5 - Retinal Vascular Disease

Editors: Tasman, William; Jaeger, Edward A.

Title: Wills Eye Hospital Atlas of Clinical Ophthalmology , The, 2nd Edition

Copyright 2001 Lippincott Williams & Wilkins

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Chapter 5

Retinal Vascular Disease

Gary C. Brown

William Tasman

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Central retinal vein obstruction associated with occlusion of a cilioretinal artery.

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Fundus Angiography

Fluorescein Angiography

Since its description by Novotny and Alvis in 1961, intravenous fluorescein angiography has become one of the most extensively used diagnostic modalities in ophthalmology. Sodium fluorescein is a hydrocarbon that is 80% bound to serum proteins when injected into the bloodstream. The 20% that is unbound can be excited by a blue light with a wavelength of 465 to 490 nm and caused to fluoresce a yellow-green color at a wavelength of 520 to 530 nm. The dye is 90% eliminated in the urine within 24 hours. It imparts an orange appearance to the skin and a yellow-orange appearance to the urine.

The complications of intravenous sodium fluorescein injection include nausea in 5% to 10% of patients and vomiting in 1% to 2%. These effects usually occur within 1 to 2 minutes after injection. Less frequently observed adverse effects include vasovagal reactions and true allergies, characterized by hives and pruritus. The incidence of true anaphylaxis is extremely low. Extravasation into extravascular spaces can lead to local tissue necrosis.

The vessels of the ciliary body and the choriocapillaris are permeable to sodium fluorescein. Ocular neovascularization is also permeable. The normal retinal vessels and the larger choroidal vessels are impermeable.

There are four phases to a normal fluorescein angiogram, although the first two may overlap (Fig. 5.1): the choroidal filling phase; the retinal arterial filling phase; the venous filling phase; and the recirculation phase.

Fluorescein dye usually enters the choroid about 10 to 15 seconds after intravenous injection, depending on the site of injection, the rapidity of injection, and the status of the systemic circulation. Filling the choroid is also referred to as the choroidal flush, because filling of the individual choriocapillaries cannot be seen. The choroid should be completely filled within 5 seconds after the first appearance of dye within it. Dye appears within a cilioretinal artery concomitantly with filling of the choroid.

The retinal arteries begin to fill approximately 1 to 2 seconds after the appearance of dye within the retinal arteries. Usually, the retinal veins are completely filled within 10 seconds after dye is first seen within the retinal arteries. During the recirculation phase, which usually begins a minute or so after the injection, there is decreasing fluorescence within the retinal vessels as the bolus of dye is distributed throughout the systemic vasculature.

Hyperfluorescence and hypofluorescence are the terms used when describing fluorescein angiographic patterns. Hyperfluorescence occurs when there is an abnormal accumulation of dye (Fig. 5.2) or a retinal pigment epithelial window defect (i.e., transmission defect), the absence or relative absence of the retinal pigment epithelium (Fig. 5.3). Hypofluorescence occurs when there is an absence of dye (Fig. 5.4) or blockage of fluorescence by blood (Fig. 5.5), melanin pigment, or some other substance.

Retinal capillary nonperfusion (Fig. 5.6) is a pattern that is important to recognize with fluorescein angiography. It is characterized by a homogenous gray appearance of fluorescence that comes predominantly from the underlying choroid. The larger remaining retinal vessels stand out in relief to the surrounding relative hypofluorescence and, in the later phases of the study, there is minimal leakage of dye into the retina in nonperfused areas.

Ocular neovascularization in the choroid, retina, or iris or on the optic disc routinely demonstrates leakage of fluorescein dye (Fig. 5.6). Fluorescence from new vessels is most often maximal during the early phases of the study. During

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the later phases, minutes after injection, it becomes more diffuse.

Figure 5.1. Normal intravenous fluorescein angiogram. A: Within 14 seconds after injection, the study is in the retinal arterial filling phase. A diffuse choroidal flush results from filling of the choriocapillaris, and several small choroidal filling defects are evident along the supertemporal retinal vascular arcade. The normal hypofluorescence in the foveal region occurs because of blockage of the choroidal fluorescence pattern in this region by taller retinal pigment epithelial cells and xanthophyll pigment in the outer retinal layers. B: Within 15 seconds after injection, the study is in the laminar venous filling phase. C: By 19 seconds after injection, the venous filling is nearly complete. D: Several minutes after injection, during the recirculation phase, the fluorescence of the choroid and the retinal vessels is less pronounced.

Figure 5.2. Hyperfluorescence caused by the abnormal presence of dye. A: Subretinal blood and subretinal fluid associated with a choroidal neovascular membrane. B: The fluorescein angiogram 17 seconds after injection reveals lacy hyperfluorescence of the membrane. C: At 429 seconds after injection, the hyperfluorescence of the membrane has increased and become more diffuse.

Figure 5.3. Hyperfluorescence from transmission defects. A: Retinal pigment epithelial (RPE) loss in the macula in an eye with atrophic, age-related macular degeneration. B: A fluorescein angiogram corresponding to (A) more than 13 minutes after injection reveals hyperfluorescence corresponding to the areas of RPE absence.

Indocyanine Green Angiography

Indocyanine green (ICG) is a tricarbocyanine dye that absorbs at 790 to 805 nm and has a peak emission at 835 nm. These spectral properties allow ICG to be visualized through the ocular pigments, blood, and serous fluids better than fluorescein. ICG is almost 98% protein bound, and fluorescein is about 80% protein bound. This high degree of protein binding results in the tendency of ICG to remain intravascular, which facilitates visualization of the choroidal vessels and, in certain cases, choroidal pathologic processes. It is excreted unchanged by the liver via the biliary system.

The dye does not produce the nausea caused by sodium fluorescein after intravenous injection, but it can cause vasovagal reactions. Because it contains approximately 5% iodine by weight, it should not be given to patients with a history of iodine allergy.

Figure 5.4. Hypofluorescence caused by an absence of dye in an eye with choroidal hypoperfusion as a result of a severe ipsilateral carotid artery obstruction.

ICG angiography usually demonstrates the choroidal vasculature better than fluorescein angiography (Fig. 5.7). Indications for the test are still being developed, but it appears most useful in exudative macular degeneration when fluorescein angiography fails to delineate the choroidal neovascularization. In some of these instances, ICG angiography can help to reveal the location and extent of choroidal neovascularization. It may also be of value in identifying the recurrence or persistence of choroidal neovascularization after laser therapy.

Figure 5.5. Hypofluorescence results from blockage by blood from a bleeding retinal arterial macroaneurysm, which can be seen as a focus of hyperfluorescence along the course of an inferotemporal retinal artery in this right eye. The preretinal blood superiorly blocks the fluorescence of the retinal and choroidal vasculature, but the subretinal blood inferiorly blocks the choroidal fluorescence and permits visualization of the retinal vessels.

Figure 5.6. A: Fundus with diabetic retinopathy and neovascularization of the optic disc. B: The fluorescein angiogram obtained 24 seconds after injection reveals retinal capillary nonperfusion extending into the central macular region. Microaneurysms are demonstrated by numerous pinpoint foci of hyperfluorescence, and the hyperfluorescence overlying the disc is the result of neovascularization. C: Within 103 seconds after injection, there is intraretinal leakage of dye from damaged retinal vessels, except in the region of retinal capillary nonperfusion. The pattern of dye leakage into the vitreous cavity overlying the optic disc has become more diffuse.

Figure 5.7. Indocyanine green angiogram. A: Fundus of an eye with occult choroidal neovascularization on fluorescein angiography. B: In the early phases of the study, the large choroidal vessels are well visualized. C: Several minutes after injection, a focus of relative hyperfluorescence can be seen, which presumably represents staining or leakage of the dye from the neovascular complex.

Figure 5.8. A: Cotton-wool spots located superotemporal to the optic nerve head. B: Histopathologic examination reveals a nerve fiber layer that is thickened by blockage of axoplasmic flow. Several cytoid bodies in a cotton-wool spot contain intensely eosinophilic nucleoids composed of dammed organelles. (Hematoxylin and eosin stain; original magnification 100; courtesy of Ralph C. Eagle Jr, M.D.)

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Cotton-Wool Spots

A cotton-wool spot is a small focus of superficial retinal opacification that develops after focal retinal ischemia with secondary axoplasmic damming.

Clinical Features

Cotton-wool spots are usually white or yellow-white lesions that are less than 0.25 disc diameter (Fig. 5.8). They are located in the nerve fiber layer of the retina in the posterior pole, but are not seen in the periphery. With fluorescein angiography, they demonstrate relative hypofluorescence. In general, they resolve within 5 to 7 weeks, although those seen in patients with diabetic retinopathy can be more persistent.

Diabetic retinopathy is the most common cause of cotton-wool spots. Cotton-wool spots have been associated with numerous other abnormalities, such as systemic arterial hypertension, collagen vascular diseases, cardiac valvular disease, carotid artery obstructive disease, coagulopathies, metastatic carcinoma, trauma, and human immunodeficiency virus infection.

Management

Cotton-wool spots require no therapy. If no underlying disease is readily apparent, a systemic workup should be undertaken, possibly including a glucose tolerance test to rule out diabetes mellitus. An underlying cause or association can be found in about 95% of cases.

