Vitreous : in health and disease

Description

Foreword Preface Commemoration Contents Contributors Is Your Vitreous Really Necessary? I. Introduction II. Mechanical Homeostasis III. Molecular Homeostasis A. Oxygen Physiology B. Angiogenic and Pro-Inflammatory Factors IV. Intravitreal Pharmacotherapy V. Ocular and Refractive Development VI. Vitreous Evolution VII. Summary References Part I: Biochemistry I.A.: Vitreous Proteins I. Introduction II. Extracellular Matrix Proteins of the Vitreous A. Vitreous Collagens 1. Collagen Structure a. Type II Collagen b. Type V/XI Collagen c. Type IX Collagen d. Type VI Collagen 2. Heterotypic Collagen Fibrils of Vitreous 3. Synthesis and Turnover of Vitreous Collagen 4. Spacing Between Vitreous Collagen Fibrils and Ageing Changes B. Non-collagenous Extracellular Matrix Components of Vitreous 1. Fibrillins 2. Fibulins 3. Versican and Link Proteins 4. Agrin and Type XVIII Collagen III. Vitreous Macromolecules That Regulate Angiogenesis A. Opticin B. Pigment Epithelium-Derived Factor C. Leucine-Rich Alpha-2 Glycoprotein (LRG1) D. Thombospondins References I.B.: Hyaluronan and Other Carbohydrates in the Vitreus I. Introduction II. Vitreus Structure III. Hyaluronan IV. Proteoglycans of the Vitreus V. Aging of the Vitreus VI. Miscellaneous Considerations A. Species Variations B. Hyaluronidase and the Vitreus C. Hyaluronan and its Derivatives as Viscoelastics in Medicine References I.C.: Hereditary Vitreo-Retinopathies I. Introduction A. Vitreous Embryology II. Classification of Inherited Vitreo-Retinopathies A. Diagnosis and Clinical Features 1. Vitreo-Retinopathies with Skeletal Abnormalities a. Stickler Syndrome i. Epidemiology ii. Diagnosis and Differential Diagnosis iii. Clinical Features 1. Ophthalmologic Features 2. Orofacial Features 3. Hearing Loss 4. Musculoskeletal Features iv. Molecular Genetic Analysis of Stickler Syndrome a. Type 1 Stickler Syndrome b. Type 2 Stickler Syndrome c. Type 3, “Non-ocular” Stickler Syndrome d. Types 4, 5, and 6 Stickler Syndrome e. “Ocular-Only” Stickler Syndrome f. Stickler Syndrome with Profound Deafness g. Unresolved b. COL2A1-Related Disorders i. Kniest Dysplasia ii. Spondyloepiphyseal Dysplasia Congenita (SEDC) iii. Vitreoretinopathy with Phalangeal Epiphyseal Dysplasia (V-PED) iv. Marshall Syndrome v. Knobloch Syndrome vi. Marfan Syndrome 2. Vitreoretinopathies with Progressive Retinal Dysfunction a. Wagner Vitreoretinopathy/Erosive Vitreoretinopathy b. Goldmann-Favre Syndrome/Enhanced S-Cone Dystrophy 3. Vitreoretinopathies with Abnormal Retinal Vasculature a. Familial Exudative Vitreoretinopathy b. Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) 4. Vitreoretinopathy Associated with Corneal Changes 5. Vireoretinopathies Associated with Dominant and/or Bilateral Rhegmatogenous Retinal Detachment (DRRD/BRRD) III. Screening and Ancillary Investigations IV. From Laboratory To Bedside: Current Research on Mechanisms for Variability in Clinical Phenotype A. Phenotypic Differences Due to Splicing Variations 1. Phenotypic Differences Due to Missense Mutations 2. Phenotypic Differences Due to Mosaicism B. Future Developments V. Prophylaxis VI. Summary References I.D.: Vitreous Cytokines and Regression of the Fetal Hyaloid Vasculature I. Introduction II. Structure of the Hyaloid Vasculature III. Timeline of Fetal Hyaloid Vasculature Regression A. Lower Mammals B. Humans IV. Vitreous Cytokine Expression A. Comparative Analysis to a Murine Model of Vitreous Embryogenesis V. Mechanisms of Fetal Vessel Regression A. Apoptosis B. Macrophagy 1. Macrophage Adhesion to Hyaloid Vessels 2. Macrophage-Induced Apoptosis C. Antiangiogenesis 1. Angiogenesis Promoters 2. Angiogenesis Inhibitors D. Autophagy E. External Stimuli VI. Miscellaneous Proteins VII. Genetic Influences Conclusi ons References I.E.: Diabetic Vitreopathy I. Introduction II. Biochemistry of Diabetes A. Advanced Glycation End Products B. Protein Kinase C C. Aldose Reductase D. Hexosamine E. Oxidative Stress III. Diabetic Retinopathy A. Epidemiology B. Pathophysiology of Diabetic Retinopathy 1. Diabetic Retinopathy and the Neurosensory Retina 2. Diabetic Retinal Vasculopathy IV. Diabetic Vitreopathy A. Molecular Alterations 1. Collagen 2. Hyaluronan 3. Extracellular Matrix Constituents B. Structural Alterations 1. Vitreoretinal Interface 2. Vitreous Body V. Physiological Considerations in Diabetic Vitreopathy A. Oxygen Physiology B. Paracrine Depot VI. Treatment Considerations in Diabetic Vitreopathy A. Pharmacotherapy 1. Aminoguanidine 2. Alagebrium 3. Vitamin B Derivatives B. Surgery C. Pharmacologic Vitreolysis VII. Asteroid Hyalosis (AH) VII. Summary References I.F.: Vitreous Biochemistry and Artificial Vitreous I. Introduction A. Rationale: Why an Artificial Vitreous? B. Vitreous Biochemistry 1. Glycosaminoglycans (GAGs) a. Hyaluronan b. Chondroitin Sulfate (CS) c. Heparan Sulfate (HS) 2. Proteins 3. HA-Collagen Interaction 4. Miscellaneous Components a. Metabolites and Enzymes b. Ascorbic Acid c. Amino and Fatty Acids d. Prostaglandins II. Roles