Mechanisms of the Glaucomas (eBook)

Preface 7
Contents 11
Contributors 15
Companion CD 19
I EPIDEMIOLOGY OF GLAUCOMA 21
Age and Racial Variation in the Prevalence of Open- Angle Glaucoma in the USA 22
INTRODUCTION 22
PREVALENCE OF OAG 23
EFFECT OF AGE 25
EFFECT OF RACE 29
ESTIMATING THE NUMBERS OF INDIVIDUALS IN THE USA WITH GLAUCOMA 32
PREVALENCE OF BLINDNESS DUE TO GLAUCOMA 32
IMPACT OF NEW TECHNOLOGY 33
POLICY IMPLICATIONS 34
CONCLUSION 34
REFERENCES 34
Epidemiology of and Risk Factors for Primary Open- Angle Glaucoma 38
INTRODUCTION 38
DEFINITIONS OF GLAUCOMA 39
STUDY DESIGN 40
PREVALENCE OF PRIMARY OPEN-ANGLE GLAUCOMA 42
INCIDENCE OF OPEN-ANGLE GLAUCOMA FROM POPULATION- BASED STUDIES 45
RISK FACTORS FOR GLAUCOMA 46
REFERENCES 47
The Reykjavik Eye Study on Prevalence of Glaucoma in Iceland and Identi . ed Risk Factors 54
INTRODUCTION 54
MATERIAL AND METHODS 55
EXAMINATION 55
DEFINITIONS 56
RESULTS 57
DISCUSSION 62
REFERENCES 64
Defined Glaucoma in Chinese Population 68
INTRODUCTION 68
PRIMARY GLAUCOMA 70
Demographic Indices 72
Age. 72
Sex. 73
Race. 73
Ocular Factors 73
Other risk factors 74
Demographic Indices 75
Age. 75
Sex. 75
Race. 75
Ocular Factors 75
Other Risk Factors 76
SECONDARY GLAUCOMA 76
CONGENITAL GLAUCOMA 77
SUMMARY 78
REFERENCES 78
The Wroclaw Epidemiological Study 82
INTRODUCTION 82
SCREENING FOR GLAUCOMA 83
THE WROCLAW EPIDEMIOLOGICAL STUDY 86
REFERENCES 96
II MECHANISMS OF INTRAOCULAR PRESSURE ELEVATION IN THE GLAUCOMAS 100
Pretrabecular Mechanisms of Intraocular Pressure Elevation 102
INTRODUCTION 102
NEOVASCULAR GLAUCOMA 102
IRIDOCORNEAL ENDOTHELIAL SYNDROME 108
EPITHELIAL AND FIBROUS MEMBRANES 111
INFLAMMATORY MEMBRANES 114
REFERENCES 115
Glaucomatous Changes in the Trabecular Meshwork 118
INTRODUCTION 118
ANATOMY 119
AGING CHANGES 123
PRIMARY OPEN-ANGLE GLAUCOMA 124
PSEUDOEXFOLIATION SYNDROME 126
PIGMENTARY GLAUCOMA 128
CORTICOSTEROID-INDUCED GLAUCOMA 131
SUMMARY 132
REFERENCES 133
Trabecular Mechanisms of Intraocular Pressure Elevation 136
INTRODUCTION 136
PATHOBIOLOGY OF PEX SYNDROME 138
OPEN-ANGLE GLAUCOMA ASSOCIATED WITH PEX SYNDROME 142
MANAGEMENT OF GLAUCOMAS ASSOCIATED WITH PEX SYNDROME 148
SUMMARY AND PERSPECTIVES 150
REFERENCES 151
Post-Trabecular Glaucomas with Elevated Episcleral Venous Pressure 158
INTRODUCTION 158
OBSTRUCTIVE MECHANISMS OF ELEVATED EPISCLERAL VENOUS PRESSURE 159
ARTERIO-VENOUS SHUNT MECHANISMS OF ELEVATED EPISCLERAL VENOUS PRESSURE 163
