neovascularization may also occur as a complication of the clinical picture.12

Vascular diseases

Vascular occlusions lead to serious complications in any organ system: in the eye, early diagnosis and prompt treatment are important. Most retinal vein occlusions are secondary to systemic diseases, most frequently to systemic arterial hypertension. In central retinal vein occlusions, the thrombus often lies at the level of the lamina cribrosa; in branch retinal vein occlusions, the thrombus is frequently at the arteriovenous crossing. Retinal hemorrhages and edema are frequently present (Figure 2.4). Retinal artery occlusions occur less frequently than vein occlusions and are usually secondary to emboli or, less frequently, inflammatory processes. The retinal arteries may appear attenuated or bloodless. The clinically seen gray area is caused by marked edema of the inner layers of the neuroretina. With complete coagulative necrosis of the posterior pole, the choroid-contained blood shows through the central fovea, which has no inner layers, and is clinically visualized as a cherry red spot.14

Loss of cell volume control mechanisms resulting in extracellular filtrates can be the cause of macular edema. Some causes of macular edema may be secondary to cataract extraction, such as in Irvine–Gass syndrome, or can be dominantly inherited. Initially reversible, accumulation of fluid is intracellular. Further accumulation of fluid causes the

cytoplasm membrane to break and fluid collects extracellularly, causing irreversible damage.15 Other causes of macular edema include retina vein occlusions, diabetic retinopathy, and uveitis.16

Coats’ disease, a congenital retinal telangiectasia, also involves vascular abnormalities (Figure 2.5). Telangiectatic retinal vessels with Leber’s miliary aneurysms, consisting of fusiform and saccular dilatations of venules and arterioles that surround a diffusely dilated capillary bed, eosinophilic transudate, and rich subneural retinal exudate containing foamy macrophages and cholesterol crystals are seen. It is caused by somatic mutations in the NDP gene.17

Toxicities

Toxic retinopathy can result due to medications. Chloroquine toxicity can initially occur with macular edema. Later punctate pigment epithelial changes develop, which may progress to bull’s-eye maculopathy in the macular region.18,19 Both phenothiazine and chloroquine toxicity findings may appear similar to those findings associated with retinitis pigmentosa. Tamoxifen toxicity is associated with impairment in color vision, possible retinal vein thrombosis, and fleck-like retinopathy.19 Gentamicin may also cause ocular toxicity in addition to its usual toxic side-effects.19 Further details on retina toxicity to drugs applied intraocularly or systemically may be found in Chapters 15 and 16.

Because of the high oxygen consumption of the photoreceptors, high concentration of long-chain polyunsaturated fatty acids in the outer

segment, and exposure to visible and ultraviolet light, the retina is highly susceptible to oxidative stress. Free radical formation may result in injury to DNA, proteins, and lipids of the retina. Though the eye has defenses against free radicals, like antioxidants, severe damage to the RPE and DNA may lead to subsequent mutations.20

Inflammatory diseases

Inflammatory diseases of the retina and choroid, generally termed “retinitis” or “chorioretinitis,” manifest pathologically with inflammatory cells infiltrating the retina and/or choroid. In retinitis there are often dilated blood vessels and increased vascular permeability leading to edema and tissue accumulation of white blood cells, and the inflammation usually occurs near the retinal vessels. Displacement of native retinal tissue by edema leads to swelling and degeneration of neural retinal cells. Retinal hemorrhages and accumulation of microglia and macrophages are also common. If inflammatory vascular occlusion leads to infarction, necrosis results in cystoid bodies due to swelling of nerve fiber axons. The inflammatory healing process can result in the formation of a chorioretinal scar or in hyaline and/or calcareous degenerations. Astrocyte proliferation in the affected areas leads to retinal gliosis. Healing might also involve the development of a fibroglial scar, which during contraction and organization can disrupt the retinal structure, potentially damaging RPE cells and promoting hypertrophy and hyperplasia of nearby RPE.21,22

Retinitis comprises both acute and chronic conditions and can remain localized to the retina or can spread to affect the vitreous, optic nerve, and/or uveal tract, particularly the choroid. Retinitis can present as either granulomatous or nongranulomatous. Moreover, retinal inflammations include those caused by both infectious and noninfectious etiologies. Noninfectious etiologies include retinal involvement of inflammatory diseases, such as sarcoidosis, pars planitis, and birdshot retinochoroidopathy. Most of these are autoimmune diseases and entail primarily T-lymphocyte infiltrates. For example, sarcoidosis demonstrates characteristic pathology, including noncaseating granulomas in the retina and choroids (Figure 2.6), infrequently with necrosis, proteinaceous exudates, or hemorrhage into the subretinal space, development of a neovascular membrane from the optic disc to the vitreous cavity, and, occasionally, retinal detachment.23,24

Infectious causes include viral, bacterial, fungus and parasitic infection, such as Candida, cytomegalovirus (CMV), toxoplasmosis, and onchocerciasis. Pathologically, CMV retinitis manifests with a primary coagulative full-thickness retinal necrosis and scant inflammatory infiltrates. Infected retinal cells were enlarged and contained a large central basophilic intranuclear inclusion, which appears as an “owl eye” due to the presence of a halo separating it from the nuclear membrane, as well as smaller basophilic cytoplasmic inclusions (Figure 2.6). Areas of clinically end-stage CMV retinitis show chorioretinal scarring with total loss of retinal cells.25 Acute retinal necrosis, most commonly caused by the varicella-zoster virus or the herpes simplex virus, involves acute peripheral necrotizing retinitis, retinal arteritis, and vitritis. On

pathology, acute retinal necrosis demonstrates Cowdry type A eosinophilic intranuclear inclusions. Zoster infection is commonly associated with occlusive vasculitis.26,27

