- •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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Fig. 8. Cystoid macular edema appears as late staining of fovea with pooling of the dye into parafoveal cyst-like spaces in a petalloid pattern.
Ozdek and colleagues attempted to correlate FA patterns of diabetic macular edema with described OCT patterns (7). Mean foveal thickness as determined by OCT was the least in the no leakage group and progressively increased in order for focal, diffuse, and combined leakage groups. In addition, 63.3% of eyes that showed evidence of cystoid macular edema by OCT were not detected by FA. OCT also showed serous retinal detachment in 9.7% of eyes, none of which were detected by FA. Kang et al. showed that focal leakage correlated closely with homogeneous focal thickening on OCT (29). Focal leakage showed the least foveal thickness and the best visual acuity among FA types. The proportion of focal leakage type decreased as diabetic retinopathy progressed. Diffuse or cystoid leakage correlated closely with outer retinal layer or subretinal fluid accumulation.
OPTICAL COHERENCE TOMOGRAPHY
Low-Coherence Interferometry
Since its first clinical application in 1991 (30), OCT has dramatically increased our understanding of the morphological changes associated with many macular diseases, including diabetic macular edema (31). Using noncontact, noninvasive scanning, OCT produces high-resolution two-dimensional cross-sectional images of ocular tissues (32–34). Analogous to B-scan ultrasonography which uses sound echoes, OCT is based on reflections of light from the retinal tissue to produce a cross-sectional image. By using light instead of sound, OCT offers considerably higher axial resolution and faster acquisition times. When light is directed into the eye, it is reflected at the boundaries of tissues with different optical properties, as well as being scattered and absorbed by the ocular tissue. Low-coherence interferometry is used to measure the time-of-flight delay of light reflected from structures within the retina.
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Fig. 9. Schematic diagram of a classic optical coherence tomography system. An interferometer splits the light source into a probe beam and a reference beam. The probe beam is reflected by retinal structures whose echoes result in a signal.
Current time-domain based OCT scanners use an infrared 200 W, 830 nm wavelength probe light from a continuous-wave superluminescent diode source that is coupled into a fiberoptic Michelson interferometer (Fig. 9). The interferometer splits the light source into a probe beam and a reference beam. The probe beam is directed into the eye and is reflected from retinal structures at different distances. The reflected probe beam is composed of multiple echoes that give information about the distance and thickness of the retinal structures. The reference beam is projected at a known distance. In order for the reference beam and the backscattered light of the probe beam to combine at a detector, the reference beam must be altered. The amount that the reference beam is altered compared to its baseline results in a signal. Software manipulations of the raw OCT image data produce a false-color map representing three-dimensional topographic retinal features and quantitative retinal thickness measurements. The images are stored on digital media to enable comparison of serial evaluations and for archiving purposes.
OCT Image Interpretation
The resulting OCT image closely approximates the histologic appearance of the retina (Fig. 10). The top of the image corresponds to the vitreous cavity. In a normal patient, this will be optically silent, or may show the posterior hyaloidal face in an eye with a posterior vitreous detachment. The posterior vitreous face appears as a thin horizontal or oblique greenish line above or inserting into the retina. The anterior surface of the retina demonstrates high reflectivity, and in the fovea of normal eyes, demonstrates the central foveal depression. The horizontally aligned nerve fiber layer demonstrates higher tissue signal strength and is thicker closer to the optic nerve. The internal structure of the retina consists of heterogeneous reflections, corresponding to the varying
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Fig. 10. OCT of a normal human macula showing the characteristic foveal contour. The nerve fiber layer (NFL) is highly backscattering. The inner and outer plexiform layers (IPL, OPL) are more hyperreflective than the inner and outer nuclear layers (INL, ONL). There is a reflection from the boundary between the inner and outer segments of the photoreceptors (IS, OS). The RPE and choriocapillaris appear as the highly backscattering boundary beyond the posterior retina.
ultrastructural anatomy. The axially aligned cellular layers of the retina (inner nuclear, outer nuclear, and ganglion cell layers) demonstrate less backscattering and back-reflection of incident OCT light, and thus appear with a lower tissue signal (darker), compared to horizontally aligned structures (internal limiting membrane, Henle’s layer, and NFL) that appear brighter. The retinal pigment epithelium, Bruch’s membrane, and choriocapillaris complex collectively comprise the highly reflective external band. Just anterior to this band is another highly reflective line representing the junction between the photoreceptors’ inner and outer segments. Reproducible patterns of retinal morphology seen by OCT have been shown to correspond to the location of retinal layers seen on light microscopic overlays in both normal and pathologic retinas (17, 35–37, 40).
Image-processing software can quantify retinal thickness from the OCT tomograms as the distance between the anterior and posterior highly reflective boundaries of the retina (38). A software algorithm known as segmentation uses the processes of smoothing, edge detection, and error correction to facilitate this process. Retinal thickness can therefore be determined at any transverse location. Hee et al. (33) developed a standardized mapping OCT protocol, consisting of six radial tomograms, each 6 mm in length, in a spoke pattern centered on the fovea. Retinal thickness is then displayed in two different manners: first as a two-dimensional color-coded map of retinal thickness in the posterior pole; and secondly as a numeric average of nine parafoveal areas corresponding the ETDRS subfields. Additional acquisition algorithms include the fast macular mapping protocol, which allows six radial scans to be performed in a single session of 1.92 s; and the high-density scan protocol consisting of six separate 6-mm radial lines, acquired in 7.32 s.
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OCT Technology Development
Over the last decade, the development of OCT has progressed rapidly (34). The first and second generations of commercial OCT instruments had an axial resolution of 10–15 m. Third generation OCT (Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) provides an axial resolution of 8–10 m. Because axial resolution depends on the “coherence length” of the light source, ultrahigh resolution images using a femtosecond titanium:sapphire laser light source can deliver resolutions of 1–3 m, approaching the theoretical limit of OCT imaging (37, 39). However, these ultrahigh resolution scanners are not yet available commercially.
To further improve imaging using commercially available OCT technology, Fourier or spectral-domain technology has been employed that delivers almost a 100-fold improvement in acquisition speed over current time-domain OCT scanners since the moving reference arm is eliminated and all data points can be analyzed at the same time. High-speed Fourier-domain OCT was first described by Wojtkowski and colleagues (40, 41), and then by Nassif and associates (42). Instead of a single detector, the detector arm of the Michelson interferometer uses a spectrometer, which measures spectral modulations produced by interference between the sample and reference reflections. A waveform that represents the amplitude of sample reflections as a function of depth is then produced. The spectrometer measurement is superior to time-domain OCT because no physical movement of the reference mirror is required, and data is therefore acquired at a much faster rate. Furthermore, this technique is able to simultaneous detect reflections from a broad range of depths, whereas time-domain OCT acquires signals from various depths sequentially. This improves the signal-to-noise ratio by a factor proportional to the number of detector elements in the spectrometer (typically 1024 or 2048). With increased imaging speed and greater signal to noise ratio, the Fourier-domain OCT scanners produce more detailed and brighter images (Fig. 11).
Fig. 11. (a) Fourier-domain OCT of a patient with diabetic macular edema. Figure courtesy of Jay Duker, MD. (b) Ultrahigh-resolution OCT of a patient with diabetic macular edema using an experimental unit at New England Eye Center, Boston, MA. Figure courtesy of Jay Duker, MD. (c) Threedimensional reconstruction of patient with diabetic macular edema with Fourier-domain OCT. Figure courtesy of Jason Slakter, MD.
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Fig. 11. (continued)
