Because of dual blood supplies to the retina, the histologic findings associated with ischemic vascular insults vary. In general, ischemia of the retinal vasculature produces inner retinal atrophy, and choroidal ischemia produces outer retinal atrophy. Occlusion of the retinal vessels leads to inner ischemic retinal atrophy with atrophy of retinal ganglion cells and astrocytes, partial atrophy of the INL, and thinning of the NFL (Fig 11-15). Occlusion of the choroidal vessels leads to outer ischemic retinal atrophy, including loss of the photoreceptor segments and nuclei, loss of the OPL, and sometimes thinning of the INL (Fig 11-16).
Figure 11-15 Inner ischemic retinal atrophy. The photoreceptor nuclei (outer nuclear layer; ONL) and the outer portion of the inner nuclear layer (INL) are normal in appearance. The inner portion of the INL is absent. There are no ganglion cells, and the nerve fiber layer is thin, appearing to merge with the inner plexiform layer. This pattern of ischemia corresponds to the supply of the retinal arteriolar circulation and may be seen after healing from retinal arterial and venous occlusions.
Figure 11-16 Outer ischemic retinal atrophy. Begin at the right edge of the photograph and trace the ganglion cell and inner nuclear layers (red arrows 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 blood supply. Compare with Figure 11-15.
Retinal ischemia can be caused by many conditions, including diabetes mellitus, retinal artery and vein occlusions, radiation retinopathy, retinopathy of prematurity, sickle cell retinopathy, vasculitis, and carotid occlusive disease (some of these diseases are discussed later in this chapter). Some of these entities result in focal retinal atrophy; others, in diffuse retinal atrophy. The development of optical coherence tomography angiography (OCTA), which depicts all capillary layers of the retina, may refine our understanding of vascular pathologies affecting this area. See BCSC Section 12, Retina and Vitreous, for further information on OCTA.
Nevertheless, certain histologic findings—both cellular and vascular responses—are common to all disorders that result in retinal ischemia.
Cellular responses Neurons in the retina are highly active metabolically, requiring large amounts of oxygen for production of adenosine triphosphate (ATP) (see 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 (>90 minutes in experimental studies), neuronal cell nuclei become pyknotic (ie, hyperchromatic and shrunken) and are subsequently phagocytosed by microglia. Microglia are involved in the phagocytosis of necrotic cells, as well as of extracellular material, such as lipid or blood, that accumulates in areas of ischemia in the CNS. Microglial cells are fairly resistant to ischemia.
Retinal neurons such as ganglion cells, photoreceptors, amacrine cells, horizontal cells, and bipolar cells have no capacity for regeneration after damage. In response to insult, the nerve fibers of the ganglion cells swell, appearing histologically as pseudo-cells, known as cytoid bodies (Fig 11-17). These localized accumulations of axoplasmic material are present in ischemic infarcts of the NFL. Cotton-wool spots are the clinical correlate of small infarctions in the NFL. They resolve over 4–12 weeks, leaving an area of inner ischemic retinal atrophy.
Like neurons, glial cells degenerate in areas of infarction. These cells may proliferate adjacent to focal areas of infarction as well as in ischemic areas without infarction, resulting in gliosis, a glial scar. The location and extent 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.
Vascular responses One of the earliest manifestations of retinal ischemia is edema, which results from transudation across the damaged inner blood–retina barrier. Fluid and serum components accumulate in the extracellular space, and the fluid pockets are delimited by the surrounding neurons and glial cells. In the perifoveal region, in the Henle fiber layer, this results in cystoid macular edema (CME) (Fig 11-18; see also BCSC Section 12, Retina and Vitreous, for additional images of CME). Lipid-rich exudate accumulation in the OPL of the macula produces a macular star configuration because of the orientation of the nerve fibers in this area (Fig 11-19A). Histologically, retinal exudates appear as sharply circumscribed eosinophilic spaces between the retinal fibers (Fig 11-19B).
Figure 11-17 Cytoid bodies (arrows) within the nerve fiber layer that represent axoplasmic swelling of ganglion cell axons secondary to ischemia. The cystoid spaces (asterisks) in the deeper retina are filled with proteinaceous fluid and represent retinal exudation.
(Courtesy of W. Richard Green, MD.)
Retinal hemorrhages may 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 NFL are flame-shaped, whereas those in the nuclear or inner plexiform layers are circular, or “dot-and-blot” (Fig 11-20). Subhyaloid hemorrhages have a boat-shaped configuration. White-centered hemorrhages (Roth spots) may be present in the retina in a number of conditions (see Fig 18-8 in BCSC Section 12, Retina and Vitreous). The white centers of these hemorrhages may contain multiple constituents, including aggregates of white blood cells, platelets and fibrin, microorganisms, or neoplastic cells, or they may be due to retinal light reflexes.
