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As the irreversible effects of glaucoma can lead to blindness, there is high demand for early diagnosis and an ongoing need for practitioners to adopt new and evolving medical and surgical treatment options to improve patient outcomes. Glaucoma, Second Edition is the most comprehensive resource in the field delivering expert guidance for the most timely and effective diagnosis and treatment of glaucoma – aimed at specialists, fellows and general ophthalmologists. More than 300 contributors from six continents provide a truly global perspective and explore new approaches in this user friendly reference which has been updated with enhanced images, more spotlights, new videos, and more.

  • Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability.
  • Get all the accuracy, expertise, and dependability you could ask for from leading specialists across six continents, for expert guidance and a fresh understanding of the subject.
  • Develop a thorough, clinically relevant understanding of all aspects of adult and pediatric glaucoma and the latest diagnostic imaging techniques including ultrasound biomicroscopy and optical coherence tomography.
  • Broaden your surgical repertoire with the latest surgical techniques - such as trabeculectomy, gonio-surgery, combined surgeries, and implant procedures.
  • Glean all essential, up-to-date, need-to-know information about stem cell research, gene transfer, and implants.
  • Find answers fast thanks to a well-organized, user-friendly full-color layout. 
  • Stay at the forefront of your field with 10 brand new chapters on trending topics including: new surgical approaches such as trabectome and canoplasty; glaucoma implications in cataract and ocular surface disease; and, updates in the costs-effectiveness of medical management.
  • Avoid pitfalls and achieve the best outcomes thanks to more than 40 brand new spotlight commentaries from key leaders providing added insight, tips and pearls of wisdom across varying hot topics and advances in the field.
  • Refine and improve your surgical skills by watching over 50 video clips depicting the latest techniques and procedures including: new trabeculectomy methods, needling, implants, valve complications, and more.
  • Prevent and plan for complications in advance by examining over 1,600 illustrations, photos and graphics (1,250 in color) capturing essential diagnostics techniques, imaging methods and surgical approaches.
  • Grasp each procedure and review key steps quickly with chapter summary boxes that provide at-a-glance quick comprehension of the key take away points.

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Published 05 September 2014
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EAN13 9780702055416
Language English
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G l a u c o m a
SECOND EDITION
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), Moorfi elds 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
London, New York, Oxford, Philadelphia, St Louis, Sydney, TorontoTable of Contents
Cover image
Title page
Copyright
Video Table of Contents
First Edition Foreword
Preface
List of Contributors
Acknowledgements
Contributor Locations
Dedication
The Editors
Volume 1 Medical Diagnosis & Therapy
Section 1 Glaucoma in the World
1 Prevalence and Geographical Variations
Introduction
Epidemiological Methods
Definition of Glaucoma for Use in Epidemiological Surveys
Regional Variation in Glaucoma Prevalence and TypeGeographical Variation in Risk Factors
References
References
References
2 Screening for Glaucoma
Introduction
Criteria for Screening
Screening Concepts
Risk Factor Screening in Open-Angle Glaucoma
Risk Factor Screening in Angle-Closure Glaucoma
References
Acknowledgments
References
3 Economics of Glaucoma Care
Introduction
Types of Economic Analysis
Framework for Looking at Costs in Glaucoma: A Common Vocabulary –
Vancouver
What is Currently Known: Costs of Visual Disorders and Blindness
What is Currently Known: Costs in Glaucoma
What is Currently Known: Benefits
Additional Issues and Future Perspectives
References
References
References
4 Practical Application of Glaucoma Care in Different Societies
Introduction
Practical Considerations in the Management of Glaucoma in Sub-Saharan AfricaGlaucoma Care: The Nongovernmental Organization Perspective
Glaucoma Services in a Developing Country Setting
References
References
Section 2 Pathogenesis
5 Functional Morphology of the Trabecular Meshwork Outflow Pathways
Introduction
The Trabecular Meshwork Outflow Pathways
Acknowledgment
References
References
6 Aqueous Humor Dynamics and Intraocular Pressure Elevation
Introduction
Aqueous Humor Dynamics in the Healthy Human Eye
Aqueous Humor Dynamics in Clinical Syndromes Affecting Intraocular Pressure
References
7 Pathogenesis of Glaucomatous Optic Neuropathy
Background
Normal Organization of the Lamina Cribrosa: Relevance to the Pathogenesis of
Glaucomatous Optic Neuropathy
Axon Organization in the Optic Nerve Head: A Role for Mechanical Factors
Astroglial Interactions within the Lamina Cribrosal: Translating the Effects of
Stress and Strain
Optic Nerve Head Astrocytes: Translating Optic Nerve Stress into Axon Damage
Blood Supply: Normal and Glaucoma
What is the Role of IOP in Initiating Axon Loss?
How Does Axon Damage Result in RGC Loss?
Retinal Factors in the Initiation of Retinal Ganglion Cell DeathConclusions
References
8 Mechanical Strain and Restructuring of the Optic Nerve Head
The Optic Nerve Head (ONH) as a Biomechanical Structure
Mechanical Environment of the Optic Nerve Head and Peripapillary Sclera
Restructuring and Remodeling of the Optic Nerve Head
Future Directions
References
9 Role of Ocular Blood Flow in the Pathogenesis of Glaucoma
Findings of Ocular Blood Flow Studies in Glaucoma and their Interpretation
Potential Mechanisms of Ocular Blood Flow Reduction in Glaucoma Patients
Current Evidence of Abnormal Ocular Blood Flow in Glaucoma
Conclusion
References
Section 3 Evaluation of Glaucoma
10 Tonometry and Intraocular Pressure Fluctuation
Introduction
Goldmann Applanation Tonometry
Noncontact Tonometry
The Tonopen
The Pascal® Dynamic Contour Tonometer
Rebound Tonometry
Home Tonometry
Continuous Tonometry
Intraocular Pressure Fluctuation
References
11 Visual FieldsIntroduction
Manual Visual Field Testing
Automated Visual Field Testing
Patterns of Visual Field Loss in Glaucoma
Measurement Variability
Interpretation of Visual Field Results
Technical Tips for Users
References
12 Long-Term Follow-Up of Visual Fields
Introduction
The Nature of Visual Field Progression in Glaucoma
Variability of Visual Fields
Practical Aspects of Monitoring Patients
Frequency of Visual Field Testing in Clinical Practice
Strategies for Longitudinal Follow-Up of Visual Fields
Global Indices for Monitoring Progression
Clinical Decision Tools and Endpoints for Clinical Trials in Glaucoma
Future Directions
References
13 Function-Specific Perimetry
Introduction
Short-Wavelength Automated Perimetry (SWAP)
Frequency Doubling Perimetry (FDT)
Comparison Among Instruments
Conclusion
References
14 Electrophysiology in Glaucoma Assessment
IntroductionMultifocal Recording Techniques for Electroretinogram/Pattern Visual Evoked
Potential (ERG/VEP)
Multifocal Techniques in Glaucoma
Mode of Action
Strengths and Limitations
Reference Population
Comparison with Other Tests
Storage and Retrieval of Data
Instrument Printouts and Interpretation of Data
Artefacts and How to Prevent Them
Technical Tips for Users
References
15 Gonioscopy
Keypoints
Introduction
Historical Background of Gonioscopy
Optical Principles
Goniolenses
Gonioscopic Techniques
Identification of Angle Structures
Grading of Angle Width
Pathological Findings
References
16 Ultrasound Biomicroscopy*
Instrumentation for Ultrasound Biomicroscopy
New High-Resolution UBMs
Examination Techniques
Measurement Parameters
UBM and GlaucomaUBM Use in Glaucoma Research
UBM and Surgical Treatment of Glaucoma
Congenital Glaucoma
Post-Traumatic Glaucoma
Study of Schlemm's Canal
UBM and Other Anterior Segment Imaging Technologies
References
17 Angle Imaging: Ultrasound Biomicroscopy and Anterior Segment Optical Coherence
Tomography
Introduction
Ultrasound Biomicroscopy (UBM)
Anterior Segment Optical Coherence Tomography (AS-OCT)
UBM and AS-OCT Compared
Other Technologies
References
18 The Impact of Central Corneal Thickness and Corneal Biomechanics on Tonometry
Introduction
The Impact of Central Corneal Thickness on Tonometry
The Ocular Hypertension Treatment Study
Central Corneal Thickness Differences Among Racial Groups
Central Corneal Thickness – Tonometry Artifact, or Something More?
The Cornea is Not a Piece of Plastic – The Impact of Material Properties
The Cornea Following Refractive Surgery
Implications for Clinical Practice
References
References
References
References19 Optic Disc Photography in the Diagnosis of Glaucoma
Introduction
Optic Disc Size
Optic Disc Shape
Neuroretinal Rim Size
Neuroretinal Rim Shape
Neuroretinal Rim Pallor
Optic Cup Size in Relation to the Optic Disc Size
Configuration and Depth of the Optic Cup
Cup-to-Disc Ratios
Position of the Exit of the Central Retinal Vessel Trunk on the Lamina Cribrosa
Surface
Optic Disc Hemorrhages
Peripapillary Chorioretinal Atrophy
Diameter of Retinal Arterioles
Evaluation of the Retinal Nerve Fiber Layer
References
References
References
20 Optic Disc Imaging
Introduction
Heidelberg Retina Tomograph
Time Domain Optical Coherence Tomography
Spectral Domain Optical Coherence Tomography
References
21 Retinal Nerve Fiber Layer (RNFL) Photography and Computer Analysis
Introduction
Red-Free Ophthalmoscopy and Photography
Confocal Scanning Laser Ophthalmoscopy: Topographic Analysis of the RNFLOptical Coherence Tomography
Scanning Laser Polarimetry
Acknowledgment
References
22 Structure–Function Relationships in Glaucoma
Introduction
Clinical Relevance of the Structure–Function Relationship
Assumptions for Inferences from Structure–Function Relationships
The Evolution of Understanding the SF Relationship
Structure–Function Dissociation
Factors Influencing the SF Relationship
Models Linking Structure and Function
The Topographical Relationship between Structure and Function
Structure–Function Relationships in the Macula
Future Directions
References
23 Measuring Glaucoma Progression in Clinical Practice
Introduction
Structural Measurements of Progression
Functional Measurements of Progression
New Models for Determining Rates and Making Predictions
Incorporating Rates into Clinical Practice
References
24 Techniques Used for Evaluation of Ocular Blood Flow
Color Doppler Imaging
Pulsatile Ocular Blood Flow Analyzer
Laser Interferometric Measurement of Fundus Pulsation
Fluorescein and Indocyanine Green AngiographyLaser Doppler Velocimetry
Laser Doppler Flowmetry
Scanning Laser Doppler Flowmetry
Laser Speckle Method/Flowgraphy
Retinal Vessel Analyzer
Bidirectional Laser Blood Flowmeter
Blue Field Entoptic Stimulation
Retinal Oximetry
Doppler Optical Coherence Tomography
Dynamic Contour Tonometry and Ocular Pulse Amplitude
Peripheral Blood Flow
Animal Experimental Methods
Limitations of Ocular Blood Flow Assessment Techniques and their Interpretations
References
References
References
25 Genetics of Glaucoma
Introduction
Primary Open-Angle Glaucoma
Genome-Wide Association Studies in POAG
Pigment Dispersion Syndrome and Glaucoma
Exfoliation Syndrome and Glaucoma
Congenital Glaucoma
Developmental Glaucomas
Angle-Closure Glaucoma
References
References
26 Genetic EpidemiologyGenetic Susceptibility to POAG
Linkage Studies
Genetic Association Studies
Future Perspectives
Conclusion
References
References
Electronic-Database Information
References
Section 4 Types of Glaucoma
27 Definitions: What is Glaucoma Worldwide?
Introduction
Terminology
The Significance of Glaucoma Worldwide
The Significance of Glaucoma by Geographic Area
Acknowledgments
References
28 Ocular Hypertension
Introduction
Definition
Prevalence
Patient Assessment
Risk of Progression to Glaucoma
Detecting Progression
Detecting Structural Evidenceof Progression
Detecting Progression on Visual Fields
Treatment
Treatment GoalsFrequency of Follow-up
References
29 Primary Open-Angle Glaucoma
Introduction
Prevalence
Risk Factors
Pathogenesis
Genetics
Diagnosis
Treatment Options and Sequencing of Therapy
Selected Major POAG Clinical Trials
References
30 Primary Angle-Closure Glaucoma
Introduction
Definition and Classification
Prevalence, Incidence, and Geographical Variation
Etiology and Mechanism
Risk Factors
Diagnosis, Differential, and Testing
Clinical Features, Signs, and Symptoms
Treatment Options, Outcomes, and Prognosis
Future Directions
References
References
31 Exfoliation Syndrome and Exfoliative Glaucoma
Introduction
Disease Prevalence and Influence
PrognosisEtiology and Pathogenesis
Diagnosis and Ancillary Testing, and Differential Diagnosis
Treatment Options
References
32 Pigmentary Glaucoma
Introduction
Disease Prevalence
Natural History and Risk Factors
Etiology and Pathogenesis
Signs and Symptoms
Differential Diagnosis
Treatment Options
Treatment Outcome and Prognosis
References
References
33 Normal-Tension Glaucoma
Introduction
Pathogenesis and Systemic Evaluation
Treatment
Treatment Outcomes and Prognosis
References
References
References
34 Childhood Glaucomas
Introduction
Evaluation of Children with Glaucoma
Definition of Glaucoma and Glaucoma Suspect
Classification of Childhood GlaucomasPrimary Congenital Glaucoma
Juvenile Open-Angle Glaucoma
Glaucoma Associated with Non-acquired Ocular Anomalies
Glaucoma Associated with Non-acquired Systemic Disease or Syndrome
Glaucoma Associated with Acquired Condition
Glaucoma Following Cataract Surgery
References
35 Secondary Angle-Closure Glaucoma
Introduction
Anatomy and Pathophysiology
Diagnostic Options
Treatment Options, Outcomes and Prognosis
Management of Specific Conditions
References
36 Uveitic Glaucoma
Introduction
Epidemiology
Etiology and Pathogenesis
Diagnosis and Classification
Clinical Features and Investigation
Management
References
References
37 Neovascular Glaucoma
Introduction
Disease Prevalence and Influence
Risk Factors for Developing Neovascular Glaucoma
Etiology and PathogenesisDiagnosis and Ancillary Testing
Differential Diagnosis
Signs and Symptoms
Stages of Neovascular Glaucoma
Treatment Options
References
38 Other Secondary Glaucomas
Lens-Induced Open-Angle Glaucomas
Glaucomas Associated with Disorders of the Corneal Endothelium
Corticosteroid-Induced Ocular Hypertension and Glaucoma
Elevated Episcleral Venous Pressure
Vitreoretinal and Retinal Disorders
Glaucoma Associated with Retinal Surgery
Epithelial and Fibrous Ingrowth
References
39 Post-Traumatic Glaucoma
Background
Prevalence and Incidence
Blunt Trauma
Mechanisms of Glaucoma Secondary to Blunt Trauma
Penetrating Trauma
References
40 Glaucoma and Intraocular Tumors
Introduction
Etiology/Pathogenesis
Diagnostic Evaluation
Differential Diagnosis: Childhood Glaucoma
Differential Diagnosis: Adult GlaucomaManagement
Prognosis
References
41 Glaucoma in the Phakomatoses and Related Conditions
Introduction
Sturge–Weber Syndrome (Encephalotrigeminal Angiomatosis)
Oculodermal Melanocytosis
Phakomatosis Pigmentovascularis
Neurofibromatosis
References
Section 5 Principles of Management
42 Management of Ocular Hypertension and Primary Open-Angle Glaucoma
Introduction
Ocular Hypertension
Primary Open-Angle Glaucoma
Compliance and Adherence
References
43 Management of Normal-Tension Glaucoma
Natural Course of Normal-Tension Glaucoma
Ocular Hypotensive Therapy with Eye Drops or Laser Trabeculoplasty
Surgical Treatment
Treatment with Systemic Drugs
References
44 An Overview of Angle-Closure Management
Introduction
Reduction of Intraocular Pressure
Reopening and Modifying the Anterior Chamber AngleControlling Intraocular Pressure
Prognosis and Outcome
References
References
References
45 Target Intraocular Pressure
Introduction
Definition
The Rationale for Target IOP
Evidence for Target IOP
Factors Influencing Target IOP
References
References
46 Quality of Life
Introduction
Definition
Why is QOL important?
Assessment of QOL in Glaucoma
Questionnaires
Performance-Based Measures
Utility Measures
Key Findings of Studies on QOL in Glaucoma
Conclusion
References
References
47 Medical Management of Glaucoma: Cost-Effectiveness
Introduction
Medical TherapyPrinciples of Economic Evaluation
Cost-Effectiveness of Medical Therapy for Glaucoma Compared with Alternative
Interventions or No Treatment
References
48 Optimizing Quality of Life: Low-Vision Rehabilitation in Glaucoma
Introduction
Consequences of Low Vision
Contextual Factors: Considerations for Rehabilitation
Low-Vision Services
References
Suggested Reading
Useful Websites
49 Ocular Hypotensive Medications: Adherence and Performance
Problem Statement
Current Therapy
Performance
Health Literacy
Clinical Relevance
Improved Therapeutics
Healthcare Economics
Future Directions
References
50 Outcomes
Introduction and Definition
Outcomes for the Patient
Clinical Outcomes: Physician's View
Outcomes for Society
References51 Benefit Versus Risk
Introduction
Number Needed to Treat (NNT) and Number Needed to be Treated to Harm One
More of Them (NNH)
Using Bayes' Theorem to Estimate Risk
Likelihood of Help versus Harm (LHH)
Relative Risk (RR), Relative Risk Reduction (RRR) and Their Use in Risk Benefit
Assessment
References
Section 6 Medical Therapy
52 Prostaglandin Analogues
Introduction
Drug Formulations
Mechanism of Action
Indications
Efficacy and Comparison With Other Agents
Contraindications
Side Effects
Drug Interactions
References
53 Beta-Blockers
Introduction
Drug Formulations and Dosing
Mechanism of Action
Indications
Intraocular Pressure-Lowering Efficacy
Side Effects and Contraindications
Drug Interactions
References54 Carbonic Anhydrase Inhibitors
Introduction
Drug Formulation: Systemic and Topical Carbonic Anhydrase Inhibitors
Mechanism of Action
Influence of Carbonic Anhydrase Inhibitors on Ocular Blood Flow and Visual
Functions
Indication
Intraocular Pressure-Lowering Efficacy and Dosage in Monotherapy and in
Combined Medication
Contraindications and Systemic Side Effects of the Carbonic Anhydrase Inhibitors
Drug Interactions with the Carbonic Anhydrase Inhibitors
References
55 Alpha Agonists
Introduction
Drug Formulations
Mechanism of Action
Indications
Efficacy and Comparison with Other Agents
Contraindications
Side Effects
Drug Interactions
References
56 Parasympathomimetics
Introduction
Classification
Mechanism of Action
Administration
Drug Interactions and Comparison with Other Agents
Contraindications and PrecautionsSide Effects
References
57 Fixed Combination Therapies in Glaucoma
Introduction
Drug Formulations
References
58 Ocular Surface Disease and the Role of Preservatives in Glaucoma Medications*
Introduction
Classification of Preservatives
Preservatives
Clinical Presentation
Recommendations
References
Section 7 Emergency Care Management
59 Acute Intraocular Pressure Rise
Introduction
Etiology
Acute Primary Angle Closure
Treatment
Practical Approach to Acute Angle Closure
Secondary Acute Intraocular Pressure Rise
Neovascular Glaucoma (NVG)
Aqueous Misdirection Syndrome (Ciliary Block Glaucoma or Malignant Glaucoma)
Posner–Schlossman Syndrome (Glaucomatocyclitic Crisis)
Herpes Simplex Keratouveitis
Drug-Induced Glaucoma
References60 Glaucoma Secondary to Trauma
Introduction
Prevalence and Epidemiology
Risk Factors Leading to Glaucoma in Traumatized Eyes
Pathogenesis of Glaucoma in Traumatized Eyes
Diagnostic Features
Treatment Options
Long-Term Prognosis
References
References
Section 8 New Horizons
61 Neuroprotection and Neurorepair
Introduction
Mechanisms of Retinal Ganglion Cell Death and Neuroprotection
Assessment of Neuroprotective Therapies – Theory
Assessment of Neuroprotective Therapies – Practice
Axoprotection
Neurorepair
References
62 Interpreting Clinical Studies on Glaucoma Neuroprotection
Introduction
Biological Plausibility
Overview of Study Methodology
The Randomized Clinical Trial
Other Types of Studies
Generalizability of Study Results
Special Considerations for Neuroprotection Trials
References63 Stem Cells: A Future Glaucoma Therapy?
Introduction
Objectives for Stem Cell Therapy in Glaucoma
Sources of Stem Cells for Transplantation Therapy
Strategies for Stem Cell Therapy in Glaucoma
Potential Hurdles
Summary
References
References
64 Gene Therapy in Glaucoma
Introduction
Virus Classification
Adenovirus
Adeno-Associated Virus (AAV)
Lentivirus
Modulation of Viral Vector Expression
Downregulation of Gene Expression Using Antisense Oligonucleotides and siRNA
Modulation of Aqueous Outflow
Neuroprotection of Retinal Ganglion Cells
References
65 Ultrastructural Imaging
Introduction
Ultrastructural Imaging with the Scanning Laser Ophthalmoscope
Ultrastructural Imaging with Optical Coherence Tomography
Future Technologies
References
Volume 2 Surgical ManagementSection 9 Introduction
66 Economics of Surgery Worldwide: Developed Countries
Introduction
The Evidence of Treatment Efficacy, Effectiveness and Cost-Effectiveness in
Preventing Visual Disability
Trends in Glaucoma Therapy
Costs and Resource Utilization
Future Steps
References
67 When to Perform Glaucoma Surgery
Introduction
Maximal Medical Therapy
Laser Trabeculoplasty
Current Practice
Stage of Glaucomatous Nerve Damage
Glaucoma Diagnosis
Effects of Medications and Laser on Trabeculectomy Outcome
Visual Outcome of Glaucoma Surgery
Noncompliance
References
68 Economics of Surgery Worldwide: Developing Countries
Introduction
Social and Economic Burden
Low Surgical Uptake
Barriers
Cost Analysis
Cost-Effectiveness of Screening
Sources of Funds for the SurgeryRecommendations
References
69 Lowering Intraocular Pressure: Surgery versus Medications
Introduction
Risk  :  Benefit Ratio
Target Intraocular Pressure
Principles of Management
Pressure Lowering in Medical and Surgical Therapy
Choosing the Appropriate Therapy in the Individual
Quality of Life/Cost Issues
Summary
References
70 The Trabecular Meshwork Outflow Pathways: Surgical Aspects
Introduction
Surgical Approaches to the Trabecular Meshwork Outflow Pathways
Acknowledgment
References
Section 10 Laser Therapy
71 Selective Laser Trabeculoplasty
Introduction
Mechanisms of Action
Selective Laser Trabeculoplasty Following and in Comparison to Argon Laser
Trabeculoplasty
Prediction of IOP Lowering
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential ModificationsPostoperative Management and Interventions
Outcomes
Complications
Other Considerations
References
References
References
References
References
72 Peripheral Iridotomy for Angle-Closure Glaucoma
Introduction
Indications for Laser Peripheral Iridotomy
Contraindications for Laser Peripheral Iridotomy
Techniques of Laser Peripheral Iridotomy
Outcomes of Laser Peripheral Iridotomy
Complications of Laser Peripheral Iridotomy
References
73 Laser Peripheral Iridoplasty
Introduction
Laser Gonioplasty
Indications
Contraindications
Surgical Technique
Postoperative Management
Complications
References
Section 11 Trabeculectomy
74 Preoperative Evaluation and Diagnostic Approach74 Preoperative Evaluation and Diagnostic Approach
Past Medical History
Clinical Examination
Technical Examinations
Choice of Technique
Timing of Surgery
Informed Consent
References
75 Preoperative Conjunctival Health and Trabeculectomy Outcome
Introduction
The Normal Conjunctiva and Wound Healing Response
The ‘Activated’ Conjunctiva
Previous Topical Glaucoma Therapy
Previous Ocular Surgery
Secondary Glaucoma
Ethnicity
Youth
Discriminating Patients at Risk of Trabeculectomy Failure
Reducing the Risk of Trabeculectomy Failure
References
76 Ophthalmic Anesthesia
Introduction
Preoperative Assessment
Sedation
General Anesthesia
Topical Anesthesia
Intracameral Anesthesia
Regional Anesthesia
Facial Nerve BlocksOcular Physiology Relevant to Anesthesia
References
77 Trabeculectomy
Introduction
Alternatives and Indications
Preoperative Considerations
Operative Technique
Postoperative Care
Outcomes and Comparisons
Complications
Reference
References
References
78 Tenon's Cyst Formation, Wound Healing, and Bleb Evaluation
Tenon's Cyst Formation and Management
Wound Healing and Bleb Evaluation after Trabeculectomy
79 Intraoperative Complications of Trabeculectomy
Introduction
Prevalence and Risk Factors
Anticoagulant Therapy-Related Complications
Surgery on the Wrong Eye/Wrong Patient
Anesthesia-Related
Traction Suture
Conjunctival Buttonhole/Tear
Mitomycin Sponge Application
Scleral Flap Dissection
Sclerostomy
Corneal InjuryIridectomy Related
Hyphema
Lens Injury
Vitreous Loss
Choroidal Effusions and Hemorrhage
References
80 Early Postoperative Increase in Intraocular Pressure
Introduction
Pressure Increase Associated with a Deep Anterior Chamber
Pressure Increase Associated with a Flat or Shallow Anterior Chamber
References
81 Shallow Anterior Chamber
Introduction
Prevalence and Risk Factors
Etiology
Preventive Measures
Management
Prognosis
References
82 Choroidal Effusion
Introduction
Causes of Choroidal Detachment
Clinical Presentation and Diagnosis
Pathophysiology of Choroidal Detachment
Incidence of Choroidal Effusion and Hemorrhage
Risk Factors for Choroidal Effusion and Hemorrhage
Prevention
ManagementChoroidal Drainage
Operative Technique
Prognosis
References
83 Trabeculectomy-Related Corneal Complications
Introduction
Post-Trabeculectomy Corneal Epitheliopathy and Endotheliopathy
Corneal Topographic Changes and Corneal Astigmatism after Trabeculectomy
Dissecting Bleb
Detachment/Stripping of the Descemet's Membrane
Corneal Complications Related to Releasable Sutures Techniques
Dellen Formation
Trabeculectomy-Related Complications after Refractive Surgery
Corneal Graft Rejection after Trabeculectomy
Trabeculectomy-Related Complications with Descemet's Stripping Automated
Endothelial Keratoplasty
Corneal Complications Related to the Use of Anti-VEGF with Trabeculectomy
Corneal Blood Staining
References
84 Aqueous Misdirection
Introduction
Prevalence and Risk Factors
Prevention
Etiology/Pathophysiology of Aqueous Misdirection
Management Options
Prognosis
References
85 Late Failure of Filtering BlebIntroduction and Definition
Prevalence and Risk Factors
Etiology and Pathophysiology
Preventive Measures
Management Options
Prognosis
References
86 Late Bleb Leaks
Significance
Incidence
Diagnosis
Management
Prevention of Late Bleb Leaks
References
87 Blebitis and Endophthalmitis
History and Introduction
Definitions
Clinical Features
Mechanism and Pathogenesis
Incidence
Microbiology
Natural History and Visual Outcome
Risk Factors
Management
Bleb-Related Endophthalmitis
References
88 Late Hypotony
Introduction and DefinitionIncidence Rate and Risk Factors
Clinical Findings
Etiology and Pathophysiology of Complications
Preventative Measures
Management Options
Prognosis
References
89 Cataract Following Trabeculectomy
Introduction and Definition
Occurrence and Risk Factors
Pathophysiology
Preventative Measures
Management Options
Prognosis
References
Section 12 Modulation of Wound Healing
90 Risk Factors for Excess Wound Healing
Introduction
High-Risk Cases for Failure of Glaucoma Filtering Surgery
Primary Glaucoma Filtering Surgery
Combined Glaucoma and Cataract Surgery
Revision of Failed Filters
Bleb Modulation in Glaucoma Drainage Implant Surgery
References
91 Modulation of Wound Healing: Choice of Antifibrosis Therapies
Introduction
5-FluorouracilMitomycin C
Comparison Between 5-FU and MMC
Other Drugs and Strategies
Indications and Choice of Antimetabolites
Special Cases
References
92 Technique
Introduction
Preoperative Considerations
Operative Techniques
Postoperative Consideration
Bleb Needling Procedures
Technique for Bleb Needling
References
93 Complications Associated with Modulation of Wound Healing in Glaucoma Surgery
Introduction
Histopathology of Episcleral Fibrosis
Corticosteroid Use
Intraoperative Complications
Bleb Failure
5-Fluorouracil-Induced Keratopathy
Bleb Leaks
Early Wound Leaks
Nonsurgical Techniques
Persistent Limbal Bleb Leaks
Delayed Bleb Leaks
Conjunctival Advancement
Choroidal EffusionHypotony
Bleb Dysesthesia
Blebitis and Endophthalmitis
Alternative Glaucoma Surgeries
References
94 Biological Drivers of Postoperative Scarring
Introduction
Growth Factors
Matrix Metalloproteinases and their Inhibitors
Reduction of Scarring
References
95 Future Strategies
Introduction
New Surgical Techniques, Including Surgical Biomaterials
Anti-inflammatory Agents
Growth Factor Modulators and Acute-Phase Proteins
Serum Amyloid P
Antiangiogenesis
Antiproliferative Agents
Modulators of Cell Motility, Matrix Contraction, and Synthesis
Improved Drug Delivery and Combinations
Acknowledgments
References
Section 13 Nonpenetrating Glaucoma Surgery
96 Principle and Mechanism of Function
Introduction
NomenclatureFunctional Anatomy of Aqueous Outflow
Physiology of Aqueous Outflow and Localization of Resistance
Functional Anatomy of Nonpenetrating Glaucoma Surgery
Pathways of Aqueous Drainage in NPGS
Aqueous Pathway Beyond the Scleral Lake
References
97 Deep Sclerectomy
Introduction
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Interventions
Outcomes and Comparison with other Filtering Techniques
Complications and How to Avoid Them
References
References
References
References
References
References
98 Viscocanalostomy
Introduction
Mechanism of Action
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential ModificationsPostoperative Management and Interventions
Outcomes and Comparison with Other Techniques
Retrospective Studies
Prospective Studies
Randomized, Controlled Studies
Complications and How to Avoid Them
Specific to Technique
References
99 Complications of Nonpenetrating Glaucoma Surgery
Introduction
Intraoperative Complications
Postoperative Complications
References
100 Postoperative Management of Nonpenetrating Glaucoma Surgery
Introduction
Assessment Parameters and Regimen
Postoperative Medication
Instructions to the Patient
Special Considerations
References
101 Results of Nonpenetrating Glaucoma Surgery
Introduction
Outcomes of Long-Term Studies
Comparisons Between Nonpenetrating Glaucoma Surgery and Trabeculectomy
Combined Nonpenetrating Glaucoma Surgery and Cataract Surgery
Nonpenetrating Glaucoma Surgery in Pseudoexfoliation-Associated Glaucoma
Nonpenetrating Glaucoma Surgery in Other Conditions
Cost-EffectivenessSummary
References
References
Section 14 Management of Co-Existing Cataract and Glaucoma
102 Cataract Surgery in Open-Angle Glaucoma
Introduction
Preoperative Assessment
Anesthesia
Surgical Techniques
Cataract Surgery and the Effect on Intraocular Pressure
Cataract Surgery after Filtration or Tube Surgery
References
103 The Role of Lens Extraction in Primary Angle-Closure Glaucoma
Introduction
Principles of Treatment in PACG
Biometry of PACG Eyes
Effects of Cataract Extraction on Anterior Chamber Anatomy and Intraocular
Pressure
PACG with Co-existing Cataract
PACG without Cataract
Role of Lens Extraction in APAC
Lens Extraction in Combination with Other Glaucoma Interventions
Technical Challenges of Lens Extraction in PACG
References
104 Cataract Surgery in Patients with Functioning Filtering Blebs
The Problem of Cataract Formation after Glaucoma Surgery
The Influence of Various Glaucoma Procedures on Cataract Formation
The Influence of Various Techniques of Cataract Extraction on the Survival ofFiltering Blebs
Intraocular Pressure Control after Cataract Surgery in Eyes with Previous
Glaucoma Surgery
Intraocular Pressure after Cataract Surgery Following Drainage Devices
The Pathogenesis of Cataract Formation after Filtering Procedures
Reasons for Filtering Bleb Failure after Cataract Surgery in Previously Filtered
Eyes
References
105 One-site Combined Surgery/Two-site Combined Surgery
Introduction
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Interventions
Outcomes and Comparisons with Other Techniques
Complications and How to Avoid Them
References
106 Combined Cataract Extraction and Glaucoma Drainage Implant Surgery
Introduction
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques
Outcomes and Comparison with Other Techniques
Complications
References
107 Combined Cataract and Nonpenetrating Glaucoma Surgery
IntroductionIndications
Preoperative Considerations
Anesthetic Considerations
Operative Technique and Potential Modifications
Postoperative Management and Interventions
Outcomes and Comparisons with Other Techniques
Avoiding Complications
References
108 Goniosynechialysis
Introduction
Indications
Contraindications
Preoperative Evaluation and Treatment
Surgical Technique
Procedure
Complications
Postoperative Management
Conclusion
References
Section 15 Drainage Devices
109 Preoperative Evaluation of Patients Undergoing Drainage Implant Surgery
Introduction
Etiology of the Glaucoma
Anatomy of the Eye and Orbit
Age and Ethnicity of the Patient
Pre-Existing Conjunctival Abnormalities
Choice of Implant
References110 Aqueous Shunts: Choice of Implant
Introduction
Shunt-Related Factors
Patient and Ocular Factors
References
111 Surgical Technique 1 (Molteno Glaucoma Implant)
Introduction
Historical Background
Indications
Preoperative Considerations
Anesthetic Considerations
The Molteno Implants
Operative Techniques and Modifications
Postoperative Management and Interventions
Complications and How to Avoid Them
Late Complications
References
112 Surgical Technique 2 (Baerveldt Glaucoma Implant)
Introduction
Indications for Use
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Interventions
Outcomes and Comparison with Other Techniques
Complications and How to Avoid Them
References
113 Surgical Technique 3 (Ahmed Glaucoma Valve Drainage Implant)Introduction
Device
Indications
Contraindications
Surgical Technique
Outcomes
Complications
Comparison with Other Techniques
References
114 Other Glaucoma Implants
Introduction
OptiMed Implant
Schocket Implant
Susanna Glaucoma Implant
Surgical Technique and Pearls of Surgical Management
References
115 Intraoperative Complications
Introduction
Description of Complications and Management
References
116 Postoperative Complications
Introduction
Intraocular Complications: Pressure-Related
Intraocular Complications: Mechanical
Intraocular Complications: Nonmechanical
External Complications
Exposure/Extrusion of Tube or Plate
References117 Glaucoma Implants: Results
Introduction
Historical Background
Recent Advances
Effect of Filtration Area
Effect of Adjunctive Antimetabolites
Effect of Biomaterial
Tube Insertion and Patching
Delayed Filtration versus Immediate Filtration
References
References
118 Aqueous Shunts after Retinal Surgery
Introduction
Preoperative Assessment
Operative Techniques and Implant Position
Implant Modifications
Postoperative Management
Outcomes
Comparison with Other Techniques
Complications
References
119 Aqueous Shunts and Keratoplasty
Introduction
Indications
Sequence of Maneuvers During Simultaneous Penetrating Keratoplasty and Shunt
Placement
Postoperative Management Considerations
Tube Shunts and Descemet's Stripping Endothelial Keratoplasty (DSEK)
Outcomes and Comparisons to Other TechniquesComplications
References
References
Section 16 Surgery for Congenital Glaucoma
120 Goniotomy and Trabeculotomy
Introduction
Indications
Preoperative Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Interventions
Outcomes and Comparison With Other Techniques
Complications and How to Avoid Them
Acknowledgments
References
121 Further Surgical Options in Children
Introduction and Indications
Anesthetic Considerations and the Exam Under Anesthesia
Filtering Surgery
Early Experience
Combined Trabeculotomy–Trabeculectomy
Antimetabolites
Glaucoma Drainage Implants
Nonvalved Implants (Table 121-3)
Valved Implants (Table 121-4)
Cyclodestructive Procedures (Table 121-5)
References
Section 17 Cyclodestructive Procedures122 Cyclodestructive Techniques
Mechanism of Action
Indications
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Interventions
Retreatment and Further Postoperative Care
Outcomes and Comparisons of TSCP with Other Techniques
Complications and How to Avoid Them
References
References
References
References
References
123 Endophotocoagulation
Introduction
Techniques
How to Photocoagulate a Ciliary Process
Indications
Combined Phaco/ECP Versus Phaco Alone for Patients with Glaucoma
Undergoing Cataract Surgery
Disclaimer
References
References
124 Complications of Cyclodestructive Procedures
Introduction
Complications of Transscleral Diode Laser Cyclophotocoagulation
Endoscopic Diode Laser CyclophotocoagulationConclusion
References
References
References
Section 18 Devices in Development and New Procedures
125 Trabectome™
Introduction
Surgical Steps
Complications
Patient Selection
Outcomes
References
126 The Ex-PRESS™ Miniature Glaucoma Implant
Introduction
Indications and Contraindications for Minimally Penetrating Glaucoma Surgery with
the Ex-PRESS™ Implant
Preoperative Considerations
Anesthetic Considerations
Operative Techniques and Potential Modifications
Postoperative Management and Reinterventions
Outcomes and Comparison with other Techniques
Complications and How to Avoid Them
References
127 Canaloplasty
Introduction
Indications and Contraindications
Preoperative Considerations
Anesthetic ConsiderationsOperative Techniques and Potential Modifications
Postoperative Management and Reinterventions
Outcomes and Comparison with Other Techniques
Complications and How to Avoid Them
References
128 New Glaucoma Surgical Alternatives
Introduction
Terminology
Classification
I Subconjunctival Filtration Strategy
II Enhanced Filtration into Schlemm's Canal Strategy
III Suprachoroidal Filtration
Miniaturized High-Intensity Focused Ultrasound Device (HIFU)
References
References
IndexC o p y r i g h t
© 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
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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
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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 2Video Table of Contents
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
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
77-3 Trabeculectomy Closure
DAVINDER S GROVER and RONALD L FELLMAN
77-4 Video spotlight: Creating a Limbal-based Conjunctival Flap
MICHAEL A COOTE
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
86. Late Bleb Leaks86-1 Video spotlight: Needling
TAREK M SHAARAWY
88. Late Hypotony
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
100. Postoperative Management of Nonpenetrating Glaucoma Surgery
100-1 Goniopuncture and Complications
TAREK M SHAARAWY
101. Results of Nonpenetrating Glaucoma Surgery
101-1 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 Video spotlight: Combined Ahmed Valve and Phacoemulsification
OSCAR ALBIS-DONADO and RICARDO DE LIMA
107. Combined Cataract and Nonpenetrating Glaucoma Surgery
107-1 Combined Phacoemulsification Nonpenetrating Glaucoma Surgery
GEMA REBOLLEDA, FRANCISCO J MUÑOZ-NEGRETE, and JAVIER
MORENOMONTAÑES
111. Surgical Technique 1 (Molteno Glaucoma Implant)
111-1 Surgical Technique for the Molteno Glaucoma Implant
ANTHONY CB MOLTENO112. 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
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
116-3 Video spotlight: Removal of Ahmed Drainage Implant Plate
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 Goniotomy
PENG TEE KHAW
120-2 Video spotlight: Classical Trabeculotomy
FRANZ GREHN
120-3 Video spotlight: 360° Trabeculotomy Using an Illuminated Catheter
FRANZ GREHN
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 BERKE125. 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
128-4 Xen Implant Surgical Technique
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
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 eld, have
demonstrated their competence by choosing some of the best people to write the
chapters for both volumes. This rst 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 di%erent genes can lead to the same phenotype while in other cases
variants in the same gene may lead to di%erent 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 di%erences in the disease and of the economic imperatives
which a%ect many aspects of the disease. The philosophy of screening, the
pathogenesis of the diseases, the role of the vascular factors, the de nition 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 a%ects the disease. If we channeled a fraction of our e%ort and resources
9