of an Artificial Vitreous III. Properties of an Artificial Vitreous A. Anatomic Considerations: Do We Need a Posterior Vitreous Cortex? IV. Vitreous Substitutes in Vitreoretinal Surgery A. Natural and Semisynthetic Polymers and Hyaluronic Hydrogels B. Synthetic Hydrogels and “Smart Hydrogels” V. Developing an Artificial Vitreous A. Experimental Models for Testing Artificial Vitreous In Vivo 1. Polyalkylimide 2. Polyethylene Glycol B. Experimental Model for Testing Artificial Vitreous In Vitro References Part II: Anatomy, Development and Aging II.A.: Development and Developmental Disorders of Vitreous I. Introduction II. Overview of Eye Development A. Embryonic Origins B. The Optic Vesicle, Cup, and Fissure III. Embryology of the Vitreous Body A. Primary Vitreous B. Secondary Vitreous IV. Structural and Molecular Factors in Vitreous Development A. Structure of the Hyaloid Vascular System B. Molecular Factors in Formation and Regression of the Hyaloid Vasculature C. Cells in the Developing Vitreous D. Molecular Changes During Vitreous Development V. Disorders of the Developing Vitreous A. Pathologies of the Primary Vitreous 1. Persistent Primary Vitreous 2. Persistent Hyperplastic Primary Vitreous Persistent Fetal Vasculature B. Pathologies of the Secondary Vitreous 1. Syndromic disorders C. Hyaloid Vascular System 1. Persistent Hyaloid Artery 2. Mittendorf’s Dot 3. Bergmeister’s Papilla 4. Persistent Pupillary Membranes 5. Vitreous Cyst Conclusion References II.B.: Myopic Vitreopathy I. Introduction A. Definition of Myopia B. Emmetropization and Axial Length II. Myopia A. Epidemiology B. Etiology 1. Genetic Factors 2. Environmental Factors 3. Vitreous Factors C. Ocular Features of Myopia 1. Scleral Changes and Axial Length 2. Myopic Vitreopathy 3. Retina and Choroid a. Retinal Lattice D. The Pathologies of Myopic Vitreopathy 1. Retinal Detachment a. Retinal Detachment After Anterior Segment Surgery 2. Myopic Maculopathy a. Myopic Macular Degeneration i. Choroidal Neovascularization b. Myopic Foveoschisis c. Premacular Membranes d. Macular Hole i. Macular Hole with Retinal Detachment e. Paravascular Retinal Microholes 3. Cataract References II.C.: Vitreous Aging and Posterior Vitreous Detachment I. Introduction II. Molecular Composition of Vitreous A. Collagens B. Non-collagenous Components III. Vitreous Structure A. Vitreous Body B. Posterior Vitreous Cortex C. Vitreous Base D. Vitreoretinal Interface IV. Aging Changes in the Vitreous Body A. Liquefaction B. Structural Changes 1. Fibrous Aggregation 2. Vitreous Base Migration 3. Vitreoretinal Interface Weakening V. Posterior Vitreous Detachment A. Epidemiology B. Pathophysiology C. Clinical Presentation 1. Time Course D. Anomalous PVD References II.D.: Hyalocytes: Essential Vitreous Cells in Vitreoretinal Health and Disease I. Introduction II. Characteristics of Hyalocytes A. Existence and Distribution of Hyalocytes 1. Morphological Characteristics of Hyalocytes a. Cell Surface Antigenic Characteristics 2. Origin of Hyalocytes III. Physiological Functional Properties of Hyalocytes A. Role of Hyalocytes During Development B. Phagocytic and Fibrinolytic Activity of Hyalocytes C. Modulator of Intraocular Immune System: Vitreous Cavity-Associated Immune Deviation IV. Functional Properties of Hyalocytes in Vitreoretinal Interface Pathology A. Proliferative Vitreoretinal Diseases 1. Formation of Proliferative Membranes 2. Cicatricial Contraction of Proliferative Membranes 3. Macular Pucker 4. Macular Holes V. Treatment A. Surgical Approach B. Pharmacotherapy VI. Summary References II.E.: Vitreoretinal Interface and  Inner Limiting Membrane I. Introduction II. Inner Limiting Membrane A. Anatomy 1. Structure 2. Topographic Variations B. Biochemical Composition of the ILM C. Biosynthesis and Assembly of the ILM D. Role of the ILM in Ocular Development E. Aging of the ILM F. Role of the ilm in Disease 1. ILM and Diabetes 2. Proliferative Diseases and the ILM 3. Tractional Disorders and the ILM a. Biophysical Properties of the ILM 4. Uveitis III. Posterior Vitreous Cortex A. Structure B. Cells of the Posterior Vitreous Cortex 1. Hyalocytes 2. Fibroblasts IV. Vitreovascular Interface V. Unresolved Questions A. Diffusion Through the ILM 1. Trans-ILM Diffusion from Vitreous to Retina and Choroid 2. Trans-ILM Diffusion from Chorioretinal Compartment to Vitreous B. Viral Penetration Through the ILM into the Retina C. Trans-ILM Cell Migration D. Vitreous-ILM Adhesion References II.F.: To See the Invisible: The Quest of Imaging Vitreous I. Introduction II. In Vitro Imaging III. In Vivo Imaging A. Physical Examination 1. Direct Ophthalmoscopy 2. Indirect Ophthalmoscopy 3. Slit-Lamp Biomicroscopy a. Preset Lens Biomicroscopy b. Contact Lens Biomicroscopy B. Clinical Imaging Technologies 1. Optical Imaging a. Scanning Laser Ophthalmoscopy b. Optical Coherence Tomography 2. Acoustic Imaging: Ultrasonography 3. Magnetic Resonance Imaging Spectroscopy IV. Future Imaging Technologies A. Raman Spectroscopy B. Dynamic Light Scattering References Part