Cornea and External Eye Disease (eBook)

Foreword 6
Preface 7
Contents 8
Contributors 14
Chapter 1 16
Immune Privilege of Corneal Allografts 16
1.1 History of Corneal Transplantation and Immune Privilege 16
1.2 How Successful Is Corneal Transplantation? 17
1.3 Immune Rejection of Corneal Allografts 18
1.3.1 Role of CD4+ T Lymphocytes in Corneal Allograft Rejection 18
1.3.2 Role of CD8+ T Lymphocytes in Corneal Allograft Rejection 18
1.3.3 Role of Antibodies in Corneal Allograft Rejection 19
1.3.4 Role of Macrophages and NK Cells in Corneal Allograft Rejection 19
1.3.5 What are the Eff ectors of Corneal Allograft Rejection? 20
1.4 Role of Atopic Diseases in Corneal Allograft Rejection 20
1.5 Immune Privilege of Corneal Allografts Is a Tripartite Phenomenon 20
1.5.1 Aff erent Blockade of the Immune Response to Corneal Allografts 21
1.5.2 Immune Deviation in the Central Processing Component of the Immune Reflex Arc 23
1.5.3 Eff erent Blockade of the Immune Response to Corneal Allografts 24
References 25
Chapter 2 28
Mechanisms of Corneal Allograft Rejection and the Development of New Therapies 28
2.1 Status of Corneal Transplantation 28
2.2 Success Rate of Corneal Transplantation 28
2.3 Maintenance and Erosion of Corneal Privilege 29
2.4 The Corneal Allograft Response 30
2.5 Antigen Uptake in the Eye 30
2.6 Antigen Processing 31
2.7 Antigen Presentation 31
2.8 T Cell Activation, Proliferation, and Clonal Expansion 32
2.9 Eff ector Arm of the Allograft Response 32
2.10 Current Management of Corneal Transplants 32
2.11 Prevention of Allograft Rejection 32
2.12 Stratifi cation of Risk 33
2.13 Protecting Immune Privilege 33
2.14 Minimizing Antigenic Diff erences Between Donor and Recipient 33
2.15 Systemic Immunosuppression 33
2.16 Surgical Techniques and Postoperative Management 33
2.17 Management of Acute Rejection Episodes 34
2.18 New Therapies with Novel Mechanisms 34
2.19 Antibody-based Immunosuppressive Agents in Transplantation 34
2.20 Engineered Antibodies for Eye Disease 34
2.21 Gene Therapy of the Donor Cornea 35
2.22 Vectors for Gene Therapy of the Cornea 35
2.23 Transgenes for Prolonging Corneal Graft Survival 35
2.24 Future Prospects 35
References 37
Chapter 3 39
New Developments in Topical and Systemic Immunomodulation Following Penetrating Keratoplasty 39
3.1 Introduction 39
3.2 Immunology 40
3.2.1 Acute Rejection 40
3.2.2 Major Histocompatibility Complex (MHC) 40
3.2.2.1 Direct Pathway of Allorecognition 40
3.2.2.2 Indirect Pathway of Allorecognition 40
3.2.3 Chronic Rejection 40
3.3 Normal-risk vs. High-risk Transplantation 41
3.3.1 Normal-risk Transplantation 41
3.3.2 High-risk Transplantation 41
3.3.3 Rationale for Systemic Immunosuppression 41
3.3.4 Why Is Immunomodulation with Topical Steroids Not Suffi cient to Prevent Immunologic Graft Rejection in High-Risk Patients? 41
3.3.5 Rationale for Topical Immunomodulation 41
3.4 Immunosuppressive Agents 42
3.4.1 History 42
3.4.2 Corticosteroids 42
3.4.3 Cyclosporine A 42
3.4.3.1 CSA in Corneal Transplantation 43
3.4.4 Tacrolimus (fk506) 43
3.4.4.1 Tacrolimus in Corneal Transplantation 43
3.4.5 Mycophenolate Mofetil (MMF) 43
MMF in Corneal Transplantation 44
