Essentials in Ophthalmology Glaucoma

F. Grehn R. StamperEditors

Essentials in Ophthalmology

G. K. Krieglstein R. N. WeinrebSeries Editors

Glaucoma

Cataract and Refractive Surgery

Uveitis and Immunological Disorders

Vitreo-retinal Surgery

Medical Retina

Oculoplastics and Orbit

Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics

Cornea and External Eye Disease

Editors Franz Grehn Robert Stamper

Glaucoma

With 68 Figures, Mostly in Colourand 18 Tables

123

Series Editors

Günter K. Krieglstein, MDProfessor and Chairman Department of Ophthalmology University of Cologne Kerpener Straße 62 50924 Cologne Germany

Robert N. Weinreb, MDProfessor and Director Hamilton Glaucoma Center Department of Ophthalmology - 0946 University of California at San Diego 9500 Gilman Drive La Jolla, CA 92093-0946 USA

Volume Editors

Franz Grehn, MDProfessor and Chairman Department of Ophthalmology University of Wuerzburg Josef-Schneider-Straße 11 97080 Wuerzburg Germany

Robert Stamper, MDDirector of Glaucoma Service Department of Ophthalmology USCF10 Kirkham Street, Rm K301 San Francisco, CA 94143 USA

ISBN-10 3-540-26220-2Springer Berlin Heidelberg NewYork

ISBN-13 978-3-540-26220-6Springer Berlin Heidelberg NewYork

ISSN 1612-3212

Library of Congress Control Number: 2004042952

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The series Essentials in Ophthalmology was initi-ated two years ago to expedite the timely trans-fer of new information in vision science and evidence-based medicine into clinical practice. We thought that this prospicient idea would be moved and guided by a resolute commitment to excellence. It is reasonable to now update our readers with what has been achieved.

The immediate goal was to transfer informa-tion through a high quality quarterly publication in which ophthalmology would be represented by eight subspecialties. In this regard, each issue has had a subspecialty theme and has been overseen by two internationally recognized volume edi-tors, who in turn have invited a bevy of experts

to discuss clinically relevant and appropriate top-ics. Summaries of clinically relevant information have been provided throughout each chapter.

Each subspecialty area now has been covered once, and the response to the first eight volumes in the series has been enthusiastically positive. With the start of the second cycle of subspecialty coverage, the dissemination of practical informa-tion will be continued as we learn more about the emerging advances in various ophthalmic subspecialties that can be applied to obtain the best possible care of our patients. Moreover, we will continue to highlight clinically relevant in-formation and maintain our commitment to ex-cellence.

G. K. Krieglstein R. N.WeinrebSeries Editors

Foreword

This second volume in the series Essentials of Ophthalmology, as in the first, seeks to bring the ophthalmic practitioner up to date on the impor-tant new advances or changes in glaucoma diag-nosis and management that has occurred in the last 10 years. The last decade has seen significant changes in our understanding of the pathophysi-ology of some glaucomas, both in our diagnostic approaches and in our management. Toward the goal of providing the most up-to-date informa-tion in a readable fashion, we have asked some of the world’s experts to discuss areas to which they have contributed in a way that will be useful for the practicing doctor.

For example, Dr. Johnstone, one pioneer in the study of trabecular meshwork, explains his new theories of how aqueous gets through the meshwork and Schlemm’s canal. He proposes that the trabecular drainage system is not just a passive screen as has been conceived for the past century but a much more dynamic system than has been heretofore acknowledged.

Electrophysiology has improved both our un-derstanding of the processes of glaucoma dam-age but has also provided new diagnostic tools. Thanks to the completion of several randomized controlled trials, we are now able to actually cal-culate the risk of developing glaucoma in a pa-tient who is a glaucoma suspect. Dr. Mansberger explains this new development.

Our understanding of the complicated issue of what factors drive our patients to follow our prescriptions or not has been given a boost by several studies in recent years. Dr. Schwartz de-scribes some of the advances in our understand-ing of patient adherence and persistence.

Health economics, rarely discussed before in this kind of ophthalmic venue, has become more important as healthcare groups, health insurers and governments grapple with the problems of providing ophthalmic care with resources that are stressed by ever-increasing demands and op-tions. This issue is addressed by Dr. Tuulonen, as is the problem of glaucoma in the developing world which, as difficult as it may be with first-rate resources, becomes even more daunting when the resources are severely limited.

Drs. Kaufman and Gabelt give us a look at the future of medical treatment. The use of new im-aging techniques has given us new insights into the pathophysiology of filtering blebs.

Dr. Freedman updates our concepts of tube-shunt procedures and offers some practical advice on how to improve results. Many of the mechanisms discussed and illustrated in this vol-ume have not appeared in textbook format be-fore. We hope that all the topics and authors we have selected are helpful in improving the under-standing of the many faces of glaucoma and will ultimately contribute to reduced visual loss and better care for our patients.

