Center, Kfar-Saba; Ein-Tal Eye Center, Tel-Aviv, Israel Ch 97 Spotlight: CO2 Laser Assisted Sclerectomy Surgery (CLASS) for Open-Angle Glaucoma Treatment

Stelios Georgoulas, MD PhD

Specialist Trainee in Ophthalmology, National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 95 Future Strategies

Annette Giangiacomo, MD

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David S Greenfield, MD

Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Palm Beach Gardens, FL, USA Video spotlight 82-1 Drainage of Choroidal Effusion

Franz Grehn, MD PhD

Chairman and Professor, Department of Ophthalmology, University Hospitals Würzburg, Würzburg, Germany Ch 104 Cataract Surgery in Patients with Functioning Filtering Blebs Video spotlight 120-2 Classical Trabeculotomy Video spotlight 120-3 360° Trabeculotomy Using an Illuminated Catheter

Daniel E Grigera, MD

Assistant Professor, Department of Ophthalmology, Emory University, Atlanta, GA, USA Ch 34 Childhood Glaucomas

Head, Glaucoma Service, Hospital Oftalmológico Santa Lucía, Assistant Professor of Ophthalmology, Universidad del Salvador, Buenos Aires, Argentina Ch 101 Results of Nonpenetrating Glaucoma Surgery

Katie Gill, BSc MSc

Ronald L Gross, MD

Zisis Gkatzioufas, MD PhD

Davinder S Grover, MD MPH

PhD Candidate, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Department of Ophthalmology University of Melbourne, Melbourne, VIC, Australia Ch 63 Spotlight: Brain Perspective Assistant Professor, Geneva University Hospitals HUG, Department of Ophthalmology, Geneva, Switzerland Ch 18 Spotlight: What a Glaucoma Specialist Needs to Know About Corneal Biomechanics Ch 18 Spotlight: New Technology to Look at Corneal Biomechanics in Clinic

Ivan Goldberg, AM MBBS(Syd) FRANZCO FRACS

Clinical Associate Professor, University of Sydney; Head, Glaucoma Unit, Sydney Eye Hospital; Director, Eye Associates, Sydney, NSW, Australia Ch 50 Outcomes Ch 71 Spotlight: Long-Term Effects

Pieter Gouws, MBChB(Pretoria) FRCOphth

Consultant Ophthalmologist and Glaucoma Specialist, Conquest Hospital, East Sussex, UK Ch 123 Spotlight: PHACO-ECP

Stuart L Graham, MBBS MS PhD FRANZCO

Professor of Ophthalmology and Vision Science, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia Ch 14 Electrophysiology in Glaucoma Assessment

Alana L Grajewski, MD

Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Director, The Samuel & Ethel Balkan International Pediatric Glaucoma Center, Bascom Palmer Eye Institute, Miami, FL, USA Ch 121 Further Surgical Options in Children

Jane McDermott Schott Chair, Professor and Chairman, Department of Ophthalmology, Director, WVU Eye Institute, West Virginia University School of Medicine, Morgantown, WV, USA Ch 115 Intraoperative Complications Attending Surgeon and Clinician, Glaucoma Associates of Texas; Clinical Assistant Professor, Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA Ch 77 Trabeculectomy Video 77-1 Trabeculectomy with Fornix-based Conjunctival Flap – Clip One Video 77-3 Trabeculectomy Closure Video spotlight 128-6 GATT: Gonioscopy Assisted Transluminal Trabeculotomy

Rafael Grytz, PhD

Assistant Professor, Center for Ocular Biomechanics and Biotransport, Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA Ch 8 Mechanical Strain and Restructuring of the Optic Nerve Head

Meenakashi Gupta, MD

Fellow in Vitreoretinal Surgery, New York Eye and Ear Infirmary, New York, NY, USA Ch 76 Ophthalmic Anesthesia

Neeru Gupta, MD PhD MBA FRCSC DipABO

Professor and Dorothy Pitts Chair, Ophthalmology and Vision Sciences, Laboratory Medicine and Pathobiology; Chief of Glaucoma, University of Toronto; Director, Glaucoma Research, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada Ch 5 Spotlight: Lymphatics and Uveolymphatic Outflow from the Eye

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List of Contributors

Carlos Gustavo de Moraes MD

Associate Professor of Ophthalmology, New York University Medical Center; Edith C. Blum Foundation Research Scientist, Einhorn Clinical Research Center of the New York Eye & Ear Infirmary, New York, NY, USA Ch 114 Other Glaucoma Implants

Ali S Hafez, MD PhD

Assistant Clinical Professor of Ophthalmology, University of Montreal; Assistant Professor of Ophthalmology, McGill University Health Center; Attending Ophthalmologist, Sacre-Coeur Hospital, Maisonneuve Rosemont Hospital, Montreal General Hospital, Montreal, QC, Canada Ch 9 Role of Ocular Blood Flow in the Pathogenesis of Glaucoma Ch 24 Techniques Used for Evaluation of Ocular Blood Flow

Farhad Hafezi, MD PhD

Professor and Chair of Ophthalmology, Department of Ophthalmology, Geneva University Hospitals HUG, Geneva, Switzerland Ch 18 Spotlight: What a Glaucoma Specialist Needs to Know About Corneal Biomechanics

Teruhiko Hamanaka, MD PhD

Director of Ophthalmology, Japanese Red Cross Medical Center, Department of Ophthalmology, Tokyo, Japan Ch 78 Spotlight: Histology of the Mature Functioning Bleb

Alon Harris, MS PhD FARVO

The late Catherine J Heatley, MRCOphth

Ophthalmologist, Moorfields Eye Hospital, London, UK Video spotlight 112-1 Baerveldt Implantion without Ligation Video spotlight 116-2 Blocked Tube and Ahmed Extender

Dale K Heuer, MD

Professor & Chairman of Ophthalmology, Medical College of Wisconsin; Director, Froedtert & Medical College of Wisconsin Eye Institute, Milwaukee, WI, USA Ch 110 Aqueous Shunts: Choice of Implant

Eve J Higginbotham, SM MD

Vice Dean, Perelman School of Medicine; Senior Fellow, Leonard Davis Institute of Health Economics; Professor, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA Ch 71 Spotlight: Laser Trabeculoplasty: A Patient-Centred View

Cornelia Hirn, MD FEBO

Honorary Research Fellow, NIHR Biomedical Research Centre at Moorfields Eye Hospital, NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; Consultant Ophthalmologist, Department of Ophthalmology, City Hospital Triemli, Zurich, Switzerland Ch 10 Tonometry and Intraocular Pressure Fluctuation

Professor of Ophthalmology, Professor of Cellular and Integrative Physiology, and Director Clinical Research, Glick Eye Institute, Department of Ophthalmology, Indiana University Medical Center, Indianapolis, IN, USA Ch 24 Spotlight: Value of Blood Flow in Studies

Roger A Hitchings, FRCS FRCOphth

Marcelo Hatanaka, MD

Gábor Holló, MD PhD DSc

Matthew J Hawker, DM FRCOphth

Ann M Hoste, MD

Head of Glaucoma Service, Department of Ophthalmology, University of São Paulo Medical School, São Paulo, Brazil Ch 114 Other Glaucoma Implants Consultant Ophthalmologist, Department of Ophthalmology, Cambridge University Hospital, Cambridge, UK Ch 75 Preoperative Conjunctival Health and Trabeculectomy Outcome

Paul R Healey, BMedSc MBBS(Hons) MMed PhD FRANZCO

Clinical Associate Professor, Sydney Medical School, University of Sydney, Sydney; Director of Glaucoma Research, University of Sydney, Centre for Vision Research (Westmead Millennium Institute); Director of Glaucoma Services, Western Sydney Eye Hospital, Westmead Hospital, Westmead, NSW, Australia Ch 2 Screening for Glaucoma

Emeritus Professor Glaucoma and Allied Studies, University of London; Consultant Surgeon (rtd), Moorfields Eye Hospital, London, UK Ch 42 Management of Ocular Hypertension and Primary Open-Angle Glaucoma Professor of Ophthalmology, Department of Ophthalmology, Semmelweis University, Budapest, Hungary Ch 54 Carbonic Anhydrase Inhibitors Glaucoma Specialist, Department of Glaucoma, Goes Eye Center, Antwerp, Belgium Ch 53 Beta-Blockers

Andrew Huck, BS

Medical Student, Glick Eye Institute, Department of Ophthalmology, Indiana University Medical Center, Indianapolis, IN, USA Ch 24 Spotlight: Value of Blood Flow in Studies

Cindy ML Hutnik, MD PhD

Professor, Department of Ophthalmology and Pathology, Ivey Eye Institute, London, ON, Canada Ch 71 Spotlight: First Line Treatment with Laser SLT

List of Contributors

Camille Hylton, MD

Glaucoma Specialist, Ophthalmic Physicians and Surgeons Ltd, Phoenix, AZ, USA Ch 34 Childhood Glaucomas

Sabita M Ittoop, MD

L Jay Katz, MD FACS

Professor, Jefferson Medical College; Director of Glaucoma Service and Attending Surgeon, Wills Eye Hospital, Philadelphia, PA, USA Ch 71 Spotlight: Selective Laser Trabeculoplasty

Attending, Glaucoma Consultants of Washington, Herndon, VA, USA Ch 58 Ocular Surface Disease and the Role of Preservatives in Glaucoma Medications

Jill E Keeffe, PhD

Farrah Ja’afar, MD

Thomas Kersey,MD

Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Ch 1 Spotlight: What Prevalence and Geographic Variations Tell Us?

Henry Jampel, MD MHS

Odd Fellows Professor of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, MD, USA Ch 45 Spotlight: Pros and Cons of Using Target Pressures in Clinical Practice

Thomas V Johnson, PhD

MD Candidate, Johns Hopkins School of Medicine, Baltimore, MD, USA Ch 63 Stem Cells: A Future Glaucoma Therapy?

Jost B Jonas, MD

Professor of Ophthalmology and Chairman, Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany Ch 1 Spotlight: China Study Ch 19 Optic Disc Photography in the Diagnosis of Glaucoma

Malik Y Kahook, MD

The Slater Family Endowed Chair in Ophthalmology, Professor of Ophthalmology, Chief, Glaucoma Service, The University of Colorado School of Medicine, Aurora, CO, USA Ch 58 Ocular Surface Disease and the Role of Preservatives in Glaucoma Medications Ch 124 Complications of Cyclodestructive Procedures

Michael A Kass, MD

Professor, L V Prasad Eye Institute, Hyderabad, India Ch 48 Optimizing Quality of Life: Low-vision Rehabilitation in Glaucoma Consultant Ophthalmologist, South Devon Hospital, Ophthalmology Department, Devon, UK Ch 122 Cyclodestructive Techniques

Naira Khachatryan, MD PhD

Postdoc Employee, University of California, San Diego, Department of Ophthalmology, CA, USA Ch 20 Optic Disc Imaging

Sir Peng Tee Khaw, PhD FRCS FRCOpth FSB FRCP FRCPath FARVO FMedSci

Professor of Glaucoma and Ocular Healing, and Consultant Ophthalmic Surgeon, National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 95 Future Strategies Ch 120 Goniotomy and Trabeculotomy Video spotlight 120-1 Goniotomy

Albert S Khouri, MD

Residency Program Director, Assistant Professor, Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ, USA Ch 29 Primary Open-Angle Glaucoma

Dan Kiage, MD

Medical Director and Glaucoma Specialist, Innovation Eye Centre, Kisii, Kenya Ch 2 Spotlight: Screening in Africa

Lee Kiang, MD PhD

Resident, W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA Ch 3 Economics of Glaucoma Care

Professor and Chairman, Ophthalmology and Visual Sciences, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, USA Ch 28 Ocular Hypertension

Daniel Kim, MD

Andreas Katsanos, MD PhD

Professor and Chairman, Hiroshima University, Department of Ophthalmology and Visual Science, Hiroshima, Japan Ch 33 Spotlight: Japanese Perspective

Assistant Professor, University Department of Ophthalmology, Ioannina, Greece Ch 57 Fixed Combination Therapies in Glaucoma

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Ophthalmologist, Facey Medical Group, Mission Hills, CA, USA Ch 37 Neovascular Glaucoma

Yoshiaki Kiuchi, MD PhD

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List of Contributors

Thomas Klink, MD PhD

Ecosse L Lamourex, PhD

Helen Koenigsman, MD

Graham Lee, MD MBBS(Qld) FRANZCO

Senior Consultant, Department of Ophthalmology, University Hospitals Würzburg, Würzburg, Germany Ch 104 Cataract Surgery in Patients with Functioning Filtering Blebs General Ophthalmology and Glaucoma Specialist, Medical Eye Center, Medford, OR, USA Ch 82 Choroidal Effusion

Anastasios GP Konstas, MD PhD

Professor of Ophthalmology, 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece Ch 57 Fixed Combination Therapies in Glaucoma

Aachal Kotecha, PhD

Senior Research Associate, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 10 Tonometry and Intraocular Pressure Fluctuation Ch 46 Quality of Life Ch 65 Ultrastructural Imaging

Avinash Kulkarni, MD

Consultant Ophthalmologist, King’s College Hospital NHS Foundation Trust, London, UK Ch 36 Uveitic Glaucoma

Alexander V Kuroyedov, MD PhD

Chief Ophthalmology Department, Mandryka Clinical Research and Traning Medical Center Moscow, Russia Video spotlight 126-2 EX-Press Shunt

Antoine Labbé, MD PhD

Professor of Ophthalmology, Quinze-Vingts National Ophthalmology Hospital, Paris; Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt; University of Versailles Saint-Quentin-en-Yvelines, Versailles; Institut de la Vision, Paris, France Ch 89 Cataract Following Trabeculectomy Ch 91 Modulation of Wound Healing: Choice of Antifibrosis Therapies

Alan Lacey, BSc

Department of Medical Illustration, Moorfields Eye Hospital, London, UK Video 88-2 Diagnosis and Management of the Cyclodialysis Cleft Video spotlight 118-1 Aqueous Shunts after Retinal Surgery

Dennis SC Lam, MD FRCOphth

Director of State Key Laboratory of Ophthalmology and Honorary Director of Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China Ch 72 Peripheral Iridotomy for Angle-Closure Glaucoma

Associate Professor, Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia Ch 46 Spotlight: Evaluation of Quality of Life Associate Professor of Ophthalmology, University of Queensland, Director of Glaucoma and Corneal Services, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia Ch 87 Blebitis and Endophthalmitis

Paul Lee, MD JD

F. Bruce Fralick Professor and Chair of Ophthalmology and Visual Sciences; Director, W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA Ch 3 Economics of Glaucoma Care

Hans G Lemij, MD PhD

Glaucoma Specialist, The Rotterdam Eye Hospital, Rotterdam, The Netherlands Ch 21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis

Anthony Leoncavallo, MD

Glaucoma Fellow, Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL, USA Ch 112 Surgical Technique 2 (Baerveldt Glaucoma Implant)

Mark R Lesk, MSc MD

Associate Clinical Professor, Director of Research, Department of Ophthalmology, Faculty of Medicine, Université Montréal; Director of Vision Health Research, Guy-Bernier Research Centre, Maisonneuve Rosemont Hospital, Montréal, QC, Canada Ch 9 Role of Ocular Blood Flow in the Pathogenesis of Glaucoma Ch 24 Techniques Used for Evaluation of Ocular Blood Flow

Christopher KS Leung, MD MB ChB MSc BMedSc FHKAM FHKOphth

Professor, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong Hong Kong SAR, People’s Republic of China Ch 18 Spotlight: Measuring Corneal Biomechanics in the Clinic

Dexter YL Leung, FRCS DRCOphth

Clinical Assistant Professor (Honorary), Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong; Consultant Ophthalmologist, Department of Ophthalmology, Hong Kong Sanatorium & Hospital, Hong Kong SAR, People’s Republic of China Ch 103 The Role of Lens Extraction in Primary Angle Closure Glaucoma

List of Contributors

Leonard A Levin, MD PhD

Professor and Chair of Ophthalmology, Canada Research Chair in Translational Visual Science, Riva & Thomas O. Hecht Family Chair in Ophthalmology, McGill University; Physician-in-Chief of Ophthalmology, McGill University Health Centre, Professeur associé au Département d’ophtalmologie de la Faculté de médecine, Université de Montréal, Montréal, QC, Canada; Professor of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, WI, USA Ch 61 Neuroprotection and Neurorepair

Richard A Lewis, MD

Eye Specialist, Sacramento Eye Consultants, Sacramento, CA, USA Ch 127 Canaloplasty

K Sheng Lim, MB ChB MD FRCOphth

Consultant Ophthalmic Surgeon, St Thomas’ Hospital, London, UK Ch 10 Tonometry and Intraocular Pressure Fluctuation Video spotlight 112-1 Baerveldt Implantion without Ligation Video spotlight 116-2 Blocked Tube and Ahmed Extender

Ridia Lim, MBBS MPH FRANZCO

Ophthalmic Surgeon, Glaucoma Unit, Sydney Eye Hospital, Sydney, NSW, Australia Ch 50 Outcomes

Ricardo de Lima, MD

Asociacion Para Evitar La Ceguera en Mexico, Coyoacan, Mexico City, Mexico Video spotlight 106-1 Combined Ahmed Valve and Phacoemulsification

Yutao Liu, MD PhD

Assistant Professor, Director of Molecular Genomics Core Facility, Center for Human Genetics, Department of Medicine & Ophthalmology, Durham, NC, USA Ch 25 Genetics of Glaucoma

Alastair Lockwood, MD

Clinical Research Fellow, National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 95 Future Strategies

Sancy Low, MRCOphth

Honorary Research fellow, NIHR Biomedical Research Centre, Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, UK Ch 30 Primary Angle-Closure Glaucoma

Fumihiko Mabuchi, MD PhD

Assistant Professor, Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan Ch 25 Spotlight: Japanese Perspective

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David A Mackey, MB BS MD FRANZCO FRACS

Managing Director and Professor, Lions Eye Institute, Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia Ch 26 Spotlight: Family Screening

Rizwan Malik, MRCOphth PhD

Fellow in Glaucoma, Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada Ch 12 Long-term Follow-Up of Visual Fields Ch 22 Structure-Function Relationships in Glaucoma

Anil K Mandal, MD

Senior Consultant, Jasti V Ramanamma Children’s Eye Care Centre; Senior consultant, VST Center for Glaucoma Care, L V Prasad Eye Institute, Hyderabad, AP, India Ch 81 Postoperative Shallow Anterior Chamber

Steven L Mansberger, MD MPH

Vice-Chair, Director of Fellowship and Glaucoma Services at Devers Eye Institute, Senior Scientist, Legacy Health, Affiliate Professor, Oregon Health Science University, Portland, OR, USA Ch 82 Choroidal Effusion

Kaweh Mansouri, MD MPH

Consultant, Glaucoma Sector, Director, Polyclinic Department of Ophthalmology, Geneva University Hospitals, Geneva, Switzerland Ch 39 Post-Traumatic Glaucoma

Giorgio Marchini, MD

Full Professor of Ophthalmology and Chairman, University Eye Clinic, Department of Neurological and Movement Sciences, University of Verona; Director of the School of Ophthalmology, University of Verona, Borgo Trento Hospital, Verona, Italy Ch 16 Ultrasound Biomicroscopy Video 16-1 UBM Accomodation

Manjula Marella, PhD

Senior Research Officer, Nossal Institute for Global Health, the University of Melbourne, Carlton, VIC, Australia Ch 48 Optimizing Quality of Life: Low-vision Rehabilitation in Glaucoma

Keith R Martin, MA DM MRCP FRCOphth

Professor of Ophthalmology, University of Cambridge, Cambridge, UK Ch 63 Stem Cells: A Future Glaucoma Therapy?

Robert H McGlynn, MD

Private Practice, Ophthalmic Consultants of Vermont, South Burlington, VT, USA Ch 86 Late Bleb Leaks

Steven H McKinley, MD

Private Practice, Eye Institute of Austin, Austin, TX, USA Ch 115 Intraoperative Complications

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List of Contributors

Stuart J McKinnon, MD PhD

Associate Professor, Departments of Ophthalmology and Neurobiology, Duke University Medical Center, Durham, NC, USA Ch 64 Gene Therapy in Glaucoma

J Ryan McManus, MD

Clinical Instructor, Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA Ch 113 Surgical Technique 3 (Ahmed Glaucoma Valve Drainage Implant)

Felipe A Medeiros, MD PhD

Professor of Ophthalmology, Director of Glaucoma Service, University of California, San Diego, CA, USA Ch 13 Function Specific Perimetry Ch 20 Optic Disc Imaging

André Mermoud, MD PD

Montchoisi Glaucoma Center, Montchoisi Clinic, Lausanne, Switzerland Ch 97 Deep Sclerectomy Video 97-1 Deep Sclerectomy Ch 126 The Ex-PRESS™ Miniature Glaucoma Implant Video 126-1 Ex-Press 200 Glaucoma Implant Under a Scleral Flap

Clive S Migdal, MD FRCS FRCOphth

Retired Senior Consultant Ophthalmologist, Glaucoma Service, Western Eye Hospital, London, UK Ch 69 Lowering Intraocular Pressure: Surgery versus Medications

Don Minckler, MD MS

Emeritus Professor of Ophthalmology, Clinical Professor of Laboratory Medicine (Eye Pathology), University of California, Irvine, CA, USA Ch 112 Spotlight: Anesthetic considerations Ch 112 Spotlight: Operative Techniques and Potential Modifications Ch 119 Aqueous Shunts and Keratoplasty Video spotlight 125-1 Trabectome

Anthony CB Molteno, MBChB FRCS(Ed)

Emeritus Professor in Ophthalmology, Department of Medicine, University of Otago Dunedin School of Medicine, Dunedin, New Zealand Ch 111 Surgical Technique 1 (Molteno Glaucoma Implant) Video 111-1 Surgical Technique for the Molteno Glaucoma Implant

Paolo Mora, MD PhD

Assistant Professor of Ophthalmology, University Eye Clinic, University of Parma, Parma, Italy Ch 32 Pigmentary Glaucoma

Javier Moreno-Montañés, MD PhD

Professor of Ophthalmology, Clinica Universidad de Navarra, OFTARED, Pamplona, Spain Ch 107 Combined Cataract and Nonpenetrating Glaucoma Surgery Video 107-1 Combined Phacoemulsification Nonpenetrating Glaucoma Surgery

James E Morgan, MA DPhil FRCOphth

Professor of Ophthalmology, Honorary Consultant Ophthalmologist, School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, UK Ch 7 Pathogenesis of Glaucomatous Optic Neuropathy

Sameh Mosaed, MD

Director of Glaucoma Services, Associate Professor of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA, USA Ch 119 Aqueous Shunts and Keratoplasty Ch 125 Trabectome

Marilita M Moschos, MD PhD

Assistant Professor of Ophthalmology, Department of Glaucoma and Electrophysiology of Vision, University of Athens, Greece Ch 128 New Glaucoma Surgical Alternatives

Kelly W Muir, MD MHSc

Associate Professor, Durham VA Medical Center; Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA Ch 49 Ocular Hypotensive Medications: Adherence and Performance

Gonzalo Muñoz, MD PhD FEBO

Consultant Ophthalmic Surgeon, Glaucoma Department, Marqués de Sotelo Ophthalmic Center, Valencia, Spain Ch 97 Spotlight: Non-stitch Suprachoroidal Technique for T-flux Implantation in Deep Sclerectomy

Francisco J Muñoz-Negrete, MD PhD

Professor of Ophthalmology, Alcala University, Hospital Ramón y Cajal, IRYCIS, OFTARED, Madrid, Spain Ch 107 Combined Cataract and Nonpenetrating Glaucoma Surgery Video 107-1 Combined Phacoemulsification Nonpenetrating Glaucoma Surgery

Arvind Neelakantan, MD FRCOphth

Physician Owner, Glaucoma Center of Texas; Clinical Associate Professor, Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Ch 90 Risk Factors for Excess Wound Healing

Anil K Negi, MB BS, MD, FRCOphth, FRCSEd

Consultant Ophthalmologist, Birmingham Heartlands Hospital, Birmingham, UK Ch 122 Cyclodestructive Techniques

List of Contributors

Peter A Netland, MD PhD

Professor and Chair, Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA Ch 113 Surgical Technique 3 (Ahmed Glaucoma Valve Drainage Implant) Video 113-1 Surgical Technique for the Ahmed Implant

Paula Anne Newman-Casey, MD MS

Assistant Professor, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI, USA Ch 49 Ocular Hypotensive Medications: Adherence and Performance

Marcelo T Nicolela, MD FRCSC

Professor of Ophthalmology, Dalhousie Department of Ophthalmology and Visual Sciences, Halifax, NS, Canada Ch 22 Structure-Function Relationships in Glaucoma

Nuwan Niyadurupola, MD FRCOphth

Consultant, Department of Ophthalmology, Norfolk and Norwich University Hospital, Norwich, UK Ch 75 Preoperative Conjunctival Health and Trabeculectomy Outcome

Magdy A Nofal, FRCOphth

Ophthalmic Surgeon, Torbay General Hospital, The Eye Department, Torquay, Devon, UK Ch 83 Trabeculectomy Related Corneal Complications

Winnie Nolan, FRCOphth MD

Consultant Ophthalmologist, National Institute for Health Research, Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK Ch 1 Prevalence and Geographical Variations Ch 17 Angle Imaging: Ultrasound Biomicroscopy and Anterior Segment Optical Coherence Tomography

Monisha E Nongpiur, MD

Senior Clinical Research Fellow, Singapore Eye Research Institute and Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Ch 30 Spotlight: Angle-Closure

Baha’a N Noureddin, MD FACS

Professor and Chairman, Department of Ophthalmology, American University of Beirut, Beirut, Lebanon Ch 60 Glaucoma Secondary to Trauma

Gary D Novack, PhD

President, PharmaLogic Development, Inc., San Rafael, CA, USA Ch 49 Ocular Hypotensive Medications: Adherence and Performance

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Brenda Nuyen, MD

Resident, Shiley Eye Center, Department of Ophthalmology, University of California, San Diego, USA Ch 39 Post-Traumatic Glaucoma

Krishnamurthy Palaniswamy, MD

Glaucoma Consultant, Aravind Eye Hospital, Pondicherry, India Ch 3 Spotlight: Economics in India of High Volume Glaucoma Care

Camille Palma, MD

Resident, University Hospitals Eye Institute/Case Western Reserve University, Cleveland, OH, USA Ch 37 Neovascular Glaucoma

Ki Ho Park, MD PhD

Professor of Ophthalmology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea Ch 33 Spotlight: Korean Perspective

Richard K Parrish II, MD

Associate Dean for Graduate Medical Education, Professor, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA Ch 90 Risk Factors for Excess Wound Healing

Maria Papadopoulos, MBBS FRACO

Consultant Ophthalmic Surgeon, Glaucoma Service, Moorfields Eye Hospital, London, UK Ch 118 Aqueous Shunts after Retinal Surgery Ch 120 Goniotomy and Trabeculotomy

Rajul S Parikh, MS

Director, Shreeji Eye Clinic and Palak’s Glaucoma Care Centre, Mumbai; Director, Department of Glaucoma and Clinical Research, Lotus Eye Hospital, Mumbai, Maharashtra, India Ch 51 Benefit Versus Risk

Louis R Pasquale, MD FARVO

Director, Glaucoma Service, Mass Eye and Ear Infirmary, Associate Epidemiologist, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA Ch 26 Spotlight: Boston Studies

Alice Pébay, PhD

Senior Research Fellow & Principal Investigator, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Department of Ophthalmology University of Melbourne, Melbourne, VIC, Australia Ch 63 Spotlight: Brain Perspective

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List of Contributors

Sergey Petrov, MD PhD

Russian Glaucoma Society, Glaucoma Department, Scientific Research Institute of Eye Diseases of the Russian Academy of Medical Sciences, Moscow, Russia Video spotlight 78-1: Needling Old Bleb with 5FU and Avastin Video spotlight 113-4 Needling Old Ahmed Valve Bleb with 5FU and Avastin

Jody Piltz-Seymour, MD

Clinical Professor of Ophthalmology, Pereleman School of Medicine, University of Pennsylvania; Director, Glaucoma Care Center, PC, Philadelphia, PA, USA Ch 38 Other Secondary Glaucomas

Luís Abegão Pinto, MD PhD

Assistant Professor, Department of Pharmacology and Neurosciences, Faculty of Medicine, Lisbon University; Ophthalmologist, Centro Hospitalar Lisboa Central, Lisbon, Portugal Ch 74 Preoperative Evaluation and Diagnostic Approach

Ian F Pitha, MD PhD

Assistant Professor of Ophthalmology, Glaucoma Center of Excellence, Wilmer Eye Institute, The Johns Hopkins University, Baltimore, MD, USA Ch 28 Ocular Hypertension

Norbert Pfeiffer, MD LTCL

Medical Director, Mainz University Medical Center, Mainz, Germany Ch 52 Prostagladin Analogues

Luciano Quaranta, MD PhD

Associate Professor, Center for the Study of Glaucoma, University of Brescia, Brescia, Italy Ch 57 Fixed Combination Therapies in Glaucoma

Pradeep Y Ramulu, MD MHS PhD

Associate Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA Ch 84 Aqueous Misdirection

Emilie Ravinet, MD ancien MER

Private Practice, Associate of the Glaucoma Center, Clinique de Montchoisi, Lausanne, Switzerland Ch 99 Complications of Nonpenetrating Glaucoma Surgery

Tony Realini, MD MPH

Associate Professor of Ophthalmology, West Virginia University Eye Institute, Morgantown, WV, USA Ch 53 Spotlight: Alternate View

Gema Rebolleda, MD PhD

Professor of Ophthalmology, Alcala University, Hospital Ramón y Cajal, IRYCIS, OFTARED, Madrid, Spain Ch 107 Combined Cataract and Nonpenetrating Glaucoma Surgery Video 107-1 Combined Phacoemulsification Nonpenetrating Glaucoma Surgery

Nic J Reus, MD PhD

Ophthalmologist, The Rotterdam Eye Hospital, Rotterdam, The Netherlands Ch 21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis

Adam C Reynolds, MD

Eye Care Consultant, Intermountain Eye Centers, Boise Medical Arts Building, Boise, ID, USA Ch 55 Alpha Agonists

Douglas J Rhee, MD

Chair, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA Ch 76 Ophthalmic Anesthesia

Isabelle Riss, MD PhD

Head of the Department of Ophthalmology, Pellegrin Hospital, Bordeaux, France Video spotlight 128-3 The InnFocus MicroShunt Surgical Technique

Robert Ritch, MD PhD

Shelley and Steven Einhorn Distinguished Chair, New York Eye and Ear Infirmary; Professor of Ophthalmology, New York Medical College, Valhalla, NY, USA Ch 31 Exfoliation Syndrome and Exfoliative Glaucoma Ch 35 Secondary Angle-Closure Glaucoma Ch 41 Glaucoma in the Phakomatoses and Related Conditions Ch 71 Selective Laser Trabeculoplasty

Charles E Riva, DSc

Professor Honoraris, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland Ch 24 Spotlight: Practicalities

Gloria Roberti, MD

Researcher, Glaucoma Research Unit, IRCCS Fondazione G.B. Bietti, Rome, Italy Ch 65 Ultrastructural Imaging

Cynthia J Roberts, PhD

Professor of Ophthalmology and Biomedical Engineering, The Ohio State University, Columbus, OH, USA Ch 18 The Impact of Central Corneal Thickness and Corneal Biomechanics on Tonometry

Alan L Robin, MD

Associate Professor, Ophthalmology and International Health, Johns Hopkins University, Baltimore; Clinical Professor, Ophthalmology, University of Maryland, Baltimore, MD, USA Ch 4 Practical Application of Glaucoma Care in Different Societies Ch 49 Ocular Hypotensive Medications: Adherence and Performance

List of Contributors

Prin Rojanapongpun, MD

Chairman, Department of Ophthalmology, Chulalongkorn University and Hospital; Consultant, Ophthalmology Unit, Bumrungrad International, Bangkok, Thailand Ch 59 Acute Intraocular Pressure Rise

Sylvain Roy, MD PhD CC

Senior Scientist, Montchoisi Clinic, Swiss Federal Institute for Technology EPFL, Lausanne, Switzerland Ch 97 Deep Sclerectomy

John F Salmon, MD FRCS

Consultant Ophthalmic Surgeon, Oxford Eye Hospital, Oxford, UK Ch 15 Gonioscopy Ch 60 Spotlight: Surgical Management of Post-TraumaticAngle-Recession Glaucoma

Juan Roberto Sampaolesi, MD

Professor, Department of Ophthalmology, UCES University, Centro Oftalmologico Sampaolesi, Buenos Aires, Argentina Video spotlight 99-1 Deep Sclerectomy-Conversion to Trabeculectomy

Chiara Sangermani, MD

Ophthalmologist, Glaucoma Clinic, Department Of Ophthalmology, Community Hospital, Piacenza, Italy Ch 32 Pigmentary Glaucoma

Usman A Sarodia, FRCOphth

Glaucoma Service, Moorfields Eye Hospital, London, UK Video 118-1 Aqueous Shunts after Retinal Surgery

Jamie Lea Schaefer, MD

Resident Physician, University of Buffalo, Ophthalmology, NY, USA Ch 69 Lowering Intraocular Pressure: Surgery versus Medications

Ursula Schloetzer-Schrehardt, PhD

Professor, Department of Ophthalmology, University of Erlangen, Nürnberg, Erlangen, Germany Ch 31 Exfoliation Syndrome and Exfoliative Glaucoma

Gregory S Schultz, PhD

Research Foundation Professor, Department of Ophthalmology, University of Florida, Gainesville, FL, USA Ch 94 Biological Drivers of Postoperative Scarring

Joel S Schuman, MD FACS

Director, UPMC Eye Center, Eye & Ear Foundation; Professor & Chairman of Ophthalmology, Professor of Bioengineering, Swanson School of Engineering University of Pittsburgh, PA, USA Ch 124 Complications of Cyclodestructive Procedures

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Leonard K Seibold, MD

Assistant Professor, Department of Ophthalmology, University of Colorado School of Medicine Aurora, CO, USA Ch 58 Ocular Surface Disease and the Role of Preservatives in Glaucoma Medications

Tarek M Shaarawy, PD MD MSc

Privat Docent, University of Geneva; Consultant Ophthalmologist and Head, Glaucoma Sector, Ophthalmology Service, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland Video spotlight 15-1 Pseudoexfoliation Ch 39 Post-Traumatic Glaucomas Video 86-1 Needling Video 88-1 Palmberg Compression Sutures and Autologous Blood Ch 96 Principle and Mechanism of Function Video spotlight 97-2 Removal of the Juxtacanalicular Trabeculum Video spotlight 97-3 Collagen Implant in Deep Sclerectomy Video spotlight 97-4 Aqueous Percolating after Full Dissection Ch 100 Postoperative Management of Nonpenetrating Glaucoma Surgery Video 100-1 Goniopuncture and Complications Video spotlight 113-3 Envelope and Trench Technique to Prevent Tube Erosion Video spotlight 116-1 Managing a Tube Erosion Video spotlight 116-3 Removal of Ahmed Drainage Implant Plate Video spotlight 126-1 Ex-Press 200 Glaucoma Implant Under a Scleral Flap Video 126-3 Laser Treatment for Blocked Ex-Press Implant Ch 128 New Glaucoma Surgical Alternatives Video 128-1 Ex-Press Aqueous Flow Video 128-2 C02 Laser-Assisted Sclerectomy Surgery Video 128-4 Xen Implant Surgical Technique Video 128-5 Stegmann Canal Expander Video 128-8 High Frequency Deep Sclerotomy Video 128-9 Hydrus Implant Video 128-10 CyPass Implant

Peter Shah, BSc(Hons) MB ChB FRCOphth FRCP(Edin)

Professor of Glaucoma, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London; UCL Partners Academic Health Science Centre, London; University Hospitals Birmingham NHS Foundation Trust, Birmingham; Centre for Health & Social Care Improvement, University of Wolverhampton, Wolverhampton, UK Ch 87 Blebitis and Endophthalmitis

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List of Contributors

Mark B Sherwood, FRCP FRCS FRCOphth

Daniels Professor, Departments of Ophthalmology and Cell Biology, Director of Vision Research Center, University of Florida, Gainesville, FL, USA Ch 42 Management of Ocular Hypertension and Primary Open-Angle Glaucoma Ch 69 Lowering Intraocular Pressure: Surgery versus Medications Ch 77 Spotlight: Releasable Sutures Ch 94 Biological Drivers of Postoperative Scarring Video spotlight 112-2 Early Control of Intraocular Pressure in Nonvalved Drainage Implant Ch 128 New Glaucoma Surgical Alternatives

Lineu Oto Shiroma, MD

Ophthalmologist, Glaucoma Service, Sadalla Amin Ghanem Eye Hospital, Joinville, Brazil Ch 56 Parasympathomimetics

Brent Siesky, PhD

Assistant Director, Glick Eye Institute, Department of Ophthalmology, Indiana University Medical Center, Indianapolis, IN, USA Ch 24 Spotlight: Value of Blood Flow in Studies

George L Spaeth, MD

Esposito Research Professor, Wills Eye Hospital, Jefferson Medical College, Philadelphia, PA, USA Ch 27 Definitions: What is Glaucoma Worldwide?

Alexander Spratt, FRCOphth

Instructor, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL, USA Ch 46 Quality of Life

Ingeborg Stalmans, MD PhD

Professor, Head of the Glaucoma Clinic, University Hospitals Leuven, Leuven, Belgium Ch 74 Preoperative Evaluation and Diagnostic Approach

Robert L Stamper, MD

Distinguished Professor of Clinical Ophthalmology, Director of the Glaucoma Service, Department of Ophthalmology, University of California, San Francisco, CA, USA Ch 85 Late Failure of Filtering Bleb

Kazuhisa Sugiyama, MD

Glaucoma Consultant, Department of Ophthalmology, Hospital São João, Porto, Portugal Ch 97 Spotlight: Implants in Deep Sclerectomy

Professor and Chairman, Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Ch 1 Spotlight: What Prevalence and Geographic Variations Tell Us?

Annapurna Singh, MD

Remo Susanna Jr., MD

Sergio Estrela Silva, MD

Associate Professor of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Ch 37 Neovascular Glaucoma Ch 40 Glaucoma and Intraocular Tumors

Arun D Singh, MD

Professor of Ophthalmology, Director, Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Ch 37 Neovascular Glaucoma Ch 40 Glaucoma and Intraocular Tumors

Kuldev Singh, MD MPH

Professor, Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Stanford, CA, USA Ch 92 Technique

Chelvin CA Sng, FRCSEd

Associate Consultant, National University Hospital, Department of Ophthalmology, Singapore Ch 44 Spotlight: An Overview of Angle-Closure Management

Brian J Song, MD

Instructor in Ophthalmology, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA Ch 23 Measuring Glaucoma Progression in Clinical Practice

Professor and Head of the Department of Ophthalmology, University of São Paulo, São Paulo, Brazil Ch 19 Spotlight: Optic Disc Photography in the Diagnosis of Glaucoma Video spotlight 113-2 Ahmed Surgical Pearls Ch 114 Other Glaucoma Implants

Orathai Suwanpimolkul, MD

Consultant, Ophthalmology Unit, Bumrungrad International, Bangkok, Thailand Ch 59 Acute Intraocular Pressure Rise

William H Swanson, PhD FAAO

Professor of Optometry, Indiana University School of Optometry, Bloomington, IN, USA Ch 22 Structure-Function Relationships in Glaucoma

Ernst R Tamm, MD

Professor and Chairman, Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany Ch 5 Functional Morphology of the Trabecular Meshwork Outflow Pathways Ch 70 The Trabecular Meshwork Outflow Pathways: Surgical Aspects

Tak Yee Tania Tai, MD

Assistant Professor of Ophthalmology, New York Eye and Ear Infirmary, New York, NY, USA Ch 38 Other Secondary Glaucomas

List of Contributors

Angelo P Tanna, MD

Vice Chairman and Associate Professor of Ophthalmology, Director, Glaucoma Service, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Ch 33 Normal Tension Glaucoma

Chaiwat Teekhasaenee, MD

Associate Professor of Ophthalmology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Ch 35 Secondary Angle-Closure Glaucoma Ch 41 Glaucoma in the Phakomatoses and Related Conditions Ch 44 An Overview of Angle-Closure Management Ch 73 Laser Peripheral Iridoplasty Ch 108 Goniosynechialysis

Clement CY Tham, FRCS FCOphthHK

S.H. Ho Professor of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong; Honorary Chief-of-Service, Hong Kong Eye Hospital; Director, CUHK Eye Centre, Faculty of Medicine The Chinese University of Hong Kong, Kowloon, Hong Kong SAR, People’s Republic of China Ch 72 Peripheral Iridotomy for Angle-Closure Glaucoma Ch 103 The Role of Lens Extraction in Primary Angle Closure Glaucoma

Hagen Thieme, MD

Director of the Department of Ophthalmology, University Hospital Magdeburg, Magdeburg, Germany Ch 52 Prostagladin Analogues

Ravi Thomas, MD FRANZCO

Professor, Queensland Eye Institute and University of Queensland, South Brisbane, QLD, Australia Ch 51 Benefit Versus Risk

Andrew M Thompson, BPharm(Hons) MBChB FRANZCO

Honorary Clinical Senior Lecturer in Ophthalmology, Department of Medicine, University of Otago Dunedin School of Medicine, Dunedin, New Zealand Ch 111 Surgical Technique 1 (Molteno Glaucoma Implant)

Ravilla D Thulasiraj, MD

Karim Tomey, MD

Ophthalmologist, Beirut Eye Specialist Hospital, Beirut, Lebanon Ch 60 Glaucoma Secondary to Trauma

Yokrat Ton, MD

Ophthalmologist, Department of Ophthalmology, Meir Medical Center, Kfar-Saba; Ein-Tal Eye Center, Tel-Aviv, Israel Ch 97 Spotlight: CO2 Laser Assisted Sclerectomy Surgery (CLASS) for Open-Angle Glaucoma Treatment

Fotis Topouzis, MD

Associate Professor of Ophthalmology, Aristotle University of Thessaloniki, Greece Ch 32 Spotlight: Iridotomy for Pigmentary Glaucoma

Carol B Toris, PhD

Director of Glaucoma Research, Department of Ophthalmology, University of Nebraska Medical Center, Omaha, NE, USA Ch 6 Aqueous Humor Dynamics and Intraocular Pressure Elevation

Roberto Tosi, MD

Ophthalmologist, Eye Clinic, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Borgo Trento Hospital, Verona, Italy Ch 16 Ultrasound Biomicroscopy

James C Tsai, MD MBA

President, New York Eye and Ear Infirmary of Mount Sinai, Chair of Ophthalmology, Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York, NY, USA Ch 79 Intraoperative Complications of Trabeculectomy

Sonal S Tuli, MD

Professor, Department of Ophthalmology, University of Florida, Gainesville, FL, USA Ch 94 Biological Drivers of Postoperative Scarring

Anja Tuulonen, MD PhD

Department Head, Tays Eye Centre, Tampere University Hospital, Tampere, Finland Ch 66 Economics of Surgery Worldwide: Developed Countries

Executive Director, Lions Aravind Institute of Community Ophthalmology, Tamil Nadu, India Ch 4 Practical Application of Glaucoma Care in Different Societies

Nicola Ungaro, MD

John Thygesen, MD

Luke Vale, MD

Associate Professor and Director, Glaucoma Services in Copenhagen, Copenhagen University Hospital, Department of Ophthalmology, Glostrup, Copenhagen, Denmark Ch 88 Late Hypotony

xxxi

Director of the Glaucoma Clinic, University Eye Clinic, University of Parma, Parma, Italy Ch 32 Pigmentary Glaucoma Professor of Health Economics, Health Foundation Chair in Health Economics, Deputy Director, University of Newcastle, Newcastle upon Tyne, UK Ch 47 Medical Management of Glaucoma: Cost-effectiveness

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List of Contributors

Leonieke ME van Koolwijk, MD

Irini C Voudouragkaki, MD

Reena S Vaswani, MD

Michael Waisbourd, MD

Rengaraj Venkatesh, MD

Mark J Walland, MB BS FRANZCO FRACS

Ophthalmologist, Glaucoma Service, Rotterdam Eye Hospital; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands Ch 26 Genetic Epidemiology Academic Chief Resident, University Hospitals Eye Institute, Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Ch 40 Glaucoma and Intraocular Tumors Chief Medical Officer, Aravind Eye Hospital, Pondicherry, India Ch 3 Spotlight: Economics in India of High Volume Glaucoma Care

Cristina Venturini

PhD Student, University College London, Institute of Ophthalmology, London, UK Ch 26 Genetic Epidemiology

Stephen A Vernon, MB CHB DM FRCS FRCOphth FCOptom (hon) DO

Honorary Professor of Ophthalmology, Consultant Ophthalmic Surgeon, University Hospital, Nottingham, UK Ch 122 Spotlight: Retreatment and Further Postoperative Care Ch 124 Spotlight: Trans-scleral Diode in Patients with Good Vision

Eranga N Vithana, PhD

Adjunct Associate Professor and Head, Ocular Genetics Group, Singapore Eye Research Institute and Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Ch 30 Spotlight: Angle-Closure

Lingam Vijaya, MS

Fellow, Glaucoma Unit, 1st University Department of Ophthalmology, AHEPA Hospital, Thessaloniki, Greece Ch 57 Fixed Combination Therapies in Glaucoma Research Manager, Wills Eye Hospital, Glaucoma Research Center, Philadelphia, PA, USA Ch 27 Definitions: What is Glaucoma Worldwide? Ch 71 Spotlight: Selective Laser Trabeculoplasty Consultant Ophthalmic Surgeon, Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia Ch 44 Spotlight: Cataract and Clear Lens Extraction

Robert N Weinreb, MD

Distinguished Professor and Chairman of Ophthalmology, Morris Gleich Chair; Director, Shiley Eye Center; Director, Hamilton Glaucoma Center, University of California, San Diego, CA, USA Ch 62 Interpreting Clinical Studies on Glaucoma Neuroprotection

Mark Werner, MD

Glaucoma Specialist, Delray Eye Associates, Delray Beach, FL, USA Ch 121 Further Surgical Options in Children

Anthony Wells, MBChB FRANZCO DMedSc

Professor, Wellington School of Medicine, Department of Surgery and Anaesthesia, Wellington, New Zealand Ch 78 Tenon’s Cyst Formation, Wound Healing, and Bleb Evaluation

Boateng Wiafe, MD MSC

Director, Smt Jadhavabai Nathmal Singhvee Glaucoma Services, Chennai, Tamil Nadu, India Ch 4 Spotlight: Glaucoma Care in South Asia

Regional Director for Africa, Operation Eyesight Universal, Accra, Ghana Ch 68 Economics of Surgery Worldwide: Developing Countries

Ananth C Viswanathan, BSc MD PhD

Jacob Wilensky, MD

Consultant Surgeon (Glaucoma), Moorfields Eye Hospital, NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK Ch 26 Genetic Epidemiology Ch 46 Quality of Life

Gabriele Vizzari, MD

Head, Low Vision and Rehabilitation Center; Surgical Fellow in Glaucoma, Eye Clinic, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Borgo Trento Hospital, Verona, Italy Ch 16 Ultrasound Biomicroscopy

Professor of Ophthalmology, Glaucoma Service, Director, Glaucoma Fellowship Program, llinois Eye and Ear Infirmary, Chicago, IL, USA Ch 86 Late Bleb Leaks

Tina T Wong, BSc MBBS FRCOphth FRCS(Ed) PhD

Consultant Ophthalmologist, Glaucoma Service, Singapore National Eye Centre (SNEC); ClinicianScientist and Head, Ocular Drug Delivery Research Group, Singapore Eye Research Institute (SERI), Singapore Ch 78 Tenon’s Cyst Formation, Wound Healing, and Bleb Evaluation

List of Contributors

Darrell WuDunn, MD PhD

Professor of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA Ch 116 Postoperative Complications

Jennifer LY Yip, MRCOphth MFPH PhD

Clinical Lecturer in Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK Ch 1 Prevalence and Geographical Variations

Yeni Yucel, MD PhD FRCPC

Professor and Director of Ophthalmic Pathology, Department of Ophthalmology and Vision Sciences, Laboratory Medicine and Pathobiology, University of Toronto; Director, Eye Pathology Research Laboratory, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada Ch 5 Spotlight: Lymphatics and Uveolymphatic Outflow from the Eye

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Linda M Zangwill, PhD

Professor, Department of Ophthalmology, University of California, San Diego, CA, USA Ch 20 Optic Disc Imaging

Virginia E Zanutigh, MD

Head, Glaucoma Service, Centro de Ojos Quimes, Quilmes, Buenos Aires, Argentina Ch 101 Results of Nonpenetrating Glaucoma Surgery

Joseph R Zelefsky, MD

Director, Glaucoma Service, Bronx-Lebanon Hospital Center, Bronx, NY; Assistant Professor of Ophthalmology, Albert Einstein College of Medicine, Bronx, NY, USA Ch 36 Spotlight: Uveitic Glaucoma

Thierry Zeyen, MD PhD

Emeritus Professor, Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium Ch 74 Preoperative Evaluation and Diagnostic Approach Video spotlight 128-7 iStent

Acknowledgements A book of this magnitude is in fact the fruit of the collective knowledge of its writers, all 321 of them, and thus carries between its pages part of their minds and souls. The editors have sought no less than the best in their fields and required nothing short of their utmost input. And we freely acknowledge that that is exactly what we got. Every contributor in this book has strived to pass along his knowledge to others and has done so diligently and patiently, and to all of them we owe loads of gratitude and appreciation. Thanks are also due to Prof S Drance for accepting to write the foreword for the first edition. A book on glaucoma cannot ask for a better preface or aspire to have a more distinguished writer.

xxxiv

We are personally grateful to our publishing team for making this book a reality. One of the few remaining pleasures of working in academia is the ability to share your professional life surrounded by brilliant minds from several generations. Credit is due to our colleagues, our staff members and our assistants for many years of support and encouragement. Groucho Marx once said “outside of a dog, a book is a man’s best friend. Inside of a dog it’s too dark to read.” We sincerely hope that in this book you will find a friend, a companion and a trustworthy ally in your professional life.

Contributor Locations Glaucoma is a collaborative effort drawing on the expertise of 321 contributors in 33 countries across 6 continents.

xxxv

This book is dedicated to a large group of people

To our Parents Samia Nada, Mounir Shaarawy, Gerald and Sylvia Sherwood, Mary and Alan Hitchings, Barry and Glenda Crowston

To our Wives Ghada, Ruth, Virmati and Joanna

To our Children Hussein and Lana, Adam and Eliana, Anita and Samantha, James and Zoe

Also to our mentors and teachers, colleagues and friends, many of whom have kindly contributed to this work

And above all else it is dedicated to our patients who have been a source of joy, inspiration and knowledge to all of us

Tarek, Mark, Roger and Jonathan

The Editors TAREK M SHAARAWY

ROGER A HITCHINGS

Tarek M Shaarawy is the Head of the Glaucoma unit and the Glaucoma surgery research group at the University of Geneva Hospitals. He obtained both his medical Bachelor and Masters Degree in ophthalmology from the University of Cairo, and his Doctorate in Medicine degree from the University of Lausanne. He trained in ophthalmology at the Cairo Research Institute of Ophthalmology and completed two glaucoma fellowships at the Universities of Lausanne and Basel. He is currently the President of the International Society of Glaucoma surgery as well as the Associate Vice President of the World Glaucoma Association. His main research interests are surgical techniques of glaucoma surgery, normal pressure glaucoma, and glaucoma patterns of practice in developed and developing countries. He is the author and editor of six textbooks on glaucoma, and more than 100 book chapters and publications in peer reviewed journals. He serves as the Editor in Chief of the Journal of Current Glaucoma Practice and is a member of the editorial boards of many ophthalmology journals, including the International Journal of Ophthalmology, Journal of Glaucoma, Canadian Journal of Ophthalmology, Middle East African Journal of Ophthalmology, Asia-Pacific Journal of Ophthalmology, among others. Tarek Shaarawy is a founding member of the Baladi foundation providing glaucoma care in the south of Egypt. He is also active in a number of NGOs dealing with the global prevention of blindness.

Roger Hitchings is an Honorary Consultant Ophthalmologist at Moorfields Eye Hospital, London and Professor Emeritus in Glaucoma and Allied Studies at the University of London. He was Director of Research and Development at Moorfields Eye Hospital. As a glaucoma specialist he has a special interest in optic nerve imaging, visual field progression, glaucoma surgery and normal tension glaucoma. He has also carried out research into the effect of topically applied medications on the conjunctiva and the success of glaucoma surgery. He has authored and edited 4 books, 15 book chapters and over 250 peerreviewed papers on glaucoma. Roger Hitchings developed the glaucoma department at Moorfields Eye Hospital into the largest in the UK and one of the largest in the world. It now functions with ophthalmologists and scientists representing all aspects of subspecialisation in glaucoma. He is currently past president of the European Glaucoma Society, and Founder Member of the World Glaucoma Association (AIGS). As Director of Research and Development he had responsibility for establishing the Clinical Trials Unit and the associated Reading Centre. The latter has become one of the key centres for the evaluation of ophthalmic clinical trials in the UK. He was responsible for developing the Royal College of Ophthalmologists’ 5 year Strategic Plan for Eye research which set out research goals in the specialty.

MARK B SHERWOOD

JONATHAN G CROWSTON

Mark B Sherwood is the Daniels Professor of Ophthalmology and Cell Biology and Director of the Vision Research Center at the University of Florida. He trained in ophthalmology at Manchester Royal Eye Hospital, St. Thomas’ Hospital, London and at Moorfields Eye Hospital and completed glaucoma fellowships at Moorfields Eye Hospital, London and the Wills Eye Hospital, Philadelphia. He joined the faculty of the University of Florida in 1986 and was Chair of the Department of Ophthalmology between 1994 and 2004. He has co-authored and edited 6 books, 18 book chapters and over 100 publications in peer-reviewed journals.

Jonathan G Crowston is a clinicianscientist and Head of Ophthalmology at Melbourne University and Director of the Centre for Eye Research Australia, He obtained his medical degree at the Royal Free Hospital. London and a PhD at the Institute of Ophthalmology, University College London. He trained in ophthalmology at Moorfields Eye Hospital and completed glaucoma fellowships at Westmead Hospital in Sydney and the University of California, San Diego where he was subsequently appointed to the Faculty. In 2006 he was appointed as the first Professor of Glaucoma in Australia. His research interests include the impact of ageing on optic nerve vulnerability to injury and neuroprotection. xxxvii

SECTION 1  GLAUCOMA IN THE WORLD

1 

Prevalence and Geographical Variations WINNIE NOLAN and JENNIFER LY YIP

Summary Glaucoma is the commonest cause of irreversible visual morbidity worldwide. The covert nature of the disease requires representative surveys to determine the true burden of glaucoma. Good-quality surveys with standardized definitions and methods are the starting point with which to tackle this global public health problem and in recent decades the number of well-conducted prevalence surveys has increased considerably. However, data from areas such as Latin America and Africa are needed to further quantify this problem. Global and regional strategies can then be developed to address the challenge of glaucoma blindness in the Vision 2020 agenda.

Introduction Glaucoma is the commonest cause of irreversible blindness worldwide.1 The World Health Organization (WHO) estimates for the number of people blind from glaucoma in 2002 were 4.4 million (12.3% of people blind worldwide). The majority of glaucoma in the world remains undiagnosed and so we rely on data collected from epidemiological surveys to estimate numbers with the disease. In recent decades there have been a number of population-based surveys investigating the prevalence of eye disease. One of the limitations of using prevalence data has been the lack of a standardized definition of glaucoma across the different surveys. The increasing use of the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) definition of glaucoma2 (Table 1-1) means it is now possible to obtain a global picture of the numbers of individuals affected by glaucoma. It also allows comparison of glaucoma prevalence and types in different regions, so highlighting populations and subgroups at increased risk of the disease. With the accumulation of epidemiological data it is clear that glaucoma affects all populations, but that some regions and racial subgroups are more affected either due to having a higher disease prevalence or because the large population of those regions means the absolute numbers of individuals with glaucoma is very large. In this chapter the methods of acquiring epidemiological data will be explained and the geographical variations in the prevalence and types of glaucoma will be illustrated together with a discussion of contributing risk factors.

Epidemiological Methods PREVALENCE AND INCIDENCE Epidemiological studies quantify and interpret frequency of disease, and factors that affect this. Two important measures that form the basis of all epidemiological studies are incidence and prevalence. Incidence is the number of new cases in a given population over a specified period of time. Prevalence is the number of all cases in a given population at one point in time, and this is commonly determined from cross-sectional studies. Both measures alone are descriptive in nature and, when used to compare frequencies in different populations or subgroups, the analysis and search for risk factors and causal factors can begin. This will lead to new understanding and practical application in clinical care and public health.

STUDY DESIGNS: POPULATION-BASED SURVEYS Prevalence is a useful measure of the burden of disease, especially in conditions with long duration such as glaucoma. Early studies used convenience samples from hospital clinics; however, as glaucoma is primarily asymptomatic, these studies would not provide an accurate assessment of glaucoma prevalence. Therefore, more recent estimates are usually ascertained from cross-sectional surveys. The scientific value of a survey is dependent on its internal and external validity. Glaucoma prevalence should be determined by population-based studies, which select a representative sample. As glaucoma is generally a disease of the older population, most glaucoma surveys focus on people who are 40 years or older, as this decreases the required sample size and saves resources. Internal validity is dependent on factors that can distort the results, leading to false estimates, whether this is due to chance, bias, or confounding. Chance errors can be minimized with adequate sample size. A low participation rate is an important source of bias in surveys, as nonparticipants may have a different experience of disease. Bias in ascertainment of disease or risk factors can result from imprecise methods and protocols. Clear criteria should be used to examine the participants and define the outcome. The ISGEO guidelines2 described below have been adopted internationally in many surveys, and are a useful standard to allow comparisons between different studies. Humans are prone to error, and objective measures are valued in scientific studies. The set of instruments used to 1

2

SECTION 1  •  Glaucoma in the World

assess the different parameters required in a glaucoma survey will vary. Gold standard instruments such as Goldmann applanation tonometer and Humphrey visual fields may not be feasible in some community-based projects. If more than one set of equipment or examiners are employed in the study, then inter-observer assessments are required to demonstrate that both teams are comparable in performance. Variation in disease frequency between different populations is a major source of epidemiological hypotheses in the investigation of causal mechanisms. These differences can be real or artefact. The first step is to establish that a real variation exists and then look for an association between the disease and a risk factor in these groups. Differences in age structures can also lead to apparent differences in prevalence. Populations with higher proportions of older people can lead to higher estimates of glaucoma compared to younger populations. One common method to account for differences in age structure is age standardization.

DEFINITIONS AND DIAGNOSTIC CRITERIA Differences in diagnostic criteria can result in difficulties when comparing differences in glaucoma prevalence. An example of this is in comparing prevalence figures for primary angle-closure glaucoma (PACG) from different surveys. The ISGEO guidelines have helped to standardize definitions used in PACG studies. Previous criteria used symptoms rather than structural or functional evidence for diagnosing glaucoma. As a result, in the first publication of the Mongolia glaucoma survey, the prevalence of PACG was 1.4%,3 but using the revised grading system, the prevalence is 0.8%. Similar problems arise when different criteria are used to evaluate glaucoma progression. Differences can occur if only disc or visual field evidence is used compared to a combination of both factors. The definitions used for perimetric progression should also be carefully assessed in each study, as this may be the true cause of an apparent variation between different areas. Care should also be taken with studies that use self-reporting as the method for case ascertainment. At least 50% of glaucoma is undiagnosed in the population, and using this method to determine association with risk factors would be biased. Current diagnostic guidelines suggest that glaucoma should be diagnosed independently of symptoms or IOP.