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 rst 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 di cult 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 nd progression which is so slow as not to endanger their visual
competence in their predicted life span probably require a di%erent 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

(


P r e f a c e
The rst 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,
evidencebased 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.
As skill transfer becomes more accessible with the convenience of the Internet, a
signi cant update of the book's video content was particularly important to our
readers. We are con dent that doubling the number of video clips in the second
edition will be valuable.
As with the rst edition, our e orts 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 CrowstonList 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
Oscar Albis-Donado MD
Glaucoma Assistant Professor, Instituto Mexicano de Oftalmología, Queretaro,
Mexico
Ch 117 Glaucoma Implants: Results
Video spotlight 106-1 Combined Ahmed Valve and Phacoemulsification
Luciana M Alencar MD PhD
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, IndianaUniversity Medical Center, Indianapolis, IN, USA
Ch 24 Spotlight: Value of Blood Flow in Studies
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
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
Ehud I Assia MD
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)
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 ChinaCh 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
Rajendra K Bansal MD
Associate Clinical Professor of Ophthalmology, Department of Ophthalmology,
Columbia University Medical Center, New York, NY, USA
Ch 79 Intraoperative Complications of Trabeculectomy
Mirko Babic
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,
QuinzeVingts National Ophthalmology Hospital, Paris; University of Versailles
SaintQuentin-en-Yvelines, Versailles; Institut de la Vision, Paris, France
Ch 91 Modulation of Wound Healing: Choice of Antifibrosis Therapies
Allen Beck MD
Professor, Department of Ophthalmology, Emory University, Atlanta, GA, USA
Ch 34 Childhood Glaucomas
Sonya L Bennett MBChB FRANZCOConsultant 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, 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
Tui H Bevin MPH
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,
Centerbased Visual Field Assessment Center, UC San Diego Shiley Eye Center, La Jolla, CA,
USA
Ch 20 Optic Disc Imaging
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
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
Catey Bunce BSc(Hons) MSc DSc
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
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-effectivenessYvonne 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
Yara Paula Catoira-Boyle MD
Associate Clinical Professor of Ophthalmology, Eugene and Marilyn Glick Eye
Institute, Indiana University School of Medicine, Indianapolis, IN, USA
Ch 116 Postoperative Complications
Piero Ceruti MD
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
Raka Chakrabarti MS
Consultant Ophthalmologist, Susrut Eye Foundation and Research Centre, Salt Lake,
Kolkata, India
Ch 81 Postoperative Shallow Anterior Chamber
Pratap Challa MDAssociate Professor of Ophthalmology, Director, Residency Training Program, Duke
University, Durham, NC, USA
Ch 80 Early Postoperative Increase in Intraocular Pressure
Errol Chan MBBS MMed FRCOphth
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
Etsuo Chihara MD
Director, Sensho-kai Eye Institute, Kyoto, Japan
Ch 119 Spotlight: Endothelial Cell Count Post-Drainage Implant Surgery
Neil T Choplin MDAdjunct 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
George A Cioffi MD
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
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 MDJohn 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
Karim F Damji MD FRCSC MBA
Professor, Department of Ophthalmology, University of Alberta, Edmonton, AB,
Canada
Ch 71 Selective Laser Trabeculoplasty
Alexander Day PhD MRCOphthNIHR 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 Patient-Centred 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
Benedetto Falsini MD
Adjunct Investigator, Ophthalmic Genetics and Visual Function Branch, National Eye
Institute, Bethesda, MD, USA
Ch 24 Spotlight: Practicalities
The late, Francisco Fantes MD
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 GlaucomaSurgery
Herbert P Fechter III, MD PE
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
Robert D Fechtner MD
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
Ann Caroline Fisher MD
Clinical Assistant Professor, Department of Ophthalmology, Byers Eye Institute,
Stanford University School of Medicine, Stanford, CA, USA
Ch 92 Technique
Frederick W Fitzke PhD
Professor of Visual Optics and Psychophysics, Division of Visual Science, UCL
Institute of Ophthalmology, University College London, London, UK
Ch 65 Ultrastructural Imaging
Brad Fortune OD PhD
Associate Scientist and Director, Electrodiagnostics Service, Discoveries in Sight
Research Laboratories, Devers Eye Institute, Legacy Health, Portland, OR, USA
Ch 14 Electrophysiology in Glaucoma AssessmentPaul Foster PhD FRCS(Ed) FRCOphth
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
Panayiota Founti MD PhD
Ophthalmologist, Undergraduate Teaching Fellow, Moorfields Eye Hospital, London,
UK
Ch 46 Quality of Life
Jeffrey Freedman MB BCh PhD FRCS(Edin) FCS(SA)
Professor of Clinical Ophthalmology, Department of Ophthalmology, SUNY, New
York, NY, USA
Ch 109 Preoperative Evaluation of Patients Undergoing Drainage Implant Surgery
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
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
Steven J Gedde MD
Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami
School of Medicine, Miami, FL, USACh 84 Aqueous Misdirection
Ch 117 Spotlight: TVT Study
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
Assistant Professor, Department of Ophthalmology, Emory University, Atlanta, GA,
USA
Ch 34 Childhood Glaucomas
Katie Gill BSc MSc
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
Zisis Gkatzioufas MD PhD
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 AssessmentAlana 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
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
Head, Glaucoma Service, Hospital Oftalmológico Santa Lucía, Assistant Professor of
Ophthalmology, Universidad del Salvador, Buenos Aires, Argentina
Ch 101 Results of Nonpenetrating Glaucoma Surgery
Ronald L Gross MD
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
Davinder S Grover MD MPH
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,
USACh 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
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
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
Marcelo Hatanaka MD
Head of Glaucoma Service, Department of Ophthalmology, University of São Paulo
Medical School, São Paulo, Brazil
Ch 114 Other Glaucoma Implants
Matthew J Hawker DM FRCOphth
Consultant Ophthalmologist, Department of Ophthalmology, Cambridge University
Hospital, Cambridge, UKCh 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
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
Roger A Hitchings FRCS FRCOphth
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
Gábor Holló MD PhD DSc
Professor of Ophthalmology, Department of Ophthalmology, Semmelweis University,
Budapest, Hungary
Ch 54 Carbonic Anhydrase Inhibitors
Ann M Hoste MD
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, USACh 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
Camille Hylton MD
Glaucoma Specialist, Ophthalmic Physicians and Surgeons Ltd, Phoenix, AZ, USA
Ch 34 Childhood Glaucomas
Sabita M Ittoop MD
Attending, Glaucoma Consultants of Washington, Herndon, VA, USA
Ch 58 Ocular Surface Disease and the Role of Preservatives in Glaucoma Medications
Farrah Ja'afar 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 and Chairman, Ophthalmology and Visual Sciences, Department of
Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis,
MO, USA
Ch 28 Ocular HypertensionAndreas Katsanos MD PhD
Assistant Professor, University Department of Ophthalmology, Ioannina, Greece
Ch 57 Fixed Combination Therapies in Glaucoma
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
Jill E Keeffe PhD
Professor, L V Prasad Eye Institute, Hyderabad, India
Ch 48 Optimizing Quality of Life: Low-vision Rehabilitation in Glaucoma
Thomas Kersey MD
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
Danny Kim MD
Ophthalmologist, Facey Medical Group, Mission Hills, CA, USA
Ch 37 Neovascular GlaucomaYoshiaki Kiuchi MD PhD
Professor and Chairman, Hiroshima University, Department of Ophthalmology and
Visual Science, Hiroshima, Japan
Ch 33 Spotlight: Japanese Perspective
Thomas Klink MD PhD
Senior Consultant, Department of Ophthalmology, University Hospitals Würzburg,
Würzburg, Germany
Ch 104 Cataract Surgery in Patients with Functioning Filtering Blebs
Helen Koenigsman MD
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 SurgeryDennis 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
Ecosse L Lamourex PhD
Associate Professor, Centre for Eye Research Australia, University of Melbourne,
Melbourne, VIC, Australia
Ch 46 Spotlight: Evaluation of Quality of Life
Graham Lee MD MBBS(Qld) FRANZCO
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,
GuyBernier 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
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 withoutLigation
Video spotlight 116-2 Blocked Tube and AhmedExtender
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, JapanCh 25 Spotlight: Japanese Perspective
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 LeaksSteven H McKinley MD
Private Practice, Eye Institute of Austin, Austin, TX, USA
Ch 115 Intraoperative Complications
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, FRCSEdConsultant Ophthalmologist, Birmingham Heartlands Hospital, Birmingham, UK
Ch 122 Cyclodestructive Techniques
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, USACh 49 Ocular Hypotensive Medications: Adherence and Performance
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, AustraliaCh 63 Spotlight: Brain Perspective
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 PhDProfessor 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
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 ofOphthalmology, Professor of Bioengineering, Swanson School of Engineering
University of Pittsburgh, PA, USA
Ch 124 Complications of Cyclodestructive Procedures
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 C0 Laser-Assisted Sclerectomy Surgery2
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, UKCh 87 Blebitis and Endophthalmitis
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
Sergio Estrela Silva MD
Glaucoma Consultant, Department of Ophthalmology, Hospital São João, Porto,
Portugal
Ch 97 Spotlight: Implants in Deep Sclerectomy
Annapurna Singh 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,
SingaporeCh 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
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
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?
Remo Susanna Jr., MD
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 MDProfessor 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
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 MDExecutive Director, Lions Aravind Institute of Community Ophthalmology, Tamil
Nadu, India
Ch 4 Practical Application of Glaucoma Care in Different Societies
John Thygesen MD
Associate Professor and Director, Glaucoma Services in Copenhagen, Copenhagen
University Hospital, Department of Ophthalmology, Glostrup, Copenhagen,
Denmark
Ch 88 Late Hypotony
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 CountriesNicola Ungaro MD
Director of the Glaucoma Clinic, University Eye Clinic, University of Parma, Parma,
Italy
Ch 32 Pigmentary Glaucoma
Luke Vale MD
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
Leonieke ME van Koolwijk MD
Ophthalmologist, Glaucoma Service, Rotterdam Eye Hospital; Department of
Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
Ch 26 Genetic Epidemiology
Reena S Vaswani MD
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
Rengaraj Venkatesh MD
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
Director, Smt Jadhavabai Nathmal Singhvee Glaucoma Services, Chennai, Tamil
Nadu, India
Ch 4 Spotlight: Glaucoma Care in South Asia
Ananth C Viswanathan BSc MD PhD
Consultant Surgeon (Glaucoma), Moorfields Eye Hospital, NHS Foundation Trust and
UCL Institute of Ophthalmology, London, UKCh 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
Irini C Voudouragkaki MD
Fellow, Glaucoma Unit, 1st University Department of Ophthalmology, AHEPA
Hospital, Thessaloniki, Greece
Ch 57 Fixed Combination Therapies in Glaucoma
Michael Waisbourd MD
Research Manager, Wills Eye Hospital, Glaucoma Research Center, Philadelphia, PA,
USA
Ch 27 Definitions: What is Glaucoma Worldwide?
Ch 71 Spotlight: Selective Laser Trabeculoplasty
Mark J Walland MB BS FRANZCO FRACS
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
Regional Director for Africa, Operation Eyesight Universal, Accra, Ghana
Ch 68 Economics of Surgery Worldwide: Developing Countries
Jacob Wilensky MD
Professor of Ophthalmology, Glaucoma Service, Director, Glaucoma Fellowship
Program, llinois Eye and Ear Infirmary, Chicago, IL, USA
Ch 86 Late Bleb LeaksTina T Wong BSc MBBS FRCOphth FRCS(Ed) PhD
Consultant Ophthalmologist, Glaucoma Service, Singapore National Eye Centre
(SNEC); Clinician-Scientist and Head, Ocular Drug Delivery Research Group,
Singapore Eye Research Institute (SERI), Singapore
Ch 78 Tenon's Cyst Formation, Wound Healing, and Bleb Evaluation
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
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)



A c k n o w l e d g e m e n t s
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 elds 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
rst edition. A book on glaucoma cannot ask for a better preface or aspire to have a
more distinguished writer.
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 sta 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 nd a friend,
a companion and a trustworthy ally in your professional life.
Contributor Locations
Glaucoma is a collaborative e ort drawing on the expertise of 3 2 1 contributors in 3 3
countries across 6 continents.D e d i c a t i o n
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 JonathanThe Editors
Tarek M Shaarawy
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 A Hitchings 3
Roger Hitchings is an Honorary Consultant Ophthalmologist at Moor2elds Eye
Hospital, London and Professor Emeritus in Glaucoma and Allied Studies at the
University of London. He was Director of Research and Development at Moor2elds
Eye Hospital. As a glaucoma specialist he has a special interest in optic nerve
imaging, visual 2eld progression, glaucoma surgery and normal tension glaucoma.
He has also carried out research into the e ect 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 peer-reviewed papers on glaucoma. Roger
Hitchings developed the glaucoma department at Moor2elds 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
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 Moor2elds Eye Hospital and completed glaucoma fellowships at Moor2elds EyeHospital, 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
Jonathan G Crowston is a clinician-scientist 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 Moor2elds 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 2rst
Professor of Glaucoma in Australia. His research interests include the impact of
ageing on optic nerve vulnerability to injury and neuroprotection.V O L U M E 1
Medical Diagnosis & Therapy
OUTLINE
Section 1 Glaucoma in the World
Section 2 Pathogenesis
Section 3 Evaluation of Glaucoma
Section 4 Types of Glaucoma
Section 5 Principles of Management
Section 6 Medical Therapy
Section 7 Emergency Care Management
Section 8 New HorizonsS E C T I O N 1
Glaucoma in the World
OUTLINE
1 Prevalence and Geographical Variations
2 Screening for Glaucoma
3 Economics of Glaucoma Care
4 Practical Application of Glaucoma Care in Different Societies


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1
Prevalence and Geographical
Variations
Winnie Nolan, 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 de nitions 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
1Glaucoma is the commonest cause of irreversible blindness worldwide. 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 de nition of glaucoma across the di0erent surveys. The increasing use
of the International Society of Geographical and Epidemiological Ophthalmology
2(ISGEO) de nition of glaucoma (Table 1-1) means it is now possible to obtain aglobal picture of the numbers of individuals a0ected by glaucoma. It also allows
comparison of glaucoma prevalence and types in di0erent regions, so highlighting
populations and subgroups at increased risk of the disease.
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
O r
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




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2
Screening for Glaucoma
Paul R Healey
Summary
The detection (or risk classi cation) of disease in individuals without symptoms is
known as disease screening. It is most e ective for serious, incurable but
preventable diseases which have long pre-symptomatic phases, such as glaucoma.
From the perspective of screening, early diagnosis is simply a diagnosis earlier
than would have occurred based on symptoms. Lead time, delay time, sojourn
time and number needed to screen are key concepts in screening. The broad
implementation of accurate, cost-e ective glaucoma screening strategies may
have the single biggest impact on the prevention of blindness and disability from
glaucoma.
Introduction
The basis for healthcare in most countries is for individuals to seek care for
symptomatic conditions. This approach has a number of requirements:
▪ Individuals must know what symptoms require health assessment and when to seek
it.
▪ Individuals must be able to access healthcare assessment and treatment.
▪ The healthcare system must be able to diagnose disease and/or treat the symptoms
satisfactorily.
No society can satisfy all factors for every member. The e ectiveness of a
symptom-based healthcare system is dependent on the outcome of the disease and its
treatment, at both individual and societal levels. For certain highly prevalent or
contagious diseases with signi cant morbidity or cost, primary prevention in the





form of treatment of all (including una ected) individuals is practiced. Primary
prevention includes vaccination against infectious diseases, water ) uoridation to
prevent dental caries, and food supplementation (e.g. iodine) to prevent diseases of
nutrient deficiency.
In contrast to primary prevention, secondary prevention aims to improve
outcomes of prevalent disease by its earlier detection and treatment. It is most
e ective for serious, incurable but preventable diseases which have long
presymptomatic phases. The detection of disease in individuals without symptoms is
known as disease screening. Successful screening shortens the time between onset of
disease and diagnosis. It can occur at an individual level within a doctor–patient
relationship or at a public health level as part of a de ned program to improve
health outcomes.
Disease screening is usually considered within the context of the detection and
treatment of a disease or disability within the entire healthcare system. Test accuracy
and cost constrain the screening population and type of screening tests used.
However the costs of treating and following positive screenees must also be
considered. For some screening programs, the aim of the screening test is not to
diagnose disease but to provide a smaller population enriched with disease that
requires further testing to make a de nitive diagnosis. This includes screening tests
for breast and prostate cancer. For other conditions, such as systemic or ocular
hypertension, the screening test may be definitive.
For public health screening to be e ective there must be a way of implementing
the screening program in the group of interest. The terms ‘mass screening’ or
‘community-based screening’ are usually used to refer to a public health program
where a group of at-risk individuals is targeted for screening. It is usually expensive,
as the target group needs to be contacted and a healthcare service episode created
specifically for the screening test.
In contrast, ‘opportunistic screening’ or ‘case detection’ o ers screening to those
who are already attending the health service for other reasons. As such, direct
program-to-target population contact is not required and the cost of screening is
marginal to the pre-existing healthcare episode.
Some screening guidelines have suggested opportunistic screening should be
considered when evidence is poor or lacking for the utility of a mass screening
1program. In this sense, it is used to justify clinical activity in the absence of good
evidence. In reality, opportunistic screening can provide the same service as mass
screening, but only to that proportion of the target population who attend the health
service intercurrently. Therefore, as a screening methodology, its e3 cacy is
dependent on the proportion of the target population that could be reached.
Criteria for Screening


The question of whether screening is worthwhile is complex. Forty years ago, Wilson
2and Junger proposed six prerequisites for screening (Box 2-1).
Box 2-1
Wilson and Junger's Prerequisites for Disease Screening
The condition sought should be an important health problem.
There must be an accepted and e ective treatment for patients with the disease
that must be more e ective at preventing morbidity when initiated in the early,
asymptomatic stage than when begun in the later, symptomatic stages.
Facilities for diagnosis and treatment should be available.
There must be an appropriate, acceptable, and reasonably accurate screening
test.
The natural history of the condition, including development from latent to
manifest disease, should be adequately understood.
The cost of case- nding (including diagnosis and treatment of patients
diagnosed) should be economically balanced in relation to possible expenditure on
medical care as a whole.
If glaucoma is assessed against these criteria, it has a number of features which
make it a good candidate for screening.
1. The condition sought should be an important health problem.
Epidemiologic studies have shown glaucoma to be an important public health
problem. Projections from these studies estimate that 79.6 million people will be
affected by open-angle and angle-closure glaucoma in 2020. Bilateral glaucoma
3blindness will affect 11.2 million people by 2020. Visual loss from glaucoma can
not be reversed.
2. There must be an accepted and effective treatment for patients with the
disease that must be more effective at preventing morbidity when initiated
in the early, asymptomatic stage than when begun in the later,
symptomatic stages.
Glaucoma is irreversible but pre-symptomatic throughout much of its course. A
severe symptomatic stage of glaucoma usually occurs when visual acuity decreases
at the end stage of the disease. Lowering intraocular pressure (IOP) with
medicines, laser, or surgery is an accepted and effective treatment for glaucoma.
4 5–7A number of studies have suggested that the onset and progression of
openangle glaucoma are delayed by these methods. Earlier disease state at
5commencement of treatment also appears to reduce the risk of progression.
3. Facilities for diagnosis and treatment should be available.
Almost all nations have resident or visiting medically trained ophthalmologists. Insome countries, optometrists also provide primary eye care. The geographic
density of diagnostic and treatment facilities for eye disease varies greatly, usually
in proportion to GDP and health spending as a whole. Access to health services
also varies greatly between and within countries, related to geographic, cultural,
3and financial factors. Estimates of glaucoma prevalence by geographic region
suggest regions where resources are more modest such as China (with 22 million
cases), India (16 million) and Africa (8 million), will comprise more than half of
all glaucoma cases worldwide by 2020.
4. There must be an appropriate, acceptable, and reasonably accurate
screening test.
Early development of screening tests for glaucoma principally focused on
open8–10angle glaucoma using IOP measurement. While such tests effectively detect
ocular hypertension, an isolated elevated IOP is not a strong predictor of either
4glaucoma prevalence or 5-year incidence. Diagnostic tests for structural or
functional abnormality in glaucoma are now in widespread use. Screening
11–14 15–21algorithms based on functional or structural criteria have been
22developed. A meta-analysis in 2008 found no test or group of tests clearly
superior. However the quality of the reviewed studies was limited. One issue that
needs to be addressed for many diagnostic tests is that diagnostic algorithms have
been developed in limited population samples and tend to favor sensitivity over
23specificity when tested in true population-based samples. For angle-closure
glaucoma, the focus has been on detection of narrow angles or angle
24–29closure. Structural measures such as limbal chamber depth have modest to
good diagnostic performance.
5. The natural history of the condition, including development from latent to
manifest disease, should be adequately understood.
The natural history of open-angle glaucoma is reasonably well understood. The
Early Manifest Glaucoma Trial reported a 62% rate of progression over 6 years
30among controls. Estimates of 10-year progression in a cohort study ranged from
3150% to 70% depending on the visual field criteria. The same study reported a
cumulative risk of blindness due to advanced field loss of 16%. Another long-term
32cohort study reported a 27% risk of blindness over 20 years. A number of
reports suggest that the risk of blindness is greater in those who first present with
33,34visual field loss, particularly moderate to advanced loss. This is consistent
with other data suggesting that the rate of visual field loss on standard automated
35,36perimetry increases with greater field loss on initial examination.
6. The cost of case-finding (including diagnosis and treatment of patients
diagnosed) should be economically balanced in relation to possible
expenditure on medical care as a whole.
The cost of case-finding depends on the mode of screening and the diagnostic
algorithm used. The least expensive form of screening would focus on short,
simple examination methods such as history taking and physical examination (of
the eye) in people already presenting to eye care services for other reasons.
Treatment and monitoring of glaucoma are major potential follow-on costs of
screening. Two papers have reported models for open-angle glaucoma screening
37,38 37in Europe. The first compared an organized mass screening program at
5year intervals between 50 and 79 years to opportunistic screening
(casedetection). The authors reported a cost of €9023 per quality-adjusted life year
(QALY) gained from the screening program with an overall prevention of 930
years of visual disability. The model was particularly sensitive to screening cost
38and specificity of diagnostic tests. The other report also modeled an organized
mass-screening program, in comparison to opportunistic screening, using a
somewhat different methodology. A 10-year interval mass-screening program in a
50-year-old cohort with a 4% glaucoma prevalence was considered likely to be
cost-effective. The model was highly sensitive to perspective on costs and test
specificity.
Screening Concepts
Because the aim of screening is to steal a march on time, temporal relationships are
critical to the understanding of when and who to screen. Figure 2-1 shows glaucoma
expressed in terms of its State, Rate, and Risk Factors. In this gure, time is shown
along the abscissa and the state of glaucomatous damage on the ordinate. The
instantaneous slope of the line represents the rate of progression. The determinants
of that rate of progression are the known and unknown risk factors for that patient's
disease.

