- •Diabetic Retinopathy
- •Preface
- •Contents
- •Contributors
- •Nonproliferative Diabetic Retinopathy
- •Nonproliferative Diabetic Retinopathy
- •Inflammatory Mechanisms
- •Microaneurysms
- •Vascular Permeability
- •Capillary Closure
- •Classification Of Nonproliferative Retinopathy
- •Macular Edema
- •Risk Factors For Progression Of Retinopathy
- •Severity of Retinopathy
- •Glycemic Control
- •The Diabetes Control and Complications Trial
- •Epidemiology of Diabetes Interventions and Complications Trial
- •The United Kingdom Prospective Diabetes Study
- •Hypertension
- •The United Kingdom Prospective Diabetes Study
- •Appropriate Blood Pressure Control in Diabetes Trials
- •Elevated Serum Lipid Levels
- •Pregnancy and Diabetic Retinopathy
- •Other Systemic Risk Factors
- •Management Of Nonproliferative Diabetic Retinopathy
- •Photocoagulation
- •Scatter Photocoagulation for Nonproliferative Diabetic Retinopathy
- •Scatter Photocoagulation for Proliferative Retinopathy
- •Focal Photocoagulation for Diabetic Macular Edema
- •Other Treatment of Diabetic Macular Edema
- •Medical Therapy
- •Aspirin And Antiplatelet Treatments
- •Aldose Reductase Inhibitors
- •Other Medical Treatments
- •Summary
- •Acknowledgment
- •References
- •Proliferative Diabetic Retinopathy
- •Development and Natural History
- •Histopathology and Early Development
- •Proliferation and Regression of New Vessels
- •Contraction of the Vitreous and Fibrovascular Proliferations
- •Retinal Distortion and Detachment
- •Burned-Out Proliferative Diabetic Retinopathy
- •Systemic Associations
- •Proliferative Diabetic Retinopathy and Glycemic Control
- •Other Risk Factors for Proliferative Diabetic Retinopathy
- •Rubeosis Iridis
- •Anterior Hyaloidal Fibrovascular Proliferation
- •Management of Proliferative Diabetic Retinopathy
- •Pituitary Ablation
- •Photocoagulation
- •Randomized Clinical Trials of Laser Photocoagulation
- •The Diabetic Retinopathy Study
- •Risks and Benefits Photocoagulation In The Drs
- •The Early Treatment Diabetic Retinopathy Study
- •Indications For Photocoagulation of Pdr
- •PRP and Macular Edema
- •PRP Treatment Techniques
- •Vitrectomy for PDR
- •Pharmacologic Treatment of PDR
- •Acknowledgment
- •References
- •Brief Historical Background
- •The Wesdr
- •Prevalence of Diabetic Retinopathy
- •Incidence of Diabetic Retinopathy
- •Diabetic Retinopathy in African American and Hispanic Whites
- •Native Americans and Asian Americans
- •Age and Puberty
- •Genetic and Familial Factors
- •Modifiable Risk Factors
- •Hyperglycemia
- •Clinical Trials of Intensive Treatment of Glycemia
- •Diabetes Control and Complications Trial
- •The United Kingdom Diabetes Prospective Study (UKPDS)
- •Hypertension
- •Lipids
- •Subclinical and Clinical Diabetic Nephropathy
- •Microalbuminuria and Diabetic Retinopathy
- •Gross Proteinuria and Retinopathy
- •Diabetic Retinopathy as a Risk Indicator of Subclinical Nephropathy
- •Other Risk Factors For Retinopathy
- •Smoking and Drinking
- •Body Mass Index and Physical Activity
- •Hormone and Reproductive Exposures in Women
- •Prevalence and Incidence of Visual Impairment
- •Conclusions
- •Acknowledgments
- •References
- •Introduction
- •Fluorescein Angiography
- •Properties
- •Side Effects
- •Normal Fluorescein Angiography
- •Terminology
- •Fluorescein Angiography in the Evaluation of Diabetic Retinopathy
- •Fluorescein Angiography in the Evaluation of Diabetic Macular Edema
- •Optical Coherence Tomography
- •Low-Coherence Interferometry
- •OCT Image Interpretation
- •OCT Technology Development
- •The Role of OCT in Diabetic Macular Edema
- •Morphologic Patterns of Diabetic Macular Edema
- •Clinical Applications of OCT in Diabetic Macular Edema
- •Conclusions
- •References
- •Diabetic primates
- •Type of Diabetes