Definition of Glaucoma for Use in Epidemiological Surveys In an attempt to overcome the problem of varying diagnostic criteria for glaucoma The Working Group for Defining Glaucoma of ISGEO developed a new scheme for the diagnostic classification of glaucoma.2 This classification emphasizes the importance of visually significant endorgan (optic nerve head) damage as a requirement for the diagnosis of glaucoma. Since the publication of the ISGEO definitions a consensus meeting of experts in the field resulted in a modification of the diagnostic criteria for primary angle-closure glaucoma.4 Table 1-1 shows an abbreviated version of the ISGEO classification of glaucoma.

Table 1-1  International Society of Geographical and Epidemiological Ophthalmology Classification of Glaucoma for Use in Population-Based Surveys Glaucoma Category 1 Diagnosis (Structural and Functional Evidence) Cup:disc ratio (CDR) or CDR symmetry ± 97.5th percentile for the normal population Or Neuroretinal rim width reduced to ≤0.1 CDR (between 11 to 1 o’clock or 5 to 7 o’clock) + A definite visual field defect consistent with glaucoma Category 2 Diagnosis (Advanced Structural Damage   with Unproved Field Loss) CDR or CDR asymmetry ≥99.5th percentile for the normal population Category 3 Diagnosis (Optic Disc Not Seen) Visual acuity 99.5th percentile Or Visual acuity 40 years affected.18 Conversely, the Japanese and Koreans have reported some of the highest prevalences of POAG in the world of >3% in the >40 population, with a majority of OAG with low IOP at diagnosis.19,20 People living in South Asia also experience a high frequency of POAG, with a markedly

4

SECTION 1  •  Glaucoma in the World

higher prevalence in urban compared to rural areas. Prevalence of PACG is higher than Western countries, but comparatively lower than East Asia.21,22

AFRICA The most comprehensive data available from Africa were provided by surveys conducted in East Africa (Tanzania) and South Africa. These reported combined primary and secondary glaucoma prevalence figures of just over 5% (see Table 1-2).23–25 The predominant glaucoma was POAG but pseudoexfoliation (in Black South Africans), aphakic, and angle-closure mechanisms composed the remaining cases. Glaucoma prevalence among Black people living in the USA is measured as being four or more times that in Caucasians.5 As the ancestors of African-Americans and the Caribbean population came from West Africa, it is suspected that glaucoma prevalence in this region may be equally high. This is now confirmed by findings from a population-based survey in Ghana, which found glaucoma to be present in 6.5% of the adult population.26 It is very likely that the prevalence and mechanism of glaucoma varies between heterogeneous populations of the African continent. However, what has been repeatedly demonstrated is that glaucoma affects a higher proportion of African-derived people, has a younger age of onset, and that it may result in a greater visual morbidity than in other populations.24,26

PRIMARY OPEN-ANGLE GLAUCOMA: PREVALENCE AND NUMBERS AFFECTED A meta-analysis by Rudnicka et al.27 reviewed all POAG surveys available in the literature, and estimated pooled prevalence by race. The plotted summary of all studies reviewed is shown in Figure 1-1, which provides a useful outline of differences in prevalence estimates. The variation in prevalence estimates between different races grouped in this manner is evident, with prevalence for Whites ranging from 10%. The overall pooled prevalence estimate was 2% (95% CI: 1.61–2.70%), which is higher than 1.69% (1.53–1.85%) presented in another meta-analysis using individual data from recent studies from the USA,

Europe, and Australia.28 There was also statistical evidence in all racial groups of heterogeneity, that is, a true variation between studies rather than variation by chance. This was attributed to differences in age groups for the different studies, survey methods, and year of publication which reflects the change in diagnostic criteria used. In this study, the prevalence is presented by different racial groups, regardless of location; therefore, glaucoma prevalence of Blacks includes surveys from Africa, the West Indies, and Black populations within Europe and the USA. This would overlook potential differences in prevalence estimates caused by environmental factors, which would be another source of heterogeneity. To address these issues, Table 1-2 shows a summary of different prevalence estimates by region from more recent surveys with comparable methods in participants over 40 years old. These and other prevalence figures have been applied to the projected global populations for 2010 to estimate the absolute numbers of individuals with glaucoma worldwide. These calculations estimate that there will be almost 45 million individuals with primary open-angle glaucoma (POAG) by 2010.14 A breakdown for these figures by region is seen in Table 1-3.

PRIMARY ANGLE-CLOSURE GLAUCOMA: PREVALENCE AND NUMBERS AFFECTED Table 1-4 shows the global variations in prevalence of PACG. Definitions of PACG vary in published studies and the majority of the surveys in Western countries have focused on detecting POAG. A systematic review of PACG in European-derived populations gives a prevalence estimate of 0.4%.29 The Proyecto VER survey of Hispanic patients in the USA reported a PACG prevalence of 0.1%,11 but there is little population-based data from Central or South America other than that from the Projeto Glaucoma survey in Brazil, which found a PACG prevalence of 0.7% in a mixed ethnicity population.13 In Africa the data available confirm that angle closure does exist in this population, with a prevalence of 0.5% in South Africa and Tanzania.23–25 Recently, there has been an expansion in the number of population-based glaucoma surveys conducted in Asia.

Table 1-3  Estimated Numbers with Open-Angle Glaucoma (OAG) and Angle-Closure Glaucoma (ACG) Worldwide, 2010 World Region

Number with OAG

World OAG %

Number with ACG

World ACG %

OAG and ACG Combined

China Europe (including USA, Australia) India Africa Latin America Japan South East Asia Middle East World

8309001 10693335 8211276 6212179 5354354 2383802 2116036 1440849 44720832

18.6 23.9 18.4 13.9 12 5.3 4.7 3.2

7473195 1371405 3733620 245844 322804 278643 20141584 177869 15744965

47.5 8.7 23.7 1.6 2.1 1.8 13.6 1.1

15782196 12064740 11944896 6458023 5677158 2662466 4257620 1618718 60465796

From Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90:262–267.

1  •  Prevalence and Geographical Variations Citation Study (age range) 19 18 22 21 24 29 27 17 23 26 11 20 25 28

30 35 34 33 32 36 2 12 37 31

4 12 41 6 2 10 44 40 49 5 1 47 39 38 3 9 46 50 48 7 8 42 43 45

Asian Hu (40+) Arkell (15-70+) Jacob (30-60) Foster (40-89) Dandona (0-102) Rahman (35-85) Ramakrishnan (40-90) Aisbirk (40+) Foster (40-81) Bourne (50-70+) Shiose (30-70+) Rauf (30-80+) Metheetrairut (60-104) Iwase (40-80+) Subtotal

1.41, 95% CI (1.00, 2.00); Q13 = 160.65, p 49 years Not screened

Not screened Screened for OH

Screened for EMOAG

25 screen positive

25 screen positive

Treated

Treated 5 years

Figure 2-2  The effect of screening on treatment benefit. (Data from Blue Mountains Eye Study (unpublished data), Ocular Hypertension Treatment Study,4 and Early Manifest Glaucoma Trial.5 OH, Ocular hypertension between 24 and 32 mmHg without evidence of glaucoma; EMOAG, Early Manifest open-angle glaucoma.)

No benefit

22.5 stable 1 worse

glaucoma in 5 years is 670 (1000/1.5). If, instead, we screen for glaucoma, we only need to screen 235 people (1000/4.25) to prevent one case of progression over the same time period. An alternative approach is to look at what benefit we can confer by screening (see Fig. 2-2). For every 1000 people screened for ocular hypertension (OH), after 5 years 1.5 would benefit from the screening (if they were all treated), one would progress despite treatment, and 22.5 would just be inconvenienced by treatment (as they would not have progressed even without treatment). In contrast, if the same 1000 were screened for OAG, after 5 years 4.25 would benefit against 9.5 who would not benefit from treatment (because their disease would not progress even if untreated). Eleven and one-quarter would progress despite treatment. Whether any of those in the ‘no treatment benefit’ groups would be better off if not screened depends on how the negative aspects of diagnosis and treatment compare to benefits not related to treatment at that time or whether there may be some later benefit (after 5 years) from screening positive. Given that those with glaucoma already have a disease, the case for a delayed or nontreatment benefit will be stronger for the OAG group compared with the OH group. The ratios of people benefiting to not benefiting from screening and treatment are 1 : 15 for OH and 1 : 2.2 for OAG. The above examples necessarily make many assumptions about disease rates and do not take into account finding previously diagnosed glaucoma when screening for glaucoma or finding glaucoma when screening for ocular hypertension. However, population studies suggest that, in developed countries, most glaucoma with raised IOP is already diagnosed and conversely most undiagnosed glaucoma is not associated with high IOP,51 making the difference between screening strategies even greater. Another important consideration is the effect of falsepositive and false-negative outcomes from the screening program and the impacts of screening frequency. The effect of false positives is to increase the number who do not benefit from screening. False negatives can be ‘caught’ in

Benefit

Benefit

1.5 (worse if not screened)

4.25 (worse if not screened)

No benefit

9.5 stable 11.25 worse

later screening cycles. The benefit they receive depends on the screening frequency. Frequent screening will pick up previous false negatives before their disease has progressed very much. But frequent screening is more costly. Screening benefit will also depend on life expectancy. From Figure 2-1, it can be seen that someone with a longer life expectancy will have more time to gain a benefit from screening. Someone screening positive close to death may not have sufficient time to benefit from treatment. These analyses demonstrate a finding that has been previously reported for other diseases,53 namely that there will always be less benefit if we screen for risk factors rather than the disease itself. That is not to say that intraocular pressure is not important. We know that, along with increasing age, increasing intraocular pressure is the strongest risk factor for the prevalence, incidence, and progression of glaucoma. As part of a strategy to screen for glaucoma, IOP measurement, along with other risk factor assessment, may well be helpful. However, the screening outcome should be glaucoma and not ocular hypertension.

Risk Factor Screening in AngleClosure Glaucoma If a very great proportion of people with a disease risk factor develop the disease, then it may indeed be worthwhile using it in screening. This is particularly true if the time from the appearance of the risk factor to the occurrence of the disease is short in relation to the sojourn time. Although less common than open-angle glaucoma, primary angleclosure glaucoma causes more blindness3 and most probably has a shorter sojourn time. Angle closure is the primary risk factor for angle-closure glaucoma, its effect being mediated through increasing intraocular pressure.49 Given this relationship, it may be feasible to screen for angle closure (with or without intraocular pressure) in order to detect angle-closure glaucoma.

16

SECTION 1  •  Glaucoma in the World

There have been few reports of screening for angle closure or even the risk of glaucoma in people with angle closure. The Liwan Eye Study reported the prevalence of narrow iridocorneal angles, angle closure, and angleclosure glaucoma in a well-defined older southern Chinese population. Ten percent of the population had gonioscopically narrow angles and, of these, one in five had primary (synechial) angle closure (2.4% of the population).46,54 Angle-closure glaucoma was found in 1.5% of the entire population,46 suggesting an ideal positive predictive value of angle closure for angle-closure glaucoma of 64% with 100% sensitivity in this higher-risk general population. If the incidence of angle-closure glaucoma was high in those with angle closure, the case for screening for angle closure would be even stronger. But this risk has not been well reported. One cohort study in Indian eyes suggested a 5-year incidence of angle-closure glaucoma of 28.5% among subjects with angle closure.55 The alternative strategy would be to screen for the glaucomatous optic neuropathy itself. But there are no studies comparing the efficacy and outcomes of these two approaches. As this disease is a major cause of glaucoma blindness, well-designed and conducted studies are urgently needed.

CURRENT STATUS SCREENING FOR GLAUCOMA There have been a number of public health analyses of open-angle glaucoma screening.56–59 The first addressed by government in North America occurred almost 20 years ago and has been reviewed several times since. The most recent review was by the United States Preventive Services Task Force (USPSTF) in 2005.57,59 It was based on an initial report in 198857and a review in 1996.58 For the 2005 review, a Medline-based literature review was undertaken to answer seven key questions (Box 2-2). The only evidence found was trials of IOP-lowering treatment which were rated good to poor as an evidence source (KQ 5, KQ 8). The recommendation statement was that: ‘There is insufficient evidence to recommend for or against routine screening for intraocular hypertension or glaucoma by

Box 2-2  Key Questions from the OTA Report on Open-Angle Glaucoma Screening KQ 1: Is there new evidence that screening for open-angle glaucoma reduces severe visual impairment? KQ 3: Is there new evidence that feasible screening tests are accurate and reliable in detecting increased intraocular pressure or open-angle glaucoma? KQ 4: Is there new evidence that treating increased intraocular pressure reduces the incidence of primary open-angle glaucoma? KQ 5: Is there new evidence that treating increased intraocular pressure reduces severe visual impairments? KQ 6: Is there new evidence that treating open-angle glaucoma with drugs, laser, and/or surgery reduces severe visual impairment? KQ 7: Is there new evidence that screening results in adverse effects? Is screening acceptable to patients? KQ 8: Is there new evidence that treatment of increased intraocular pressure and/or open-angle glaucoma results in adverse effects? Note: there was no KQ 2 in the list.

primary care clinicians.’ This was the same conclusion reached in previous assessments and underscored a relatively negative attitude to glaucoma screening in a contemporary editorial by a task force member.60 In 2008, the World Glaucoma Association published a worldwide consensus on Glaucoma Screening.61 It identified the following key needs: More data on the effects of glaucoma on quality of life. Population-based data from regions of the world where currently no such data exist. ■ Identification of facilities for diagnosis and treatment and barriers to care. ■ Development of screening test algorithms with high specificity. ■ More data of the velocity of progression for treated and untreated glaucoma. ■ More regional economic evaluations of glaucoma screening. ■ ■

As more data are collected, and the gaps in our knowledge are filled, we will have a better idea of the role of screening for glaucoma and how best to improve it. In 2010 Yip et al. published the outcomes of a population-based randomized controlled trial of screening for angle-closure glaucoma, the first such trial of its type.62 After excluding glaucoma, 4583 participants with ultrasonic anterior chamber depth of 209,000 QALYs, about 85,000 due to blindness and 124,000 due to visual impairment. Converting QALYs into dollars at $50,000 per QALY, as an example, results in a $16 billion per year loss.16 In Australia, the cost of visual disorders in 2004 was estimated at A$9.85 billion, with A$1.8 billion in direct costs, A$3.2 billion in indirect costs and A$4.8 billion in loss of wellbeing. In terms of direct costs, visual disorders ranked 7th among various health conditions in Australia for 2000–2001, ahead of ischemic heart disease, depression, stroke, and diabetes.15 Importantly, the costs of interventions to address vision loss were deemed to be cost savings – i.e., there was more than one dollar in savings for every dollar spent.21

What is Currently Known:   Costs in Glaucoma Direct costs have been estimated at $2.9 billion annually for glaucoma in the US, with the majority of direct medical costs arising from outpatient care and the costs of medications.10 While individual cost estimates related to glaucoma vary across studies, several themes emerge.11,22–26 Studies consistently show that certain factors are associated with higher cost of treatment for glaucoma. Individuals with OAG have higher costs than those only suspected of having OAG or who only have ocular hypertension. Treatment costs are higher in the first year of diagnosis, due to additional testing and treatment initiation. Costs are also greater for individuals with more severe disease, measured by visual field, optic nerve head structure, or by IOP. Also, costs are increased if side effects develop or if the glaucoma state is

22.e1

3  •  Economics of Glaucoma Care

Table 3-1  Resource Use and Cost in Visual Disorders and in Glaucoma – Examples of Studies Direct

Study VISUAL DISORDERS Taylor HR et al. The economic impact and cost of visual impairment in Australia Frick KD et al. Economic impact of visual impairment and blindness in the US Rein DB et al. The economic burden of major adult visual disorders in the US GLAUCOMA Lee PP et al. Glaucoma in US and Europe: predicting costs and surgical rates based upon stage of disease Stein JD et al. Longitudinal trends in resource use in an incident cohort of open-angle glaucoma patients Lee PP et al. Cost of patients with primary open-angle glaucoma Lee PP et al. A multicenter retrospective pilot study of resource use and costs associated with severity of disease in glaucoma Seider MI et al. Cost of selective Laser Trabeculoplasty v Topical medications for glaucoma Traverso et al. Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilization in Europe Sharma A et al. An economic comparison of hospital-based and community-based glaucoma clinics Neymark et al. The costs of treating glaucoma with combinations of topical drugs in Spain. Kobelt G et al. Treatment of glaucoma in clinical practice. Four-year results from a patient registry in France. Kobelt G, Jonsson L. Modeling cost of patient management with new topical treatments for glaucoma. Results for France and the UK.

Indirect

Hospital input Output (Monetary Cost of Care)

Out-ofHospital (Monetary Cost of Care)

Other Health: (Monetary Cost of Care)

(Monetary Costs Other Than Healthcare)

Caregivers (Loss of Family Deadweight Member Losses from Income) Transfers

Lost Production

Loss of Well-Being

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

3  •  Economics of Glaucoma Care

more resistant to IOP lowering. The average cost-perperson-per-year has been estimated to range from $1248 to $1796.11,22,23 Charges were highest in the first 6 months after OAG diagnosis ($955.37) decreasing to about $500 per subsequent 6-month interval.23 The charge per person in the first year after diagnosis22 accounted for 11.7% of total healthcare charges, and decreased in subsequent years while overall healthcare charges increased. The cost of care has been estimated to increase with progression of disease stages, as seen in Figure 3-3.

COST OF MEDICATIONS Medications have been found to be major cost-drivers, accounting for 38–52% of costs. The variation in estimates stems from the impact of adjustments for medication adherence and Medicare reimbursement levels11 and are likely to be lower in the first year after diagnosis due in part to greater diagnostic expenses (as low as 25% of POAG-related charges in the first year after diagnosis).11,22 Additionally, differences among studies may be attributed to different patient populations, sampling biases, severity of the disease stage in the study population, length of follow up, frequency of progression of disease stage during the study (or the stability of the disease), the type of practice in which the patient is seen, whether charges or costs are considered, and if the dollar amount per service reflects the charge, the actual amount paid, or the Medicare allowable rate (with the last two generally being significantly less costly). Recent studies have focused on prostaglandin analogs (PGAs), which have surpassed beta blockers as the most common topical medication.27,28 They are more efficacious, with a favorable side effect profile, and a higher cost than older topical therapies.29 A prospective observational registry study of patients in France using PGAs for the first time found that direct mean annual costs were €487 for all patients and €428 for de novo patients,24 which is less than the €527 annual cost (adjusted to 2008 costs) in a study of newly diagnosed patients in the mid-1990s before the use of prostaglandins (also by the same authors).25 The studies indicate that the greater effectiveness of PGAs was associated with fewer surgeries and less frequent follow-up care, resulting in both lower costs and a reduced proportion of costs due to surgery. Costs were correlated with baseline IOP and with the number of treatment changes. A cost-minimization model of progression and cost for a hypothetical pool of 9500 PGA-treated patients over 7 years found that if all patients were treated exclusively with bimatoprost, disease progression would be prevented in 136 patients, leading to cost savings of $4009 and $4543 for avoided early and advanced glaucoma, respectively compared to other PGAs.30 The study arrived at this conclusion by modeling that bimatoprost lowers IOP by 1 mm Hg more than latanoprost and travoprost. Additional model assumptions were that higher IOP had a higher probability of disease progression, POAG prevalence was 1.9%, the cost of generic latanoprost was 80% of the brand name and all drugs had the same IOP fluctuation characteristics and that no PGAs had costly side effects. The model and study demonstrates the impact of the underlying assumptions and model variables on study results and would have yielded different results with different assumptions.

23

US VERSUS OTHER COUNTRIES Studies consistently find the per-capita direct costs of glaucoma care in the US to exceed those in other countries, likely due to the relative cost of medications and healthcare, as well as differences in healthcare structure and financing. While the annual costs of therapy are higher for more severe disease and higher IOP at baseline,26 severity stagespecific comparisons demonstrate the higher costs in the US. Compared to European countries and Canada, the USA has the highest per patient costs (e.g. US mean cost of care per year at glaucoma specialty centers of US$1581 vs. €540 to €960 in Italy and Germany, respectively).11,26,31 Figures 3-3A and B provide illustrations of the total direct medical costs per patient and the relative components in the USA and Europe. Interestingly, patients with higher (worse disease) baseline stage and an IOP increase were more likely to receive surgery in the US than in Europe. Finally, costs also vary by the healthcare system and care delivery structure. Sharma et al. examined the costs of glaucoma follow-up by optometrists in London, who cared for patients in hospital-based as well as High Street community-based clinics. The cost to the system per patient was more than two-fold greater in the community clinic compared to in-hospital care, mostly due to associated overhead costs.32 Total direct and indirect costs to patients were essentially equal at £6 in either location. The authors found that to compensate for higher overhead, community optometrists would need to increase their patient volume to 25 patients daily to make costs comparable to the hospital clinic.

What is Currently Known: Benefits The use of cost-effectiveness analyses has been systematized in countries outside the US, particularly Europe and Australia. In each setting, drug approval includes the determination of the cost per QALY or DALY of a given therapy. While there is growing pressure within the US to rein in healthcare costs, it is notable that the enactment of healthcare reform in the Patient Protection and Affordable Care Act (PPACA) included an explicit prohibition against the use of CEA in approval and coverage decisions by the US government. Nevertheless, understanding current methods of stating the benefits of healthcare is an important element in the economics of glaucoma care. The first task is to define and understand the use of QALYs and DALYs. Each is a measure of the impact of a condition or disease on an individual’s perceived value of their life, with a lower value indicating a lower preferred state. When the impact of a treatment in reducing the level of perceived impairment (i.e., raising the perceived value compared to alternative(s)) is multiplied by the number of years of duration of the treatment effect (or the expected years remaining in a person’s life), then the number of DALYs or QALYs can be derived.

COST-EFFECTIVENESS The standards for what is cost-effective vary widely internationally. In the US, generally, a cost of less than $50,000

24

SECTION 1  •  Glaucoma in the World

per QALY is considered cost-effective, while greater than $100,000 per QALY is not. The WHO has defined costeffectiveness standards relative to the gross national product (GNP) per capita. An intervention costing less than the GNP is considered highly cost-effective, whereas a DALY cost of one to three times the GNP is moderately cost-effective.33

1.0

COST-EFFECTIVENESS OF TREATMENT

0.6

Glaucoma Screening Results of analyses of whether screening for open-angle glaucoma is cost-effective are uncertain at best, both in the US and abroad.35,36 Ocular Hypertension Treatment A cost-utility analysis in glaucoma based on the results of the Ocular Hypertension Treatment Study (OHTS),37 found that treating all patients similar to the OHTS population who had a 5% or greater risk of progressing to glaucoma per year would have an incremental cost-effectiveness ratio of US $3670 per QALY compared to US $42,430 per QALY if all patients with a 2% or greater annual risk were treated. Cost-effectiveness also depends on the patient’s overall life expectancy, when modeled by the same group.38 Glaucoma Diagnosis and Treatment Modeling by Rein et al. using the AAO Preferred Practice Pattern and Early Manifest Glaucoma Trial (EMGT) and Collaborative Initial Glaucoma Treatment Study (CIGTS) clinical trials data found that diagnosis and treatment of POAG (in the US) would halve the percentage of patients developing mild field loss (27% to 5–12%), and reduce years of visual impairment from 5.2 to 1.0–2.6 years, at a cost of $28,000 or 46,000 per QALY for CIGTS and EMGT treatment efficacy, respectively (Fig. 3-4).39 This was sensitive to both cost of treatment and value of a QALY (Fig. 3-5). By WHO standards this would be very and moderately costeffective, respectively.39 Somewhat different modeling of the economic impact of POAG in Australia which did take into account productivity and indirect costs found that increasing POAG diagnosis rates in Australia to 70–90% would cost A$153,000–167,000 per DALY avoided.40 This begins to exceed to estimated value of a life year, as defined in the same article, of A$162,561. Different Treatment Courses: Medication versus Laser Studies The cost-effectiveness of prostaglandin analogs versus argon laser trabeculoplasty (ALT) in managing newly diagnosed mild OAG has been examined in several studies.34,41,42 One study found that PGAs are more costeffective than ALT.34 However, if this assumed effectiveness was reduced by 25%, e.g. due to poor compliance, ALT was

Routine treatment

Probability

0.8

0.4 0.2 0.0 0

20,000

A

40,000

60,000

80,000

100,000

Willingness to pay ($)

No treatment

Routine treatment

1.0 0.8

Probability

The cost-effectiveness of detection and treatment at various stages in the natural history of glaucoma has been analyzed by modeling, and is unsurprisingly sensitive to the types of costs included, cost estimates, and QALY assignments. These Markov models represent a mathematical method for quantifying the costs and health consequences of disease as patients transition through various disease stages over time.34

No treatment

0.6 0.4 0.2 0.0 0

B

20,000

40,000

60,000

80,000

100,000

Willingness to pay ($)

Figure 3-4  Cost-effectiveness acceptability curves for routine assessment and care compared with no care. The probability that the intervention is cost-effective at different WTP values for the routine diagnosis and subsequent treatment compared with no treatment given (A) the efficacy seen in the EMGT and (B) the efficacy seen in the CIGTS. CIGTS = Collaborative Initial Glaucoma Treatment Study; WTP = willingness-to-pay. (From Rein DB, Wittenborn JS, Lee PP, Wirth KE, Sorensen SW, Hoerger TJ, et al. The cost-effectiveness of routine office-based identification and subsequent medical treatment of primary open-angle glaucoma in the United States. Ophthalmology 2009; 116(5):823–832.)

more cost-effective. Incremental cost-effectiveness over no treatment was $14,179/QALY for PGA and $16,824/ QALY for ALT. A separate model found that SLT was more cost-effective than most brand-name medications after 1 year, and was more cost-effective than generic latanoprost and timolol after 13 and 40 months, respectively.41 ALT is estimated to have lower cumulative 5 year costs than either medications or filtering surgery among patients who were not adequately controlled on two medications.42

3  •  Economics of Glaucoma Care

25

the political system, the relationship to political considerations and governmental decisions is also integral to our understanding.

Treatment costs 2 times as much QALY losses half as severe Blindness increases risk of mortality by 20%

IMPACT ON OVERALL HEALTHCARE COSTS

Progression is twice as severe Discount rate = 0%, 5% Routine screening rate ± 25% 0 A

20

40

60

80

100 120

$ Thousand Cost per QALY for routine care compared to no treatment given EMGT effectiveness Treatment costs 2 times as much QALY losses half as severe Progression is twice as severe

Patients who have glaucoma also have increased overall healthcare costs in addition to the direct costs of their glaucoma care. Estimates of additional costs incremental to the eye care costs, if not associated with visual impairment, have been modeled to be $137 per year.44 Progression to severe visual impairment in glaucoma has been estimated to add to overall total healthcare costs.44,45 Visual impairment associated with any diagnosis increases Medicare non-eye care costs; those with moderate loss had annual excess non-eye-related costs of $2193, while those with severe loss and blindness had excess non-eye-related costs of $3301 and $4443 respectively.46 Visual impairment was associated with $2.14 billion in 2003 non-eye care costs46 and excess expenditure of $2.8 billion in 2004 costs.16

Blindness increases risk of mortality by 20%

DISCOUNTING

Discount rate = 0%, 5% Routine screening rate ± 25% 0 B

20

40

60

80

100 120

$ Thousand Cost per QALY for routine care compared to no treatment given CIGTS effectiveness

Figure 3-5  Sensitivity of cost-effectiveness ration to changes in major model parameters. The cost-effectiveness of routine diagnosis and subsequent treatment compared with no treatment given (A) the efficacy seen in the EMGT and (B) the efficacy seen in the CIGTS. CIGTS = Collaborative Initial Glaucoma Treatment Study; EMGT = Early Manifest Glaucoma Trial; QALY = quality adjusted life year. (From Rein DB, Wittenborn JS, Lee PP, Wirth KE, Sorensen SW, Hoerger TJ, et al. The costeffectiveness of routine office-based identification and subsequent medical treatment of primary open-angle glaucoma in the United States. Ophthalmology 2009; 116(5):823–832.)