Franz GrehnRobert L. Stamper

Preface

Basics and Diagnosis

Chapter 1A New Model Describes an Aqueous Outflow Pump and Explores Causes of Pump Failure in GlaucomaMurray A. Johnstone

1.1 Introduction . . . . . . . . . . . . . . . . 31.1.1 Overview . . . . . . . . . . . . . . . . . . . 31.1.2 The Trabecular Meshwork

Is the Wall of a Vessel . . . . . . . 41.1.3 The Aqueous Outflow

System Is Part of a VascularCirculatory Loop . . . . . . . . . . . . 4

1.1.4 Circulatory LoopsReturn Fluid to the Heartby Pumping Mechanisms . . . 5

1.2 Laboratory Evidenceof a Mechanical AqueousOutflow Pump . . . . . . . . . . . . . . 6

1.2.1 Anatomic Relationships ThatPermit Pulsatile Flow . . . . . . . 6

1.2.2 IOP Transients MoveTrabecular Tissues to Powerthe Pump . . . . . . . . . . . . . . . . . . 7

1.2.3 IOP Decreases CauseTrabecular Tissue Recoil . . . . . 8

1.2.4 Trabecular Tissues Respondto IOP Transients . . . . . . . . . . . 8

1.2.5 Trabecular Tissues Movewith the Ocular Pulse . . . . . . . 8

1.3 The Aqueous Valves . . . . . . . . 91.3.1 Appearance and

Relationships . . . . . . . . . . . . . . . 91.3.2 Valves in SC Carry Aqueous . 91.4. Trabecular Tissues and

Aqueous Valves Are thePump . . . . . . . . . . . . . . . . . . . . . 12

1.4.1 Trabecular Tissues Distendand Recoil with IOPChanges . . . . . . . . . . . . . . . . . . 12

1.4.2 Trabecular Tissue MovementMoves Aqueous . . . . . . . . . . . 12

1.4.3 IOP Transients ProvideEnergy to Power the Pump 12

1.5 Clinical Evidence of aMechanical AqueousOutflow Pump . . . . . . . . . . . . . 12

1.5.1 Clinical Evidence of PulsatileAqueous Flow . . . . . . . . . . . . . 13

1.6 Pump Regulation ofPressure and Flow: ShortTerm . . . . . . . . . . . . . . . . . . . . . . 14

1.6.1 Length-to-TensionRelationships Govern StrokeVolume . . . . . . . . . . . . . . . . . . . 14

1.6.2 Clinical Evidence of Pump-Dependent PressureRegulation . . . . . . . . . . . . . . . . 15

1.7 Pump Regulationof Pressure and Flow:Long Term . . . . . . . . . . . . . . . . . 16

1.7.1 Trabecular TissueInformation Networks . . . . . 16

1.7.2 Trabecular Tissue Tethersand Signaling Mechanisms 17

1.7.3 Endothelial Cells RegulateTrabecular TissueComposition . . . . . . . . . . . . . . 17

1.7.4 Regulation of TrabecularTissue Composition Is PumpRegulation . . . . . . . . . . . . . . . . 18

1.8 The Pump Fails to ControlPressure in Glaucoma . . . . . . 19

1.8.1 Overview of the FailureMechanism . . . . . . . . . . . . . . . . 19

1.8.2 Laboratory Evidence:Pump Failure Mechanismsin Living Eyes . . . . . . . . . . . . . . 19

1.8.3 Laboratory Evidence:Pump Failure Mechanismsin Enucleated Eyes . . . . . . . . . 22

Contents

X Contents

1.9 Clinical Evidence of PumpFailure Mechanismsin Glaucoma . . . . . . . . . . . . . . . 28

1.9.1 Pulsatile Aqueous FlowDecreases in GlaucomaEyes . . . . . . . . . . . . . . . . . . . . . . . 28

1.9.2 Pulsatile Aqueous FlowStops As IOP Increasesin Glaucoma Eyes . . . . . . . . . . 28

1.9.3 Pulsatile Aqueous FlowStops with Episcleral VenousPressure Increases . . . . . . . . . 29

1.9.4 Pilocarpine: PulsatileAqueous Flow IncreasesWhen SC Expands . . . . . . . . . 29

1.9.5 SC Blood Reflux:Measure of TrabecularTissue Movement . . . . . . . . . . 29

1.10 Conclusion . . . . . . . . . . . . . . . . 32References . . . . . . . . . . . . . . . . 32

Chapter 2Risk Calculators: Evidence-Based Care of Ocular Hypertension and Glaucoma PatientsSteven L. Mansberger and Emily L. Patterson

2.1 Introduction . . . . . . . . . . . . . . . 362.2 Evidence from Recent

Randomized Clinical Trials . 362.2.1 Preventing or Delaying

Glaucoma: The OcularHypertension TreatmentStudy . . . . . . . . . . . . . . . . . . . . . 37

2.2.2 Treating Newly DiagnosedGlaucoma: the EarlyManifest Glaucoma Trialand the Collaborative InitialGlaucoma Treatment Study 37