Figure 11-18 Cystoid macular edema. Cystoid spaces in the inner nuclear and outer plexiform layers (asterisks) of the macula.
(Courtesy of Nasreen A. Syed, MD.)
A, Clinical appearance of intraretinal lipid deposits, or hard exudates. B, PAS stain showing intraretinal exudates (asterisks) surrounding intraretinal microvascular abnormalities (IRMA) (arrow).
(Part A courtesy of David J. Wilson, MD; part B courtesy of W. Richard Green, MD.)
Figure 11-20 Retinal hemorrhage. A, Fundus photograph shows dot-and-blot (arrowhead) and flame-shaped (arrow) intraretinal hemorrhages and boat-shaped preretinal hemorrhage (asterisk) in proliferative diabetic retinopathy. B, Fundus photograph shows dot-and-blot intraretinal hemorrhages (arrowheads).C, Fundus photograph shows multiple flame-shaped hemorrhages (bracket) in the retina surrounding the nerve. D, Histologically, preretinal hemorrhage may be just inside the internal limiting membrane (ILM) in the vitreous (between arrows) or just outside the ILM, creating a bullous hemorrhage in the innermost retina (asterisk).E, Histologically, the dot-and-blot hemorrhage corresponds to blood in the middle layers (inner nuclear and outer plexiform layers) of the retina (arrowhead), whereas flame-shaped hemorrhage corresponds to blood in the nerve fiber layer (arrow).
(Parts A and E courtesy of Robert H. Rosa Jr, MD; part B courtesy of Benjamin J. Kim, MD; part D courtesy of Nasreen A. Syed, MD.)
Chronic retinal ischemia leads to architectural changes in the retinal vessels. The capillary bed undergoes atrophy of the endothelial cells and pericytes and becomes acellular in an area of vascular occlusion. Adjacent to acellular areas, irregular dilated vascular channels known as intraretinal microvascular abnormalities (IRMAs) (Fig 11-21) and microaneurysms often appear. Microaneurysms are fusiform or saccular outpouchings of the retinal capillaries and are best seen clinically with FA and histologically with trypsin digest flat mounts stained with periodic acid–Schiff (PAS) stain (Fig 11-22). The density of the endothelial cells that line IRMAs and microaneurysms frequently varies, with microaneurysms evolving from being thin-walled and hypercellular to being hyalinized and hypocellular.
Figure 11-21 Trypsin digest preparation of the retina shows acellular capillaries (arrowheads) adjacent to IRMAs (arrows) (PAS stain).
(Courtesy of W. Richard Green, MD.)
Figure 11-22 Retinal trypsin digest preparation (PAS stain) shows retinal microaneurysms in diabetic retinopathy (arrows).
In some cases of retinal ischemia, most commonly in diabetes mellitus and central retinal vein occlusion, neovascularization of the retina and the vitreous occurs. Retinal neovascularization arises from existing retinal blood vessels and penetrates the ILM, extending into the vitreous (Fig 11-23). Hemorrhage may develop from retinal neovascularization as the vitreous exerts traction on fragile new vessels.
Many of the vascular changes in retinal ischemia are mediated by vascular endothelial growth factor (VEGF), which is a potent stimulus of vascular permeability and angiogenesis. Biologic agents that inhibit VEGF (eg, bevacizumab, ranibizumab, and aflibercept) and intravitreally administered triamcinolone acetonide are used to treat various retinal diseases associated with macular edema and choroidal neovascularization. In studies that used these treatments for diabetic macular edema, retinal vein occlusion, and choroidal neovascularization, improvement in vision, mostly secondary to a decrease in macular edema and subretinal fluid, was shown (Fig 11-24). See BCSC Section 12, Retina and Vitreous, for more information on retinal neovascularization.
Figure 11-23 Retinal neovascularization. New blood vessels have broken through the internal limiting membrane into the vitreous (PAS stain).
Figure 11-24 Cystoid macular edema (CME) before and after therapy with anti–vascular endothelial growth factor (anti-VEGF). A, SD-OCT shows mild CME (arrowhead), subretinal fluid (asterisks), and irregular elevation and detachment of the RPE (white arrow) secondary to neovascular age-related macular degeneration. Note the outer aspect of Bruch membrane (red arrows).B, SD-OCT of the same retina after anti-VEGF therapy shows resolution of the CME 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.)