FIGURE 2-1 The State/Rate/Risk Factor graph as it relates to
open-angle glaucoma screening. (From Spaeth GL. Visual loss
in a glaucoma clinic. I. Sociological considerations. Invest
Ophthalmol 1970; 9: 73–82.)
While the aim of screening is to detect disease earlier than the symptomatic
period, the earliest state of the disease may not be detectable. A theoretical threshold
of detection is shown as a light-blue line. For visual eld loss on standard automated
perimetry, it has been proposed that 40% neuronal loss is required for
39,40detection. The error bars around the blue line represent the uncertainty of
diagnosis. The orange line represents the average state at which the vision loss might
become su3 ciently symptomatic for eye care to be sought. This level has not been
40reported. However, it can be estimated as between 80% and 90%. The red line
represents a theoretical level at which vision loss meets the criteria for blind
40registration (less then 10° of intact visual field).
Lead Time, Delay Time and Sojourn Time
The time between positive screening and onset of symptoms is the time gained by
screening. It is known as the ‘lead time.’ However, if the time of positive screening
occurs after the disease state crosses the detection threshold then some potential lead
time is lost. This is known as the ‘delay time.’ The lead time and delay time together
make up the ‘sojourn time.’
The yellow line represents an imaginary person with open-angle glaucoma (OAG)
to illustrate the features of the gure. In this case, the glaucomatous neural loss







commenced some time before age 40. At age 49, the person screens negative because
of the insensitivity of the tests used. From age 50, the test would be able to detect the
OAG, but the person does not return for screening until age 60, by which time almost
two-thirds of the optic nerve neurons have been lost. At this stage, disc and eld
changes are so great that screening is positive. Although 10 years and 25% of
neurons have been lost by the delay (delay time), the positive diagnosis at age 60
has gained 10 years and 25% of neurons from the time the person would have
presented with reduced vision (lead time). If aggressive risk factor reduction (in the
absence of being able to directly arrest the cellular processes) changed the rate of
loss (slope of the yellow line) to approximate the green ‘normal’ rate, the subject
may retain useful vision until death in his eighties. This 10-year lead time would
prevent 10 years of blindness if the same rate of improvement was initiated at the
time of symptomatic presentation.
Both lead and delay time vary with sojourn time, which is a function of the
sensitivity of the test and the rate of progression. Sojourn time can vary with disease
subtype and age. In breast cancer, sojourn time was estimated as 2 years in women
aged 40–49 years regardless of histological type. In women aged 50–69 years,
41sojourn time varied strongly with histological type (between 1.2 and 7.7 years).
42This has led to increased screening frequency in younger women.
There are few data in the glaucoma literature concerning estimates and risk
factors for sojourn time. Given that glaucoma is symptomatic only at an advanced
stage, it might be reasonable to use advanced visual eld loss or blindness as a
surrogate for symptomatic presentation and use cohort data (most of whom would be
treated) to gauge a rough idea of the lead time of cases detected by current screening
methods. Jay and Murdoch used ages at presentation for patients with early and
advanced eld loss to estimate rates of progression for untreated open-angle
43glaucoma. They reported that IOP had an important in) uence, with lead times of
14.4 years for IOPs of 21–25 mmHg, 6.5 years for IOPs 25–30 mmHg, and 2.9 years
for IOPs over 30 mmHg. A number of studies have con rmed IOP as a risk factor for
5,44,45progression, and some have also found older age at diagnosis to be a risk
5,45factor as well. It is not known whether sojourn or lead times vary with glaucoma
subtype. Primary angle-closure glaucoma causes disproportionately more blindness
46–48for its prevalence, suggesting it is a more aggressive disease. However, this
may be an IOP e ect, as a stronger correlation between IOP and visual eld loss has
49been reported in angle-closure glaucoma compared with open-angle glaucoma.
While increasing lead time diagnoses cases with less disease burden and increases
the opportunity for treatment, the trade-o is less reliable screening because
screening points lie closer to the limit of detection. The magnitude will depend on
the characteristics of the screening test. This e ect was seen in the Ocular










Hypertension Treatment Trial, which followed 1636 subjects with ocular
hypertension and no detectable OAG for 5 years, with one half randomized to
receive IOP-lowering treatment. Of 703 reliable visual eld tests that showed the
rst development of glaucomatous eld loss, 604 (85.9%) did not show the eld loss
50on repeated testing. In addition to con rmed glaucomatous eld loss, study end
points also included loss of neural rim tissue observed by trained graders of
stereooptic disc photographs. Of con rmed OAG cases, initial end points were found on
optic disc grading in 50% of treated and 57% of control subjects. This contrasts with
42% of treated and 33% of control subjects for whom visual eld testing provided
4the first OAG end point.
The reliability of testing for glaucoma will have an important impact on not only
sensitivity, but also health resources due to false-positive screening. The ideal region
within the sojourn time to screen would be one where a simple, inexpensive
screening test would be quite reliable, yet still giving patients enough lead time for
treatment to be effective.
What Constitutes Early Diagnosis?
An important misconception concerns what constitutes early glaucoma diagnosis.
Frequently, it is thought to mean diagnosis at either an extremely early stage of the
disease, or even diagnosis before any damage has occurred. Studies of early diagnosis
have examined ocular hypertension or the use of sophisticated and sensitive
technologies for detecting the earliest evidence of structural or functional damage.
Focusing on this stage of the disease is not only unnecessary; it causes a multitude of
problems related to the uncertainty of diagnosis and dilutes the e ectiveness of
intervention. From a public health perspective, early diagnosis means diagnosis at
an earlier stage than would have presented symptomatically. Given that
symptomatic presentation of glaucoma occurs at its end stage, almost any stage of
glaucoma is early disease from the point of view of screening. If we ask a screening
strategy to deliver a complete cohort of at-risk patients with the earliest signs of
disease, it will fail. But if we focus later in the sojourn period, our diagnostic
accuracy will be much improved, the group detected will be closer to symptomatic
disease and the time to blindness, and therefore, the time-bene t of treatment will
be, in general, much greater. An additional problem with trying to screen for the
earliest disease is that screening cycles need to be very short, greatly increasing cost.
Moving further into the sojourn time allows more cost-e ective screening frequency.
As seen in Figure 2-1, decades of lead time can be gained from early detection
without being overly concerned with minimizing delay time.
Risk Factor Screening in Open-Angle Glaucoma
Focusing on screening for the earliest stages of glaucoma naturally leads to the idea







of screening for and treating ocular hypertension in order to prevent glaucoma. This
is perhaps the primary fault with previous glaucoma screening strategies. The Ocular
4Hypertension Treatment Study (OHTS) demonstrated a reduction in the
development of glaucoma if people with ocular hypertension are treated with
pressure-lowering medications. Indeed, only 4.4% of those treated developed
5glaucoma. This contrasts with the results of the Early Manifest Glaucoma Trial
(EMGT) which treated people discovered to have glaucoma after screening for the
disease. In this study, the rate of glaucoma progression in the treatment group was
45% over a similar time period. At face value, it would seem that there is a much
better chance to prevent glaucoma if we detect and treat ocular hypertension rather
than wait for glaucoma to develop. However, the reason for conducting randomized,
controlled trials is to compare the treatment group to the control group, and this
analysis paints quite a di erent picture. In the OHTS, only 9.5% of the untreated
control group developed glaucoma compared with 62% of the control group of the
EMGT. The reduction in risk that treatment confers is the di erence in rate between
treatment and control. The Early Manifest Glaucoma Trial showed a 17% absolute
reduction in risk of progression compared to 5.1% in the OHTS (or 6.6% for the
comparative [white] group of OHTS subjects).
The reason for this is that there are known and unknown risk and protective
factors which alter the e ect of a particular risk factor on the onset of a disease. For
some people, ocular hypertension leads to a rapid progression to glaucoma. For this
group, treatment is certainly worthwhile as would be nding them through IOP
screening. However, for others with ocular hypertension, glaucoma may not develop
for many decades, or may never develop at all. For this latter group, there is a
bene t in not screening, as it would save the individuals from anxiety, cost, and
treatment of side e ects. For the former group, any bene t of IOP screening will
depend on whether there is gain in starting treatment immediately compared to
waiting until the disease became detectable. We do not yet know the answer to this
question and trial evidence would be helpful. While protective factors may also occur
in someone with glaucoma, the fact that the disease has already occurred shows that
the risk factors outweigh the protective factors and make further progression of the
disease much more likely. To explore the bene t of screening on outcome, we can
examine the number of people we would need to screen to prevent one case of
progressing glaucoma (Fig. 2-2). This is called the number needed to screen.


FIGURE 2-2 The effect of screening on treatment
benefit. (Data from Blue Mountains Eye Study (unpublished
4data), Ocular Hypertension Treatment Study, and Early
5Manifest Glaucoma Trial. OH, Ocular hypertension between 24
and 32 mmHg without evidence of glaucoma; EMOAG, Early
Manifest open-angle glaucoma.)
The Number Needed to Screen
Using the Blue Mountains Eye Study as an older screening population, for every
1000 people we screen with IOP measurement using OHTS criteria, we will nd
about 25 with ocular hypertension between 24 mmHg and 32 mmHg (Healey PR;
unpublished data). Data from the OHTS non-African-American population tells us
that of these 25, about 2.5 will develop glaucoma over 5 years if untreated. If
everyone who screened positive was treated successfully one person would develop
glaucoma, sparing 1.5 people who would have otherwise developed the disease over
the 5-year period.
If we screened another 1000 people for manifest glaucoma with a matching optic
51disc and visual eld examination, about 30 cases of glaucoma would be found.
52Excluding advanced disease leaves us with 25 people. The EMGT tells us that over
5 years, glaucoma will progress in 15.5 of these if untreated and 11.25 if treated,
leaving 4.25 people whose glaucoma progression was prevented.
If we optimistically regard progression in both ocular hypertension and manifest
glaucoma to be equally bad and compliance with treatment to be equally good, there
would still be almost threefold more people who bene t from glaucoma rather than
ocular hypertension screening. Under these ideal conditions, the number needed to
screen for ocular hypertension screening to prevent one case of 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 bene t we can confer by screening (see
Fig. 2-2). For every 1000 people screened for ocular hypertension (OH), after 5 years
1.5 would bene t 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 bene t against 9.5 who would not
bene t 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 bene t’ groups would be better o if not screened depends on how
the negative aspects of diagnosis and treatment compare to bene ts not related to
treatment at that time or whether there may be some later bene t (after 5 years)
from screening positive. Given that those with glaucoma already have a disease, the
case for a delayed or nontreatment bene t will be stronger for the OAG group
compared with the OH group. The ratios of people bene ting to not bene ting 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 nding previously diagnosed glaucoma when screening for
glaucoma or nding 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
51associated with high IOP, making the di erence between screening strategies even
greater.
Another important consideration is the e ect of false-positive and false-negative
outcomes from the screening program and the impacts of screening frequency. The
e ect of false positives is to increase the number who do not bene t from screening.
False negatives can be ‘caught’ in later screening cycles. The bene t 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 bene t 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 bene t from screening. Someone screening positive close to death may not
have sufficient time to benefit from treatment.
These analyses demonstrate a nding that has been previously reported for other
53diseases, namely that there will always be less bene t 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 Angle-Closure 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,
3primary angle-closure glaucoma causes more blindness and most probably has a
shorter sojourn time.
Angle closure is the primary risk factor for angle-closure glaucoma, its e ect being
49mediated through increasing intraocular pressure. Given this relationship, it may
be feasible to screen for angle closure (with or without intraocular pressure) in order
to detect angle-closure glaucoma.
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 angle-closure glaucoma in a
wellde ned older southern Chinese population. Ten percent of the population had
gonioscopically narrow angles and, of these, one in ve had primary (synechial)
46,54angle closure (2.4% of the population). Angle-closure glaucoma was found in
461.5% of the entire population, suggesting an ideal positive predictive value of
angle closure for angle-closure glaucoma of 64% with 100% sensitivity in this
higherrisk 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
55closure. The alternative strategy would be to screen for the glaucomatous optic
neuropathy itself. But there are no studies comparing the e3 cacy and outcomes of
these two approaches. As this disease is a major cause of glaucoma blindness,
welldesigned and conducted studies are urgently needed.
Current Status Screening for Glaucoma
There have been a number of public health analyses of open-angle glaucoma
56–59screening. The rst 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
57,59 57 582005. It was based on an initial report in 1988 and a review in 1996.
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 insu cient evidence to recommend for
or against routine screening for intraocular hypertension or glaucoma by primary care
clinicians.’ This was the same conclusion reached in previous assessments and
underscored a relatively negative attitude to glaucoma screening in a contemporary
60editorial by a task force member.
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 e ects? 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.
In 2008, the World Glaucoma Association published a worldwide consensus on
61Glaucoma Screening. 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 lled, 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
62trial of screening for angle-closure glaucoma, the rst such trial of its type. Afterexcluding glaucoma, 4583 participants with ultrasonic anterior chamber depth of3
Economics of Glaucoma Care
Lee Kiang, Paul Lee
Summary
▪ Glaucoma is a growing and costly disease.
▪ Modeling suggests treatment of glaucoma is cost-effective, but more research is needed to establish which
populations stand to benefit the most from different courses of treatment.
▪ With looming changes in healthcare coverage, it will be incumbent upon providers and researchers to develop
analyses, employ rigorous methodologies and advocate for accurate analyses.
Without evidence and advocacy, resources may be misdirected and patients will have higher rates of vision loss
or disability
Introduction
Glaucoma is the leading cause of permanent blindness worldwide and the second leading cause of all blindness
1,2worldwide after cataracts. An estimated 3% of world population over the age of 40 was a$ icted in 2010, with a
3,4prevalence of 10% for those over age 80. There is an estimated ratio of 3 : 1 for primary open-angle glaucoma
2(POAG) compared to primary angle-closure glaucoma (PACG). In the US POAG a1ects over 2 million people and is
5,6the leading cause of blindness of African-Americans. In developed countries, over 50% of those with glaucoma
2,7(typically POAG) are estimated to be undiagnosed. While this is often assumed to be due to lack of eye care, or
insidious onset or presumed asymptomatic nature of early disease, in one study 49% of patients with undiagnosed
glaucoma had seen an eye care provider within the previous year and the diagnosis was either not made at that visit
7or the patient did not recall the diagnosis.
3Worldwide, the prevalence of all forms of glaucoma is increasing (Fig. 3-1). The 60.5 million a$ icted in 2010
2are expected to increase to nearly 80 million by 2020, with China and India accounting for 40% of the prevalence.
2By 2020, those bilaterally blind from POAG are expected to increase from 4.5 million to 5.9 million.
FIGURE 3-1 Projected rise in prevalence of glaucoma between 2010 and 2020. (From Varma
R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of
glaucoma. Am J Ophthalmol 2011; 152(4):515–522; data from Quigley and Broman.)
In 2010, the US devoted 17.6% of its gross domestic product (GDP) to healthcare, more than twice the average
8among Organization for Economic Co-operation and Development (OECD) countries. Even when adjusted for
prices across countries, the purchasing power parity per capita spending was $8233, over 2.5-fold that of other
relatively rich countries like France, Sweden and the UK (Fig. 3-2).FIGURE 3-2 Health expenditure per capita, public and private expenditure, OECD countries,
2010. Data are expressed in US dollars adjusted for purchasing power parities (PPPs), which
provide a means of comparing spending between countries on a common base. PPPs are the
rates of currency conversion that equalize the cost of a given ‘basket’ of goods and services in
different countries. 1. In the Netherlands, it is not possible to distinguish clearly the public and
private share for the part of health expenditures related to investments. 2. Total expenditure
excluding investments. (From: OECD Health Data 2012 How Does Austria Compare
http://www.oecd.org/dataoecd/46/37/38973610.pdf)
9,10An estimated $1–2.9 billion annually in direct costs is devoted to POAG. Cost increases with disease stage, and
11in the US is primarily medication-related (Fig. 3-3). Since these costs apply only to diagnosed cases, the true cost
could be as much as two-fold greater to account for those that are undiagnosed or not under treatment (though with
potential savings from those being treated currently who do not have glaucoma). These estimates also do not
include indirect costs related to loss of productivity of both patient and family and wellbeing, which are the primary
3costs in late-stage disease.FIGURE 3-3 (A) Direct medical costs of glaucoma care in the United States by stage of
disease. Costs adjusted for national Medicare allowable rates and for realistic adherence and
persistence in use of medications. (From 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; 124:12–19.) (B) Direct medical costs of glaucoma care in
Europe by stage of disease. (From 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; 89:1245–1249.)
Beyond the direct cost of care, glaucoma carries a large humanistic burden. There is a decrease in quality of life
and loss of productivity for those a1ected and their caregivers. Glaucoma is associated with depression, fear of
blindness, social isolation, decreased ability to perform Activities of Daily Living (ADLs) as well as more frequent
3,12 3,12falls and motor vehicle accidents. The effect increases with bilateral disease.
The monetary and societal burden of glaucoma can only be expected to increase on the global scale as the
5population ages and prevalence increases. This growing problem demands attention to its costs, the e1ectiveness
of treatment, and analysis of groups most likely to be a1ected who utilize the most resources or incur the greatest
burdens, in order to better provide more efficient diagnosis and treatment.
Types of Economic Analysis
In the context of healthcare, economic analyses assess the cost or beneCt of a given intervention. The analysis can
be a description of the costs associated with glaucoma or can be relative to one or more interventions or the costs of
13,14non-intervention. Costs are assessed from a particular perspective, e.g. patient, provider, payor, society, and
this should be well deCned in analyses as they inDuence the outcome. Types of analyses include cost-minimization,
cost-benefit, and cost-effectiveness.
Cost-minimization analysis evaluates costs of interventions that lead to the same benefit, seeking the least costly.
Since treatments seldom lead to identical benefits, these analyses are less common.
Cost-benefit analysis (CBA): evaluates costs and benefits of intervention in a single metric, typically monetary.
This may require that the benefit be characterized in a dollar amount.
Cost-effectiveness analyses (CEA) are the most common method of evaluation. They describe the monetary
amount of resources put toward intervention and a single or summary outcome in a separate metric, usually a
single most important clinical outcome or some form of summary measure.▪ The Incremental Cost-Effectiveness Ratio (ICER) defines the cost required to gain a net unit of effectiveness:
▪ One type of CEA is a Cost Utility Analysis (CUA), conducted with decision analysis, where outcome is QALY or
DALY (quality-adjusted life year or disability-adjusted life year). This takes into account a person's subjective
quality of life ranging from 0 (dead) to 1 (optimal) and the person's life expectancy. Several studies have
15–20estimated the utility value of unilateral and bilateral blindness.
Cost-consequence analysis (CCA): monetary amount of resources used and multiple outcome measures in natural
units, for a diverse view of the impact of the interventions.
Framework for Looking at Costs in Glaucoma: A Common Vocabulary –
Vancouver
While many studies on the cost of glaucoma exist, lack of a consensus in describing the costs of glaucoma has made
comparison of studies diI cult. To begin to address this challenge, the Vancouver Economic Burden of Vision Loss
14,15Group in 2007 deCned a common vocabulary, based in part around the work by Taylor et al. To facilitate
more direct and meaningful comparison of analyses, the Group recommended the following standard categorization:
A. Direct (monetary cost of care)
Hospital, which includes inpatient and outpatient physician and hospital visits, procedures.
Out-of-hospital, physician visits, procedures.
Other health, such as pharmaceuticals, imaging, pathology, diagnostic tests, optical costs (e.g., IOLs,
spectacles), aged care, other health professionals, other medical expense, nursing home care.
B. Indirect
Aids/adaptations (monetary costs other than care) such as Braille, stair lighting, guide dogs, travel costs of
patient and family.
Caregivers (loss of family member income).
Deadweight losses from transfers, accounting for the fact that something more productive could have been
done with the money/resources spent. This includes tax revenue, social welfare payments and payments from
one economic agent to another.
Lost production (loss of patient income and taxes).
C. Loss of well-being.
While this framework provides insight and guidance as to identifying the speciCc factors included in any cost
analysis, the ability to obtain accurate and reliable information for these factors varies signiCcantly across countries
and speciCc factors. Particularly in the case of the loss of well-being, the diI culty could center on (1) placing
numerical values on a qualitative, subjective and individualized experience; (2) translating well-being into a speciCc
monetary value; and (3) determining if values should be placed before the disease or condition occurs.
What is Currently Known: Costs of Visual Disorders and Blindness
I n Table 3-1 (online supplement), we refer to recent studies on resource use and cost in visual disorders and
glaucoma, according to the Vancouver consensus framework.
Table 3-1
Resource Use and Cost in Visual Disorders and in Glaucoma – Examples of StudiesDirect Indirect
Hospital
Out-of- Other Caregiversinput (Monetary Loss of
Hospital Health: (Loss ofHospital Health: (Loss of DeadweightOutput Costs Other DeadweightOutput Costs OtherSSttuuddyy WWeellll--LLoosstt(Monetary (Monetary Family(Monetary (Monetary Family Losses from(Monetary Than BeingProduction
Cost of Cost of Member TransfersCost of Healthcare)
Care) Care) Income)Care)
VISUAL DISORDERS
Taylor HR et al. The X X X X X X X X
economic impact
and cost of visual
impairment in
Australia
Frick KD et al. X X X X
Economic impact of
visual impairment
and blindness in
the US
Rein DB et al. The X X X X X
economic burden of
major adult visual
disorders in the US
GLAUCOMA
Lee PP et al. Glaucoma X X X
in US and Europe:
predicting costs and
surgical rates based
upon stage of
disease
Stein JD et al. X X X
Longitudinal trends
in resource use in
an incident cohort
of open-angle
glaucoma patients
Lee PP et al. Cost of X X X
patients with
primary open-angle
glaucoma
Lee PP et al. A X X X X
multicenter
retrospective pilot
study of resource
use and costs
associated with
severity of disease
in glaucoma
Seider MI et al. Cost of X X Xselective Laser Direct Indirect
Trabeculoplasty v
Hospital
Topical medications Out-of- Other Caregiversinput (Monetary Loss offor glaucoma Hospital Health: (Loss of DeadweightOutput Costs OtherTraverso et al. Direct X X XStudy Well-Lost
(Monetary (Monetary Family Losses from(Monetary Thancosts of glaucoma BeingProduction
Cost of Cost of Member TransfersCost of Healthcare)and severity of the
Care) Care) Income)Care)disease: a
multinational long
term study of
resource utilization
in Europe
Sharma A et al. An X X X X X X
economic
comparison of
hospital-based and
community-based
glaucoma clinics
Neymark et al. The X X X
costs of treating
glaucoma with
combinations of
topical drugs in
Spain.
Kobelt G et al. X X X
Treatment of
glaucoma in
clinical practice.
Four-year results
from a patient
registry in France.
Kobelt G, Jonsson L. X X X
Modeling cost of
patient
management with
new topical
treatments for
glaucoma. Results
for France and the
UK.
Cost Estimates for Visual Disorders
Visual disorders in the US were estimated to account for $35.4 billion in costs in 2004 with $16.2 billion from direct
10medical costs, $11.1 billion in direct ‘other’ costs, $8 billion from productivity losses. Rein et al. estimated the
annual government budget impact at $13.7 billion. Visual impairment and blindness accounted for $5.5 billion
16annually in medical and home care, not including productivity losses, in an analysis by Frick et al.
Individuals with visual disorders and visual impairment had lower employment levels, resulting in lower annual
incomes. Forty-four per cent of visually impaired and 30% of those who were blind were employed, earning $23,345
10,16and $21,074 annually, compared to 85% and yearly earnings of $33,195 for those with normal vision. The
lower level of employment contributes $6.3 billion to the estimated productivity lost, while the decrease in earnings
by the visually impaired and blind contributes $1.7 billion. Frick et al. calculated a loss of >209,000 QALYs, about85,000 due to blindness and 124,000 due to visual impairment. Converting QALYs into dollars at $50,000 per QALY,
16as an example, results in a $16 billion per year loss.
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,
15and diabetes. Importantly, the costs of interventions to address vision loss were deemed to be cost savings – i.e.,
21there was more than one dollar in savings for every dollar spent.
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
10costs arising from outpatient care and the costs of medications. While individual cost estimates related to
11,22–26glaucoma vary across studies, several themes emerge. 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 Crst year of
diagnosis, due to additional testing and treatment initiation. Costs are also greater for individuals with more severe
disease, measured by visual Celd, optic nerve head structure, or by IOP. Also, costs are increased if side e1ects
develop or if the glaucoma state is more resistant to IOP lowering. The average cost-per-person-per-year has been
11,22,23estimated to range from $1248 to $1796. Charges were highest in the Crst 6 months after OAG diagnosis
23($955.37) decreasing to about $500 per subsequent 6-month interval. The charge per person in the Crst year after
22diagnosis 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
11stems from the impact of adjustments for medication adherence and Medicare reimbursement levels and are likely
to be lower in the Crst year after diagnosis due in part to greater diagnostic expenses (as low as 25% of
POAG11,22related charges in the Crst year after diagnosis). Additionally, di1erences among studies may be attributed to
di1erent 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 reDects the
charge, the actual amount paid, or the Medicare allowable rate (with the last two generally being signiCcantly less
costly).
Recent studies have focused on prostaglandin analogs (PGAs), which have surpassed beta blockers as the most
27,28common topical medication. They are more eI cacious, with a favorable side e1ect proCle, and a higher cost
29than older topical therapies. A prospective observational registry study of patients in France using PGAs for the
24Crst time found that direct mean annual costs were €487 for all patients and €428 for de novo patients, which is
less than the €527 annual cost (adjusted to 2008 costs) in a study of newly diagnosed patients in the mid-1990s
25before the use of prostaglandins (also by the same authors). The studies indicate that the greater e1ectiveness 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,
30respectively compared to other PGAs. 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 Ductuation characteristics and that no PGAs had costly side e1ects.
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.US Versus Other Countries
Studies consistently Cnd 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 di1erences in healthcare structure and
26Cnancing. While the annual costs of therapy are higher for more severe disease and higher IOP at baseline,
severity stage-speciCc 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
11,26,31of US$1581 vs. €540 to €960 in Italy and Germany, respectively).
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
32costs. 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-e1ectiveness 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 A1ordable 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 Crst task is to deCne 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 e1ect (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-e1ective vary widely internationally. In the US, generally, a cost of less than $50,000
per QALY is considered cost-e1ective, while greater than $100,000 per QALY is not. The WHO has deCned
coste1ectiveness standards relative to the gross national product (GNP) per capita. An intervention costing less than the
GNP is considered highly cost-e1ective, whereas a DALY cost of one to three times the GNP is moderately
cost33effective.
Cost-Effectiveness of Treatment
The cost-e1ectiveness 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
34consequences of disease as patients transition through various disease stages over time.
Glaucoma Screening
Results of analyses of whether screening for open-angle glaucoma is cost-e1ective are uncertain at best, both in the
35,36US and abroad.
Ocular Hypertension Treatment
37A cost-utility analysis in glaucoma based on the results of the Ocular Hypertension Treatment Study (OHTS),
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-e1ectiveness 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-e1ectiveness also depends on
38the patient's overall life expectancy, when modeled by the same group.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 Celd 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
39treatment eI cacy, respectively (Fig. 3-4). This was sensitive to both cost of treatment and value of a QALY (Fig.
393-5). By WHO standards this would be very and moderately cost-e1ective, respectively. Somewhat di1erent
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
40avoided. This begins to exceed to estimated value of a life year, as defined in the same article, of A$162,561.
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
officebased identification and subsequent medical treatment of primary open-angle glaucoma in the
United States. Ophthalmology 2009; 116(5):823–832.)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 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.)
Different Treatment Courses: Medication versus Laser Studies
The cost-e1ectiveness of prostaglandin analogs versus argon laser trabeculoplasty (ALT) in managing newly
34,41,42diagnosed mild OAG has been examined in several studies. One study found that PGAs are more
cost34effective than ALT. However, if this assumed e1ectiveness was reduced by 25%, e.g. due to poor compliance, ALT
was more cost-e1ective. Incremental cost-e1ectiveness over no treatment was $14,179/QALY for PGA and
$16,824/QALY for ALT. A separate model found that SLT was more cost-e1ective than most brand-name
medications after 1 year, and was more cost-e1ective than generic latanoprost and timolol after 13 and 40 months,
41respectively. ALT is estimated to have lower cumulative 5 year costs than either medications or Cltering surgery
42among patients who were not adequately controlled on two medications.
The Centre for Eye Research Australia study also examined cost-e1ectiveness 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
43medications; (3) trabeculotomy in the Australian study gave a cost savings of $2.50 for each dollar spent.
Additional Issues and Future Perspectives
Analyses of the costs and beneCts of glaucoma and its treatment implicate important policy matters. Questions such
as to what extent do patients with glaucoma or those with visual impairment a1ect 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 inDation (or deDation) into the future that can signiCcantly alter the results of analyses. As
economics is inextricably intertwined with policy decisions and the political system, the relationship to political
considerations and governmental decisions is also integral to our understanding.
Impact on Overall Healthcare Costs
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 visual44impairment, have been modeled to be $137 per year. Progression to severe visual impairment in glaucoma has
44,45been estimated to add to overall total healthcare costs. 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,
46while those with severe loss and blindness had excess non-eye-related costs of $3301 and $4443 respectively.
46Visual impairment was associated with $2.14 billion in 2003 non-eye care costs and excess expenditure of $2.8
16billion in 2004 costs.
Discounting
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 inDation, 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%
47annually.
Disparities
2With the anticipated increased prevalence of glaucoma and aging populations around the world in the future,
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
48utilization of eye care services and thus costs of therapy for societies and the individuals newly diagnosed.
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
28(43%) not to be seen or treated in a year's time.
Hispanics are the fastest growing minority group in the US and Hispanic men are projected to constitute the
49,50largest subgroup with POAG by 2035. 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
28white or black subjects to receive treatment in a given year. Asians with POAG are also less likely than Whites
28(94%) to receive treatment in a given year and the number of Asians with POAG is anticipated to increase nearly
505-fold by 2050.
Future Access to Eye Care and Cost
Current US healthcare legislation has increased the volume of patients who will receive eye care, increasing
diagnosis 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, signiCcant 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 undeCned, 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 beneCciary premiums,
increasing Medicare beneCciary cost sharing, restricting beneCts, or modifying eligibility criteria [Patient Protection
and A1ordable 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-e1ectiveness or other CBA techniques (from which it is barred), the IPAB may in part
resemble the National Institute for Health and Clinical Excellence (NICE) in the UK, whose independent advisory
committees provide evidence-based guidelines on clinical e1ectiveness and cost-e1ectiveness 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.
An example of its work is the use of simulation modeling. One simulation comparing Cve 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
NICErecommended 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 less51costly and more effective than the NICE strategies.
With the Cscal 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 ‘proCled’ 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
47US, it is likely that some elements of beneCts will become part of the consideration in coverage decisions by
payors and policymakers. Those services that are highly cost-e1ective will be much more likely to be covered or to
have lower patient payments, while those with less cost-effectiveness will be left to greater payment by patients.
Spotlight 1
Economics of Glaucoma Care in Asian Countries
An Overview
Errol Chan, Paul TK Chew
1Glaucoma ranks as the second leading cause of blindness in Asia. Financing glaucoma care in Asia presents
several unique challenges due to the wide variation in socioeconomic proCle, glaucoma disease patterns, and
healthcare systems in Asia.
In keeping with trends in the global glaucoma burden, the number of people a$ icted with glaucoma in Asia is
1expected to increase to 49.3 million in 2020. 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 di1erences in the POAG  :  PACG ratio may also indicate di1erential
countryspeciCc strategies for glaucoma screening and treatment. From an economic perspective, many individuals in
developing Asian countries remain economically underprivileged, imposing challenges in treatment a1ordability.
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 acute-angle closure attack in Singapore range between US$879
2to US$2576 to the individual, and between US$261,741 and US$287,560 for the healthcare system. The cost of
3,4glaucoma medications varies widely even in individual countries. Although prostaglandin analogs are
increasingly used because of their eI cacy and side-e1ect proCle, 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-e1ective analyses can be conducted, clinical justiCcation of eI cacy has to be demonstrated. We
await data on the clinical eI cacy of laser iridotomy (LI) for PACD from the Zhongshan Angle Closure Prevention
5(ZAP) Trial, 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 eI cacy (70–80% sensitivity/speciCcity) with
6the Heidelberg Retinal Tomograph in Singapore Malays. In addition, accurate information on the rate of visual
Celd progression in Asian eyes is required, to generate reliable economic models and estimates. Country-speciCc
analyses are also indicated due to the vast di1erences in healthcare systems. A limitation of quality-of-life studies
in glaucoma in Asia for the purpose of cost-e1ectiveness analyses is that the outcomes assessed, i.e. vision-speciCc
7functioning, activity limitation, falls, or psychological well-being, do not readily translate into quality- ordisability-adjusted life years (QALYs or DALYs). As QALYs and DALYs are standard metrics for comparison with
other diseases, there is limited information to guide policy-makers in prioritizing scarce healthcare resources for
glaucoma.
The large and severe glaucoma burden in Asia highlights a need to identify key priorities that di1er from that
in North America, Europe or Australia. For screening to be cost-e1ective, 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 o1set
major cost-drivers. Increasing accessibility to generic glaucoma medications, and determining the eI cacy, costs,
and cost-e1ectiveness 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;262–267.
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;32:578–583.
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;16:594–597.
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;17:321–332.
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;117:290–297.
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;54:1169–1175.
Spotlight 2
Economics in India of High-Volume Glaucoma Care
Rengaraj Venkatesh, Krishnamurthy Palaniswamy
Glaucoma is far di1erent 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
1glaucoma in India and an additional 28.1 million are suspect glaucoma (OHTN/PAC/PACS). The economic
burden of glaucoma increases as the disease progresses; treatment delaying disease progression could
2signiCcantly reduce health economic burden. Direct costs of glaucoma care include physician and hospital visits,
medication(s), glaucoma procedures, transportation, and nursing home care. Indirect costs include lost
3productivity at work and productivity costs borne by family members and friends. In one African study,
middleincome earners spent over 50% of their monthly income and low-income earners spent all their monthly earnings
4on treatment for glaucoma, resulting in non-compliance and poor follow-up, likely similar to the Indian
scenario.
E1orts 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
5,6inability to leave family and work responsibilities, the need for escorts, and fear about their disease. Hence the
need to design a comprehensive yet sustainable eye care program that must be easily accessible and a1ordable 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, andsimple digital cameras are slightly modiCed 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 diI cult to evaluate, and this
7helps reduce the burden of disease.
Medical management remains the mainstay of treatment in India. Low-cost generic drugs have Dooded 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 issues. The cost of trabeculectomy surgery in a
private hospital varies from $200 to $400, while a phacoemulsiCcation combined with trabeculectomy would cost
somewhere from $500 to $1000. Government-sponsored 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-e1ective technique, has a minimum of complications, and has a short
8learning curve.
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-e1ective tube
shunt called the Aurolab Aqueous Drainage Implant (AADI). This tube shunt will help glaucoma surgeons deal
with failed Clters and diI cult cases with relative ease. To conclude, quality generic medications, early primary
Cltering 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;19:391–397.
2. Varma R, Lee PP, Goldberg I, et al. An assessment of the health and economic burdens of glaucoma. Am J
Ophthalmol. 2011;152:515–522.
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–
2031.
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):1393–1399.
7. Khurana M, Kader MA, Ramakrishnan R. Opportunistic glaucoma screening in rural India: Role of vision
centers. ARVO. 2013.
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–
146.
Access Table 3-1 online at http://www.expertconsult.com
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4
Practical Application of Glaucoma
Care in Different Societies
Alan L Robin, Donald L Budenz, Nathan G Congdon, Ravilla D Thulasiraj
Summary
Diagnosis of glaucoma and delivery of e ective treatment is di cult everywhere, but
additional challenges are evident in less a uent 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 south-east Asia including China
and India and countries in sub-Saharan Africa. The relatively low priority given to
glaucoma by vision-related and other nongovernmental organizations (NGOs) due to
di culties faced in delivering e ective glaucoma screening and therapeutic interventions
are discussed, together with possible future directions for increasing resources and
priority for glaucoma care in poor areas.
Introduction
1Cataract is the major cause of treatable blindness in less developed countries. It is
relatively simple to diagnose; the therapy is standardized, simple and e cient and requires
a single, cost-e ective 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
2blindness is irreversible. Glaucoma therapy in less developed countries is challenging and
requires a di erent set of thought processes and skills than are currently used in more
developed nations. Problems faced in developing nations are appreciably magni1ed and
reach a greater level of signi1cance 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 1nancial
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,
3Maryland, USA) almost 50% of subjects with glaucoma were unaware of their diagnosis.
Similar patterns of low rates of prior glaucoma diagnosis have been seen in other parts of