2.2.3 Treating Moderateto Advanced NormalTension Glaucoma: theCollaborative Normal-Tension Glaucoma Study . . . 37

2.2.4 Treating UncontrolledGlaucoma: the AdvancedGlaucoma InterventionStudy . . . . . . . . . . . . . . . . . . . . . 37

2.2.5 Integrating Informationfrom Studies . . . . . . . . . . . . . . 38

2.3 How Do Clinicians Use ThisImportant Informationto Take Care of Patients? . . . 38

2.4 Implementing Informationfrom Clinical Studies intoClinical Care of Patients . . . . 40

2.4.1 A Current Risk Calculator:The Devers OcularHypertension to GlaucomaRisk Calculator . . . . . . . . . . . . . 40

2.4.2 Benefits to Eye CareProviders . . . . . . . . . . . . . . . . . . 40

2.4.3 Benefits to Patients . . . . . . . . 412.4.4 Benefits to Society of a Risk

Calculator . . . . . . . . . . . . . . . . . 422.4.5 Disadvantages of Risk

Calculators . . . . . . . . . . . . . . . . 422.4.6 Future Risk Calculators . . . . . 432.4.7 Conclusion . . . . . . . . . . . . . . . . 44

References . . . . . . . . . . . . . . . . 44

Chapter 3Dynamic Contour TonometryEvelin Schneider, Hartmut E. Kanngiesser, Christoph Kniestedt

3.1 Intraocular Pressure . . . . . . . 473.1.1 IOP Measurement in

Glaucoma Diagnosis . . . . . . . 473.1.2 Principles and Problems of

IOP Measurement Methods 483.1.3 Comparison of Common

Tonometers . . . . . . . . . . . . . . . 493.2 Dynamic Contour

Tonometry . . . . . . . . . . . . . . . . 503.2.1 Physical Methodology . . . . . 503.2.2 Measurement Procedure . . . 513.2.3 Absolute and Relative

Accuracy . . . . . . . . . . . . . . . . . . 533.3 Clinical Application

of Dynamic ContourTonometry . . . . . . . . . . . . . . . . 56

3.3.1 Dynamic ContourTonometry or ApplanationTonometry with CorrectionFactor? . . . . . . . . . . . . . . . . . . . . 56

3.3.2 DCT in LASIK Eyes . . . . . . . . . 563.3.3 DCT in Clinical Practice:

Experiences, Advantages,and Disadvantages . . . . . . . . 58References . . . . . . . . . . . . . . . . 61

Contents XI

Chapter 4Effect of Corneal Thickness on Applanation Tonometry, Pneumotonometry, and Tonopen MeasurementsLutz E. Pillunat, Markus Kohlhaas, Andreas G. Boehm, Eberhard Spoerl

4.1 Influencing Factors inApplanation Tonometry . . . 65

4.2 Approach to a ClinicalStudy . . . . . . . . . . . . . . . . . . . . . 65

4.3 Results of a Clinical Study . . 674.4 Results of a Clinical Study

Pitfalls and Solutions forTonometric Measurements 69

4.5 Conclusion . . . . . . . . . . . . . . . . 70References . . . . . . . . . . . . . . . . 71

Chapter 5Electrophysiology in the Diagnosis of GlaucomaThomas Meigen and Michael Bach

5.1 Introduction . . . . . . . . . . . . . . . 735.1.1 Glaucomatous Damage

of Ganglion Cells . . . . . . . . . . 735.1.2 The Importance of Early

Detection of Glaucoma . . . . 745.1.3 Electrophysiological

Proceduresin Ophthalmology . . . . . . . . . 75

5.2 Early Detection of GlaucomaUsing PERG Recordings . . . . 76

5.2.1 PERG Recordings . . . . . . . . . . 765.2.2 Neural Origin of PERG

Responses . . . . . . . . . . . . . . . . . 775.2.3 PERG Changes

in Glaucoma . . . . . . . . . . . . . . . 785.2.4 The “Freiburg” PERG

Paradigm . . . . . . . . . . . . . . . . . . 815.3 VEP Recordings

in Glaucoma . . . . . . . . . . . . . . . 835.3.1 Conventional VEP

Recordings in Glaucoma . . . 835.3.2 Multifocal VEP Recordings

in Glaucoma . . . . . . . . . . . . . . . 85References . . . . . . . . . . . . . . . . 86

Chapter 6Adherence and Persistence in GlaucomaGail F. Schwartz

6.1 Introduction . . . . . . . . . . . . . . . 916.2 Adherence . . . . . . . . . . . . . . . . 926.3 Persistence . . . . . . . . . . . . . . . . 966.4 Barriers to Adherence

and Persistence . . . . . . . . . . . . 996.4.1 Patient Demographics . . . 1006.4.2 Behavioral Factors . . . . . . . 1006.4.3 Treatment Regimen

Characteristics . . . . . . . . . . . 1016.4.4 Situational Factors . . . . . . . 1016.4.5 Health Care System Issues 1016.5 Improving Adherence

and Persistence . . . . . . . . . . 1016.5.1 Improve Motivation

and Knowledgeby Reinforcing theImportance of Adherenceand Persistence . . . . . . . . . . 102

