immunocompromised persons. In patients with reactivated disease, ocular toxoplasmosis typically presents as a posterior uveitis or panuveitis with marked vitritis and focal retinochoroiditis adjacent to a pigmented chorioretinal scar. The absence of prior chorioretinal scarring suggests newly acquired disease. Microscopic examination of active toxoplasmic retinitis reveals necrosis of the retina, a prominent infiltrate of neutrophils and lymphocytes, and Toxoplasma organisms in the form of cysts and tachyzoites (Fig 11-9). There is generally a prominent lymphocytic infiltrate of the vitreous and the anterior segment and, not uncommonly, granulomatous inflammation in the inner choroid. Healing brings resolution of the inflammatory cell infiltrate with encystment of the organisms in the retina adjacent to the chorioretinal scar.
Noninfectious
Noninfectious (autoimmune) inflammatory conditions involving the retina are discussed in BCSC Section 9, Intraocular Inflammation and Uveitis, and Section 12, Retina and Vitreous.
Figure 11-9 A, Chorioretinal scars with pigmentation (double arrow) typical of prior infection with toxoplasmosis. Active retinitis (arrowhead) and perivascular sheathing (arrow) are present. B, Cysts (arrow) and released organisms (tachyzoites,
arrowhead) in active toxoplasmosis. (Courtesy of Hans E. Grossniklaus, MD.)
Degenerations
Typical and Reticular Peripheral Cystoid Degeneration and Retinoschisis
Typical peripheral cystoid degeneration (TPCD) is a universal finding in the eyes of persons older than 20 years. In TPCD, cystic spaces develop in the outer plexiform layer of the retina. Reticular peripheral cystoid degeneration (RPCD) is less common. In RPCD, the cystic spaces are present in the NFL. When present, RPCD occurs posterior to areas of TPCD (Fig 11-10). Coalescence of the cystic spaces of TPCD forms typical degenerative retinoschisis, which is usually inferotemporal in location. In reticular degenerative retinoschisis, the splitting of retinal layers occurs in the NFL.
Figure 11-10 Retinal degeneration. Typical peripheral cystoid degeneration consists of cystoid spaces in the outer plexiform layer (asterisk) on the lower left (anterior retina). In the upper right (posterior retina), reticular peripheral cystoid degeneration (arrow) is present.
Lattice Degeneration
Lattice degeneration may be a familial condition (Fig 11-11). It is found in up to 10% of the general population, but only a small number of affected persons develop retinal detachment. In contrast, lattice degeneration is seen in up to 40% of all rhegmatogenous detachments. The most important histopathologic features of lattice degeneration include
discontinuity of the ILM of the retina
an overlying pocket of liquefied vitreous
sclerosis of the retinal vessels, which remain physiologically patent condensation and adherence of vitreous at the margins of the lesion variable degrees of atrophy of the inner layers of the retina
Although atrophic holes often develop in the center of the lattice lesion, they are rarely the cause of retinal detachment because the vitreous is liquefied over the surface of the lattice, and thus no vitreous traction occurs. Retinal detachment associated with lattice degeneration is generally the result of
vitreous adhesion at the margin of lattice degeneration, leading to retinal tears in this location with vitreous detachment. Radial perivascular lattice degeneration has the same histopathologic features as typical lattice degeneration but occurs more posteriorly along the course of retinal vessels.
Figure 11-11 Retinal lattice degeneration. A, Lattice degeneration may present as prominent sclerotic vessels (arrows) in a wicker or lattice pattern. The clinical presentation has many variations. B, The vitreous directly over lattice degeneration is liquefied (asterisk), but formed vitreous remains adherent at the margins (arrowheads) of the degenerated area. The internal limiting membrane is discontinuous, and the inner retinal layers are atrophic.
Paving-Stone Degeneration
In contrast to retinal vascular occlusion, which leads to inner retinal ischemia, occlusion of the choriocapillaris can lead to loss of the outer retinal layers and RPE. This type of atrophy, called cobblestone or paving-stone degeneration, is very common in the retinal periphery. The welldemarcated, flat, pale lesions seen clinically correspond to circumscribed areas of outer retinal and RPE atrophy with adherence of the inner nuclear layer to the Bruch membrane (Fig 11-12).
Ischemia
There are many causes of retinal ischemia, including diabetes mellitus, retinal artery and vein occlusion, radiation retinopathy, retinopathy of prematurity, sickle cell retinopathy, vasculitis, and carotid occlusive disease. The specific aspects of some of these diseases are discussed later in the chapter. However, certain histopathologic findings are common to all the disorders that result in retinal ischemia. The retinal changes that occur with ischemia can be grouped into cellular responses and vascular responses.