4 5–9the United States as well as through Western Europe and Australia.
The prevalence of the disease and the lack of therapy may be di erent 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
10blindness varied between 1.3% and 5.3%. 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
11that 93% had not been previously diagnosed with the disease. 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
12is due to lack of adequate training. This may be a question of priorities, skill levels, or
inadequate time. The issue of sta ng is not only that the absolute number of
ophthalmologists per capita is far less. This situation is compounded by the fact that the
13proportion of ophthalmologists who are well trained in glaucoma is even smaller. 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 di cult to
diagnose in eyes with cataract in which the lens opacity makes it challenging to either view
the fundus or perform perimetry.
14Cataract and refractive error have become major hurdles in themselves. The mere
diagnosis of, and surgery for, visually disabling cataract alone is often a signi1cant
problem. The skilful performance of cataract surgery with intraocular lens insertion is now
10becoming commonplace. 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 opaci1cation. 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 every-other-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
15and pseudophakic eyes and blindness due to glaucoma is seen in 22% in either one or
both conditions in developing countries.
Detecting glaucoma can be di cult 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
nonstereoscopic fundus examinations are the rule, if they occur at all. Gonioscopy is not often
16done even in developed countries like the United States. In the majority of more
developed nations, the primary angle-closure glaucomas are relatively infrequent whereas
in developing nations they can account for one-half of primary glaucomas and despite their
decreased prevalence remain a leading cause of disability and blindness. Likewise many
17with normal-tension glaucoma have IOPs lower than 21 mmHg at presentation. 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-e ective because of the relatively low
prevalence of the disease and problems with both sensitivity and speci1city of most
screening tests. However, if screening for glaucoma is coupled with other disease screening,
such as screening for diabetic retinopathy or cataract, it may become much more
coste ective 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
18being attempted for diabetic retinopathy. These types of screenings can make a large
impact as digitalized images and telemedicine become more widely utilized. Digital
photographic screening can o er 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 better-quality 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 1rst 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 a ordable 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 di cult to get anything more than pilocarpine or
timolol, making it useless to prescribe other IOP-lowering 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 inJuence 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 small di erences in
co19–23payments may have significant effects on adherence and disease progression.
In developing nations, some but not all topical IOP-lowering 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 di erences in costs may
make tremendous di erences in use and in adherence. The National Bureau of Statistics in
24China in 2004 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 1rst 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
25acupuncture, are still considered costless therapy. In parts of China, as in India, even the
medications with the lowest costs are not available.
26What are the costs of glaucoma care in China? The cost of a laser trabeculoplasty
ranges from US$40 to US$70, while the cost of 1ltration 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
27ophthalmic antibiotics and have seen that generic glaucoma medications do not lower IOP
28as well as nongeneric preparations. This, however, may lead to a quandary. Does one use
a potentially inferior but inexpensive generic medication or ask a patient to pay a
signi1cant part of his or her salary for a slightly more reliable and e cacious 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 signi1cant 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 pro1ciency with a slit lamp,
29which may not be acquired in residency. Should laser trabeculoplasty be used in
developing nations? Some reports have found it potentially e ective in a limited number of
30subjects for a relatively short time period. However, long-term studies are needed.
Additionally, in many areas, reliable electric power and equipment maintenance are
limiting factors. For a laser to be e ective, it must be durable, ideally it should be portable,
and have a self-contained battery power source because Juctuations in power can result in
31permanent damage to circuitry. Additionally, since lasers are relatively expensive, they
may not be cost-e ective in settings that lack a high proportion of paying patients.
Although laser trabeculoplasty may be as e ective as a single medication, even those
patients who have a good initial response will eventually need medications as the e ect of
the laser wears o over time. Diode laser cyclophotocoagulation has been studied as an
32initial therapy in a developing country. 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
33cataracts, and there is a small risk of sympathetic ophthalmia which make the relative
risks outweigh the benefits of ease of application and cost.
At 1rst glance, initial incisional surgery would seem like a good option. But if one
considers a 1ltering procedure, should one just perform a trabeculectomy? Cataract is one of
34the most common complications of 1ltering surgery. An asymptomatic subject with 6/6
visual acuity could go in for glaucoma surgery, seeing well, and after 1ltration 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,
35leaving the patient back where he or she started, but two surgeries later. 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
36alone? 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 signi1cant 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.
Various skill levels are required for 1ltering surgery. As an example of the variability of
training and surgical skills, the authors 1rst will examine cataract surgery, the bread and
37butter of ophthalmic surgery. In Madurai, India, fewer than 1.9% of patients had 1nal
38visual acuities less than 6/18, whereas in Hyderabad 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 1ltering 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-e ective, 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 bene1t surgical intervention. CO lasers are now available that2
can create deep sclerotomies. The learning curve is slight and the results appear similar to
39(but have not been compared to) trabeculectomies. The ability to create a standardized
procedure that is easy to learn and has predictable outcomes is desirable. Non-penetrating
procedures such as this should result in fewer Jat chambers, endophthalmitis, cataracts, and
hypotony-related 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%
40 41of people 40 years and older in glaucoma surveys done in Ghana, Tanzania, and South
42–44Africa. In studies conducted in West Africa, glaucoma accounts for 16% to 24% of
45–47blindness, falling just behind cataract. Second, glaucoma in Blacks has an earlier age
48–53 54,55of onset and can take a more aggressive course, leading to visual disability and
blindness at an earlier age. And third, the extremely limited resources in the developing
56countries of sub-Saharan Africa make diagnosis and management difficult.
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 1eld equipment would be
ideal, but equipment is expensive and di cult to both obtain and maintain in developing
countries. Portable, inexpensive, and less technology- and 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 non-Blacks. 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
57–59Caucasians. 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
40population survey done there (2.5%), a clinic survey found a prevalence of closed angles
60in patients being treated for glaucoma of 6.6% 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 1eld 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 di culty in obtaining them. Verrey and
61colleagues 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 1rst-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 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 e orts 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
62–64Caucasians, presumably due to a more vigorous wound-healing response in the
65former. Several investigators have reported success and safety when using anti1brotic
66–68 66agents in black Africans. A prospective, randomized trial by Egbert et al. showed a
clear advantage to using a single intraoperative application of 5-Juorouracil (5-FU)
(50 mg/mL on a soaked surgical sponge applied for 5 minutes) compared to no anti1brotic
67agent in glaucoma patients undergoing trabeculectomy in Ghana. Mermoud et al.
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 anti1brotic 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
68et al., 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 di cult, 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 sta ng,
supplies, and education. The following section provides an NGO perspective of care.
Current Situation
69Although glaucoma is the second leading cause of blindness in the world, 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
70cause of blindness in the world; studies have demonstrated excellent potential for return
71to normal vision with extraction of the cataractous lens in both the developed and
2developing 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 e cient programs. Primarily for these reasons, most blindness
72–74prevention NGOs have focused on cataract as their primary target.
Studies have also demonstrated treatment of vitamin A de1ciency (VAD) to be a highly
75e ective and inexpensive way to prevent blindness, and programs to alleviate VAD are
76an important part of the portfolio of NGOs such as Helen Keller International. Childhood


refractive error, childhood cataract, trachoma, and onchocerciasis are other diseases
a ecting vision for which proven treatments exist and in which one or more blindness
prevention NGOs have invested signi1cant 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 1gures as a primary objective for NGOs is that glaucoma
screening is di cult to perform. Screening usually involves assessment of the optic nerve
and/or testing for typical changes in the visual 1eld. Existing technologies and/or
combinations of technologies have not been demonstrated to produce good sensitivity and
77speci1city in screening for glaucoma. Evaluation of the optic nerve even among
78experienced observers may be subject to signi1cant variation. Machines which might
replace or supplement human evaluation of the optic nerve 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 1eld testing in a developing world setting, particularly with regards to
79sensitivity. Gonioscopy remains the standard modality to screen for the presence of
narrow anterior chamber angles, but is often poorly taught, subjective, and requires
signi1cant training and the presence of a slit lamp. Newer modalities to evaluate the
80angle 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
81impractical in rural areas, where 60% of Asia's population, for example, resides. The
quality, safety, and e cacy 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
82–86have become common in modern glaucoma surgery. As glaucoma drainage surgery
results in the deliberate creation of a 1stula 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 signi1cant 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
87 88satisfaction in both the developed and developing world. Blindness prevention NGOs
and others attempting to create sustainable cataract surgical programs often depend in their
1nancial planning on the word-of-mouth advertising provided by satis1ed patients. This is
in distinction to glaucoma treatment: negative impact on quality of life has been



89demonstrated with both medical and surgical glaucoma therapies. 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 e cient 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 signi1cantly reduce the e ciency of cataract programs. The ‘competition’
argument does not represent a signi cant impediment to NGOs beginning to support clinic-based
programs to detect and operate on advanced glaucoma at this time. As both glaucoma and
90–92diabetic retinopathy are prevalent in most underdeveloped nations 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 1eld 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 full-dependence on others, and hopefully maintaining self-su ciency. The
presence of dense cataracts mandates that some patients will not be identi1ed 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 su cient
93 94to control IOP without surgery once an acute attack and/or optic nerve damage 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
programs at this time. Training of clinical sta 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 di cult 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 e cacy of LPI is not su cient to
warrant population-based screening programs, the technique is su ciently 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,
longerlasting procedures 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. 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
95outreach eye camp only about 7% of the people in need of eye care are able to access it.
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 o ered 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.
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
1–3(PACG) varied from 0.2% to1.1%. 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
2rates in the West (70% to 92%). 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 e ect will not be reJected 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
1had IOP readings within statistically normal range. In such a case only the optic disc
examination clinches the diagnosis. Studies have shown that 40% of previously diagnosed
1POAG actually had PACG. This highlights the importance of gonioscopy in detecting
glaucoma. The solution to these problems seems to be advocating comprehensive
examination for all. The 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
1for glaucoma detection.
Challenges with Treatment.
1Cost and accessibility will be major hurdles in glaucoma treatment. Low-cost generic
glaucoma medications are plentiful in this region. In spite of concerns about the e cacy
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 these1iatrogenic glaucomas can be eliminated.
R e f e r e n c e s
1. George R, Ve RS, Vijaya L. Glaucoma in India: Estimated burden of disease. J
Glaucoma. 2010;19(6):391–397.
2. Ronnie G, Ve RS, Velumuri L, et al. Importance of population-based studies in
clinical practice. Indian J Ophthalmol. 2011;59(7):11–18.
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):759–764.
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Pathogenesis
OUTLINE
5 Functional Morphology of the Trabecular Meshwork Outflow Pathways
6 Aqueous Humor Dynamics and Intraocular Pressure Elevation
7 Pathogenesis of Glaucomatous Optic Neuropathy
8 Mechanical Strain and Restructuring of the Optic Nerve Head
9 Role of Ocular Blood Flow in the Pathogenesis of Glaucoma






"



5
Functional Morphology of the
Trabecular Meshwork Outflow
Pathways
Ernst R Tamm
Summary
Intraocular pressure is generated in the trabecular out ow pathways in which
aqueous humor passes through the trabecular meshwork into Schlemm’s canal. The
juxtacanalicular region of the pathways provides out ow resistance for aqueous
humor. The resistance is under the in uence of two contractile systems, the
anterior part of the ciliary muscle, and the contractile myo broblast-like cells in
the trabecular out ow pathways. Resistance is lowered through contraction of the
ciliary muscle or relaxation of the contractile cells in the trabecular out ow
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 out ow 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
1–3humor. The major drainage regions are the conventional or trabecular out ow
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 out ow pathways it drains
into the episcleral venous system. In addition to the trabecular meshwork out ow
pathways, there is an unconventional or uveoscleral out ow 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











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anterior surface of the ciliary body. When passing through the uveoscleral out ow
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,
4 5unconventional or uveoscleral out ow is found to account for 10% or 25–57% of
the total out ow in the human eye. Uveoscleral out ow is generally regarded as
pressure-insensitive, whereas ow from the anterior chamber across the trabecular
meshwork into Schlemm's canal is pressure-dependent. The trabecular meshwork
out ow pathways provide a resistance to aqueous humor out ow 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 ow driven by the pressure gradient; any active
transport is not involved, as neither metabolic poisons nor temperature a ects this
6,7flow. At steady-state IOP, uid ow across the trabecular out ow resistance is at
the same rate as it is produced by the ciliary body. Out ow resistance in the
8–10trabecular meshwork out ow pathways increases with aging. In primary
openangle glaucoma (POAG), IOP is elevated because the resistance to aqueous humor
11,12out ow in the trabecular meshwork is abnormally high. Out ow 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, out ow resistance is normal. This chapter will focus on
the functional morphology of the trabecular meshwork out ow pathways. For
detailed information on the overall structure of the trabecular meshwork out ow
pathways, the reader is referred to the electronic text of this chapter available online
at http://www.expertconsult.com
The Trabecular Meshwork Outflow Pathways
The critical elements that form the trabecular meshwork out ow 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 bers. 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
lterlike structure. Anteriorly, the trabecular beams are attached near the end of"
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Descemet's membrane and extend posteriorly to the stroma of ciliary body and iris 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
ltering portion of the trabecular meshwork can be di erentiated from a
non ltering portion which has no Schlemm's canal behind it (see Fig. 5-1). Iris
processes, which are at 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.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.
Structure of the Trabecular Meshwork
The trabecular meshwork consists of three regions that di er 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)."
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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
13,14region that is surrounded by a cortical zone (Fig. 5-4). 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 bers (see Fig. 5-4). The
15collagen bers are mostly formed by collagen types I and III. The elastic bers
di er in their ultrastructure from those in other parts of the body, as they contain
considerable amounts of electron-dense material. The presence of elastin has been
con rmed by both enzymatic treatment with elastase and by immunohistochemistry
16,17with speci c antibodies. The bers are surrounded by a sheath that thickens
with age. The sheath is less electron dense than the elastic ber 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"
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brils that enter the aggregates of long-spacing collagen have been shown to label
18with antibodies against collagen type VI. 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
19cells are capable of phagocytosis and may contain pigment particles (Fig. 5-6B).
The phagocytic capabilities of trabecular meshwork cells may be important as
selfcleaning mechanisms of the trabecular lter. The basal lamina of the trabecular
20,21meshwork cells is rich in collagen type IV and laminin.
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.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."
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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.
The Juxtacanalicular Tissue
The juxtacanalicular tissue is a loose connective tissue where trabecular cells are
surrounded by brillar elements of the extracellular matrix. As the connective tissue
brils 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
17prefer the term cribriform meshwork. The cells in the juxtacanalicular tissue form"
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elongated processes by which they attach to one another, to extracellular matrix
brils, or to the cells of the endothelial lining of Schlemm's canal (Fig. 5-7). Between
cells and extracellular matrix bers, there are open spaces that serve as pathways for
aqueous humor. Although a ground substance of various proteoglycans and
22–24hyaluronan has been described in these spaces, the extent to which the ground
substance lls 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 con rm that there is more extracellular matrix in the juxtacanalicular
25tissue as seen by conventional electron microscopy. A characteristic structural
element of the juxtacanalicular tissue is a layer of elastic bers (cribriform plexus)
(see Fig. 5-7) which has been shown to form a brous network in sections tangential
26to the endothelial lining of Schlemm's canal. The elastic bers 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.
Socalled connecting brils consisting of elastic ber material and ne brils emerge
from the cribriform plexus and connect it with the inner wall endothelium of
Schlemm's canal (Fig. 5-8).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."
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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.
Schlemm's Canal
The inner wall endothelium of Schlemm's canal forms large outpouchings (so-called
giant vacuoles) in response to the ow of aqueous humor (Fig. 5-9A). Accordingly,
giant vacuoles are only observed when the chamber angle tissue is xed by
perfusion, but not when it is xed by immersion. Micrometer-sized pores are quite
often associated with the giant vacuoles and allow passage of microparticles 200–
27500 nm in sizes. Bill and Svedbergh calculated the hydraulic conductivity and the
ow resistance generated by the pores and concluded that the inner wall
endothelium could generate not more than 10% of total trabecular out ow
28resistance. Consistent with a minor role of the inner wall endothelium for out ow
resistance is the fact that the endothelium has one of the highest hydraulic
29conductivities in the body, comparable only to that of fenestrated endothelia.
However, more recent experiments indicate that the number of pores increases with
the amount of xative perfused through an enucleated eye and that the total number
of pores identi ed by electron microscopy in xed tissues is likely considerably
10,12smaller than that in the living eye. The pores in Schlemm's canal endothelium
very likely originate from minipores with a diameter of 62–68 nm, which are bridged
30,31across their opening by a thin 5-6 nm non-membranous diaphragm. Similar
30diaphragms cover the caveolae of Schlemm's canal endothelium. Plasmalemma
vesicle-associated protein (PLVAP) is essential for the formation of the
30diaphragms. The endothelial cells of Schlemm's canal are connected by a
junctional complex that contains tight junctions which should restrict paracellular
ow (Fig. 5-9B, C). On the basal side of the endothelial cells, there is ne brillarmaterial 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).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).

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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.
The Site of Outflow Resistance
Because of their high porosity, the uveal and corneoscleral parts of the trabecular
meshwork do not provide signi cant resistance to aqueous humor out ow. Support
for this comes from experimental studies, which show that cutting through the inner
32parts of the trabecular meshwork does not a ect out ow facility, and from
33theoretical calculations using Poiseuille's law. In contrast, there is considerable
evidence that normal aqueous humor out ow resistance resides in the inner wall
8,29region of Schlemm's canal, which is formed by the juxtacanalicular tissue and the
inner wall endothelium. The extracellular spaces between the cells and brillar
elements of the juxtacanalicular tissue appear to be a likely site of out ow
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 signi cant out ow resistance,
unless the pathways are lled with an extracellular matrix gel of unknown nature
34that is not visualized by conventional microscopy. Another possible site of out ow"
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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 xative (see electronic text of this chapter available online at
http://www.expertconsult.com). There is currently much active debate and research
regarding the speci c role of the inner wall endothelium of Schlemm's canal or the
juxtacanalicular connective tissue for the formation of trabecular out ow resistance.
Trabecular meshwork cells have some contractile properties and an increase in their
tone causes an increase in out ow resistance presumably by changing the geometry
35,36of the trabecular meshwork out ow pathways. In contrast, relaxation of
trabecular meshwork cells leads to a decrease in out ow 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
37and causes relaxation of trabecular meshwork cells.
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.
511B). The same banded material that forms the sheaths of the elastic bers 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
lled with banded material. The outer muscle bundles of the longitudinal portion of
the ciliary muscle also form tendons, but connect with the extracellular matrix bers
of the scleral spur. The scleral spur contains collagen and elastic bers that are
circumferentially arranged (Fig. 5-12A). The elastic bers 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
38scleral spur (Fig. 5-12B). More inwardly, they do not bend, but insert to elastic
bers that are continuous with the circumferentially arranged elastic bers 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
14and widens the trabecular spaces, thereby inducing changes in the geometry of the
trabecular meshwork that lead to a reduction in outflow resistance.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)."
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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.)
In addition to ciliary muscle cells, there is another contractile cell population in
38this area which a ects the tone of the trabecular meshwork. The resident cells
within the scleral spur have a myo broblast-like character as they contain numerous
actin laments (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 intermediate lament 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 bers of the scleral spur (see Fig. 5-13A,
B). As this material is continuous with the elastic bers in the core of the trabecular
meshwork beams and the cribriform plexus, changes in the tone of scleral spur cells
are likely to modulate out ow resistance by altering trabecular meshwork
architecture.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
514B 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.)
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.)
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
39myelinated axons. The structure of the nerve endings is very similar to that of
mechanosensors in other parts of the body. The endings contain abundant"
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neuro laments, 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 bers of the scleral spur. The contact between nerve
terminal and connective tissue bers is a very characteristic feature of
mechanosensors, as it is required to measure the tone of the extracellular bers. 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
40,41pressure."

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 Open-Angle Glaucoma
The most characteristic structural change of the trabecular out ow pathways in
primary open-angle glaucoma is an increase in extracellular material in the
14juxtacanalicular region. The material is referred to as sheath-derived plaque
material, as it involves mainly the sheaths of the elastic bers 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"
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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 out ow
42resistance in primary open-angle glaucoma. Another structural change in chronic
open-angle glaucoma involves the number of pores in Schlemm's canal endothelium,
which is decreased signi cantly from normal eyes, even after accounting for the
12volume of xative perfused. Multiple studies have found higher than normal
concentrations of transforming growth factor- β2 (TGF- β2) in the aqueous humor of
43patients with primary open-angle glaucoma. TGF- β2 increases extracellular matrix
synthesis and contractility of trabecular meshwork cells, e ects that are largely
mediated through connective tissue growth factor (CTGF). In genetically modi ed
mice, CTGF induces a myo broblast-like phenotype in trabecular meshwork cells,
44quite similar to that observed in the human scleral spur. The phenotype includes
both an increase in actin-mediated contractility and brillary 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
44glaucoma. A similar scenario may well be responsible for the increase in out ow
resistance in humans with primary open-angle glaucoma.