The Centre for Eye Research Australia study also examined cost-effectiveness of the sequence of treatment. In contrast to Rein et al., whose modeled treatment course was (1) topical medications; followed by (2) laser trabeculoplasty; then (3) trabeculotomy, changing the course of treatment to (1) laser trabeculoplasty; (2) topical medications; (3) trabeculotomy in the Australian study gave a cost savings of $2.50 for each dollar spent.43

Additional Issues and Future Perspectives Analyses of the costs and benefits of glaucoma and its treatment implicate important policy matters. Questions such as to what extent do patients with glaucoma or those with visual impairment affect the overall costs of healthcare, or how general economic conditions affect glaucoma economics arise. In addition, there are basic concepts related to the costs of money and inflation (or deflation) into the future that can significantly alter the results of analyses. As economics is inextricably intertwined with policy decisions and

In calculating costs and QALYs/DALYs, discounting should be applied. Discounting accounts for the value of a dollar and good health today as compared to in the future. The assertion is that a dollar/given monetary amount and good health are worth more today than they are in the future, in addition to inflation, because they can be invested productively in other activities. As such, their value in the future should be adjusted, typically by a minimum of 3% annually.47

DISPARITIES With the anticipated increased prevalence of glaucoma and aging populations around the world in the future,2 disparities in glaucoma care are likely to widen. In the US, the PPACA has extended healthcare to over 30 million previously uninsured people in whom glaucoma may be diagnosed and treated, which can be expected to add to the utilization of eye care services and thus costs of therapy for societies and the individuals newly diagnosed.48 Current estimates are that among those with glaucoma and Medicare coverage, 27% do not see a physician for this condition in follow-up in any given year, with Medicare– Medicaid dually eligible recipients even more likely (43%) not to be seen or treated in a year’s time.28 Hispanics are the fastest growing minority group in the US and Hispanic men are projected to constitute the largest subgroup with POAG by 2035.49,50 After controlling for age and gender, the prevalence of glaucoma in the US Latino/ Hispanic population is similar to that in African-Americans, but Hispanics are nearly 30% less likely than white or black subjects to receive treatment in a given year.28 Asians with POAG are also less likely than Whites (94%) to receive treatment in a given year28 and the number of Asians with POAG is anticipated to increase nearly 5-fold by 2050.50

FUTURE ACCESS TO EYE CARE AND COST Current US healthcare legislation has increased the volume of patients who will receive eye care, increasing diagnosis

26

SECTION 1  •  Glaucoma in the World

and total costs to society. The aging of the Baby Boomer population and the growing costs of technology in healthcare have combined to put the Medicare program onto an unsustainable path. Thus, significant changes in payment and financing will impact patients, providers, and society in the next decade. Most notably, the Independent Payment Advisory Board (IPAB), created under the PPACA, is a 15-member organization tasked with developing a plan to reduce Medicare

spending, should the estimated growth rate of Medicare cost per capita exceed a given goal for each coming year. While its precise function is as yet undefined, it is likely to become central in determining coverage and payment rates for providers who care for Medicare patients. It is prohibited from rationing healthcare based on costs, raising taxes (revenues) or Medicare beneficiary premiums, increasing Medicare beneficiary cost sharing, restricting benefits, or modifying eligibility criteria [Patient Protection and

Spotlight 1  Economics of Glaucoma Care in Asian Countries: An Overview Errol Chan and Paul TK Chew

Glaucoma ranks as the second leading cause of blindness in Asia.1 Financing glaucoma care in Asia presents several unique challenges due to the wide variation in socioeconomic profile, glaucoma disease patterns, and healthcare systems in Asia. In keeping with trends in the global glaucoma burden, the number of people afflicted with glaucoma in Asia is expected to increase to 49.3 million in 2020.1 Current prevalence estimates for glaucoma range from 1.8% in Bhaktapur Nepalese to 5% in the Tajimi Japanese population. Exponential increases are predicted in future decades due to increased longevity and the transition to an aging population. Asia therefore contains the largest current and future burden of glaucoma worldwide. Second, access to ophthalmic care, particularly in rural settings, low awareness of eye diseases, and the vast number of undiagnosed glaucoma cases are of concern. Primary angle-closure disease (PACD) is more common in Asia than in the West, although primary open-angle glaucoma (POAG) still remains the major glaucoma type. Normotension glaucoma (NTG) constitutes most of POAG cases in Japan. Regional differences in the POAG : PACG ratio may also indicate differential country-specific strategies for glaucoma screening and treatment. From an economic perspective, many individuals in developing Asian countries remain economically underprivileged, imposing challenges in treatment affordability. Additionally, healthcare spending by Asian governments could be prioritized lower over other economic concerns. Economic evaluations of glaucoma in Asia thus far highlight only the direct disease-related costs. We know that the estimated 5-year cumulative direct costs of an acuteangle closure attack in Singapore range between US$879 to US$2576 to the individual, and between US$261,741 and US$287,560 for the healthcare system.2 The cost of glaucoma medications varies widely even in individual countries.3,4 Although prostaglandin analogs are increasingly used because of their efficacy and side-effect profile, the main drawback of cost would be an important consideration in many Asian countries. Data on glaucoma-related income losses are non-existent. Before cost-effective analyses can be conducted, clinical justification of efficacy has to be demonstrated. We await data on the clinical efficacy of laser iridotomy (LI) for PACD from the Zhongshan Angle Closure Prevention (ZAP) Trial,5 in terms of delaying progression to PAC and development of an acute angle-closure attack. To date, population-based glaucoma screening has revealed only moderate efficacy (70–80% sensitivity/specificity) with the Heidelberg Retinal Tomograph in Singapore Malays.6 In addition, accurate information on the rate of visual field progression in Asian

eyes is required, to generate reliable economic models and estimates. Country-specific analyses are also indicated due to the vast differences in healthcare systems. A limitation of quality-of-life studies in glaucoma in Asia for the purpose of cost-effectiveness analyses is that the outcomes assessed, i.e. vision-specific functioning,7 activity limitation, falls, or psychological well-being, do not readily translate into quality- or disability-adjusted life years (QALYs or DALYs). As QALYs and DALYs are standard metrics for comparison with other diseases, there is limited information to guide policymakers in prioritizing scarce healthcare resources for glaucoma. The large and severe glaucoma burden in Asia highlights a need to identify key priorities that differ from that in North America, Europe or Australia. For screening to be costeffective, strategies targeting risk groups, e.g. older individuals, those with more advanced disease or who are visually impaired, and employment of low-cost screening equipment, may be needed. Facilitating insurance or governmental subsides for treatment could offset major cost-drivers. Increasing accessibility to generic glaucoma medications, and determining the efficacy, costs, and cost-effectiveness of laser iridotomy and routine cataract surgery in angle-closure eyes to prevent glaucoma development, are likely important priorities. References 1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;262–7. 2. Wang JC, Chew PT. What is the direct cost of treatment of acute primary angle closure glaucoma? The Singapore model. Clin Exp Ophthalmol 2004;32:578–83. 3. Ikeda H, Sato E, Kitaura T, et al. Daily cost of ophthalmic solutions for treating glaucoma in Japan. Jpn J Ophthalmol 2001;45:99–102. 4. Gao Y, Wu L, Li A. Daily cost of glaucoma medications in China. J Glaucoma 2007;16:594–7. 5. Jiang Y, Friedman DS, He M, et al. Design and methodology of a randomized controlled trial of laser iridotomy for the prevention of angle closure in southern China: the Zhongshan angle closure prevention trial. Ophthal Epidemiol 2010;17:321–32. 6. Zheng YF, Wong TY, Lamoureux E, et al. Diagnostic ability of Heidelberg Retina Tomography in detecting glaucoma in a population setting: the Singapore Malay Eye Study. Ophthalmology 2010;117:290–7. 7. Chan EW, Chiang PP, Wong TY, et al. Impact of glaucoma severity and laterality on vision-specific functioning: the Singapore Malay eye study. Invest Ophthalmol Vis Sci 2013;54:1169–75.

3  •  Economics of Glaucoma Care

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Spotlight 2  Economics in India of High-Volume Glaucoma Care Rengaraj Venkatesh and Krishnamurthy Palaniswamy

Glaucoma is far different from cataract. Cataract is symptomatic and involves a single intervention with close to 100% perceived improvement of visual function and quality of life. Glaucoma, however, involves the preservation rather than the acquisition of vision. There are 11.2 million persons above the age of 40 with glaucoma in India and an additional 28.1 million are suspect glaucoma (OHTN/PAC/ PACS).1 The economic burden of glaucoma increases as the disease progresses; treatment delaying disease progression could significantly reduce health economic burden.2 Direct costs of glaucoma care include physician and hospital visits, medication(s), glaucoma procedures, transportation, and nursing home care. Indirect costs include lost productivity at work and productivity costs borne by family members and friends.3 In one African study, middle-income earners spent over 50% of their monthly income and low-income earners spent all their monthly earnings on treatment for glaucoma, resulting in non-compliance and poor follow-up,4 likely similar to the Indian scenario. Efforts to reduce glaucoma blindness have been limited by inadequate screening and diagnosis, low use of eye care services and poor adherence to treatment and follow-up recommendations. Various reasons have been attributed for not seeking eye care in spite of visual problems such as lack of funds, time constraints, and inability to leave family and work responsibilities, the need for escorts, and fear about their disease.5,6 Hence the need to design a comprehensive yet sustainable eye care program that must be easily accessible and affordable to the rural population and at the same time ensure high quality in terms of screening, treatment and referral services. Keeping this in mind, Aravind Eye Care System (AECS) in addition to base hospital-based glaucoma screening, established vision centers (VCs) to provide primary eye care. These VCs are equipped with basic ophthalmic equipment and run by well-trained ophthalmic assistants who perform the standard examinations (slit lamp examination, refraction) as well as treat minor ailments. Records in these VCs are kept electronically, and simple digital cameras are slightly modified to be used as fundus cameras. Patients examined at the VCs interact via tele-consultation with an ophthalmologist at the base hospital. Should there be the need for further treatment, the patient is referred to the base hospital. In the presence of limited economic resources, VCs are used for opportunistic glaucoma screening in rural populations which would otherwise be difficult to evaluate, and this helps reduce the burden of disease.7 Medical management remains the mainstay of treatment in India. Low-cost generic drugs have flooded the market, though quality control is inconsistent. Generic drugs are often not as potent as the original formulations, but they are the only hope for many. Primary treatment with trabeculectomy is an ideal option for patients with advanced glaucomatous damage, given compliance and follow-up

Affordable Care Act, Pub. L. No. 111–148, §2702, 124 Stat. 119, 318–319 (2010)]. As such, reducing or changing the payment structure for healthcare providers is one of the few tools that the IPAB has to achieve its objectives. Other than the use of cost-effectiveness or other CBA techniques (from which it is barred), the IPAB may in part resemble the National Institute for Health and Clinical

issues. The cost of trabeculectomy surgery in a private hospital varies from $200 to $400, while a phacoemulsification combined with trabeculectomy would cost somewhere from $500 to $1000. Governmentsponsored health insurance schemes in some states of India provide glaucoma surgery and combined procedures free of cost, which is very favorable for people living below the poverty line. Many patients in outreach screening camps (especially those with advanced age) present with advanced cataract and glaucoma, and trabeculectomy combined with manual small-incision cataract surgery is a boon for such patients as it is a safe, cost-effective technique, has a minimum of complications, and has a short learning curve.8 Managing glaucoma after trabeculectomy failure continues to be a challenge, as most of the glaucoma tube shunts are expensive. Aurolab, a manufacturing division of AECS, has recently developed a cost-effective tube shunt called the Aurolab Aqueous Drainage Implant (AADI). This tube shunt will help glaucoma surgeons deal with failed filters and difficult cases with relative ease. To conclude, quality generic medications, early primary filtering procedures, rural-based healthcare delivery programs and government-sponsored health insurance schemes would help tackle the burden of glaucoma in India. References 1. George R, Ramesh S, Viajaya L, et al. Glaucoma in India: Estimated burden of disease. J Glaucoma 2010;19:391–7. 2. Varma R, Lee PP, Goldberg I, et al. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol 2011;152:515–22. 3. Lee PP, Walt JG, Doyle JJ, et al. A multicentre, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol 2006;124(1):12–19. 4. Adio AO, Onua AA. Economic burden of glaucoma in Rivers State, Nigeria. Clin Ophthalmol 2012;6:2023–31. 5. Robin AL, Nirmalan PK, Krishnadas R, et al. The utilization of eye care services by persons with glaucoma in rural south India. Trans Am Ophthalmol Soc 2004;102:47–55. 6. Fletcher AE, Donoghue M, Devavaram J, et al. Low uptake of eye services in rural India: a challenge for programs of blindness prevention. Arch Ophthalmol 1999;117(10):1393–9. 7. Khurana M, Kader MA, Ramakrishnan R. Opportunistic glaucoma screening in rural India: Role of vision centers. ARVO 2013 Poster. 8. Venkatesh R, Sengupta S, Robin AL. Mitomycin C-augmented trabeculectomy combined with single-site manual small-incision cataract surgery through a tunnel flap technique. Asia-Pac J Ophthalmol 2012;1:142–6.

Excellence (NICE) in the UK, whose independent advisory committees provide evidence-based guidelines on clinical effectiveness and cost-effectiveness of disease interventions. It issues recommendations for the National Health Service, the universal healthcare system of the UK. In April 2013 it transitioned from a Department of Health-funded Body to a Non-Departmental Public Body.

28

SECTION 1  •  Glaucoma in the World

An example of its work is the use of simulation modeling. One simulation comparing five strategies for glaucoma care, including hospital and community-based monitoring and intensive and conservative strategies previously recommended by NICE found that biennial hospital monitoring as well as intensive and conservative NICE-recommended strategies reduced the number of cases of glaucoma conversion and increased QALYs compared to annual community-based monitoring. While biennial hospital monitoring had an ICER of over £30,000, it was less costly and more effective than the NICE strategies.51 With the fiscal situation becoming more pressing across the Western world, it is more a matter of when and not if cost-limiting restrictions will be instituted. Incentives for better performance, such as in the Physician Quality Reporting System (PQRS) are giving way to larger penalties associated with meaningful use and other measures designed to incentivize the development of larger groups and greater electronic collaboration in care. Already, payors have ‘profiled’ physicians for the resources they use in providing care, either refusing to cover care by ‘more expensive’ providers or ‘tiering’ physicians by out-of-pocket payments, such as co-payments, that patients are required to pay. For providers who are deemed to be ‘low cost,’ patients may have no or minimal co-payments while those deemed by the payor to be ‘high cost’ will have larger patient payments as an incentive for patients to use what payors believe are ‘lower’ cost providers. In such a world, the accuracy of costs analyses and the assignment of costs is critical to all concerned, particularly the providers and the payors in question, as well as the patient. Finally, because estimates show that cost-utility analysis could save 7% of national healthcare expenditures in the US,47 it is likely that some elements of benefits will become part of the consideration in coverage decisions by payors and policymakers. Those services that are highly costeffective will be much more likely to be covered or to have lower patient payments, while those with less costeffectiveness will be left to greater payment by patients. Access Table 3-1 online at http://www. expertconsult.com

References 1. Taylor HR. Glaucoma: Where to now? Ophthalmology 2009;116(5): 821–2. 2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3): 62–7. 3. Varma R, Lee PP, Goldberg I, et al. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol 2011;152(4): 515–22. 4. Weih LM, Nanjan M, McCarty CA, et al. Prevalence and predictors of open-angle glaucoma: Results from the visual impairment project. Ophthalmology 2001;108(11):1966–72. 5. Friedman DS, Wolfs RC, O’Colmain BJ, et al. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 2004;122(4):532–8. 6. Fiscella RG, Green A, Patuszynski DH, et al. Medical therapy cost considerations for glaucoma. Am J Ophthalmol 2003;136(1): 18–25. 7. Wong EYH, Keeffe JE, Rait JL, et al. Detection of undiagnosed glaucoma by eye health professionals. Ophthalmology 2004;111(8): 1508–14. 8. OECD Health Data 2012: How Does the United States Compare; 2012.

9. Fiscella RG, Jensen MK. Cost analysis of glaucoma medications. Am J Ophthalmol 2008;145(6):1108–9. 10. Rein DB, Zhang P, Wirth KE, et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol 2006;124(12):1754–60. 11. Lee PP, Walt JG, Doyle JJ, et al. A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol 2006;124(1):12–19. 12. Jampel HD, Frick KD, Janz NK, et al. Depression and mood indicators in newly diagnosed glaucoma patients. Am J Ophthalmol 2007; 144(2):238–44.e1. 13. Kymes SM. An introduction to decision analysis in the economic evaluation of the prevention and treatment of vision-related diseases. Ophthal Epidemiol 2008;15(2):76–83. 14. Frick KD, Kymes SM, Lee PP, et al. The cost of visual impairment: purposes, perspectives, and guidance. Invest Ophthalmol Visual Sci 2010;51(4):1801–5. 15. Taylor HR, Pezzullo ML, Keeffe JE. The economic impact and cost of visual impairment in Australia. Br J Ophthalmol 2006;90(3): 272–5. 16. Frick K, Gower E, Kempen J, et al. Economic impact of visual impairment and blindness in the United States. Arch Ophthalmol 2007; 125(4):544–50. 17. Brown MM, Brown GC, Sharma S, et al. Healthcare economic analyses and value-based medicine. Surv Ophthalmol 2003;48(2): 204–23. 18. Jampel HD, Schwartz A, Pollack I, et al. Glaucoma patients’ assessment of their visual function and quality of life. J Glaucoma 2002;11(2):154–63. 19. Kobelt G, Jonsson B, Bergström A, et al. Cost-effectiveness analysis in glaucoma: what drives utility? Results from a pilot study in Sweden. Acta Ophthalmol Scand 2006;84(3):363–71. 20. Gupta V, Srinivasan G, Mei SS, et al. Utility values among glaucoma patients: an impact on the quality of life. Br J Ophthalmol 2005; 89(10):1241–4. 21. Taylor HR. LXIII Edward Jackson Memorial Lecture: Eye Care: Dollars and Sense. Am J Ophthalmol 2007;143(1):1–8.e1. 22. Lee PP, Levin LA, Walt JG, et al. Cost of patients with primary openangle glaucoma: A retrospective study of commercial insurance claims data. Ophthalmology 2007;114(7):1241–7. 23. Stein JD, Niziol LM, Musch DC, et al. Longitudinal trends in resource use in an incident cohort of open-angle glaucoma patients: Resource use in open-angle glaucoma. Am J Ophthalmol 2012;154(3): 452–9.e2. 24. Kobelt G, Texier-Richard B, Buchholz P, et al. Treatment of glaucoma in clinical practice: four-year results from a patient registry in France. J Glaucoma 2010;19(3):199–206. 25. Kobelt G, Jonsson L. Modeling cost of treatment with new topical treatments for glaucoma. Results from France and the United Kingdom. Int J Technol Assess Healthcare 1999;15(1): 207–19. 26. Traverso CE, Walt JG, Kelly SP, et al. Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe. Br J Ophthalmol 2005;89(10):1245–9. 27. Stein JD, Sloan FA, Lee PP. Rates of glaucoma medication utilization among older adults with suspected glaucoma, 1992 to 2002. Am J Ophthalmol 2007;143(5):870–2.e1. 28. Stein JD, Ayyagari P, Sloan FA, et al. Rates of glaucoma medication utilization among persons with primary open-angle glaucoma, 1992 to 2002. Ophthalmology 2008;115(8):1315–19.e1. 29. Rylander NR, Vold SD. Cost analysis of glaucoma medications. Am J Ophthalmol 2008;145(1):106–13. 30. Berenson KL, Kymes S, Hollander DA, et al. Cost-offset analysis: Bimatoprost versus other prostaglandin analogues in open-angle glaucoma. Am J Managed Care 2011;17(9):e365–374. 31. Lee PP, Kelly SP, Mills RP, et al; Costs of Glaucoma Study Group. Glaucoma in the United States and Europe: predicting costs and surgical rates based upon stage of disease. J Glaucoma 2007;16(5): 471–8. 32. Sharma A, Jofre-Bonet M, Panca M, et al. An economic comparison of hospital-based and community-based glaucoma clinics. Eye 2012;26(7):967–71. 33. Hutubessy R, Chisholm D, Edejer T. Generalized cost-effectiveness analysis for national-level priority-setting in the health sector. Cost Eff Resour Alloc 2003;19(1).

3  •  Economics of Glaucoma Care 34. Stein JD, Kim DD, Peck WW, et al. Cost-effectiveness of medications compared with laser trabeculoplasty in patients with newly diagnosed open-angle glaucoma. Arch Ophthalmol 2012;130(4):497–505. 35. Vaahtoranta-Lehtonen H, Tuulonen A, Aronen P, et al. Cost effectiveness and cost utility of an organized screening programme for glaucoma. Acta Ophthalmol Scand 2007;85(5):508–18. 36. 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. 37. Kymes SM, Kass MA, Anderson DR, et al. Management of ocular hypertension: a cost-effectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141(6):997– 1008.e3. 38. Kymes S, Plotzke M, Kass M, et al. Effect of patient’s life expectancy on the cost-effectiveness of treatment for ocular hypertension. Arch Ophthalmol 2010;128(5):613–18. 39. Rein DB, Wittenborn JS, Lee PP, et al. The cost-effectiveness of routine office-based identification and subsequent medical treatment of primary open-angle glaucoma in the United States. Ophthalmology 2009;116(5):823–32. 40. Dirani M, Crowston JG, Taylor PS, et al. Economic impact of primary open-angle glaucoma in Australia. Clin Exp Ophthalmol 2011;39(7): 623–32. 41. Seider M, Keenan D, Han Y. Cost of selective laser trabeculoplasty vs. topical medications for glaucoma. Arch Ophthalmol 2012;130(4): 529–30. 42. Cantor LB, Katz LJ, Cheng JW, et al. Economic evaluation of medication, laser trabeculoplasty and filtering surgeries in treating patients with glaucoma in the US. Curr Med Res Opin 2008;24(10): 2905–18.

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43. Taylor HR. Tunnel vision – the economic impact of primary angle glaucoma 2008 – A dynamic economic model: Centre for Eye Research Australia; 2008. 44. Kymes SM, Plotzke MR, Li JZ, et al. The increased cost of medical services for people diagnosed with primary open-angle glaucoma: A decision analytic approach. Am J Ophthalmol 2010;150(1): 74–81. 45. Bramley T, Peeples P, Walt JG, et al. Impact of vision loss on costs and outcomes in Medicare beneficiaries with glaucoma. Arch Ophthalmol 2008;126(6):849–56. 46. Javitt JC, Zhou Z, Willke RJ. Association between vision loss and higher medical care costs in Medicare beneficiaries: costs are greater for those with progressive vision loss. Ophthalmology 2007;114(2):238– 45.e1. 47. Brown GC, Brown MM, Sharma S. Healthcare economic analyses. RETINA 2004;24(1):139–46. 48. Zhang X, Lee P, Thompson T, et al. Health insurance coverage and use of eye care services. Arch Ophthalmol 2008;126(8):1121–6. 49. 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):1439–48. 50. Vajaranant TS, Wu S, Torres M, et al. The changing face of primary open-angle glaucoma in the United States: Demographic and geographic changes from 2011 to 2050. Am J Ophthalmol 2012; 154(2):303–14.e3. 51. Burr JM, Botello-Pinzon P, Takwoingi Y, et al. Surveillance for ocular hypertension: an evidence synthesis and economic evaluation. Health Technol Assess 2012;16(29):1–271, iii-iv.

4 

Practical Application of Glaucoma Care in Different Societies ALAN L ROBIN, DONALD L BUDENZ, NATHAN G CONGDON and RAVILLA D THULASIRAJ

Summary Diagnosis of glaucoma and delivery of effective treatment is difficult everywhere, but additional challenges are evident in less affluent parts of the world, where the largest numbers of patients with this disease are living. The problems of providing good glaucoma care are examined with especial reference to southeast Asia including China and India and countries in sub-Saharan Africa. The relatively low priority given to glaucoma by visionrelated and other nongovernmental organizations (NGOs) due to difficulties faced in delivering effective glaucoma screening and therapeutic interventions are discussed, together with possible future directions for increasing resources and priority for glaucoma care in poor areas.

Introduction Cataract is the major cause of treatable blindness in less developed countries.1 It is relatively simple to diagnose; the therapy is standardized, simple and efficient and requires a single, cost-effective intervention; and patients perceive a positive outcome and a marked improvement in their quality of life. Glaucoma is the second leading cause of blindness worldwide and unlike cataract its blindness is irreversible.2 Glaucoma therapy in less developed countries is challenging and requires a different set of thought processes and skills than are currently used in more developed nations. Problems faced in developing nations are appreciably magnified and reach a greater level of significance because of generally poorer training, later diagnosis, less access to care, poorer utilization of care, as well as folklore and beliefs. In essence, there are more extremes. Even in situations where there is the best of care, the detection of glaucoma in a prosperous population is relatively poor. In a more developed society, one would expect that with a high number of physicians and optometrists per capita, and with a financial incentive to capture each new patient, hardly anyone with a disease would go undetected. Glaucoma, however, because it is generally an asymptomatic disease, is often not detected. Even within a 5-mile radius of the Wilmer Institute (Johns Hopkins University, Baltimore, Maryland, USA) almost 50% of subjects with glaucoma were unaware of their diagnosis.3 Similar patterns of low rates of prior glaucoma diagnosis have been 30

seen in other parts of the United States4 as well as through Western Europe and Australia.5–9 The prevalence of the disease and the lack of therapy may be different in the elderly (those over 75 years). In a recent study in Salisbury, Maryland, USA, almost 20% of subjects with glaucoma had a best corrected presenting vision of less than 6/12 and the rate of blindness varied between 1.3% and 5.3%.10 Additionally, one-third of those who were diagnosed with glaucoma were never told previously that they had the disease. The prevalence of glaucoma increased in Whites from 3.4% to 9.4% in those over 75 and in Blacks from 5.7% to 23.2% in the same age group. In developing nations, this problem becomes more extreme. In south India, investigators found that 21% of subjects in a population-based survey (mean age 60 years) were blind in either eye at presentation and that 93% had not been previously diagnosed with the disease.11 There are many possible reasons for this discrepancy between developed and less developed nations. One common reason is that many in less developed nations accept visual impairment as a natural consequence of aging. The concept of ‘white hair and white eyes’ as a normal occurrence is not uncommon. That is, as one accepts the natural aging and whitening of hair, blindness is also an accepted consequence of maturation. Concepts of public health and preventive care are foreign to most, even in more developed nations. Individuals are unaware of diseases such as glaucoma or diabetic retinopathy, so they do not routinely access care. Visual impairment is as much an accepted part of daily life as is poor mobility from arthritis. The infrastructure is also diminished and eye care providers are clustered in cities so that it is harder to find an appropriate doctor. When individuals do present for care, as their vision is dimming, doctors and paramedical personnel are usually geared towards cataract blindness and often do not measure the intraocular pressure, do not perform perimetry, and do not examine the fundus. Part of this is due to lack of adequate training.12 This may be a question of priorities, skill levels, or inadequate time. The issue of staffing is not only that the absolute number of ophthalmologists per capita is far less. This situation is compounded by the fact that the proportion of ophthalmologists who are well trained in glaucoma is even smaller.13 In many places, applanation tonometry is not commonly done and physicians rely upon digital intraocular pressure (IOP) measurements. Slit lamps may be a luxury in underserved areas of China and Africa. Likewise, diseases such as normal-tension glaucoma are difficult to diagnose in eyes with cataract in which the lens

4  •  Practical Application of Glaucoma Care in Different Societies

opacity makes it challenging to either view the fundus or perform perimetry. Cataract and refractive error have become major hurdles in themselves.14 The mere diagnosis of, and surgery for, visually disabling cataract alone is often a significant problem. The skilful performance of cataract surgery with intraocular lens insertion is now becoming commonplace.10 Following surgery, subjects are often sent back to their homes and villages without a thorough fundus examination. Little counseling outside of postoperative cataract care is given. Later, subjects may become visually disabled from posterior capsule opacification. If that occurs, they may return to the clinic and receive a capsulotomy. Following the capsulotomy, poor training, lack of equipment and time often dictate that the fundus is not viewed. Minimal postoperative instructions are given to the patient outside of those necessary for a capsulotomy. The actions and outcomes associated with this pattern of care teach the patient an incorrect lesson. They have twice seen that, if they lose vision, it can be easily restored by either surgery or laser. The implication is that there is no need for yearly or everyother-yearly preventive visits. If the patient then develops glaucoma or diabetic retinopathy, he will not return until he has become blind since he has learned that blindness can be reversed. However, as people age, the prevalence of irreversible blinding diseases such as glaucoma markedly increases, especially over the age of 75. It may also be that the prevalence of glaucoma may be increased in both aphakic and pseudophakic eyes15 and blindness due to glaucoma is seen in 22% in either one or both conditions in developing countries. Detecting glaucoma can be difficult in developing countries. Modern equipment such as computerized perimetry and imaging equipment is not commonly available in many urban and most rural centers. Tactile or Schiotz intraocular pressure measurements and non-stereoscopic fundus examinations are the rule, if they occur at all. Gonioscopy is not often done even in developed countries like the United States.16 In the majority of more developed nations, the primary angle-closure glaucomas are relatively infrequent whereas in developing nations they can account for onehalf of primary glaucomas and despite their decreased prevalence remain a leading cause of disability and blindness. Likewise many with normal-tension glaucoma have IOPs lower than 21 mmHg at presentation.17 The accurate diagnosis of angle-closure disease is imperative for prompt and appropriate care, and these cases need to be discovered early to prevent permanent synechial closure and the need for more involved surgery. In many regions of the world, lasers are not available, but surgical iridectomy is relatively easy to perform. It may be more difficult to perforate a thick brown iris with a laser in a narrow anterior chamber and if iridotomy closure occurs, the patient may not have returned for follow-up care and may be totally unaware of this problem. Additionally, care has to be taken to train surgeons to convince patients to have preventative surgery on fellow eyes. Screening for glaucoma alone is not often cost-effective because of the relatively low prevalence of the disease and problems with both sensitivity and specificity of most screening tests. However, if screening for glaucoma is coupled with other disease screening, such as screening for

31

diabetic retinopathy or cataract, it may become much more cost-effective as both diseases require disc and fundus photography. Simple perimetry testing such as frequency doubling technology (FDT) can be cost-effective when coupled with fundus examinations or either dilated or undilated fundus photography. Computerized evaluations and scanning of digital disk photographs may be useful for reliable screening as is currently being attempted for diabetic retinopathy.18 These types of screenings can make a large impact as digitalized images and telemedicine become more widely utilized. Digital photographic screening can offer the advantages of immediate more accurate screening, allowing trained manpower the opportunity to perform other tasks. Currently, telemedicine is being performed at two separate institutions in both Chennai and Madurai, India. Telemedicine has the capability to bring eye care screening to the people, rather than having patients come to eye care centers. This is more convenient for patients and frees them to get expert opinions without being subject to long-distance travel and allows them potentially freer access to betterquality eye care. Most importantly, telemedicine screening results in an increased number of people being screened overall. Since subjects with glaucoma often present with more advanced disease in developing countries, the presence of so many visually impaired and monocular patients makes it necessary to be more aggressive in treatment, much more so than one might be with either high-risk ocular hypertensives or early glaucoma subjects in more developed countries. Once the diagnosis of open-angle glaucoma is made, the main question is how to proceed with therapy. Although the American Academy of Ophthalmology states that all newly diagnosed glaucoma patients should be given the option of either medical, surgical, or laser therapy, in the USA medical therapy is predominantly the first choice. Medical therapy is problematic from many perspectives in developing countries. These potential problems include not only cost, adherence, and the ability of a patient with an eye of low visual function to successfully get a drop into the eye, but also quality and accessibility of pharmaceutical agents. Few formal medication compliance studies in glaucoma have been published in developing nations, but some have suggested that compliance may be much poorer. Within 5 years of diagnosis, fewer than 10% of patients still continue follow-up care or return for therapy (unpublished data, Aravind Hospital System, Coimbatore, India). The cost of locally produced drugs is often affordable with medications such as pilocarpine hydrochloride, timolol maleate, and brimonidine tartrate, often costing less than US$1 per bottle. There is, however, a distribution problem. In cities, it is usually possible to get any type of medication. In rural areas, it may be difficult to get anything more than pilocarpine or timolol, making it useless to prescribe other IOPlowering medications. This limits the options available to more rural patients before surgical intervention is needed. Also, as urban dwellers may earn more than rural patients, the influence of cost may unduly hamper those who are more rural. Costs of therapy are, of course, as important in the developing world as they are in the more developed world. In the United States, the cost of therapy can cause patients to use their medications less often than prescribed. Even relatively