3.4.6 Rapamycin (Sirolimus) 44
3.4.7 RAD (Everolimus) 44
3.4.8 FTY 720 45
3.4.9 FK788 45
3.5 Pimecrolimus 45
3.5.1 Pimecrolimus in Corneal Transplantation 45
3.5.2 Biologic Agents 45
3.5.2.1 Basiliximab and Daclizumab 45
3.6 Guidelines for Practitioners 46
3.6.1 Systemic Immunosuppression with Drugs with Proven Effi cacy in Corneal Transplantation 46
3.6.1.1 Preoperative Evaluation 46
3.6.1.2 How to Use Cyclosporine in High-risk Corneal Transplantation 46
3.6.1.3 How to Use MMF in High-risk CornealTransplantation 46
3.6.2 Topical Immunosuppression 47
3.7 Conclusion 47
References 47
Chapter 4 51
Cytokine Analysis of the Aqueous Humor in the Context of Penetrating Keratoplasty 51
4.1 Immune Privilege of the Anterior Ocular Segment 52
4.1.1 Anterior Chamber-Associated Immune Deviation (ACAID) 52
4.1.2 The Th1/Th2 Paradigm 52
4. 2 Pitfalls in the Determination of Cytokine Levels from Aqueous Humor 52
4.3 Relevance of Individual Cytokines in Corneal Transplantation 54
4.3.1 Interleukin 1b 54
4.3.1.1 General Functions from In Vitro Experiments 54
4.3.1.2 Eff ects in Animal Models of Corneal Transplantation 54
4.3.1.3 Interleukin 1b Levels in Human Aqueous Humor 54
4.3.2 Interleukin 2 54
4.3.2.1 General Functions from In Vitro Experiments 54
4.3.2.2 Eff ects in Animal Models of Corneal Transplantation 54
4.3.2.3 Interleukin 2 Levels in Human Aqueous Humor 54
4. 3.3 Interleukin 6 55
4.3.3.1 General Functions from In Vitro Experiments 55
4.3.3.2 Eff ects in Animal Models of Corneal Transplantatoin 55
4.3.3.3 Interleukin 6 Levels in Human Aqueous Humor 55
4.3.4 Interleukin 10 55
4.3.4.1 General Functions from In Vitro Experiments 55
4.3.4.2 Eff ects in Animal Models of Corneal Transplantation 55
4.3.4.3 Interleukin10 Levels in Human Aqueous Humor 55
4.3.5 Interferon Gamma (IFN- gamma ) 56
4.3.5.1 General Functions from In Vitro Experiments 56
4.3.5.2 Eff ects in Animal Models of Corneal Transplantation 56
4.3.5.3 INF- gamma Levels in Human Aqueous Humor 56
4.3.6 Tumor Necrosis Factor Alpha (TNF- alpha ) 56
4.3.6.1 General Functions from In Vitro Experiments 56
4.3.6.2 Eff ects in Animal Models of Corneal Transplantation 56
4.3.6.3 TNF- a Levels in Human Aqueous Humor 56
4.3.7 Transforming Growth Factor Beta (TGF- beta) 57
4.3.7.1 General Functions from In Vitro Experiment 57
4.3.7.2 Eff ects in Animal Models of Corneal Transplantation 58
4.3.7.3 TGF- b 2 Levels in Human Aqueous Humor 58
4.3.8 Fas, Fas Ligand and Soluble Fas Ligand 58
4.3.8.1 General Functions from In Vitro Experiments 58
4.3.8.2 Eff ects in Animal Models of Corneal Transplantation 59
4.3.8.3 sFasL Levels in Human Aqueous Humor 59
4.3.9 Further Cytokines and Immunomodulative Factors 59
4.3.9.1 Interleukin 1 Receptor Antagonist 59
4. 3.9.2 Interleukin 4 60
4.3.9.3 Interleukin 5 60
4.3.9.4 Interleukin 8 60
4.3.9.5 Interleukin 12 60
4. 3.9.6 Alpha-Melanocyte-Stimulating Hormone/ Calcitonin Gene-Realted Peptide/ Thrombospondin/Somatostatin 60
4. 4 Cytokine Profi les in the Context of Corneal Transplantation 63
4.4.1 Cytokine Profi les in Animal Models 63
4.4.2 Cytokine Profi les in Humans 63
4.4.2.1 Cytokines in the Serum of Patients Following PK 63
4.4.2.2 Cytokines in Human Corneas 63