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.
Spotlight 1
Lymphatics and Uveolymphatic Out ow from the Eye
Neeru Gupta, Yeni Yucel
Most intraocular pressure-lowering glaucoma therapies target conventional and
uveoscleral aqueous out ow pathways and improve drainage of aqueous humor.
Lymphatics play a major role in maintaining tissue– uid balance in most organs
by draining extracellular uid, 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
"

"
"

"
"
1eye using cell-specific markers and electron microscopy with evidence for distinct
lymphatic channels within the human eye ciliary body. These ndings have been
con rmed in sheep, with uorescent nanospheres identi ed in lymphatic channels
1also located within the ciliary body. More recently, lymphatic drainage from the
2eye has been measured in a sheep model.
Lymphatics likely contribute to uid drainage from the eye, and developing
methods to visualize lymphatic ow in vivo is relevant to glaucoma studies. We
used a combination of nanotracers and in vivo hyperspectral imaging to map
3ocular lymphatic drainage in mouse. 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 nding was con rmed by examining
3immunofluorescence stained sections (Fig. 1).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.)
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
4lymphatic drainage from the eye (Fig. 2). 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."


FIGURE 2 Histogram shows mean and SD of QD drainage
−1rate (hours ) for latanoprost-treated (black) and control
(white) groups. *P (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.)
Lymphatic out ow from the eye is a novel pathway that has yet to be exploited
as it relates to our understanding of normal physiological out ow, and to
glaucoma and its treatment. Our nding 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):810–819.
2. Kim M, Johnston MG, Gupta N, et al. A model to measure lymphatic
drainage from the eye. Exp Eye Res. 2011;93(5):586–591.
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.
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.
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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 out ow facility. Changes in
uveoscleral out ow are not consistent among the various syndromes. Uveoscleral out ow
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 ow 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 speci%c abnormality is a logical approach in the
management of ocular hypertension and glaucoma.
Introduction
A %ne balance between the production, circulation, and drainage of ocular aqueous humor
(aqueous humor dynamics) is essential to maintain intraocular pressure (IOP) at a
steadystate 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 out ow (out ow facility, the inverse of out ow
resistance), the rate of uid drainage through the uveoscleral out ow pathway, and the
pressure in the episcleral veins (Fig. 6-1). When one or more of these parameters is altered
and the balance between in ow and out ow is disturbed, various pathological conditions
a, ecting IOP can result. Elevated IOP is usually attributed to an increase in resistance to
out ow 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.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.)
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 ush 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
in ammatory 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 owing through the core of the ciliary processes. Plasma from the blood moves by
ultra%ltration into the tissue spaces of the ciliary process stroma, a process involving the
ow of water and water-soluble substances across the capillary endothelium in response to a
1hydrostatic pressure gradient. 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 di, usion ofwater 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
ow of uid into the posterior chamber. Nutrients and other substances necessary for the
survival of the avascular ocular tissues are added by di, usion to this uid as it courses
through the anterior chamber. Additionally, some solutes such as iodopyracet,
paminohippurate, and prostaglandins are removed from the aqueous humor by the ciliary
2,3epithelium itself.
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.
The rate of aqueous ow is relatively constant, with little physiological need for variation.
A true regulatory mechanism to control the ow rate has not been found. There is a
predictable rhythm of aqueous ow throughout a 24-hour day (Table 6-1). In healthy
humans, aqueous ow is highest in the late morning and lowest in the middle of the night.
4The ow rate at night during sleep is only 43% of the rate in the morning after awakening.
Daytime aqueous ow averages about 2.9 µL/min in young healthy humans and 2.2 µL/min
5in those over 80 years of age. During one's lifetime, the rate of aqueous ow slows at a rate
5of about 2.4% per decade.
Table 6-1
Average Values of Aqueous Humor Dynamics in Healthy Humans
Method of Select
Parameter Mean Value Comments
Measurement ReferencesIOP (mmHg) 18.7 ± 0.7 (OD Lower at night Tonometry Perlman et al.Method of Select
Parameter Mean Value Commentsday) (supine) 200787
Measurement References
16 ⋅6 ± 0.6 (OD
night)
15 ⋅7 ± 0.5 Higher at night Tonometry Liu et al.
(day) (seated) 200388
17 ⋅4 ± 0.6
(night)
20.0 ± 0.3 Higher at night Liu et al.
(day) (supine) 200388
21.3 ± 0.4
(night)
13 ⋅9 ± 0.3 No change at Tonometry Sit et al.
(day) night 200725
(seated)
13 ⋅2 ± 0.4
(night)
19.3 ± 0.4 Lower at night Sit et al.
(day) (supine) 200725
18.1 ± 0.3
(night)
Aqueous flow 3 ⋅0 ± 0.8 Slower at night Fluorophotometry Brubaker 1991;
(µL/min) (morning) Brubaker
19985,6
2.7 ± 0.6
(afternoon)
1.3 ± 0.4
(night)
2.9 ± 0.9 Slower with Fluorophotometry Toris et al.
(young) aging 199920
2.4 ± 0.6 (old)
Outflow facility 0 ⋅28 ± 0.01 Lower with Tonography Gaasterland
(µL/min/mmHg) (young) aging et al.
197823
0.19 ± 0.01
(old)0.21 ± 0.10 No change with Fluorophotometry Toris et al.Method of Select
Parameter Mean Value Comments(young) aging 199920
Measurement References
0.25 ± 0.10
(old)
0.29 ± 0.02 Lower at night Tonography Sit et al.
(day) 200725
0.25 ± 0.01
(night)
0.23 ± 0.01 Lower at night Tonography Liu et al.
(day) 201124
0.19 ± 0.01
(night)
Episcleral venous 10 ⋅1 ± 1.3 No change with Various methods Zeimer 198927
pressure aging
(mmHg)
8 ⋅8 ± 2.0 Higher in the Venomanometry Sultan et al.
(seated) supine 200389
position
9 ⋅5 ± 1.9
(supine)
6.3 ± 0.4 Video recording Venomanometry Sit et al.
(young enhancement 201133
adult)
10.2 ± 0.2 Higher at night Venomanometry Fan et al. in
(day) in the supine press90
position
11.2 ± 0.2
compared to
(night)
daytime in
the seated
position
Uveoscleral outflow 1.52 ± 0.81 Slower with Calculation Toris et al.
(µl/min) (young) aging 199920
1.10 ± 0.81
(old)
1.38 ± 0.44 Slower at night, Calculation Liu et al.
(day, old) several 201124
different
0.07 ± 0.13
calculations
(night, old)
reportedThe mechanisms regulating the circadian rhythm of aqueous ow have been elusive. A
6series of clinical studies has found that aqueous ow is stimulated by β-adrenergic agonists
including epinephrine, norepinephrine, terbutaline, and isoproterenol. Corticosteroids
7appear to augment the catecholamine e, ect. Melatonin might be involved in the nocturnal
8nadir of aqueous ow. Inconsistent with these %ndings are other studies reporting that
9subjects treated with topical epinephrine had reduced rather than increased aqueous ow
and patients with surgical adrenalectomy who completely lacked circulating epinephrine had
10normal rhythms of aqueous ow. 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 uid through the anterior
chamber (aqueous ow). In a clinical research setting, aqueous ow is measured by the
11method known as uorophotometry (Fig. 6-3). First, multiple drops of uorescein are
applied topically to the cornea to establish a corneal depot. Over a period of several hours,
uorescein from the cornea di, uses into the anterior chamber, mixes with aqueous humor,
and begins to drain through the anterior chamber angle. With a uorophotometer, the
uorescein concentrations in the cornea and anterior chamber are measured periodically for
several hours. The log of the uorescein concentrations is plotted over time. The total
uorescein mass in the anterior segment is the product of the uorescein concentrations in
the cornea and anterior chamber and their respective volumes. The aqueous ow rate is
calculated by the mass of uorescein lost from the cornea and anterior chamber over time,
6divided by the average concentration in the anterior chamber during the time interval.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).
12Fluorophotometry is a very well-established method with good reproducibility but four
important limitations and assumptions associated with this technique require consideration:
6,131. Diffusion of fluorescein into the iris, limbal vessels, and tear film is assumed. 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 of the blood–aqueous barrier and the change in diffusion rate of
14fluorescein.
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
15the lens–iris barrier. The accuracy of fluorophotometry is diminished if the lens–iris
barrier is missing or compromised such as in pseudophakia, a dilated pupil, or a previousiridotomy or iridectomy.
4. Several hours of fluorophotometric scans taken at intervals of at least 30 minutes are
6required to determine a reasonably accurate aqueous flow rate in humans. 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 ow via one of two pathways (see Fig. 6-1). The trabecular out ow pathway is
illustrated in Figure 6-4. The uveal meshwork is a forward extension of the ciliary muscle
consisting of large overlapping holes and attened 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,
%broblasts, and endothelial-like cells. Elastic %bers 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 predictions indicate that normal aqueous
16,17humor out ow resistance resides in the inner wall region of Schlemm's canal. 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 out ow resistance is
17generated by the funneling of aqueous humor into the pores of the inner wall endothelium.
Another pathway, composed of the open spaces in the juxtacanalicular connective tissue
creates an insigni%cant fraction of out ow resistance, unless extracellular matrix material
%lls the spaces. Interestingly, the amount of extracellular matrix material in the
juxtacanalicular tissue increases with aging, thus providing an explanation for the apparent
18reduction in outflow facility in older subjects.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.)
Other factors a, ecting trabecular out ow 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 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 uid ow. Trabecular cells
actively change shape, altering the geometry of the open spaces in the meshwork, and they
modulate extracellular matrix turnover which %lls or empties the spaces in the
19juxtacanalicular connective tissue.
20–23Out ow facility in healthy human eyes ranges between 0.1 and 0.4 µL/min/mmHg.
24,25Recent studies report that out ow facility is less at night than during the day. By
tonography or perfusion of enucleated human cadaver eyes, trabecular out ow resistance
18increased with aging. However, when measured by uorophotometry in healthy humans
20on no known prescription drugs, no age-related changes in outflow facility were observed.
Critical evaluation of published studies of out ow facility requires an understanding of the
methods by which this parameter is accessed. Tonography and uorophotometry 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 ow, to account for the IOP change, is obtained from the
26Friedenwald Tables. Out ow facility is the ratio of the change in ow to change in IOP.
Tonographic out ow facility includes trabecular out ow facility, uveoscleral out ow facility
(considered to be small), and pseudofacility (also considered to be small) in the
measurement. Another factor, ocular rigidity (a measure of the sti, ness of the eye), a, ects
the measurement of IOP during tonography. A uorophotometric method (see Fig. 6-3)measures rather than assumes an aqueous ow change with an IOP change. The changes in
IOP and aqueous ow are induced by administering an aqueous ow suppressant such as
acetazolamide, dorzolamide, or timolol. The uorophotometric 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
27veins. In healthy humans the pressure in the episcleral veins ranges from 7 to 14 mmHg,
with values between 9 and 10 mmHg being reported most often (see Table 6-1). There does
28not appear to be a correlation between episcleral venous pressure and age. 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
29parallel the 24-hour variations in episcleral venous pressure. In addition to postural
30changes, other factors a, ect episcleral venous pressure including inhalation of O ,2
31 32application of cold temperature, and vasoactive drugs.
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 identi%ed 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. Identi%cation and
visualization of an appropriate vessel can be diK cult. 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
33which the vessel begins to collapse. It still remains unclear as to which stage of collapse
(beginning, half or total collapse) is the real episcleral venous pressure.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).
Uveoscleral Outflow
Drainage of aqueous humor from the anterior chamber other than through the trabecular
meshwork is called uveoscleral out ow. Unlike the trabecular out ow pathway, the
uveoscleral out ow pathway does not contain recognizable channels and vessels. Instead,
uid seeps through the anterior face of the ciliary muscle and other tissues in and around the
34uvea. In 1965, Anders Bill observed that large tracers, as markers of bulk ow, 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
ow probably do not traverse the sclera but instead are absorbed into the suprachoroidal
space and choroidal vessels.
Drainage of uid through the uvea is sometimes described as ‘unconventional out ow’
because it seeps through tissue rather than ows through channels, or ‘pressure-independent
out ow’ because it does not depend on IOP to the same extent as trabecular out ow. It
should be clari%ed that some pressure dependence is required of all ow. Although very
small, there is a pressure gradient for ow from the anterior chamber into the supraciliary
and suprachoroidal spaces. Studies of monkeys have shown that uveoscleral out ow changes
35little at IOPs in the normal to high range (11–35 mmHg). A change in IOP apparently haslittle e, ect on the pressure gradient between the anterior chamber and the suprachoroidal
space. When IOP is well below normal (4 mmHg), uveoscleral out ow does become
pressure36dependent.
Uveoscleral out ow in healthy subjects 20–30 years of age is reported to be in the range of
20,37,38 2025–57% of total aqueous ow. As one ages, uveoscleral out ow gradually slows.
One study of 104 healthy subjects divided into two age groups found that the group 20–30
years of age had uveoscleral out ow rates that were 54% of total aqueous ow whereas the
group over 60 years of age had signi%cantly slower uveoscleral out ow rates that were 45%
of total aqueous ow. Even in the older subjects, uveoscleral out ow was substantially
39greater than what was %rst reported in the original pivotal human study. In that classic
study, uveoscleral out ow 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 out ow 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 out ow is the most diK cult
to determine in a clinical setting. It cannot be measured directly but it is calculated from the
modified Goldmann equation:
Aqueous ow (F ), out ow facility (C), IOP, and episcleral venous pressure (P ) area ev
measured and uveoscleral out ow (F ) is calculated mathematically. Inherent variabilityu
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 out ow, occasionally in uveoscleral out ow, and rarely in aqueous ow.
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 %eld
defects. The IOP is considered abnormal when it is at least 21 mmHg, which is two standard
40deviations above the mean in several population-based studies. When patients with ocular
hypertension are compared with age-matched healthy volunteers with ocular normotension,
5,41 21,41aqueous ow is within the normal range but both out ow facility and uveoscleral41outflow are signi%cantly reduced. The elevated IOP in ocular hypertension can be
explained by pathologic changes in both outflow pathways (Table 6-2).
Table 6-2
Aqueous Humor Dynamics in Syndromes Associated with Ocular Hypertension and
Related Conditions Associated with Ocular Normotension
Syndrome IOP F C P Fa ev u
Ocular hypertension ↑ ↔5,41,78 ↓21,41,78 ↔41 ↓41
GLAUCOMA
Primary open-angle ↑ ↔day and ↓21,42,44 ↑44
glaucoma ↑night42 (on maximally
tolerated medical
therapy)
Normal-tension ↔ ↔61 ↔61
glaucoma
PIGMENT DISPERSION SYNDROME (PDS)
PDS with normal IOP ↔ ↔63,64 ↔63,64 ↔64 ↔64
PDS with ocular ↑ ↔63,64 ↓63,64 ↔64 ↔64
hypertension
EXFOLIATION SYNDROME (XFS)
XFS with normal IOP ↔ ↔68,70 ↔68,70 ↔70 ↓70
XFS with ocular ↑ ↔70 ↓70 ↔70 ↓70
hypertension
INFLAMMATORY CONDITIONS
Glaucomatocyclitic ↑ ↑75,84,86 ↓21,72–76
crisis
↔21,74,85
Fuch's heterochromic ↔ ↓14 ↔14
iridocyclitis
Superscripted numbers indicate key citations. Arrows indicate values greater than ( ↑),
unchanged from ( ↔) or less than ( ↓) healthy age-matched subjects. C, outflow facility; F ,a
aqueous flow; F , uveoscleral outflow; IOP, intraocular pressure; P , episcleral venousu ev
pressure.
Primary Open-Angle Glaucoma
Primary open-angle glaucoma (POAG) is a disease involving disturbance of the structural orfunctional integrity of the eye leading to elevated IOP accompanied by progressive damage
to the optic nerve and visual %eld loss. The glaucomatous damage often can be arrested or
diminished by adequate lowering of IOP. When compared with healthy age-matched subjects,
aqueous ow in patients with primary open-angle glaucoma was found to be normal during
42the day but signi%cantly elevated at night. This nocturnal aqueous ow e, ect is small and
not suK cient 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 uid ow through the
21 43 42trabecular meshwork. This was reported in 1951, 1961, and again in 1995 using
tonography as the method of measurement. There is little known about uveoscleral out ow
44in patients with primary open-angle glaucoma other than a small study of 14 patients
with IOPs uncontrolled on maximally tolerated medical therapy. In that study, it was found
that uveoscleral out ow was substantially elevated as much as 80% of total out ow in
severely glaucomatous eyes, compared to 37% in contralateral eyes with less severe
glaucoma. Out ow facility when measured by the uorophotometric method was very low in
44these patients on multiple medications (0.02 µL/min/mmHg) compared to a separate
20study 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 di, erence in
uveoscleral out ow 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 ow is less dependent on IOP. In support of this idea is a
45study of untreated monkeys with experimentally induced unilateral glaucoma from laser
46burns to the trabecular meshwork to establish a stable chronic elevation in IOP. Out ow
facility was signi%cantly 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 out ow (2.25 µL/min) when compared to the contralateral control eyes
45 41(1.05 µL/min). These clinical and animal studies suggest that, in ocular hypertension
and the initial stages of glaucoma, uveoscleral out ow and out ow facility are below
normal. As the disease progresses, trabecular out ow facility continues to decline while the
facility of uveoscleral out ow remains constant (pressure independent). When trabecular
out ow 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 out ow pathway in patients with
glaucoma. Within the trabecular meshwork of glaucomatous specimens, endothelial cell
47numbers are decreased 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 elastic-like %bers that
make up a subendothelial tendon sheath. The increased thickness of the sheath of the elastic%bers and connecting %brils reduces the intertrabecular spaces and narrows the ow
pathways to the inner wall endothelium. The presence of plaques also increases with aging
48but the total amount of this material is greater in eyes with POAG. 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
49orientation, and abnormal spacing. Fibronectin is deposited in the subendothelial region
of Schlemm's canal. Expression of myocilin and the amount of αB-crystalline, a small stress
50protein, is increased in the trabecular meshwork of some glaucomatous eyes. The
51interaction of the extracellular matrix components with proteins such as cochlin may lead
to the formation of deposits that obstruct the out ow pathway. Clearly many complex
changes within the trabecular meshwork contribute to increased out ow 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
52 53–56reported that blood pressure decreases and habitual IOP increases at night, both
factors reported to increase the risk of glaucomatous damage to the retina. Additionally,
cerebrospinal uid (CSF) pressure may be involved in glaucoma pathophysiology. CSF
57,58pressure is decreased in primary open-angle glaucoma resulting in a large
translaminar pressure di, erence (the di, erence between IOP and CSF pressure), and greater
stress on the optic nerve. On the other hand, the CSF pressure is high in ocular
59hypertension (compared to controls), the translaminar pressure di, erence is relatively
60normal and glaucomatous optic nerve damage is not detected.
Normotension Glaucoma
Normotension glaucoma is de%ned as cupping and visual %eld loss characteristic of glaucoma
despite IOPs within the ‘normal’ range. Ten patients with normotension glaucoma had no
change in daytime IOP, aqueous ow or out ow facility, or nighttime aqueous ow when
61compared to 10 age-matched healthy controls (see Table 6-2). The primary di, erence in
62patients with normal-tension glaucoma is increased variability of nighttime blood pressure
and nocturnal hypotension that may reduce the optic nerve head blood ow to an unhealthy
52level. 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 ushed into the anterior chamber and the trabecular meshwork where
it may become trapped in the drainage pathway. Patients with pigment dispersion syndrome
63have deeper anterior chambers than normal which predisposes them to the condition.
When pigment dispersion syndrome is not accompanied by ocular hypertension, aqueous
humor in ow and out ow are normal. When pigment dispersion is accompanied by ocular63 64hypertension, out ow facility is reduced but uveoscleral out ow remains normal. This is
distinctly di, erent from ocular hypertension without pigment dispersion syndrome, in which
41both uveoscleral outflow and outflow facility are reduced (see Table 6-2).
Exfoliation Syndrome
Exfoliation syndrome is characterized by white deposits on the anterior capsule of the lens
65and tissues of the ciliary body, iris, cornea, and trabecular meshwork. Exfoliation
syndrome tends to convert into exfoliation glaucoma mainly in elderly patients. This is
because there is age-related narrowing of the out ow pathways to the inner wall of
66Schlemm's canal and build-up of extracellular material and other debris. This material is
easily ushed from the trabecular meshwork in young persons, but becomes trapped in the
trabecular meshwork of older persons. When exfoliative material becomes trapped in
suK cient 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
out ow pathways. The amount of trapped material has been positively correlated with
67increasing IOP and the presence of glaucoma.
Distinct changes in aqueous humor dynamics have been found in exfoliation syndrome.
When comparing the a, ected eye of 18 untreated patients with unilateral exfoliation
68syndrome and ocular normotension with its contralateral una, ected eye, there was no
di, erence in mean IOP (14 mmHg and 12 mmHg, respectively), aqueous ow rate
(2.4 µL/min in both eyes) and outflow facility (0.15 µL/min/mmHg and 0.19 µL/min/mmHg,
69respectively). When exfoliation syndrome was accompanied by ocular hypertension (mean
IOP of 32 mmHg in the a, ected eye and 18 mmHg in the una, ected eye, n = 10), aqueous
ow and out ow facility were signi%cantly lower in the a, ected eye (2.02 µL/min and
0.07 µL/min/mmHg, respectively) than the una, ected eye (2.38 µL/min and
0.15 µL/min/mmHg, respectively). The lower rate of aqueous ow was originally thought to
69be due to damage to the ciliary epithelia from the disease process. However, later it was
thought that the lower aqueous ow was the result of insuK cient time for washout of the
6 70timolol that had been used to treat the a, ected eye. In a more recent study 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 ow was not di, erent between groups (2.05 ± 0.73 in the
exfoliation group and 2.23 ± 0.61 µL/min in the control group) but uveoscleral out ow was
significantly (p Table 6-2).
Fuchs' Heterochromic Iridocyclitis
Chronic, unilateral iridocyclitis characterized by iris heterochromia are hallmarks of Fuchs'
uveitis syndrome or Fuchs' heterochromic iridocyclitis. Abnormal uveal pigment is associated
with chronic low-grade in ammation that is believed to cause iris atrophy and secondary
glaucoma in some patients. In the a, ected eyes of 10 patients with unilateral Fuchs' uveitis
syndrome and normal IOP (17 mmHg) no change was found in out ow facility but the
permeability of the blood–aqueous barrier was increased when compared with the una, ected14contralateral eye. When uorescein was applied to both eyes to measure aqueous ow,
there was 7% greater clearance of uorescein in the a, ected eye, which may have been
caused by increased di, usion of uorescein. Di, erences in the di, usion rate of uorescein
may be interpreted as di, erences in aqueous ow that may not be real. Nevertheless, the
authors suggested that aqueous ow could be lower in eyes with Fuchs' uveitis syndrome (see
36Table 6-2). In agreement with this, a study in monkeys with experimental iridocyclitis
found hypotony associated with a reduction in aqueous ow and an increase in uveoscleral
outflow.
Glaucomatocyclitic Crisis (Posner–Schlossman Syndrome)
A condition with recurrent episodes of markedly elevated IOP usually ranging between 40
and 60 mmHg accompanied by anterior chamber in ammation is called glaucomatocyclitic
71crisis or Posner–Schlossman syndrome. It appears that the cause of the elevated IOP is a
72reduction of out ow facility (see Table 6-2). During the interval between attacks, out ow
facility returns to normal or slightly increases compared to the contralateral healthy
21,73–75 76eye. One study found reduced out ow facility in both the a, ected and healthy
eye in six of 11 patients. It has been proposed that the in ammation is mediated by
prostaglandins. Prostaglandin E has been found in higher concentration in the aqueous
77humor of patients during but not between attacks. Evidence against this theory is found in
78–83studies reporting topical prostaglandins increase, rather than decrease out ow facility,
which would contribute to a reduction, not an increase, in IOP.
75,84Two studies have reported that an increase in aqueous ow contributed to the
21,74,85elevated IOP in glaucomatocyclitic crisis. To complicate matters, three studies that
evaluated this parameter did not %nd an aqueous ow increase. All of these studies were
conducted decades ago when uorophotometry was not available and aqueous ow was
determined in an indirect manner using the Goldmann equation. Uveoscleral out ow was
not considered in the calculation and episcleral venous pressure was assumed to be normal.
86Later, when uorophotometry was used to measure aqueous ow, the clearance rate of
uorescein was found to be reduced, suggesting that aqueous ow was increased during an
attack. However, measurement of intracameral uorescein may have been fraught with
12errors from the presence of proteins and are in the anterior chamber. Taking this into
consideration, it is unlikely that hypersecretion contributes to the elevated IOP in
72glaucomatocyclitic crisis.
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2014.7
Pathogenesis of Glaucomatous Optic
Neuropathy
James E Morgan
S u m m a r y
▪ The optic nerve is the focal point for the loss of retina ganglion cells.
▪ Both focal and diffuse damage in the optic nerve head can generate the characteristic patterns of retinal
ganglion cell death.
▪ The shape and structure of any given optic nerve may increase its vulnerability to damage.
▪ Stress/strain and mechanical factors at the level of the lamina cribrosa will influence the initiation of retinal
ganglion cell death.
▪ Vascular factors such as systemic hypotension or vasospasm may exacerbate RGC death.
▪ Other elements with the retina may influence the pattern of RGC death; for example the presence of immune
cells in the ONH and retina (microglia) and the involvement of the innate and reactive immune system in
glaucoma.
Background
The loss of retinal ganglion cells (RGCs) is a signature event in glaucoma. The loss of visual ' eld usually occurs in
arcuate fashion to match the location of damage within the retinal nerve ' ber and the optic nerve head. These
clinical observations provide compelling evidence that the pathophysiological events initiating RGC loss occur at the
optic nerve head. Secondary changes such as hemorrhages in the peripapillary retinal nerve ' ber layer, posterior
deviation of the lamina cribrosa or loss of cribrosal tissue with the development of optic nerve head pits are all
associated with the exacerbation of vision loss.
Our knowledge of the clinical risk factors for the development of glaucoma has been important in shaping our
views of the events that occur in the optic nerve head in this disease. Advancing age remains the single most
important (but untreatable) risk factor. Of the treatable risk factors, elevated intraocular pressure is the most easily
identi' ed though it is likely that refractive error and optic disc size also play a role. In addition, there is strong
evidence the blood supply of the optic nerve head in- uences retinal ganglion cell survival. More recently work in
experimental glaucoma and clinical studies suggest a role for the immune system in modulating the retinal response
to damage. It is now clear that these risk factors do not act in isolation; the challenge has been the development of
a framework in which they can interact to generate vision loss.
In the past the pathophysiological processes that result in axon loss have been considered separately as either
mechanical or vascular factors in the initiation and propagation of retinal ganglion cell death. A more
contemporary view is that they can be treated as a continuum in which each factor contributes to the damage of
retinal ganglion cell axons. Therefore, rather than being mutually exclusive it now seems likely that vascular and
mechanical and immune factors combine to cause axon loss. Our understanding of the way in which these forces can
result in neural damage has advanced considerably in the last decade. It has highlighted the importance of
determining not just the gross organization of the optic nerve head and lamina cribrosa, but also the behaviors of its
various cellular elements under stress.
Normal Organization of the Lamina Cribrosa: Relevance to the Pathogenesis
of Glaucomatous Optic Neuropathy
The human optic disc represents an elliptical opening in the sclera through which optic nerves pass to leave the eye
and enter the retrobulbar optic nerve. For the million or so axons that comprise the optic nerve this is a zone of
transition and vulnerability. Axons have to rotate through 90 degrees to exit the eye and in doing this to rearrangeso that they come to lie in the appropriate topographic organization within the optic nerve. The posterior part of
the optic nerve also sees the myelination of the axons as each is invested in an oligodendrocyte-derived sheath to
facilitate saltatory conduction. Retinal ganglion cells are unique in the retina in that they are the only cells to
generate action potentials. This is an energy-intensive process; analysis of retinal nerve ' ber layer anatomy has
1shown that the mitochondria tend to concentrate in varicosities along the retinal ganglion cell axons. It is perhaps
not surprising that RGCs are particularly vulnerable to the diseases where mitochondrial function is compromised.
Studies of the distribution of mitochondrial enzymes such as cytochrome-c oxidase have shown that they are
2concentrated at the optic nerve head (Figs 7-1 and 7-2).
FIGURE 7-1 Differential interference contrast (DIC) image of a primate optic nerve head
showing the relationship between the retinal nerve fiber layer and lamina cribrosa. The arrow
indicates the demarcation between the anteriorly located glial pre-lamina and the scleral lamina
cribrosa. (Reproduced with permission from Br J Ophthalmol 1998; 82:6.)FIGURE 7-2 (A) Axon varicosities in the retinal nerve fiber layer of a whole mounted human
retina from an 85-year-old patient. The varicosities coincide with regions in the axon where
mitochondria and other organelles are concentrated. (From Wang L, Dong J, Cull G, et al.
Varicosities of intraretinal ganglion cell axons in human and nonhuman primates. Invest
Ophthalmol Vis Sci 2003; 44:2–9.) (B) Distribution of cytochrome oxidase activity in the human
optic nerve head. (From Andrews RM, Griffiths PG, Johnson MA, Turnbull DM. Histochemical
localization of mitochondrial enzyme activity in human optic nerve and retina. Br J Ophthalmol
1999; 83:231–5.)
Axons are supported in this passage by a complex arrangement of glial supportive tissue in the anterior part of
the optic nerve head which lies in continuity with pores running through the lamina cribrosa. These glial processes
are contiguous with those lying within the retinal nerve ' ber layer. The optic nerve head is divided into an anterior
glial pre-lamina region that lies anterior to the collagenous lamina cribrosa. At the part of the optic nerve that is
clinically apparent as the lamina cribrosa, the lamina is comprised of the collagenous cribrosal plates,
3approximately 10 layers thick that lie at the level of the scleral opening. Each plate is perforated to provide room
for the axons to pass in bundles approximately 100 microns wide. When viewed in cross-section, the plates appear
to be discrete and separated. Digest studies which removed cellular components and the glial prelamina have
revealed that the plates have abundant connections between each other and form a compact three-dimensional
4array of pores through which the axon bundles run (Fig. 7-3). The scleral lamina can therefore be regarded as a
mesh-like structure in which any forces that result in distortion of one part will be transmitted throughout the
lamina cribrosa.FIGURE 7-3 (A and B) Immunofluorescent staining of cross-section through the human lamina
cribrosa stained with antibodies against collagens I and III. Scale 100 µm. (From Albon J,
Karwatowski WS, Avery N, et al. Changes in the collagenous matrix of the aging human lamina
cribrosa. Br J Ophthalmol 1995; 79:368–75.) (C and D) Scanning electron micrographs of
human optic nerve head following partial enzymatic digestion. (From Albon J, Farrant S, Akhtar
S, et al. Connective tissue structure of the tree shrew optic nerve and associated ageing