Hard Exudates

Hard exudates in the posterior segment represent the deposition of lipid from chronic leakage of plasma from incompetent vessels of the retina, choroid, or optic disc.

Clinical Features

Hard exudates appear as discrete, bright yellow lesions that are most frequently seen in the posterior pole. They can be globular or have a linear appearance (Fig. 5.9A). These exudates are typically located in the outer plexiform layer of the retina (i.e., Henle's layer; Fig. 5.9B), but in instances of severe exudation, such as Coats' disease, they can dissect into the subretinal space. In marked cases, the hard exudates can become confluent and extend into the central macula, usually causing severe visual loss (Fig. 5.9C). Hard exudates are usually undetectable with fluorescein angiography.

These lipid deposits are constantly changing. If leakage from the abnormal vessels worsens, the exudates can increase. If the leakage lessens or stops, the exudates eventually regress because of phagocytosis of the lipid by macrophages (i.e., gitter cells).

Hard exudates are associated with numerous retinal vascular diseases, including diabetic retinopathy, hypertensive retinopathy, retinal venous obstruction, retinal arterial macroaneurysm, radiation retinopathy, Coats' disease, and capillary hemangioma of the retina (i.e., von Hippel's lesion). The exudates are frequently associated with choroidal neovascularization in exudative macular degeneration and also with optic neuropathies. A unique variant is the macular star, which occurs most frequently with hypertensive retinopathy and optic neuropathies.

Management

Hard exudation in the central macular can lead to severe visual loss. Treatment of the underlying, leaking vascular abnormalities can be accomplished with laser photocoagulation in many instances, depending on the underlying disease.

Venous Obstructive Disease

Central Retinal Vein Obstruction

Michel is usually given credit for categorizing central retinal vein obstruction as a distinct clinical entity in 1878. Green and associates histopathologically studied 29 eyes with central retinal vein obstruction and found a thrombus within

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the lumen of the central retinal vein at or near the lamina cribrosa in each case. It has been suggested that the central retinal artery compresses the central retinal vein in the vicinity of the lamina cribrosa, leading to turbulence, endothelial damage, and subsequent thrombus formation in many cases.

Figure 5.9. A: Multiple, discrete, yellow, hard exudates in the posterior pole of an eye with background diabetic retinopathy. B: Hard exudates are pools of proteinaceous fluid. Most are located in the outer plexiform layer, which is the watershed zone between the two circulations of the retina. (Hematoxylin and eosin stain; original magnification 100; courtesy of Ralph C. Eagle Jr, M.D.) C: Severe, confluent hard exudation in an eye with marked background diabetic retinopathy of a patient with a serum triglyceride level approximately 10 times the normal level. The condition eventually progressed to proliferative diabetic retinopathy.

Clinical Features

Central retinal vein obstruction usually develops in persons with a mean age of 65 years. Men appear to be affected at a higher rate than women, and in approximately 10% of cases, there is a history of a central or branch retinal vein obstruction in the contralateral eye.

Fundus examination typically shows dilated and tortuous retinal veins and a swollen optic disc (Fig. 5.10). Retinal hemorrhages are usually present in the posterior pole and the periphery. Macular edema is common. Neovascularization of the optic disc or retina may develop, although neovascularization of the iris is much more common.

Figure 5.10. Central retinal vein obstruction.

Several nomenclature systems have been developed to describe central retinal vein obstruction. The obstructions can probably be best classified as nonischemic (i.e., perfused; Fig. 5.11) and ischemic (i.e., nonperfused) variants. A vein obstruction is considered to be nonperfused (Fig. 5.12) if retinal capillary dropout of at least 10 disc areas is evident on fluorescein angiography in a posterior pole view that also extends for a radius of 4 to 5 disc areas more peripheral to the macula. Electroretinography is also useful in classifying central retinal vein obstruction into these two basic categories. Clinically, the ischemic variants tend to have prominent relative afferent pupillary defects, poor visual acuity, numerous cotton-wool spots, and extensive intraretinal hemorrhages. Approximately one fourth to one third of all central retinal vein obstructions are ischemic in nature, and about 10% to 20% of the nonischemic cases progress to significant ischemia.

Overall, approximately 20% of eyes with central retinal vein obstruction develop iris neovascularization. Within the ischemic group, the rate rises to 50% of affected eyes. Iris neovascularization usually becomes evident between 2 weeks and 2 years after the obstructive event occurs, with a mean of 4 to 5 months.

Figure 5.11. A: Nonischemic (i.e., perfused) central retinal vein obstruction in an eye with a visual acuity of 20/100. B: In the fluorescein angiogram obtained 30 seconds after injection, the retinal capillary bed is well perfused.

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Whether or not posterior or anterior segment neovascularization occurs, the retinal hemorrhages from the obstruction slowly resolve over several months. Chronic cystoid macular edema and retinal pigment epithelial disruption in the macula are frequent sequelae that typically limit visual recovery. Frank macular ischemia also can contribute to permanently decreased vision. Optociliary collateral vessels often form on the optic disc after several months, as the hemorrhages resolve.

Systemic abnormalities associated with central retinal vein obstruction include systemic arterial hypertension, diabetes mellitus, and hyperviscosity states. Increased intraocular pressure also appears to be associated. Increased intraocular pressure can bow the lamina cribrosa posteriorly, theoretically contributing to compression of the central retinal vein, turbulence, and subsequent thrombus formation.

Management

No treatment has been consistently effective in stabilizing or improving the visual acuity of eyes with central retinal vein obstruction. Correction of associated systemic abnormalities, such as polycythemia, may benefit some patients.

Figure 5.12. A: Examination of an ischemic (i.e., nonperfused) central retinal vein obstruction in an eye with visual acuity limited to hand motions shows marked intraretinal hemorrhage and numerous cotton-wool spots. B: The fluorescein angiogram corresponding to (A), obtained 48 seconds after injection, reveals widespread retinal capillary nonperfusion.

Panretinal laser photocoagulation can cause regression of iris neovascularization when it develops in the setting of central retinal vein obstruction. For ischemic central retinal vein obstructions, panretinal laser photocoagulation before the development of iris neovascularization (Fig. 5.13) appears to reduce the risk of forming these new vessels and progression to neovascular glaucoma.

Branch Retinal Vein Obstruction

Branch retinal vein obstruction (i.e., occlusion) is a retinal vascular disease that usually affects persons in their sixties. Men and women appear to be affected equally. The disorder is more common in those with a history of systemic arterial hypertension. Approximately 10% of people with a branch retinal vein obstruction in one eye eventually develop a venous obstruction in the second eye.

Clinical Features

The obstruction usually occurs at an arteriovenous crossing, where the two vessels are bound by a common adventitial sheath. The retinal artery, which is typically located anterior to the vein, most likely compresses the

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vein, leading to turbulence, endothelial damage, and thrombus formation. If the blockage does not occur at an arteriovenous crossing, an inflammatory cause, such as sarcoidosis, is more likely.

Figure 5.13. A: Panretinal laser photocoagulation in an eye with a nonperfused central retinal vein obstruction and vision limited to hand motions. B: One year later, the intraretinal blood has been reabsorbed, and changes in the retinal pigment epithelium are evident in the central macula. Such pigmentary changes are commonly seen after severe central or branch retinal vein obstructions.

Intraretinal hemorrhage and edema are seen in the distribution of the blocked vessel (Fig. 5.14). Cotton-wool spots may also be present. If the obstruction occurs within one of the vessels on the optic disc, the disc may be swollen. In longstanding cases, optociliary collaterals can develop on the optic disc, as can pigmentary changes in the central macula.

The visual acuity can range from 20/20 to counting fingers. The most common reason for decreased vision is macular edema, but retinal capillary nonperfusion and vitreous hemorrhage occurring secondary to posterior segment neovascularization are other causes. Traction and/or rhegmatogenous retinal detachment can occur in some cases. The rhegmatogenous component can develop when a retinal tear occurs adjacent to a tuft of retinal neovascularization under traction from the overlying vitreous gel.

Intravenous fluorescein angiography most often reveals a delay in retinal venous filling of the involved vessels; there may also be delayed retinal arterial filling. Areas of retinal capillary nonperfusion can be seen, and in the late phases, there is often intraretinal leakage of dye, particularly in areas where the retinal capillary bed is intact (Fig. 5.15).

Figure 5.14. A: Superotemporal branch retinal vein obstruction. B: Fluorescein angiogram demonstrates retinal capillary nonperfusion in the distribution of the obstructed vessel.

Retinal neovascularization or neovascularization of the optic disc can develop in eyes with vein obstructions that are ischemic, which is defined as significant retinal capillary nonperfusion ( 5 disc diameters) on fluorescein angiography. Approximately 50% of the cases of branch retinal vein obstruction involving at least a quadrant of the fundus have significant ischemia. About 40% of such eyes eventually develop posterior segment neovascularization (Fig. 5.16).

Abnormalities that can be confused with branch retinal vein obstruction include retinal arterial macroaneurysm and certain cases of cavernous hemangioma of the retina. Exudative macular degeneration can mimic branch retinal vein obstructions that primarily involve the macula.

Management

Medical therapy has not benefitted eyes with branch retinal vein obstruction. Nevertheless, control of systemic arterial hypertension could theoretically be of benefit in preventing additional venous obstructive events.