- •Histopathology and Rate of Development of the Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic dogs
- •Type of Diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic cats
- •Type of Diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic rats
- •Type of Diabetes
- •Type 1 diabetes
- •Type 2 diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Vascular disease
- •Neuronal disease
- •Therapies or Gene Modifications Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic mice
- •Type of Diabetes
- •Type 1 diabetes
- •Type 2 diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Vascular disease
- •Neural disease
- •Therapies or Gene Modifications Studied in this Model
- •Advantages and Disadvantages of the Model
- •Other Rodents
- •Galactose Feeding
- •Nondiabetic Models in Which Growth Factors are Altered
- •VEGF overexpression
- •IGF overexpression
- •PDGF-B-deficient mice
- •Oxygen-Induced Retinopathy
- •Sympathectomy
- •Retinal Ischemia–Reperfusion
- •Summary
- •References
- •Introduction
- •Biochemistry and Genetics of The Polyol Pathway
- •Aldose Reductase
- •The Aldose Reductase Enzyme
- •The Aldose Reductase Gene
- •Polymorphisms of the AR Gene
- •Sorbitol Dehydrogenase
- •The Sorbitol Dehydrogenase Enzyme
- •The Sorbitol Dehydrogenase Gene
- •Ar Polymorphisms and Risk of Diabetic Retinopathy
- •Sdh Polymorphisms and Diabetic Retinopathy
- •Ar Overexpression
- •Sdh Overexpression
- •Ar “Knockout” Mice
- •Sdh-Deficient Mice
- •Osmotic Stress
- •Oxidative Stress
- •Activation of Protein Kinase C
- •Generation of AGE Precursors
- •Proinflammatory Events and Apoptosis
- •Ari Structures and Properties
- •Effects of Aris in Experimental Diabetic Retinopathy
- •The Polyol Pathway in Human Diabetic Retinopathy
- •The Sorbinil Trial
- •Perspective and Needs
- •Rationale for Defining the Pathogenic Role of the Polyol Pathway
- •Needs to be Met to Arrive at Anti-Polyol Pathway Therapy
- •References
- •Introduction to Diabetic Retinopathy
- •Biochemistry of Age Formation
- •Pathogenic Role of Ages In Diabetic Retinopathy
- •AGEs and Clinical Correlation of Diabetic Retinopathy
- •AGE Accumulation in the Eye
- •Effect of AGEs on Retinal Cells
- •RAGE in Diabetic Retinopathy
- •Other AGE Receptors in Diabetic Retinopathy
- •Anti-Age Strategies For Diabetic Retinopathy
- •Conclusion
- •References
- •Introduction
- •Dag-Pkc Pathway
- •Diabetes and Retinal Blood Flow
- •Basement Membrane and Ecm Changes
- •Vascular Permeability and Angiogenesis
- •Conclusions
- •References
- •Sources of Oxidative Stress in The Diabetic Retina
- •Overview
- •Mitochondrial Electron Transport Chain (ETC)
- •Advanced Glycation End (AGE) Product Formation
- •Cyclo-oxygenase (COX)
- •Flux Through Aldose Reductase (AR) Pathway
- •Activation of Protein Kinase C (PKC)
- •Endothelial NO Synthase (eNOS)
- •Inducible NOS (iNOS)
- •NADPH Oxidase
- •Antioxidants in Diabetic Retinopathy
- •Overview
- •Glutathione (GSH)
- •Superoxide Dismutase (SOD)
- •Catalase
- •Effects of Oxidative Stress in The Diabetic Retina
- •Overview
- •Growth Factors and Cytokines
- •Cytoxicity
- •Therapeutic Strategies For Reducing Oxidative Stress
- •Overview
- •Antioxidants
- •PKC Inhibitors
- •Inhibitors of the Renin-Angiotensin System
- •Inhibitors of the Polyol Pathway
- •HMG-CoA Reductase Inhibitors (Statins)
- •PEDF
- •Cannabinoids
- •Cyclo-oxygenase-2 (COX-2) Inhibitors
- •References
- •Pericyte Loss in the Diabetic Retina
- •Introduction
- •Origin and Differentiation
- •Morphology and Distribution
- •Identification
- •Function
- •Contractility
- •Role in Vessel Formation and Stabilization
- •Loss In Diabetic Retinopathy
- •Rats
- •Mice
- •Chinese Hamster
- •Animal Models Mimicking Retinal Pericyte Loss
- •Pdgf-B-Pdgf-Ssr
- •Angiopoietin-Tie
- •Vegf-Vegfr2
- •Mechanisms of Loss
- •Biochemical Pathways
- •Aldose Reductase