III: Pathology/Pathobiology III.A.: Congenital Vascular Vitreoretinopathies I. Introduction II. Retinopathy of Prematurity A. Classification B. Pathophysiology 1. Mechanism of Retinal Detachment C. Risk Factors D. Prevention 1. Screening E. Treatment 1. Cryotherapy 2. Laser Photocoagulation 3. Pharmacotherapy a. Bevacizumab b. Pharmacologic Vitreolysis 4. Treatment of Retinal Detachment III. Persistent Fetal Vasculature A. Anterior Persistent Fetal Vasculature 1. Persistent Pupillary Membrane 2. Iridohyaloid Blood Vessels 3. Mittendorf’s Dot 4. Muscae Volitantes 5. Retrolental Membrane B. Posterior Persistent Fetal Vasculature 1. Bergmeister’s Papilla 2. Persistent Hyaloid Artery 3. Congenital Nonattachment of the Retina and Retinal Detachment 4. Globe Malformations 5. Macular Abnormalities 6. Optic Nerve Head Abnormalities C. Genetics D. Treatment of Persistent Fetal Vasculature IV. Familial Exudative Vitreoretinopathy A. Clinical Presentation B. Clinical Classification C. Genetics 1. Ancillary Testing 2. Systemic Associations D. Treatment 1. FEVR Treatment Outcomes References III.B.: Anomalous Posterior Vitreous Detachment and Vitreoschisis I. Introduction II. Vitreous Biochemistry III. Aging A. Vitreous Body Aging 1. Pathogenesis of Liquefaction 2. Structural Changes B. Aging of the Vitreoretinal Interface IV. Posterior Vitreous Detachment A. Diagnosis of PVD 1. Ultrasound 2. Optical Coherence Tomography (OCT) a. Vitreoretinal Interface by OCT b. Vitreous Body Imaging by OCT B. Conditions Predisposing to PVD 1. Cataract Surgery 2. Myopia 3. Trauma a. Blunt Trauma b. Penetrating Trauma V. Anomalous Posterior Vitreous Detachment (APVD) A. Etiology of Anomalous PVD B. Retinal Effects of Anomalous PVD 1. Peripheral Retinal Effects of APVD 2. Macular Effects of Anomalous PVD a. Full-Thickness Vitreomacular Traction i. Vitreomacular Traction (VMT) ii. Age-Related Macular Degeneration iii. Cystoid Macular Edema (CME) and Macular Cysts iv. Diabetic Macular Edema b. Partial-Thickness Vitreomacular Traction (Vitreoschisis) i. Anterior vs. Posterior Split ii. Macular Pucker iii. Macular Hole References III.C.: Pathology of Vitreomaculopathies I. Introduction II. Vitreomacular Traction Syndrome III. Macular Pucker A. Cell Types B. Cell Locations C. Cell Origins IV. Macular Hole A. Immunocytochemistry References III.D.: Vitreo-Macular Adhesion/Traction and Macular Holes: Pseudo, Lamellar, and Full-Thickness I. Pathophysiology and Classification of Vitreo-Macular Adhesion (VMA) and Vitreo-Macular Traction (VMT) A. Pathophysiology of Posterior Vitreous Detachment (PVD) and Effects on the Vitreo-Macular Interface (VMI) B. Definition and Classification of VMA C. Definition and Classification of VMT II.   Pathophysiology and Classification of Macular Holes A. Pseudohole B. Lamellar Hole C. Full-Thickness Macular Hole (FTMH) Conclusion References III.E.: Vitreo-Papillary Adhesion and Traction I. Introduction II. Anatomy A. Vitreo-Retinal Interface B. Vitreo-Papillary Interface III. Pathology A. Vitreo-Papillary Adhesion and Traction B. Retinal Disorders 1. Macular Diseases 2. Intraretinal Cysts 3. Vascular Disorders a. Peripapillary, Subretinal, and Intrapapillary Hemorrhage b. Diabetic Vitreo-Retinopathy c. Central Retinal Vein Occlusion C. Optic Neuropathies 1. Non-arteritic Anterior Ischemic Optic Neuropathy 2. Gaze-Evoked Amaurosis 3. Optic Nerve Pit Conclusion References III.F.: Vitreous in the Pathobiology of Macular Pucker I. Introduction II. Epidemiology III. Anatomy A. Vitreoretinal Interface IV. Pathology A. Structure and Composition of Macular Pucker Membranes V. Pathophysiology A. Pathophysiology of Visual Disturbance in Macular Pucker VI. Clinical Presentation A. Distinguishing Macular Pucker from Vitreo-­Macular Traction Syndrome B. Measuring the Impact of Macular Pucker on Vision Conclusion References III.G.: Vitreous in Age-Related Macular Degeneration I. History II. Epidemiology of Vitreo-Macular Adhesion in AMD A. Posterior Vitreous Detachment (PVD) in AMD Study B. Vitreous in Unilateral Exudative AMD Study III. Morphology of Vitreo-Macular Adhesion in AMD A. Imaging 1. Three-Dimensional OCT B. Vitreo-Macular Adhesion 1. Adhesion Versus Traction C. Vitreopapillary Adhesion/Traction 1. Vitreoschisis IV. Role of Vitreous in Conversion from Dry to Exudative AMD V. Impact of Vitreous on Treatment of Exudative AMD A. Spontaneous PVD B. Nonresponders C. Polypoidal Choroidal Vasculopathy and Retinal Angiomatous Proliferation D. Vitrectomy E. Pharmacologic Vitreolysis VI. The Putative Role of Vitreous in the Pathogenesis of AMD A. Traction B. Low-Grade Inflammation C. Barrier Function 1. Hypoxia 2. Macular Cytokine Load References III.H.: Peripheral Vitreo–Retinal Pathologies I. Structure A. Peripheral Vitreo–Retinal Attachments 1. Vitreous Base 2. Ora Bays 3. Meridional Folds 4. Meridional Complexes 5. Peripheral Retinal Excavations 6. Retinal Tufts a. Non-Cystic Retinal Tufts b. Cystic Retinal Tufts c. Zonular Traction Tufts 7. Spiculated and Nodular Pigment Epithelial Hyperplasia 