Figure 5.15. A: Macular branch retinal vein obstruction. B: The fluorescein angiogram demonstrates an absence of retinal capillary perfusion 49 seconds after injection. There is pronounced intraretinal leakage of dye 245 seconds after injection.

Figure 5.16. A: Preretinal bleeding in an eye with neovascularization of the retina occurring secondary to a superotemporal branch retinal vein obstruction. B: The fluorescein angiogram obtained 27 seconds after injection reveals hyperfluorescence of two neovascular foci. Adjacent retinal capillaries are not perfused peripheral to the new vessels. C: Diffuse leakage of dye overlies the neovascularization at 318 seconds after injection.

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The Branch Vein Occlusion Study was a clinical trial that evaluated the efficacy of laser photocoagulation in eyes with branch retinal vein for improving visual acuity and for preventing posterior segment neovascular sequelae.

In affected eyes with 20/40 or worse vision (primarily caused by macular edema), an obstruction present 3 to 18 months, and absence of foveolar blood, the mean visual acuity in eyes treated with macular grid laser therapy was 20/40 to 20/50 at 3 years, but untreated eyes had a mean visual acuity of 20/70. When confluent intraretinal hemorrhage was present in the macula, treatment was delayed until the blood cleared sufficiently to assess macular capillary perfusion with fluorescein angiography and deliver laser treatment if indicated.

Treatment consisted of argon laser photocoagulation using 100- m yellow-white burns in a grid fashion (Fig. 5.17). The treatment extended from the edge of the foveal avascular zone to the temporal macular vascular arcade. If macular edema was still present at 4 months after treatment and the vision remained decreased, treatment was repeated if fluorescein angiography still demonstrated retinal leakage.

Eyes with significant retinal capillary nonperfusion (i.e., >5 disc diameters wide on fluorescein angiography) were also randomized to receive sector scatter laser photocoagulation, delivering 200- to 500- m, yellow-white burns to the area affected by the obstruction (Fig. 5.18). This type of treatment was not administered closer than 2 disc diameters to the center of the fovea. If posterior segment neovascularization was diagnosed at the time of entrance into the study, the treatment reduced the incidence of vitreous hemorrhage from approximately 60% to 30% at 3-year follow-up. In eyes without posterior segment neovascularization initially,

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the chance of developing neovascularization was reduced from 31% to 19% with treatment. Overall, the Branch Vein Occlusion Study report recommended following these cases, with particularly close attention to the ischemic variants, and treating with sector scatter laser therapy after neovascularization develops.

Figure 5.17. A: Superotemporal branch retinal vein obstruction. B: The fluorescein angiogram several minutes after injection reveals intraretinal leakage of dye and absence of retinal capillary nonperfusion. C: Several months after focal laser therapy, the macular edema has lessened. D: The fluorescein angiogram discloses decreased intraretinal leakage of dye after the laser therapy.

Figure 5.18. An equator-plus photograph demonstrates a sector panretinal photocoagulation with a full-scatter pattern in an eye with posterior segment neovascularization secondary to a branch retinal vein obstruction.

Arterial Obstructive Disease

Central Retinal Artery Obstruction

Central retinal artery obstruction is seen in about 1 of 10,000 outpatient ophthalmic visits. It is typically unilateral, and although it can be seen in all ages, the mean age of affected patients is about 65 years. The causes include emboli, hemorrhage under an atherosclerotic plaque, thrombosis, inflammation, spasm, systemic hypotension, hypertensive arterial necrosis, and dissecting carotid artery aneurysm.

Clinical Features

Patients with acute central retinal artery obstruction typically present with a history of sudden, painless visual loss. The fundus appearance is characterized by superficial retinal whitening that is most pronounced in the posterior pole (Fig. 5.19). A cherry red spot can be seen in the foveola, where the retina is thinnest.

The visual acuity is most often decreased to the range of counting fingers or hand motions. In approximately 10% of cases; however, a patent cilioretinal artery supplies the foveola (Fig. 5.20), and the vision may not significantly decrease or even improve to 20/20 to 20/50 within a few weeks after the onset of the obstruction.

Emboli are seen in the retinal arterial system in 20% of eyes with acute central retinal artery obstruction. Cholesterol emboli (i.e., Hollenhorst plaques; Fig. 5.21) appear as small, glistening crystals and are thought to originate predominantly from the carotid arteries. Calcific emboli (Fig. 5.22), usually originating from the cardiac valves, tend to be whiter and larger than the cholesterol variant. Both types can be present on the optic disc or lodged at arterial bifurcations.

Figure 5.19. Acute central retinal artery obstruction with superficial retinal whitening and a cherry red spot in the foveola.

Figure 5.20. Central retinal artery obstruction with cilioretinal sparing between the disc and the fovea.

Figure 5.21. Hollenhorst plaque within a retinal arteriole in the fundus in an eye without a clinically evident retinal arterial obstruction.

Figure 5.22. Inferior branch retinal artery obstruction secondary to a white calcific plaque. (Courtesy of Larry Magargal, M.D., Philadelphia, PA.)

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Approximately 18% of eyes with a central retinal artery obstruction develop iris neovascularization, usually by 4 to 6 weeks after the obstruction. If iris neovascularization is already present when the central retinal artery obstruction occurs, the possibility of concurrent ocular ischemic syndrome should be considered.

Acute ophthalmic artery obstruction and combined central retinal artery and central retinal vein obstruction can be confused with acute central retinal artery obstruction. With an acute ophthalmic artery obstruction, the visual acuity is generally worse (often no light perception), the posterior pole whitening is more severe, and a cherry red spot is often absent (Fig. 5.23).

Eyes with a combined central retinal artery and central retinal vein obstruction have clinical features suggestive of both these entities (Fig. 5.24): superficial retinal whitening, a cherry red spot, dilated and tortuous retinal veins, and retinal hemorrhages. Retrobulbar injection and inadvertent penetration of the optic nerve is a common cause of this relatively rare combination. Approximately 80% of affected eyes progress to iris neovascularization with a median time of 6 weeks.

Management

The visual prognosis for eyes with acute central retinal artery obstruction and no cilioretinal foveolar sparing is grim, with most remaining legally blind. Globe massage, anterior chamber paracentesis, oxygen carbon dioxide combination inhalation therapy, oral vasodilator treatments, and the use of systemic anticoagulants have all been advocated, but no consistent or significant improvement in vision has been demonstrated. If iris neovascularization develops, panretinal laser photocoagulation can be successful in promoting regression in as many as 65% of cases.

A thorough workup should be considered to ascertain underlying causes. More common underlying abnormalities include carotid artery obstructive disease, cardiac valvular disease, and collagen vascular diseases. In younger patients, the possibility of migraine and coagulopathies should also be entertained. Giant cell arteritis is seen in about 1% to 2% of cases and should be ruled out in any retinal arterial obstructive event in patients older than 55 years. Giant cell arteritis should be included in the differential diagnosis if the arterial obstruction is bilateral.

Figure 5.23. Acute ophthalmic artery obstruction. The inner and outer portions of the retina are severely opacified, and a cherry red spot is absent. Visual testing revealed no light perception.

Figure 5.24. Combined central retinal artery and central retinal vein obstruction in a 20-year-old woman with systemic lupus erythematosus.

Branch Retinal Artery Obstruction

Branch retinal artery obstruction can occur as two variants: true branch retinal artery obstruction and cilioretinal artery obstruction.

Clinical Features

Patients with branch retinal artery obstructions usually present with a history of sudden, painless visual loss in part of the visual field of the affected eye. Superficial retinal whitening is seen in the distribution of the fundus supplied by the vessel (Fig. 5.25). The visual acuity generally returns to 20/40 or better. Although the visual defect may decrease in size, some residual field loss usually remains.

The causes of true branch retinal artery obstruction are similar to those of central retinal artery obstruction. Uncommonly, entities not associated with central retinal artery obstruction, such as toxoplasmosis retinochoroiditis

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and thrombosis within a retinal arterial macroaneurysm, can cause branch retinal artery obstruction.

Figure 5.25. Branch retinal artery obstruction.

Cilioretinal arteries are direct or indirect (through the choroid) branches of the posterior ciliary arteries. They typically emerge from the temporal aspect of the optic disc separately from the central retinal artery. Three types of cilioretinal artery obstructions have been described: isolated cilioretinal artery obstruction (Fig. 5.26); cilioretinal artery obstruction associated with central retinal vein obstruction; and cilioretinal artery obstruction associated with anterior ischemic optic neuropathy (Fig. 5.27). Ninety percent of eyes with isolated cilioretinal artery obstruction eventually achieve 20/40 vision, and 70% of eyes with cilioretinal artery obstruction and associated central retinal vein obstruction reach 20/40 vision. Eyes with cilioretinal artery obstruction associated with anterior ischemic optic neuropathy usually remain legally blind.

The fundus appearance for a true branch retinal artery or cilioretinal artery obstruction is fairly characteristic. Viral retinitides, toxoplasmic retinochoroiditis, and fungal retinitides may rarely cause confusion.

Management

Ocular treatment is generally not given for branch retinal artery obstruction because it is not particularly effective and because the visual prognosis is relatively good.

The medical workup for branch retinal artery obstruction is similar to that for central retinal artery obstruction. The possibility of coexistent giant cell arteritis ranks high in the differential diagnosis in cases of cilioretinal artery obstruction associated with anterior ischemic optic neuropathy.