changes. Invest Ophthalmol Vis Sci 2007; 48:2134–44.)
Axon Organization in the Optic Nerve Head: A Role for Mechanical Factors
5The detailed organization of axons as they pass through the optic nerve remains a source of continued debate. At a
coarse level axon bundles are arranged so that those arising from peripheral parts of the retina come to lie in the@
@
6periphery of the optic nerve. Analysis of the movement of the cribrosal plates in glaucoma has shown that these
rotate around the margin of the scleral opening (Elschnig's rim) in a way that is likely to induce the greatest
compressive force on axons lying in the peripheral part of the optic nerve. This pattern of events ' ts with clinical
observations that peripheral loss of visual ' eld is a characteristic feature in glaucoma. Electron microscopic studies
of retinal ganglion cell axons in experimental glaucoma provide con' rmatory evidence that axons may be damaged
7as the cribrosal structures are distorted and collapse (Fig. 7-4).
FIGURE 7-4 (A) Scanning electron micrographs of human optic nerve head in glaucoma
showing characteristic rotation of the plates of the lamina cribrosa at the edge of the optic nerve.
(From Quigley HA, Addicks EM. Regional differences in the structure of the lamina cribrosa and
their relation to glaucomatous optic nerve damage. Arch Ophthalmol 1981; 99:137–43.) (B)
Diagrammatic representation of the orientation of the glial columns in the pre-lamina part of the
human optic nerve head, based on staining for GFAP, a marker of astrocytes. (From Triviño A,
Ramírez JM, Salazar JJ, et al. Immunohistochemical study of human optic nerve head astroglia.
Vis Res 1996; 36:2015–28.)
While these events are likely to occur in the end stages of disease, the extent to which this occurs with early axon
damage is unclear. Detailed analysis of the trajectories taken by individual axons through the optic nerve head
suggests that even minor displacement of the lamina cribrosa could have an adverse e ect on axonal function.
When the paths taken by individual axons are traced it is apparent that they can deviate from the expected path
5,8observed when the population is considered as a whole. This topographic ‘noise’ can give rise to populations of
axons in which some pass between the cribrosal plates which might render them more vulnerable to the pressure on
the optic nerve head. A degree of axon deviation is to be expected when the di erences in the dimensions of the
anterior and posterior parts of the scleral lamina is considered. The anterior part of the scleral lamina receives
unmyelinated axons whereas the posterior part interfaces with the junction at which axons become myelinated. As a
result, the number of pores increases with depth in the lamina cribrosa such that there are more pores in the deeper
3part of the lamina, compared with the superficial part (Figs 7-5 and 7-6).FIGURE 7-5 Path taken by axons within the primate (macaque) retinal nerve fiber layer. Note
that axons from the superficial layers of the retinal nerve fiber layer are distributed throughout
the optic nerve at the level of the scleral canal. (Redrawn from Ogden TE. Nerve fiber layer of
the macaque retina: retinotopic organization. Invest Ophthalmol Vis Sci 1983; 24:85–98.)
FIGURE 7-6 Axon deviation in the human lamina cribrosa. A single axon is indicated that
passes between the plates of the lamina cribrosa (the middle of a plate is shown by the
asterisk). (From Morgan JE, Jeffery G, Foss AJ. Axon deviation in the human lamina cribrosa.
Br J Ophthalmol 1998; 82:680–3.)
Astroglial Interactions within the Lamina Cribrosal: Translating the Effects of
Stress and Strain
In the early stages of glaucoma, it is unlikely that the cribrosal plates are grossly distorted in ways that will result in
axonal constriction. A simple mechanical model of axon damage therefore seems unlikely in the early stages of the
disease. Studies indicating local axon enlargement with accumulation of mitchondria at the level of the lamina
2cribrosa now seem more likely to re- ect axonal metabolic demands rather than gross axon compression. Clinical
evaluation of the optic nerve head suggests little distortion of the lamina cribrosa and this has been con' rmed by
digital imaging studies of the optic nerve head. Yet even at this stage in glaucoma, axons are lost and the challenge
has been in determining the mechanisms by which this can occur.
Several key studies have been undertaken recently which have analyzed the interaction between the shape of the
optic nerve and the stress and strain that might be built up in the optic nerve head. These have been based on
meticulous high-resolution reconstructions of the optic nerve head which have allowed the generation of
three9,10dimensional computer models of the nerve head. These models can then be subject to ' nite element analysis in
which the forces that lie within the beams of the lamina cribrosa are modeled to develop three-dimensional stress
and strain maps of the lamina cribrosa. An important ' nding from this work is that it has highlighted the stresses
that can build up in the lamina cribrosa and that these changes can occur shortly after experimental elevation in
9IOP (Fig. 7-7).@
@
@
FIGURE 7-7 (A) Digital reconstruction of a primate optic nerve showing the effects of
experimental elevation of intraocular pressure on the scleral lamina. Note the posterior bowing of
the lamina with preservation of the pore alignment. The rotation of the laminar plates is greatest
at the periphery of the nerve. (B) Image shows the thickening in the lamina cribrosa that occurs
with a short-term increase in IOP in the primate. (Part A from Burgoyne CF, Downs JC, Bellezza
AJ, Hart RT. Three-dimensional reconstruction of normal and early glaucoma monkey optic
nerve head connective tissues. Invest Ophthalmol Vis Sci 2004; 45(12):4388–99. Part B
redrawn from Yang H, Downs JC, Girkin C, et al. 3-D histomorphometry of the normal and early
glaucomatous monkey optic nerve head: lamina cribrosa and peripapillary scleral position and
thickness. Invest Ophthalmol Vis Sci 2007; 48(10):4597–607.)
Forces acting within the optic nerve head are dynamic and re- ect pulsation in the central retinal artery and its
interaction with the intraocular pressure. The degree to which the lamina cribrosa can be distorted varies with age.
In younger eyes it shows considerable elasticity and can, after increased pressure has been removed, return to its
normal con' guration. With older eyes, the elasticity of the tissue is less and there is less of a tendency for the
11deformation to resolve with resolution of the imposed pressure. These observations all point to the lamina
cribrosa as playing a key role in mediating axon damage.
Recent evidence that the lamina cribrosa thickness increases following short-term elevation of intraocular
12pressure in the primate is consistent with the idea that changes in the optic nerve are dynamic. The increase could
arise from axonal swelling or from remodeling of the cribrosa itself with the deposition of new connective tissue. It
is important to note that these data are derived from observations on young eyes. Further work is required to
determine the extent to which these changes occur in older eyes.
Optic Nerve Head Astrocytes: Translating Optic Nerve Stress into Axon
Damage
13Astrocytes are the predominant glial support cell in the optic nerve head. They surround the beams of the lamina
14cribrosa and are connected and communicate via a network of gap junctions to form, e ectively, a syncytium to
provide an environment to support the retinal ganglion cell axons. The close association of these cells and the
beams of the lamina cribrosa where they are interposed between the cribrosa and the axons, makes them ideally
15placed to mediate the e ects of changes in the cribrosal beams to the axon population. Since axons conduct
action potentials, it is critical that the appropriate extracellular environment is maintained to support the
associated ionic changes.
Numerous experiments have shown that astrocytes can go from exerting a supportive e ect on axons to one in
which they can in- ict damage. If the ability of astrocytes to support axons is compromised then this will result in
axonal stress and loss. For example, astrocytes can generate harmful agents such as NO by upregulating the
expression of NOS-2 which can result in direct axonal damage (Fig. 7-8). There is some evidence that agents limiting
16the generation of NO can reduce the loss of retinal ganglion cells in a model of experimental glaucoma.
Astrocytes lying at the boundary of the lamina cribrosa and the myelinated part of the optic nerve (the myelin
transition zone) also play a phagocytic role by internalizing axonal evulsions in both normal and glaucomatous
17eyes. In experimental glaucoma this activity may be upregulated and contribute to axon damage at the posterior
aspect of the lamina.@
@
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FIGURE 7-8 Immunohistochemistry for NOS-2 (red) and GFAP (green) in the normal (A) and
glaucomatous (B) optic nerve head. NB, nerve bundle, CP: cribriform plate. (From Liu B,
Neufeld AH. Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human
glaucomatous optic nerve head. Glia 2000; 30:78–86. Reprinted with permission of Wiley-Liss,
Inc., a subsidiary of John Wiley & Sons, Inc.)
18,19In addition to astrocytes a signi' cant population of lamina cribrosal cells has been isolated. These are
19classed as glial cells but di er in that they do not express glial ' brillary acid protein (GFAP). These cells are
starshaped and lie within the cribriform plates. They are likely to be important in maintaining their integrity but are
localized to the scleral lamina. In experiments where the cells are subject to the stresses and strains that might be
seen in glaucoma, these cells can upregulate the expression of genes such as TGF- β that may be important in2
19regulating the remodeling of the lamina cribrosa.
Blood Supply: Normal and Glaucoma
The Blood Supply of the Optic Nerve Head
Clinical studies suggest that de' cits in the blood supply of the optic nerve head may be important in generating
RGC loss. Glaucoma-like cupping of the optic nerve head has been observed in patients in which the systemic blood
20supply has been compromised (by systemic hypotension ). The blood supply of the optic nerve is complicated and
unusual in that the central retinal artery does not contribute to the supply of the optic nerve head. Instead, the
blood supply comes from a series of 15–20 short posterior ciliary arteries coming o the long posterior ciliary
21,22arteries which in turn branch o the ophthalmic artery. These arteries lie within the scleral tissue to form an
incomplete anastomosis (the circle of Zinn-Haler) around the optic nerve at the level of the scleral lamina. The
precise anatomy of these vessels has been characterized by resin cast studies of the post-mortem tissue in which the
optic nerve vasculatures is ' lled with resin and then exposed by chemical digestion of the surrounding tissues.
Small, end arterial branches are sent from this circle into the optic nerve head to supply it with oxygen (Fig. 7-9).@
FIGURE 7-9 Scanning electron micrograph of a corrosion cast of human optic nerve head
vasculature. (A) Anastomosis of Zinn Haller indicated (arrows) sending short posterior ciliary
vessels into the optic nerve head at the level of the lamina cribrosa. (B) Arrow indicates area
where the anastomosis is narrowed. (From Olver JM, Spalton DJ, McCartney AC. Quantitative
morphology of human retrolaminar optic nerve vasculature. Invest Ophthalmol Vis Sci 1994;
35(11):3858–66.)
These end arteries expose the optic nerve to the risk of hypoxic damage if the systemic blood supply is
compromised; this is consistent with clinical observations that systemic hypotension can increase the risk of
glaucoma progression. Patients with conditions such as Raynaud's syndrome also appear to be at slightly increase
the risk of developing glaucoma. There is evidence that patients with low tension glaucoma may demonstrate
23abnormalities in the peripheral circulation in response to changes in temperature.
These observations do not, in themselves prove that de' cits in the blood supply are important factors, but they
are persuasive. Clinical studies have reported that some glaucoma patients have an elevated systemic level of
endothelin-1, a potent vasoconstrictor. In the rodent and primate models of glaucoma, chronic delivery of
endothelin which results in vasoconstriction of the SPCAs can result in the loss of axons in a distribution that is
24similar to that seen in glaucoma associated with elevated intraocular pressure. In the mouse glaucoma model,
changes in endothelin expression have been identi' ed as one of the earliest changes to occur following IOP
25elevation and that inhibition with an endothelin receptor antagonist provides robust axonal protection.
What is the Role of IOP in Initiating Axon Loss?
The relationship between IOP and axon loss is complex. The IOP level remains a key in- uence on the health of the
22axon population; even small di erences in IOP correlate with glaucoma severity. The long-term - uctuation in
26IOP can also in- uence the degree of optic nerve damage, eyes with a greater - uctuation in IOP also have an@
@
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@
@
increased risk of progressive visual ' eld loss. These observations ' t nicely with the idea that stress and strain in the
lamina cribrosa, acting through cellular elements will promote the loss of retinal ganglion cell axons. It now seems
likely that the non-neuronal, glial cell population plays a major role in integrating the e ects of IOP elevation, and
- uctuation with exacerbating factors such as a compromised optic nerve head circulation. For any given case, the
relative importance of these factors will vary to generate a similar pattern of optic nerve damage.
How Does Axon Damage Result in RGC Loss?
Early studies of the e ects of elevated intraocular pressure on axonal anatomy revealed axon ballooning in regions
27with compression of the plate of the lamina cribrosa. This provided an attractive hypothesis for the way in which
axons could be damaged and how this would cause the loss of retinal ganglion cells. Axons are important in
regulating the activity and survival of the cell soma by the retrograde transport of neurotrophins from the target
regions contacted by the axons. They terminate in both the LGN and the superior colliculus and these are sites which
produce neurotrophins that are then retrogradely transported to the retinal ganglion cells. Compromised transport
of neurotrophins from these target locations to the retinal ganglion cells would predispose to cell death. Histological
studies demonstrating the building of TRKB receptor in the optic nerve head of rodent and primate glaucomatous
28optic nerves support this hypothesis. However, it is not yet clear the extent to which other cells in the retina (and
optic nerve) can compensate by local production of neurotrophins. Upregulation of BDNF levels in experimental
29glaucoma is associated with reduced loss of retinal ganglion cells but further work is required to see if this is a
persistent effect.
Retinal Factors in the Initiation of Retinal Ganglion Cell Death
It is possible that retinal ganglion cell loss in itself will in- uence the viability of surviving cells. Of most interest in
this respect has been the suggestion that the release of glutamate from dying cells is directly toxic to surrounding
RGCs. Measurement of glutamate levels from the vitreous of patients with glaucoma suggested a selective rise in
30 31,32glutamate which can cause neural damage. However, subsequent studies have not con' rmed this elevation
and the consensus is now that an elevated glutamate concentration in the vitreous is unlikely to be a prime factor in
the initiation of retinal ganglion cell death. These ' ndings do not exclude a role for glutamate in mediating retinal
ganglion cell damage. In experimental glaucoma, the glutamate uptake mechanism can be compromised following
33 34IOP elevations in the absence of a significant increase in vitreal levels of excitatory amino acids.
Mitochondrial Factors
The energy demands of retinal ganglion cells are considerable, as evidenced by the abundance of mitochondria
through the cell soma, axon and dendrites. The concentration of mitochondria at points of damage – the lamina
cribrosa is consistent with their role in protecting RGCs from damage by ensuring an appropriate local supply of
35ATP. Mitochondria are also critical for the maintenance of synaptic integrity. In models where mitochondrial
function is compromised (e.g. in OPA1 models) retinal ganglion cell atrophy occurs in a fashion similar to that seen
36in experimental glaucoma. Patients with open-angle glaucoma have been reported to have defects in complex 1
37of the oxidative phosphorylation pathway which may compromise RGC viability when subject to other stresses.
Light exposure may also have a deleterious e ect on the function of healthy mitochondria by the generation of
38reactive oxygen intermediates, particularly following exposure to short-wavelength light.
Immunological Factors in Glaucomatous Optic Neuropathy
Clinical investigations have revealed that immunological factors are likely to be important in in- uencing the degree
of retinal ganglion cell death in glaucoma. Systemic investigations are consistent with activation of the immune
system in initiating retinal ganglion cell loss: for example with elevation of autoantibodies to both retinal and optic
39nerve antigens. Whether these changes are secondary to the loss of retinal ganglion cells remains unclear.
Treatments based on immunomodulation by boosting the protective e ects of T cells within the CNS have shown
40some bene' t in limiting retinal ganglion cell death in a rodent glaucoma model. The protective e ect also
41extends to acute increases in IOP but not to the prevention of secondary retinal ganglion cell loss in models of
42more severe optic nerve damage (e.g. by partial optic nerve transection).
Histological studies of the human optic nerve head have suggested that microglial cells which can be resident or@
@
43recruited from the systemic circulation are important in the initiation of retinal ganglion cell death. Microglia are
important in the CNS and can act in both a protective and destructive role; there is good evidence for their role in
44retinal conditions such as uveitis and photoreceptor degeneration. They usually act as scavengers to clear the
debris of dead or dying neurons but can also harm cells by the release of cytokines such as TNF alpha (Fig. 7-10). In
experimental models of glaucoma there is evidence that microglia are activated as a result of the elevation in
45intraocular pressure. The activity of these cells can be reduced by the application of agents such as minocycline
46and it is possible that this can be beneficial in reducing the degree of retinal ganglion cell loss.
FIGURE 7-10 Immunohistochemistry for microglia in the human optic nerve head: (A) clusters
of HLA-DR labeled cells and (B) Cells positive for CD45. The cells are clustered along Bruch's
membrane which extends beyond the termination of the retinal pigment epithelium. (From
Neufeld AH. Microglia in the optic nerve head and the region of parapapillary chorioretinal
atrophy in glaucoma. Arch Ophthalmol 1999; 117:1050–6.)
More recently monocytes have been shown to mediate axonal damage in the mouse glaucoma model and the
47inhibition of this process has a profound protective e ect. These changes have been traced to activation of a
leukocyte transendothelial migration pathway which allows proin- ammatory leukocytes to enter the optic nerve
head. Subsequent work has shown that irradiation can be neuroprotective by reducing the activation of optic nerve
48microglia. The extent to which these changes and therapeutic bene' ts can be applied to human glaucoma has yet
to be determined.
The innate immune system has also been implicated in the initiation of retinal ganglion cell damage. Evidence
from the rodent model of glaucoma has indicated the deposition of C1q, C3 and membrane attack complex (MAC)
49within the retinal ganglion cell layer following the induction of experimental glaucoma (Fig. 7-11). Whether
complement activation per se can be an initiator of RGC damage is unclear. Clinically, patients with mutations in
proteins that control complement activation (e.g. Complement Factor H (CFH), an inhibitor of complement
activation) have not been noted to have a higher rate of glaucoma, in contrast to the deleterious e ects these
mutations can have on macular degeneration. CFH levels have been reported to be lower in human glaucoma and
studies in cultured retinal ganglion cells support the hypothesis that oxidative damage can suppress CFH levels
50thereby predisposing to increase complement activation.@
@
FIGURE 7-11 Immunohistochemistry showing the distribution of membrane attack complex
(MAC) in normal (A) and oculohypertensive (B) eyes. (From Kuehn MH, Kim CY, Ostojic J, et al.
Retinal synthesis and deposition of complement components induced by ocular hypertension.
Exp Eye Res 2006; 83:620–8.)
Conclusions
Considerable progress has been made in our understanding of the factors that in- uence axon loss in glaucoma.
There is a broad consensus that the lamina cribrosa and its cellular elements play a key role in initiating axonal
damage, which then precipitates retinal ganglion cell death. The relationship between the beams of the lamina
cribrosa and surrounding astrocytes provide a pivotal point for the generation of cytokines and agents that would
damage passing axons. The pool of agents that in- uence axonal viability continues to expand, con' rming the
multifactorial drivers of RGC damage in glaucoma. Thus, the energetic state of retinal ganglion cells which is
in- uenced by the age of the patient and exposure to reactive oxygen intermediates may set the threshold for other
factors to initiate damage. The increasing evidence for involvement of the immune system, both innate and
adaptive, is particularly exciting since it may o er therapeutic interventions with profound and long-lasting
protective e ects in glaucoma. The challenge in evaluating these pathways remains in the translation from animal
models to human disease.
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Mechanical Strain and Restructuring of
the Optic Nerve Head
J Crawford Downs, Claude F Burgoyne, Rafael Grytz
S u m m a r y
The ONH is of particular interest from a biomechanical perspective because it is a weak spot within
an otherwise strong corneo-scleral envelope. Overwhelming evidence suggests that the lamina
cribrosa is the principal site of retinal ganglion cell axon insult in glaucoma, so glaucomatous optic
neuropathy can be viewed as an axonopathy occurring at the ONH. We present a framework of ONH
biomechanics as a central mechanism in glaucoma pathophysiology, wherein IOP not only determines
the mechanical environment in the ONH, but also mediates IOP-induced connective tissue remodeling,
reductions in blood flow, and cellular responses through various pathways.
The Optic Nerve Head (ONH) as a Biomechanical Structure
The ONH is of particular interest from a biomechanical perspective because it is a weak spot within an
otherwise strong corneo-scleral envelope. While there may be important aspects of glaucoma
pathophysiology within the lateral geniculate, visual cortex, and retinal ganglion cell (RGC) soma,
overwhelming evidence suggests that the lamina cribrosa is the principal site of RGC axonal insult in
1glaucoma. In this sense, glaucomatous optic neuropathy can be viewed as an axonopathy, where
1damage to the visual pathway is driven by insult to RGC axons as they exit the eye at the ONH. The
mechanisms of RGC axonal insult at the ONH insult are poorly understood, but we present a framework
of IOP-driven ONH biomechanics as a central mechanism in the pathophysiology of glaucoma.
The lamina cribrosa provides structural and functional support to the RGC axons as they pass from the
relatively high-pressure environment in the eye to a low-pressure region in the retrobulbar cerebrospinal
2space. To protect the RGCs in this unique anatomic region, the lamina cribrosa in higher primates has
developed into a complex structure composed of a three-dimensional (3D) network of - exible beams of
connective tissue (Fig. 8-1). The ONH is nourished by the short posterior ciliary arteries, which penetrate
the immediate peripapillary sclera to feed capillaries contained within the laminar beams. This
intrascleral and intra-laminar vasculature is unique in that it is encased in load-bearing connective tissue,
either within the scleral wall adjacent to the lamina cribrosa, or within the laminar beams themselves
(Fig. 8-1). Glaucoma is a multifactorial disease, and we believe that biomechanics not only determines
the mechanical environment in the ONH, but also mediates IOP-related reductions in blood - ow and
cellular responses through various pathways (Fig. 8-2).FIGURE 8-1 The optic nerve head (ONH) is a three-dimensional (3D) structure
comprised of multiple interactive tissue systems that exist on different scales. This
complexity has been a formidable deterrent to characterizing its mechanical
environment. (A) While clinicians are familiar with the clinically visible surface of the
optic nerve head (referred to as the optic disc), in fact the ONH (B) is a dynamic, 3D
structure (seen here in an illustrated sectional view) in which the retinal ganglion cell
(RGC) axons in bundles (white) surrounded by glial columns (red), pass through the
connective tissue beams of the lamina cribrosa (light blue), isolated following trypsin
digestion in an scanning electron micrograph (SEM) of the scleral canal in (C). The
blood supply for the connective tissues of the lamina cribrosa (D) derives from the
posterior ciliary arteries and the circle of Zinn–Haller (Z-H). (E–F) The relationship of
the laminar beams to the axon bundles is shown in schematic form in (E). (F)
Individual beams of the lamina cribrosa are lined by astrocytes. Together they
provide structural and metabolic support for the adjacent axon bundles. Within the
lamina, the RGC axons have no direct blood supply. Axonal nutrition requires
diffusion of nutrients from the laminar capillaries (solid red), across the endothelial
and pericyte basement membranes, through the extracellular matrix (ECM) of the
laminar beam (stippled), across the basement membranes of the astrocytes (thick
black), into the astrocytes (yellow), and across their processes (not shown) to the
adjacent axons (vertical lines). Chronic age-related changes in the endothelial cell
and astrocyte basement membranes, as well as intraocular pressure (IOP)-induced
changes in the laminar ECM and astrocyte basement membranes may diminish
nutrient diffusion to the axons in the presence of a stable level of laminar capillary
volume flow. In advanced glaucoma, the connective tissues of the normal lamina
cribrosa (sagittal view of the center of the ONH; vitreous above, orbital optic nerve
below), (G) remodel and restructure into a cupped and excavated configuration (H).FIGURE 8-2 IOP-related stress and strain are a constant presence within the ONH
at all levels of IOP. IOP acts mechanically on the tissues of the eye, producing
deformations, strain and stress within the tissues. These deformations depend on
the eye-specific geometry and material properties of the tissues. In a biomechanical
paradigm, the stress and strain will alter the blood flow (primarily), and the delivery of
nutrients (secondarily) through chronic alterations in connective tissue stiffness and
diffusion properties. IOP-related stress and strain also induce connective tissue
damage directly (laminar beam yield), or indirectly (cell mediated remodeling), which
drives a connective tissue remodeling process that alters the tissues' geometry and
mechanical response to loading. This feeds back directly onto the mechanical effects
of IOP. (Adapted from Sigal IA, Roberts MD, Girard MJA, Burgoyne CF, Downs JC.
Chapter 20: Biomechanics Changes of the Optic Disc. In: Levin LA, Albert DM (eds),
Ocular Disease: Mechanisms and Management. London: Elsevier; 2010:153–64.)
Consideration of the anatomy of the lamina cribrosa and peripapillary sclera suggests that the classic
‘mechanical’ and ‘vascular’ mechanisms of glaucomatous injury are inseparably intertwined (Figs 8-1 and
8-2). For example, prior to structural damage, purely IOP-related stress could detrimentally a3ect the
blood supply to the laminar segments of the axons through deformation of the capillary-containing
connective tissue structures. Also, IOP-related remodeling of the extracellular matrix (ECM) of the
laminar beams could limit the di3usion of nutrients to RGC axons in the ONH. Reciprocally, primary
insu7 ciency in the blood supply to the laminar region could induce cell-mediated connective tissue
changes that would serve to weaken the laminar beams, making them more prone to failure under
previously ‘safe’ levels of IOP-related mechanical stress.
To incorporate these concepts into a global conceptual framework, we have previously proposed that
2–4the ONH is a biomechanical structure. This paradigm assumes that IOP-related stress
(force/crosssectional area) and strain (local relative deformation of the tissues) are central determinants of both the
physiology and pathophysiology of the ONH tissues and their blood supply (Fig. 8-2) at all levels of IOP.
These changes include not only alterations to the load-bearing connective tissues of the lamina cribrosa
and the peripapillary sclera, but also the cellular components of these tissues, including astrocytes, glial
cells, endothelial cells, and pericytes, along with their basement membranes and the RGC axons in the
ONH. Experienced over a lifetime at physiologic levels, they underlie ‘normal’ ONH aging. However,
acute or chronic exposure to pathophysiologic levels results in glaucomatous damage.
Although clinical IOP-lowering remains the only proven method of preventing the onset andprogression of glaucoma, the role of IOP in the development and progression of the disease remains
controversial. This largely arises from the clinical observation that signi; cant numbers of patients with
normal IOPs develop glaucoma (e.g. normotensive glaucoma), while other individuals with elevated IOP
show no signs of the disease. This could mean that IOP (or some factor driven by IOP) is a primary
causative factor in glaucoma, and IOP vulnerability varies between individuals. Another possibility is
that clinical characterization of mean IOP using infrequent snapshot measurements fails to capture
exposure to larger, injurious IOP fluctuations that are partly driving the disease in these ‘normotensive’
glaucoma patients, which undermines the study of the IOP–glaucoma relationship. Recent data indicate
that IOP - uctuates as much as 5 mmHg day-to-day and hour-to-hour, and 15 to 40 mmHg
second-to5second when measured continuously via telemetry in unrestrained, awake monkeys (Fig. 8-3). Very
little is known about IOP - uctuations in humans and how the eye responds to those - uctuations, but IOP
levels at all timescales have the potential to injure the RGC axons in the ONH.
FIGURE 8-3 High- and low-frequency IOP fluctuation in the monkey. (A) Screen
capture of approximately 7 seconds of the continuous IOP tracing from an
unrestrained awake primate showing baseline mean IOP of ~8–13 mmHg and IOP
fluctuations up to 12 mmHg associated with blinks and saccadic eye movements.
IOP fluctuations can be much larger and of longer duration, especially when the
animal squints or is agitated or stressed. (B) Plot of the 10-minute time-window
average of 24 hours of continuous IOP showing low-frequency IOP fluctuation from a
single monkey. The color of the plot points and lines indicate how much data were
removed from each 10-minute window after post-hoc digital filtering of signal dropout
and noise. Green indicates that 100% of the continuous IOP data were used in the
10-minute average IOP plotted in each point, and yellow indicates that 50% were
eliminated due to signal dropout or noise. Note the fluctuations in IOP are substantial
even when the high-frequency IOP spikes seen in the top plot are averaged
out. (Adapted from Downs JC, Burgoyne CF, Seigfreid WP, Reynaud JF, Strouthidis
NG, Sallee V. 24-hour IOP telemetry in the nonhuman primate: implant system
performance and initial characterization of IOP at multiple timescales. Invest
Ophthalmol Vis Sci 2011; 52:7365–75.)
Whether it is mean IOP and/or IOP - uctuations that drive glaucomatous pathogenesis, there is a wide
spectrum of individual susceptibility to IOP-related glaucomatous vision loss, the biomechanical e3ects of
IOP on the tissues of the ONH likely play a central role in the development and progression of the
disease at all IOPs. The individual susceptibility of a particular patient's ONH to IOP insult is likely a
function of the biomechanical response of the constituent tissues and the resulting mechanical, ischemic
and cellular events driven by that response. Hence eyes with a particular combination of tissue geometry
and material properties may be susceptible to damage at normal IOP, while others may have a
combination of ONH tissue geometry and material properties that can withstand even high levels of IOP.
In this chapter, we focus on ocular biomechanics along two main themes: What is known about howmechanical forces and the resulting deformations are distributed in the posterior pole and ONH
(biomechanics) and what is known about how the living system responds to those deformations
(mechanobiology).
Mechanical Environment of the Optic Nerve Head and Peripapillary
Sclera
Basic Engineering Concepts
The following are fundamental terms and concepts from engineering mechanics that may not be familiar
to clinicians and non-engineering scientists. The interested reader may pursue these ideas in greater
depth by referring to appropriate textbooks on engineering science, mechanics of materials, and
6,7biomechanics.
Stress is a measure of the load applied to, transmitted through, or carried by a material or tissue. Stress
can be de; ned as the amount of force applied to a tissue divided by the cross-sectional area over which it
acts (e.g., pressure has the same unit as stress and can be expressed in pounds per square inch or psi).
Stress may be decomposed into components that act in perpendicular (tension or compression) and
tangential directions (Fig. 8-4). The perpendicular components are called normal stresses and act to
elongate or compress the tissue. The tangential components are called shear stresses and act to distort the
shape of the tissue (Fig. 8-4).
FIGURE 8-4 Normal and shear components of stress and strain. (A) The normal
tensile and compressive stresses acting on a small square in the manner shown will
act to elongate the region in one direction and compress it in the other. (B) The
shear stresses acting on a similar region will act to distort the shape of the region.
Because tissues generally exhibit spatial variations in shape, cross-sectional area, material composition
and loading conditions, the stress within a biologic structure can vary considerably from region to
region. Some regions may bear very little stress while other regions experience very high stresses due to
their proximity to a tissue sti3ness transition or geometric feature. It is important to note that stress is a
mathematical quantity that can be calculated, but cannot be measured, felt, or observed. Furthermore,