- •Age Formation
- •Modification of Ldl
- •Loss Through Active Elimination
- •Capillary Dropout in Diabetic Retinopathy
- •Diabetic Retinopathy
- •Methods to Measure and Detect Capillary Dropout
- •Models to Study Retinal Capillary Dropout in Diabetes
- •Potential Mechanisms For Capillary Dropout
- •Capillary Cell Apoptosis
- •Proinflammatory Changes/Leukostasis
- •Microthrombosis/Platelet Aggregation
- •Consequences of Capillary Dropout
- •Macular Ischemia
- •Neovascularization
- •Macular Edema
- •Acknowledgments
- •References
- •Neuroglial Dysfunction in Diabetic Retinopathy
- •The Neurons of The Retina
- •The Glial Cells of The Retina
- •Diabetes Reduces Retinal Function
- •Diabetes Induces Neurodegeneration in The Retina
- •Neuroinflammation in Diabetic Retinopathy
- •Historical Perspective on Diabetic Retinopathy
- •Neuroglial Dysfunction in Diabetic Retinopathy.
- •References
- •Introduction
- •Inflammatory Cells Promote and Regulate The Development of Ischemic Ocular Neovascularization
- •VEGF as a Proinflammatory Factor in Diabetic Retinopathy
- •VEGF164/165 as a Proinflammatory Cytokine
- •Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
- •Corticosteroids
- •Anti-VEGF Agents
- •Pegaptanib
- •Ranibizumab and Bevacizumab
- •Conclusions
- •Acknowledgment
- •References
- •Glia-Endothelial Interaction
- •Specialized Retinal Vessels Control Flux into Neural Tissue
- •Overview of Tight Junction Proteins
- •Claudins Confer Tight Junction Barrier Properties
- •Occludin Regulates Barrier Properties
- •Alterations in Occludin in Diabetic Retinopathy
- •Ve-Cadherin and Diabetic Retinopathy
- •Permeability in Diabetic Retinopathy
- •Summary and Conclusions
- •References
- •Introduction
- •Stages of Angiogenesis
- •Vascular Endothelial Growth Factor
- •Regulation of Vegf Expression in The Retina
- •Regulation of VEGF in Proliferative Diabetic Retinopathy
- •Regulation of VEGF in Nonproliferative Diabetic Retinopathy
- •Basic Vegf Biology
- •Receptors
- •Vegf’S Multiple Actions on Retinal Endothelial Cells
- •Main Signaling Pathways
- •Other Actions of Vegf
- •Proinflammatory Effects of VEGF
- •VEGF and Retinal Neuronal Development
- •VEGF and Neuroprotection
- •Modulation of Vegf Action By Other Growth Factors
- •Conclusion
- •References
- •Insulin-Like Growth Factor
- •Basic Fibroblast Growth Factor
- •Angiopoietin
- •Erythropoietin
- •Hepatocyte Growth Factor
- •Tumor Necrosis Factor
- •Extracellular Proteinases
- •The Urokinase Plasminogen Activator System (uPA/uPAR System)
- •Proteinases in Retinal Neovascularization
- •Integrins
- •Endogenous Inhibitors of Neovascularization
- •Pigment Epithelium Derived Growth Factor
- •Angiostatin and Endostatin
- •Thrombospondin-1
- •Tissue Inhibitor of Matrix Metalloproteinases
- •Clinical Implications
- •Acknowledgments
- •References
- •Introduction
- •Pathogenesis
- •Vascular Endothelial Growth Factor (Vegf)
- •Vegf in Physiological and Pathological Angiogenesis
- •Vegf in Ocular Neovascularization
- •Vegf and Diabetic Retinopathy
- •Clinical Application of Anti-VEGF Drugs
- •Pegaptanib
- •Bevacizumab
- •Ranibizumab
- •Use of Anti-VEGF Therapies in Diabetic Retinopathy
- •Safety
- •Clinical Experience with Bevacizumab in Diabetic Retinopathy
- •Ranibizumab in Diabetic Macular Edema
- •Effect on Foveal Thickness and Macular Volume
- •Effect on Visual Acuity
- •Summary
- •References
- •Introduction
- •Pkc Inhibition With Ruboxistaurin
- •Early Clinical Trials With Rbx
- •Rbx and Progression of Diabetic Retinopathy
- •Ongoing Trials With Rbx
- •Rbx and Other, Nonocular Complications of Diabetes
- •Safety Profile of Rbx
- •Clinical Status of Rbx
- •Conclusions
- •References
- •The Role of Intravitreal Steroids in the Management of Diabetic Retinopathy
- •Clinical Efficacy
- •Safety
- •Pharmacology