Neoplasms

Tumors of the retina can arise from any number of cell types, including photoreceptors, RPE, glia, and others. Photoreceptor neoplasms include retinoblastoma and retinocytoma. Retinoblastomas are comprised of undifferentiated cells and possess multifocal growth, including bilateral involvement. They classically form rosettes and pseudorosettes, possess high nuclear-to-cytoplasm ratios, and contain significant areas of necrosis and/or calcification (Figure 2.7).28 Retinocytomas are rare benign small placoid, noninvasive neoplasms involving cells that have differentiated into photoreceptor elements, numerous fleurettes, lack of mitotic activity, and less necrosis.29

RPE tumors include RPE adenoma and RPE adenocarcinoma. Histopathology of RPE adenomas demonstrates an abrupt transition between normal RPE and neoplastic RPE, which consists of polyhedralappearing epithelial cells with variable pigmentation arranged in papillary, solid, or mixed form. While mitotic figures are rare, nuclear atypia is common. Adenocarcinomas are malignant and appear much like adenomas, but with increased cellular pleomorphism.30

Phakomatoses are a group of hereditary disseminated hamartomas, including von Hippel–Lindau (VHL) disease, Wyburn–Mason syndrome, and retinal cavernous hemangioma. One such phakomatosis is VHL disease, an inherited cancer syndrome associated with retinal angiomas, cerebellar hemangioblastomas, renal cysts, pheochromocytomas, pancreatic cysts, epididymal cysts, and retinal hemangioblastomas.31 These retinal hemangioblastomas appear as a network of endothelium-lined vascular channels among the foamy “stromal” cells, which are the true tumor cells with a mutated or deleted VHL gene.31,32 The complications include leaky capillaries, arteriovenous shunt, hemorrhages, exudates, and retinal detachment.31

Retinal detachment

Retinal detachment refers to the separation of the RPE from Bruch’s membrane (RPE detachment) or of the photoreceptor layer from the RPE (neurosensory retinal detachment). The two major types of detachment are rhegmatogenous and nonrhegmatogenous retinal detachments; the former arises from a retinal hole or tear, the latter does not usually have a retinal hole or tear and may be either serous or tractional type. Retinal detachments can occur by three major mechanisms: accumulation of fluid beneath the intact retina (nonrhegmatogenous, e.g., hypertension, subneural retinal hemorrhages, choroidal tumors, vascular lesions of the retina), vitreous traction (e.g., secondary to trauma, surgical aphakia, vitreous bands from diabetes mellitus), or accumulation of fluid beneath a broken neural retina (i.e., rhegmatogenous retinal detachment).33

Involvement of systemic diseases

A multitude of systemic diseases, including blood diseases, genetic metabolic storage diseases, vascular diseases, collagen vascular diseases, and phakomatoses, may present various types of chorioretinal alterations.

Sickle-cell disease manifests with peripheral arteriolar occlusion, peripheral arteriolovenular anastomoses, vascular sclerosis, “sea fan”- shaped neovascular proliferations, fibrous proliferations, vitreous hemorrhage, and/or neural retinal detachment (Figure 2.8).36 Another blood disease, leukemia, may present with retinopathy, which manifests histologically with leukemic cellular infiltration surrounding by retinal hemorrhages, often accompanied with choroidal infiltration by leukemic cells, even leading to RPE disruption or detachment. Other features include venous congestion and dilation, perivascular infiltration, retinal microaneurysm, capillary loss, and proliferative retinopathy.37

Metabolic storage diseases, including mucopolysaccharidoses, mucolipidoses, and sphingolipidoses, can cause hereditary secondary retinal dystrophies. As their name implies, these diseases are marked by the accumulation of storage substance in retinal cells, in particular, ganglion cells, leading eventually to cell injury and death. For example, the autosomal-recessive sphingolipidosis, Tay–Sachs disease, results in the accumulation of ganglioside mainly in retinal ganglion cells, which induce cell death and extracellular deposition of the ganglioside, and finally, develop optic atrophy.38

Vascular diseases which lead to retinopathy include hypertension, diabetes, arteriosclerosis, and ocular ischemia due to reduction in blood flow through the ophthalmic or carotid arteries. In the initial vasoconstrictive stage of hypertensive retinopathy, vasospasm and increased arteriolar tone lead to narrowing of retinal arterioles. Consequently, the sclerotic stage of hypertensive retinopathy is associated with intimal thickening, media hyperplasia, and hyaline degeneration, leading to worsened arteriolar narrowing. Subsequently disruption of the blood– retina barrier and necrosis of vascular cells may lead to the development of microaneurysms, hemorrhages, and cystoid degeneration.39

Early diabetic retinopathy is initially caused by a loss of pericytes from retinal capillaries, followed by loss of capillary endothelial cells, microaneurysms, and hemorrhages. Ischemia and microinfarction lead to the development of cystoid degeneration. Retinal edema is caused by leakage of plasma from small blood vessels, and retinal exudates are due to resorption of the fluid elements of the leaked plasma secondary to deposition of lipid and lipoprotein components. The ischemic processes might lead eventually to proliferative diabetic retinopathy characterized by retinal neovascularization. If the neovascular membranes extend to the vitreous and hemorrhage into it, visual loss and tractional retinal detachments might ensue. Neovascularization might also occur in the iris (rubeosis irides), impeding aqueous humor outflow and leading to the so-called neovascular glaucoma.40

Collagen vascular diseases such as systemic lupus erythematosus (SLE), polyarteritis nodosa, and giant-cell arteritis may also present