Ocular Ischemic Syndrome

In 1963, Kearns and Hollenhorst described the ocular symptoms and signs attributable to chronic, severe carotid artery obstruction, and they called the entity venous stasis retinopathy. The same term has been used to describe mild central retinal vein obstruction, a distinctly different entity. To avoid confusion, the term ocular ischemic syndrome is preferable to designate the ocular findings found in conjunction with severe carotid artery obstruction.

Figure 5.26. Isolated cilioretinal artery obstruction.

Figure 5.27. Cilioretinal artery obstruction associated with anterior ischemic optic neuropathy in a patient with giant cell arteritis.

The disease affects twice as many men as women, and the mean age at the time of diagnosis is 65 years. A carotid artery stenosis of at least 90% is necessary to cause the ocular ischemic syndrome (Fig. 5.28), although approximately 50% of patients have a 100% stenosis. Chronic ophthalmic artery insufficiency can also cause the ocular ischemic syndrome. Bilaterality is seen in 20% of cases.

Noninvasive vascular testing (e.g., duplex carotid ultrasonography) is about 90% successful in detecting a carotid artery stenosis of 50% or greater.

Atherosclerosis is the most common cause. Giant cell arteritis, inflammatory conditions of the large vessels, and Eisenmenger's syndrome are other known causes.

Clinical Features

Approximately 90% of patients with the ocular ischemic syndrome relate a history of visual loss

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in the affected eye, usually occurring over a period of weeks to months. Forty percent relate a history of aching pain in the orbital region. The recovery time may be increased after exposure to bright light.

Figure 5.28. A carotid arteriogram reveals marked stenosis of the ipsilateral internal carotid artery in a patient with the ocular ischemic syndrome.

Figure 5.29. Examination of the fundus of a patient with the ocular ischemic syndrome reveals dilated, but not tortuous, retinal veins.

Rubeosis iridis affects two thirds of eyes at the time of diagnosis. Nevertheless, the intraocular pressure is elevated in only about half of the eyes with rubeosis, probably because of decreased aqueous production due to poor ciliary body perfusion. A mild anterior chamber cell and flare response is observed in about 20% of eyes.

Posterior segment signs (Fig. 5.29) include narrowed retinal arteries and dilated, but not tortuous, retinal veins in most eyes, with retinal hemorrhages in 80% (Fig. 5.30), and neovascularization of the disc or retina in about 35%. The retinal hemorrhages are generally dot and blot types, with a predilection for the midperipheral fundus. Less common signs include microaneurysms, a cherry red spot, cotton-wool spots, spontaneous pulsations of the retinal arteries, macular edema, and anterior ischemic optic neuropathy.

Fluorescein angiography reveals delayed choroidal filling in 60% of eyes (Fig. 5.31), a delayed retinal arteriovenous transit time in 95%, and late staining of the retinal vessels, especially the arteries, in 85%. Electroretinography shows diminution of the a and b waves (Fig. 5.32), indicating ischemia of the inner and outer retinal layers.

Figure 5.30. Retinal hemorrhages in a case of ocular ischemic syndrome.

Figure 5.31. A: Fundus of the left eye in a patient with the ocular ischemic syndrome. The retinal arteries are narrowed, and myelinated nerve fibers are present at the inferior border of the optic disc. B: The fluorescein angiogram of the same eye discloses delayed choroidal filling approximately 1 minute after injection. C: At approximately 7.5 minutes after injection, there is marked staining of the large retinal vessels, particularly the arteries. (Courtesy of Larry Magargal, M.D.)

The 5-year mortality rate is about 40%, with death usually caused by cardiovascular disease. Systemic arterial hypertension is encountered in almost three fourths of patients,

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diabetes in about half, previous cerebrovascular accident in one fourth, and peripheral vascular disease severe enough to require a bypass in about one fifth.

Figure 5.32. Electroretinogram of a normal left eye (lower tracing) and a right eye (upper tracing) with the ocular ischemic syndrome. There is diminution of the a and b waves in the ocular ischemic syndrome eye.

The disorder most likely to be confused with the ocular ischemic syndrome is mild central retinal vein obstruction. Helpful differentiating features include disc swelling seen with central retinal vein obstruction (i.e., the optic disc usually appears normal with the ocular ischemic syndrome), venous tortuosity with vein obstruction, and more retinal hemorrhages with venous disease. Light digital pressure on the lid can often induce retinal arterial pulsations with the ocular ischemic syndrome, although not in eyes with central retinal vein obstruction.

Diabetic retinopathy can mimic the ocular ischemic syndrome and can coexist with it. Eyes with the ocular ischemic syndrome alone do not usually have hard exudates. In markedly asymmetric cases of diabetic retinopathy, the ocular syndrome can exacerbate the proliferative retinopathy changes.

Management

The natural course of the ocular ischemic syndrome is uncertain. Nevertheless, after rubeosis iridis develops, more than 90% of eyes are legally blind within 1 year of diagnosis.

Panretinal photocoagulation causes regression of iris neovascularization in about 35% of cases, but it appears to be a temporizing procedure.

When a carotid obstruction is 100%, endarterectomy is generally unsuccessful. Extracranial to intracranial bypass has been advocated. Unfortunately, with long-term follow-up, this procedure does not favorably affect visual outcome or reduce the incidence of stroke compared with a group treated medically with antiplatelet agents.

Carotid endarterectomy can help to preserve or restore the vision in some cases. Moreover, in symptomatic patients with a 70% to 99% stenosis, it has reduced the incidence of severe stroke over a 2-year period from 26% to 9% compared with treatment using antiplatelet agents alone.

Diabetic Retinopathy

Diabetic retinopathy is a leading cause of blindness in the industrial countries. It accounts for approximately 10% of cases of legal blindness (visual acuity 20/200) in the United States, and in patients between 45 and 74 years of ages, it causes 20% of the cases of new blindness. Blindness from diabetic retinopathy appears to be more common in women than men and in persons of African descent, particularly women, than Caucasians. Since 60% of diabetic patients are women, women comprise a majority of patients with diabetic retinopathy.

The most reliable predictor of diabetic retinopathy is duration of the disease. Among insulin-dependent diabetics, there is virtually no clinically apparent retinopathy within 4 to 5 years after the diagnosis is made. After 5 to 10 years, 25% to 50% of patients have retinopathy, and after 10 to 15 years, it can be detected in 75% to 95% of patients. Proliferative diabetic retinopathy is rare before 10 years of diabetes' duration, but after 20 to 25 years, it can be seen in 18% to 40% of patients.

It is uncertain exactly why diabetic retinopathy develops. Increased platelet adhesiveness and aggregation, decreased deformability of red and white blood cells, increased basement membrane formation in the retinal capillaries, and loss of autoregulation in the retinal vessels are all associated abnormalities that may lead to the damage seen in the retinal blood vessels.

Strict control of the serum glucose levels in type I (insulin-dependent) diabetics has reduced the onset of diabetic retinopathy and slowed the progression of mild disease. It has also slowed the onset and progression of nephropathy and neuropathy. It is uncertain whether the same data hold for type II (non insulin-dependent) cases, although, theoretically, this should also be the case.

Clinical Features

Diabetic retinopathy can be subdivided into two basic forms: nonproliferative (i.e., background) and proliferative.

In nonproliferative diabetic retinopathy, the first fundus sign of background diabetic retinopathy is often a microaneurysm. These outpouchings from the retinal capillaries can be found in the superficial and deep retinal capillary beds (Fig. 5.33). They are 12 to 100 m in diameter, although only those greater than 30 m across are visible ophthalmoscopically. It is uncertain why they occur, but it has been suggested that a loss of intramural pericytes in diabetic retinal capillaries leads to weakening of the walls of the vessels. Microaneurysms can be differentiated from retinal hemorrhages, because they are generally hyperfluorescent, unlike hypofluorescent hemorrhages.

Retinal hemorrhages can be the splinter variants that occur in the nerve fiber layer, but more commonly, they are the dot and blot type and occur predominantly in the outer plexiform layer (Fig. 5.34). They are caused by leakage from microaneurysms and damaged retinal capillaries and

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venules. Hard exudates and retinal edema also occur primarily in the outer plexiform layer (Fig. 5.35). The hard exudates are constantly changing because of phagocytosis by macrophages. Cotton-wool spots in the nerve fiber layer can also be seen in many cases (Fig. 5.36). Intraretinal microvascular abnormalities are telangiectatic capillary and small vessel changes seen in severe nonproliferative disease (Fig. 5.37).

Figure 5.33. A: Fundus of an eye with background diabetic retinopathy. B: The fluorescein angiogram at approximately 1 minute after injection reveals multiple foci of pinpoint hyperfluorescence occurring secondary to the filling of microaneurysms with dye. C: At more than 8 minutes after injection, there is diffuse intraretinal leakage of dye from the microaneurysms.

Retinal edema in the macula is commonly referred to as macular edema. When cystoid changes are visible, it is called cystoid macular edema. The Early Treatment Diabetic Retinopathy Study (ETDRS) emphasized an important term: clinically significant macular edema (Figs. 5.38 and 5.39). Eyes with clinically significant macular edema benefit from focal laser therapy. Clinically significant macular edema is determined ophthalmoscopically (not by fluorescein angiography) and is defined as:

Retinal thickening within 500 m of the center of the fovea (Fig. 5.39A) or

Hard exudation within 500 m of the center of the fovea if associated with retinal thickening (Fig. 5.39B) or

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Retinal thickening 1 disc area, any part of which is located within 1 disc diameter (1,500 m) from the center of the fovea (Fig. 5.39C).