6.5.2 Provide Literature to Readat Home . . . . . . . . . . . . . . . . . 102

6.5.3 Write Down All DropDirections; Consideran Easy-to-Read Chart . . . 102

6.5.4 Regularly Evaluatethe Treatment Regimen . . 102

6.5.5 Improve Patient Skillsby Monitoring DropInstillation Techniques . . . 102

6.5.6 Question PatientsConcerning Adherenceand Persistence . . . . . . . . . . 102

6.5.7 Help Patients Fitthe Treatment RegimenInto Their Routines . . . . . . 102

6.5.8 Consider Health SystemIssues . . . . . . . . . . . . . . . . . . . 103

6.6 Conclusion . . . . . . . . . . . . . . 103References . . . . . . . . . . . . . . 103

XII Contents

Epidemiology and Related Fields

Chapter 7Glaucoma Care in Developing Countries of AsiaPaul J. Foster and Ravi Thomas

7.1 The Problem . . . . . . . . . . . . 1107.2 Primary Open-Angle

Glaucoma . . . . . . . . . . . . . . . 1107.3 Primary Angle-Closure

Glaucoma . . . . . . . . . . . . . . . 1107.3.1 Defining Primary Angle-

Closure Glaucoma . . . . . . . 1107.3.2 Incidence of Primary

Angle Closure . . . . . . . . . . . 1127.3.3 Prevalence of Primary

Angle Closure . . . . . . . . . . . 1127.3.4 Risk Factors . . . . . . . . . . . . . 1137.4 Impact of Glaucoma

on Patients and Accessto Care . . . . . . . . . . . . . . . . . . 114

7.5 Medical Therapy . . . . . . . . . 1147.6 Laser Treatment . . . . . . . . . 1157.7 Surgery . . . . . . . . . . . . . . . . . 1167.8 Political Considerations . . 1177.9 The Pharmaceutical

Industry . . . . . . . . . . . . . . . . . 1177.10 Conclusion . . . . . . . . . . . . . . 118

References . . . . . . . . . . . . . . 119

Chapter 8Health Economics, Cost-Effectiveness, and Glaucoma CareAnja Tuulonen and Harri Sintonen

8.1 Health Economics . . . . . . . 1238.1.1 Basics . . . . . . . . . . . . . . . . . . . 1238.1.2 Role of Micro-Economic

Evaluation . . . . . . . . . . . . . . . 1258.2 Efficacy, Effectiveness,

and Efficiency . . . . . . . . . . . 1258.2.1 Methods of Economic

Evaluation . . . . . . . . . . . . . . . 1258.2.2 Guidelines for Economic

Evaluation . . . . . . . . . . . . . . . 1278.3 Economic Evaluation

and Glaucoma Care . . . . . . 128

8.3.1 Cost-EffectivenessAnalyses of Screeningfor Glaucoma . . . . . . . . . . . . 129

8.3.2 Pharmacoeconomic Studiesin Glaucoma . . . . . . . . . . . . . 129

8.3.3 Other Cost Studiesin Glaucoma . . . . . . . . . . . . . 130

8.4 Future . . . . . . . . . . . . . . . . . . . 1308.4.1 Future Challenges in Health

Economics . . . . . . . . . . . . . . 1308.4.2 What Kind of Information

Do We Need AboutGlaucoma Care? . . . . . . . . . 131References . . . . . . . . . . . . . . 132

Therapy – Surgery

Chapter 9Future of IOP-Lowering Medication for Glaucoma TherapyPaul L. Kaufman and B’Ann True Gabelt

9.1 Introduction . . . . . . . . . . . . . 1389.2 Outflow Enhancement . . . 1389.2.1 Trabecular Outflow . . . . . . 1389.2.2 Uveoscleral Outflow . . . . . 1469.3 Inflow Suppression . . . . . . 1489.3.1 Basic Structure . . . . . . . . . . 1499.3.2 Opioids . . . . . . . . . . . . . . . . . 1499.3.3 Cannabinoids . . . . . . . . . . . 1509.4 Drug Delivery . . . . . . . . . . . 1509.4.1 Vesicular Drug Delivery . . 1509.4.2 Contact Lenses . . . . . . . . . . 1519.4.3 Penetration Enhancers . . . 1529.4.4 Bioadhesives . . . . . . . . . . . . 1529.4.5 Ocular Inserts . . . . . . . . . . . 1529.5 IOP Monitoring . . . . . . . . . . 1539.5.1 Contact Lenses . . . . . . . . . . 1539.5.2 Implantable Sensor . . . . . . 153

Acknowledgements . . . . . 153References . . . . . . . . . . . . . . 153

Contents XIII

Chapter 10Filtering Bleb Imaging with Confocal Laser Technology (Rostock Cornea Module)Rainer Guthoff, Günther Schlunck, Thomas Klink, Franz Grehn