IDIOPATHIC ELEVATED EPISCLERAL VENOUS PRESSURE 169
REFERENCES 170
Angle-Closure Glaucomas 178
INTRODUCTION 178
POST-INFLAMMATORY ANGLE-CLOSURE GLAUCOMA 179
PROLIFERATIVE CAUSES OF ANGLE-CLOSURE GLAUCOMA 180
CONCLUSION 182
REFERENCES 182
Angle-Closure Glaucomas 186
MECHANISM OF PUPILLARY BLOCK ANGLE CLOSURE 186
CLINICAL FINDINGS 187
PROVOCATIVE TESTS 187
MANAGEMENT 188
LENS-INDUCED MECHANISMS OF PUPILLARY BLOCK ANGLE CLOSURE 188
POSTERIOR SYNECHIA 190
REFERENCES 191
Angle-Closure Glaucomas 192
INTRODUCTION 192
ANGLE CLOSURE ORIGINATING AT THE LEVEL OF THE CILIARY BODY 194
ANGLE CLOSURE ORIGINATING AT THE LEVEL OF THE LENS 197
ANGLE CLOSURE ORIGINATING POSTERIOR TO THE LENS 200
ACKNOWLEDGMENTS 202
REFERENCES 202
III GENETICS OF GLAUCOMA 208
Genetics and Glaucoma Susceptibility 210
RELEVANCE OF GENETICS 210
GENETIC SUSCEPTIBILITY AND PROGRESS IN GENE LOCALIZATION AND IDENTIFICATION 211
COLLABORATION BETWEEN CLINICAL AND BASIC RESEARCHERS 219
CONCLUSION 219
REFERENCES 219
Myocilin Mutations and Their Role in Open- Angle Glaucoma 224
INTRODUCTION 224
IDENTIFICATION OF THE MYOCILIN GENE 225
MUTATION ANALYSIS OF THE MYOC GENE IN OAG 225
THE Q368STOP MUTATION 227
EVIDENCE OF A FOUNDER EFFECT FOR THE Q368STOP MUTATION IN MYOC 227
THE Q368STOP AND GLAUCOMA PHENOTYPE 228
THE Q368STOP IN UNAFFECTED INDIVIDUALS 230
THE Q368STOP AND MODIFIER GENES 231
CONCLUSION 232
REFERENCES 232
The Functional Role of Myocilin in Glaucoma 238
INTRODUCTION 238
THE NATURE OF MYOCILIN 239
THE ROLE OF NORMAL OR WILDTYPE MYOCILIN FOR GLAUCOMA 241
THE ROLE OF MUTANT MYOCILIN FOR GLAUCOMA 242
REFERENCES 245
Roles of CYP1B1, Optineurin, and WDR36 Gene Mutations in Glaucoma 252
INTRODUCTION 252
CYTOCHROME P4501B1 ( 254
OPTINEURIN ( 264
WD REPEAT DOMAIN 36 ( 272
SUMMARIES AND CONCLUSION 279
REFERENCES 280
Genetic Association in the Open-Angle Glaucomas 294
INTRODUCTION 294
GLAUCOMA AND APOPTOSIS 296
GLAUCOMA AND AUTOIMMUNITY 297
GLAUCOMA AND CYTOKINES 297
GLAUCOMA AND INTERLEUKIN-1 297
GLAUCOMA AND TUMOR NECROSIS FACTOR-ALPHA 298
GLAUCOMA AND TRANSPORT OF ANTIGENIC PEPTIDES 298
GLAUCOMA AND TISSUE MORPHOGENESIS 300
GLAUCOMA AND OXIDATIVE STRESS 301
SUMMARY 302
REFERENCES 303
ApoE Polymorphisms and Severity of Open- Angle Glaucoma 308
INTRODUCTION 308
CLINICAL PRESENTATIONS OF PRIMARY OPEN-ANGLE GLAUCOMA 310
RISK FACTORS AND PROGNOSTIC FACTORS FOR PRIMARY OPEN- ANGLE GLAUCOMA 311
THE 312
GENE 312
PATHOPHYSIOLOGICAL ROLES OF APOE 315
POLYMORPHISMS AND GLAUCOMA 317
CONTRIBUTIONS OF 318