32

SECTION 1  •  Glaucoma in the World

small differences in co-payments may have significant effects on adherence and disease progression.19–23 In developing nations, some but not all topical IOPlowering medications are far cheaper in terms of US dollars compared with their prices in the USA or even Europe. However, they are expensive in terms of an individual’s daily income and small differences in costs may make tremendous differences in use and in adherence. The National Bureau of Statistics in China in 200424 found that the average income per person in rural China was US$0.97/day and US$3.11/day in urban China. That needs to cover the average cost of food per day (US$0.34/day and US$0.90/ day in rural and urban China, respectively), and housing (US$0.11/day and US$0.24/day, rural and urban China, respectively). China has some basic medical insurance that means that the government will pay 80% of the cost of further medical treatment for a person after the person has paid the first US$241.00. This, however, does not apply to some urban and most rural citizens. In most cities in China, basic medical insurance does not cover the relatively new glaucoma medications such as prostaglandins and topical carbonic anhydrase inhibitors. Medical insurance is becoming more widely available in China, even in rural areas, but generally does not cover the cost of medications. In some parts of China, especially rural China, traditional treatments, such as acupuncture, are still considered costless therapy.25 In parts of China, as in India, even the medications with the lowest costs are not available. What are the costs of glaucoma care in China?26 The cost of a laser trabeculoplasty ranges from US$40 to US$70, while the cost of filtration surgery was US$70. The average costs of medications (assuming full compliance and no wasting) is US$1/day in China. The quality of many generics medications is often suspect. The authors have seen this with ophthalmic antibiotics27 and have seen that generic glaucoma medications do not lower IOP as well as nongeneric preparations.28 This, however, may lead to a quandary. Does one use a potentially inferior but inexpensive generic medication or ask a patient to pay a significant part of his or her salary for a slightly more reliable and efficacious medication? Often, this decision is made on the basis of cost. In addition, as in India, some but not all generic medications such as timolol and pilocarpine are widely available and can be sourced almost anywhere. Training and skill sets are important factors in China as a large percentage of glaucoma is angle closure rather than open angle. The ability to accurately diagnose the type of glaucoma becomes a significant issue. If gonioscopy is not performed properly or at all, angle-closure glaucoma may be inappropriately treated with medications rather than laser or surgical intervention, resulting in needless blindness. The diagnosis of all forms of angle closure requires an adequate skill set, including gonioscopy and proficiency with a slit lamp, which may not be acquired in residency.29 Should laser trabeculoplasty be used in developing nations? Some reports have found it potentially effective in a limited number of subjects for a relatively short time period.30 However, long-term studies are needed. Additionally, in many areas, reliable electric power and equipment maintenance are limiting factors. For a laser to be effective, it must be durable, ideally it should be portable, and have a

self-contained battery power source because fluctuations in power can result in permanent damage to circuitry.31 Additionally, since lasers are relatively expensive, they may not be cost-effective in settings that lack a high proportion of paying patients. Although laser trabeculoplasty may be as effective as a single medication, even those patients who have a good initial response will eventually need medications as the effect of the laser wears off over time. Diode laser cyclophotocoagulation has been studied as an initial therapy in a developing country.32 This instrument is sturdy and portable, which is a major advantage in that it is unlikely to need costly repairs and can be transported from clinic to clinic. This technology also has the potential advantage of being easy to perform after appropriate training, rapidly administered, and requiring minimal intraoperative and postoperative care. However, IOP-lowering results are not adequate, the treatment causes cataracts, and there is a small risk of sympathetic ophthalmia33 which make the relative risks outweigh the benefits of ease of application and cost. At first glance, initial incisional surgery would seem like a good option. But if one considers a filtering procedure, should one just perform a trabeculectomy? Cataract is one of the most common complications of filtering surgery.34 An asymptomatic subject with 6/6 visual acuity could go in for glaucoma surgery, seeing well, and after filtration surgery, have worse vision from subsequent cataract. The ‘worse vision’ would be blamed on the glaucoma surgery and this could be an undesirable situation, especially in someone who was asymptomatic before glaucoma surgery was performed. In the best of situations, this approach takes someone temporarily out of the workforce and requires a second trip to the operating room. This increases the risk not only of endophthalmitis, but also bleb failure, leaving the patient back where he or she started, but two surgeries later.35 This could be compounded by poor cataract surgical techniques in some regions. Also, one poor result could, through negative social marketing, destroy the relationship between the eye care providers and the community. Therefore, should one consider a combined cataract and glaucoma operation so the patient might feel better than one might after a trabeculectomy alone?36 In a disease where there are no symptoms until too late in the disease, adding symptoms because of surgical intervention might cause the person and also the people associated with him to lose faith in the healthcare provider. Since most individuals who present with glaucoma do not have visually significant cataracts, usually they do not have better vision after combined surgery. In addition, the IOP-lowering that results from combined procedures is inferior to glaucoma surgery alone. If not trabeculectomy, then perhaps a glaucoma drainage device could be used as primary surgery. Glaucoma drainage device surgery has less surgical technique variability and requires minimal postoperative manipulation. Although in some studies the results appear comparable between trabeculectomy and glaucoma drainage devices, the initial cost of a shunt ($600–800 US dollars) is prohibitive in developing countries. Of note, the AADI, an inexpensive glaucoma drainage device similar to the Baerveldt glaucoma drainage implant is available through Aurolab in Madurai, India, and is priced at less than US$80.00.

4  •  Practical Application of Glaucoma Care in Different Societies

Various skill levels are required for filtering surgery. As an example of the variability of training and surgical skills, the authors first will examine cataract surgery, the bread and butter of ophthalmic surgery. In Madurai, India,37 fewer than 1.9% of patients had final visual acuities less than 6/18, whereas in Hyderabad38 41.6% had visual disability or blindness following cataract surgery. This suggests that if the skill level needed for cataract surgery can vary so much in a developing nation where cataract is a frequently performed procedure, the outcomes for filtering surgery might vary even more since this is not as standardized a surgical procedure. Ideally, surgery should be the best option, as it could be a one-time procedure that would obviate compliance issues, be cost-effective, and be socially acceptable. Work is currently going on in various centers to help develop easy, universal surgical techniques. However, as of now, this is not the case, nor does it appear to be the case for the near future. New technology might benefit surgical intervention. CO2 lasers are now available that can create deep sclerotomies. The learning curve is slight and the results appear similar to (but have not been compared to) trabeculectomies.39 The ability to create a standardized procedure that is easy to learn and has predictable outcomes is desirable. Nonpenetrating procedures such as this should result in fewer flat chambers, endophthalmitis, cataracts, and hypotonyrelated complications.

Practical Considerations in the Management of Glaucoma in Sub-Saharan Africa Sub-Saharan Africa, because of its paucity of trained healthcare providers, rural settings, and lack of infrastructure, may require additional consideration compared to other areas of the world. The following description of the management of glaucoma in Africa is based solely on personal experience in Ghana, West Africa, and may not be generalizable to the entire continent, but is likely to relate to many developing sub-Saharan African countries. Several factors contribute to the unique management of glaucoma in sub-Saharan Africa. First, the prevalence of primary open-angle glaucoma in black Africans is estimated at 3–7% of people 40 years and older in glaucoma surveys done in Ghana,40 Tanzania,41 and South Africa.42–44 In studies conducted in West Africa, glaucoma accounts for 16% to 24% of blindness, falling just behind cataract.45–47 Second, glaucoma in Blacks has an earlier age of onset48–53 and can take a more aggressive course,54,55 leading to visual disability and blindness at an earlier age. And third, the extremely limited resources in the developing countries of sub-Saharan Africa make diagnosis and management difficult.56 The diagnosis of glaucoma in West Africa is most often based on intraocular pressure alone. Manual kinetic perimetry requires relatively expensive equipment, skilled perimetrists, and considerable time to perform. Automated visual field equipment would be ideal, but equipment is expensive and difficult to both obtain and maintain in developing countries. Portable, inexpensive, and less technology- and

33

personnel-dependent perimetry has not gained popularity in West Africa. Relying on IOP and optic disc visualization alone to diagnose and follow glaucoma is problematic. Screening for glaucoma most often involves a single measurement of IOP alone, which can miss over 60% of people who have glaucoma. Further complicating IOP monitoring is the fact that Blacks have thinner corneas than nonBlacks. Thus, many cases of glaucoma are missed because of ‘normal’ IOPs on screening examinations that do not include optic disc visualization. The cup-to-disc ratio is known to be larger and more variable in Blacks with a mean of 0.4 compared to 0.3 in Caucasians.57–59 Due to the high cost of fundus photographic instrumentation, following optic discs for evidence of increased cupping is not feasible in developing parts of the world. There appears to be little or no emphasis placed on gonioscopy for classifying and treating glaucoma. While angle closure was an infrequent cause of glaucoma in Ghana in the largest population survey done there (2.5%),40 a clinic survey found a prevalence of closed angles in patients being treated for glaucoma of 6.6%60 emphasizing the need for gonioscopy in patients with glaucoma and high IOP in this population. Not uncommonly, the diagnosis of glaucoma in developing Africa is made after unilateral blindness is discovered by the patient. Following known glaucoma patients for evidence of progression is also hindered by the same lack of technology mentioned above. Baseline stereophotographs of the optic disc would be useful in follow-up but are rarely available, and serial visual field analysis is uncommon. In general, IOP is the only parameter followed. Ideally, if the IOP has been lowered 30–50% from baseline, the patient is considered ‘stable’, although it is known that a subset of these patients will progress. Practically speaking, medical management of glaucoma is rarely successful in sub-Saharan Africa due to the cost of the medications and difficulty in obtaining them. Verrey and colleagues61 reviewed the records of 397 patients with chronic glaucoma in rural Ghana and found that only 17% of patients receiving medical treatment had IOPs lower than 22 mmHg. In contrast, 84% of patients treated surgically had IOPs lower than 22 mmHg. As in India and China, even generic β-blockers and miotics may cost more per day than basic necessities such as food. Medications are also not practical, even for those with money. The hot climate and periods without electricity, sometimes lasting weeks, can render some glaucoma medication compounds ineffective. Given the problems with medical and laser therapy of glaucoma in sub-Saharan Africa, primary surgical treatment might appear to be a reasonable first-line therapy for people with sight-threatening glaucoma in this part of the world. However, in interactions and discussions with ophthalmologists in West Africa, the authors have discovered reluctance to treat glaucoma with surgery. Since cataract extraction remains the most commonly performed ocular surgical procedure in West Africa, patient expectations, based upon outcomes after cataract surgery, are generally high after any type of eye surgery. Patients often cannot distinguish between blindness caused by cataract and glaucoma. They therefore may expect ‘cataract surgery-like success’ after glaucoma surgery. With glaucoma surgery, the best visual outcome to be expected is retention of

34

SECTION 1  •  Glaucoma in the World

preoperative vision. Patients who have lost central vision from glaucoma are disappointed when their visual acuity does not improve following trabeculectomy as with acquaintances who have had cataract surgery. Despite the best efforts of ophthalmologists to temper expectations, such outcomes are not exactly ‘practice builders’. Social marketing of services is very important. Good results after cataract surgery build trust and inspire other members of the community to have their cataracts operated upon. This, in turn, inspires still others to have surgery. Glaucoma surgery, despite warnings, results in negative social marketing. This is, in fact, a good way to alienate a community from ophthalmic care. Rather than bringing sight to a village, performing glaucoma surgery does not allow many to see better and may cause some to lose vision and experience discomfort. Communities may quickly lose faith even in the best of surgeons performing procedures that do not offer visual improvement. Standard trabeculectomy is known to have a higher risk for failure in Blacks compared to Caucasians,62–64 presumably due to a more vigorous wound-healing response in the former.65 Several investigators have reported success and safety when using antifibrotic agents in black Africans.66–68 A prospective, randomized trial by Egbert et al.66 showed a clear advantage to using a single intraoperative application of 5-fluorouracil (5-FU) (50 mg/mL on a soaked surgical sponge applied for 5 minutes) compared to no antifibrotic agent in glaucoma patients undergoing trabeculectomy in Ghana. Mermoud et al.67 compared a series of black South African patients treated with low-dose mitomycin C (0.2 mg/ mL on a soaked surgical sponge for 5 minutes) to historical controls who received no antifibrotic agents. These investigators found an 83% success rate in the mitomycin C group compared to 37% in the control group, after an average follow-up of 9 months. Singh et al.,68 in a prospective, randomized trial compared intraoperative 5-FU (50 mg/mL for 5 minutes) versus high-dose mitomycin C (0.5 mg/mL on a soaked surgical sponge for 3.5 minutes) in glaucoma patients undergoing trabeculectomy in Ghana. This study found that the success rate in the mitomycin C group was 93% compared to 73% in the 5-FU group after an average follow-up of 10 months. Practically speaking, it makes little sense to perform trabeculectomy without mitomycin C, even as a primary procedure, in this population. The value of glaucoma drainage tube implant (GDI) surgery has yet to be evaluated in this population. The availability of inexpensive glaucoma drainage devices like the AADI implant may make this option practical in developing countries as long as their introduction is accompanied by adequate training. However, the lack of tissue for patch grafts may limit their use. New methods for covering glaucoma tubes using patients’ own scleral tissue may help in this regard. In summary, glaucoma management in sub-Saharan Africa is difficult, as it is in other parts of the developing world, due to scarce resources and lack of infrastructure. Added to this is the fact that the prevalence of glaucoma is very high in this population; glaucoma takes on an apparently more aggressive form; failure of trabeculectomy is higher in this racial group; and the problems are compounded. Practically speaking, if one is sure a patient has glaucoma, primary trabeculectomy with mitomycin C is currently the best option. Yet a marked lack of skilled

surgeons makes this impractical to some extent as well. Hopefully, a simpler and more successful operation will be developed that will help the treatment of glaucoma in this part of the world.

Glaucoma Care: The Nongovernmental   Organization Perspective In many nations, there is reliance upon nongovernmental organizations (NGOs) for staffing, supplies, and education. The following section provides an NGO perspective of care.

CURRENT SITUATION Although glaucoma is the second leading cause of blindness in the world,69 it has rarely been engaged by blindness prevention NGOs. This is now beginning to change, as a number of these organizations begin to take on glaucoma in Asia and Africa. The following areas are often mentioned as barriers to wider glaucoma programming on the part of blindness prevention NGOs. First, there is a competition for resources between glaucoma and other ophthalmic diseases, such as cataract. Cataract remains the leading cause of blindness in the world;70 studies have demonstrated excellent potential for return to normal vision with extraction of the cataractous lens in both the developed71 and developing2 world. The production of low-cost intraocular lenses, sutures, and medications, together with high-volume surgical approaches, has generally brought the cost per case into the range of US$25–40 in efficient programs. Primarily for these reasons, most blindness prevention NGOs have focused on cataract as their primary target.72–74 Studies have also demonstrated treatment of vitamin A deficiency (VAD) to be a highly effective and inexpensive way to prevent blindness,75 and programs to alleviate VAD are an important part of the portfolio of NGOs such as Helen Keller International.76 Childhood refractive error, childhood cataract, trachoma, and onchocerciasis are other diseases affecting vision for which proven treatments exist and in which one or more blindness prevention NGOs have invested significant resources. Diabetic retinopathy is now increasingly seen as a global threat which takes up a growing proportion of NGO resources in the healthcare sector. Given the limited resources of most blindness prevention NGOs, new programs to combat glaucoma blindness would be in direct competition with programs for these other diseases, all of which still remain important causes of blindness. Another reason glaucoma rarely figures as a primary objective for NGOs is that glaucoma screening is difficult to perform. Screening usually involves assessment of the optic nerve and/or testing for typical changes in the visual field. Existing technologies and/or combinations of technologies have not been demonstrated to produce good sensitivity and specificity in screening for glaucoma.77 Evaluation of the optic nerve even among experienced observers may be subject to significant variation.78 Machines which might replace or supplement human evaluation of the optic nerve

4  •  Practical Application of Glaucoma Care in Different Societies

are expensive and ill-suited for use in the rural areas of the developing world where many blindness prevention NGOs operate (and where 90% of world blindness exists). Important questions remain about the accuracy of visual field testing in a developing world setting, particularly with regards to sensitivity.79 Gonioscopy remains the standard modality to screen for the presence of narrow anterior chamber angles, but is often poorly taught, subjective, and requires significant training and the presence of a slit lamp. Newer modalities to evaluate the angle80 are expensive and not appropriate to the rural developing world setting. Even if on-line training (gonioscopy.org) is available, there is often no gonioprism or expert to help with the learning curve. Additionally, there are many problems with our current treatment modalities. In general, medical therapy for glaucoma requires lifetime treatment. Though low-cost eyedrop medications (as little as US$1 per bottle or less in India and China) are sold in many countries, rural availability is limited and the follow-up involved in chronic drop therapy impractical in rural areas, where 60% of Asia’s population, for example, resides.81 The quality, safety, and efficacy of inexpensive, locally available drop preparations is often not known. Surgical therapy is known to be limited because of the risks of infection after incisional glaucoma. This is especially true in the presence of the antimetabolite agents that have become common in modern glaucoma surgery.82–86 As glaucoma drainage surgery results in the deliberate creation of a fistula into the eye, the prevalence of endophthalmitis after glaucoma surgery is higher than for cataract surgery. The risk of endophthalmitis after glaucoma surgery, particularly in rural areas where treatment for this complication may not be delivered in a timely fashion, is a significant concern for many NGO program planners considering large-scale glaucoma interventions. Well-performed cataract surgery has been reported to have a high potential for patient satisfaction in both the developed87 and developing world.88 Blindness prevention NGOs and others attempting to create sustainable cataract surgical programs often depend in their financial planning on the word-of-mouth advertising provided by satisfied patients. This is in distinction to glaucoma treatment: negative impact on quality of life has been demonstrated with both medical and surgical glaucoma therapies.89 There is concern on the part of program planners that ‘negative social marketing’ as a result of glaucoma treatments, particularly surgery, might undercut the success of cataract programs as mentioned above.

WHAT ARE THE ACTUAL REQUIREMENTS FOR BLINDNESS PREVENTION TO ENABLE NONGOVERNMENTAL ORGANIZATIONS TO TAKE A MORE ACTIVE ROLE IN GLAUCOMA PROGRAMMING? This section assesses the arguments made above against NGO programming for glaucoma, and attempts to determine what is actually needed before NGOs begin widespread programs targeting glaucoma.

Competition From Other Diseases In fact, there is a growing consensus in the NGO community that vertical, disease-targeted programs are not an

35

efficient way to deliver eye care. Potential areas of synergy and program overlap are most obvious for glaucoma with adult cataract: Both diseases affect principally older age groups. The preoperative examination for cataract surgery may be the only opportunity to detect glaucoma in a rural resident with little access to healthcare. ■ The setting of cataract surgery may provide an appropriate venue to intervene surgically for glaucoma at the same time. ■ ■

Though research in this area is badly needed, it seems unlikely that carrying out a basic examination for advanced glaucoma and combined cataract/trabeculectomy surgery where indicated would significantly reduce the efficiency of cataract programs. The ‘competition’ argument does not represent a significant impediment to NGOs beginning to support clinic-based programs to detect and operate on advanced glaucoma at this time. As both glaucoma and diabetic retinopathy are prevalent in most underdeveloped nations90–92 it may be wise to screen for both simultaneously. Most images of the macula and areas of interest for diabetic retinopathy would also contain the disc. Similar training and equipment are utilized in the diagnosis of both diseases. In this way, those who have normal vision could be screened for both diabetes and glaucoma. Likewise, in those with decreased vision, but clear media both diabetic retinopathy and/or glaucoma could be detected. Detection of early glaucoma is a challenge even for specialists in the area. However, in a setting of limited resources and restricted access to eye care, the appropriate focus is likely to be on patients with advanced disease, who can be detected by simple disc examination, without the need for visual field testing. Although they may be disabled, the goal of detection in these patients would be to help maintain their current level of visual function, preventing fulldependence on others, and hopefully maintaining selfsufficiency. The presence of dense cataracts mandates that some patients will not be identified until the postoperative period. This implies that careful inspection of the optic nerve at the one month postoperative examination is imperative. The ability to detect even moderately advanced glaucoma by examination of the disc presupposes familiarity with stereo examination of the optic nerve and the presence of simple equipment (e.g. 90 D lens) which may not exist in many settings. This sort of low-cost, high-yield ‘opportunistic screening’ strategy should be incorporated into all cataract programs in developing countries. With regard to angle closure, there exists growing evidence that LPI may not be sufficient to control IOP without surgery once an acute attack93 and/or optic nerve damage94 have occurred. It is thus desirable to identify patients with narrow angles requiring treatment before they progress to this stage. In a hospital-based program, this would imply routine gonioscopic screening of all patients with laser treatment as needed on eyes not scheduled for cataract surgery. This presupposes the ready availability of a goniolens and the knowledge to use it, which may not exist in many settings. Screening for glaucoma and narrow angles requiring treatment in a clinic-based, developing world setting is not complex and does not pose an impediment to NGOs undertaking such

36

SECTION 1  •  Glaucoma in the World

Spotlight 1  Glaucoma Care in South Asia Lingam Vijaya

Background.  South Asia consists of Bangladesh, India, Bhutan, Nepal, Pakistan, Sri Lanka, and the Maldives, and is considered the poorest region in the world after sub-Saharan Africa. Burden of Glaucoma.  Information from population-based studies suggests that the prevalence of primary open-angle glaucoma (POAG) varied from 1.8% to 3.5% and primary angle-closure glaucoma (PACG) varied from 0.2% to1.1%.1–3 In more than 90% of cases the disease was undetected. The risk factors for POAG were age and intraocular pressure. For PACG, age, biometric parameters and female gender were the risk factors. Glaucoma is the major cause for irreversible blindness in this region. Secondary glaucomas are mainly due to pseudoexfoliation or following cataract surgery. Challenges and Remedies.  Poor detection rates are the major cause for high blindness rates from glaucoma. Underdiagnosis of the disease seems to be a major problem. The reasons for this could be patient-related, such as awareness, or physician-related in terms of examination methods. In general, the awareness of glaucoma in the region is very poor. It was 0.27% in a rural population and 13.3% in an urban cohort. These are much lower than the awareness rates in the West (70% to 92%).2 There seems to be an inverse relationship between awareness and detection rates. Improving the awareness may result in a greater number of people seeking eye examination. Unless physicians improve the detection rates in clinics the effect will not be reflected on undetected cases. Main reasons for missing out the glaucoma are over-dependence on IOP measurements and lack of comprehensive examination for all. In the population-based studies a large proportion of POAG subjects had IOP readings within statistically normal range.1 In such a case only the optic disc examination clinches the diagnosis. Studies have shown that 40% of previously diagnosed POAG actually had PACG.1 This highlights the importance of gonioscopy in detecting glaucoma. The solution to these problems seems to be advocating comprehensive examination for all. The

programs at this time. Training of clinical staff in basic disc examination and gonioscopy will be a key feature of such programs. The tools and skills required for glaucoma screening: slit lamp, gonioprism, and 90 diopter lens are not different from what is required for basic eye examinations. Trabeculectomy is probably less expensive and less difficult to perform than cataract surgery, but follow-up requirements and manipulations are comparatively burdensome and the risk of sight-threatening complications (cataract, endophthalmitis) is probably higher. Medicines are unlikely to be appropriate for use in the rural developing world. While the current state of information regarding the safety and efficacy of LPI is not sufficient to warrant populationbased screening programs, the technique is sufficiently well understood for routine hospital-based use. The current state of glaucoma surgery is not an absolute impediment to the involvement of NGOs in hospital-based glaucoma screening and treatment programs, but for such programs to become widespread, new, safer, longer-lasting procedures

reasons for not doing comprehensive examination could be either reluctance or poor training. Both should be addressed and corrected by the health policy protocols. With an increase in the aging population the burden of glaucoma will worsen. Available ophthalmologists may not be able to cover all. There is a need to depend upon the other eye care personnel such as ophthalmic assistants and optometrists. The major issue here is provision of uniform quality training for them. The second challenge will be how to reach out to the public. Screening is not ideal for glaucoma detection. Cataract and glaucoma both are age-related diseases, and thanks to cataract blindness programs there are well-placed protocols for cataract surgical programs. By incorporating glaucoma examination components into those programs one could use available resources for glaucoma detection.1 Challenges with Treatment.  Cost and accessibility will be major hurdles in glaucoma treatment.1 Low-cost generic glaucoma medications are plentiful in this region. In spite of concerns about the efficacy of these drugs, the prescriptions will continue mainly due to the cost. Surgical options may look like attractive, however early or late postoperative surgical complications should be kept in mind. Surgical options should be taken on a case by case basis. The majority of secondary glaucomas are related to cataract surgery, and by improving the surgical techniques and better follow-ups in cataract blindness control programs these iatrogenic glaucomas can be eliminated.1 References 1. George R, Ve RS, Vijaya L. Glaucoma in India: Estimated burden of disease. J Glaucoma 2010;19(6):391–7. 2. Ronnie G, Ve RS, Velumuri L, et al. Importance of population-based studies in clinical practice. Indian J Ophthalmol 2011;59(7):11–8. 3. Thapa SS, Paudyal I, Khanal S, et al. A population-based survey of the prevalence and types of glaucoma in Nepal: the Bhaktapur Glaucoma Study. Ophthalmology 2012;119(4):759–64.

are needed. Research in the area of patient satisfaction with glaucoma surgery and the ability of educational messaging to mediate satisfaction levels is an important prerequisite for large-scale NGO involvement in glaucoma programming. NGOs themselves are well positioned to take a role in such research. The following are suggested roles for NGOs in the area of glaucoma programming in the near future: 1. Support hospital-based identification and surgical treatment of advanced glaucoma as a part of comprehensive ophthalmic care provided in NGO cataract programs. 2. Support educational initiatives to improve the skills of medical practitioners in three key areas: slit-lamp use, stereoscopic examination of the optic nerve, and (indentation) gonioscopy. 3. Support simple studies on patient satisfaction with glaucoma surgery, and the impact on satisfaction of simple educational messages.

4  •  Practical Application of Glaucoma Care in Different Societies

4. Develop on-line interactive programs to assist in training for basic examination and therapeutic skills. 5. Develop curricula that are appropriate to ensure a minimal level of understanding is needed.

Glaucoma Services in a Developing Country Setting It is important to understand the context in which eye care in general is provided in developing countries. In these countries, the ratio of population to ophthalmologist varies from 100,000 to one million plus per ophthalmologist. In many African countries, the population density is also very low. The population in these countries lives largely in rural areas; in many countries over 80% of the population lives in rural areas. On the other hand, the ophthalmologists and eye hospitals are usually located in urban centers, with most of them being in the capital or bigger cities in the country. All these factors make access to even very basic eye care service a major challenge. Studies have shown that even in an outreach eye camp only about 7% of the people in need of eye care are able to access it.95 Not only this, but there are also issues relating to affordability. It is in this context that one has to view the treatment of glaucoma. In most places, eye care is largely synonymous with cataract surgery and correction of refractive errors. Even when patients present themselves at a hospital or an eye camp, examination for glaucoma is not done routinely. In most hospitals, measurement of intraocular pressure using Schiotz tonometers and fundus examination are the only means of detecting glaucoma. In many areas, especially the smaller African countries, such facilities may not be available anywhere in the country. Apart from the lack of infrastructure, the diagnostic and clinical management skills among ophthalmologists are also wanting. In many of the residency programs, either the required equipment, skills, or both, are not in place, resulting in inadequately trained ophthalmologists. As a consequence of the challenges in the community and the inadequacy among some providers, the discipline of glaucoma treatment is quite underdeveloped in most of the developing countries. Looking ahead, this is a challenge that needs to be addressed, especially in view of the commitment to eliminate avoidable blindness by the year 2020. Some initiatives are already in place to address this. To bridge the skills gap among the ophthalmologists, a short-term skills development course of 8 weeks’ duration is being offered to train them in diagnostic, laser, and surgical procedures. Guidelines are being formulated for routine examination for glaucoma as they enter the eye care system through eye camps or an eye hospital. In order to enhance community access, rural primary eye care centers called Vision Centers are being established at a density of one for every 50,000 population. In these centers, slit-lamp examination, fundus examination, and applanation tonometry are being recommended with reference to screening for glaucoma. As these developments are falling into place, the ophthalmologist and the other eye care providers have to develop other innovative methods for reaching those at risk and scale up the other initiatives described above.