Figure 5.34. Retinal hemorrhages with background diabetic retinopathy. Most intraretinal hemorrhages are dot and blot types, although a streak hemorrhage in the nerve fiber layer can be seen superotemporal to the optic disc. Multiple foci of yellow, hard exudate are also evident.

Figure 5.35. Hard exudates seen in diabetic retinopathy are located primarily in the outer plexiform layer of the retina. (Hematoxylin and eosin stain; original magnification 40.)

Figure 5.36. A: Cotton-wool spots in the nerve fiber layer of the retina in an eye with background diabetic retinopathy. B: Within 47 seconds after injection, the fluorescein angiogram of the eye in (A) reveals multiple foci of relative hypofluorescence corresponding to areas of retinal capillary nonperfusion in the regions of the cotton-wool spots.

The term preproliferative (i.e., advanced or severe nonproliferative) diabetic retinopathy has been used to describe eyes that are at high risk of developing posterior segment neovascularization. Among the important signs of preproliferative retinopathy are numerous retinal hemorrhages in all four quadrants, venous abnormalities such as beading (Fig. 5.37) in two or more quadrants or loops (Fig. 5.40), and intraretinal microvascular abnormalities in one or more quadrants. The ETDRS found that the presence of one or more of these signs indicated a 50% or higher risk of developing proliferative retinopathy within 1 year.

In proliferative diabetic retinopathy, the eyes demonstrate, singularly or in combination, neovascularization of the disc (NVD), neovascularization of the retina (neovascularization elsewhere [NVE]), or neovascularization of the iris (NVI).

NVD arises from the optic disc or from the retina within 1 disc diameter of the optic disc (Fig. 5.41). It can grow along the posterior hyaloid face or anteriorly within Cloquet's canal. NVE arises from the retinal capillaries and veins and, less commonly, from the arteries. It grows through the internal limiting membrane of the retina to attach to the posterior hyaloid face (Fig. 5.42). Ninety percent of the posterior segment neovascularization seen with proliferative diabetic retinopathy is found within 6 disc diameters of the optic disc. As is the case with other proliferative retinopathies, the new vessels appear to stimulate contracture of the overlying vitreous, which subsequently places traction on the vessels and results in preretinal or vitreous hemorrhage (Fig. 5.43).

Figure 5.37. Telangiectatic vascular abnormalities (i.e., intraretinal microvascular abnormalities) in an eye with diabetic retinopathy. Venous beading is prominent.

The Diabetic Retinopathy Study (DRS) identified certain posterior segment neovascular features that portended a particularly high risk of developing severe visual acuity loss (<5/200). These high-risk characteristics were as follows:

NVD greater than or equal to one fourth to one third of a disc area (one fourth of a disc area in eyes with large optic

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discs and one third of a disc area in eyes with small optic discs; Fig. 5.44) or

NVD of any size associated with preretinal or vitreous bleeding (Fig. 5.45) or

NVE at least 0.5 disc area and associated with preretinal or vitreous bleeding (Fig. 5.46).

Figure 5.38. Diabetic fundus with clinically significant macular edema. The central, hard exudate is associated with retinal thickening.

Figure 5.39. Clinically significant macular edema. A: Retinal thickening within 500 m of the center of the fovea. B: Hard exudates, associated with retinal thickening, are located within 500 m of the center of the fovea. C: Retinal thickening greater than 1 disc area, part of which is located within 1 disc diameter from the center of the fovea. (Courtesy of the Early Treatment Diabetic Retinopathy Study Group.)

Figure 5.40. A: Venous loop in an eye with severe, nonproliferative diabetic retinopathy. B: In the fluorescein angiogram corresponding to (A), obtained almost 17 seconds after injection, retinal capillary nonperfusion is evident adjacent to the loop.

Figure 5.41. Pronounced neovascularization of the disc in an eye with proliferative diabetic retinopathy.

Figure 5.42. A: Neovascularization of the retina along the inferotemporal arcade in the fundus of an eye with proliferative diabetic retinopathy. B: The fluorescein angiogram obtained 24 seconds after injection reveals hyperfluorescence of the new vessels and retinal capillary nonperfusion adjacent and peripheral to the new vessels. C: Within 109 seconds after injection, the fluorescence of the neovascularization becomes more intense, and widespread retinal capillary nonperfusion is evident.

Entities that can mimic diabetic retinopathy include radiation retinopathy, central retinal vein obstruction, the ocular ischemic syndrome, hypertensive retinopathy, and retinopathy of anemia. Sarcoidosis, Eales disease, and talc retinopathy can cause changes similar to those seen with proliferative diabetic retinopathy.

Figure 5.43. Traction on optic disc neovascularization by the vitreous gel in an eye with proliferative retinopathy. Intravitreal blood is also seen. (Hematoxylin and eosin stain; original magnification 40).

Management

Strict glucose control can help to prevent the onset and progression of diabetic retinopathy. With a mean follow-up time of 6.5 years, the Diabetes Control and Complications Research Group demonstrated that strict glucose control in type I diabetics can reduce the chance of development of retinopathy by 76% and slow the progression in those who already have retinopathy by 54%. It also reduced the manifestations of nephropathy by approximately 50% and neuropathy by 60%.

Figure 5.44. High-risk neovascularization of the optic disc is neovascularization greater than 25% to 33% of the disc area. (Courtesy of the Diabetic Retinopathy Study Group.)

Figure 5.45. Neovascularization of the disc associated with preretinal bleeding.

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For eyes with clinically significant macular edema or high-risk proliferative diabetic retinopathy, the mainstay of therapy is laser photocoagulation. The ETDRS demonstrated that eyes with clinically significant macular edema benefit from focal laser photocoagulation therapy. Microaneurysms within the temporal vascular arcade are treated directly with 50- to 100- m spot burns, and 100- m burns in the form of a grid pattern (burns spaced 0.5 burn width apart) are applied to areas of diffuse leakage or nonperfusion (Figs. 5.47 and 5.48). Nonperfused areas involving the fovea are not treated.

The ETDRS demonstrated that, at the end of 3 years, the progression of visual loss is halved with laser therapy in eyes with clinically significant macular edema. Overall, 12% of treated eyes had a doubling of the visual angle (e.g., 20/20 to 20/40, 20/40 to 20/80) during this period, whereas the corresponding rate for untreated eyes was 24%.

The DRS showed that eyes with high-risk characteristics benefited from full-scatter (i.e., panretinal) laser photocoagulation. In general, 1,500 to 2,000 burns, each approximately 500 m in diameter, are applied to the peripheral retina, outside the macula (Fig. 5.49). Clinically significant macular edema should be treated concomitantly or, if possible, before starting panretinal treatment. Panretinal photocoagulation can also promote regression of iris neovascularization and therefore has the potential to stabilize or prevent neovascular glaucoma.

Figure 5.46. Neovascularization of the retina associated with preretinal bleeding into the subhyaloid space.

Figure 5.47. Focal treatment for the microaneurysmal abnormalities in an eye with background diabetic retinopathy and clinically significant macular edema.

Among eyes with high-risk characteristics that were treated with panretinal photocoagulation, the incidence of severe visual loss (acuity 20/800) over a 5-year period was halved compared with the control eyes, which did not receive laser treatment. The percentage of eyes with severe visual loss at last follow-up was reduced from 30% to 15% with treatment. The complications of panretinal photocoagulation include decreased dark adaptation, peripheral visual field loss (i.e., construction of visual field), and decreased central vision (i.e., loss of visual acuity), primarily resulting from exacerbation of preexisting macular edema.

Pars plana vitrectomy can benefit eyes with proliferative diabetic retinopathy if there is significant nonclearing vitreous hemorrhage or macular retinal detachment, or if traction retinal detachment is threatening to occur (Fig. 5.50). Vitrectomy also is used if there is rubeosis iridis with an open anterior chamber angle and media opacification (e.g., vitreous hemorrhage) that would preclude delivery of panretinal photocoagulation. The Diabetic Retinopathy Vitrectomy Study (DRVS) demonstrated that, when the visual acuity is 20/800 or less secondary to vitreous hemorrhage, type I diabetic patients benefit more from early vitrectomy (1 to 2 months) than from waiting 6 months or longer for the hemorrhage to clear. Type II diabetic patients with dense vitreous hemorrhage can probably wait several months to allow spontaneous clearing unless there is underlying macular-threatening traction retinal detachment or some other condition, such as iris neovascularization, that necessitates earlier surgery. Overall, approximately 80% of eyes that undergo vitrectomy for nonclearing vitreous hemorrhage experience at least a two-line improvement in vision. The corresponding figure for traction retinal detachment is approximately 60%. Eyes with severe proliferative disease appear to have a better chance of retaining good vision

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with early vitrectomy (i.e., 44% had 20/40 vision 4 years after surgery) versus delayed vitrectomy (i.e., 28% had 20/40 vision), but the possibility of total visual loss as a result of the surgical procedure must be considered.