Specific ischemic retinal disorders
Central and branch retinal artery occlusions
Central retinal artery occlusion (CRAO) results from localized arteriosclerotic changes, embolus, and in rare instances, vasculitis (as in giant cell arteritis). As the retina becomes ischemic, it swells and loses its transparency. This swelling is best seen clinically and histologically in the posterior pole, where the NFL and the GCL are thickest (Fig 11-25). Because the GCL and the NFL are thickest in the macula and absent in the fovea, a cherry-red spot can be appreciated clinically in the fovea, owing to the stark contrast between the normal color of the choroid and the surrounding swollen white retina. When this sign is observed clinically, it suggests a CRAO. The retinal swelling eventually clears, leaving the classic histologic picture of inner ischemic retinal atrophy. After a CRAO, scarring and neovascularization are rare.
Figure 11-25 Central retinal artery occlusion (CRAO). A, Histologically, necrosis occurs in the inner retina (asterisk), corresponding to the retinal whitening observed on ophthalmoscopic examination. Note the pyknotic nuclei (arrows) in the inner aspect of the inner nuclear layer. B, SD-OCT reveals increased reflectivity in the area of retinal necrosis (asterisks).C, SD-OCT performed at a later date in the same patient as in part B reveals thinning of the inner retina (inbrackets) with loss of the normal lamellar architecture up to the outer plexiform layer–outer nuclear layer junction. ELM = external limiting membrane; ONL = outer nuclear layer.
(Courtesy of Robert H. Rosa Jr, MD.)
Branch retinal artery occlusion (BRAO) is usually the result of an embolus that lodges at the bifurcation of a retinal arteriole. As with CRAO, this embolic event may be the first or most important clue to a significant systemic disorder, such as carotid vascular disease (Hollenhorst plaques), cardiac valvular disease (calcific emboli), or cardiac thromboembolism (platelet-fibrin emboli). However, Hollenhorst plaques, which are cholesterol emboli within retinal arterioles, seldom occlude these vessels (see also BCSC Section 5, Neuro-Ophthalmology). In the acute phase, BRAO is characterized histologically by swelling of the inner retinal layers with early cell death. As the edema resolves, the classic picture of inner ischemic atrophy emerges in the distribution of the retina supplied by the occluded arteriole, with loss of cells in the NFL, GCL, IPL, and INL (see Fig 11-15). Arteriolar occlusions result in infarcts with subsequent complete atrophy of the affected layers.
Central and branch retinal vein occlusions
Central retinal vein occlusion (CRVO) is due to structural changes in the central retinal artery and lamina cribrosa that lead to compression of the central retinal vein. This compression creates turbulent flow in the vein and predisposes the patient to thrombosis. The pathophysiology of CRVO, which is similar to that of hemiretinal vein occlusion but different from that of branch retinal vein occlusion (see the following discussion), occurs in arteriosclerosis, hypertension, diabetes mellitus, and glaucoma.
CRVO occurs in 2 forms:
milder, perfused type, with <10 disc areas of nonperfusion on FA
more severe, nonperfused (ischemic) type, with >10 disc areas of nonperfusion on FA
Both forms of CRVO are recognized clinically by the presence of retinal hemorrhages in all 4 quadrants. Usually, prominent edema of the optic nerve head is noted, along with dilatation and tortuosity of the retinal veins, variable numbers of cotton-wool spots, and macular edema.
Histologically, acute ischemic CRVO is characterized by marked retinal edema, focal retinal necrosis, and extensive intraretinal hemorrhage. With long-standing CRVO, glial cells respond to the insult by replication and intracellular deposition of filaments (gliosis). The hemorrhage, disorganization of the retinal architecture, hemosiderosis, and gliosis seen in vein occlusions distinguish the final histologic picture from that of CRAO (Fig 11-26). After a CRVO, numerous microaneurysms develop in the retinal capillaries, and acellular capillary beds are present to a variable degree. With time, dilated collateral vessels develop at the optic nerve head. A significant amount of VEGF is often elaborated by oxygen-deprived retinal cells and endothelial cells, with resultant neovascularization of the iris and angle, and less often, the retina.
Figure 11-26 Central retinal vein occlusion (CRVO). A, Gross appearance of diffuse retinal hemorrhage after CRVO. B, Photomicrograph of a long-standing CRVO showing loss of the normal lamellar architecture of the retina, marked edema with cystoid spaces (asterisks) containing blood and proteinaceous exudate, and vitreous hemorrhage.
(Part B courtesy of Robert H. Rosa Jr, MD.)
In branch retinal vein occlusion (BRVO), occlusion of a tributary retinal vein occurs at the site of an arteriovenous crossing. At the crossing of a branch retinal artery and vein, the 2 vessels share a common adventitial sheath. With arteriovascular changes in the arteriole, the retinal venule may become compressed, leading to turbulent flow and thrombosis similar to that causing CRVO. Systemic arteriosclerosis and hypertension are risk factors for developing BRVO. BRVO leads to sectoral retinal hemorrhages and cotton-wool spots; however, because it does not always result in total inner retinal ischemia, neovascularization is unlikely unless the ischemia is extensive (>5 disc diameters). Findings in eyes with permanent vision loss from BRVO include CME, retinal nonperfusion, macular edema with hard lipid exudates, late pigmentary changes in the macula, subretinal fibrosis, and epiretinal membrane formation.