10.1 Introduction . . . . . . . . . . . . . 15710.2 Confocal In Vivo FB

Microscopy with the RCM/HRT II Based on the Laser-Scanning Technique . . . . . 158

10.3 Biomicroscopic FBAnalysis . . . . . . . . . . . . . . . . . 160

10.3.1 Early Postsurgical FBBiomicroscopy . . . . . . . . . . 160

10.3.2 Biomicroscopy ofFunctioning FB with Goodor Over-Filtration . . . . . . . . 160

10.3.3 Tenon‘s Cyst . . . . . . . . . . . . . 16010.3.4 Scarring FB . . . . . . . . . . . . . . 16010.3.5 Standardized FB

Classification and BlebScore . . . . . . . . . . . . . . . . . . . . 160

10.4 General AnatomicalConsiderations . . . . . . . . . . 161

10.4.1 Normal Anatomy of the FBRelevant Region . . . . . . . . . 161

10.4.2 Histopathology of FB . . . . 16110.5 FB Confocal In Vivo Laser-

Scanning Microscopy . . . . 16310.5.1 Normal Anatomy of the FB

Relevant Region . . . . . . . . . 16410.5.2 Filtering Blebs . . . . . . . . . . . 16510.5.3 Clinical Relevance of

Confocal In Vivo Laser-Scanning Microscopy inFiltering Bleb Evaluation . 168References . . . . . . . . . . . . . . 168

Miscellaneous

Chapter 11Update on Tube-Shunt Procedures for GlaucomaJeffrey Freedman

11.1 Introduction . . . . . . . . . . . . . 17311.1.1 Basics . . . . . . . . . . . . . . . . . . . 17311.1.2 Bleb Physiology . . . . . . . . . 17311.1.3 Therapeutic Options Related

to Bleb Physiology . . . . . . . 17411.2 Indications for Implant

Use . . . . . . . . . . . . . . . . . . . . . 17511.2.1 Which Implants to Use . . . 17511.2.2 Significance of Plate Size . 17511.3 Surgical Techniques for

Tube-Shunt Implantation 17711.3.1 Technique for Supra-Tenon

Placement of a Single-PlateMolteno Implant . . . . . . . . 177

11.4 The Cornea and GlaucomaImplants . . . . . . . . . . . . . . . . 179

11.4.1 Corneal Decompensationin the Presence of a Pre-existing Tube Shunt . . . . . 179

11.4.2 Penetrating KeratoplastyMay Result in Glaucoma . 179

11.4.3 Summarized Informationfrom Publications RegardingSuccess of GlaucomaImplants and PenetratingKeratoplasty . . . . . . . . . . . . . 180

11.5 Neovascular Glaucoma . . 18011.6 Complications of Glaucoma

Implants . . . . . . . . . . . . . . . . 18111.6.1 Tube-Related Problems . . 18111.6.2 Plate-Related Problems . . 18111.6.3 Motility Problems . . . . . . . . 18211.6.4 The “Hypertensive Phase” 18211.6.5 Bleb Fibrosis . . . . . . . . . . . . . 18211.7 New Glaucoma Implants . 18311.7.1 The Ex-Press Glaucoma

Shunt . . . . . . . . . . . . . . . . . . . 18311.8 The Future for Glaucoma

Implants . . . . . . . . . . . . . . . . 183References . . . . . . . . . . . . . . 183

Subject Index . . . . . . . . . . . . . . . . 187

Michael Bach, Prof. Dr.Universitäts-Augenklinik Freiburg Killianstraße 5 79106 Freiburg Germany

Andreas G. Böhm, Priv.-Doz. Dr.Augenklinik der Technischen Universität Fetscherstraße 74 01307 Dresden Germany

Paul Foster, MDInstitute of Ophthalmology Bath Street London EC1 V 9EL UK

Jeffrey Freedman, MD, PhDDepartment of Ophthalmology SUNY Downstate Medical Center 450 Clarkson Avenue, Brooklyn NY 11203 USA

B’Ann True Gabelt, Associate ScientistDepartment of Ophthalmology and Visual Sciences University of Wisconsin 600 Highland Avenue Madison, WI 53792-3284 USA

Franz Grehn, Prof. Dr. Dr. h.c.Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Rainer Guthoff, Dr.Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Murray A. Johnstone, MDSwedish Medical Center Department of Ophthalmology 1221 Madison #1124 Seattle, WA 98104 USA

Hartmut E. Kanngiesser, Dr.Manager R&D SMT Swiss Mictrotechnology AG Allmendstrasse 11 2562 Port Switzerland

Paul Kaufman, MD, PhDProfessor and Chairman Department of Ophthalmology University of Wisconsin 600 Highland Avenue Madison, WI 53792-3284 USA

Thomas Klink, Dr. Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Christoph Kniestedt, Dr.Kantonsspital Winterthur Augenklinik Brauerstrasse 15, 8401 Winterthur Switzerland

Contributors

XVI Contributors

Markus Kohlhaas, Prof. Dr.St. Johannes-Hospital Johannesstraße 9–17 44137 Dortmund Germany