Figure 5.48. A: Grid pattern of focal therapy for diffuse, clinically significant diabetic macular edema. B: Fluorescein dye demonstrates that the microaneurysms and areas of retinal capillary nonperfusion have been treated. The eye had already received panretinal photocoagulation because of high-risk characteristics of proliferative diabetic retinopathy. C: Several months after (A), the hard exudate has been absorbed by macrophages.

Figure 5.49. Argon laser, full-scatter, panretinal photocoagulation in an eye with proliferative diabetic retinopathy. The burns are located approximately one half of a burn width apart.

Figure 5.50. A: Proliferative diabetic retinopathy with traction retinal detachment in the macula. B: After vitrectomy, the retina is flat.

Hypertensive Retinopathy

Many researchers have attempted to classify the changes seen with hypertensive retinopathy. One popular system is that described by Keith, Wagener, and Barker in 1939.

Clinical Features

Keith, Wagener, and Barker stratified the hypertensive changes into four groups (Figs. 5.51, 5.52, 5.53, 5.54):

Group I: minimal narrowing of the retinal arteries

Group II: narrowing of the retinal arteries in conjunction with regions of focal narrowing and arteriovenous nicking

Group III: abnormalities seen in groups I and II, as well as retinal hemorrhages, hard exudation, and cotton-wool spots

Group IV (i.e., malignant hypertension): abnormalities encountered in groups I through III, as well as swelling of the optic nerve head

The changes seen in groups I and II are typically chronic, and those encountered in groups III and IV are seen with more acute rises in blood pressure. In an adult, diastolic blood pressure 110 mm Hg is usually necessary to induce the fundus changes seen in group III, and diastolic pressure 130 mm Hg usually correlates with the changes in group IV. The changes of groups III and IV can be seen in younger individuals at lower blood pressures.

Keith, Wagener, and Barker evaluated patients with hypertensive retinopathy before the use of effective antihypertensive regimens. In essentially untreated groups, they found the 3-year survival rates to be 70% for group I, 62% for group II, 22% for group III, and 6% for group IV. With the development and use of modern antihypertensive medications, survival rates have improved in all groups.

Figure 5.51. In grade I hypertensive retinopathy, the retinal arteries and arterioles have become narrowed.

Figure 5.52. In grade II hypertensive retinopathy, the retinal arteries are narrowed, and arteriovenous nicking is evident.

Hypertensive choroidopathy frequently accompanies hypertensive retinopathy when the changes of group IV, and sometimes those of group III, are present. In the acute phase, yellow spots are visible at the level of the retinal pigment epithelium (Fig. 5.55). They are hyperfluorescent on fluorescein angiography and appear to occur secondary to fibrinoid necrosis within the choriocapillaris, leading to damage to the overlying retinal pigment epithelium. In severe cases, the intense leakage of plasma from these foci contributes to serous retinal detachment (Fig. 5.55). Over a period of weeks, these spots become pigmented or depigmented (Fig. 5.56). When the spots occur in a linear fashion, they are referred to as Siegrist's streaks.

Management

Treatment includes control of the blood pressure. With adequate systemic treatment, the fundus changes seen in groups III and IV resolve over a period of weeks to months. If visual acuity is affected in the short term, some improvement may be expected with resolution of the fundus changes such as the serous retinal detachments. However, visual recovery may be limited by retinal pigment epithelial disruption in the macula or optic nerve damage. Local ocular treatment has not been beneficial.

Figure 5.53. Grade III hypertensive retinopathy. The eye has retinal hemorrhages and hard exudates in the form of a hemimacular star.

Figure 5.54. A: Grade IV hypertensive retinopathy. In addition to the changes seen with grade III retinopathy, the optic disc is swollen. A serous retinal detachment has occurred inferiorly. B: In a fluorescein angiogram obtained approximately 17 seconds after injection, retinal capillary nonperfusion is marked. C: At more than 3 minutes after injection, the dye is seen leaking from the retinal vessels.

Figure 5.55. A: Acute hypertensive choroidopathy. Yellow, acute Elschnig's spots can be seen at the level of the retinal pigment epithelium. B: The fluorescein angiogram corresponding to (A) reveals leakage of dye corresponding to the yellow spots.

Figure 5.56. Chronic Elschnig's spots, characterized by pigmentary changes at the level of the retinal pigment epithelium.

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Peripheral Proliferative Retinopathies

Peripheral proliferative retinopathies are characterized by retinal neovascularization peripheral to the temporal vascular arcades. Although the predisposing factors are similar to those causing neovascularization of the optic disc and iris, the presence of concomitant optic disc neovascularization precludes the diagnosis. Sickle cell disease is the most common case of peripheral proliferative retinopathy.

Clinical Features

Peripheral proliferative retinopathy is seen in conjunction with a variety of systemic or ocular vascular conditions that have in common the potential to shut down the retinal vascular bed. This includes inflammatory conditions, such as sarcoidosis and pars planitis, that can lead to retinal vascular compromise.

In about 90% of cases, an underlying cause can be found. In the series of Brown and associates, sickle cell disease accounted for 49% of cases of peripheral retinal neovascularization. Other associated disorders included branch retinal vein obstruction (20%), diabetic retinopathy (9%), sarcoidosis (4%), intravenous drug abuse (4%; Fig. 5.57), ocular ischemic syndrome (1%), pars planitis (1%), Coats' disease (1%), and retinitis pigmentosa (1%). A list of disorders associated with peripheral retinal neovascularization is shown in Table 5.1.

Proliferative sickle retinopathy deserves special mention. Peripheral retinal neovascularization is seen most commonly in patients with hemoglobin SC disease, followed in order by hemoglobin SThal and hemoglobin SS disease. Approximately 29% of patients older than 50 years of age with sickle cell hemoglobinopathy have peripheral proliferative disease (Fig. 5.58). Signs of nonproliferative sickle retinopathy may accompany the proliferative changes and include salmon patches (Fig. 5.59), acute retinal hemorrhages that occur secondary to ruptured retinal vessels. When the hemorrhages are in the superficial retina, they can lead to iridescent spots, which are fine crystalline deposits under the internal limiting membrane of the retina that become evident as the blood resorbs. When the bleeding dissects to the level of the retinal pigment epithelium, a black sunburst (Fig. 5.60) or focal pigment epithelial hypertrophy may develop after the subretinal hemorrhage resolves.

Figure 5.57. Talc particles are evident in the small retinal vessels of an eye of a chronic intravenous drug abuser with peripheral retinal neovascularization.

Table 5.1. Conditions Associated with Peripheral Retinal Neovascularization

Sickle cell hemoglobinopathies
   Hemoglobin SC
   Hemoglobin S thalassemia
   Hemoglobin SS
   Hemoglobin AS
   Hemoglobin AC
   Hemoglobin CB thalassemia
Diabetes mellitus
Venous obstructive disease
Inflammatory diseases
   Sarcoidosis
   Pars planitis
   Bird-shot chorioretinopathy
   Beh et's disease
   Acute retinal necrosis
Collagen vascular disease
   Systemic lupus erythematosus
   Scleroderma
Embolic disease
   Intravenous drug abuse
   Rheumatic fever
Arterial obstructive disease
   Ocular ischemic syndrome large-vessel obstructive disease (e.g., aortic arch, carotid artery, ophthalmic artery)
   Branch retinal artery obstruction
Miscellaneous
   Retinopathy of prematurity
   Familial exudative vitreoretinopathy
   Eales disease
   Incontinentia pigmenti
   Chronic retinal detachment
   Retinitis pigmentosa
   Leukemia
   Radiation-induced retinopathy

The stages of proliferative sickle retinopathy have been classified by Goldberg:

Stage I: retinal capillary nonperfusion and other background changes

Stage II: arteriolar-venular anastomoses at the juncture of perfused and nonperfused retina

Stage III: peripheral retinal neovascularization

Stage IV: vitreous hemorrhage

Stage V: traction or rhegmatogenous retinal detachment

Eyes with peripheral proliferative retinopathy can have reduced vision secondary to vitreous hemorrhage, retinal detachment, macular edema, or retinal capillary nonperfusion involving the macula.

Management

A workup to determine the underlying cause should be undertaken for patients with peripheral proliferative retinopathy. The history alone often reveals the associated systemic disease, but a laboratory workup may be

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necessary, including but not be limited to a complete blood count, fasting blood glucose level, hemoglobin electrophoresis, chest x-ray film, and angiotensin-converting enzyme level.

Figure 5.58. A: Peripheral retinal neovascularization in the eye of a patient with hemoglobin SC disease. B: The fluorescein angiogram corresponding to (A), obtained 29 seconds after injection, reveals hyperfluorescence of the seafan-shaped neovascularization and peripheral retinal capillary nonperfusion that extends posteriorly to the posterior border of the seafan. Arteries that supply seafans are typically more tortuous (i.e., superior vessel) than the draining veins (i.e., inferior vessel).

Figure 5.59. Retinal hemorrhage, also referred to as a salmon patch, in the eye of a patient with sickle hemoglobinopathy.

Figure 5.60. A black sunburst occurs as a sequela of a salmon patch.

Scatter laser photocoagulation in the areas of retinal capillary nonperfusion has decreased the incidence of vitreous hemorrhage in eyes with proliferative sickle retinopathy. The same result has been demonstrated when the neovascularization occurs secondary to branch retinal vein obstruction. Eyes with diabetes-related retinal neovascularization and preretinal bleeding also benefit from scatter laser therapy.

