The Natural Course of Human Diabetic Retinopathy

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The two most characteristic features of incipient diabetic retinopathy are increased vascular permeability and progressive vascular occlusion. The method of retinal digest preparations, developed by Kuwabara and Cogan, allowed inspection and quantitation of changes in the affected retina liberated from neuroglial tissues due to differential susceptibility against trypsin digestion. As a result of their work and that of others presented later, pericyte loss was identified as the earliest change in the diabetic retina. With time, microvascular endothelial cell loss, in part due to programmed cell death, and progressive capillary occlusion occur. Acellular capillaries are the most significant lesions in the diabetic retina, as they (1) represent the phenotype of hyperglycemia-induced vascular cell damage, which is a general feature of diabetic complications, and (2) are the likely harbingers of all subsequent changes. Micro-aneurysms, which are the first clinically detectable lesions in the eye of a diabetic patient, are found predominantly around areas of occluded capillaries (Figure 2). As sug

Figure 2 Retinal digest preparation (original magnification 400x; stained with PAS) showing retinal capillaries of a 12-month-old rat. Note the distribution of endothelial cells and pericytes within the basement membrane tube.

gested by Ashton, microaneurysms are considered a first, abortive attempt at neovascularization due to focal retinal ischemia.

With more extended nonperfused areas due to progressive capillary occlusions, larger retinal areas react forming intravascular endothelial proliferations in hypercellular vessels (not necessarily capillaries!). The subsequent formation of venous beadings indicates progressive retinal ischemia, representing the extension of the response to ischemic injury to the veins. With long-standing diabetes, and progressive vascular regression, the retina starts to form new blood vessels that enter the vitreous body. The number of newly formed vessels frequently correlates with the extent of non-perfusion in the retina. Neovascularizations tend to spread within the preretinal vitreous and are prone to rhexis and preretinal bleeding. They are often accompanied by matrix-producing cells such as fibroblasts and by inflammatory cells. Both tractive forces due to formation of membranes, which tend to shrink, and the fragility of the newly formed vessels explain the high risk of vitreous hemorrhages in patients with proliferative diabetic retinopathy.

Microaneurysms are often locations of increased vascular permeability, and leaky microaneurysms may lead to macular edema and hard exudates. Focal hard exudates and dot-blot hemorrhages are direct indicators of a breakdown of the blood-retinal barrier. Increased vascular permeability infrequently occurs when other typical retinal lesions are still absent, when glucose control is inadequate, and disappear upon normalization of hyperglycemia.

Pericyte dropout in the retina has not been clearly related to diabetes duration in humans, nor is it pathognomonic for the diabetic retina, since pericyte dropout can occur in various other ocular and systemic diseases such as venous occlusion, polycythemia, and hypertension. Permeability changes in the diabetic retina can be focal or diffuse, suggesting that predilections exist unrelated to pericyte dropout.

The time course of the initial hyperglycemic capillary damage has been most carefully studied in diabetic animal models. Here, the first appreciable sign of structural vascular damage is the loss of pericytes. Pericyte loss has been demonstrated in a variety species (mice, hamsters, rats, dogs, cats, monkeys), and with various modes of diabetes (chemical, genetic). In streptozotocin-diabetic rats, pericyte loss starts between 4 and 8 weeks of diabetes. Subsequently, there is a steady increase in the number of endothelial cells per capillary area unit, indicating random distribution of endothelial cell proliferation. This change becomes significant after 4 to 5 months of hyperglycemia. In parallel with the increase of endothelial cell numbers, acellular occluded capillaries occur, starting with a unilateral focal obstruction in the vicinity of capillaries that still contain cells. This phenotype favors the idea that capillary occlusion in the diabetic retina is the result of both endothelial cell damage (and loss) and extraluminal factors. Although in vivo experiments suggest that intraluminal obstruction may occur through cellular components, acellular capillaries in retinal digest preparations of diabetic rats are typically devoid of cellular debris or blood cells. Acellular capillaries are also present in nondiabetic animals, but are more numerous in diabetic animals, and become more frequent after 3 to 4 months of diabetes. Microaneurysms resembling very early lesions in human retinae (i.e., a unilateral outpouching of the capillary) are occasionally found in diabetic rodents, appearing after 5 to 6 months of hyperglycemia.

Although microaneurysms are occasionally observed in diabetic rodents, and much more frequently in diabetic dogs, there is no consistent evidence of sprouting vessels or pro-liferative changes in diabetic rats or mice despite a level of pericyte dropout that can reach 50 percent.

Abnormal vascular permeability measured by dye techniques is observed as early as 1 week after induction of chemical diabetes in rats. A relation to pericyte dropout has not been determined, but is unlikely to happen, given the discrepant time courses of both changes.

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