Steven Mansberger, MDDevers Eye Institute 1040 NW 22nd Avenue #200 Portland, OR 97210 USA

Thomas Meigen, Priv.-Doz. Dr.Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Emily L. Patterson, MDDevers Eye Institute 1040 NW 22nd Avenue #200 Portland, OR 97210 USA

Lutz E. Pillunat, Prof. Dr.Augenklinik der Technischen Universität Fetscherstraße 74 01307 Dresden Germany

Günther Schlunck, Dr.Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Evelin Schneider, Dr.Universitäts-Augenklinik Würzburg Josef-Schneider-Straße 11 97080 Würzburg Germany

Gail F. Schwartz, MDGlaucoma Consultants 6565 N. Charles Street, Suite 302 Baltimore, MD 21204 USA

Harri Sintonen, PhDDepartment of Public Health University of Helsinki and FinOHTA P.O. Box 41 00014 University of Helsinki Finland

Eberhard Spörl, Dr.Augenklinik der Technischen Universität Fetscherstraße 74 01307 Dresden Germany

Robert Stamper, MDProfessor and Chairman Department of Ophthalmology UCSF 10 Kirkham Street, Rm K301 San Francisco, CA 94143 USA

Ravi Thomas, MDProfessor and Chairman LV Prasad Eye Institute Banjara Hills Hyderabad Andhra Pradesh India

Anja Tuulonen, MDDepartment of Ophthalmology P.O. Box 5000 University of Oulu FIN-90014 Oulu Finland

Basics and Diagnosis

Core Messages

■ The aqueous outflow system is structur-ally organized to act as a mechanical pump. The aqueous outflow system is part of a vascular circulatory loop. All other vascular circulatory loops return fluids to the heart by pumping mecha-nisms.

■ The trabecular meshwork actively dis-tends and recoils in response to IOP transients such as the ocular pulse, blinking, and eye movement. Trabecular meshwork flexibility is essential to nor-mal function.

■ Aqueous valves transfer aqueous from the anterior chamber to SC. The valves are oriented circumferentially in SC and their normal function requires that tra-becular tissues retain their ability to re-coil from SC external wall.

■ The aqueous pump provides short-term pressure control by varying stroke vol-ume in response to pressure changes.

■ The aqueous pump provides long-term pressure control by modulating trabecu-lar meshwork constituents that control stroke volume.

■ The aqueous outflow pump fails in glau-coma because of SC wall apposition and trabecular tissue stiffening. The trabecu-lar meshwork (TM) stiffening is progres-sive and becomes irreversible.

■ Clinically visible manifestations of pump failure are lack of pulsatile aqueous dis-charge into the aqueous veins and grad-ual failure in the ability to reflux blood into SC.

■ Reversal of pump failure requires Schlemm’s canal lumen enlargement. Precisely targeted surgical techniques directed at the scleral spur and its cili-ary body attachment should reverse the structural abnormality without damag-ing the pump.

1.1 Introduction

1.1.1 OverviewPrimary open-angle glaucoma is an enigma in-volving abnormal aqueous outflow. Constructing a model that explains normal control of pressure and flow is necessary before the enigma can be resolved. Laboratory studies describe an aqueous

outflow system with properties that enable it to act as a pump. A recently proposed model de-scribes such a pump that controls both pressure and flow [34]. This chapter summarizes confir-matory evidence that supports the pump model. It further explores how malfunction of mecha-nisms central to the model can explain laborato-ry and clinical abnormalities found in glaucoma. The ability to predict and explain laboratory and

1A New Model Describes an Aqueous Outflow Pump and Explores Causes of Pump Failure in GlaucomaMurray A. Johnstone

Chapter 1

4 A New Model Describes an Aqueous Outflow Pump and Explores Causes of Pump Failure in Glaucoma

1clinical observations provides a means of assess-ing the model’s strength.

The initial reports by both Ascher [2] and Goldmann [16] of the presence of aqueous veins point out that a mechanism is present to transmit the intraocular pulse across the trabecular mesh-work to Schlemm’s canal (SC) and the aqueous veins. Goldmann, Ascher, and others provide ex-quisitely detailed descriptions of the effect of the pumping mechanism that moves aqueous from SC into the episcleral veins [4]. It is best to start with a brief overview of the pumping mecha-nism model. Flexible trabecular tissue move-ment pumps aqueous from the anterior chamber to SC through a series of valves spanning SC (Figs. 1.1, 1.2). Trabecular tissue movement then pumps aqueous from SC to the aqueous veins. The aqueous outflow pump receives its power from transient IOP increases such as during sys-tole of the cardiac cycle, respiration, blinking, and eye movement. These IOP transients cause deformation of the elastic structural elements of the trabecular tissues (Fig. 1.3). During systole, the pressure increase moves the trabecular tis-sues outward, toward SC and eventually into it (Fig. 1.4A,B). Outward movement of the Sch-lemm’s canal endothelium (SCE) narrows SC, forcing aqueous from SC into collector channel ostia and then into the aqueous veins. Concur-rently, the transient IOP increase forces aqueous from the trabecular meshwork interstices into one-way collector vessels or valves spanning SC. Decay of the pressure spike causes the elastic tra-becular elements to respond by recoiling to their diastolic configuration. Trabecular tissue recoil causes a pressure reduction in SC that induces aqueous to flow from the aqueous collector ves-sels or valves into SC.