4. 4.2.3 Cytokines in Human Aqueous Humor 63
References 64
Chapter 5 67
Limbal Stem Cell Transplantation: Surgical Techniques and Results 67
5.1 Introduction 67
5.1.1 The Corneal Epithelium 67
5.1.2 The Limbus and Corneal Epithelial Homeostasis 67
5.2 Corneal LESC Defi ciency 69
5.2.1 Diagnosis and Classifi cation of Corneal LESC Defi ciency 69
5.3 Management of Patients with Limbal Stem Cell Defi ciency 71
5.3.1 Conservative Options 71
5.3.2 Surgical Options for Partial Limbal Stem Cell Defi ciency 71
5.3.3 Surgical Options for Total Limbal Stem Cell Defi ciency 71
Correct any dry eye disease and lid abnormality that is contributing to ocular surface failure 71
Remove the conjunctival epithelium from the cornea and restore a normal stromal environment 71
Transplant corneal LESCs to reestablish an intact and transparent epithelium 71
5.4 Surgical Techniques for Transplanting Corneal Limbal Stem Cells 72
5.4.1 Conjunctival Limbal Autograft (CLAU) 72
5.4.2 Living-Related Conjunctival Limbal Allograft Transplant (lr-CLAL) 72
5.4.2.1 Clinical Outcomes of CLAU and lr-CLAL 73
5.4.3 Keratolimbal Allograft Transplant 73
5.4.4 Ex Vivo Expansion and Transplantation of Cultured Limbal Stem Cells 74
5.4.5 Regulations Governing the Clinical Use of Ex vivo Cultured Tissue 74
5.4.6 Evidence of the Presence of Stem Cells in Ex vivo Cultures and Grafts 75
5.4.7 Assessing Outcomes Following LESC Transplantation 75
5.4.8 Evidence for Donor Cell Survival Following Ex Vivo Cultured LESC Transplantation 75
5.4.9 Role of Tissue Matching in Transplantation of Allogeneic Tissue or Cells 76
5.4.10 Alternative Sources of Autologous Stem Cells 76
5.4.11 Issues Surrounding Ex Vivo Cultured LESC Transplantation that Require Further Investigation 76
5.5 Conclusion 77
References 77
Chapter 6 82
Cell Cycle Control and Replication in Corneal Endothelium 82
6.1 Relationship of Endothelial Barrier Function to Corneal Transparency 83
6.2 Corneal Endothelial Cell Loss and Repair Mechanisms 84
6.2.1 Causes of Cell Loss 84
6.2.2 Repair of the Endothelial Monolayer 84
6.3 Are Human Corneal Endothelial Cells Able to Divide? 84
6.3.1 Proliferative Status In Vivo 84
6.3.2 Evidence that HCEC Retain Proliferative Capacity 84
6.4 The Cell Cycle 85
6.4.1 Positive Regulation of the Cell Cycle 85
6.4.2 Negative Regulation of G1-Phase of the Cell Cycle 86
6.5 Potential Causes for Inhibition of HCEC Proliferation In Vivo 87
6.5.1 Cell–Cell Contacts Inhibit Division 87
6.5.2 Endothelium In Vivo Lacks Effective Paracrine or Autocrine Growth Factor Stimulation 88
6.5.3 TGF-Beta2 Has a Suppressive Effect on S-phase Entry 88
6.6 Proliferative Capacity of HCEC Differs with Donor Age 89
6.6.1 Analysis of pRb Hyperphosphorylation 90
6.6.2 Analysis of Replication Competence 90
6.6.3 Analysis of CKI Protein Expression 90
6.7 Efforts to Stimulate Corneal Endothelial Proliferation by Interfering with G1-phase Inhibition 91
6.7.1 Overcoming G1-phase Inhibition 92
6.7.2 Bypassing G1-phase Inhibition 92
6.8 Endothelial Topography Affects the Proliferative Capacity of HCEC 92
6.8.1 Differences in Proliferative Capacity 92
6.8.2 Differences in Senescence Characteristics 93