Prospective clinical trials have not been performed to demonstrate the efficacy of preventing visual loss in eyes with peripheral retinal neovascularization from many of the causes listed in Table 5.1, although many clinicians believe that the data from studies with diabetic retinopathy, sickling hemoglobinopathy, and branch retinal vein obstruction can be extrapolated to these other conditions.

As with proliferative diabetic retinopathy, vitrectomy may be beneficial in instances of nonclearing vitreous hemorrhage or retinal detachment associated with the other causes of peripheral proliferative retinopathy.

Retinal Vasculitis

Vasculitis refers to inflammation of the blood vessels. The site of involvement may occur predominantly on the arterial side of the retinal circulation, the venous side, or both. In some instances, the vasculitis appears to affect the retinal vasculature alone, but in others, the ocular changes are a manifestation of a widespread systemic vasculitis that affects multiple organs.

Figure 5.61. A: Macula of a patient with retinal arteritis and phlebitis as a result of Crohn's disease. Retinal whitening secondary to obstruction of a retinal arteriole is seen in the papillomacular bundle. B: Same fundus as in (A), 2 months later. Sheathing of the retinal vessels, particularly the veins, is conspicuous. C: In the fluorescein angiogram corresponding to (B), prominent staining of the sheathed retinal veins can be seen. D: A more peripheral fluorescein angiographic view demonstrates an area of confluent retinal capillary nonperfusion.

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Clinical Features

There is an overlap between the arterial and venous changes seen with retinal vasculitis, although certain signs are seen more frequently with one type than another. The signs of retinal arteritis include arterial sheathing, arterial attenuation, cotton-wool spots, and superficial retinal opacification secondary to obstruction of larger arterioles and arteries. The signs of retinal phlebitis include retinal hemorrhages, retinal edema, telangiectases, microaneurysms, venous sheathing, venous dilations, and venous attenuation. Commonly, some combination of arterial and venous changes are seen (Fig. 5.61). Conditions that mainly affect the retinal veins include sarcoidosis (Fig. 5.62), multiple sclerosis, pars planitis, Eales disease, acute frosted retinal periphlebitis, and Crohn's disease. Conditions that result primarily in the signs of retinal arteritis include systemic lupus erythematosus, polyarteritis nodosa, and Beh et's syndrome.

Figure 5.62. Sarcoidosis-related retinal phlebitis with perivascular exudates known as candle-wax drippings.

Other signs of retinal vasculitis are anterior uveitis, cells in the vitreous cavity, and retinal or optic disc neovascularization. The neovascularization usually is associated with significant or widespread shutdown of the retinal vascular bed. Disorders causing vasculitis are shown in Table 5.2. The workup includes a careful history, physical examination, and appropriate laboratory evaluation.

Management

Regardless of whether there is active disease elsewhere, significant posterior segment vasculitis changes that affect or threaten vision may warrant the use of systemic corticosteroids. Although periocular steroids may be sufficient to control some cases, topical agents alone usually

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do not make a significant impact on posterior segment changes. In more advanced stages, when there is retinal capillary nonperfusion and retinal or optic disc neovascularization, full-scatter laser photocoagulation applied to the areas of retinal capillary nonperfusion may help to stabilize or cause regression of the neovascularization.

Table 5.2. Conditions Associated with Retinal Vasculitis

Infectious associations
   Herpes zoster virus
   Herpes simplex virus
   Cytomegalovirus
   Acquired immunodeficiency syndrome
   Syphilis
   Tuberculosis
   Toxoplasmosis
Collagen vascular diseases
   Systemic lupus erythematosus
   Polyarteritis nodosa
   Wegener's granulomatosis
   Giant cell arteritis
   Scleroderma
Other systemic diseases
   Diabetes mellitus
   Sarcoidosis
   Beh et's disease
   Multiple sclerosis
   Malignancy
   Ocular ischemic syndrome
   Crohn's disease
   Ankylosing spondylitis
   Goodpasture's syndrome
   Churg-Strauss syndrome
   L ffler's syndrome
   Whipple's disease
Miscellaneous
   Acute frosted retinal periphlebitis
   Eales disease
   Pars planitis
   Idiopathic conditions
Adapted from Brown GC. Retinal vasculitis. In: Margo CE. Diagnostic problems in clinical ophthalmology. Philadelphia: WB Saunders, 1994, with permission.

Figure 5.63. Slit lamp view of the anterior portion of a persistent hyaloid artery in an adult eye. Despite its appearance, the vessel was not filled with blood.

Congenital Malformations

Persistent Hyaloid Artery

During embryogenesis, the hyaloid artery gives rise to the vasa hyaloidea propria, which nourishes the primary vitreous, and the tunica vasculosa lentis, the series of vessels nourishing the lens. These two sets of vessels later regress, followed by regression of the hyaloid artery itself; the hyaloid artery usually regresses by 8.5 months of gestation. In approximately 3% of full-term neonates, the hyaloid artery still contains blood.

Clinical Features

A persistent hyaloid artery appears clinically as a sinuous single vessel extending from the optic disc, through Cloquet's canal, to insert on the posterior capsule of the lens. Its point of insertion on the capsule is called a Mittendorf's dot. In the adult, the vessel is usually bloodless (Fig. 5.63). Occasionally, it is blood-filled. Vitreous hemorrhage has been reported in adults with a blood-filled persistent hyaloid artery.

Persistent hyaloid arteries can be confused with larger, congenital precapillary arterial loops. Loops, however, have afferent and efferent branches and typically do not extend more than 5 mm into Cloquet's canal. Neovascularization of the optic disc occasionally also manifests with large vessels growing into Cloquet's canal. These are associated with proliferative disorders such as diabetic retinopathy, retinal vein obstruction, and the ocular ischemic syndrome from carotid artery obstruction.

Management

For most cases, no treatment is required for a persistent hyaloid artery. If a severe vitreous hemorrhage develops, pars plana vitrectomy may be necessary to facilitate clearing of the hemorrhage and restoration of visual acuity.

Figure 5.64. Prepapillary arterial loop surrounded by a fibroglial sheath that is probably a remnant of Bergmeister's papilla. The optic disc is pale, and the cilioretinal artery is sheathed secondary to the effects of toxemia of pregnancy 15 years earlier.

Figure 5.65. The prepapillary arterial loop is associated with a branch retinal arterial obstruction in the quadrant of the retina supplied by the loop.

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Prepapillary Vascular Loops

Prepapillary vascular loops can be arterial or venous. The venous variant can be congenital or acquired. Acquired venous prepapillary vascular loops usually are multiple and referred to as optociliary collateral vessels.

Clinical Features

Congenital prepapillary loops are usually unilateral and single, and have an afferent and efferent limb that extend into Cloquet's canal. They vary in height from 0.5 to 5.0 mm (Fig. 5.64). Approximately one third are pulsatile, and about half are enclosed in a glial-appearing sheath that is probably a remnant of Bergmeister's papilla. Although some have a venous appearance, 95% are arterial. Seventy-five percent of affected eyes also have at least one cilioretinal artery.

The major complication associated with prepapillary arterial loops is retinal arterial obstruction in the sector of the retina supplied by the loop (Fig. 5.65). Approximately 10% of cases of loops reported have been associated with arterial obstruction. Amaurosis fugax has been described, as has vitreous hemorrhage, particularly in association with posterior vitreous detachment.

Figure 5.66. A: Multiple optociliary collateral veins on the optic disc developed after a branch retinal vein obstruction. B: The fluorescein angiogram reveals telangiectatic abnormalities in the superior macula. A hyperfluorescent area of retinal neovascularization is present along the vascular arcade inferotemporal to the optic disc.

Figure 5.67. Multiple optociliary collateral veins are seen on a pale optic disc in the eye of a patient with a central nervous system meningioma. Macular retinal pigment epithelial changes resulted from a retinal venous obstruction.

When multiple prepapillary loops are seen on the disc, they are almost always venous and acquired (Fig. 5.66). These optociliary collaterals arise secondary to retinal venous obstructive disease. They have been demonstrated to drain into the peripapillary choroidal circulation. Underlying causes include central retinal vein obstruction, branch retinal vein obstruction, optic nerve meningioma and glioma, glaucoma, and increased intracranial pressure. Optociliary collaterals associated with progressive visual loss and optic nerve pallor should increase the physician's index of suspicion concerning a possible optic nerve meningioma (Fig. 5.67).

A persistent hyaloid artery should not be confused with a prepapillary loop. The hyaloid artery is a single vessel that extends anteriorly to the posterior lens capsule.

Neovascularization of the optic disc can occasionally mimic a prepapillary loop when it extends into Cloquet's canal. Neovascularization is typically associated with abnormalities such as diabetic retinopathy, retinal venous

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obstruction and the ocular ischemic syndrome resulting from carotid artery obstruction. Neovascularization of the disc leaks on fluorescein angiography, but prepapillary loops do not leak fluorescein.

Figure 5.68. A: Grade I arteriovenous communication of the retina (retinal macrovessel). An enlarged retinal vein traverses the horizontal raphe, and a small foveolar cyst is present. B: Fluorescein angiogram reveals the small arteriovenous communication bordering the superior foveal avascular zone. A small focus of hyperfluorescence corresponds to the foveolar cyst.