37

References 1. Robin AL, Thusasiraj RD. Cataract blindness [Solicited Editorial]. Arch Ophthalmol 2012;130(11):1452–5. 2. Prajna NV, Chandrakanth KS, Kim R, et al. The Madurai Intraocular Lens Study. II: clinical outcomes. Am J Ophthalmol 1998;125(1): 14–25. 3. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991;266:369–74. 4. Quigley HA, West SK, Rodriguez MD, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects. Arch Ophthalmol 2001;119:1819–26. 5. Dielemans I, Vingerling JR, Wolfs RCW, et al. The prevalence of primary open-angle glaucoma in a polpulation-based study in The Netherlands: The Rotterdam Study. Ophthalmology 1994;101: 1851–5. 6. Mitchell P, Smith W, Attebo K, et al. Prevalence of open-angle glaucoma in Australia: The Blue Mountains Eye Study. Ophthalmology 1996;103:1661–9. 7. Leske MC, Connell AMS, Schachat AP, et al. The Barbados Eye Study: prevalence of open angle glaucoma. Arch Ophthalmol 1994;112: 821–9. 8. Klein BEK, Klein R, Sponsel WE, et al. Prevalence of glaucoma: the Beaver Dam Eye Study. Ophthalmology 1992;99:1499–2504. 9. Wensor MD, McCarty CA, Stanislavsky YL, et al. The prevalence of glaucoma in the Melbourne Visual Impairment Project. Ophthalmology 1998;105:733–9. 10. Friedman DS, Jampel HD, Munoz B, et al. The prevalence of openangle glaucoma among blacks and whites 73 years and older: the Salisbury Eye Evaluation Glaucoma Study. Arch Ophthalmol 2006;124:1625–30. 11. Ramakrishnan R, Nirmalan PK, Krishnadas R, et al. Glaucoma in a rural population of southern India: the Aravind Comprehensive Eye Survey. Ophthalmology 2003;110:1484–90. 12. Thomas R, Dogra M. An evaluation of medical college departments of ophthalmology in India and change following provision of modern instrumentation and training. Ind J Ophthalmol 2008;56: 9–16. 13. Grover AK. Postgraduate education in India: are we on the right track? Ind J Ophthalmol 2008;56:3–4. 14. Resnikoff S, Pascolini D, Mariotti SP, et al. Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bull World Health Organ 2008;86:63–70. 15. Arvind H, George R, Raju P, et al. Glaucoma in aphakia and pseudophakia in the Chennai Glaucoma Study. Br J Ophthalmol 2005; 89:699–703. 16. Freemont AM, Lee PP, Mangione CM, et al. Patterns of care for openangle glaucoma in managed care. Arch Ophthalmol 2003;121: 777–83. 17. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262–7. 18. Abramoff MD, Reinhardt JM, Russell SR, et al. Automated Early Detection of Diabetic Retinopathy. Ophthalmology 2010;117:1147–54. 19. Madden JM, Graves AJ, Zhang F, et al. Cost-related medication nonadherence and spending on basic needs following Implementation of Medicare Part D. JAMA 2008;299(16):1922–8. 20. Doshi JA, Zhu J, Lee BY, et al. Impact of prescription copayment increase on lipid-lowering medication adherence in Veterans. Circulation 2009;119:390–8. 21. Kim YA, Rascati KL, Prasla K, et al. Clin Therapeut 2011; 2011(5):598–607. 22. Patterson ME, Blalock SJ, Smith AJ, et al. Associates Between prescription copayment levels and beta-blocker medication adherence in commercially insured heart failure patients 50 years and older. Clin Therapeut 2011;33 (5):608–16. 23. Hill JJ, Galusha D, Slade MD, et al. Drug adherence after price changes in a previously compliant population. Am J Managed Care 2013; 19;(3):236–7. 24. China Statistical Yearbook 2005. National Bureau of Statistics of China. 2005. 25. Xujing LU, Aiqin L, Pinzheng L. A review of literature on present situation of glaucoma for research and treatment with Acupuncture. Chinese Tradit Ophthalmol 2003;13(2):119–21. 26. Ying G, Lingling W, Jijun L. Daily cost of glaucoma medications in China. J Glaucoma (in press).

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SECTION 1  •  Glaucoma in the World

27. Weir RE, Zaidi FH, Charteris DG, et al. Variability of the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol 2005;89: 1094–6. 28. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Ind J Ophthalmol 2007;55(2):127–31. 29. Thomas R, Mangat T. An evaluation of medical college departments of ophthalmology in India and change following provision of modern instrumentation and training. Ind J Ophthalmol 2007;56:9–16. 30. Thomas JV, El-Mofty A, Hamdy EE, et al. Argon laser trabeculoplasty as initial therapy for glaucoma. Arch Ophthalmol 1984;102(5): 702–3. 31. Robin AL, Arkell S, Gilbert SM, et al. Q-switched neodymium:YAG laser iridotomy. A field trial with a portable laser system. Arch Ophthalmol 1986;104:526–30. 32. Egbert PR, Fiadoyor S, Budenz DL, et al. Trans-scleral diode laser cyclophotocoagulation as a primary surgical treatment for primary open angle glaucoma. Arch Ophthalmol 2001;119:345–50. 33. Lam S, Tessler HH, Lam BL, et al. High incidence of sympathetic ophthalmia after contact and noncontact neodymium:YAG cyclotherapy. Ophthalmology 1993;100(6):798–9. 34. Robin AL, Ramakrishnan R, Krishnadas R, et al. A long-term dose response study of mitomycin C in glaucoma filtration surgery. Arch Ophthalmol 1997;115:969–74. 35. Husain R, Liang S, Foster PJ, et al. Arch Ophthalmol 2011;329, doi:10.1001/archophthalmol. 36. Budenz DL, Hoffman K, Zacchei A. Glaucoma filtering bleb dysesthesia. Am J Ophthalmol 2001;131:626–30. 37. Natchiar GN, Thulasiraj RD, Negrel AD, et al. The Madurai Intraocular Lens Study. I: A randomized clinical trial comparing complications and vision outcomes of intracapsular cataract extraction and extracapsular cataract extraction with posterior chamber intraocular lens. Am J Ophthalmol 1998;125:1–35. 38. Dandona L, Dandona R, Naduvilath TJ, et al. Population-based assessment of the outcome of cataract surgery in an urban population in southern India. Am J Ophthalmol 1999;127:650–8. 39. Geffen N, Ton Y, Degani J, et al. CO2 laser-assisted sclerotomy surgery, part 2. Multicenter clinical preliminary study. Journal of Glaucoma 2012;21(3):193–8. 40. Budenz DL, Barton K, Whiteside de-Vos J, et al. Prevalence of glaucoma in an urban West African population. The TEMA eye Survey. JAMA Ophthalmol 2013;131(5):651–8. 41. Buhrmann RR, Quigley HA, Barron Y, et al. Prevalence of glaucoma in a rural East African population. Invest Ophthalmol Vis Sci 2000; 41:40–8. 42. Rotchford AP, Kirwan JF, Muller MA, et al. Temba Glaucoma Study: a population-based cross-sectional survey in urban South Africa. Ophthalmology 2003;110:376–82. 43. Ayanryo JO. Blindness in the Midwestern state of Nigeria. Tropical Geogr Med 1974;26:325–32. 44. Schwab L, Steinkuller PG. Surgical treatment of open angle glaucoma is preferable to medical management in Africa. Soc Sci Med 1983;17:1723–7. 45. Nwosu SNN. Blindness and visual impairment in Anambra State, Nigeria. Trop Geogr Med 1994;46:346–9. 46. Abdull MM, Sivasubramaniam S, Gudlavalleti VSM, et al. Causes of Blindness and Visual Impairment in Nigeria: The Nigeria National Blindness and Visual Impairment Survey. IOVS 2009;50:4114–20. 47. Budenz DL, Jagadeesh RB, Barton K, et al. Blindness and visual impairment in an urban West African population. The TEMA eye survey. Ophthalmology, 2012;119:1744–53. 48. Tielsch JM, Sommer A, Witt K, et al. Blindness and visual impairment in an American urban population: the Baltimore Eye Survey. Arch Ophthalmol 1990;108:286–90. 49. Mason RP, Kosoko O, Wilson MR, et al. National survey of the prevalence and risk factors of glaucoma in St. Lucia, West Indies. Part I. Prevalence findings. Ophthalmology 1989;96:1363–8. 50. Olurin O, Ghandi N, Pan T. Primary glaucoma in Nigeria. E African Med J 1972;49:725–34. 51. Wallace J, Lovell H. Glaucoma and intra-ocular pressure in Jamaica. Am J Ophthalmol 1969;67:93–100. 52. Wilensky JT, Gandhi N, Pan T. Racial influences in open angle glaucoma. Ann Ophthalmol 1978;10:1398–402.

53. Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol 1996;80:389–93. 54. Grant WM, Burke JF. Why do some people go blind from glaucoma? Ophthalmology 1982;89:991–8. 55. Hiller R, Khan H. Blindness from glaucoma. Am J Ophthalmol 1975;80:62–9. 56. Budenz DL, Singh K. Glaucoma care in West Africa. J Glaucoma 2001;10:348–53. 57. Beck RW, Messner DK, Musch DC, et al. Is there a racial difference in physiologic cup size? Ophthalmology 1985;92:873–6. 58. Chi T, Beck RW, Messner DK, et al. Racial differences in optic nerve head parameters. Arch Ophthalmol 1989;107:836–9. 59. Varma R, Tielsch JM, Quigley HA, et al. Race-, age-, gender-, and refractive error-related differences in the normal optic disc. Arch Ophthalmol 1994;112:1068–76. 60. Herndon LW, Challa P, Ababio-Danso B, et al. Survey of glaucoma in an eye clinic in Ghana, West Africa. J Glaucoma 2002;11:421–5. 61. Verrey JD, Foster A, Wormald R, et al. Chronic glaucoma in northern Ghana – a retrospective study of 397 patients. Eye 1990;4:115–20. 62. Welsh NH. Trabeculectomy with fistula formation in the African. Br J Ophthalmol 1972;56:32–6. 63. Freedman J, Shen E, Ahrens M. Trabeculectomy in a black American glaucoma population. Br J Ophthalmol 1976;60:573–4. 64. Merrit JC. Filtering procedures in American blacks. Ophthalmic Surg 1980;11:91–4. 65. Skuta GL, Parrish RK. Wound healing in glaucoma filtering surgery. Surv Ophthalmol 1987;32:149–70. 66. Egbert PR, Williams AS, Singh KS, et al. A prospective trial of intraoperative fluorouracil during trabeculectomy in a black population. Am J Ophthalmol 1993;116:612–16. 67. Mermoud A, Salmon JF, Murray AND. Trabeculectomy with mitomycin C for refractory glaucoma in Blacks. Am J Ophthalmol 1993; 116:72–8. 68. Singh KS, Egbert PR, Byrd S, et al. Trabeculectomy with intraoperative 5-fluorouracil vs. mitomycin C. Am J Ophthalmol 1997;123:48–53. 69. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3):262–7. 70. Gl S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82(11):844–51. 71. Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and complications following cataract extraction with intraocular lens implantation. Cataract Patient Outcome Research Team. Arch Ophthalmol 1994:239–52. 72. Online. Available: www.cbmuk.org.uk/what/cataracts.html (accessed 20 February 2007). 73. Online. Available: www.sightsavers.org/What%20We%20Do/Eye% 20Conditions/Cataract/World1414.html (accessed 20 February 2007). 74. Online. Available: www.orbis.org/bins/content_page.asp?cid=589598-693-1444&lang=9 (accessed 20 February 2007). 75. Loevinsohn BP, Sutter RW, Costales MO. Using cost-effectiveness analysis to evaluate targeting strategies: the case of vitamin A supplementation. Health Policy Plan 1997;12(1):29–37. 76. Online. Available: http://www.hki.org/programs/vitamina.htm (accessed 20 February 2007). 77. Tielsch JM, Katz J, Singh K, et al. A population-based evaluation of glaucoma screening: the Baltimore Eye Survey. Am J Epidemiol 1991;134(10):1102–10. 78. Hanson S, Krishnan SK, Phillips S. Observer experience and cup:disc ratio assessment. Optom Vis Sci 2001;78(10):701–5. 79. Mansberger SL, Johnson CA, Cioffi GA, et al. Predictive value of frequency doubling technology perimetry for detecting glaucoma in a developing country. J Glaucoma 2005;14(2):128–34. 80. 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): 1053–9. 81. Online. Available: www.un.org/esa/population/publications/wup 1999/WUP99ANNEXTABLES.pdf (accessed 12 January 2007). 82. Wolner B, Liebmann JM, Sassani JW, et al. Late bleb-related endophthalmitis after trabeculectomy with adjunctive 5-fluorouracil. Ophthalmology 1991;98:1053–60. 83. Higginbotham EJ, Stevens RK, Musch DC, et al. Bleb-related endophthalmitis after trabeculectomy with mitomycin C. Ophthalmology 1996;103:650–6.

4  •  Practical Application of Glaucoma Care in Different Societies 84. Greenfield DS, Suner IJ, Miller MP, et al. Endophthalmitis after filtering surgery with mitomycin. Arch Ophthalmol 1996;114:943–9. 85. Mills KB. Trabeculectomy: a retrospective long-term follow-up of 444 cases. Br J Ophthalmol 1981;65:790–5. 86. The Fluorouracil Filtering Surgery Study Group. Five-year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol 1996; 121:349–66. 87. Lundstrom M, Stenevi U, Thorburn W, et al. Catquest questionnaire for use in cataract surgery care: assessment of surgical outcomes. J Cataract Refract Surg 1998;24(7):968–74. 88. Fletcher A, Vijaykumar V, Selvaraj S, et al. The Madurai Intraocular Lens Study. III: visual functioning and quality of life outcomes. Am J Ophthalmol 1998;125(1):26–35. 89. Janz NK, Wren PA, Lichter PR, et al. CIGTS Study Group. The Collaborative Initial Glaucoma Treatment Study: interim quality of life findings after initial medical or surgical treatment of glaucoma. Ophthalmology 2001;108(11):1954–65. 90. Budenz DL, Bandi JR, Barton K, et al. Blindness and visual impairment in an urban West African population: the Tema Eye Survey. Ophthalmology 2012;119 (9):744–52.

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91. Nirmalan PK, Katz J, Robin AL, et al. Prevalence of vitreo-retinal disorders in a rural population of southern India: The Aravind Comprehensive Eye Study. Arch Ophthalmology 2004;122:581–6. 92. Thulasiraj RD, Nirmalan PK, Ramakrishnan R, et al. Blindness and vision impairment in a rural population of southern India: The Aravind Comprehensive Eye Survey. Ophthalmology 2003;110: 1491–8. 93. Aung T, Ang LP, Chan SP, et al. Acute primary angle-closure: longterm intraocular pressure outcome in Asian eyes. Am J Ophthalmol 2001;131:7–12. 94. Rosman M, Aung T, Ang LP, et al. Chronic angle-closure with glaucomatous damage: long-term clinical course in a North American population and comparison with an Asian population. Ophthalmology 2002;109:2227–31. 95. Fletcher AE, Donoghue M, Devavaram J, et al. Low uptake of eye services in rural India: a challenge for programs of blindness prevention. Arch Ophthalmol 1999;117(10):1393–9.

SECTION 2  PATHOGENESIS

5 

Functional Morphology of the Trabecular Meshwork Outflow Pathways ERNST R TAMM

Summary Intraocular pressure is generated in the trabecular outflow pathways in which aqueous humor passes through the trabecular meshwork into Schlemm’s canal. The juxtacanalicular region of the pathways provides outflow resistance for aqueous humor. The resistance is under the influence of two contractile systems, the anterior part of the ciliary muscle, and the contractile myofibroblast-like cells in the trabecular outflow pathways. Resistance is lowered through contraction of the ciliary muscle or relaxation of the contractile cells in the trabecular outflow pathways. In primary open-angle glaucoma, resistance in the juxtacanalicular region is abnormally high. The cause of the increase is related to an increase in transforming growth factor-β/connective tissue growth factor signaling. The cells of the trabecular meshwork outflow pathways are likely stimulated to acquire a stronger contractile phenotype involving both an increase in their actin cytoskeleton and in their surrounding fibrillar extracellular matrix.

Introduction Intraocular pressure (IOP), the main risk factor for primary open-angle glaucoma (POAG), is determined by the production, circulation, and drainage of aqueous humor.1–3 The major drainage regions are the conventional or trabecular outflow pathways, which are comprised of the trabecular meshwork (made up by the uveal and corneoscleral meshworks), the juxtacanalicular connective tissue (JCT), the endothelial lining of Schlemm’s canal, the collecting channels, and the aqueous veins. When aqueous humor has passed through the trabecular outflow pathways it drains into the episcleral venous system. In addition to the trabecular meshwork outflow pathways, there is an unconventional or uveoscleral outflow route which is open to the aqueous humor at the chamber angle in the region of the anterior insertion of the ciliary muscle, as there is no complete endothelial or epithelial layer that covers the anterior surface of the ciliary body. When passing through the uveoscleral outflow pathways, aqueous humor exits the anterior chamber through the ciliary body into the supraciliary and suprachoroidal space and out through the sclera into the extraocular tissues. Fluid in the uveoscleral pathways ultimately drains into the lymphatic system. Depending on the method that is used to measure it, unconventional or uveoscleral outflow is found to account for 10%4 or 25–57%5 of the total outflow in the human eye. Uveoscleral outflow is 40

generally regarded as pressure-insensitive, whereas flow from the anterior chamber across the trabecular meshwork into Schlemm’s canal is pressure-dependent. The trabecular meshwork outflow pathways provide a resistance to aqueous humor outflow and IOP builds up in response to this resistance until it is high enough to drive aqueous humor across the trabecular meshwork into Schlemm’s canal. Aqueous humor passes through the trabecular meshwork as bulk flow driven by the pressure gradient; any active transport is not involved, as neither metabolic poisons nor temperature affects this flow.6,7 At steady-state IOP, fluid flow across the trabecular outflow resistance is at the same rate as it is produced by the ciliary body. Outflow resistance in the trabecular meshwork outflow pathways increases with aging.8–10 In primary open-angle glaucoma (POAG), IOP is elevated because the resistance to aqueous humor outflow in the trabecular meshwork is abnormally high.11,12 Outflow resistance is increased in primary open-angle glaucoma, ocular hypertension, and exfoliation and pigment dispersion syndromes with accompanying ocular hypertension. When IOP is normal in these syndromes, outflow resistance is normal. This chapter will focus on the functional morphology of the trabecular meshwork outflow pathways. For detailed information on the overall structure of the trabecular meshwork outflow pathways, the reader is referred to the electronic text of this chapter available online at http://www.expert consult.com

THE SITE OF OUTFLOW RESISTANCE Because of their high porosity, the uveal and corneoscleral parts of the trabecular meshwork do not provide significant resistance to aqueous humor outflow. Support for this comes from experimental studies, which show that cutting through the inner parts of the trabecular meshwork does not affect outflow facility,32 and from theoretical calculations using Poiseuille’s law.33 In contrast, there is considerable evidence that normal aqueous humor outflow resistance resides in the inner wall region of Schlemm’s canal,8,29 which is formed by the juxtacanalicular tissue and the inner wall endothelium. The extracellular spaces between the cells and fibrillar elements of the juxtacanalicular tissue appear to be a likely site of outflow resistance. Morphometric analyses of the juxtacanalicular aqueous humor pathways as visualized by electron microscopy combined with theoretical calculations indicate that the juxtacanalicular tissue cannot account for a significant outflow

5  •  Functional Morphology of the Trabecular Meshwork Outflow Pathways

The Trabecular Meshwork Outflow Pathways The critical elements that form the trabecular meshwork outflow pathways are mostly localized in the internal scleral sulcus, a circular groove on the inner aspect of the corneoscleral limbus. The scleral sulcus extends from the peripheral edge of Descemet’s membrane of the cornea that is called Schwalbe’s line to the scleral spur, a wedge-shaped circular ridge. Schlemm’s canal, a circular vascular tube, lies in the outer portion of the scleral sulcus, while the trabecular meshwork occupies most of its inner aspects (Fig. 5-1). The trabecular meshwork is a spongework of connective tissue beams or lamellae that have a core of collagenous and elastic fibers. Flat trabecular meshwork cells, which rest on a basal lamina, cover each trabecular beam. The beams attach to one another in several layers and form a porous filter-like structure. Anteriorly, the trabecular beams are attached near the end of Descemet’s membrane and extend posteriorly to the stroma of ciliary body and iris

A

40.e1

at their junction, and to the scleral spur (see Fig. 5-1). Trabecular beams branch as they extend posteriorly, which gives the trabecular meshwork a triangular shape with the apex near Descemet’s membrane and the base at the scleral spur. As Schlemm’s canal is shorter in the anterior–posterior direction than the trabecular meshwork, a filtering portion of the trabecular meshwork can be differentiated from a nonfiltering portion which has no Schlemm’s canal behind it (see Fig. 5-1). Iris processes, which are flat bands of iris stroma, may bridge the chamber angle from the iris root to the outer (uveal) beams of the trabecular meshwork into which they merge (Fig. 5-2). Iris processes are phylogenetically homologous with remnants of the pectinate ligaments in the chamber angle of the eyes of nonprimate mammalian species such as rodents and ungulates. In most human eyes, they are sparse in number.

STRUCTURE OF THE TRABECULAR MESHWORK The trabecular meshwork consists of three regions that differ in structure: the inner uveal meshwork, the deeper corneoscleral meshwork and the juxtacanalicular tissue or cribriform region that is localized directly adjacent to the inner wall endothelium of Schlemm’s canal (see Fig. 5-1B). The uveal meshwork, which originates from the anterior aspect of the ciliary body, consists of one to three layers of trabecular beams or lamellae (Fig. 5-3). The corneoscleral meshwork forms 8–15 trabecular layers, which are thicker than those of the uveal trabecular meshwork and originate from the scleral spur (see Fig. 5-3). The juxtacanalicular tissue, which is localized directly to the endothelial lining of Schlemm’s canal, is the smallest part of the trabecular meshwork with a thickness of only 2–20 µm. The juxtacanalicular tissue does not form trabecular lamellae or connective tissue beams, but rather represents a typical loose connective tissue with 2–5 layers of loosely arranged cells that are embedded in a thinly distributed fibrillar extracellular matrix (see Fig. 5-3).

B Figure 5-1  Light micrographs of meridional sections of the anterior chamber angle (A) and the trabecular meshwork (B). The dotted line in A marks the boundary between filtering and nonfiltering trabecular meshwork. SC, Schlemm’s canal; TM, trabecular meshwork; SS, scleral spur; Ir, iris; CB, ciliary body; PC, posterior chamber; AC, anterior chamber; JCT, juxtacanalicular tissue; CSTM, corneoscleral trabecular meshwork; UVTM, uveal trabecular meshwork. Magnification bars: 100 µm (A), 50 µm (B).

Figure 5-2  Chamber angle of a human eye, meridional section. Arrows indicate an iris process that bridges the chamber angle from the iris root to the uveal trabecular meshwork. SC, Schlemm’s canal; TM, trabecular meshwork; SS, scleral spur; CM, ciliary muscle. Magnification bar: 100 µm.

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A

B Figure 5-3  Meridional sections of the trabecular meshwork (light micrographs). (A) Open arrows denote the beams of the uveal trabecular meshwork, and solid arrows the thicker ones of the corneoscleral meshwork. (B) Inner wall region. Open arrows mark the boundary between juxtacanalicular tissue and corneoscleral trabecular meshwork. The endothelium of the inner wall of Schlemm’s canal forms numerous giant vacuoles (solid arrows). SS, scleral spur, SC, Schlemm’s canal. Magnification bars: 10 µm.

THE TRABECULAR BEAMS Each beam or lamella in the uveal or corneoscleral trabecular meshwork has a core region that is surrounded by a cortical zone (Fig. 5-4).13,14 The cortical zone is separated from the trabecular cells that cover the beams by their basal lamina (Fig. 5-5). The core contains densely packed collagen and elastic fibers (see Fig. 5-4). The collagen fibers are mostly formed by collagen types I and III.15 The elastic fibers differ in their ultrastructure from those in other parts of the body, as they contain considerable amounts of electrondense material. The presence of elastin has been confirmed by both enzymatic treatment with elastase and by immunohistochemistry with specific antibodies.16,17 The fibers are surrounded by a sheath that thickens with age. The sheath is less electron dense than the elastic fiber proper and may show an 80–120 nm periodicity. Clumps of similar material and periodicity are numerous in the cortical zone (so-called long-spacing collagen) (see Fig. 5-5). Fine fibrils that enter the aggregates of long-spacing collagen have been shown to label with antibodies against collagen type VI.18 The cells covering the trabecular meshwork beams have long processes that connect with those of neighboring beams (Fig. 5-6A). In addition, the cells may bridge intertrabecular spaces to cover two adjacent beams and to establish a three-dimensional network. Trabecular meshwork

Figure 5-4  Electron micrograph of a corneoscleral trabecular meshwork beam. The core (Co) of the beam contains densely packed collagen (C) and elastic fibers (E). The cortical region (CR) contains numerous aggregates of long-spacing collagen (arrows). The beam is completely covered by flat trabecular meshwork cells (TMC). Magnification bar: 2 µm.

cells are capable of phagocytosis19 and may contain pigment particles (Fig. 5-6B). The phagocytic capabilities of trabecular meshwork cells may be important as self-cleaning mechanisms of the trabecular filter. The basal lamina of the trabecular meshwork cells is rich in collagen type IV and laminin.20,21

THE JUXTACANALICULAR TISSUE The juxtacanalicular tissue is a loose connective tissue where trabecular cells are surrounded by fibrillar elements of the extracellular matrix. As the connective tissue fibrils form an irregularly arranged network (in contrast to the more regular structure of the beams in the inner parts of the trabecular meshwork), some authors prefer the term cribriform meshwork.17 The cells in the juxtacanalicular tissue form elongated processes by which they attach to one another, to extracellular matrix fibrils, or to the cells of the endothelial lining of Schlemm’s canal (Fig. 5-7). Between cells and extracellular matrix fibers, there are open spaces that serve as pathways for aqueous humor. Although a

5  •  Functional Morphology of the Trabecular Meshwork Outflow Pathways

40.e3

A

Figure 5-5  Electron micrograph of a corneoscleral trabecular meshwork beam (higher magnification of Fig. 5-4). Open arrows denote the basal lamina of the trabecular meshwork cells, while solid arrows point to aggregates of long-spacing collagen. C, collagen fibers; E, elastic fibers. Magnification bar: 2 µm.

ground substance of various proteoglycans and hyaluronan22–24 has been described in these spaces, the extent to which the ground substance fills the open spaces is not clear. This uncertainty is due to the fact that proteoglycans are not readily retained during processing of tissue for conventional electron microscopy. Indeed, recent studies using quick-freeze/deep-etch methodology confirm that there is more extracellular matrix in the juxtacanalicular tissue as seen by conventional electron microscopy.25 A characteristic structural element of the juxtacanalicular tissue is a layer of elastic fibers (cribriform plexus) (see Fig. 5-7) which has been shown to form a fibrous network in sections tangential to the endothelial lining of Schlemm’s canal.26 The elastic fibers of the cribriform plexus have an electron-dense core and a sheath of banded material, and show basically the same ultrastructural characteristics as those in the trabecular beams. So-called connecting fibrils consisting of elastic fiber material and fine fibrils emerge from the cribriform plexus and connect it with the inner wall endothelium of Schlemm’s canal (Fig. 5-8).

SCHLEMM’S CANAL The inner wall endothelium of Schlemm’s canal forms large outpouchings (so-called giant vacuoles) in response to the flow of aqueous humor (Fig. 5-9A). Accordingly, giant vacuoles are only observed when the chamber angle tissue is fixed by perfusion, but not when it is fixed by immersion. Micrometer-sized pores are quite often associated with the giant vacuoles and allow passage of microparticles 200–500 nm in sizes.27 Bill and Svedbergh calculated the hydraulic conductivity and the flow resistance generated by the pores and concluded that the inner wall endothelium could generate not more than 10% of total trabecular outflow resistance.28 Consistent with a minor role of the inner wall endothelium for outflow resistance is the fact

B Figure 5-6  Electron microscopy of corneoscleral trabecular meshwork cells. (A) A corneoscleral trabecular meshwork cell (TMC) that covers trabecular meshwork beams forms long processes which connect with those of neighboring beams. In addition, the cell bridges an intertrabecular space to cover two adjacent beams. (B) Trabecular meshwork cells (TMC) containing phagocytosed pigment granules (arrows). Magnification bars: 2 µm.

that the endothelium has one of the highest hydraulic conductivities in the body, comparable only to that of fenestrated endothelia.29 However, more recent experiments indicate that the number of pores increases with the amount of fixative perfused through an enucleated eye and that the total number of pores identified by electron microscopy in fixed tissues is likely considerably smaller than that in the living eye.10,12 The pores in Schlemm’s canal endothelium very likely originate from minipores with a diameter of 62–68 nm, which are bridged across their opening by a thin 5-6 nm non-membranous diaphragm.30,31 Similar diaphragms cover the caveolae of Schlemm’s canal endothelium.30 Plasmalemma vesicle-associated protein (PLVAP) is essential for the formation of the diaphragms.30 The

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SECTION 2  •  Pathogenesis

SC GV A

E

B

SC

C

SC

Figure 5-7  Electron micrograph of the inner wall region including juxtacanalicular tissue and Schlemm’s canal (SC) endothelium. The cells in the juxtacanalicular tissue form elongated processes (open arrows). Solid arrows mark the elastic fibers of the cribriform plexus. GV, giant vacuole. Magnification bar: 5 µm.

D Figure 5-9  Electron micrographs of the endothelium of Schlemm’s canal (SC) inner wall. (A) The inner wall endothelium forms giant vacuoles (GV) in response to flow of aqueous humor. Pores (arrow) are often associated with the luminal side of the vacuoles. (B, C) Junctional complex (arrow) between two neighboring inner wall endothelial cells. (C) is higher magnification of (B). The arrow in (C) denotes a tight junction. (D) The basal side of Schlemm’s canal endothelial cells is in contact with fine fibrillar material (asterisk) and is often not covered by a basal lamina (open arrow). The solid arrow marks a junctional complex between two adjacent endothelial cells. Magnification bars: 2 µm (A), 250 nm (B), 125 nm (C), 500 nm (D).

Figure 5-8  Electron micrograph of connecting fibrils (open arrows) in the juxtacanalicular tissue, which emerge from the cribriform plexus (solid arrows) and connect it with the inner wall endothelium of Schlemm’s canal (SC). Magnification bar: 1 µm.

endothelial cells of Schlemm’s canal are connected by a junctional complex that contains tight junctions which should restrict paracellular flow (Fig. 5-9B, C). On the basal side of the endothelial cells, there is fine fibrillar material that varies in amount. The basal lamina of Schlemm’s canal endothelium is often interrupted and considerable areas of the basal cell membrane are in direct contact with the open spaces of the juxtacanalicular tissue (Fig. 5-9D). The lumen of Schlemm’s canal is frequently divided by septa through which juxtacanalicular tissue is in direct contact with tissue of the outer wall (Fig. 5-10A). Another characteristic is diverticulae that extend from the lumen of the canal into the juxtacanalicular tissue (Sondermann’s canals) and which increase the surface area of the inner wall of Schlemm’s canal (Fig. 5-10B).