6.9 Identification of Mechanisms Responsible for Decreased Proliferative Capacity 93
6.9.1 Are Critically Short Telomeres Responsible for Decreased Proliferative Capacity? 94
6.9.2 Is Sub-lethal Oxidative DNA Damage Responsible for Decreased Proliferative Capacity? 94
6.10 Future Directions 95
References 96
Chapter 7 100
Current State of the Art of Fitting Gas-Permeable (GP) Contact Lenses 100
7.1 Corneal Topography and Automatic Fitting Programs 100
7.2 Fitting CLs 101
7.3 The Keratoconus 101
7.3.1 KC Peculiarities in Conjunction with CL 101
7.3.1.1 Corneal Sensitivity and Maximum Resilience 101
7.3.1.2 Corneal Contour-KC Stage-KC Type 102
7.3.2 Forms of Correction 102
7.3.2.1 Soft Lenses 102
7.3.2.2 GP Contact Lenses 102
7.3.2.3 Piggyback 102
7.3.2.4 Hybrid Lenses 102
7.3.3 Fitting Techniques 102
7.3.3.1 The Reshape and Splint Method 102
7.3.3.2 The Three-Point Touch Method 102
7.3.3.3 The Apical Clearance Method 103
7.3.3.4 Scleral Fitting Method 103
7.3.4 GP Fitting Following Cross Linking 103
7.4 CL Fitting Following Penetrating Keratoplasty 104
7.4.1 Indications for CLs Following PK 104
7.4.2 Indications for CLs Following PK in Comparison with Newer Surgical Techniques 104
7.4.3 PK Peculiarities in Conjunction with CLs 105
7.4.3.1 Corneal Sensitivity, Fitting Quality, and Frequent Follow-Ups 105
7.4.3.2 The Endothelium and Choice of GP Materials 105
7.4.3.3 Immune Reactions 105
7.4.4 When to Fit? 105
7.4.5 Fitting Techniques 106
7.4.5.1 PK with One or Two Sutures 106
7.4.5.2 CL Fitting Following Suture Removal 106
Abbreviations 107
References 107
Chapter 8 110
Allergic Disease of the Conjunctiva and Cornea 110
8.1 Introduction and Classification 110
8.2 Clinical Forms 111
8.2.1 Seasonal and Perennial Allergic Conjunctivitis 111
8.2.2 Vernal Keratoconjunctivitis 111
8.2.3 Atopic Keratoconjunctivitis 113
8.2.4 Giant Papillary Conjunctivitis 114
8.2.5 Contact Blepharoconjunctivitis 114
8.2.6 Drug-Induced Conjunctivitis or Keratoconjunctivitis 114
8.2.7 Urban Eye Allergy Syndrome 115
8.3 Diff erential Diagnosis 116
8.4 Diagnostic Tests in Ocular Allergy 117
8.5 Ocular Immunity and the Allergic Reaction 117
8.5.1 Innate Immunity and Ocular Allergy 117
8.5.2 The Allergic Process 118
8.5.3 Allergic Infl ammation 119
8.6 The Cornea in Allergic Diseases 120
8.6.1 Corneal Immunology 120
8.6.2 Allergic Infl ammation and Corneal Damage 120
8.6.3 Tear Instability and Corneal Involvement 120
8.6.4 Corneal Clinical Manifestations in Ocular Allergy 121
8.6.5 Confocal Microscopy and Allergic Keratoconjunctivitis 121
8.6.6 Keratoconus and Allergic Conjunctivitis 122
8.6.7 Keratoglobus 122
8.6.8 Allergic Keratoconjunctivitis and Corneal Infection 123
8.6.9 Allergy and Corneal Transplant 123
8.6.9.1 Immunology 123
8.6.9.2 Clinical Outcomes 124
8.7 Treatment of Ocular Allergy 124
8.7.1 Nonpharmacological Management 125
8.7.2 Treatment of Allergic Conjunctivitis 125
8.7.2.1 Topical Ocular Pharmacological Treatment 125
8.7.2.2 Topical Nonocular Pharmacological Treatment 126
8.7.2.3 Systemic Pharmacological Treatment 126
8.7.2.4 Specifi c Immunotherapy 127
8.7.3 Treatment of GPC 127
8.7.4 Treatment of Vernal Keratoconjunctivitis 127
8.7.4.1 Corticosteroids 127