TO OPTIC NERVE DEGENERATION 318
IN GLAUCOMA 318
CONCLUDING REMARKS 319
ACKNOWLEDGMENTS 319
REFERENCES 320
IV MOLECULAR AND CELLULAR RESPONSES IN THE EYE TO GLAUCOMA 328
Changes in Aqueous Humor Dynamics with Age and Glaucoma 330
INTRODUCTION: AGEING AND AGE-RELATED DISEASE 330
CHANGES IN AQUEOUS HUMOR DYNAMICS 331
ULTRASTRUCTURAL CHANGES WITH AGE AND GLAUCOMA 333
PUTATIVE MECHANISMS UNDERLYING AGEING AND AGE- RELATED DISEASE 336
CONCLUSIONS 340
REFERENCES 341
Mechanosensitive Genes in the Trabecular Meshwork at Homeostasis 348
INTRODUCTION 348
TECHNOLOGIES TO EVALUATE CHANGES IN GENE EXPRESSION 349
MODELS TO STUDY GENE RESPONSE TO MECHANICAL STRESS: ELEVATED IOP AND STRETCH 353
HOW PRESSURE AFFECTS THE TRABECULAR MESHWORK: HOMEOSTASIS AND GLOBAL GENE EXPRESSION 357
EFFECTS OF MECHANICAL STRESS ON SINGLE GENES 365
COMPREHENSIVE SELECTION OF POTENTIALLY RELEVANT MECHANOSENSITIVE GENES 369
CONCLUDING THOUGHTS FOR FUTURE DIRECTIONS 371
ACKNOWLEDGMENTS 371
REFERENCES 371
Reactive Astrocytes in the Glaucomatous Optic Nerve Head 382
PRIMARY OPEN-ANGLE GLAUCOMA AND ELEVATED INTRAOCULAR PRESSURE 382
ONH ASTROCYTES IN POAG 383
CELL CULTURE MODELS OF MECHANOTRANSDUCTION IN ONH ASTROCYTES 384
SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN THE TRANSITION OF QUIESCENT TO REACTIVE ASTROCYTES 385
FUNCTIONS OF REACTIVE ASTROCYTES 390
CONCLUSIONS 401
ACKNOWLEDGMENTS 402
REFERENCES 402
Optic Neuropathy and Ganglion Cell Degeneration in Glaucoma 412
INTRODUCTION 412
DIVERSE CELLULAR EVENTS ASSOCIATED WITH GLAUCOMA 413
MOLECULAR MECHANISMS ASSOCIATED WITH GLAUCOMATOUS NEURONAL DAMAGE 417
CONTROLLING THE GLAUCOMATOUS DAMAGE: NEURONAL PROTECTION, PLASTICITY, AND REGENERATION 423
CONCLUSION 429
REFERENCES 429
Proteomics in Defining Pathogenic Processes Involved in Glaucomatous Neurodegeneration 444
IMPORTANCE OF THE COMPREHENSIVE ANALYSIS OF PROTEIN EXPRESSION TO IDENTIFY PATHOGENIC MECHANISMS OF GLAUCOMATOUS NEURODEGENERATION 444
CURRENT APPLICATIONS OF PROTEOMICS IN GLAUCOMATOUS NEURODEGENERATION 445
REFERENCES 457
Proteomic Advances Toward Understanding Mechanisms of Glaucoma Pathology 462
INTRODUCTION 462
COCHLIN 463
PEPTIDYL ARGININE DEIMINASE 2 467
SUMMARY AND PROSPECTS 473
ACKNOWLEDGMENTS 474
REFERENCES 474
Molecular and Cellular Responses in the Eye to Glaucoma 478
ANIMAL MODELS FOR GLAUCOMA RESEARCH 478
ANALYSIS OF GENE EXPRESSION USING THE MICROARRAY SYSTEM 482
REFERENCES 484
V OCULAR TISSUE AND PSYCHOPHYSIOLOGICAL RESPONSES IN GLAUCOMA 488