8. Retinal Lattice 9. White-With-Pressure, White-Without-Pressure 10. Verruca II. Mechanics of Peripheral Vitreo–Retinal Traction III. Alterations of Peripheral Vitreo–Retinal Structure A. Post-Traumatic Retinal Healing B. Aging Changes at the Peripheral Vitreo-Retinal Interface C. Retinal Breaks Unrelated to PVD IV. Effects of Anomalous PVD A. Vitreous Traction on Peripheral Retina 1. Retinal Tags 2. Retinal Folds 3. Cystic Degeneration and Peripheral Retinoschisis 4. Retinal Pits (Lamellar Retinal Tears) 5. Retinal Tears V. Vasculopathies of the Peripheral Fundus A. Tractional Avulsion of Retinal Vessels B. Sickle-Cell Vasculopathies C. Coats’ Disease VI. Pars Planitis A. Epidemiology and Clinical Presentation B. Sequelae C. Therapy References III.I.: Role of Vitreous in the Pathogenesis of Retinal Detachment I. Introduction II. Maintenance of Retinal Apposition A. Structural Factors B. Molecular Movement Within and from Vitreous 1. Hydrostatic Pressure 2. Colloid Osmotic Pressure 3. Diffusion C. Measurement of Retinal Adhesion D. Retinal Adhesion In Vivo and Post-Enucleation E. Effect of pH F. Role of the RPE G. Inhibition of RPE Metabolism H. Surface Energy and Electrostatic Forces I. Flow Conductivity and Retinal Adhesion III. Exudative Retinal Detachment IV. Rhegmatogenous Retinal Detachment A. Vitreous Degeneration B. Vitreous Traction 1. Macular Holes 2. Retinal Breaks C. Synchisis, Syneresis, and Vitreous Currents V. Developmental Abnormalities VI. Effects of Retinal Detachment on Vitreous and Other Ocular Tissues References III.J.: Cell Proliferation at the Vitreoretinal Interface in Proliferative Vitreoretinopathy and Related Disorders I. Introduction II. Clinical Features of PVR A. Risk Factors of PVR B. Clinical Signs and Staging of PVR C. Histopathology of PVR D. Pathophysiology of PVR 1. Cell Types in PVR a. Retinal Pigment Epithelial (RPE) Cells b. Macrophages/Hyalocytes c. Glial Cells d. Myofibroblasts e. Immune Cells 2. Cytokines of PVR a. Tumor Necrosis Factor-α (TNF-α) b. Transforming Growth Factor-β (TFG-β) c. Platelet-Derived Growth Factor Receptor-α (PDGFR-α) d. Miscellaneous Cytokines III. Treatment of PVR A. Surgery of PVR B. Pharmacotherapy of PVR References III.K.: Vitreous in Retinovascular Diseases and Diabetic Macular Edema I. Introduction A. Retinal Vein Occlusion 1. Definition 2. Epidemiology 3. Pathogenesis and Risk Factors 4. Clinical Classification 5. Symptoms 6. Complications B. Diabetic Macular Edema 1. Definition 2. Epidemiology 3. Pathogenesis and Risk Factors 4. Clinical Classification 5. Symptoms II. Role of Vitreous in RVO and DME A. Biochemical Role of Vitreous 1. Inflammatory and Angiogenic Proteins in Vitreous 2. Crystallin in Vitreous After Ischemia-­Reperfusion Injury B. Structural Role of Vitreous 1. Vitreous Attachment in RVO III. Role of Vitreous in Diabetic Macular Edema A. Structural 1. Vitreous Detachment and Vitreoschisis in DME 2. Vitreo-Retinal Interface in DME B. Biochemistry of Vitreous in DME 1. Advanced Glycation End Products in DME 2. Inflammatory Factors in Vitreous of DME References III.L.: Proliferative Diabetic Vitreoretinopathy I. Introduction A. Diabetes B. Diabetic Retinopathy 1. Nonproliferative Diabetic Retinopathy (NPDR) 2. Proliferative Diabetic Vitreoretinopathy (PDVR) II. Role of Vitreous in PDVR A. Classification of PDVR 1. Airlie House Classification 2. International Clinical Diabetic Retinopathy Severity Scale 3. Kroll’s Classification III. Therapeutic Considerations IV. Summary References Part IV: Physiology and Pharmacotherapy IV.A.: Vitreous Physiology I. Introduction II. Physiology A. Molecular Transport in the Vitreous 1. Viscosity of Vitreous B. Oxygen Physiology III. Pathology A. Vitreous Aging 1. Clearance of Molecules in the Vitreous B. Iris Neovascularization C. Retinal Neovascularization D. Macular Edema 1. Origins of Macular Edema a. Increased Hydrostatic Pressure Gradient b. Decreased Osmotic Pressure Gradient 2. Diabetic Macular Edema 3. Macular Edema in Retinal Vein Occlusions 4. Vitreoretinal Traction and Edema 5. Treating Macular Edema a. Decreasing Hydrostatic Pressure Gradient b. Increasing Osmotic Pressure Gradient c. The Central Role of Oxygen E. Age-Related Macular Degeneration (AMD) F. Vitrectomy and Cataract G. Vitrectomy and Glaucoma References IV.B.: Oxygen in Vitreoretinal Physiology and Pathology I. Introduction A. The Oxygen Hypothesis II. Intraocular Oxygen Tension A. Experimental Measurements 1. Vitreous 2. Lens 3. Trabecular Meshwork III. Intraocular Oxygen Tension Regulation A. Intraocular Oxygen Gradients B. Vitreous Gel Regulates Intraocular Oxygen 1. Vitreous Gel Metabolizes Oxygen 2. Gel Vitreous Consumes Oxygen Better Than Liquid Vitreous 3. Biophysical Properties of Gel Vitreous IV. Vitreous Liquefaction or Vitrectomy Increases Oxygen V. Pathogenic Effects of Increased Intraocular Oxygen A. Nuclear Sclerotic Cataract 1. Oxygen and Nuclear Sclerosis 2. Role of Vitreous in Nuclear Sclerosis 3. The “Oxygen Hypothesis” for Nuclear Sclerosis B. Primary Open-Angle Glaucoma (POAG) 1. Oxygen and POAG 2. Role of Vitreous and Cataract Surgery in POAG 3. The “Oxygen Hypothesis” for POAG VI. Oxygen Ameliorates VEGF-Mediated Retinopathies A. Age-Related Macular Degeneration (AMD) B. Diabetic Retinopathy C. Retinal Vein Occlusions VII. The Future VIII. Summary References IV.C.: Vitreous and Iris Neovascularization I. Introduction II. Foundations of Vitreous Neovascular Pathology A. Biochemical Mediator Hypothesis B. Clinical Pathology of Retinal Hypoxia C. Experimental Retinal Hypoxia and Vitreous Neovascularization III. Clinical Vitreous Neovascularization A. Retinal Vessel Occlusions B. Spatial Characteristics of Intraocular Neovascularization C. Temporal Characteristics of Intraocular Neovascularization IV. Role of the Choroid in Intraocular Neovascularization A. A Graduated Metabolic Oxygen Barrier B. Additional Oxygen Sources V. Therapeutic Intervention and Intraocular Oxygen Physiology A. Modulating Intraocular Oxygenation by Laser Photocoagulation 1. Targeting the Penumbra Obscura with Scatter (PRP) Photocoagulation B. Vitreoretinal Surgery and Vitreous Neovascularization 1. Anterior Vitreous Neovascularization 2. Vitreous and Iris Neovascularization after Vitrectomy 3. Vitreous and Iris Neovascularization after PVD a. Peduncular Avulsion Induces Vitreous Hemorrhage VI. Molecular Basis of Vitreous and Iris Neovascularization A. Identity of Michaelson’s Biochemical Mediator B. Extracellular Matrix Coupling Enables Rete Expansion C. Sources of Michaelson’s Biochemical Mediator References IV.D.: Physiology of Accommodation and Role of the Vitreous Body I. Introduction II. Accommodation Theories A. Lens Support of Accommodation (d’après Helmholtz) B. Catenary Theory of Vitreous Support for Accommodation (d’après Coleman) III. Imaging of Accommodation IV. Observed Changes in Lens Shape During Accommodation V. Summary References IV.E.: Principles and Practice of Intravitreal Application of Drugs I. Introduction II. Fundamental Principles of Intravitreal Drug Delivery III. The Practice of Intravitreal Injection of Drugs A. Technique for Intravitreal Drug Injection B. Special Considerations in Infants C. Complications IV. Intravitreal Drug Therapy A. Short-Term Therapy 1. Antibacterial Agents 2. Antifungal Agents 3. Antiviral Agents 4. Steroids 5. Anti-inflammatory/ Antineoplastic Agents 6. Anti-VEGF Agents 7. Pharmacologic Vitreolysis B. Sustained-Release Drug Delivery 1. Implants 2. Encapsulated Cell Technology 3. Microspheres 4. Porous Silicon Particles 5. Liposomes 6. Suprachoroidal Microinjection and Microneedles V. Future Drug Delivery Approaches and Considerations A. Iontophoresis B. Refillable Delivery Systems C. Advances in Sustained-Release Intravitreal Injectables D. Emerging Methods for Local Delivery E. Vitreous Structure and Intravitreal Drug Delivery References IV.F.: Pharmacotherapy of Proliferative Vitreoretinopathy I. Introduction II. Clinical Classification of PVR III. Pathophysiology of PVR A. Blood-Retinal Barrier Breakdown B. Cell Accumulation and Proliferation C. Extracellular Matrix Production and Fibrin Deposition D. Formed Membrane Contraction IV. Adjunctive Agents and Target A. Anti-inflammatory Agents 1. Corticosteroids a. Preclinical Evidence b. Clinical Evidence 2. Nonsteroidal Anti-inflammatory Agents a. Preclinical Evidence b. Clinical Evidence B. Inhibitors of Cell Proliferation 1. Fluoropyrimidines a. Preclinical Evidence b. Clinical Evidence 2. Daunorubicin a. Preclinical Evidence b. Clinical Evidence 3. Retinoids a. Preclinical Evidence b. Clinical Evidence 4. Immunotoxins a. Preclinical Evidence 5. Colchicine a. Preclinical Evidence b. Clinical Evidence C. ECM Modifiers 1. Cis-hydroxyproline a. Preclinical Evidence 2. Matrix Metalloproteinases a. Preclinical Evidence 3. Heparin/Low Molecular Weight Heparin (LMWH) a. Clinical Evidence i. High-Risk Retinal Detachments ii. Established PVR iii. Unselected Primary Retinal Detachments References IV.G.: Physiology of Vitreous Substitutes I. Introduction II. Short-Acting Vitreous Substitutes A. Aqueous Vitreous Substitutes 1. Isotonic Saline 2. Lactated Ringer’s Solution 3. Balanced Salt Solution B. Gaseous Vitreous Substitutes 1. Physical Properties of Intraocular Gases a. Air b. Long-Acting Gases 2. Functional Properties of Intraocular Gases a. Internal Tamponade b. Flatten Folded Retina c. Enable Visualization d. Restore Globe Volume e. Reduce Intraocular Fluid Currents 3. Dynamic Properties of Gas Inside the Eye a. Expansion b. Equilibration c. Dissolution 4. Physiologic Changes of Gas in Special Circumstances a. Interaction with General Anesthesia b. Effects of Variations in Altitude III. Long-Acting Vitreous Substitutes A. Perfluorocarbon Liquids 1. Properties 2. Retinal Toxicity B. Silicone Oil 1. Chemical Properties of Silicone Oil 2. Physical Properties of Silicone Oil a. Specific Gravity b. Buoyancy c. Surface Tension and Interfacial Tension d. Viscosity e. Viscoelasticity Conclusion References Part V.A.: Posterior Vitreo-Retinal Surgery V.A.1.: Age-Related Macular