Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of new blindness in adults in the United States. Although the etiology of AMD is poorly understood, evidence suggests that both genes and environmental factors are involved. Genome-wide and candidate association studies have identified risk loci for AMD and implicated certain genes, particularly CFH and ARMS2. Older age, tobacco use, positive family history, and cardio-vascular disease increase the risk of AMD development. In addition, randomized clinical trials showing the benefit of antioxidant supplementation in AMD suggest that oxidative stress has a role in disease progression.
Several characteristic changes in the retina, RPE, Bruch membrane, and choroid occur in AMD. The first detectable pathologic change is the appearance of deposits between the basement membrane of the RPE and the elastic portion of Bruch membrane (basal linear deposits) and similar deposits between the plasma membrane and the basement membrane of the RPE (basal laminar deposits). Electron microscopy can distinguish between these types of deposits; in advanced cases, the deposits may become confluent and visible with light microscopy without being clinically apparent (Fig 11-30). This histologic appearance has been described clinically 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, extracellular PAS-positive deposits between the RPE and Bruch membrane. Drusen may be transient in their clinical appearance. Clinical types of drusen with their histologic descriptions are listed in Table 11-1, and Figures 11-31, 11-32, and 11-33 depict some of these drusen.
Figure 11-30 Diffuse drusen. Note the diffuse deposition of eosinophilic material (arrowheads) beneath the RPE. Choroidal neovascularization (asterisk) is present between the diffuse drusen and the elastic portion of Bruch membrane (arrows) (PAS stain).
(Courtesy of Hans E. Grossniklaus, MD.)
Table 11-1 Clinical and Histologic Appearance of Drusen
Figure 11-31 Photomicrograph illustrating a dome-shaped, nodular, hard druse (arrow) and attenuation of the overlying RPE.
(Courtesy of Robert H. Rosa Jr, MD.)
Histochemical and molecular/biological analyses have demonstrated that the major constituents of human drusen include albumin, apolipoproteins, complement factors and related proteins, immunoglobulins, lipids, and β-amyloid. Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, are extracellular material interposed between the photoreceptor inner/outer segments and the RPE that contain membranous debris, unesterified cholesterol, complement factors and related proteins, and apolipoproteins but lack opsins. RPD may be associated with progression to advanced AMD (geographic atrophy and choroidal neovascularization). 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.
Figure 11-32 Confluent soft drusen. A, Clinical photograph of soft drusen. Note the pigment clumping overlying the confluent drusen in the central macula. B, Photomicrograph shows thick eosinophilic deposits (asterisks) between the RPE and Bruch membrane. The separation between the retina and RPE and the RPE and Bruch membrane is artifact. Note the marked attenuation of the photoreceptor cell nuclei in the outer nuclear layer and the loss of the outer segments over the confluent drusen.
(Part A courtesy of Robert H. Rosa Jr, MD; part B courtesy of Nasreen A. Syed, MD.)
Photoreceptor atrophy occurs to a variable degree in macular degeneration. This atrophy may be a primary abnormality of the photoreceptors or may be secondary to the underlying changes in the RPE, Bruch membrane, and/or choriocapillaris. In addition to photoreceptor atrophy, large zones of RPE atrophy may appear. When RPE atrophy occurs in the macular region, it is termed geographic atrophy (Fig 11-34). Drusen, photoreceptor atrophy, and RPE atrophy may all be present to varying degrees in dry, or nonneovascular,AMD. In addition, neovascular buds arising from the choriocapillaris are present in areas adjacent to the atrophic areas and in the peripheral choroid.
In eyes with choroidal neovascularization (neovascular AMD; also called wet, or exudative, AMD), fibrovascular tissue is present between the inner and outer layers of Bruch membrane, beneath the RPE, and/or in the subretinal space (Fig 11-35). Excised choroidal neovascular membranes (CNVMs) have demonstrated vascular channels, RPE, and various other components of the RPE–Bruch membrane complex, including photoreceptor outer segments, basal laminar and linear deposits, and inflammatory cells. CNVMs are classified as type 1, type 2, or type 3 depending on their pathologic and clinical features (see Fig 11-35C–E). Type 1 CNVM is characterized by neovascularization originating from the choriocapillaris that involves the Bruch membrane and the sub-RPE space (see Fig 11-35A, C). It is typically associated with basal laminar deposits and diffuse drusen. RPE atrophy and/or hyperplasia may overlie type 1 CNVM. Type 2 CNVM (see Fig 11-35B, D) occurs in the subretinal space and generally features only a small defect in the RPE. Type 1 CNVM is more characteristic of AMD, whereas type 2 is more characteristic of ocular histoplasmosis. Type 3 CNVM (see Fig 11-35E), previously referred to as retinal angiomatous proliferation, arises from the deep capillary plexus of the retina and grows toward the RPE.
Figure 11-33 Reticular pseudodrusen. A, Color photograph shows the ill-defined, yellowish reticular pattern (between arrowheads) in the superior macula. B, Fundus autofluorescence (FAF) image shows the corresponding region (between arrowheads) with dotlike areas of decreased and increased FAF. C, Near-infrared image (upper panel) shows similar dotlike areas of decreased reflectance that, on SD-OCT (lower panel), correspond to deposits (arrows) interposed between the photoreceptor outer segments and the RPE with focal disruption of the ellipsoid zone. D, Subretinal drusenoid deposits (yellow arrowheads) are the histologic correlate of reticular pseudodrusen. Note their location in the region of the outer segments. HF = Henle fiber layer; ONL = outer nuclear layer; IS = inner segment; OS = outer segment; RPE = retinal pigment epithelium; BrM = Bruch membrane; Ch = choroid; Sc = sclera. (Toluidine blue stain).
(Parts A–C courtesy of Robert H. Rosa Jr, MD; part D courtesy of Christine A. Curcio, PhD.)
The choroidal and subretinal neovascular 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 with intravitreally administered anti-VEGF agents has been shown to reduce macular edema, slow progression of the neovascularization, and improve visual outcomes of patients with neovascular (wet) AMD. For further information, see BCSC Section 12, Retina and Vitreous.
Figure 11-34 Geographic atrophy of the RPE. A, Fundus photograph shows focal geographic atrophy of the RPE (arrowhead) and drusen in nonneovascular age-related macular degeneration. B, Histologically, there is loss of the photoreceptor cell layer, RPE, and choriocapillaris (left of arrow) with an abrupt transition zone (arrow) to a more normal-appearing retina and RPE (right of arrow). Note the thick multicellular ganglion cell layer that identifies the macular region.
(Courtesy of Robert H. Rosa Jr, MD.)
Seddon JM, McLeod DS, Bhutto IA, et al. Histopathological insights into choroidal vascular loss in clinically documented cases of age-related macular degeneration. JAMA Ophthalmol. 2016;154(11):1272–1280.
Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.