Cellular responses
The neurons in the retina are highly active metabolically, requiring, on a per gram of tissue basis, large amounts of oxygen for production of adenosine triphosphate (ATP) (see also BCSC Section 2, Fundamentals and Principles of Ophthalmology, Part IV, Biochemistry and Metabolism). This makes them highly sensitive to interruption of their blood supply. With prolonged oxygen deprivation (greater than 90 minutes in experimental studies), the neuronal cells become pyknotic; they are subsequently phagocytosed, and they disappear. The extent and the location of the area of atrophic retina resulting from ischemia depend on the size of the occluded vessel and on whether it is a retinal or a choroidal blood vessel. As described earlier, the retinal circulation supplies the inner retina, and the choroidal circulation supplies the outer retina and RPE. Infarctions of the retinal circulation lead to inner ischemic retinal atrophy (Fig 11-13), and infarctions of the choroidal circulation lead to outer ischemic retinal atrophy (Fig 11-14).
Figure 11-12 A, Paving-stone degeneration appears as areas of depigmentation (arrows) in the periphery of the retina near
the ora serrata. B, Histologically, paving-stone degeneration consists of atrophy of the outer retinal elements and chorioretinal adhesion to the remaining inner retinal elements. A sharp boundary (arrowheads) exists between normal and atrophic retina, corresponding to the clinical appearance of paving-stone degeneration.
The neuronal cells of the retina have no capacity for regeneration after ischemic damage. Following ischemic damage to the nerve fibers of the ganglion cells, cytoid bodies (swollen axons) become apparent histologically (Fig 11-15). These are localized accumulations of axoplasmic material that are present in ischemic infarcts of the NFL. Cotton-wool spots are the clinical correlate of ischemic infarcts of the NFL that resolve over 4–12 weeks, leaving an area of inner ischemic atrophy.
Glial cells, like axons, degenerate in areas of infarction. Proliferation of the glial cells may occur adjacent to local areas of infarction or in areas of ischemia without infarction, resulting in a glial scar.
Figure 11-13 Inner retinal ischemia. The photoreceptor nuclei (outer nuclear layer, ONL) and the outer portion of the inner nuclear layer (INL) are identifiable. The inner portion of the inner nuclear layer is absent. There are no ganglion cells, and the NFL is absent. This pattern of ischemia corresponds to the supply of the retinal arteriolar circulation and may be observed in arterial and venular occlusions.
Figure 11-14 Begin at the right edge of the photograph and trace the ganglion cell and the inner nuclear layer toward the left. In this case, there is loss of the nuclei of the photoreceptor layer (outer nuclear layer, arrow), the photoreceptor inner and outer segments, and the RPE (arrowhead). This is the pattern of outer retinal atrophy, secondary to interruption in the choroidal vascular blood supply. Compare with Figure 11-13.
Figure 11-15 Cytoid bodies (arrows) within the NFL. Cystoid spaces (asterisks) are filled with proteinaceous fluid. (Courtesy of
W. Richard Green, MD.)
Microglial cells are actually tissue macrophages rather than true glial cells. These cells are involved in the phagocytosis of necrotic cells as well as of extracellular material, such as lipid and blood, that accumulates in areas of ischemia. Microglial cells are fairly resistant to ischemia.
Vascular responses
Many of the vascular changes in retinal ischemia are mediated by vascular endothelial growth factor (VEGF). This growth factor is a potent mediator of vascular permeability and angiogenesis. It has been shown to play a role in numerous ocular conditions associated with vascularization.
In addition to those changes secondary to ischemia itself, vascular changes may be caused by the specific disease process responsible for the ischemia. Edema and hemorrhages are common with acute retinal ischemia. Retinal capillary closure, microaneurysms, lipid exudates, and neovascularization may develop with chronic retinal ischemia.
Edema, one of the earliest manifestations of retinal ischemia, is a result of transudation across the inner blood–retina barrier (Fig 11-16). Fluid and serum components accumulate in the extracellular space, and the fluid pockets are delimited by the surrounding neurons and glial cells. Exudate accumulating in the outer plexiform layer of the macula (Henle layer) produces a star figure because of the orientation of the nerve fibers in this layer (Fig 11-17). In cases of chronic edema, the extracellular deposits will become richer in protein and lipids, as the water component of the exudate is more efficiently removed, resulting in so-called hard exudates. Histologically, retinal exudates appear as eosinophilic, sharply circumscribed spaces within the retina (Fig 11-18). Chronic edema
may result in intraretinal lipid deposits that are contained within the microglial cells.