Ocular Biomechanics in Glaucoma 490
INTRODUCTION 490
BIOMECHANICS OF AQUEOUS HUMOR DRAINAGE 491
BIOMECHANICS OF THE AQUEOUS HUMOR AND IRIS 494
BIOMECHANICS OF THE OPTIC NERVE HEAD IN GLAUCOMA 497
REFERENCES 502
Intraocular Pressure, Perfusion Pressure, and Optic Nerve Energy Metabolism 510
INTRODUCTION 510
OCULAR BLOOD FLOW AND AUTOREGULATION 511
OPTIC NERVE OXYGEN TENSION AND ITS REGULATION 513
IOP AND OPTIC NERVE HEAD OXIDATIVE METABOLISM 518
OPTIC NERVE OXYGEN PHYSIOLOGY AND GLAUCOMA 520
OCULAR BLOOD FLOW IN GLAUCOMA 522
CARBONIC ANHYDRASE INHIBITORS AND OCULAR BLOOD FLOW 523
CARBONIC ANHYDRASE INHIBITORS AND OPTIC NERVE OXYGEN TENSION 525
CONCLUSION 529
REFERENCES 530
Optic Nerve 536
GLAUCOMATOUS OPTIC NEUROPATHY AND ITS IOP-INDUCED MECHANISM 536
HISTOLOGICAL CHANGE OF THE ONH IN GLAUCOMA 537
CELL-BIOLOGICAL CHANGES OF THE ONH IN GLAUCOMA 538
ONH AS A BIOMECHANICAL STRUCTURE 539
APPLICATION OF OCULAR HYPERTENSION ANIMAL MODELS FOR GON 540
FUTURE DIRECTIONS 541
REFERENCES 541
Psychophysiology of Glaucoma 546
INTRODUCTION 546
FORM (STRUCTURE) 547
FUNCTION 553
STRUCTURE/FUNCTION RELATIONSHIPS 561
REFERENCES 563
VI MODELS OF GLAUCOMA 568
The Primate Model of Experimental Glaucoma 570
INTRODUCTION 570
BACKGROUND 571
APPLICATIONS OF THE PRIMATE MODEL OF GLAUCOMA 574
NON-INVASIVE ASSESSMENT OF GLAUCOMA ONSET AND PROGRESSION 581
SUMMARY 584
REFERENCES 585
Involvement of Inflammation in a Mouse Model of Inherited Pigmentary Glaucoma 598
INTRODUCTION 598
PDS AND PIGMENTARY GLAUCOMA 599
THE DBA/2J MOUSE IS A MODEL OF PROGRESSIVE PIGMENTARY GLAUCOMA 600
GENETIC MUTATIONS IN THE DBA/2J MOUSE 603
IMMUNE DYSFUNCTION IN THE DBA/2J MOUSE 605
INVOLVEMENT OF IL-18 IN THE PATHOGENESIS OF GLAUCOMA IN THE DBA/ 2J MOUSE 606
OTHER BIOCHEMICAL ALTERATIONS IN THE IRIS OF THE DBA/ 2J MOUSE 608
IL-18-DEFICIENT DBA/2J MICE 610
CONCLUSION 615
ACKNOWLEDGMENTS 615
REFERENCES 615
Use of Purified Retinal Ganglion Cells for an In Vitro Model to Study Glaucoma 620
INTRODUCTION 620
DEVELOPMENT OF RGCS 621
PURIFICATION OF RGCS 621
PROCEDURE 622
CONTROVERSY CONCERNING NMDA EXCITOTOXICITY IN RGCS 624
CONCLUSIONS 625
REFERENCES 626
INTRODUCTION 628
VII THERAPEUTIC MODALITIES 628
Pharmacological Therapies for Managing Glaucoma 630
INTRODUCTION 630
BIOAVAILABILITY OF TOPICAL DRUGS 632
GUIDELINES FOR THE MEDICAL THERAPY OF GLAUCOMA 633
ADRENERGIC AGONISTS 635
-ADRENERGIC ANTAGONISTS 637
CARBONIC ANHYDRASE INHIBITORS 639
CHOLINERGICS 640