- •Pharmacokinetics
- •Combination With Laser Treatment
- •Clinical Guidelines
- •Macular Edema Caused by Focal Parafoveal Leak
- •Widespread Heavy Diffuse Leak
- •Macular Edema and High-Risk Proliferative Retinopathy
- •Macular Edema Prior to Cataract Surgery
- •Juxtafoveal Hard Exudate With Heavy Leak
- •Control of Systemic Risk Factors
- •The Future of Intravitreal Steroid Therapy
- •References
- •Overview
- •Introduction and Historical Perspective
- •Growth Hormone and Diabetic Retinopathy
- •The IGF-1 System and Retinopathy
- •The Role of SST in Diabetic Retinopathy
- •Rationale for the Clinical use of Octreotide
- •Clinical evidence for sst as a therapeutic for pdr
- •Potential Reasons for Mixed Success in Clinical Trials
- •Future Direction: Sst Analogs in Combination Therapy
- •Conclusion
- •Acknowledgements
- •Introduction
- •Diabetic Retinopathy and Mortality
- •Diabetic Retinopathy and Cerebrovascular Disease
- •Diabetic Retinopathy and Heart Disease
- •Diabetic Retinopathy, Nephropathy, and Neuropathy
- •Conclusion
- •References
- •Name Index
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Fourier-domain OCT of the macula has been shown to provide greater detail (1125 A-scans vs. 512 A-scans) than commercially available time-domain OCT systems image in a shorter period of time (0.072 vs. 1.23 s) (43). This dramatically decreases motion artifact, which appears as undulating of the retina in the slower time-domain OCT image. Because motion-correcting algorithms are not required, the images better represent the true topography of the retina. Moreover, the faster scanning time allow a larger area to be scanned and offers more precise registration. It is also possible to acquire three-dimentional OCT data that achieve comprehensive retinal coverage and allow correlation between OCT images and clinical fundus features (44). The significant advantages of the Fourier-domain OCT will likely be the basis of the next generation of retinal OCT systems.
Doppler OCT has been used for measurement of blood flow using both time-domain (45, 46). and Fourier-domain OCTs (47, 48). The Doppler shift is localized in depth by use of joint time–frequency analysis algorithms, which generate depth-resolved Doppler frequency spectra of the reflected light. Rapid acquisition of retinal flow data in a few milliseconds allows the extraction of dynamic flow properties, such as the retinal vascular response to changes in perfusion pressure or oxygen content. Doppler OCT offers superior spatial resolution compared with Doppler ultrasound and Doppler scanning laser ophthalmoscopy. Unlike angiography, Doppler OCT is more quantitative and does not require injection of a contrast agent.
The Role of OCT in Diabetic Macular Edema
OCT retinal thickness measurements in diabetic patients have been shown in a number of studies to be highly reproducible. Retinal thickness measurements reproducible to within ±5% and ±6% were found for normal and diabetes subjects with diabetic macular edema, respectively (49)−24 Thus, changes in central retinal thickness greater than 6% for healthy patients and greater than 10% for diabetic patients are likely to be due to true changes in retinal thickness rather than inconsistencies in the OCT measurements.
Changes in macular thickness may be reported in absolute values before and after treatment or in percentage change. However, no uniform method currently exists for reporting changes in macular thickness. Chan and Duker suggested a standardized method for reporting changes in macular thickness as a percentage of total possible change based on normative OCT data (50). Standardizing reported changes in macular thickening may be required to better evaluate the efficacy of therapeutic intervention, as well as to compare various treatment strategies.