The histologic picture of BRVO resembles that of CRVO, but the changes are localized to the retinal area in the distribution of the occluded vein. Inner ischemic retinal atrophy is a characteristic late histologic finding in both retinal arterial and venous occlusions (see Fig 11-15). Numerous microaneurysms and dilated collateral vessels may be present. Acellular retinal capillaries are present to a variable degree, correlating with retinal capillary nonperfusion on retinal angiography.
See BCSC Section 12, Retina and Vitreous, for additional discussion of BRVO and CRVO.
Baseline and early natu ral history report: the Central Vein Occlusion Study. Arch Ophthalmol. 1993;111(8):1087–1095.
Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997;115(4):486–491.
Diabetic retinopathy is one of the most common causes of new blindness in the United States and remains the leading cause among 20- to 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 and include
thickening of the retinal capillary basement membrane
selective loss of capillary pericytes
retinal capillary closure (histologically recognized as acellular capillary beds)
Dilated intraretinal telangiectatic vessels, or IRMAs, may develop (see Figs 11-19, 11-21), and neovascularization may follow (see Fig 11-23). Intraretinal edema, hemorrhages, exudates, and microinfarcts of the NFL may develop secondary to primary retinal vascular changes. Acutely, microinfarcts of the NFL (see Fig 11-17) manifest as cotton-wool spots. Subsequently, focal inner ischemic atrophy appears (see Fig 11-15).
Laser photocoagulation, used in the treatment of diabetic retinopathy, results in focal destruction of the retina and RPE and occlusion of the choriocapillaris (Fig 11-27). These burns heal by proliferation of the underlying RPE and glial scarring, forming a chorioretinal adhesion.
In patients with diabetes mellitus, alterations to the choroid are common in addition to retinal findings. Risk factors for diabetic choroidopathy include diabetic retinopathy, poor diabetic control, and the diabetic treatment regimen. Histologic studies have shown loss of the choriocapillaris, tortuous blood vessels, microaneurysms, drusenoid deposits on the Bruch membrane, and choroidal neovascularization. Most of these findings occur at or anterior to the equator.
Figure 11-27 Laser photocoagulation scars. A, Clinical photograph (upper panel) and SD-OCT (lower panel) show a focal laser scar (arrowheads) and area of peripapillary atrophy (brackets). The double-headed arrow (upper panel) indicates the meridian of the SD-OCT scan through the macula (lower panel). In the lower panel, note the disruption of the outer plexiform layer, outer nuclear layer, ellipsoid zone, and RPE in the region of the focal laser scar (bracket).B, In light applications of laser photocoagulation, focal disruption and attenuation of the outer nuclear layer (asterisks), inner/outer segments, and RPE (brackets) may occur. C, In more intense laser applications, loss of the photoreceptor cell layer and RPE and obliteration of the choriocapillaris (bracket) may occur. Note the thin subretinal fibrosis (asterisk) in the laser scar. Variable RPE hypertrophy, hyperplasia, and migration into the retina (arrowhead), as well as breaks in Bruch membrane, can occur.
(Courtesy of Robert H. Rosa Jr, MD.)
Other intraocular changes in diabetes mellitus
In diabetes mellitus, prolonged hyperglycemia can result in many intraocular changes. The corneal epithelial basement membrane thickens and can result in inadequate adherence of the epithelium to the underlying Bowman layer. This change predisposes patients with diabetes mellitus to corneal abrasions and poor corneal epithelial healing. Lacy vacuolation of the iris pigment epithelium (Fig 11-28A) occurs in association with acute hyperglycemia. Histologically, the intraepithelial vacuoles contain glycogen, which is PAS-positive and diastase-sensitive. Thickening of the basement membrane of the pigmented ciliary epithelium (Fig 11-28B) is almost universally present in the eyes of patients with long-standing diabetes mellitus. The incidence of cataract formation is also increased.
Figure 11-28 Histologic intraocular changes in diabetes mellitus. A, Photomicrograph (PAS stain) shows iris neovascularization (black arrowhead), angle closure by peripheral anterior synechiae (between white arrows), and lacy vacuolation of the iris pigment epithelium (red arrowheads).B, High-magnification photomicrograph shows PAS-stained ciliary body with marked thickening of the basement membrane of the pigmented ciliary epithelium (arrowheads).
(Part A courtesy of Tatyana Milman, MD; part B courtesy of Nasreen A. Syed, MD.)
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.