Degeneration Surgery I. Submacular Surgery A. History 1. Trauma and PVR 2. Choroidal Neovascular Membranes in AMD B. Instrumentation for Submacular Surgery C. Indications for Submacular Surgery D. Technique of Submacular Surgery 1. Complications of Submacular Surgery E. Functional Results of Submacular Surgery II. Macular Translocation in AMD A. History B. Surgical Technique 1. Limited Translocation a. Scleral Infolding b. Outfolding Technique 2. Full Macular Translocation (MTS 360) C. Complications D. Functional Results III. RPE Transplantation A. Rationale B. History 1. Transplantation of Ocular Tissues 2. Retinal Pigment Epithelial Transplantation 3. RPE Transplantation in Human Eyes C. Surgical Techniques 1. Cell Suspensions (See Video V.A.1-1) 2. RPE/Bruch’s Membrane/Choroid Patch D. Functional Results IV. Surgical Management of Submacular Hematoma A. History B. Surgery for Submacular Hematoma 1. History 2. Tissue Plasminogen Activator 3. Surgery a. Technique b. Complications References V.A.2.: Vitreomaculopathy Surgery I. Macular Pucker A. Prognostic Factors and Indications for Surgery B. Surgical Technique 1. Inner Limiting Membrane (ILM) Peeling with and without Chromodissection C. Surgical Outcomes 1. Complications II. Macular Pseudoholes III. Lamellar Macular Holes A. Prognostic Factors and Indications for Surgery B. Surgical Technique C. Surgical Outcomes and Complications IV. Full-Thickness Macular Hole (FTMH) A. Prognostic Factors B. Surgical Technique 1. Chromodissection 2. Internal Tamponade 3. Contemporaneous Cataract Surgery 4. Pharmacologic Vitreolysis C. Surgical Outcomes and Complications V. Vitreomacular Traction (VMT) A. Surgical Technique and Outcomes References V.A.3.: Chromodissection in Vitreoretinal Surgery I. Introduction A. Rationale: Why Chromodissection? II. Chromodissection Techniques A. Staining Substances 1. Indocyanine Green (ICG) 2. Trypan Blue 3. Brilliant Blue 4. Other Experimental Dyes B. Surgical Techniques 1. Single Staining 2. Double Staining III. Tissue-Dye Interaction: Staining and Beyond IV. Clinicopathological Correlations V. Future Perspectives References V.A.4.: Macular Hole and Macular Pucker Surgery with Special Emphasis on Reoperations* I. Introduction II. Macular Hole A. Pathogenesis of Macular Hole B. Therapy of Macular Hole 1. Macular Hole Surgery a. Benefits and Risks of ILM Chromodissection C. Primary Failure Versus Macular Hole Reopening III. Macular Pucker A. Pathogenesis of Macular Pucker B. Macular Pucker Surgery C. Primary Failure Versus Macular Pucker Recurrence IV. Retreatment of Persistent/Recurrent Disease A. Retreatment Strategies 1. Macular Hole Reoperations 2. Macular Pucker Reoperations B. Inner Retinal Optic Neuropathy (IRON) C. Timing of Reoperations References V.A.5.: Surgery of Diabetic Vitreo-Retinopathy and Diabetic Macular Edema I. Introduction II. Indications and Timing of Surgery A. Cataract B. Vitreous Hemorrhage C. Diabetic Maculopathy D. Retinal Detachment E. Neovascular Glaucoma III. Surgical Procedures A. Preparation and Anesthesia B. Modern Surgical Equipment 1. Microscope 2. Vitrectomy Machine 3. Surgical Instruments 4. Viewing Systems 5. Chromodissection 6. Internal Tamponade C. Cataract Surgery D. Glaucoma Surgery 1. Aqueous Shunt Procedures 2. Cyclodestruction E. Vitrectomy Surgery 1. Sclerotomies 2. Pars Plana Vitrectomy a. Management of Incomplete Posterior Vitreous Cortex Separation 3. Retinal breaks and Detachment 4. Endolaser Photocoagulation 5. Vitreous Substitutes 6. Wound Closure IV. Surgical Complications A. Intraoperative Complications 1. Anterior Segment a. Corneal Opacification b. Small Pupil c. Lens 2. Posterior Segment a. Intraocular Hemorrhage b. Subretinal Infusion c. Retinal Breaks and Detachment B. Postoperative Complications 1. Anterior Segment a. Conjunctiva b. Cornea c. Uveitis or Iritis d. Intraocular Pressure Elevation 2. Vitreous Hemorrhage 3. Fibrinoid Syndrome 4. Anterior Hyaloidal Fibrovascular Proliferation (AHFVP) References V.A.6.: Vitreous Surgery of Arterial and Venous Retinovascular Diseases I. Introduction II. Retinal Artery Occlusions A. Surgical Treatment of Non-arteritic Retinal Artery Occlusions 1. Local Intra-arterial Fibrinolysis (LIF) a. European Assessment Group for Lysis in the Eye (EAGLE) Study 2. Surgical Embolectomy a. Retinal Arterial Occlusion Study (RAO) III. Retinal Vein Occlusions A. Surgical Treatment of Central Retinal Vein Occlusion 1. Radial Optic Neurotomy (RON) a. Rationale b. Technique c. Results i. Long-Term Results d. Complications 2. Comparing Surgery to Pharmacotherapy: The ROVO Study a. Controversies 3. Retina Endovascular Surgery (REVS) in CRVO a. Vitreoretinal Approach i. Concerns b. Neuroradiological Approach B. Surgical Treatment of Branch Retinal Vein Occlusion (BRVO) 1. Rationale of Arteriovenous Adventitial Sheathotomy 2. Technique (See Video V.A.6-4) 3. Complications 4. Results 5. Controversies Regarding Sheathotomy Conclusions References Part V.B.: Peripheral Vitreo-Retinal Surgery V.B.1.: The History of Vitrectomy