5  •  Functional Morphology of the Trabecular Meshwork Outflow Pathways

A

B Figure 5-10  Light micrographs of Schlemm’s canal (SC). (A) The lumen of Schlemm’s canal is divided by a septum (arrows) through which juxtacanalicular tissue is in direct contact with tissue of the outer wall. (B) A diverticulum (Sondermann’s canal) extends from the lumen of the canal into the juxtacanalicular tissue (arrows) SC, Schlemm’s canal. Magnification bars: 10 µm.

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5  •  Functional Morphology of the Trabecular Meshwork Outflow Pathways

resistance, unless the pathways are filled with an extracellular matrix gel of unknown nature that is not visualized by conventional microscopy.34 Another possible site of outflow resistance is the inner wall endothelium of Schlemm’s canal, a concept that would require that most inner wall pores are indeed artefacts caused by prolonged perfusion with fixative (see electronic text of this chapter available online at http://www.expertconsult.com). There is currently much active debate and research regarding the specific role of the inner wall endothelium of Schlemm’s canal or the juxtacanalicular connective tissue for the formation of trabecular outflow resistance. Trabecular meshwork cells have some contractile properties and an increase in their tone causes an increase in outflow resistance presumably by changing the geometry of the trabecular meshwork outflow pathways.35,36 In contrast, relaxation of trabecular meshwork cells leads to a decrease in outflow resistance. Studies of genetically engineered mouse models provided evidence for a role of nitric oxide (NO) as a pressure-dependent regulator of trabecular outflow resistance. Presumably, NO is released from Schlemm’s canal endothelial cells upon increased shear stress and causes relaxation of trabecular meshwork cells.37

CILIARY MUSCLE AND SCLERAL SPUR The muscle bundles of the radial portion of the ciliary muscle and the inner bundles of its longitudinal portion form tendons in the region of their anterior insertion that are continuous with the extracellular matrix of the trabecular meshwork beams (Fig. 5-11A, B). The tendons of the inner muscle bundles of the longitudinal portion pass the scleral spur at its inner aspect to continue to the trabecular meshwork (Fig. 5-11B). The same banded material that forms the sheaths of the elastic fibers in the core region of the trabecular beams is the main structural element of the tendons. The banded material comes in direct contact with the cell membrane of the muscle cell which forms dense bands at the cytoplasmic site (Fig. 5-11C). In the region of contact with the tendons, the muscle bundles taper and form deep furrows which are filled with banded material. The outer muscle bundles of the longitudinal portion of the ciliary muscle also form tendons, but connect with the extracellular matrix fibers of the scleral spur. The scleral spur contains collagen and elastic fibers that are circumferentially arranged (Fig. 5-12A). The elastic fibers are continuous with those of the core of the corneoscleral meshwork beams or the cribriform plexus in the juxtacanalicular tissue. The outermost muscle bundles of the longitudinal portion of the ciliary muscle bend clockwise or counterclockwise before they attach to the scleral spur (Fig. 5-12B).38 More inwardly, they do not bend, but insert to elastic fibers that are continuous with the circumferentially arranged elastic fibers of the scleral spur (Fig. 5-12C). Because of the structural connections between ciliary muscle and scleral spur, contraction of the ciliary muscle pulls the spur posteriorly and widens the trabecular spaces,14 thereby inducing changes in the geometry of the trabecular meshwork that lead to a reduction in outflow resistance. In addition to ciliary muscle cells, there is another contractile cell population in this area which affects the tone of the trabecular meshwork.38 The resident cells within the

41

A

B

C Figure 5-11  Light (A, B) and electron microscopy (C) of anterior ciliary muscle tendons. (A, B) The muscle bundles of the radial portion of the ciliary muscle (RCM, A) and the inner bundles of its longitudinal portion (LCM, B) form tendons (arrows) in region of their anterior insertion that are continuous with the extracellular matrix of the trabecular meshwork beams. CCM, circular portion of the ciliary muscle. (A) The tendons of the radial portion continue to the uveal trabecular meshwork (UTM). (B) The tendons of the inner muscle bundles of the longitudinal portion pass the scleral spur (SS) at its inner aspect to continue to the corneoscleral trabecular meshwork (CTM). (C) The banded material of the ciliary muscle tendons (solid arrows) comes in direct contact with the cell membrane of the muscle cell (MC) which forms dense bands at the cytoplasmic site (open arrows). In region of contact with the tendon, the muscle cell forms deep furrows which are filled with banded material. Magnification bars: 10 µm (A, B), 500 nm (C).

scleral spur have a myofibroblast-like character as they contain numerous actin filaments (Fig. 5-13A) that stain with antibodies against α-smooth muscle actin (Fig. 5-14A, C). In contrast to the muscle cells of the longitudinal portion of the ciliary muscle, scleral spur cells are circumferentially oriented (Fig. 5-14C) and do not stain for desmin, the

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SECTION 2  •  Pathogenesis

A

B

C

Figure 5-12  Meridional (A) and tangential sections (B, C) of the scleral spur (SS) and the anterior insertion of the ciliary muscle (CM). (A) The scleral spur contains numerous elastic fibers (white arrows) which are continuous with those of the trabecular meshwork (TM). Solid arrows denote anterior tendons of the longitudinal portion of the ciliary muscle. (B) Near its insertion to the scleral spur, a muscle bundle bends in the circular direction (arrows). (C) Ciliary muscle bundles insert to the scleral spur by means of elastic tendons which form arcades, finally bending in a circular direction (arrows). Magnification bars: 10 µm (A), 30 µm (B, C). ((B) and (C) are from Tamm E, Flügel C, Stefani FH, et al. Contractile cells in the human scleral spur. Exp Eye Res 1992; 54:531–43.)

intermediate filament that is characteristic for ciliary muscle cells (Fig. 5-14B, D). Scleral spur cells are innervated and coupled to each other by gap junctions (see Fig. 5-13C). They form tendon-like contacts with the banded material that surrounds the elastic fibers of the scleral spur (see Fig. 5-13A, B). As this material is continuous with the elastic fibers in the core of the trabecular meshwork beams and the cribriform plexus, changes in the tone of scleral spur cells are likely to modulate outflow resistance by altering trabecular meshwork architecture. Throughout the entire circumference of the scleral spur, club-shaped nerve endings are found (Fig. 5-15A, B), which have a diameter of about 3–5 µm and derive from myelinated axons.39 The structure of the nerve endings is very similar to that of mechanosensors in other parts of the

body. The endings contain abundant neurofilaments, numerous granular and agranular vesicles, mitochondria, and lamellated lysosome-like structures. The cell membrane of the nerve endings is in direct contact with the elastic fibers of the scleral spur. The contact between nerve terminal and connective tissue fibers is a very characteristic feature of mechanosensors, as it is required to measure the tone of the extracellular fibers. The mechanosensors of the scleral spur may act as proprioreceptive tendon organs for the ciliary muscle, or modulate the tone of the scleral spur cells. Alternatively, they could perform a baroreceptor function in response to changes in intraocular pressure. Indeed, physiological studies indicate that such sensors might exist, as sensory discharges have been recorded in response to changes in intraocular pressure.40,41

5  •  Functional Morphology of the Trabecular Meshwork Outflow Pathways

Figure 5-13  Meridional (A, B) and tangential sections (C, D) through ciliary muscle (CM), scleral spur (SS), and trabecular meshwork (TM) stained with antibodies against α-smooth muscle actin (A, C) or desmin (B, D). (A) Ciliary muscle cells and vascular smooth muscle cells stain positively with antibodies against α-smooth muscle actin. Arrows indicate the scleral spur, where all cells show intense immunoreactivity for α-smooth muscle actin. (B) Immunostaining with antibodies against desmin. Ciliary muscle cells stain brightly positive, whereas the scleral spur is not labeled for desmin. (C) Tangential section of scleral spur, trabecular meshwork, and ciliary muscle. The plane of the section is the same as in Fig. 5-12C. Positively stained cells oriented in a circular direction are seen throughout the entire spur tissue. While ciliary muscle cells also stain positive, no staining is seen in the trabecular meshwork. (D) Tangential section of scleral spur and ciliary muscle after staining for desmin. The plane of the section is the same as in Figures 5-14B and 5-12C. Ciliary muscle cells stain brightly positive, whereas the cells of the scleral spur remain unstained. Magnification bars: 30 µm. (From Tamm E, Flügel C, Stefani FH, et al. Contractile cells in the human scleral spur. Exp Eye Res 1992; 54:531–43.)

A

A

B

C

D

B

43

C

Figure 5-14  Electron microscopy of scleral spur cells. (A) Scleral spur cells (SSC) are in close contact with banded sheath material (asterisks) of elastic fibers. The cytoplasm of the cells is filled with abundant 6–7 nm thin (actin) filaments which run parallel to the long axis of the cells (solid arrows). The cell membrane shows numerous membrane-bound caveolae (open arrows). (B) Scleral spur cells may form long processes to contact the elastic fibers (asterisk) in the scleral spur. In region of contact, dense bands (arrows) are formed at the cell membrane of the scleral spur cell. (C) Scleral spur cells are connected by gap junctions (arrow). Magnification bars: 1 µm (A, B), 125 nm (C). ((A and C) are from Tamm E, Flügel C, Stefani FH, et al. Contractile cells in the human scleral spur. Exp Eye Res 1992; 54:531–43.)

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A

B

Figure 5-15  Mechanosensors in the scleral spur. (A) Whole mount of the scleral spur stained with antibodies against neurofilament proteins. Axons are labeled that terminate as bulb- or club-shaped structures (arrows). (B) Electron micrograph of a mechanoreceptive nerve terminal in the scleral spur. The terminal is bulb- or club-shaped and contains numerous neurofilaments, mitochondria, and vesicles of different sizes. The elastic fibers of the scleral spur (E, open arrows), and the scleral spur cells (solid arrows) are in close proximity to the terminal. SS, scleral spur. Magnification bars: 5 µm (A), 1 µm (B).

THE TRABECULAR MESHWORK IN PRIMARY OPENANGLE GLAUCOMA The most characteristic structural change of the trabecular outflow pathways in primary open-angle glaucoma is an increase in extracellular material in the juxtacanalicular region.14 The material is referred to as sheath-derived plaque material, as it involves mainly the sheaths of the elastic fibers which form the cribriform plexus underneath the endothelial lining of Schlemm’s canal. Although the amount of sheath-derived plaque material correlates with glaucomatous axonal damage in the optic nerve, it does not correlate with intraocular pressure, indicating that the material alone is not causative of the increase in trabecular outflow resistance in primary open-angle glaucoma.42 Another structural change in chronic openangle glaucoma involves the number of pores in Schlemm’s canal endothelium, which is decreased significantly from normal eyes, even after accounting for the volume of fixative perfused.12 Multiple studies have found higher than normal concentrations of transforming growth factor-β2 (TGF-β2) in the aqueous humor of patients with primary open-angle glaucoma.43 TGF-β2 increases extracellular matrix synthesis and contractility of trabecular meshwork cells, effects that are largely mediated through connective tissue growth factor (CTGF). In genetically modified mice, CTGF induces a myofibroblast-like phenotype in trabecular meshwork cells, quite similar to that observed in the human scleral spur.44 The phenotype includes both an increase in actin-mediated contractility and fibrillary extracellular matrix that is connected to the cells via integrin-mediated cell–matrix adhesions (Fig. 5-16). In the mouse eye, the changed nature of trabecular meshwork cells causes an increase in intraocular pressure, optic nerve damage, and primary open-angle glaucoma.44 A similar scenario may well be responsible for the increase in outflow resistance in humans with primary open-angle glaucoma.

Normal

CTGF

TGF-β

POAG

Figure 5-16  Schematic drawing depicting the change in the phenotype of a trabecular meshwork cell that is under the influence of increased TGF-β and CTGF signaling in primary open-angle glaucoma (POAG). A myofibroblast-like phenotype is induced as the actin cytoskeleton (red) becomes more pronounced causing an increase in contractility. Simultaneously, the cell synthesizes more and thicker fibrillary extracellular matrix (green) to transmit force. The fibrillary extracellular matrix is connected with the trabecular meshwork cell by integrin-based cell–matrix adhesions (blue circles) which are also in contact with the intracellular actin fibers.

Acknowledgment The author gratefully acknowledges the excellent technical help of Margit Schimmel and Anthonie Maurer’s expert processing of photographs. Access (additional text and Figures 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8, 5-9, 5-10) online at http://www .expertconsult.com.

Spotlight 1  Lymphatics and Uveolymphatic Outflow from the Eye

Most intraocular pressure-lowering glaucoma therapies target conventional and uveoscleral aqueous outflow pathways and improve drainage of aqueous humor. Lymphatics play a major role in maintaining tissue–fluid balance in most organs by draining extracellular fluid, solutes, and proteins. They are also critical for immune surveillance. The eye, with optically clear aqueous humor with minimal amounts of protein despite high metabolic activity, has been considered to be devoid of a lymphatic system for over a century. We have reported the presence of lymphatics in the ciliary body of the human eye using cell-specific markers1 and electron microscopy with evidence for distinct lymphatic channels within the human eye ciliary body. These findings have been confirmed in sheep, with fluorescent nanospheres identified in lymphatic channels also located within the ciliary body.1 More recently, lymphatic drainage from the eye has been measured in a sheep model.2 Lymphatics likely contribute to fluid drainage from the eye, and developing methods to visualize lymphatic flow in vivo is relevant to glaucoma studies. We used a combination of nanotracers and in vivo hyperspectral imaging to map ocular lymphatic drainage in mouse.3 Quantum dots have unique physical and near-infrared characteristics that make them suitable during non-invasive in vivo imaging. Intracamerally injected quantum dots were detected in vivo in the submandibular node and this finding was confirmed by examining immunofluorescence stained sections (Fig. 1).3

Among the anti-glaucoma drugs, prostaglandin F2-alpha analogs such as latanoprost are the most potent, and this is ascribed to its action on the uveoscleral pathway. We have demonstrated that latanoprost stimulates lymphatic drainage from the eye (Fig. 2).4 The combined use of near-infrared tracer and hyperspectral in vivo imaging is a novel tool to study potential new treatments to reduce eye pressure in glaucoma models.

2.5 *

Quantum Dot Drainage Rate (hours–1)

Neeru Gupta and Yeni Yucel

2.0

1.5

1.0

0.5

0.0 Latanoprost

Control

Figure 2  Histogram shows mean and SD of QD drainage rate (hours−1) for latanoprost-treated (black) and control (white) groups. *P < 0.05. (Reprinted with permission from Tam AL, Gupta N, Zhang Z, Yucel YH. Latanoprost stimulates ocular lymphatic drainage: an in vivo nanotracer study. Trans Vis Sci Tech 2013;2(5):3.)

A

B Figure 1  Quantum dots in red are contained within the lymph node surrounded by capsule in blue (anti-collagen IV) against a green background of cell nuclei (Sytox green). Scale = 250 µm. (Reprinted with permission from Tam AL, Gupta N, Zhang Z, Yucel YH. Nanotechnology 2011; 21;22(42):425101.)

Lymphatic outflow from the eye is a novel pathway that has yet to be exploited as it relates to our understanding of normal physiological outflow, and to glaucoma and its treatment. Our finding that latanoprost increases ocular lymphatic drainage suggests that selective stimulation of lymphatic drainage from the eye may provide a new class of drug treatment options to reduce blindness from glaucoma. References 1. Yucel YH, Johnston MG, Ly T, et al. Identification of lymphatics in the ciliary body of the human eye: a novel ‘uveolymphatic’ outflow pathway. Exp Eye Res 2009;89(5):810–19. 2. Kim M, Johnston MG, Gupta N, et al. A model to measure lymphatic drainage from the eye. Exp Eye Res 2011;93(5):586–91. 3. Tam AL, Gupta N, Zhang Z, et al. Quantum dots trace lymphatic drainage from the mouse eye. Nanotechnology 2011;22(42):425101. 4. Tam AL, Gupta N, Zhang Z, et al. Latanoprost stimulates ocular lymphatic drainage: an in vivo nanotracer study. Translat Vis Sci 2013;2(5):3.

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SECTION 2  •  Pathogenesis

References 1. Bill A, Maepea O. Mechanisms and routes of aqueous humor drainage. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 206–25. 2. Johnson M, Erickson K. Mechanisms and routes of aqueous humor drainage. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Philadelphia: WB Saunders; 2000. p. 2577–95. 3. Tamm ER, Toris CB, Crowston JG, et al. Basic science of intraocular pressure. In: Weinreb RN, Brandt JD, Garway-Heath D, et al, editors. Intraocular pressure. Reports and consensus statements of the 4th global AIGS consensus meeting on intraocular pressure. Amsterdam: Kugler; 2007. p. 1–14. 4. Bill A, Phillips C. Uveoscleral drainage of aqueous humor in human eyes. Exp Eye Res 1971;12:275. 5. Townsend DJ, Brubaker RF. Immediate effect of epinephrine on aqueous formation in the normal eye as measured by fluorophotometry. Invest Ophthalmol Vis Sci 1980;196:256–66. 6. Bárány EH. In vitro studies on the resistance to flow through the angle of the anterior chamber. Acta Soc Med Ups 1953;59:260. 7. Van Buskirk EM, Grant WM. Influence of temperature and the question of involvement of cellular metabolism in aqueous outflow. Am J Ophthalmol 1974;77:565–72. 8. Ethier CR, Coloma FM, Sit AJ, et al. Two pore types in the inner-wall endothelium of Schlemm’s canal. Invest Ophthalmol Vis Sci 1998; 39:2041–8. 9. Gabelt BT, Kaufman PL. Changes in aqueous humor dynamics with age and glaucoma. Prog Retin Eye Res 2005;24:612–37. 10. Sit AJ, Coloma FM, Ethier CR, et al. Factors affecting the pores of the inner wall endothelium of Schlemm’s canal. Invest Ophthalmol Vis Sci 1997;38:1517–25. 11. Grant WM. Clinical measurements of aqueous outflow. Arch Ophthalmol 1951;46:113–31. 12. Johnson M, Chan D, Read AT, et al. The pore density in the inner wall endothelium of Schlemm’s canal of glaucomatous eyes. Invest Ophthalmol Vis Sci 2002;43:2950–5. 13. Bron AJ, Tripathi RC, Tripathi BJ. Anterior chamber and drainage angle. In: Bron AJ, Tripathi RC, Tripathi BJ, editors. Wolff ’s anatomy of the eye and orbit. London: Chapman & Hall Medical; 1997. p. 279–307. 14. Lütjen-Drecoll E, Rohen JW. Functional morphology of the trabecular meshwork. In: Tasman W, Jaeger EA, editors. Duane’s foundations of clinical ophthalmology. Philadelphia: JB Lippincott; 2001. p. 1–30. 15. Marshall GE, Konstas AG, Lee WR. Immunogold ultrastructural localization of collagens in the aged human outflow system. Ophthalmology 1991;98:692–700. 16. Gong H, Trinkaus-Randall V, Freddo TF. Ultrastructural immunocytochemical localization of elastin in normal human trabecular meshwork. Curr Eye Res 1989;8:1071–82. 17. Lütjen-Drecoll E, Futa R, Rohen JW. Ultrahistochemical studies on tangential sections of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1981;21:563–73. 18. Lütjen-Drecoll E. Functional morphology of the trabecular meshwork in primate eyes. Prog Retin Eye Res 1999;18:91–119. 19. Rohen JW, van der Zypen E. The phagocytic activity of the trabecular meshwork endothelium. An electron-microscopic study of the vervet (Cercopithecus aethiops). Graefe’s Arch Klin Exp Ophthalmol 1968; 175:143–60. 20. Marshall GE, Konstas AG, Lee WR. Immunogold localization of type IV collagen and laminin in the aging human outflow system. Exp Eye Res 1990;51:691–9. 21. Murphy CG, Yun AJ, Newsome DA, et al. Localization of extracellular proteins of the human trabecular meshwork by indirect immunofluorescence. Am J Ophthalmol 1987;104:33–43.

22. Gong H, Freddo TF, Johnson M. Age-related changes of sulfated proteoglycans in the normal human trabecular meshwork. Exp Eye Res 1992;55:691–709. 23. Lütjen-Drecoll E, Schenholm M, Tamm E, et al. Visualization of hyaluronic acid in the anterior segment of rabbit and monkey eyes. Exp Eye Res 1990;51:55–63. 24. Tawara A, Varner HH, Hollyfield JG. Distribution and characterization of sulfated proteoglycans in the human trabecular tissue. Invest Ophthalmol Vis Sci 1989;30:2215–31. 25. Gong H, Ruberti J, Overby D, et al. A new view of the human trabecular meshwork using quick-freeze, deep-etch electron microscopy. Exp Eye Res 2002;75:347–58. 26. Rohen JW, Futa R, Lütjen-Drecoll E. The fine structure of the cribriform meshwork in normal and glaucomatous eyes as seen in tangential sections. Invest Ophthalmol Vis Sci 1981;21: 574–85. 27. Johnson M, Johnson DH, Kamm RD, et al. The filtration characteristics of the aqueous outflow system. Exp Eye Res 1990;50:407–18. 28. Bill A, Svedbergh B. Scanning electron microscopic studies of the trabecular meshwork and the canal of Schlemm – an attempt to localize the main resistance to outflow of aqueous humor in man. Acta Ophthalmol 1972;50:295–320. 29. Johnson M. What controls aqueous humor outflow resistance? Exp Eye Res 2006;82:545–57. 30. Herrnberger L, Ebner K, Junglas B, et al. The role of plasmalemma vesicle-associated protein (PLVAP) in endothelial cells of Schlemm’s canal and ocular capillaries. Exp Eye Res 2012;105:27–33. 31. Tamm ER. The trabecular meshwork outflow pathways: structural and functional aspects. Exp Eye Res 2009;88:648–55. 32. Grant WM. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 1963;69:783–801. 33. McEwen W. Application of Poiseuille’s law to aqueous outflow. Arch Ophthalmol 1958;60:290–4. 34. Ethier CR, Kamm RD, Palaszewski BA, et al. Calculations of flow resistance in the juxtacanalicular meshwork. Invest Ophthalmol Vis Sci 1986;27:1741–50. 35. Tian B, Geiger B, Epstein DL, et al. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci 2000;41:619–23. 36. Wiederholt M, Thieme H, Stumpff F. The regulation of trabecular meshwork and ciliary muscle contractility. Prog Retin Eye Res 2000;19:271–95. 37. Stamer WD, Lei Y, Boussommier-Calleja A, et al. eNOS, a pressuredependent regulator of intraocular pressure. Invest Ophthalmol Vis Sci 2011;52:9438–44. 38. Tamm E, Flügel C, Stefani FH, et al. Contractile cells in the human scleral spur. Exp Eye Res 1992;54:531–43. 39. Tamm ER, Flügel C, Stefani FH, et al. Nerve endings with structural characteristics of mechanoreceptors in the human scleral spur. Invest Ophthalmol Vis Sci 1994;35:1157–66. 40. Belmonte C, Simon J, Gallego A. Effects of intraocular pressure changes on the afferent activity of ciliary nerves. Exp Eye Res 1971; 12:342–55. 41. Zuazo A, Ibanez J, Belmonte C. Sensory nerve responses elicited by experimental ocular hypertension. Exp Eye Res 1986;43: 759–69. 42. Gottanka J, Johnson DH, Martus P, et al. Severity of optic nerve damage in eyes with POAG is correlated with changes in the trabecular meshwork. J Glaucoma 1997;6:123–32. 43. Fuchshofer R, Tamm ER. The role of TGF-β in the pathogenesis of primary open-angle glaucoma. Cell Tissue Res 2012;347: 279–90. 44. Junglas B, Kuespert S, Seleem AA, et al. Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork. Am J Pathol 2012;180:2386–403.

6 

Aqueous Humor Dynamics and Intraocular Pressure Elevation CAROL B TORIS

Summary A primary function of the production and circulation of aqueous humor is the maintenance of IOP at a healthy and stable level. When IOP becomes elevated, as seen in ocular hypertension, primary open-angle glaucoma, and various syndromes described in this chapter, it is always accompanied by a reduction in outflow facility. Changes in uveoscleral outflow are not consistent among the various syndromes. Uveoscleral outflow is reduced with aging, ocular hypertension, and exfoliation syndrome, unchanged in pigment dispersion syndrome accompanied by elevated IOP, and may be increased in severe glaucoma. Aqueous flow is increased in glaucomatocyclitic crisis, and unchanged in all other conditions in which IOP is increased. It is clear that each of these conditions associated with elevated IOP produces distinctive changes in aqueous humor dynamics. Tailoring a treatment to target the specific abnormality is a logical approach in the management of ocular hypertension and glaucoma.

Introduction A fine balance between the production, circulation, and drainage of ocular aqueous humor (aqueous humor dynamics) is essential to maintain intraocular pressure (IOP) at a steady-state level, provide nutritive support to avascular ocular tissues, and keep the shape of the globe constant. Parameters of aqueous humor dynamics include the rate of aqueous humor production, the facility of trabecular outflow (outflow facility, the inverse of outflow resistance), the rate of fluid drainage through the uveoscleral outflow pathway, and the pressure in the episcleral veins (Fig. 6-1). When one or more of these parameters is altered and the balance between inflow and outflow is disturbed, various pathological conditions affecting IOP can result. Elevated IOP is usually attributed to an increase in resistance to outflow but other factors may be involved. Understanding the complex mechanisms that regulate aqueous humor circulation is essential for better management of glaucoma. To that end, this chapter explores aqueous humor dynamics in healthy eyes and in various syndromes affecting IOP.

Aqueous Humor Dynamics in the Healthy Human Eye AQUEOUS FLOW Ocular aqueous humor is produced continuously by the ciliary processes of the ciliary body to supply nutrients to

the lens, cornea, and avascular tissues of the anterior chamber angle and to flush away their metabolic waste products. Other functions include transport of neurotransmitters, stabilization of the ocular structure, and regulation of the homeostasis of ocular tissues. The circulation of aqueous humor also provides the mechanism for removal of inflammatory cells and mediators under some pathological conditions, and it enables drugs to be distributed to the different ocular structures. Aqueous humor is produced in a series of steps (Fig. 6-2), starting with a copious amount of blood flowing through the core of the ciliary processes. Plasma from the blood moves by ultrafiltration into the tissue spaces of the ciliary process stroma, a process involving the flow of water and water-soluble substances across the capillary endothelium in response to a hydrostatic pressure gradient.1 Next, anions, cations, and other substances are actively transported across the nonpigmented ciliary epithelial cells and deposited into the clefts between cells. The ions create a hyperosmotic environment and subsequent diffusion of water into the intercellular spaces. The intercellular spaces are closed by tight junctions at the apical end and opened to the posterior chamber at the basal end, a design that directs the flow of fluid into the posterior chamber. Nutrients and other substances necessary for the survival of the avascular ocular tissues are added by diffusion to this fluid as it courses through the anterior chamber. Additionally, some solutes such as iodopyracet, p-aminohippurate, and prostaglandins are removed from the aqueous humor by the ciliary epithelium itself.2,3 The rate of aqueous flow is relatively constant, with little physiological need for variation. A true regulatory mechanism to control the flow rate has not been found. There is a predictable rhythm of aqueous flow throughout a 24-hour day (Table 6-1). In healthy humans, aqueous flow is highest in the late morning and lowest in the middle of the night. The flow rate at night during sleep is only 43% of the rate in the morning after awakening.4 Daytime aqueous flow averages about 2.9 µL/min in young healthy humans and 2.2 µL/min in those over 80 years of age.5 During one’s lifetime, the rate of aqueous flow slows at a rate of about 2.4% per decade.5 The mechanisms regulating the circadian rhythm of aqueous flow have been elusive. A series of clinical studies6 has found that aqueous flow is stimulated by β-adrenergic agonists including epinephrine, norepinephrine, terbutaline, and isoproterenol. Corticosteroids appear to augment the catecholamine effect.7 Melatonin might be involved in the nocturnal nadir of aqueous flow.8 Inconsistent with these findings are other studies reporting that subjects treated with topical epinephrine had reduced rather than 47

48

SECTION 2  •  Pathogenesis Trabecular meshwork

Cornea

11

Schlemm’s canal

Anterior chamber

Collector channel 5 Iris

Episcleral vein Lymphatic vessel

6

6 8

4 10

Sclera

3

11

1

11 Lens

9 Ciliary Ciliary muscle processes

7

Emissarial canal 6 Choroid 9 7

Choroidal blood vessel

2

Vitreous cavity

Figure 6-1  Aqueous humor dynamics. Aqueous humor that is secreted into the posterior chamber (1) flows across the vitreous cavity (2) or through the pupil into the anterior chamber (3). Fluid circulates around the anterior chamber and eventually drains into the anterior chamber angle (4). Aqueous humor drains from the anterior chamber angle via two routes, the trabecular meshwork, Schlemm’s canal, collector channels and episcleral veins (5), or the uveoscleral outflow route. The latter route starts with the ciliary muscle. From there, fluid may flow in many directions, including: across the sclera (6), within the supraciliary and suprachoroidal spaces (7), through emissarial canals (8), into uveal vessels (9) and vortex veins (not drawn), and possibly into ciliary processes (10) where it could be secreted again. Lymphatic vessels, recently identified in the uvea, also may contribute to ocular fluid dynamics. (Redrawn with permission, from Figures 1 and 3 of Toris CB. Aqueous humor dynamics I, measurement methods and animal studies. The eye’s aqueous humor. In: Mortimer M. Civan, ed. Current topics in membranes, Vol. 62. Elsevier: San Diego; 2008; 193–229.)

increased aqueous flow9 and patients with surgical adrenalectomy who completely lacked circulating epinephrine had normal rhythms of aqueous flow.10 A mixture of various hormonal factors of varying concentrations may be only a part of the complex formula needed to regulate the circadian rhythm of aqueous flow. The rate of aqueous production by the ciliary processes cannot be measured in the living eye but it can be estimated by monitoring the movement of fluid through the anterior chamber (aqueous flow). In a clinical research setting, aqueous flow is measured by the method known as fluorophotometry (Fig. 6-3).11 First, multiple drops of fluorescein are applied topically to the cornea to establish a corneal depot. Over a period of several hours, fluorescein from the cornea diffuses into the anterior chamber, mixes with aqueous humor, and begins to drain through the anterior chamber angle. With a fluorophotometer, the fluorescein concentrations in the cornea and anterior chamber are measured periodically for several hours. The log of the fluorescein concentrations is plotted over time. The total fluorescein mass in the anterior segment is the product of the fluorescein concentrations in the cornea and anterior chamber and their respective volumes. The aqueous flow rate is calculated by the mass of fluorescein lost from the cornea and anterior chamber over time, divided by the average concentration in the anterior chamber during the time interval.6 Fluorophotometry is a very well-established method with good reproducibility12 but four important limitations and assumptions associated with this technique require consideration: 1. Diffusion of fluorescein into the iris, limbal vessels, and tear film is assumed.6,13 It also is assumed that the diffusion rate remains undisturbed during an experimental manipulation. It is difficult to measure aqueous flow in eyes with uveitis because of the increased permeability

Posterior chamber Nonpigmented ciliary epithelium Ciliary process core

Pigmented ciliary epithelium

Endothelium Secretion Ciliary process

Solute pump Osmotic water flux

Ultrafiltration

Tight junction Ciliary body

Water and solute flow Solute pump

Blood flow

Figure 6-2  Aqueous humor production. Aqueous humor is produced in a series of steps. An ultrafiltrate of blood that flows through the ciliary process moves across the leaky capillaries into the core of the process (ultrafiltration). Solute and fluid from the core are actively transported via solute pumps into the intercellular spaces of the nonpigmented epithelium (secretion). An osmotic gradient draws water into the intercellular space. Water and solute diffuse in the direction opposite the tight junction at the apical end, and into the posterior chamber. The figure on the right is an enlargement of the intercellular spaces between two nonpigmented ciliary epithelial cells.