Intravitreally administered triamcinolone acetonide (IVTA) and recently developed biologic agents inhibiting VEGF (pegaptanib, ranibizumab, and bevacizumab) are now being employed in the treatment of various retinal diseases associated with macular edema and choroidal neovascularization. Gain in visual acuity, which is mostly secondary to a decrease in macular edema, has been demonstrated in studies in which these treatments were used for such conditions as diabetic macular edema, central and branch retinal vein occlusions, uveitic macular edema, and retinal and choroidal neovascularization (Fig 11-19). Hypotheses regarding the mechanism of action of IVTA include an anti-inflammatory effect, inhibition of VEGF, improvement in diffusion, and reestablishment of the blood–retina barrier through a reduction in permeability. VEGF inhibition in the eye arrests angiogenesis and reduces vascular permeability. Pegaptanib is an RNA aptamer (an oligonucleotide ligand) that binds specifically to the VEGF165 isoform, thereby preventing receptor binding of the VEGF isoform. Ranibizumab is a recombinant humanized monoclonal antibody fragment, whereas bevacizumab is a full-length monoclonal antibody. Both ranibizumab and bevacizumab inhibit receptor binding of all isoforms of VEGF-A, which may explain the enhanced anatomical and visual effects that have been observed clinically with use of these agents.
Figure 11-16 Cystoid spaces in inner nuclear and outer plexiform layers (asterisks). (Courtesy of W. Richard Green, MD.)
Figure 11-17 Intraretinal lipid deposits, or hard exudates. (Courtesy of David J. Wilson, MD.)
Figure 11-18 Intraretinal exudates (asterisks) surrounding intraretinal microvascular abnormalities (arrow). (Courtesy of W.
Richard Green, MD.)
Figure 11-19 A, SD-OCT shows cystoid macular edema (arrowhead), subretinal fluid (asterisks), and irregular elevation and detachment of the RPE (white arrow) secondary to exudative age-related macular degeneration. Note the outer aspect of Bruch membrane (red arrows). B, SD-OCT after anti-vascular endothelial growth factor therapy shows resolution of the cystoid macular edema and detachment of the RPE. Focal areas of geographic atrophy of the RPE with attenuation of the photoreceptor cell layer are more apparent (between arrowheads). Note the hyperreflectivity (between dashed lines) in the choroid corresponding to the areas of geographic atrophy. (Courtesy of Robert H. Rosa, Jr, MD.)
Retinal hemorrhages also develop as a result of ischemic damage to the inner blood–retina barrier. As with edema and exudates, the shape of the hemorrhage conforms to the surrounding retinal tissue. Consequently, hemorrhages in the nerve fiber are flame-shaped, whereas those in the nuclear or inner plexiform layer are circular, or “dot and blot” (Fig 11-20). Subhyaloid and sub-ILM hemorrhages have a boat-shaped configuration. White-centered hemorrhages (Roth spots) may be present in a number of conditions. The white centers of the hemorrhages can have a number of causes, including aggregates of white blood cells, platelets, and fibrin; or they may be due to retinal light reflexes. Hemorrhages clear over a period of time ranging from days to months.
Chronic retinal ischemia leads to architectural changes in the retinal vessels. The capillary bed becomes acellular in an area of vascular occlusion. Adjacent to acellular areas, dilated irregular vascular channels known as intraretinal microvascular abnormalities (IRMA) and microaneurysms often appear (Figs 11-21, 11-22). Microaneurysms are fusiform or saccular outpouchings of the retinal capillaries best seen clinically with fluorescein angiography and histologically with PASstained trypsin digest preparations (see Fig 11-22). The density of the endothelial cells lining the
microaneurysms and IRMA is frequently variable. Microaneurysms evolve from thin-walled hypercellular microaneurysms to hyalinized, hypocellular microaneurysms.
Figure 11-20 Intraretinal hemorrhage. A, Fundus photograph showing dot-and-blot (arrowhead), flame-shaped (arrow), and boat-shaped (asterisk) hemorrhages in diabetic retinopathy. B, Histologically, the dot-and-blot hemorrhage corresponds to blood in the middle layers (inner nuclear and outer plexiform layers) of the retina (arrowhead). The flame-shaped hemorrhage corresponds to blood in the NFL (arrow), and the boat-shaped hemorrhage corresponds to subhyaloid blood. (Courtesy of
Robert H. Rosa, Jr, MD.)
Figure 11-21 Trypsin digest preparation, illustrating acellular capillaries (arrowheads) adjacent to intraretinal microvascular
abnormalities (IRMA, arrow). (Courtesy of W. Richard Green, MD.)
Figure 11-22 Retinal trypsin digest preparation, showing diabetic microaneurysms (arrows).