Age-related macular degeneration (AMD) is the leading cause of new blindness in the United States. Although the etiology of AMD remains unknown, evidence suggests that both genes and environmental factors play a role in the disease pathogenesis. Recently, single nucleotide polymorphisms within the complement factor H gene (CFH) have been found to be associated with the development of AMD in 60% of cases. Increasing age, cigarette smoking, positive family history, and cardiovascular disease increase the risk of developing AMD. In addition, randomized clinical trials showing the benefit of antioxidant supplementation in AMD provide support for the role of oxidative stress in progression of the disease. See BCSC Section 12, Retina and Vitreous, for additional discussion.
Several characteristic changes in the retina, RPE, Bruch membrane, and choroid occur in AMD. Perhaps the first detectable pathologic change is the appearance of deposits between the basement membrane of the RPE and the elastic portion of the Bruch membrane (basal linear deposits) and similar deposits between the plasma membrane of the RPE and the basement membrane of the RPE (basal laminar deposits). These deposits are not clinically visible and may require electron microscopy to be distinguished. In advanced cases, these deposits may become confluent and can be seen at the light microscopic level (Fig 11-28). This appearance has been described as diffuse drusen.
The first clinically detectable feature of AMD is the appearance of drusen. The clinical term drusen has been correlated pathologically to large PAS-positive deposits between the RPE and Bruch membrane. Many eyes with clinically apparent drusen (especially soft drusen) are found to have basal laminar and/or basal linear deposits and diffuse drusen on histologic analysis. Drusen, which may be transient, have been classified clinically as follows:
hard (hyaline) drusen: the typical discrete, yellowish lesions that are PAS-positive nodules composed of hyaline material between the RPE and Bruch membrane (Fig 11-29)
soft drusen: drusen with amorphous, poorly demarcated boundaries, usually >63 µm in size; histologically, they represent cleavage of the RPE and basal laminar or linear deposits from the Bruch membrane (Fig 11-30)
basal laminar or cuticular drusen: diffuse, small, regular, and nodular deposits of drusenlike material in the macula
calcific drusen: sharply demarcated, glistening, refractile lesions usually associated with RPE atrophy
Photoreceptor atrophy occurs to a variable degree in macular degeneration. It is not clear whether this atrophy is a primary abnormality of the photoreceptors or is secondary to the underlying changes in the RPE and Bruch membrane. In addition to photoreceptor atrophy, large zones of RPE atrophy may appear (Fig 11-31). When this occurs centrally, it is termed geographic atrophy (formerly, central areolar atrophy of the RPE). Drusen, photoreceptor atrophy, and RPE atrophy may all be present to varying degrees in dry, or nonexudative, AMD.
Eyes with choroidal neovascularization (neovascular, wet, or exudative AMD) have fibrovascular tissue present between the inner and outer layers of the Bruch membrane, beneath the RPE, or in the subretinal space (Fig 11-32). The new blood vessels leak fluid and may rupture easily, producing the exudative consequences of neovascular AMD, including macular edema, serous retinal detachment, and subretinal and intraretinal hemorrhages. VEGF inhibition achieved with intravitreally administered anti-VEGF agents (pegaptanib, ranibizumab, or bevacizumab) has been shown to reduce the macular edema, slow the progression of the choroidal neovascularization, and improve the visual outcomes of patients with neovascular AMD (also see the section “Vascular responses”).
Subretinal choroidal neovascular membranes have been classified as type 1 or type 2, based on their pathologic and clinical features. Type 1 neovascularization (Fig 11-32A) is typically associated with the presence of basal laminar deposits and diffuse drusen and characterized by neovascularization within the Bruch membrane in the sub-RPE space. In this type of neovascularization, the RPE is often abnormally oriented or absent across a broad expanse of the inner portion of Bruch membrane. Type 2 neovascularization (Fig 11-32B) occurs in the subretinal space and generally features only a small defect in which the RPE is abnormally oriented or absent. Type 1 neovascularization is more characteristic of AMD, whereas type 2 is more characteristic of ocular histoplasmosis. Type 2 membranes are more amenable to surgical removal than are type 1 membranes because native RPE would be excised with a type 1 membrane, leaving an atrophic lesion (without RPE) in the area of membrane excision.
Surgically excised choroidal neovascular membranes (see Fig 11-32) are composed of vascular channels, RPE, and various other components of the RPE–Bruch membrane complex, including photoreceptor outer segments, basal laminar and linear deposits, hyperplastic RPE, and inflammatory cells.
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