Stroke volume is responsible for the amount of aqueous discharged from SC with each IOP transient, thus providing short-term IOP homeo-stasis. The stroke volume moves up or down an IOP-dependent length–tension curve. Optimiza-tion of the stroke volume setpoint is a function of the trabecular tissue properties that determine distention and recoil. Trabecular endothelial cells regulate trabecular tissue properties. Tra-becular endothelial cells act as sensors constantly monitoring information related to pressure and flow. Using the information, the endothelial cells

employ mechanotransduction mechanisms to optimize their own properties as well as the con-stituent properties of the formed extracellular elements.

In this model, the pump controls flow and pressure; the problem of glaucoma is explained by a failure of pump function. Pump failure re-sults from abnormally diminished trabecular tis-sue movement (Fig. 1.4C). Reduced trabecular tissue movement in turn results from two related abnormalities. The first abnormality is intrinsic trabecular tissue stiffening; the second is abnor-mal persistence of trabecular tissue apposition to SC external wall. Persistent trabecular tissue apposition develops because of both intrinsic ex-cess distention of trabecular tissues and extrin-sic factors. Extrinsic factors alter the position of trabecular tissue attachments to the scleral spur, Schwalbe’s line, and ciliary body. Alterations in corneoscleral relationships, corneoscleral flex-ibility, and changes in ciliary body tone are exam-ples of extrinsic factors that move the trabecular insertion within the eye. Laboratory and clinical evidence follows which provides confirmatory evidence to support the model.

1.1.2 The Trabecular Meshwork Is the Wall of a Vessel

Ashton’s anatomic studies [5, 6] demonstrate that SC is the wall of a vascular sinus that com-municates directly with the venous system; thus, the trabecular side of SC is the highly modified wall of a vessel. When we couple Ashton’s obser-vations with those of Ascher [4] and Goldmann [16], it becomes apparent that the aqueous out-flow system functions in the broader sense as one of the vascular circulatory loops returning fluids that originated from the blood (blood derived) to the heart.

1.1.3 The Aqueous Outflow System Is Part of a Vascular Circulatory Loop

The cardiac pulse pumps blood to the ciliary processes. Ciliary-process epithelia then convert aqueous constituents of the blood into aque-

Fig. 1.1 Aqueous outflow anatomy when IOP is nor-mal or decreased. TM trabecular meshwork, SCE

Schlemm’s canal endothelium, EW Schlemm’s canal external wall, AV aqueous valve. (From [30])

Fig. 1.3 Appearance of aqueous outflow system at physiologic IOP. Arrows depict deforming forces of pressure that act on Schlemm’s canal endothelium. The IOP forces transmit through cellular processes to the trabecular lamellae. (From [32])

Fig. 1.2 Aqueous valve discharging aqueous into Schlemm’s canal. Blood, intentionally refluxed into SC, is visible through the trabecular meshwork tissue (TM). Pulsatile movement of clear aqueous is visible in the funnel (F) and cylindrical (C) portion of the valve. Aqueous ejection to SC is apparent because of the whirling eddies of an aqueous–blood mixture (M)that develops with each systole. (Gonioscopic video courtesy of R. Stegmann)

ous humor that flows into the anterior cham-ber. Aqueous flows from the anterior chamber through the trabecular meshwork into SC. From SC aqueous flows into aqueous veins and epi-scleral veins completing the closed circulatory loop that returns aqueous to the heart.

1.1.4 Circulatory Loops Return Fluid to the Heart by Pumping Mechanisms

Other circulatory loops, such as the veins and lymphatics, pump fluid back to the heart by

1.1 Introduction 5

6 A New Model Describes an Aqueous Outflow Pump and Explores Causes of Pump Failure in Glaucoma

1means of pressure transients that drive fluid in one direction through a series of valves. These valves permit pulsatile flow toward the heart in response to transients such as the cardiac pulse, respiration, muscle, and viscera movement. Vas-cular tissue composition determines the proper-ties that optimize flow and pressure relationships in other vascular circulatory loops [27]. The cur-rently proposed model uses the same physiologic principles to explain mechanisms that optimize pressure and flow relationships in the aqueous circulatory loop.

Summary for the Clinician

■ Since the trabecular meshwork is the wall of a vessel, we can expect it to have anatomic features and physiologic be-havior analogous to vessels elsewhere.

■ Examination of vascular system behav-ior points to pumping mechanisms as a means of returning fluids to the heart.