PROSTAGLANDIN ANALOGUES 642
FIXED COMBINATION AGENTS 645
HYPEROSMOTIC AGENTS 647
FUTURE DIRECTIONS 648
CONCLUSION 649
REFERENCES 649
Redox-Based Therapies for Neuroprotection 664
RETINAL GANGLION CELL DEATH IS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL OPTIC NEUROPATHIES 664
THERE ARE MULTIPLE MECHANISMS BY WHICH AXONAL DAMAGE CAN TRANSDUCE AN INJURY SIGNAL 665
SUPEROXIDE IS AN INTRACELLULAR SIGNALING MOLECULE FOR RGC DEATH 666
REDUCTION OF OXIDIZED THIOLS INHIBITS RGC DEATH AFTER AXOTOMY IN VITRO AND IN VIVO 667
NOVEL AGENTS THAT REDUCE OXIDIZED THIOLS PROTECT 668
RGCS IN VITRO AT LOW CONCENTRATIONS 668
SUMMARY AND OUTLOOK FOR THE FUTURE 669
ACKNOWLEDGMENTS 670
REFERENCES 671
Neuroprotective Signaling Pathways in Glaucoma 676
INTRODUCTION 676
THE NEUROTROPHINS 678
CILIARY NEUROTROPHIC FACTOR 682
BASIC FIBROBLAST GROWTH FACTOR 684
GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR 685
PEPTIDOMIMETIC LIGANDS 686
ANTI-APOPTOTIC SIGNALING 687
SUMMARY AND FUTURE DIRECTIONS 689
ACKNOWLEDGMENTS 689
REFERENCES 690
Role of Selective Laser Trabeculoplasty in the Management of Glaucoma 702
PRINCIPLE 702
HISTOPATHOLOGY 703
MECHANISMS 705
TREATMENT TECHNIQUE 707
REFERENCES 709
Mechanisms and Mechanics of Incisional Surgery for Glaucoma 712
INTRODUCTION 712
THE MECHANISMS OF GLAUCOMA SURGERY 713
PREOPERATIVE PLANNING 715
ANESTHESIA 716
MECHANICS OF TRABECULECTOMY 716
MECHANICS OF NON-PENETRATING DEEP SCLERECTOMY 729
SUMMARY 730
REFERENCES 731
Aqueous Shunts 734
THE EVOLVING CONCEPT 734
PATHOPHYSIOLOGY 737
EXPLANT ENCAPSULATION AND CORRELATIONS WITH IOP AND FUNCTION 738
EXPLANT SURFACE AREA 740
VALVED VERSUS NON-VALVED DEVICES 740
ULTRASOUND AND AQUEOUS SHUNTS 743
ANTERIOR CHAMBER VERSUS PARS PLANA TUBE INSERTION 743
SCHOCKET AND MODIFIED SCHOCKET 743
ONE- VERSUS TWO-QUADRANT SURGERY—SUPERIOR OR INFERIOR LOCATION 744
TUBE INSERTION AND METHODS OF TEMPORARY LIGATURE FOR NON- VALVED DEVICES 744
CLINICAL INDICATIONS FOR SHUNTS 746
ANTIFIBROTICS (5-FU AND MITOMYCIN) AND AQUEOUS SHUNTS 747
COMPLICATIONS OF SHUNTS 747
PEDIATRIC GLAUCOMAS 750
CLINICAL FAILURE AND ITS MANAGEMENT 750
RANDOMIZED TRIALS INVOLVING AQUEOUS SHUNTS 751
NEW CONCEPTS AND INNOVATIONS 751
SUMMARY 751
REFERENCES 751
New Approaches to the Surgical Management of the Glaucomas 758
INTRODUCTION 758
SHORTCOMINGS OF CURRENT GLAUCOMA SURGERY 759
AREAS OF RESEARCH FOR NEW GLAUCOMA SURGERY 761
CONCLUSIONS 766
ACKNOWLEDGMENTS 766
REFERENCES 766
Index 772