8.7.4.2 Cyclosporine and Other Immunosuppressive Treatments 128
8.7.5 Treatment of AKC 128
8.7.5.1 Cyclosporine and Other Immunosuppressive Treatments 128
8.7.6 Surgical Treatment of Keratoconjunctivitis 129
References 129
Chapter 9 134
Trachoma 134
9.1 Introduction 134
9.1.1 Overview 134
9.1.2 History 134
9.2 Clinical Features 135
9.2.1 Symptoms and Signs 135
9.2.2 Trachoma Grading Systems 136
9.2.3 Diff erential Diagnosis 136
9.3 Chlamydia Trachomatis 136
9.4 Laboratory Diagnosis 137
9.5 Clinical Signs and Infection 138
9.6 Epidemiology 138
9.6.1 Prevalence and Distribution 138
9.6.2 Age and Gender 139
9.6.3 Risk Factors for Active Trachoma and C. Trachomatis Infection 139
9.7 Pathophysiology of Trachoma 140
9.7.1 The Stimulus for Infl ammation and Scarring in Trachoma 140
9.7.2 Histopathology 141
9.7.3 The Immune Response in Trachoma 141
9.7.4 Immunopathogenesis of Conjunctival Scarring 142
9.8 Trachoma Control 143
9.8.1 The SAFE Strategy 143
9.8.2 Surgery for Trichiasis 143
9.8.3 Antibiotics 143
9.8.4 Face Washing 145
9.8.5 Environmental Improvements 145
9.10 Conclusion 145
References 146
Chapter 10 149
Keratoprosthesis 149
10.1 Introduction 149
10.2 Prognostic Hierarchy 150
10.3 Defi ning Patient Subtypes 150
10.3.1 Patient Subtype A: The Noninfl amed Eye 150
10.3.2 Patient Subtype B: The Infl amed Eye 150
10.4 Experience with Kpro in Patient Subtype A 150
10.4.1 Boston Type 1 Kpro 150
10.4.1.1 Pediatric Application of Boston Type 1 Kpro 151
10.4.2 AlphaCor Kpro 152
10.5 Experience with Kpro in Patient Subtype B 152
10.5.1 Osteo-Odonto Keratoprosthesis (OOKP) 152
10.5.2 Boston Type 2 Kpro 153
10.6 Other Kpro Designs 153
10.6.1 Pintucci Kpro 153
10.6.2 Seoul-Type Kpro 153
10.6.3 Worst-Singh Kpro 153
10.6.4 Russian/Ukrainian Experience 154
10.7 New Directions in Kpro Research 154
10.7.1 Hydroxyapatite Biologic Haptics 154
10.7.2 Biologic Coatings 154
10.7.3 Biologic Scaff olds and Enhanced Hydrogels 154
10.8 Conclusion 154
References 155
Chapter 11 157
Posterior Lamellar Keratoplasty in Perspective 157
11.1 Introduction 157
11.2 Choosing Endothelial Keratoplasty Procedures 158
11.2.1 Indications 158
11.2.2 Preoperative Considerations 158
11.2.2.1 Confi rming the Extent of Endothelial Dysfunction 158
11.2.2.2 Corneal Scarring 159
11.2.2.3 Cataract and Intraocular Lens Status 159
11.2.2.4 Lens/Iris Diaphragm Status 159
11.2.2.5 Intraocular Pressure 160
11.2.2.6 Retinal Function 160
11.3 PLK Surgical Technique 160
11.3.1 Donor Preparation 160
11.3.2 Host Dissection for DSEK/DSAEK 160
11.3.3 Donor Insertion 161
11.3.4 Techniques for Graft Centration 161
11.3.5 Techniques for Promoting Donor Adhesion 162
11.3.6 Post-operative Care 163
11.3.7 Surgery for Complex Cases 163
11.3.7.1 Failed Grafts 163
11.3.7.2 Aniridics, Vitrectomised and Aphakic Eyes 165
11.3.7.3 Anterior Chamber Lens 165
11.4 Clinical Results and Complications 165
11.4.1 Visual Acuity 165
11.4.2 Astigmatism 165
11.4.3 Spherical Equivalent 165
11.4.4 Endothelial Cell Loss 166
11.4.5 Corneal Donor Dislocation 167
11.4.6 Pupillary Block 168
11.4.7 Primary Graft Failure 168
11.4.8 Rejection 168
11.4.9 Other Complications 168
11.5 Conclusion 169
References 169
Index 172