1.2 Laboratory Evidence of a Mechanical Aqueous Outflow Pump

1.2.1 Anatomic Relationships That Permit Pulsatile Flow

1.2.1.1 SC Pressure Gradients Are in the “Wrong Direction” Requiring Adaptations

Although Schlemm’s canal is the modified wall of a vessel, in other vessels pressure levels are high-er in the vessel lumen than in the tissues around them. By contrast, pressure is higher in the tissue outside SC lumen than it is on the inside. Fluid also moves into rather than out of SC lumen. Pres-sure gradient and flow reversals require a unique series of adaptations of the trabecular wall of SC. The adaptations provide a means of resisting the pressure gradients that would otherwise force SC endothelium away from the trabecular lamellae and toward Schlemm’s canal.

Fig. 1.4 Trabecular meshwork (TM) movement fol-lowing IOP reduction allows TM collapse, Schlemm’s canal (SC) expansion, and blood reflux. A Intraocu-lar pressure zero, episcleral venous pressure (EVP) ~8 mm Hg. The higher pressure in SC causes the highly flexible trabecular TM to collapse. The pressure on the collapsed TM forces it inward and posteriorly carrying the scleral spur (SS) and ciliary body (CB) attachment with the TM, thus greatly enlarging SC. B Intraocular pressure 25 mm Hg, EVP ~8 mm Hg. The IOP causes SC endothelium to distend outward carrying the TM with it. TM movement toward SC also forces the at-tached SS and CB toward SC causing closure of SC lu-men. C Tissue fixation in the living eye at 25 mm Hg experimentally stiffens TM tissues. Tissue stiffening then prevents experimentally induced SC blood reflux seen in A, and simulates TM sclerosis thought to be the cause of inability to reflux blood into SC in glau-comatous eyes. Rhesus macaque. A is the fellow eye of B and C.

1.2.1.2 Trabecular Tissue Attachment Mechanisms Provide a “Right Direction”

At the heart of the current model is a system of cellular attachments that integrate the trabecu-lar tissues into a functional unit (Fig. 1.3) [31]. Pressure does not force SC endothelium against a basement membrane to provide intimate contact as in other vessels. The SC inner wall endothe-lium has only a sparse – and in some areas an absent – basement membrane; instead, in place of a basement membrane, numerous cytoplasmic processes of Schlemm’s canal endothelial cells project into the juxtacanalicular space. Cytoplas-mic processes of SC endothelium attach to pro-cesses projecting from juxtacanalicular cells. Jux-tacanalicular cells also have processes projecting toward the trabecular lamellae. Endothelial cells covering the trabecular lamellae in turn have processes projecting toward and attaching to the juxtacanalicular cells’ cytoplasmic processes. The result is that cellular processes of SC endothe-lium attach to cellular processes of endothelial cells covering trabecular lamellae.

Trabecular lamellae also attach to one another by cytoplasmic processes rather than by intertra-becular collagen beams that are infrequent and difficult to find microscopically. Endothelial cells covering the trabecular lamellae are the origin of the cytoplasmic processes. The cellular processes throughout the trabecular meshwork meet in the intertrabecular space with a complex zone of ap-position involving robust desmosomes and gap junctions [23, 24].

1.2.2 IOP Transients Move Trabecular Tissues to Power the Pump

1.2.2.1 IOP Increases Cause Trabecular Tissue Distention

As pressure increases, the entire tissue mono-layer of SC endothelium moves outward into SC (Fig. 1.4) [31, 34, 35]. At the same time individ-ual endothelial cells throughout the monolayer change shape from a round appearance to an

elongated plate-like shape. Individual cells tether to underlying processes and in the areas between tethering processes balloon outward to create the appearance of a series of undulating spherical structures along the monolayer when seen from SC lumen. The ballooning appearance of the dis-tending endothelial cells is associated with the misnomer of “giant vacuoles.”

Only tissues resisting a force undergo force-induced deformation [27]. All studies examin-ing IOP-induced tissue changes observe that SC endothelium is the principal tissue undergoing force-induced deformation (See [34] for com-plete reference list). All these studies thus point to the Schlemm’s canal endothelial monolayer as the site of resistance to aqueous flow within the trabecular meshwork.

1.2.2.2 SC Endothelium Tethering to Trabecular Lamellae Limits Movement

The following observations demonstrate that the trabecular lamellae limit SC endothelium out-ward movement by means of restraining tension exerted through cell processes (Fig. 1.3) [31, 35]. At cell process origins of SC endothelium, the cy-toplasm and nucleus of the cells reorganize from a flat to an elongated cone-shaped configuration. Juxtacanalicular cell cytoplasmic process origins also change from a round- to a cone-shaped ap-pearance. Cytoplasmic processes throughout the meshwork undergo progressive changes from an orientation parallel to trabecular beams to a per-pendicular orientation. At the same time, the cy-toplasmic processes change from a short, stubby appearance to an elongated and thin configura-tion. As SC endothelium stretches and moves outward into SC, the juxtacanalicular space en-larges. As IOP increases further, the trabecular lamellae stretch progressively outward toward SC lumen increasing the space between adjacent lamellae.

1.2 Laboratory Evidence of a Mechanical Aqueous Outflow Pump 7