Figure 11-25 A, Diffuse retinal hemorrhage following CRVO. The damaged retina will be replaced by gliosis. B, Histology of long-standing CRVO shows loss of the normal lamellar architecture of the retina, marked edema with cystic spaces (asterisk) containing blood and proteinaceous exudate, vitreous hemorrhage, and nodular hyperplasia of the RPE (arrow).

(Part B courtesy of Robert H. Rosa, Jr, MD.)

Diabetic Retinopathy

Diabetic retinopathy is 1 of the 4 most frequent causes of new blindness in the United States and the leading cause among 20to 60-year-olds. Early in the course of diabetic retinopathy, certain physiologic abnormalities occur:

impaired autoregulation of the retinal vasculature alterations in retinal blood flow

breakdown of the blood–retina barrier

Histologically, the primary changes occur in the retinal microcirculation. These changes include

thickening of the retinal capillary basement membrane

selective loss of pericytes compared with retinal capillary endothelial cells microaneurysm formation (see Fig 11-22)

retinal capillary closure (see Fig 11-21) (histologically recognized as acellular capillary beds)

Dilated intraretinal telangiectatic vessels, or intraretinal microvascular abnormalities (IRMA), may develop, as shown in Figure 11-21 and neovascularization may follow (see Fig 11-23). Intraretinal edema, hemorrhages, exudates, and microinfarcts of the inner retina may develop secondary to the primary retinal vascular changes. Acutely, microinfarcts of the inner retina (see Fig 11-15) are characterized clinically as cotton-wool spots. Subsequently, focal inner ischemic atrophy appears (see Fig 11-13).

Other histologic changes in diabetes

In diabetes, the corneal epithelial basement membrane is thickened. This change is associated with inadequate adherence of the epithelium to the underlying Bowman layer, predisposing diabetic patients to corneal abrasions and poor corneal epithelial healing. Lacy vacuolation of the iris pigment epithelium (Fig 11-26) occurs in association with hyperglycemia; histologically, the intraepithelial vacuoles contain glycogen (PAS-positive and diastase-sensitive). Histopathologically, thickening of the pigmented ciliary epithelial basement membrane (see Fig 11-26) is almost universally present in diabetic eyes. The incidence of cataract formation is increased.

Argon laser photocoagulation, used in diabetic retinopathy, results in variable destruction of the outer retina, destruction of the RPE, and occlusion of the choriocapillaris (Fig 11-27). These lesions heal by proliferation of the adjacent RPE and glial scarring.

Figure 11-26 Photomicrograph showing iris neovascularization (black arrowhead), lacy vacuolation of the iris pigment epithelium (red arrowheads), and thickening of the basement membrane of the pigmented ciliary epithelium (red arrow). These histologic findings are typically found in the eyes of patients with diabetes.

Figure 11-27 Laser photocoagulation scar characterized by absence of the RPE centrally (asterisk) with peripheral RPE hyperplasia (arrows) and loss of the photoreceptors, the outer nuclear layer, and a portion of the inner nuclear layer. (Courtesy

of David J. Wilson, MD.)

Retinopathy of Prematurity

Retinal ischemia also plays a role in retinopathy of prematurity (ROP). This ischemia develops not because of the occlusion of existing vessels but rather because of the absence of retinal vessels in the incompletely developed retinal periphery. A decrease in retinal blood flow from oxygen-induced vasoconstriction may also be a contributing factor.

The clinical and histologic features of ROP are somewhat different from those present in other retinal ischemic states. Retinal edema and exudates do not develop. Retinal hemorrhages and retinal vascular dilation develop only in the most severe cases (plus or rush disease). Neovascularization of the retina and vitreous may develop as a result of proliferation of new vessels at the border between the vascularized and avascular peripheral retina. Fibrovascular proliferation into the vitreous at this site may lead to tractional retinal detachment, macular heterotopia, and high myopia. See BCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 12, Retina and Vitreous, for a more detailed discussion.

Age-Related Macular Degeneration

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. Genome-wide and candidate association studies have identified risk loci for AMD and implicated certain genes, including CFH, C3, C2-CFB, CFI, HTRA1/LOC387715/ARMS2, CTEP, TIMP3, LIPC, VEGFA, COL10A1, TNFRSF10A, and APOE. 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.

Figure 11-28 Diffuse drusen. There is diffuse deposition of eosinophilic material (arrowheads) beneath the RPE. Choroidal neovascularization (asterisk) is present between the diffuse drusen and the elastic portion of the Bruch membrane (arrows).

(Courtesy of Hans E. Grossniklaus, MD.)

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)

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.

Figure 11-31 Geographic atrophy of the RPE. A, Fundus photograph shows focal geographic atrophy of the RPE (arrowhead) and drusen in nonexudative AMD. 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/RPE (right of arrow). Note the thickened ganglion cell layer identifying the macular region. (Courtesy of Robert H. Rosa, Jr, MD.)

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.