Instrumentation: A Personal Account of a Transoceanic Australian-USA Collaboration I. Introduction II. Surgical R&D Down Under III. The Eye World Discovers IV. The Hard Work Begins A. Prototype to Prodigious Innovation B. Innovation Progresses to Benevolent Production V. Teach the World VI. Diversification References V.B.2.: Modern Vitrectomy Cutters: An Improved Understanding of Vitreous Cutting I. Introduction II. Measuring Vitreous Flow and Cut Rates A. Water Versus Vitreous B. Vitreous Cutting Efficiency and Duty Cycle C. Vitreous Flow Related to Cut Rate III. Traction Forces Transmitted to the Retinal Surface References V.B.3.: The Future of Vitrectomy I. Introduction II. Improving Current Vitrectomy Technology A. Improving the Vitrectomy Probe 1. Size 2. Cutting 3. Aspiration B. Improving Intraoperative Visualization 1. Wide-Angle Viewing 2. Illumination III. Future Vitreoretinal Surgery Approaches A. Augmented Reality 1. Supplementing Intraoperative Information 2. Implementing Augmented Reality in Vitreoretinal Surgery 3. Presenting Augmented Inputs to the Vitreoretinal Surgeon B. Future Surgical Strategies 1. Internal Tamponades 2. Femtosecond Laser Surgery 3. Robotic Vitreoretinal Surgery 4. Retinal Prosthesis C. Future Pharmacotherapies 1. New Drug Delivery Systems 2. Gene Therapy and Stem Cell-Based Therapies References V.B.4.: Prophylaxis and Cure of Rhegmatogenous Retinal Detachment I. Introduction II. Prophylaxis of Retinal Detachment A. Risk Factors for Retinal Detachment B. Categories of Eyes and Lesions Considered for Preventative Therapy 1. Eyes with Symptomatic PVD a. Tears with Persistent Vitreoretinal Traction b. Breaks and Precursors Unassociated with Vitreoretinal Traction 2. Asymptomatic Vitreoretinal Lesions in Phakic Non-fellow Eyes a. Retinal Lattice (Degeneration) b. Cystic Retinal Tufts c. Degenerative Retinoschisis 3. Asymptomatic Retinal Breaks in Phakic Non-­fellow Eyes 4. Asymptomatic Vitreoretinal Lesions and Retinal Breaks in Non-phakic Non-fellow Eyes 5. Asymptomatic Vitreoretinal Lesions and Retinal Breaks in Patients with a History of Retinal Detachment in the Fellow Eye a. Phakic Fellow Eyes i. Retinal Lattice ii. Retinal Breaks iii. Miscellaneous b. Aphakic and Pseudophakic Fellow Eyes C. Summary III. Repair of Retinal Detachment A. Surgery for Uncomplicated Retinal Detachment 1. Scleral Buckling a. Advantages of Scleral Buckling b. Disadvantages of Scleral Buckling 2. Pneumatic Retinopexy a. Advantages of Pneumatic Retinopexy b. Disadvantages of Pneumatic Retinopexy 3. Vitrectomy a. Advantages of Vitrectomy b. Disadvantages of Vitrectomy B. Surgery for Complicated Retinal Detachments IV. Conclusions References V.B.5.: Management of Proliferative Vitreoretinopathy I. Introduction II. Diagnosis and Classification A. Clinical Findings B. Posterior PVR C. Anterior PVR III. Surgical Management A. Principles of Surgery B. Techniques of Surgery 1. Lens Removal 2. Scleral Buckle 3. Vitrectomy 4. Membrane Peeling 5. Relaxing Retinotomies and Retinectomies 6. Reattachment of the Retina 7. Laser Photocoagulation 8. PFCL Removal 9. Fluid or PFCL-Silicone Oil Exchange 10. Intraocular Tamponade C. Postoperative Management IV. Prognosis and Results References V.B.6.: Retinectomy for Recalcitrant Retinal Detachments I. Introduction II. Pathophysiology III. Surgical Approach A. Retinotomy and Retinopexy B. Vitreous Substitutes C. Complications IV. Future Developments A. Surgical B. Pharmacologic References V.B.7.: Pneumatic Retinopexy I. History II. Clinical Considerations A. Case Selection B. Expanded Indications for Pneumatic Retinopexy C. Contraindications for Pneumatic Retinopexy III. Methodology of In-Office Pneumatic Retinopexy A. Examination B. Retinopexy 1. Diathermy 2. Cryopexy 3. Laser Photocoagulation C. Intravitreal Bubble Injection 1. Pure Air 2. Long-Acting Expansile Gases a. Perfluorocarbons b. Sulfur Hexafluoride D. Post-Operative Positioning E. Modified Pneumatic Retinopexy IV. Outcomes A. Results B. Complications C. Benefits of Pneumatic Retinopexy V. Conclusion References V.B.8.: Vitreous Floaters and Vision: Current Concepts and Management Paradigms I. Introduction II. Background A. Etiology of Floaters III. Diagnostic Considerations A. Clinical Presentation B. Clinical Characterization of Floaters 1. Structural Assessment of Floaters a. Ultrasonography b. Combined OCT/SLO c. Dynamic Light Scattering 2. Effects of Floaters on Vision a. Straylight b. Contrast Sensitivity Function IV. Therapeutic Considerations A. Vitrectomy 1. Efficacy of Vitrectomy for Floaters 2. Safety of Vitrectomy for Floaters a. Endophthalmitis b. Retinal Tears and Retinal Detachment c. Cataracts Conclusions References V.B.9.: Rare Indications for Vitrectomy: Tumor Excision, Optic Nerve Pits, and Malignant Glaucoma I. Introduction II. Tumors A. Retinoblastoma B. Malignant Melanoma C. Vascular Tumors III. Optic Nerve Pits IV. Malignant Glaucoma References Part VI: Pharmacologic Vitreolysis VI.A.: Pharmacologic Vitreolysis I. Introduction II. Classification of Approaches