6  •  Aqueous Humor Dynamics and Intraocular Pressure Elevation

49

Table 6-1  Average Values of Aqueous Humor Dynamics in Healthy Humans Parameter

Mean Value

Comments

Method of Measurement

Select References

IOP (mmHg)

18.7 ± 0.7 (OD day) 16⋅6 ± 0.6 (OD night) 15⋅7 ± 0.5 (day) 17⋅4 ± 0.6 (night) 20.0 ± 0.3 (day) 21.3 ± 0.4 (night) 13⋅9 ± 0.3 (day) 13⋅2 ± 0.4 (night) 19.3 ± 0.4 (day) 18.1 ± 0.3 (night) 3⋅0 ± 0.8 (morning) 2.7 ± 0.6 (afternoon) 1.3 ± 0.4 (night) 2.9 ± 0.9 (young) 2.4 ± 0.6 (old) 0⋅28 ± 0.01 (young) 0.19 ± 0.01 (old) 0.21 ± 0.10 (young) 0.25 ± 0.10 (old) 0.29 ± 0.02 (day) 0.25 ± 0.01 (night) 0.23 ± 0.01 (day) 0.19 ± 0.01 (night) 10⋅1 ± 1.3 8⋅8 ± 2.0 (seated) 9⋅5 ± 1.9 (supine) 6.3 ± 0.4 (young adult) 10.2 ± 0.2 (day) 11.2 ± 0.2 (night)

Lower at night (supine)

Tonometry

Perlman et al. 200787

Higher at night (seated)

Tonometry

Liu et al. 200388

Aqueous flow (µL/min)

Outflow facility (µL/min/ mmHg)

Episcleral venous pressure (mmHg)

Uveoscleral outflow (µl/ min)

1.52 ± 0.81 (young) 1.10 ± 0.81 (old) 1.38 ± 0.44 (day, old) 0.07 ± 0.13 (night, old)

Liu et al. 200388

Higher at night (supine) No change at night (seated)

Tonometry

Sit et al. 200725 Sit et al. 200725

Lower at night (supine) Slower at night

Fluorophotometry

Brubaker 1991; Brubaker 19985,6

Slower with aging

Fluorophotometry

Toris et al. 199920

Lower with aging

Tonography

Gaasterland et al. 197823

No change with aging

Fluorophotometry

Toris et al. 199920

Lower at night

Tonography

Sit et al. 200725

Lower at night

Tonography

Liu et al. 201124

No change with aging Higher in the supine position

Various methods Venomanometry

Zeimer 198927 Sultan et al. 200389

Video recording enhancement Higher at night in the supine position compared to daytime in the seated position Slower with aging

Venomanometry Venomanometry

Sit et al. 201133 Fan et al. in press90

Calculation

Toris et al. 199920

Slower at night, several different calculations reported

Calculation

Liu et al. 201124

of the blood–aqueous barrier and the change in diffusion rate of fluorescein.14 2. The distribution of fluorescein throughout the anterior chamber and cornea is uniform. Nonuniformity of fluorescein may occur in some conditions such as keratoconus. In these eyes, measurements of fluorescein concentration over time could be more variable, and consequently the accuracy of the aqueous flow determination would be poor. 3. The back flow of tracer from the anterior chamber into the posterior chamber is blocked by the lens–iris barrier.15 The accuracy of fluorophotometry is diminished if the lens–iris barrier is missing or compromised such as in pseudophakia, a dilated pupil, or a previous iridotomy or iridectomy. 4. Several hours of fluorophotometric scans taken at intervals of at least 30 minutes are required to determine a reasonably accurate aqueous flow rate in humans.6 Rapid and brief changes in aqueous flow in humans cannot be detected by fluorophotometry.

TRABECULAR OUTFLOW Once in the anterior chamber, aqueous humor drains through the anterior chamber angle by passive flow via one of two pathways (see Fig. 6-1). The trabecular outflow pathway is illustrated in Figure 6-4. The uveal meshwork is a forward extension of the ciliary muscle consisting of large overlapping holes and flattened sheets which branch and interconnect in multiple planes. The middle layer, the corneoscleral meshwork, includes several perforated sheets of connective tissue extending between the scleral spur and Schwalbe’s line. The openings in these sheets are small and do not overlap. The sheets are interconnected by tissue strands and endothelial cells. The juxtacanalicular meshwork, lying adjacent to the inner wall of Schlemm’s canal, contains collagen, glycosaminoglycans, glycoproteins, fibroblasts, and endothelial-like cells. Elastic fibers also are present that may provide support for the inner wall of Schlemm’s canal. This meshwork contains very narrow, irregular openings. Experimental evidence and theoretical

50

SECTION 2  •  Pathogenesis

Cornea

loge fluorescein concentration

2

4. Administer aqueous flow suppressant. Wait for IOP to drop

1. Administer fluorescein to the cornea

4 6

7. Calculate outflow facility C=

2. Determine aqueous flow (Fa1)

8

Cornea

Anterior chamber

Fa1 – Fa2 IOP1 – IOP2

Sclera Uveal meshwork

Corneoscleral Juxtacanalicular meshwork meshwork Intrascleral vein

5. Determine aqueous flow (Fa2)

Collector channel Schlemm’s canal Inner wall Scleral spur

10 Slope = A

12 14

6. Measure IOP2

Slope = A

16

Slope = B

Equilibrium

Nonequilibrium

3. Measure IOP1 1

2

3

4

5

6

7

8

9

10

11

12

Time (hours) Figure 6-3  Fluorescein decay curves used to determine aqueous flow and outflow facility. Plotted are curves of fluorescein concentration in the cornea and anterior chamber over time. Steps 1 and 2 are used to measure aqueous flow. Steps 1–7 are needed to determine outflow facility. (1) Fluorescein drops are applied to the eye. (2) Starting 4–8 hours later, the cornea and anterior chamber fluorescein concentrations are measured at 45–60-minute intervals for several hours using a fluorophotometer. The disappearance rates of fluorescein from the cornea and anterior chamber are the decay slope A. Aqueous flow is calculated from the equilibrium data when the cornea and anterior chamber decay curves are parallel and the volumes of the cornea and anterior chamber remain constant (Fa1). If one wishes to determine outflow facility, the experiment continues by (3) measuring intraocular pressure (IOP1) then (4) administering an aqueous flow suppressant, such as a carbonic anhydrase inhibitor. Aqueous flow suppressants will change the slope of the curve, after a period of nonequilibrium, to a new slope, slope B. (5) The post-treatment aqueous flow rate (Fa2) is determined by fluorophotometry and (6) IOP is measured again (IOP2). (7) Outflow facility (C) is calculated as the ratio of the change in flow (Fa1 minus Fa2) to change in IOP (IOP1 minus IOP2).

predictions indicate that normal aqueous humor outflow resistance resides in the inner wall region of Schlemm’s canal.16,17 This region is composed of an endothelial layer, its basement membrane, and the adjacent juxtacanalicular (cribriform, subendothelial) connective tissue. The presence of micron-size pores in the inner wall endothelium explains why this endothelium has one of the highest hydraulic conductivities in the body, comparable only to that of fenestrated endothelia. The endothelium allows passage of microparticles 200–500 nm in size. Some outflow resistance is generated by the funneling of aqueous humor into the pores of the inner wall endothelium.17 Another pathway, composed of the open spaces in the juxtacanalicular connective tissue creates an insignificant fraction of outflow resistance, unless extracellular matrix material fills the spaces. Interestingly, the amount of extracellular matrix material in the juxtacanalicular tissue increases with aging, thus providing an explanation for the apparent reduction in outflow facility in older subjects.18 Other factors affecting trabecular outflow resistance are ciliary muscle tone and trabecular cell function. The ciliary muscle is connected to the juxtacanalicular region and inner wall endothelium of the trabecular meshwork. When

Anterior chamber

Ciliary muscle

Iris

Figure 6-4  Trabecular outflow route. In the anterior chamber angle, aqueous humor percolates through the uveal and corneoscleral meshwork, juxtacanalicular connective tissue, and endothelial lining of Schlemm’s canal (inner wall) before reaching the lumen of the canal. Fluid in Schlemm’s canal is drained by 25–35 collector channels into aqueous veins and episcleral veins before entering the systemic circulation (veins not drawn). (From Figure 2 of Toris CB. Aqueous humor dynamics I, measurement methods and animal studies. The eye’s aqueous humor. In: Mortimer M. Civan, ed. Current topics in membranes, Vol. 62. Elsevier: San Diego; 2008, 193–229.)

the ciliary muscle contracts, this region is mechanically deformed in such a way as to open up the spaces in the trabecular meshwork and dilate Schlemm’s canal, thus decreasing the resistance to fluid flow. Trabecular cells actively change shape, altering the geometry of the open spaces in the meshwork, and they modulate extracellular matrix turnover which fills or empties the spaces in the juxtacanalicular connective tissue.19 Outflow facility in healthy human eyes ranges between 0.1 and 0.4 µL/min/mmHg.20–23 Recent studies report that outflow facility is less at night than during the day.24,25 By tonography or perfusion of enucleated human cadaver eyes, trabecular outflow resistance increased with aging.18 However, when measured by fluorophotometry in healthy humans on no known prescription drugs, no age-related changes in outflow facility were observed.20 Critical evaluation of published studies of outflow facility requires an understanding of the methods by which this parameter is accessed. Tonography and fluorophotometry are the two methods used in clinical studies. Two or four minutes of tonography measures a reduction in IOP from application of a standard weight placed on the eye of a supine subject. A corresponding change in aqueous flow, to account for the IOP change, is obtained from the Friedenwald Tables.26 Outflow facility is the ratio of the change in flow to change in IOP. Tonographic outflow facility includes trabecular outflow facility, uveoscleral outflow facility (considered to be small), and pseudofacility (also considered to be small) in the measurement. Another factor, ocular rigidity (a measure of the stiffness of the eye), affects the measurement of IOP during tonography. A fluorophotometric method (see Fig. 6-3) measures rather than assumes an aqueous flow change with an IOP change. The changes in IOP and aqueous flow are induced by administering an aqueous flow suppressant such as acetazolamide,

6  •  Aqueous Humor Dynamics and Intraocular Pressure Elevation

51

dorzolamide, or timolol. The fluorophotometric method avoids pseudofacility and ocular rigidity but the measurement takes several hours to complete and is more variable than tonography. Neither method works well in ocular normotensive volunteers who do not have much change in IOP during the assessment.

EPISCLERAL VENOUS PRESSURE Aqueous humor traversing the trabecular meshwork eventually drains into the episcleral veins. In healthy humans the pressure in the episcleral veins ranges from 7 to 14 mmHg,27 with values between 9 and 10 mmHg being reported most often (see Table 6-1). There does not appear to be a correlation between episcleral venous pressure and age.28 Episcleral venous pressure increases from 1 to 9 mmHg by changing body position from seated to supine and this in turn increases IOP directly. When body position does not change, episcleral venous pressure is relatively stable. A change in episcleral venous pressure of 0.8 mmHg corresponds to a change in IOP of 1 mmHg. The 24-hour variations in IOP parallel the 24-hour variations in episcleral venous pressure.29 In addition to postural changes, other factors affect episcleral venous pressure including inhalation of O2,30 application of cold temperature,31 and vasoactive drugs.32 Measurement of episcleral venous pressure in human subjects is usually made with a commercially available venomanometer (Eyetech, Morton Grove, IL) attached to a slit lamp (Fig. 6-5). The membrane at the tip of the device is placed on the conjunctiva near the limbus. Episcleral veins underlying the conjunctiva are identified with the aid of the slit lamp biomicroscope. By turning the dial on the side of the device, the pressure within the membrane tip is raised until the appropriate vessel collapses. This pressure is considered episcleral venous pressure. The procedure requires a cooperative, unmoving subject and a clear conjunctiva to allow an unobstructed view of an appropriate vessel. Identification and visualization of an appropriate vessel can be difficult. The method has been improved recently by the addition of a video monitor to the venomanometer that allows one to photograph the vessels and later to determine the image and corresponding pressure in which the vessel begins to collapse.33 It still remains unclear as to which stage of collapse (beginning, half or total collapse) is the real episcleral venous pressure.

UVEOSCLERAL OUTFLOW Drainage of aqueous humor from the anterior chamber other than through the trabecular meshwork is called uveoscleral outflow. Unlike the trabecular outflow pathway, the uveoscleral outflow pathway does not contain recognizable channels and vessels. Instead, fluid seeps through the anterior face of the ciliary muscle and other tissues in and around the uvea. In 1965, Anders Bill34 observed that large tracers, as markers of bulk flow, exited the anterior chamber through the ciliary muscle and out through the sclera into the extraocular tissues and ultimately into the lymphatic system. Normally, most constituents of aqueous flow probably do not traverse the sclera but instead are absorbed into the suprachoroidal space and choroidal vessels.

Figure 6-5  Venomanometry. An episcleral venomanometer (blue arrow) is mounted on a simple Haag Streit slit lamp. With the aid of the binoculars on the slit lamp, the lighted membrane (red arrow) is positioned on a vessel near the limbus. The silver dial (green arrow) is used to increase the pressure behind the membrane until the vessel collapses. The reading on the dial is considered episcleral venous pressure (mmHg).

Drainage of fluid through the uvea is sometimes described as ‘unconventional outflow’ because it seeps through tissue rather than flows through channels, or ‘pressureindependent outflow’ because it does not depend on IOP to the same extent as trabecular outflow. It should be clarified that some pressure dependence is required of all flow. Although very small, there is a pressure gradient for flow from the anterior chamber into the supraciliary and suprachoroidal spaces. Studies of monkeys have shown that uveoscleral outflow changes little at IOPs in the normal to high range (11–35 mmHg).35 A change in IOP apparently has little effect on the pressure gradient between the anterior chamber and the suprachoroidal space. When IOP is well below normal (4 mmHg), uveoscleral outflow does become pressure-dependent.36 Uveoscleral outflow in healthy subjects 20–30 years of age is reported to be in the range of 25–57% of total aqueous flow.20,37,38 As one ages, uveoscleral outflow gradually slows.20 One study of 104 healthy subjects divided into two age groups found that the group 20–30 years of age had uveoscleral outflow rates that were 54% of total aqueous flow whereas the group over 60 years of age had significantly slower uveoscleral outflow rates that were 45% of total aqueous flow. Even in the older subjects, uveoscleral outflow was substantially greater than what was first

52

SECTION 2  •  Pathogenesis

reported in the original pivotal human study.39 In that classic study, uveoscleral outflow was measured using a radioactive tracer perfused just prior to enucleation. Several hours later, the enucleated eyes were analyzed for radioactivity. In the two nonglaucomatous eyes that had received no ocular drug for 48 hours prior to the study, uveoscleral outflow was 4% and 14% of total drainage. Three decades later we have learned that uveoscleral outflow in humans is substantially greater than once thought. Of all the parameters of aqueous humor dynamics, uveoscleral outflow is the most difficult to determine in a clinical setting. It cannot be measured directly but it is calculated from the modified Goldmann equation: Fu = Fa − C(IOP − Pev ) Aqueous flow (Fa), outflow facility (C), IOP, and episcleral venous pressure (Pev) are measured and uveoscleral outflow (Fu) is calculated mathematically. Inherent variability with this method is great and reproducibility is fair. Improved techniques are sorely needed to advance our understanding of uveoscleral outflow in the healthy and diseased human eye.

Aqueous Humor Dynamics in Clinical Syndromes Affecting Intraocular Pressure Clinical syndromes associated with IOP elevations may not lead to glaucoma but glaucomatous damage is often the result. The pressure elevations are usually attributed to an imbalance in aqueous humor dynamics. The source of the problem is attributed to changes often in trabecular outflow, occasionally in uveoscleral outflow, and rarely in aqueous flow. Following is a review of syndromes associated with an elevation in IOP for which aqueous humor dynamics have been measured. Related conditions associated with ocular normotension are included for comparison.

OCULAR HYPERTENSION Ocular hypertension is the condition in which the IOP is elevated above what is considered normal but the eye remains healthy with no pathologic optic nerve cupping and visual field defects. The IOP is considered abnormal when it is at least 21 mmHg, which is two standard deviations above the mean in several population-based studies.40 When patients with ocular hypertension are compared with age-matched healthy volunteers with ocular normotension, aqueous flow is within the normal range5,41 but both outflow facility21,41 and uveoscleral outflow41 are significantly reduced. The elevated IOP in ocular hypertension can be explained by pathologic changes in both outflow pathways (Table 6-2).

PRIMARY OPEN-ANGLE GLAUCOMA Primary open-angle glaucoma (POAG) is a disease involving disturbance of the structural or functional integrity of the eye leading to elevated IOP accompanied by progressive

damage to the optic nerve and visual field loss. The glaucomatous damage often can be arrested or diminished by adequate lowering of IOP. When compared with healthy age-matched subjects, aqueous flow in patients with primary open-angle glaucoma was found to be normal during the day but significantly elevated at night.42 This nocturnal aqueous flow effect is small and not sufficient to explain the elevated IOP. The major contributing factor for the elevated IOP in primary open-angle glaucoma, and most other glaucomas accompanied by ocular hypertension for that matter, appears to be increased resistance to fluid flow through the trabecular meshwork. This was reported in 1951,21 1961,43 and again in 199542 using tonography as the method of measurement. There is little known about uveoscleral outflow in patients with primary open-angle glaucoma other than a small study44 of 14 patients with IOPs uncontrolled on maximally tolerated medical therapy. In that study, it was found that uveoscleral outflow was substantially elevated as much as 80% of total outflow in severely glaucomatous eyes, compared to 37% in contralateral eyes with less severe glaucoma. Outflow facility when measured by the fluorophotometric method was very low in these patients on multiple medications (0.02 µL/min/ mmHg)44 compared to a separate study20 of healthy subjects (0.25 µL/min/mmHg) on no known prescription drug. A summary of aqueous humor dynamics in patients with primary open-angle glaucoma is found in Table 6.2. Systemic and ocular medications may have contributed to this large difference in uveoscleral outflow between studies but another possibility exists. The aqueous humor may have been redirected from the trabecular meshwork, an area of abnormally high resistance, to the uvea, a region where flow is less dependent on IOP. In support of this idea is a study45 of untreated monkeys with experimentally induced unilateral glaucoma from laser burns to the trabecular meshwork to establish a stable chronic elevation in IOP.46 Outflow facility was significantly reduced in the hypertensive eyes (0.06 µL/min/mmHg) when compared with the contralateral healthy eyes (0.16 µL/min/mmHg). In the absence of drugs that might alter uveoscleral drainage, the hypertensive eyes also demonstrated elevated uveoscleral outflow (2.25 µL/min) when compared to the contralateral control eyes (1.05 µL/min).45 These clinical and animal studies suggest that, in ocular hypertension41 and the initial stages of glaucoma, uveoscleral outflow and outflow facility are below normal. As the disease progresses, trabecular outflow facility continues to decline while the facility of uveoscleral outflow remains constant (pressure independent). When trabecular outflow facility is reduced to a critical level, aqueous humor is redirected from the trabecular to the uveal pathway. Morphological and biochemical changes in the tissues of the drainage pathways help to explain the increased resistance in the trabecular outflow pathway in patients with glaucoma. Within the trabecular meshwork of glaucomatous specimens, endothelial cell numbers are decreased47 yet basement membrane is thickened, suggesting increased cellular activity. Plaques consisting of clusters of material appear in the corneoscleral beams and juxtacanalicular meshwork. These plaques appear to be derived from elasticlike fibers that make up a subendothelial tendon sheath. The increased thickness of the sheath of the elastic fibers

6  •  Aqueous Humor Dynamics and Intraocular Pressure Elevation

53

Table 6-2  Aqueous Humor Dynamics in Syndromes Associated with Ocular Hypertension and Related Conditions Associated with Ocular Normotension Syndrome

IOP

Fa

C

Ocular hypertension

↑

↔

↓

GLAUCOMA Primary open-angle glaucoma

↑

↔day and ↑night42

↓21,42,44

Normal-tension glaucoma

↔

↔61

↔61

5,41,78

21,41,78

Pev

Fu

↔

↓41

41

↑44 (on maximally tolerated medical therapy)

PIGMENT DISPERSION SYNDROME (PDS) PDS with normal IOP PDS with ocular hypertension

↔ ↑

↔63,64 ↔63,64

↔63,64 ↓63,64

↔64 ↔64

↔64 ↔64

EXFOLIATION SYNDROME (XFS) XFS with normal IOP XFS with ocular hypertension

↔ ↑

↔68,70 ↔70

↔68,70 ↓70

↔70 ↔70

↓70 ↓70

INFLAMMATORY CONDITIONS Glaucomatocyclitic crisis

↑

↓21,72–76

Fuch’s heterochromic iridocyclitis

↔

↑75,84,86 ↔21,74,85 ↓14

↔14

Superscripted numbers indicate key citations. Arrows indicate values greater than (↑), unchanged from (↔) or less than (↓) healthy age-matched subjects. C, outflow facility; Fa, aqueous flow; Fu, uveoscleral outflow; IOP, intraocular pressure; Pev, episcleral venous pressure.

and connecting fibrils reduces the intertrabecular spaces and narrows the flow pathways to the inner wall endothelium. The presence of plaques also increases with aging but the total amount of this material is greater in eyes with POAG.48 Alteration of the extracellular matrix components that are produced and maintained by trabecular meshwork cells has been found. Collagen abnormalities in POAG include fragmentation, altered orientation, and abnormal spacing. Fibronectin49 is deposited in the subendothelial region of Schlemm’s canal. Expression of myocilin and the amount of αB-crystalline, a small stress protein, is increased in the trabecular meshwork of some glaucomatous eyes.50 The interaction of the extracellular matrix components with proteins such as cochlin51 may lead to the formation of deposits that obstruct the outflow pathway. Clearly many complex changes within the trabecular meshwork contribute to increased outflow resistance in glaucomatous eyes. It should be mentioned that factors other than aqueous humor drainage may be involved in the elevated IOP and optic neuropathy in primary open-angle glaucoma. It has been reported that blood pressure decreases52 and habitual IOP increases at night,53–56 both factors reported to increase the risk of glaucomatous damage to the retina. Additionally, cerebrospinal fluid (CSF) pressure may be involved in glaucoma pathophysiology. CSF pressure is decreased in primary open-angle glaucoma57,58 resulting in a large translaminar pressure difference (the difference between IOP and CSF pressure), and greater stress on the optic nerve. On the other hand, the CSF pressure is high in ocular hypertension59 (compared to controls), the translaminar pressure difference is relatively normal and glaucomatous optic nerve damage is not detected.60

NORMOTENSION GLAUCOMA Normotension glaucoma is defined as cupping and visual field loss characteristic of glaucoma despite IOPs within the

‘normal’ range. Ten patients with normotension glaucoma had no change in daytime IOP, aqueous flow or outflow facility, or nighttime aqueous flow when compared to 10 age-matched healthy controls (see Table 6-2).61 The primary difference in patients with normal-tension glaucoma is increased variability of nighttime blood pressure62 and nocturnal hypotension that may reduce the optic nerve head blood flow to an unhealthy level.52 Fluctuations in ocular perfusion pressure cause episodes of ischemia during which time the optic nerve head is at great risk of permanent damage. These events are not detectable on routine clinical examination and are independent of aqueous humor dynamics.

PIGMENT DISPERSION SYNDROME Pigment dispersion syndrome is a condition in which friction between the posterior surface of the iris making contact with the anterior zonules of the lens releases pigment and cells from the iris, debris that is flushed into the anterior chamber and the trabecular meshwork where it may become trapped in the drainage pathway. Patients with pigment dispersion syndrome have deeper anterior chambers than normal which predisposes them to the condition.63 When pigment dispersion syndrome is not accompanied by ocular hypertension, aqueous humor inflow and outflow are normal. When pigment dispersion is accompanied by ocular hypertension, outflow facility is reduced63 but uveoscleral outflow remains normal.64 This is distinctly different from ocular hypertension without pigment dispersion syndrome, in which both uveoscleral outflow and outflow facility are reduced (see Table 6-2).41

EXFOLIATION SYNDROME Exfoliation syndrome is characterized by white deposits on the anterior capsule of the lens and tissues of the ciliary body, iris, cornea, and trabecular meshwork.65 Exfoliation

54

SECTION 2  •  Pathogenesis

syndrome tends to convert into exfoliation glaucoma mainly in elderly patients. This is because there is age-related narrowing of the outflow pathways to the inner wall of Schlemm’s canal66 and build-up of extracellular material and other debris. This material is easily flushed from the trabecular meshwork in young persons, but becomes trapped in the trabecular meshwork of older persons. When exfoliative material becomes trapped in sufficient quantity near the endothelial cells of the trabecular meshwork and Schlemm’s canal, it causes degradation of the tissues and further obstruction of the aqueous humor outflow pathways. The amount of trapped material has been positively correlated with increasing IOP and the presence of glaucoma.67 Distinct changes in aqueous humor dynamics have been found in exfoliation syndrome. When comparing the affected eye of 18 untreated patients with unilateral exfoliation syndrome and ocular normotension with its contralateral unaffected eye,68 there was no difference in mean IOP (14 mmHg and 12 mmHg, respectively), aqueous flow rate (2.4 µL/min in both eyes) and outflow facility (0.15 µL/min/mmHg and 0.19 µL/min/mmHg, respectively). When exfoliation syndrome was accompanied by ocular hypertension69 (mean IOP of 32 mmHg in the affected eye and 18 mmHg in the unaffected eye, n = 10), aqueous flow and outflow facility were significantly lower in the affected eye (2.02 µL/min and 0.07 µL/min/mmHg, respectively) than the unaffected eye (2.38 µL/min and 0.15 µL/min/mmHg, respectively). The lower rate of aqueous flow was originally thought to be due to damage to the ciliary epithelia from the disease process.69 However, later it was thought that the lower aqueous flow was the result of insufficient time for washout of the timolol that had been used to treat the affected eye.6 In a more recent study70 aqueous humor dynamics in 40 patients with exfoliation syndrome with and without ocular hypertension were compared to a group of 40 age- and IOP-matched patients without exfoliation syndrome. Aqueous flow was not different between groups (2.05 ± 0.73 in the exfoliation group and 2.23 ± 0.61 µL/min in the control group) but uveoscleral outflow was significantly (p 30 mmHg. Ernest112 reported similar findings with perfusion pressures >50 mmHg. Breakdown of autoregulation was reported to take place at an ocular perfusion pressure of 40 mmHg. In an in vivo manometric study of adult Chinese eyes, the Tonopen underestimated true IOP by an average 2 mmHg, with a range of error between –8 mmHg and +4 mmHg. The variation of IOP readings and disagreement between true IOP and Tonopen-measured IOP increased at higher levels of true IOP. Studies assessing the repeatability of the Tonopen find repeatability coefficients up to 4.3 mmHg.3 In clinical studies, the Tonopen has been shown to relatively underestimate GAT, particularly at higher levels of IOP whilst other studies find good agreement between the devices with minimal systematic bias.3

The Pascal® Dynamic Contour Tonometer The Pascal® Dynamic Contour Tonometer (DCT; Swiss Microtechnology® AG, Port, Switzerland) was introduced in 2002. The tonometer is a non-applanating, slit-lampmounted, contact tonometer (Fig. 10-5).

TONOMETER PRINCIPLE Applanation tonometers measure the force required to flatten a defined area of the cornea. The force required is proportional to the IOP, but readings may be affected by

Figure 10-5  Pascal DCT.

complex corneal biomechanical properties leading to measurement error (see Chapter 18 for further details). The design purpose of the DCT was to develop a noninvasive and direct method for IOP measurement that would be relatively unaffected by the inter-individual variations of corneal biomechanics. The DCT measurement principle is based on contour matching, which assumes that if the eye were enclosed by a contoured, tight-fitting shell, the forces generated by IOP would act on the shell wall. Replacing part of the shell wall with a pressure sensor would enable measurement of these forces and therefore the IOP.13 The DCT has a contoured tonometer tip surface that is designed to facilitate IOP measurement less affected by corneal biomechanics when the corneal curvature matches the contour of the tonometer tip. The radius of curvature of the tip is 10.5 mm with a contact surface approximately 7 mm in diameter. A piezoresistive pressure sensor of diameter