features of diabetic retinopathy, including microaneurysms, cotton wool spots (CWS), retinal edema, exudates, venous abnormalities and neovascularization, are all secondary to compromised capillary endothelium, which leads to increased capillary permeability and fragility. Widespread small vessel damage leads to areas of ischemia, which can promote intraocular angiogenesis.
Numerous hypotheses explaining the microvascular complications of diabetes have been investigated, including the role of the polyol pathway, glycosylated end products, growth factors and oxidative stress (18-20). Angiogenic factors, such as growth hormone and vascular endothelial growth factor (VEGF) are being evaluated for their mechanistic and potential therapeutic role in diabetic retinopathy. Increased concentrations, or overexpression of intraocular VEGF has been shown to lead to neovascularization, as well as increased permeability of retinal vasculature. Furthermore, inhibitors of VEGF have been shown to prevent ischemia-induced neovascularization in several animal models (21,22).
Protein kinase C (PKC) activation is required for VEGF to induce its effects on vascular endothelium. Orally ingested inhibitors of PKC, currently in clinical trials, have shown promise as an effective way of preventing many of the diabetes-induced vascular complications. Interest in the interaction between components of blood flow, including blood viscosity and red-cell deformability, has also increased recently. Blood viscosity, a potentially modifiable factor, has been shown in small studies to impact the progression and visual impact of diabetic retinopathy (23,24).
Microaneurysms are the most common, and usually the first detectable, signs of retinopathy. These saccular out-pouching of capillaries appear as small discrete red dots within the retina, which tend to increase in number and size with progression of NPDR. Retinal hemorrhages, another early finding, result from ruptured micro aneurysms, capillaries or venules. The morphology of retinal hemorrhages depends on how deep within the retina they lie. The deeper "dot-blot" hemorrhages are round with distinct borders; whereas superficial nerve fiber layer hemorrhages assume a flame or splinter shape (Fig. 2). These early, often subtle,
manifestations of NPDR are important to recognize, because an increasing number of microaneurysms may indicate deterioration of retinopathy (25).
Cotton wool spots are seen ophthalmoscopically as superficial white lesions with feathery margins (Fig. 3). Although they are commonly called "soft exudates," they result from ischemia, not exudation. Local ischemia causes effective obstruction of axoplasmic flow in the normally transparent nerve fiber layer; the subsequent swelling of the nerve fibers gives CWS their characteristic white appearance. CWS are not specific for diabetes, and are commonly seen in association with hypertension, collagen-vascular disease, AIDS, carotid obstruction and cardiac valvular disease. The presence of even a single CWS deserves a systemic evaluation (26).
Hard exudates are extracellular deposits of lipid within the retina. They are sharply demacated yellow "waxy" lesions of varying size and configuration that, unlike CWS, have well-defined borders. This lipid derives from leaky vessels; hard exudates are therefore often associated with areas of retinal edema.
Macular edema, which is defined as thickening of the central retina, is the leading cause of legal blindness in diabetics (27). Clinically significant macula edema (CSME) is edema or hard exudates that involve or threaten the part of the retina which subserves central vision (the fovea) (28). This important sign is often difficult to visualize, because alterations of retinal thickness are subtle. It is best evaluated through the stereoscopic view provided by a contact lens and slit-lamp biomicroscope.
As NPDR advances, signs of retinal ischemia appear. These include increasing CWS, hemorrhages, venous irregularities and intraretinal microvascular abnormalities (IRMA). Venous beading (irregularly dilated venules) and IRMA (telangiectatic capillaries that shunt blood around areas of non-perfusion) often portend progression to proliferative changes. The Early Treatment Diabetic Retinopathy Study found that multiple retinal hemorrhages, venous beading, IRMA and widespread capillary non-perfusion were the clinical signs that best predicted progression to proliferative retinopathy. Eyes that had many of these features in excess have up to a 50% risk of progression to PDR after 1 year (29). Although the macular edema, exudates, and capillary occlusions that occur in NPDR can occasionally cause legal blind ness, affected patients usually maintain at least ambulatory vision. Proliferative diabetic retinopathy, on the other hand, is more likely to result in disabling, severe vision loss.
Proliferative Diabetic Retinopathy
Proliferative retinopathy is heralded by the growth of neovascular and fibrous tissue. The overall prevalence of PDR in type 2 diabetics is 10%, but the rate is higher in those requiring insulin (14%) compared with those not requiring insulin (3%) (4). Blood vessel growth from the optic nerve is termed neovascularization of the disc (NVD); whereas vessels arising from any other part of the retina is referred to as neovascularization elsewhere (NVE) (Figs. 4 and 5). Neovascular tissue extends into the vitreous—the clear delicate connective tissue that fills the space bounded posteriorly by the retina and anteriorly by the lens. The complications of PDR are related to the propensity for new vessels to bleed (vitreous hemorrhage), as well as
FIGURE 5 Neovascularization elsewhere.
the tendency of the vitreous body to shrink and pull the retina forward (traction retinal detachment) (Fig. 6). Bleeding within the vitreous causes sudden painless loss of acuity.
The extent and location of the hemorrhage determine the magnitude of vision loss. Examining eyes with vitreous hemorrhage is difficult because blood in the vitreous obscures retinal details. When necessary, intraocular structures are assessed with ultrasonography. Tractional retinal detachments, the other major complication of PDR, appear as elevations of all or portions of the retina. Tractional retinal detachment occurs when fibrous tissue pulls on the retina, overwhelming the adhesive forces keeping it attached. Patients with detached retinas present with loss of vision corresponding to the part of the retina that has detached. For example, a superior retinal detachment will cause an inferior visual field defect because of the inverted topographic representation of the retina. Vision loss is often preceded by the sensation of flashing lights or floaters. If suspected, prompt referral to an ophthalmologist experienced in the repair of retinal detachments is critical.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...