to Pharmacologic Vitreolysis A. Chemical Action of Pharmacologic Vitreolysis Agents B. Biological Action of Pharmacologic Vitreolysis Agents III. Pharmacologic Vitreolysis Agents A. Agents with Failed or Discontinued Development 1. Hyaluronidase (Vitrase®) [See chapter VI.F. Hyaluronidase] 2. Chondroitinase [See chapter VI.H. Chondroitinase] 3. Nattokinase 4. Vitreosolve® 5. RGD Peptides B. Agents Under Development 1. Dispase (Vitreolysin™) [See chapter VI.G. Dispase] C. Agents Approved for Pharmacologic Vitreolysis 1. Ocriplasmin [see chapter VI.E.1. Pharmacologic vitreolysis with ocriplasmin: basic science studies and VI.E.2. Pharmacologic vitreolysis with ocriplasmin: clinical studies] a. Case Study b. Case Selection IV. Future Considerations A. Enhancing Drug Delivery B. Improving Vision Outcome Measures C. Combination Therapy D. Prevention 1. Prophylactic Posterior Vitreous Detachment 2. Anomalous PVD Prevention References VI.B.: The History of Pharmacologic Vitreolysis I. Introduction II. Pharmacologic Vitreolysis Approaches A. Hyaluronidase B. Collagenases C. Management of Intraocular Hemorrhage D. Induction of Posterior Vitreous Detachment E. Physiologic Effects of Pharmacologic Vitreolysis III. Targeting Specific Disease States IV. Summary References VI.C.: Pharmacologic Vitreolysis with Tissue Plasminogen Activator I. Introduction II. Properties of Tissue Plasmin Activator A. Biochemical B. Methods of Generating Intravitreal tPA C. Clearance of tPA D. Toxicity of tPA III. Ophthalmic Indications and Applications of tPA A. Submacular Hematoma B. Induction of Posterior Vitreous Detachment (PVD) C. Proliferative Diabetic Vitreoretinopathy D. Retinal Vein Occlusions E. Age-Related Macular Degeneration (AMD) F. Miscellaneous Conditions References VI.D.1.: Pharmacologic Vitreolysis with Plasmin: Basic Science Experiments I. Introduction II. Plasmin A. Biochemistry B. Plasmin Procurement III. Experimental Models A. Animals 1. Rabbit Model a. Efficacy b. Safety 2. Other Experimental Models and Considerations B. Ex Vivo Human Experimental Models IV. Future Considerations References VI.D.2.: Pharmacologic Vitreolysis with Plasmin: Clinical Studies I. Introduction II. Plasmin Procurement A. Activation of Plasminogen into Plasmin Enzyme B. Preparation of Autologous Plasmin Enzyme 1. Standard Purification System 2. Rapid Purification System III. Clinical Application of Autologous Plasmin Enzyme A. Macular Hole B. Diabetic Macular Edema C. Retinopathy of Prematurity D. Retinal Vein Occlusion (RVO) Conclusions References VI.E.1.: Pharmacologic Vitreolysis with Ocriplasmin: Basic Science Studies I. Introduction II. Structural and Physiologic Characteristics III. Pharmacokinetics of Ocriplasmin IV. Pharmacodynamics of Ocriplasmin A. Effects on Vitreous B. Toxicology V. Future Directions References VI.E.2.: Pharmacologic Vitreolysis with Ocriplasmin: Clinical Studies I. Introduction II. Clinical Trials with Ocriplasmin for sVMA and VMT A. Summary B. Phase 2 Trials 1. Intravitreal Microplasmin During Surgical Vitrectomy (MIVI-I) (TG-MV-001) 2. Multi-dosing in Patients with Vitreomacular Traction (MIVI-IIT) (TG-MV-004) 3. Safety and Efficacy of Inducing PVD (MIVI-III) (TG-MV-003) C. Phase 3 Trials 1. Background and Study Design 2. Efficacy Findings 3. Safety Findings III. Phase 2 Trials of Ocriplasmin in Patients with VMA and Concomitant Retinal Disease A. Diabetic Macular Edema [MIVI-II-DME (TG-MV-002)] B. Age-Related Macular Degeneration [MIVI-V (TG-MV-005)] Conclusions References VI.F.: Hyaluronidase as a Vitreous Liquefactant I. Introduction II. Mechanism of Action and Pharmacodynamics A. Hyaluronidase Enzyme Activity B. Biological Activity III. Clinical Experience A. Study Design B. Results C. Complications D. Conclusions IV. Future Directions and Applications References VI.G.: Pharmacologic Vitreolysis with Purified Dispase (Vitreolysin™) I. Introduction II. Chemistry and Mechanism of Action A. Substrate Specificity B. Structure C. Inhibition D. Pharmacokinetics and Pharmacodynamics III. Potential Applications A. Induce Posterior Vitreous Detachment B. Facilitate the Surgical Removal of Pathologic Preretinal Membranes IV. Drug Development A. Purification and Toxicity B. Stability C. Potential Advantages V. Safety and Efficacy A. In Vitro Studies 1. Efficacy 2. Effect on Retinal Cell Viability and Structure 3. Effect on Mechanical Properties of the Sensory Retina B. In Vivo Studies 1. PVD Induction 2. Effect on Retinal Electrophysiology References VI.H.: Chondroitinase as a Vitreous Interfactant: Vitreous Disinsertion in the Human I. Introduction II. Biochemistry A. Proteoglycans and the Vitreoretinal Interface B. Biochemistry of Chondroitinase Enzymes and Substrates III. Chondroitin Sulfate at the Vitreoretinal Interface IV. Chondroitinase Pharmacologic Vitreolysis A. Preliminary Monkey Studies B. Human Proof-of-Concept Study C. FDA Phase I/II Study and its Implications 1. Efficacy a. Proliferative Diabetic Retinopathy b. Macular Hole 2. Safety Conclusions References Erratum Index