the notion of stress as a mathematical description of mechanical load bearing is not synonymous with
notions of stress typically used in physiologic or metabolic contexts (e.g., ischemic or oxidative stress).
Strain is a measure of the local deformation in a material or tissue induced by an applied stress, and is
usually expressed as the percentage change in length of the original geometry (e.g. a wire that was
originally 10 mm long that has been stretched an additional 1 mm, exhibits 10% strain). Like stress,
strain may also be decomposed into normal (tensile or compressive) and shear (distortional) components
(Fig. 8-4). It is important to recognize that strain, unlike stress, may be observed and measured
experimentally. It is also important to appreciate the distinction between the deformation of a structureand strain within its constituent parts. While a structure may exhibit an overall, global deformation in
response to an applied load, the localized relative displacement described by the strain provides a
measurable indicator of the level of micro-deformation (stretch, compression, or shearing) experienced
by the tissue. In the ONH, an increase in IOP may induce a net posterior displacement of the lamina
cribrosa, but it will also stretch (strain) the constituent laminar beams themselves. Local strain is known
8to induce cellular mechanotransduction, and strain in collagen ; brils has been shown to passively
9protect the ; brils from enzymatic degradation by matrix metalloproteases. Both these strain-driven
mechanisms likely play important roles in connective tissue remodeling.
The material properties of a tissue describe its ability to resist deformation under applied load and
therefore relate stress to strain (i.e. load to deformation). Material properties can be thought of as the
sti3ness or compliance of a particular tissue or material that is intrinsic to the material itself. Hence, a
sti3 tissue such as sclera can have high stress, but low strain, while an equal volume of compliant tissue
like retina might have high strain even at low levels of stress. The material properties of a tissue are
characterized by the sti3ness, morphology and interactions of its constituents (e.g. elastin, collagen
; brils, proteoglycans, and cells). Material properties are generally determined through rigorous
experimental testing of the material in tension, compression, and shear.
Material properties are often described in terms of their material symmetry (isotropic or anisotropic),
the nature of the relationship between load and deformation (linear or nonlinear), and the
timedependence of their response to loading (elastic or viscoelastic). Isotropic materials exhibit identical
resistance to load in all directions while anisotropic materials can exhibit higher or lower sti3ness
properties along di3erent directions. For instance, concrete may be isotropic by itself, but the
introduction of rebar during fabrication would produce an anisotropic material with higher resistance to
tension along the direction of the rebar. The load–deformation, or stress–strain relationship that
characterizes a material can also be described in terms of whether it is linear or nonlinear. In linear
materials, stress is directly proportional to strain, by a constant factor known as the Young's modulus.
Nonlinear materials, on the other hand, have a non-constant proportionality between stress and strain,
and hence don't have a unique or constant Young's modulus. Figure 8-5 illustrates the behavior of a
nonlinear anisotropic material.FIGURE 8-5 The material properties of the peripapillary sclera are influenced by
nonlinearity and collagen fiber orientation (anisotropy). Separate from its thickness,
the behavior of the sclera is governed by its material properties, which in turn are
influenced by nonlinearity and fiber orientation. (A) Nonlinearity is an engineering
term for tissues or structures whose material properties are altered by loading. Part
A demonstrates that the sclera becomes stiffer as it is loaded uniaxially (in one
direction). In the case of the sclera, this is likely due to the straightening of collagen
fibers, which are embedded within the surrounding ground matrix. Collagen fibers
start out crimped and progressively straighten as alignment of the load is increased.
This conformational change in the fibrils accounts for the transition from an initially
compliant, nonlinear response to a stiffened linear response as IOP increases. (B)
Apart from nonlinearity, collagen fiber orientation (anisotropy) within the sclera
strongly influences its mechanical behavior. Fiber orientation can be totally random
(isotropic – not shown) or have a principal direction (anisotropic – three idealized
cases shown). Finite element (FE) models of an idealized posterior pole with principal
collagen fiber orientation in the circumferential, helicoidal, and longitudinal directions
are shown. As the displacement plots show, the underlying fiber orientation can have
profound effects on the deformation that occurs for a given IOP. Note that the
displacement scale is exaggerated for illustrative purposes.
In some materials, the load–deformation response is time-dependent. Viscoelastic materials, for
instance, exhibit higher resistance when loaded quickly than when loaded slowly (similar to the behavior
of a hydraulic shock absorber). Viscoelastic materials also exhibit the phenomena of creep and stress
relaxation. Creep refers to the tendency of a material to deform over time under a constant load.
Similarly, stress relaxation refers to the phenomenon wherein the mechanical stress borne by a material
diminishes with time following an imposed constant displacement. It is important to note that
viscoelastic material responses are not necessarily indicative of mechanical yield or failure (see below).
Materials that exhibit no time-dependent behavior are termed elastic materials.
The simplest material property description is that of an isotropic, linearly elastic material (e.g., steel).
Biologic soft tissues (e.g., sclera or tendon), are usually nonlinear, anisotropic, viscoelastic materials and
so exhibit increased resistance to strain at higher load levels, are sti3er in a particular loading direction,
and respond to load in a rate- and time-dependent manner. Characterization of the material properties
of biologic soft tissues is a formidable undertaking and requires extensive experimental e3ort. Once
established, material descriptions for tissues may be used in conjunction with descriptions of geometry
and loading conditions to model the stress and strain fields borne throughout a structure.
Recent advances in understanding the underlying mechanisms in the elastic response of soft tissues led
to the development of mechanistic models that attempt to derive the tissue's material properties from its
microstructure. The development of mechanistic material models opens a new avenue for understanding
ocular biomechanics, where microstructural observation, such as the orientation and crimp shape of
collagen ; brils, can be used to estimate the anisotropic and nonlinear material properties of the soft
10tissue. Note that biological tissues are living matter and their material properties are not constant but
change over the lifespan due to aging, remodeling, wound healing, and disease.
Another useful concept in biomechanics is structural sti ness, which incorporates both the material
properties and geometry of a complex load-bearing structure into a composite measure of the structure's
resistance to deformation. In the cornea, both the geometry (thickness) and the material properties
contribute to its structural sti3ness and, hence, in- uence the accuracy of IOP measurements that rely on
the corneal deformation response to an applied load. In the posterior pole, both the geometry and
material properties of the sclera and lamina cribrosa contribute to structural sti3ness, and hence
determine the deformation of the ONH and peripapillary sclera when exposed to IOP. As such, individual
ONH biomechanics is governed by the geometry (size and shape of the scleral canal, scleral thickness,
regional laminar density and beam orientation) and the material properties (sti3ness) of the lamina
cribrosa and sclera. Hence, two eyes exposed to identical IOPs may exhibit very di3erent strain ; elds
due to differences in their structural stiffness (Fig. 8-6).
FIGURE 8-6 The thickness of the peripapillary sclera, and the size and shape of the
scleral canal influence the magnitude and distribution of IOP-related stress within the
peripapillary sclera. Von Mises stress plots within 3D biomechanical models of the
posterior sclera and ONH demonstrate that stress concentrates around an
inhomogeneity (scleral canal) in a pressure vessel (eye) and varies according to the
geometry of the peripapillary sclera and scleral canal. The idealized model in (A)
shows the stress concentration around a circular canal in a perfectly spherical
pressure vessel with uniform wall thickness (the ONH has been removed from these
images for visualization purposes). The model in (B) shows the IOP-related stress
concentration around an anatomically shaped scleral canal with realistic variation in
peripapillary scleral thickness. In this case, the highest stresses (red) occur where
the sclera is thinnest and the lowest stresses (blue) occur where the sclera is
thickest, and also tend to concentrate around areas of the scleral canal with the
smallest radius of curvature. The response of the sclera to this load is determined by
its structural stiffness, which is the combination of geometry (how much tissue is
bearing the load) and material properties (how rigid or compliant is the tissue).
Overview of the Mechanical Environment of the ONH and Peripapillary Sclera
From an engineering perspective, the eye is a vessel with in- ow and out- ow facilities that regulate its
internal pressure. IOP imposes a pressure load normal to the inner surface of the eye wall, generating an
in-wall circumferential stress known as the hoop stress (Fig. 8-7). This IOP-generated stress is primarilyborne by the sti3, collagenous sclera, while the more compliant retina and nerve ; ber tissues bear little
of the in-wall stress load and are therefore primarily following the IOP-dependent, local deformations of
the sclera. IOP is borne in the ONH by the fenestrated connective tissues of the lamina cribrosa, which
span the scleral canal opening and tether into the sti3 outer ring of circumferential collagen and elastin
7; bers in the peripapillary sclera (like a trampoline). While Laplace's Law is useful to describe the
pressure–deformation relationship in a thin-walled spherical vessel, it is inadequate for describing the
eye's response to variations in IOP. There are several characteristics of the ocular load-bearing tissues
that complicate the study of the mechanical environment to which the ONH and its resident cell
populations are exposed.
FIGURE 8-7 Stress, relative to IOP (red arrows) in the lamina cribrosa (light green)
and peripapillary sclera (gray) engendered by IOP loading. Cut-away diagram of
IOP-induced stress in an idealized spherical scleral shell with a circular scleral canal
spanned by a more compliant lamina cribrosa. In this case, the majority of the stress
generated by IOP (red arrows) is transferred into a hoop stress borne within the
thickness of the sclera and lamina (blue arrows) that is concentrated
circumferentially around the scleral canal (green arrows). Note that the difference
between IOP (red arrows) and the retrolaminar cerebrospinal fluid pressure (pink
arrows) is the translaminar pressure gradient that generates both a net posterior
force on the surface of the lamina and a hydrostatic pressure gradient within the
neural and connective tissues of the pre-laminar and laminar regions.
First, the three-dimensional connective tissue geometry of the eye is complex and di7 cult to measure.
For instance, the thickness of sclera can vary as much as 4-fold from the equator to the peripapillary
11region and the 3D morphology of lamina cribrosa is more regionally complex and individualized than
13,14 10,15is generally appreciated. Second, the cornea, sclera and lamina cribrosa have extremely
complex ECM microstructures with highly anisotropic collagen and elastin ; bril orientations. As a result,
the experimental characterization and theoretical/mathematical description of their constituent material
properties are complex and di7 cult to obtain. Third, the cells that maintain the ocular connective tissues
are biologically active. As such, the geometry and material properties of the sclera and lamina cribrosa
change in response to both physiologic (age) and pathologic (IOP-related damage) factors. Fourth, the
eye is exposed to ever-changing loading conditions because IOP is extremely dynamic, with short-term
5and long-term fluctuations ranging from blinks and eye rubs to circadian rhythms (Fig. 8-3).
Finally, IOP-related stress generates strain patterns in the ONH and peripapillary sclera that are not
only dependent on di3ering connective tissue geometries and material properties but are also in- uenced
by complex loading conditions. The important factors contributing to this biomechanical component
include the alignment and density of collagen ; brils in each tissue (sti3ness and anisotropy), the rate of
change in IOP (via tissue viscoelasticity) and the level of IOP-related strain at the time of altered loading
(via tissue nonlinearity). In broad terms, the ONH connective tissues should be sti3er when there is
already considerable strain present and/or if the IOP load is applied quickly. Conversely, the ONH
should be more compliant in response to slow changes in IOP and/or at low levels of strain.
Mechanical Response of the ONH to Acutely Elevated IOPIt is important to note that the ONH responds to IOP elevations as a structural system, so the acute
mechanical response of the lamina cribrosa is confounded with the responses of the peripapillary sclera,
prelaminar neural tissues, and retrolaminar optic nerve (Video 8-1 ). Also, because the lamina cribrosa
lies underneath the prelaminar neural tissues and the acute structural responses of these two tissues to
acute IOP elevations are quite di3erent, acute laminar deformation cannot be directly measured from
16,17imaging the surface topography of the ONH. A ; nal confounding e3ect is the cerebrospinal - uid
pressure, which along with IOP determines the translaminar pressure gradient that must be borne by the
18lamina cribrosa.
Intuitively, it may seem that for a given acute increase in IOP, the lamina cribrosa should deform
posteriorly. Yang, Burgoyne and colleagues have acquired 3D histologic ONH reconstruction studies from
a large group of bilaterally normal monkeys that were perfusion-; xed one eye at 10 mmHg and the
other at IOP 30 or 45 mmHg. Their results show that while acute IOP elevation causes expansion of the
scleral canal, in most monkey eyes there is no net posterior laminar deformation from the plane of the
sclera. Thus, our current understanding of the aggregate response of the young adult monkey ONH to
acute IOP elevation is that expansion of the scleral canal pulls the lamina taut within the plane of the
19sclera, making it more resistant to posterior deformation out of that plane (Fig. 8-8). These data have
been con; rmed to some extent by in vivo imaging studies in both humans and monkeys, in which the
laminar position was measured in optical coherence tomography (OCT) images at baseline and after
acute IOP elevation. While there was modest laminar deformation in some eyes (both anteriorly and
16,17posteriorly), the laminar deformation after acute IOP increase was on average very small. A
computational study using parametric ; nite element models showed that while there is a strong
relationship between scleral canal expansion and laminar deformation in most eyes, the relationship is
complex and the hypothesis that scleral canal expansion is pulling the lamina taut and therefore
20preventing posterior laminar deformation when IOP is elevated is not universal for all eyes.
FIGURE 8-8 There are two components of acute IOP-induced ONH deformation in
normal and early glaucoma eyes. (A) Sagittal section diagram of the ONH, showing
the peripapillary sclera (hatched) and the lamina cribrosa for normal (upper) and
early glaucoma (lower) eyes. Note that the early glaucoma eye has undergone
permanent changes in ONH geometry including thickening of the lamina, posterior
deformation of the lamina and peripapillary sclera, and posterior scleral canal
expansion. Upon acute IOP elevation we believe two phenomena occur
simultaneously and with interaction: the lamina displaces posteriorly due to the direct
action of IOP (B), but much of this posterior laminar displacement is counteracted as
the lamina is pulled taut by simultaneous scleral canal expansion (C). It is important
to note that even though the net result of these IOP-related deformations is a small
amount of posterior displacement of the lamina, substantial levels of IOP-related
strain are induced in both the peripapillary sclera and lamina in this scenario.
It is important to note that the apparent lack of anterior-to-posterior laminar deformation with acute
IOP elevation does not mean that the lamina is not strained. In this scenario, the expansion of the canal
stretches the lamina cribrosa within the plane of the sclera generating substantial strain within the
laminar beams. Estimation of laminar beam strain within these same 3D reconstructions is one of the
outputs of ; nite element modeling (FE), an engineering technique that is discussed in the section onEngineering Models of Stress and Strain in the ONH, below.
The Contribution of the Sclera to ONH Biomechanics
The data described above, as well as the closed form analyses and computational models described in the
next section, suggest that the sclera plays an important role in ONH biomechanics. The peripapillary
sclera provides the boundary conditions for the ONH. By this we mean that the peripapillary sclera is the
tissue through which load and deformation are transmitted to the ONH, and that the structural sti3ness
of the peripapillary sclera, therefore, in- uences how the lamina deforms (Fig. 8-8). This can be
understood from the discussion above in which a compliant sclera allows the scleral canal to expand
following an acute IOP elevation, tightening the laminar beams within the canal and thereby increasing
laminar resistance to posterior deformation. In contrast, a rigid sclera allows less expansion of the canal
or none at all, forcing the structural sti3ness of the lamina alone to bear the IOP-related stress. Hence,
characterization of both components of scleral structural sti3ness (geometry and material properties) is
essential to understanding the effects of IOP on the ONH.
Scleral Geometry.
21,22Maps of the thickness variation for the posterior pole of human eyes show extreme spatial
variation in scleral thickness, with very thin regions near the equator (as low as 300 µm in the human).
The peripapillary sclera is notably thicker (1000 µm in the human). Interestingly, this thick ring of
peripapillary sclera is absent in the nasal quadrant of monkey eyes due to the oblique nasal insertion of
the optic nerve through the scleral canal. Such variations in peripapillary scleral thickness, whether they
occur naturally or in pathologic conditions such as myopia, may be important in assessing individual
susceptibility to glaucomatous damage.
Scleral Material Properties.
Uniaxial testing of scleral strips has been used to estimate scleral material properties in various species.
However, uniaxial testing of scleral strips is limited in its ability to describe the nonlinear and
anisotropic responses of the sclera in its natural shape (Fig. 8-5), leading Girard and colleagues to
develop an inflation testing approach. This approach is based on a customized scleral shell pressurization
apparatus with precise IOP control, and laser-based electronic speckle pattern interferometry to measure
23,24IOP-induced 3D deformations of the entire posterior scleral shell in monkeys and humans. Their
results have shown that the posterior sclera is highly nonlinear (it gets sti3er as IOP increases) and
anisotropic (the underlying collagen ; bril distribution is non-uniform and changes throughout the scleral
shell, which a3ects directional sti3ness) (Fig. 8-9). In addition, Fazio has measured the regional strains
in the human eye, and found that peripapillary strains are higher than those further away from the ONH,
25and are highest in the temporal and inferior quadrants. By using a numerical back; tting method,
Girard and colleagues estimated the nonlinear and anisotropic material properties of the sclera, and
26have shown that the sclera sti3ens signi; cantly with age and remodels in response to chronic IOP
27exposure in the monkey. Grytz and colleagues performed a similar study in human donor eyes using
10an improved material property constitutive model, which showed that the human sclera sti3ens with
28,29age and is stiffer in persons of African ancestry when compared to persons of European ancestry.FIGURE 8-9 Experimental results and finite element model predictions of the
nonlinear, anisotropic displacement behavior for both eyes (both shown in right eye
configuration) of one donor (81 years old) for three IOP elevations from 5 to 15, 30,
and 45 mmHg. Top: The rows show the comparison between the experimentally
measured and computationally predicted meridional, circumferential, and radial
surface displacements. The inhomogeneity of the experimental displacement
patterns are indicative of underlying tissue anisotropy. Bottom: the predicted collagen
fibril architecture for both eyes showing the concentration of collagen fibrils (contour
plot) along their preferred orientations (white lines). A ring of circumferentially aligned
collagen fibrils is seen in the peripapillary scleral region around the scleral canal. Exp,
Experimental. (Reproduced with permission from Grytz R, Fazio MA, Girard MJA,
et al. Material properties of the posterior human sclera. J Mech Behav Biomed Mat
2014;29:602–17.)
Engineering Models of Stress and Strain in the ONH and Peripapillary Sclera
Numerical Simulations – Finite Element (FE) Analysis.
Attempts to mathematically model the mechanical environment of the ONH generally fall into two broad
categories – closed form solutions and numerical simulations. In closed form solutions, engineering
principles are used to derive equations that can be analyzed to understand the e3ects of selected
biological parameters. However, closed form solutions are of limited utility because they cannot capture
the complexity of the ONH and peripapillary scleral tissues (e.g., the non-uniform and asymmetric
geometry and material properties). To overcome the inherent limitations of closed form solutions,
researchers often utilize numerical simulation methods to study more complex biological systems. One of
the most powerful of these is FE analysis. In FE analysis, complex load-bearing structures are broken into
small, regularly shaped elements (Fig. 8-5). Stress and strain within each element is calculated and then
superposed to predict the mechanical response of the entire structure.
The power of FE analysis lies in its ability to model structures with highly complex geometries using
material properties with varying levels of complexity as warranted (e.g., inhomogeneous, anisotropic,nonlinear, or viscoelastic material descriptions). The three inputs necessary for FE models are the 3D
geometry of the tissue structure to be modeled, the material properties of the di3erent tissues in the
model, and appropriate loading and boundary conditions. These requirements have spurred the
development of methodologies to isolate and describe the 3D geometry of the ONH and peripapillary
sclera and experimentally characterize their constituent material properties (Fig. 8-9).
There are two basic approaches to FE modeling of the ONH: parametric and individual-speci; c.
Parametric modeling involves computing stress and strain in average, idealized geometries that do not
conform to any individual's particular anatomy. Within these models, parameters such as peripapillary
scleral thickness and laminar sti3ness can be varied independently to gauge that parameter's e3ects on
ONH biomechanics as a whole. This is a similar approach to closed form analysis, but the analyzed
geometries are much more ; delic and the results more relevant and intuitive. Although parametric FE
models are by nature simpli; ed in their geometries and there are limited cases that can be modeled,
these investigations yield interesting insight into the contributions of individual anatomical elements and
tissue material properties to overall ONH biomechanics.
Bellezza et al. used parametric FE modeling to study the mechanical environment of an idealized 3D
30model of the posterior pole. In this study, the e3ects of the size and shape (aspect ratio) of an
elliptical scleral canal within a spherical scleral shell of uniform thickness were studied. Idealized
beamlike structures spanning the ONH were also incorporated into the model to simulate the lamina
cribrosa. This study illustrated that IOP-related stress concentrations within the load-bearing connective
tissues of the ONH are substantial, even at low levels of IOP. Speci; cally, models with larger scleral
canal diameters, more elliptical canals, and thinner sclera all showed increased stresses in the ONH and
peripapillary sclera for a given level of IOP. In the peripapillary sclera and ONH, stresses were as much
as one and two orders of magnitude greater than IOP, respectively. While the model used in this study
was idealized in terms of its material properties and geometry, it served to reinforce the concept of the
peripapillary sclera and ONH as a high-stress environment even at normal levels of IOP.
Sigal and coworkers used idealized axisymmetric FE models to pursue a more complex parametric
31analysis of the factors that in- uence the biomechanical environment within the ONH (Fig. 8-10). In
these studies, various geometric and material details of a generic model were parameterized and
independently varied to assess their impact on a host of outcome measures such as strain in the lamina
cribrosa and prelaminar neural tissue (Fig. 8-10). This work identi; ed the ; ve most important
determinants of ONH biomechanics (in rank order) as: the sti3ness of the sclera, the size of the eye, IOP,
the sti3ness of the lamina cribrosa, and the thickness of the sclera. The ; nding that scleral sti3ness plays
a key role in ONH biomechanics is especially interesting. Parametric studies such as these are useful
because they can be used to identify important biomechanical factors that warrant more in-depth study,
thus narrowing and focusing future experimental and modeling efforts.FIGURE 8-10 Parametric models can be used to study the influence of geometric
and material property factors. To model the ONH, Sigal and colleagues created an
idealized, axisymmetric (symmetric about the anterior-to-posterior axis) reference
geometry and varied geometric and material property factors to assess their
69influence on various outcome measures of stress and strain within the model. This
type of parametric sensitivity analysis is useful for identifying the tissues and
anatomic structures that may be most important in the mechanical response of the
ONH. Such information can serve to focus future biomechanics research and clinical
device development efforts on the tissues and structures determined to be most
important in ONH biomechanics. (Figure courtesy of Ian Sigal, MD.)
To address the limitations of idealized geometric and material property descriptions inherent in
parametric FE models, individual-speci; c FE models can be created from the reconstructed geometries of
32,33particular eyes. At present, individual-speci; c modeling is based on high-resolution 3D
reconstructions of monkey and human cadaver eyes (Fig. 8-11), with a long-term goal to build models
based on clinical imaging of living eyes so as to use them in the assignment of target IOP in clinical
management of glaucoma. This is especially important given that the 3D geometry of the scleral canal
and peripapillary sclera largely determine the stress and strain transmitted to the contained ONH (Fig.
86 shows speci; cally how the 3D geometry of the scleral canal and peripapillary sclera alter the stress
environment). Anatomically accurate 3D models are necessary to capture the biomechanics of
anisotropic scleral material properties (varying collagen ; bril orientation), scleral canals that are
noncircular and have varying optic nerve insertion angles (i.e. the optic nerve inserts from the nasal side
resulting in a thinner peripapillary sclera in that quadrant), and regional variations in laminar density
and beam orientation (Fig. 8-12). When modeling an ONH with anatomic ; delity, the tissue geometries
can be constructed either by serial histologic methods or 3D imaging, and material properties are
generally determined through direct mechanical testing (Fig. 8-9). Unfortunately, imaging of the lamina
in vivo is not yet possible at the resolutions required for modeling, and no technology exists for
experimental biomechanical testing of laminar beams. As a result, ONH FE models are typically
constructed from eyes that are perfusion or immersion ; xed at a selected IOP, and then undergo ex vivo
3D reconstruction of their connective tissues.FIGURE 8-11 Construction and results from a macro-scale continuum FE model of
the posterior scleral shell and ONH of a normal monkey eye. (A) To construct the
model geometry, the 3D-delineated lamina cribrosa and surrounding peripapillary
sclera (see Figure 8-8) of an individual eye are incorporated into a generic anatomic
scleral shell with regional thickness variations mapped from previous histologic
measurements. The segmented 3D reconstruction of the laminar connective tissue
(shown) is represented in each model. (B) A continuum FE mesh of the posterior
pole is generated from the geometry. The sclera in this model is assigned uniform
isotropic material properties based on previous experimental testing. The continuumelements representing the porous load-bearing laminar architecture are assigned
anisotropic material properties that reflect the microstructure of the lamina enclosed
by each laminar FE. This material property description is defined using a combination
of the connective tissue volume fraction (CTVF) and the predominant laminar beam
orientation. A visualization of the CTVF and predominant beam orientation are
presented. Note that in this visualization, an anisotropy value of 1 would represent an
isotropic material with no predominant orientation while larger values imply oriented
laminar beams that impart higher stiffness in the direction of the plotted arrow. (C, D,
E) FE results showing predicted displacement, strain, and stress distributions due to
an increase in IOP from 10 to 45 mmHg. Note that in this eye, the model predicts
that the ONH tilts inferiorly, the strains are highest along the superior–inferior axis of
the ONH, and that the sclera bears most of the IOP-related stress.FIGURE 8-12 Regional differences in laminar microarchitecture in a normal monkey
eye, and the predicted relationship between regional CTVF and strain.
Characterization of the laminar microarchitecture (A) utilizes the element boundaries
of a continuum finite mesh to partition the lamina cribrosa connective tissue into
forty-five sub-regions (B). The connective tissue volume fraction (CTVF) for each
region is expressed as a percentage and mapped to a grayscale value in the
background. The arrows indicate the predominant orientation of the laminar beams in
each region, with higher values (color-coded) indicating regions in which the beams
are more highly oriented. Note that in the peripheral regions of the lamina, the
beams are tethered radially into the scleral canal wall. FE model simulations show
that strains are highest in areas where the laminar density is lowest, and strains are
32lowest in areas where laminar density is highest (C).
Burgoyne and colleagues developed a histologic technique to 3D reconstruct the trabeculated structure
of the lamina cribrosa from individual monkey eyes that have been perfusion ; xed at varying levels of
IOP (Fig. 8-12). The resulting 3D data sets form the geometries of individual-speci; c FE models of the
ONH at the macro- and micro-scale. Roberts, Downs, and co-workers have developed macro-scale
continuum FE models of the posterior pole and ONH connective tissues from individual monkey eyes
32(Figs 8-11 and 8-12). In these models, the laminar microarchitecture is modeled using a continuum
approach, with anisotropic material properties assigned to each FE in the ONH based on the connective
tissue volume fraction and the predominant beam orientation of the contained laminar microarchitecture
(Figs 8-11 and 8-12). Regional variations in connective tissue volume fraction and predominant
orientation are translated into variations in local oriented sti3ness so that regions of higher and lower
porosity re- ect greater and lesser compliance, respectively. The inclusion of regional laminar material
properties (connective tissue volume fraction and beam orientation) into FE models has a pronounced
e3ect on the ONH's response to IOP (Fig. 8-12). This indicates that the regional variations in laminar
geometry and structural sti3ness must be represented in models to fully capture the biomechanical
behavior of the ONH and suggests that the lamina is biologically optimized to withstand IOP-induced
deformation. Furthermore, these results show that regional laminar density is signi; cantly associated
with regional stress and strain, with areas of high laminar density showing less strain and regions of low
32laminar density exhibiting high strains (Fig. 8-12). OCT imaging has the ability to resolve laminar
beams to some extent, and therefore regional laminar density could serve as a biomarker for areas that
are under increased strain relative to neighboring regions.
Numerical Growth and Remodeling.
The previously discussed numerical simulations were designed to estimate the stress and strain
environment in the ONH for a given material or collagen architecture. Recent advances in numerical
remodeling allow us to gain insight into the origin of these anisotropic collagen structures in the eye. In
these studies, stress or strain is not merely a predicted variable but is also used to predict the collagen
34; bril architecture (anisotropy) based on a remodeling rule. Biomechanically induced remodeling of
tissue anisotropy was estimated by allowing collagen ; bers to be adaptively reoriented towards optimalload-bearing conditions based on the IOP-related tissue stress. This numerical approach was used to
35predict the physiological collagen ; ber architecture in the peripapillary sclera and lamina cribrosa.
Figure 8-13 shows the di3erent stages of the remodeling simulation. The simulation began with random
(isotropic) orientations of collagen ; bers and ended with the prediction of a ring of circumferentially
aligned collagen ; bers in the peripapillary sclera and radial aligned ; bers in the periphery of the lamina
cribrosa. Both numerically predicted morphologies agree with experimental observations in both the
15 14sclera and lamina cribrosa (Fig. 8-12). The numerical results suggest that the anisotropic collagen
; bril architecture in the peripapillary sclera and lamina cribrosa evolved to establish optimal
