Early Nonproliferative Diabetic Retinopathy
The retina is particularly sensitive to the metabolic changes and ischemia seen in diabetes because it is one of the most metabolically active tissues in the body (8). Even before clinical or histological evidence of DR begins, retinal pericytes and vascular endothelial cells have already begun to die at an accelerated rate (18).
The first clinically detectable change is microaneurysm formation (Fig. 1). This occurs as capillary walls weaken secondary to pericyte loss. Hypercellular outpouchings form, and vascular integrity becomes increasingly compromised with lipid and proteinacious material leaking and accumulating as "hard" exudates (Fig. 2) (7). As weakening continues, capillaries begin to rupture. If they bleed deep in the retina, "dot and blot" hemorrhages are seen, whereas, superficial bleeds are seen as "splinter-" or "flame-"shaped hemorrhages
(Fig. 2). These latter bleeds are identical to those seen in systemic hypertension, and consequently, blood pressure should be measured if present.
As the capillaries continue to leak and hemorrhage, retinal thickening in the form of macular edema can manifest as decreased vision (Fig. 3). The edema scatters light and opacifies the retina. It is the leading cause of legal blindness in diabetics, and it is important to note that it can occur in the early stages of nonproliferative diabetic retinopathy (NPDR) and can only be seen with a slit lamp in conjunction with high-power lenses.
Once retinal microvascular disease progresses to the point of causing inner retinal hypoxia, signs of advanced NPDR begin to appear in the form of cotton-wool spots, venous beading and loops, intraretinal microvascular abnormalities (IRMA), and areas of capillary nonper-fusion on fluorescein angiography (FA). Cotton-wool spots, also called "soft" exudates, are actually nerve fiber layer infarcts. As hypoxia develops in the nerve fiber layer, axoplasmic flow is halted and leads to swelling giving a white, fluffy appearance. Venous beading and looping are the result of sluggish circulation and exuberant endothelial replacement of previously damaged vascular endothelium (Fig. 4) (7). IRMAs are dilated capillaries that seem to function as collaterals. They do not leak and therefore can be distinguished from neovascularization using FA.
The Early Treatment Diabetic Retinopathy Study (ETDRS) found that multiple retinal hemorrhages, venous beading, and looping, IRMA, widespread capillary nonperfusion, and leakage on FA were all significant risk factors for progressing to proliferative DR; however, cotton-wool spots were not (19,20). Roughly half of patients with advanced NPDR develop proliferative diabetic retinopathy (PDR) within 1 year (21).
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