Some variability in retinal thickness measurements may be observed due to artifacts that impair the correct detection of retinal boundaries by the OCT analysis software (49, 51). For example, intraretinal exudates appear as spots of high reflectivity with areas of lowreflective shadowing behind them, and are found primarily in the outer retinal layers (Fig. 12). Large collections of hard exudates can confuse the analysis algorithm. Epiretinal membrane appears as highly reflective horizontal signal at the anterior surface of the retina (Fig. 13). Thus, epiretinal membranes or a low lying posterior hyaloidal face can confuse the analysis algorithm and incorrectly increase reported retinal thickness (52).
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Fig. 12. OCT scan of intraretinal exudates appearing as spots of high reflectivity with areas of low-reflective shadowing behind them.
Fig. 13. OCT scan of epiretinal membrane appearing as highly reflective horizontal signal on the inner surface of the retina, with irregularities of the retinal surface beneath.
Morphologic Patterns of Diabetic Macular Edema
Studies have described the presence of at least five different morphologic patterns of diabetic macular edema seen on OCT (7, 29, 53–55). Diffuse retinal thickening appears as increased sponge-like retinal thickness greater than 200 m with reduced intraretinal reflectivity, particularly in the outer retinal layers (Fig. 14). Cystoid macular edema appears as small, round or oval, hyporeflective lacunae with highly reflective septae bridging the retinal layers and separating the cystoid-like cavities (Fig. 15). The cystoid spaces are located primarily in the outer retinal layers, leaving a thin outer layer in the fovea. Some morphologic differences exist between newly developed and long-standing cystoid macular edema (53). In early cystoid macular edema, cystoid spaces primarily are located in the outer retinal layers, and the inner retinal layers are relatively preserved. In chronic cystoid macular edema, the septa of each cystoid space disappear, forming confluent large cystoid cavities (Fig. 16). Large cystoid spaces may involve the entire retinal layer, appearing as retinoschisis.
Posterior hyaloidal traction is defined as a highly reflective signal arising from the inner retinal surface and extending toward the optic nerve or peripherally (Fig. 17) (54). Subretinal fluid or serous retinal detachment appears as a shallow elevation of the retina resembling a dome, with an optically clear space between the retina and the RPE, and
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Fig. 14. OCT scan of diffuse macular edema appearing as increased sponge-like retinal thickening with reduced intraretinal reflectivity, particularly in the outer retinal layers. Note the intraretinal exudates.
Fig. 15. OCT scan of cystoid macular edema appearing as round or oval, hyporeflective cystoid-like intraretinal spaces with septae bridging the retinal layers and separating the cavities. The cystoid spaces are located primarily in the outer retinal layers.
Fig. 16. OCT scan of chronic cystoid macular edema showing a large intraretinal cystoid cavity with loss of septae.
a distinct outer border of the detached retina (Fig. 18). The identification of the highly reflective posterior border of detached retina distinguishes subretinal from intraretinal fluid. Finally, tractional retinal detachment is defined as a peak-shaped detachment of the retina with an area of low signal underlying the highly reflective border of the neurosensory retina, and is accompanied by posterior hyaloidal traction (Fig. 19).
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Fig. 17. OCT scan of posterior hyaloidal traction showing a highly reflective signal arising from the inner retinal surface and extending in an anterior–posterior direction. Note the diffuse macular edema.
Fig. 18. OCT scan of subretinal fluid appearing as a shallow elevation of the retina with an optically clear space between the retina and the RPE. Cystoid macular edema is seen as well.
Fig. 19. OCT scan of a shallow tractional retinal detachment with posterior hyaloidal traction. A highly reflective signal corresponding to posterior hyaloidal traction arises from the inner retinal surface. A peak-shaped detachment of the retina can be seen with a hyporeflective area underneath the highly reflective border of the neurosensory retina.
While diffuse retinal thickening and cystoid macular edema may be detected by biomicroscopy, OCT seems particularly helpful in the analysis of the vitreomacular relationship. OCT is much more accurate than biomicroscopy in determining the status of the posterior hyaloid when it is only slightly detached from the macular surface (35, 56–58). Evidence of posterior hyaloidal traction on OCT indicates vitreomacular traction