loadbearing conditions in the connective tissues. Furthermore, the numerical remodeling simulation provides
insight into the signi; cant e3ects of these underlying collagen ; ber orientations on the IOP-related
deformation of the ONH. The simulations shows that the circumpapillary ring of collagen ; bers protects
the ONH from large scleral canal expansions and as such shields the lamina cribrosa and neural canal
tissues from high tensile stresses. In contrast, the radial alignment of ; bers in the periphery of the
lamina cribrosa seems to reinforce the lamina cribrosa against posterior deformations and high
transversal shear stresses.FIGURE 8-13 Computational remodeling simulation suggesting that the anisotropic
collagen fiber architecture in the peripapillary sclera and lamina cribrosa evolved to
establish optimal load-bearing conditions in the connective tissues. Shown are
different stages of the remodeling simulation of an idealized posterior shell with
principal fiber orientations that range from totally random (isotropic – dark red) to
perfectly aligned (anisotropic – blue). (A) Unloaded state of the numerical model. The
initial collagen architecture was initially assigned a random (isotropic) collagen fiber
architecture. (B) Applying a normal IOP load (16 mmHg) to the initial model with
isotropic collagen fiber orientations leads to a large scleral expansion. (C) During the
simulation, a circumpapillary ring of collagen fibrils was formed first. This ring was
found to shield the ONH from large scleral expansion and tensile forces. (D) At the
final state of the simulation, a radial alignment of collagen fibers was predicted in the
periphery of the lamina cribrosa. These radial fibers were found to reinforce the ONH
against posterior deformation. As the displacement plots show, the underlying fiber
orientation can have profound effects on the deformation of the ONH. Note that thedisplacement scale is exaggerated for illustrative purposes. Adapted from Grytz R,
Meschke G, Jonas JB. The collagen fibril architecture in the lamina cribrosa and
peripapillary sclera predicted by a computational remodeling 2011;10:371-82.
Experimental studies have shown that collagen ; bril synthesis, degradation and remodeling in soft
tissues is modulated by mechanical stress and strain. Furthermore, recent ; ndings suggest that growth
and remodeling mechanisms occur in soft tissues to establish and maintain optimal load-bearing
9,36conditions and these optimal conditions seem to be de; ned at the collagen ; bril level. Based on
these ; ndings, Grytz and colleagues developed a numerical growth and remodeling method and applied
it to the ONH. This study predicted the formation of a lamina cribrosa in human eyes suggesting that the
lamina cribrosa is necessary to establish optimal load-bearing conditions at the human ONH (Fig.
83714). The simulation also suggests that smaller eyes such as those in rodents might not need a lamina
cribrosa due to their small scleral canal.
FIGURE 8-14 Computational growth and remodeling simulation provides a possible
explanation of the lamina cribrosa (LC) thickening seen in early experimental
glaucoma. The simulation is based on recent findings that growth and remodeling
mechanisms in the soft tissues seem to occur in effort to maintain a homeostatic
strain level at the level of collagen fibrils. The numerical results show the predicted
collagen fibril volume fraction in the neural canal tissues, which represent the
preand retro-laminar tissues, and the lamina cribrosa. Neural canal tissues with a
collagen fibril density of 10% or more were defined to represent the lamina cribrosa.
The simulation starts with an initial homogeneous collagen fibril density (6%)
throughout the neural canal tissues without presupposing the existence of a lamina
cribrosa. After reaching model homeostasis at normal IOP (15 mmHg), the model
predicted the existence of a lamina cribrosa-like structure spanning the scleral canal
of similar dimensions, shape and location of the normal lamina cribrosa in vivo. To
regain model homeostasis after IOP elevation to 25 mmHg, the model predicted the
significant thickening of the lamina cribrosa due to local increase in collagen fibril
density in the pre- and retrolaminar tissues and the recruitment of these tissues into
the lamina cribrosa. The borders of the lamina cribrosa insertion into the surrounding
sclera also migrated as the LC thickened. These numerical results support the notion
that the lamina cribrosa thickening seen in experimental early glaucoma is driven by
biomechanical mechanisms. (Reproduced with permission from Grytz R, Sigal IA,
Ruberti JW, Meschke G, Downs JC. Lamina cribrosa thickening in early glaucoma
predicted by a microstructure motivated growth and remodeling approach. Mech
Mater 2012; 44:99–109.)Multi-Scale Simulations.
Downs and colleagues have also used the 3D reconstruction and continuum modeling approaches to
38characterize and explore laminar beam biomechanics. This micro-scale modeling approach utilizes a
substructuring technique based on parent macro-scale FE models to calculate the IOP-related stress and
38strain ; elds in laminar beams (Fig. 8-15). This technique reveals a complexity of IOP-related strains
and stresses within the lamina cribrosa microarchitecture that is not available through macro-scale FE
modeling. There have been several important results from this work. First, stress and strain in the
laminar microarchitecture are likely higher than predicted by macro-scale models of the ONH. Second,
even at normal levels of IOP, the micro-FE models predict that while the majority of laminar beams are
within physiologic strain ranges, there are individual laminar beams with levels of IOP-related strain
that are likely pathologic. Third, mean strain within the laminar beams of di3erent monkeys varies
greatly, and is generally dependent on the 3D geometry of each eye's ONH connective tissues. Finally,
strain is not equally distributed though the ONH, and is concentrated in regions with less dense laminar
beams. This approach holds the possibility of testing hypotheses about failure mechanisms and cellular
responses at the level of the laminar beams.FIGURE 8-15 Construction and analysis of micro-FE models of the laminar
microarchitecture of a monkey eye. The complexity of the stresses and strains at the
laminar beam level is not captured in the macro-scale continuum FE models because
the details of the microstructure are homogenized into a bulk material description. To
address this limitation, a sub-structuring technique has been developed to
characterize the beam-level strain environment within ONH models. The
displacement field calculated from a continuum model is used along with individual
element boundaries to define input loading conditions for micro-scale FE models of
sub-regions of the 3D reconstructed lamina cribrosa. These micro-FE models
illustrate that the stress and strain borne by the individual laminar beams are highly
variable and complex. Modeling of individual beam mechanics will be necessary to
predict the stress of individual beams, model changes in blood flow in the laminar
capillaries, and determine the strains to which laminar astrocyte basement
membrane are subjected.
39A fully coupled two-scale numerical analysis of the ONH was performed wherein a simpli; ed model
of the lamina cribrosa microstructure was used to investigate the impact of the macroscopic IOP load on
the stress and strain environment of the retinal ganglion axons within the porous microstructure of the
lamina cribrosa. The results of this analysis suggest that the circumpapillary ring of collagen ; bers and
the porous beam structure of the lamina cribrosa provide mechanical support to the axons by shielding
them from high tensile stresses at elevated IOP. However, shear stresses in the axonal tissue were found
to increase with increasing IOP at the posterior laminar insertion into the neural canal wall, which may
contribute to a mechanical insult of the retinal ganglion cell axons in glaucoma.
Other Acute, IOP-Related Changes in the ONH40,41ONH, retinal, and choroidal blood - ow are all a3ected in di3erent ways by acute IOP elevations.
These studies using microspheres have suggested that volume - ow within the prelaminar and anterior
laminar capillary beds is preferentially diminished once ocular perfusion pressure (de; ned as the systolic
arterial blood pressure plus of the di3erence between systolic and diastolic pressures minus IOP) is
less than 30 mmHg.
While a direct link to mechanical strain has not been established, axonal transport is compromised in
42the lamina cribrosa at physiologic levels of IOP and is further impaired following acute IOP
43,44elevations. Several hypotheses regarding this behavior emerge when considering ONH
biomechanics. First, as the pores in the lamina cribrosa change conformation due to IOP-related
mechanical strain, the path of the axons through those pores may be disrupted, thereby directly impeding
axoplasmic transport. Second, it may be that the IOP-related reduction in blood - ow in the laminar
region impairs the mitochondrial metabolism that drives axoplasmic transport. Finally, axoplasmic
transport could be sensitive to the magnitude of the translaminar pressure gradient, and as that
hydrostatic pressure gradient gets larger with increasing IOP (or lower cerebrospinal - uid pressure), the
mechanisms driving that transport are unable to overcome the resistance of the pressure gradient (Figs
82 and 8-7). A recent retrospective clinical study has shown that patients with a lower cerebrospinal - uid
pressure have a higher prevalence of glaucoma at similar IOPs, which suggests that the translaminar
45pressure gradient is important in disease pathogenesis.
In summary, while connective tissue dynamics should directly and indirectly in- uence astrocyte and
glial metabolism and axonal transport, glaucomatous damage within the ONH may not necessarily occur
at locations with the highest levels of IOP-related connective tissue strain, but rather at those locations
where the translaminar tissue pressure gradient is greatest and/or where the axons, blood supply, and
astrocytes and glia are the most vulnerable. Further studies are necessary to elucidate the link(s)
between IOP, mechanical strain, blood flow, astrocyte, glial, and axonal homeostasis in the ONH, in both
the physiologic and diseased states.
Restructuring and Remodeling of the Optic Nerve Head
Normal Aging
The ONH connective tissues are exposed to substantial levels of IOP-related stress and strain at normal
levels of IOP (Fig. 8-7). We believe that physiologic levels of stress and strain experienced over a lifetime
induce a broad spectrum of changes in both the connective tissues and vasculature that are central to
normal aging. Thus the restructuring and remodeling of glaucomatous damage (described in the
following sections), should be understood to occur in the setting of the physiologic restructuring and
remodeling inherent in normal aging.
Age-related alterations of the laminar ECM have been reported to include increased collagen
deposition, thickening of astrocyte basement membranes and increased rigidity of the lamina and
46,47sclera. The aged ONH is thus more likely to have sti3 connective tissues. Age-related hardening of
the laminar ECM signi; cantly reshapes the biomechanical environment of the ONH. But aging not only
sti3ens the connective tissues; it should also diminish nutrient di3usion from the laminar capillaries
through the laminar ECM, across the astrocyte basement membranes, and into the adjacent axons (Fig.
8-1). Thus, in addition to the e3ects of age-related changes in ONH biomechanics, decreases in the
volume - ow within the laminar capillaries, axonal nutrition in the aged eye may be further impaired as
a result of diminished nutrient diffusion from the laminar capillaries to the center of the axon bundles.
Alterations in the ONH in Early Glaucoma
Downs and colleagues have proposed a comprehensive framework within which to understand the
48biomechanics-driven remodeling changes associated with glaucoma cupping (Fig. 8-2).
Pathophysiologic stress and strain induce pathologic changes in cell synthesis and tissuemicroarchitecture that exceed the e3ects of aging and underlie the two governing pathophysiologies in
glaucoma: (1) growth and/or remodeling of the load-bearing connective tissues of the ONH (Figs 8-2 and
8-14); and (2) progressive damage to the adjacent axons by a variety of mechanisms (Fig. 8-2).
Early glaucomatous damage has not been rigorously studied in humans because human cadaver eyes
with well-characterized early damage are rare. In monkeys, following moderate experimental IOP
elevations, we have described the following changes in ONH and peripapillary scleral connective tissue
architecture and material properties at the onset of confocal scanning laser tomography-detected ONH
49surface change (clinical cupping): (1) enlargement and elongation of the neural canal; (2) posterior
50deformation and thickening of the lamina cribrosa; (3) outward migration of the posterior lamina
51insertion point and signi; cant but less pronounced outward migration of the anterior lamina insertion
51 27,52point; (4) alteration in the elastic and viscoelastic material properties of the peripapillary sclera.
The increase in laminar thickness in these early glaucoma monkey eyes is likely due to connective
tissue remodeling and new connective tissue synthesis. Quanti; cation of the amount of connective tissue
within 3D reconstructions of the lamina showed an increase in connective tissue volume of 44% to 82%
in early glaucoma compared to their contralateral control eyes, which is at least partially driven by the
14recruitment of retrolaminar septa into the load-bearing 3D laminar structure. These data strongly
support the notion that connective tissue remodeling and new connective tissue synthesis are very active
in this early stage of the neuropathy. Furthermore, the work of Yang, Burgoyne and co-workers has
shown that the lamina cribrosa migrates posteriorly in the neural canal during glaucomatous
51progression, and that process starts early in the disease (Fig. 8-16). This laminar migration can be
very large over the relatively short duration of disease progression in monkeys. One animal in that study
demonstrated that the laminar insertion into the neural canal wall can migrate posteriorly along a
distance greater that the full thickness of the lamina (Fig. 8-16). In a recent comprehensive review,
Downs and colleagues proposed a framework that supports biomechanics-driven progressive laminar
remodeling and migration as the central mechanism underlying the change in lamina cribrosa
48morphology from normal to the cupped and excavated shape typical of glaucoma.FIGURE 8-16 The pathophysiology of early experimental glaucomatous damage to
the monkey ONH includes not only thickening but regional migration of the laminar
insertion away from the sclera to the point that complete pialization of the laminar
insertion is achieved in a subset of eyes. Neural canal landmarks (red – neural canal
opening (end of Bruch's membrane); blue – anterior scleral canal opening; yellow –
anterior laminar insertion; green – posterior laminar insertion; purple – posterior
scleral canal opening) and segmented connective tissue (dark gray – lamina
cribrosa; purple – peripapillary sclera; light green – pial sheath) within digital section
images from the inferior region of the normal (top) and the contralateral early
experimental glaucoma (bottom) ONH of a representative monkey. In most normal
monkey eyes, the lamina inserts into the sclera as seen in this monkey's normal eye
(top). However, at an identical location in the early experimental glaucoma eye of this
animal (bottom) the laminar insertion has migrated outward such that both the
51anterior and posterior lamina effectively insert into the pial sheath in addition to the
lamina being thickened and posteriorly deformed. While regions of laminar insertion
70into the pia have been reported in normal human eyes, these findings are the first
to suggest that active remodeling of the laminar insertion from the sclera into the pia
46,51,71is part of the pathophysiology of glaucomatous ONH damage. This
phenomenon has important implications for the mechanism of axonal insult within
these regions. (Reproduced with permission from Burgoyne CF. A biomechanical
paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp
Eye Res 2011; 93:120–32.)
In vivo OCT imaging studies in which the laminar position was measured relative to Bruch's membrane
opening at baseline and after acute IOP elevation in monkeys with experimental glaucoma have
revealed changes in the structural sti3ness of the lamina cribrosa that occur in early glaucoma.
Preliminary results indicate that the lamina cribrosa deforms signi; cantly more posteriorly in response
to an acute IOP elevation from 10 to 30 mmHg in most glaucoma eyes compared to their contralateral
normal controls, and that laminar compliance is signi; cantly related to the peak IOP measured after
chronic IOP elevation was induced. This suggests that IOP-driven remodeling is altering laminar
structural sti3ness as glaucoma progresses. FE modeling studies in monkey early glaucoma have
supported this hypothesis, and predict that even though the lamina cribrosa adds a signi; cant volume of
connective tissue through remodeling very early in the disease, the laminar connective tissue is
weakened considerably during that process, resulting in a more substantial lamina that is still
53structurally more compliant than its contralateral control eye. These results lend credibility to the
notion that the remodeling cascade in the laminar ECM begins with a reorganization process that
weakens the tissues very early in the disease process, which is followed by a consolidation and sti3ening
process (Fig. 8-17).FIGURE 8-17 Progression of connective tissue morphology from normal health to
early glaucoma to end-stage glaucoma. (A) Diagram of normal ONH connective
tissue showing the thickness of the lamina cribrosa (x) and the in-wall hoop stress
generated by IOP in the peripapillary sclera. (B) In early experimental glaucoma,
recent studies suggest there is permanent posterior deformation and thickening (y)
of the lamina rather than failure of the laminar beams that occurs in the setting of
permanent expansion of the posterior scleral canal. These changes indicate that a
combination of growth and remodeling of the connective tissues occur very early in
glaucoma that is not yet accompanied by frank excavation. (C) As the disease
progresses to end-stage damage, the lamina compresses (z) and scars, the laminar
insertion into the sclera migrates posteriorly, and the scleral canal enlarges to the
typical cupped and excavated morphology. Very little is known about the
biomechanics, cellular processes, and remodeling that drives the morphological
progression from the earliest detectable stage of glaucoma to end-stage damage,
but it is likely that these processes continue to be driven by the distribution of
IOPrelated stress and strain within the connective tissues either primarily or through their
effects on the astrocytes and capillaries contained within the laminar
beams. (Modified from Burgoyne CF, Downs JC, Bellezza AJ, Francis Suh JK, Hart
RT. The optic nerve head as a biomechanical structure: a new paradigm for
understanding the role of IOP-related stress and strain in the pathophysiology of
glaucomatous optic nerve head damage. Prog Retin Eye Res 2005; 24:39–73.)
Recent numerical growth and remodeling simulations have given us additional con; dence in the
hypothesis that local biomechanics is driving ONH remodeling in glaucoma. Grytz and colleagues
performed a FE simulation study based on a homeostatic control mechanisms that predicted that the
lamina cribrosa has to thicken by about 40% to maintain optimal load-bearing conditions at the collagen54fibril level for a chronic IOP elevation from 15 to 25 mmHg (Fig. 8-14). Their study also suggested that
the thickening of the LC is mainly due to the recruitment of pre- and retro-laminar tissue into the lamina
14cribrosa, which agrees with previous experimental studies.
Alterations in cellular activity in early glaucoma have been described in animal models, but these
studies have yet to be con; rmed in humans. In a recent study in rat eyes (which have a very minimal
lamina cribrosa) Johnson and co-workers used genomic techniques to characterize the alterations in the
55genome of ONH tissues following 5 weeks exposure to experimental elevated IOP. Within the large
group of animals studied, a subset of eyes had an early focal stage of orbital optic nerve axon loss.
Within these animals, expression of genes governing initiation of cell division was maximally elevated
(compared to later stages of damage) as well as the genes for several ECM components including ; bulin
2, tenascin C, and the matrix metalloproteinase inhibitor TIMP-1. While gene expression for TGF β1
increased linearly with severity of damage in all studied eyes, gene expression for TGF β2 was lowest in
the focally damaged eyes suggesting di3erential expression of TGFB isoforms at this early stage of the
neuropathy. Similar to TGF β2, gene expression for the principal water channel protein in astrocytes,
aquaporin-4, demonstrated the largest degree of down-regulation in focal damage. Most importantly,
their study characterized gene expression patterns in a group of 2-week optic nerve transection eyes and
found a pattern of expression similar to the most severely damaged high IOP eyes, suggesting that the
changes in gene expression in the focal group were likely IOP-related, not simply a re- ection of early
axonal loss.
Howell and colleagues have performed studies in the DBA/2J mouse, which is a rodent model of
glaucoma based on age-related spontaneous iris degeneration and subsequent elevation of IOP through
aqueous out- ow blockade. Their results show that in DBA/2J mice, the RGC axons degenerate from the
RGC soma to the brain. In BAX-de; cient DBA/2J mice, wherein the RGC somas are protected, the axons
degenerate only from the anterior ONH to the brain, while the axonal segments from the RGC soma to
56the ONH are protected. In additional work from this group, radiation treatment to the eye prevented
transendothelial migration of pro-in- ammatory leukocytes into the optic nerve, which in turn prevented
57detectable damage to the RGC axons. Injection of endothelin-2, a damaging protein produced by
leukocytes, into the irradiated eyes resulted in neural damage comparable to eyes not treated with
leukocyte-blocking radiation. This work shows that migration of pro-in- ammatory cells into the ONH
after IOP-related insult is a key component in the glaucomatous damage cascade.
Marsh-Armstrong and co-workers have described a potentially new RGC axonal degradation pathway
58in a study in murine astrocytes. Their work showed that there is a constant interplay between ONH
and myelination transition zone astrocytes and RGC axons at the posterior border of the lamina cribrosa,
wherein the astrocytes phagocytose axonal evulsions, even in normal mouse eyes. In eyes exposed to IOP
elevations however, this phagocytic process is upregulated, and may result in astrocytes playing a direct
role in damaging the axons in the ONH region after elevated IOP exposure.
Studies of alterations in axoplasmic transport and blood - ow in early glaucoma are only just
beginning. Recent studies by Wang and co-workers have shown that basal blood - ow in the ONH is
59signi; cantly decreased in early experimental glaucoma in monkeys. They also reported changes in the
60time course of blood - ow autoregulation, which indicate that chronic alterations in blood - ow
accompany the alteration in connective tissue architecture and material properties described above.
Together, these studies paint a complex picture of glaucomatous pathogenesis that involves simultaneous
alterations in the connective tissues, cells, and vasculature. The unifying theme that ties these
mechanisms together is the involvement of ONH biomechanics in the disease cascade.
Alterations in the ONH in the Later Stages of Glaucomatous Damage
The classic descriptions of profound posterior laminar deformation, excavation of the scleral canalbeneath the optic disc margin, and thinning and scaring of the lamina cribrosa are largely based upon
human and monkey eyes with moderate, severe and end-stage glaucomatous damage. Because these
studies describe a broad range of damage that has occurred in response to an IOP insult that is
uncharacterized in magnitude and duration, a common description of events has yet to emerge.
However, astrocyte basement membrane disruption and thickening as well as damage to elastin and
61remodeling of the ECM are consistent phenomena within these reports. It is assumed that IOP-induced
alterations in the synthetic activities of the cells associated with these tissues underlie these
62,63changes.
Within the more severely damaged eyes in Johnson's rat study (above), expression of genes governing
initiation of cell division was also elevated (compared to normal eyes) but to a lesser degree than in eyes
with focal damage. Genes associated with activation of microglia, immune response, ribosomes and
lysosomes were all linearly elevated in the more severely damaged eyes. Genes for the ECM components
including ; bulin 2, tenascin C and the matrix metalloproteinase inhibitor TIMP-1 were elevated
nonlinearly (most elevated in early damage, elevated less in more severe) while genes for periostin, collagen
IV, and collagen VI were elevated linearly. Di3erential gene expression for TGF β1 and TGF β2, as well as
non-linear expression of aquaporin are described above.
Axoplasmic transport alterations at the lamina cribrosa and a complex array of ONH, retinal and
choroidal blood - ow alterations have been described following chronic IOP elevation in monkey and
human eyes. We lack a comprehensive set of tools to study primary interactions between IOP- and
nonIOP-induced alterations in ONH blood - ow, ONH connective tissue integrity, ONH glial cell activity and
RGC axonal transport within individual human and animal eyes. Work is continuing on multiple fronts
to develop a suite of experimental tools to assess these variables in both animal and human studies.
It has been proposed that ONH astrocytes and lamina cribrosa cells play a central role in mediating
the laminar ECM remodeling response and the resulting axonal insult. Cell activity associated with ECM
remodeling has been observed in response to glaucoma in humans and exposure to chronically elevated
IOP in animal models. Agapova and colleagues showed that matrix metalloproteases (MMPs) are
elevated in the lamina cribrosa of monkeys with experimental glaucoma, but not those with optic nerve
62transection. These compounds are known to break down the ECM and allow cells to migrate and
63rebuild the matrix.
Taken together, these results support the hypothesis that elevated IOP, and presumably mechanical
insult to the cells and/or reduced blood - ow in the laminar region, underlie the signi; cant ECM
remodeling observed in glaucomatous eyes. Interestingly, these mechanisms are both driven by exposure
to chronically elevated IOP, a biomechanical insult, and are not simply a secondary e3ect of axonal
damage and death.
Biomechanical Manipulation of ONH and Peripapillary Scleral Cells in Culture
Several studies have investigated the mechanisms of cell mechanotransduction in astrocyte and LC cells
in vitro. Kirwan and colleagues have shown that cyclical mechanical stretch of the substrate on which
cells were grown induced signi; cant increases in TGF- β1 mRNA synthesis after 12 hours and TGF- β1
64protein secretion after 24 hours. Both applied cyclical stretch and exogenously delivered TGF- β1
significantly increased MMP-2 activity in cell media.
Integrins are proteins that span the laminar astrocyte basement membranes and bind the cell
cytoskeleton to the surrounding ECM. Thus, integrins are particularly well suited to act as
mechanosensory elements in the lamina. Morrison has described the location and alteration of integrin
subunits in normal and glaucomatous human and monkey eyes and proposed them as an important link
between laminar deformation, IOP-induced cell stretch and damage, laminar connective tissue
remodeling and laminar astrocyte-mediated axonal insult in glaucoma. In an in vitro study, O'Brien and
2+colleague have shown that hypotonic membrane stress activates stretch-activated channels and Ca -+ 63dependent maxi-K channels in LC cells, which could act as another potential mechanotransduction
mechanism in the lamina.
It has been established in other systems that the biologic response of tissues and cells depends strongly
on the mode of the strain stimulus (tension, compression or shear), as well as on their magnitudes and
66temporal profiles. It is therefore of interest to determine which modes of strain and stress the tissues of
33the ONH are exposed to as IOP is elevated. Note that strains are generally not homogenous, so when
the LC deforms, some regions could be highly strained in di3erent modes, while others remain largely
una3ected. This is important because the biological e3ects on cells are likely to be more dependent on
67the local levels of strain or stress than on global levels. Eventually, strain predictions from FE models
and data on IOP - uctuation from telemetric IOP monitoring studies will allow these experiments to more
closely model physiologic/pathophysiologic conditions in the normal and glaucomatous human and
animal eye.
Future Directions
Clinical Implications
There are currently no science-based tools to predict at what level of IOP an individual ONH will be
damaged. As described herein, FE modeling is a computational tool for predicting how a biological tissue
of complicated geometry and material properties will behave under varying levels of load. The goal of
FE modeling in monkey and human cadaver eyes is to learn what aspects of ONH neural, vascular and
connective tissue architecture are most important to the ability of a given ONH to maintain structural
integrity, nutritional and oxygen supply, and axoplasmic transport at physiologic and pathophysiologic
levels of IOP. Further advances of numerical growth and remodeling simulation tools are crucial to gain
insight into the underlying mechanisms that lead to the profound structural changes in glaucoma and
their potential role in axonal insult.
In the future, clinical imaging of the ONH will seek to capture the connective tissue architectures so as
to allow clinically derived biomechanical models of individual patient ONHs to make predictions
regarding physiologic and pathophysiologic levels of growth and remodeling. Eventually knowing the
relationship between IOP, IOP - uctuations, mechanical strain- or stress-driven remodeling, systemic
blood pressure, and the resultant astrocyte and axonal mitochondrial oxygen levels will drive the clinical
assessment of safe target IOP. Clinical characterization of the actual IOP insult through continuous,
telemetric IOP monitoring will eventually allow us to understand the biomechanical loads in the eye.
Finally, these FE modeling-driven targets for deep (sub-surface) ONH imaging will likely allow early
detection of glaucomatous remodeling of the ONH based on lamina cribrosa deformation and thickening.
Once clinically detectable, early stabilization, and perhaps reversal, of these laminar changes will
become a new end point for target IOP lowering in most ocular hypertensive and all progressing eyes.
Once validated, predictive computational remodeling simulation can be become useful tools to estimate
patient-specific risk and treatment strategies in glaucoma.
Basic Research Directions
From an engineering standpoint, large challenges remain to achieve basic and clinical knowledge
regarding: (1) the components of IOP and its - uctuations that are potentially damaging; (2) the
mechanisms of IOP-related growth and remodeling in the laminar beams and peripapillary sclera; (3) the
mechanobiology of the astrocytes, scleral ; broblasts, and lamina cribrosa and glial cells; (4) the
mechanobiology of axoplasmic - ow within the lamina cribrosa; (5) the - uid–structure interactions
governing the blood flow within the laminar capillaries and scleral and laminar branches of the posterior
ciliary arteries; and (6) nutrient di3usion to the astrocytes in young and aged eyes. We predict that
knowledge gained from these studies will contribute to new therapeutic interventions aimed at the ONH
and peripapillary sclera of glaucomatous eyes.References
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9
Role of Ocular Blood Flow in the
Pathogenesis of Glaucoma
Ali S Hafez, Mark R Lesk
S u m m a r y
A great body of evidence suggests that abnormal ocular blood ow contributes to the
pathophysiology of open-angle glaucoma. Large clinical studies have linked low ocular perfusion
pressure to the prevalence, incidence, and progression of glaucoma. Reduced blood ow has been
reported in the retina, optic nerve, choroid and retrobulbar vasculature in glaucoma, as well as
systemically. Putative mechanisms include vasospasm or vascular dysregulation, defective
autoregulation, low or uctuating blood pressure, atherosclerosis, and autoimmune or rheological
mechanisms, which reduce the eye's ability to adapt to abnormal or changing IOP and blood pressure.
There is evidence that different mechanisms may play a role in different patients.
Although the clinical picture of glaucoma is well described, the exact mechanism leading to this
speci%c type of damage to the optic nerve head (ONH) is not yet clear. It is generally accepted that the
1mechanism of damage in glaucoma is almost certainly multifactorial. But while elevated IOP remains
the risk factor most commonly associated with glaucomatous optic neuropathy (GON), numerous other
2–7variables involved in the development and progression of glaucoma have been identi%ed. Vascular
8,9risk factors in particular have been extensively studied. These include systemic blood pressure
10–12 13,14 15–18 19–24alterations, diabetes, reduced ocular blood flow (OBF), and vasospasm.
Conventionally, two theories have been presented for the pathogenesis of glaucoma, pressure and
vascular:
1. Pressure theory, introduced by Muller, supposes that GON is a direct consequence of elevated IOP,
25damaging the lamina cribrosa and neural axons, whereas the:
2. Vascular theory, suggested by von Jaeger, considers GON as a consequence of insufficient blood supply
26to the ONH due to either elevated IOP or to other risk factors reducing OBF.
Both theories have been vigorously studied and defended by various research groups for over a
century.
Both experimental as well as clinical studies have proven the role of IOP and the bene%ts of
IOPlowering therapy in glaucoma. Yet therapeutic IOP reduction does not always stop progression of the
disease. The existence of NTG on one hand and OHT on the other indicates that other factors might be
involved in the pathogenesis of GON either directly or by rendering the eye more sensitive to the
influence of IOP.
Findings of Ocular Blood Flow Studies in Glaucoma and their
Interpretation
Investigations using epidemiological, histological and non-invasive clinical techniques point to defective
27–33ocular blood ow as an important risk factor in glaucoma. Among the vascular theories,
hypoperfusion of the ONH was reported to be associated with atherosclerosis, vasospasm and vascular