Management

No specific ocular treatment is indicated for prepapillary loops. With multiple venous loops associated with progressive visual loss and optic nerve pallor, imaging should be considered to rule out the possibility of an optic nerve tumor. Chronic papilledema from increased intracranial pressure should also be entertained as a possible cause for venous loops in this setting.

Congenital Retinal Arteriovenous Communications

A congenital retinal arteriovenous communication is an enlarged retinal vessel that acts as a shunt between the retinal arterial and venous circulations. The disorder typically occurs unilaterally.

Clinical Features

Archer and associates classified congenital arteriovenous communications of the retina into three groups.

Figure 5.69. A: Grade II arteriovenous communication of the retina. B: The large communication extends to the midperipheral retina.

Group 1 arteriovenous communications are the mildest variant and, clinically, can be very subtle. They are most readily recognized by their association with congenital retinal macrovessels, large retinal vessels (usually veins) that cross the horizontal raphe (Fig. 5.68). Foveolar cysts, which may be transient, have been seen with this abnormality and usually only mildly reduce the visual acuity.

Group 2 arteriovenous communications (Fig. 5.69) are larger than those of group 1. Each communication appears as a large vessel that leaves the optic disc, traverses the retina, and then returns to the disc, and there can be multiple arteriovenous communications. The visual acuity is usually normal.

Group 3 arteriovenous communications (Fig. 5.70) are conglomerations of large vessels that can be so pronounced that they replace optic nerve tissue. The abnormality can change its configuration with time. The visual acuity can vary from normal to severe visual loss.

Ocular complications that have been observed with larger arteriovenous communications include central retinal vein obstruction, neovascular glaucoma, macular hole,

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macroaneurysmal abnormalities, retinal hemorrhage, and vitreous hemorrhage. The arteriovenous communications do not demonstrate leakage of dye during fluorescein angiography.

Figure 5.70. Grade III arteriovenous communication of the retina. Most of the optic nerve has been replaced by the enlarged vessels. Visual acuity testing revealed no light perception, and the patient also had an arteriovenous communication in the jaw. (Courtesy of Jerry Shields, M.D.)

The larger and more pronounced the communication, the greater the chance it is associated with an arteriovenous communication in the central nervous system, face, or skin. Wyburn-Mason's syndrome has been used to describe the retinal arteriovenous communication when it is associated with other systemic arteriovenous communications. Theron and associates observed that, among the 80 cases reported by 1974, 25 (30%) were seen in conjunction with central nervous system arteriovenous communications. They typically occur ipsilateral to the ocular lesion or in the midline, often following the visual pathway. Subarachnoid hemorrhage can result.

Facial arteriovenous communications have occurred in about 40% of patients with retinal and central nervous system arteriovenous communications. They can occur in the maxilla, mandible, buccal mucosa, palate, or nasopharynx. Recurrent epistaxis and bleeding can occur with dental extraction. Skin lesions have been detected in approximately 25% of patients with retinal and central nervous system arteriovenous communications.

Acquired retinal arteriovenous communications can occur with retinal arterial obstructive diseases, including sickle cell retinopathies, retinal venous obstructive disease, diabetic retinopathy, and the ocular ischemic syndrome resulting from carotid artery obstructive disease. Enlarged retinal vessels on the optic disc can be seen with retinal capillary hemangioma (i.e., von Hippel lesion), retinoblastoma, and choroidal melanoma.

Management

The ocular lesions themselves are usually observed. If macroaneurysmal abnormalities occur and there is retinal edema or hard exudation into the fovea, laser therapy applied to the aneurysms can be considered.

Unfortunately, the central nervous system lesions are most often located deeply, making surgical excision difficult. Dental extraction should be approached cautiously because of the possibility of severe hemorrhaging from an arteriovenous communication located in the maxilla or mandible.

Coats' Disease

Coats' disease is usually diagnosed between 2 and 16 years of age. In most cases, the diagnosis is made as a result of failing an eye test in school or, in infants, the appearance of a yellowish rather than red reflex. The disease occurs most often in boys, although girls may be affected. Unilaterality is the rule, but bilateral involvement does occur in about 8% of patients.

Clinical Features

Coats' disease is characterized by vascular abnormalities that appear as small, red light bulbs in the retinal periphery and by associated intraretinal and subretinal hard exudation (Fig. 5.71). The vascular changes include aneurysmal alterations, and on fluorescein angiography, capillary nonperfusion in the affected area of the retina is evident (Fig. 5.72). The exudate tends to accumulate in the posterior pole and the area of peripheral vascular abnormalities (Fig. 5.73).

The disease in children younger than 4 years of age may be expressed differently than in older children. Children younger than 4 years of age often present with leukocoria or strabismus and must be examined to rule out retinoblastoma. If the exudate is in the macular area, there is generally poor fixation in the affected eye. Although many eyes do not have an associated serous retinal detachment, some patients may present with a total retinal detachment, with the retina ballooned just behind the lens. In advanced cases for which there is no resolution of the disease after treatment, neovascularization of the iris may lead to neovascular glaucoma.

The most important disorder that must be differentiated from Coats' disease is the malignant intraocular tumor of infancy and childhood, retinoblastoma. The most difficult diagnostic scenario is when the retinoblastoma grows in an exophytic fashion, with the tumor primarily located beneath and detaching the retina.

Figure 5.71. Peripheral retinal telangiectasia of Coats' disease.

Figure 5.72. The fluorescein angiogram demonstrates nonperfusion in the area of a retinal vascular abnormality.

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Haik suggests that computed tomography scanning is the single most valuable test for deciding this diagnostic dilemma, because it can help establish the diagnosis of retinoblastoma by identifying calcified subretinal densities, vascularities within the subretinal space (with contrast enhancement), and any associated orbital or intracranial abnormalities. Magnetic resonance imaging can also be helpful in providing insights into the structure and composition of tissues, but it is limited in its ability to detect calcium.

Another condition that must be differentiated from Coats' disease is angiomatosis retinae or retinal capillary hemangioma. This vascular anomaly can produce significant exudation like that seen in Coats' disease. Multiple retinal angiomas presenting in young patients are likely to be part of the angiophakomatosis, von Hippel Lindau disease. This autosomal dominantly inherited condition is associated with visceral and central nervous system hemangioblastomas, with the latter occurring in about 18% of patients. Visceral cysts and tumors such as renal cell carcinoma and pheochromocytoma can also be part of this potentially life-threatening syndrome.

Cavernous hemangioma of the retina occurs in both sexes equally, is usually localized, has no associated exudation, and on fluorescein angiography, the lesion is demonstrated by dye within saccular vascular channels that do not exhibit any leakage.

Figure 5.73. Exudation in the posterior pole secondary to the abnormal vasculature seen in Figure 5.72.

Other conditions to be differentiated from Coats' disease include Toxocara endophthalmitis, persistent primary hyperplastic vitreous, familial exudative retinopathy, and retinopathy of prematurity (ROP). The diagnosis of these latter conditions can usually be made on the basis of the patient's history, clinical examination, and family history.

Management

Cryotherapy and laser photocoagulation applied to the areas of retinal telangiectasia have been used to reduce associated leakage. In our experience, cryotherapy has been more effective than laser therapy in cases with a significant amount of exudation. In cases with associated and frank retinal detachment, our preference is to perform cryotherapy for the abnormal vessels, external drainage of subretinal fluid, and scleral buckling to bring the retina into apposition with the pigment epithelium. Vitrectomy with internal drainage of subretinal fluid followed by photocoagulation or cryotherapy is also an option. Visual recovery in cases of massive retinal detachment is usually very limited.

Retinal Arterial Macroaneurysm

Retinal arterial macroaneurysm was first described as a distinct clinical entity in 1973 by Robertson.

Clinical Features

Acquired retinal arterial macroaneurysms appear as fusiform dilations of retinal arteries or larger arterioles. They usually are located in the posterior pole, and approximately 10% of cases are bilateral. Women comprise 70% to 80% of cases, and approximately two thirds of affected patients have systemic arterial hypertension. In approximately 20% of patients, there are multiple macroaneurysms in an eye. The disease most commonly occurs in the sixth decade and beyond.

Macroaneurysms can cause decreased vision through two mechanisms: hemorrhage and macular edema. About 50% of patients present initially with hemorrhage. Hemorrhaging usually occurs only once. Hemorrhage from a macroaneurysm can occur into the retina, the subretinal space, or the vitreous cavity. The location of the blood is likely to be determined by the site of rupture of the aneurysm and/or the amount of bleeding that occurs. A pattern seen in about 40% of eyes with hemorrhage is the hourglass hemorrhage, with blood at two or more levels in the posterior pole (Fig. 5.74). Approximately 50% of eyes with hemorrhage from a microaneurysm eventually achieve 20/40 vision, but about 25% remain at a level of counting fingers or worse. Bleeding into the subretinal spaces carries a worse visual prognosis than bleeding at other levels.

Retinal edema can extend into the central fovea and adversely affect the vision. Hard exudates can also accumulate from chronic leakage of plasma from the abnormality (Fig. 5.75A). Depending on the series, approximately 30% to

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60% of eyes have hard exudates at the time of diagnosis. If the central fovea is involved by edema, about 50% of eyes progress to 20/200 vision.

Figure 5.74. A: Subretinal and preretinal hemorrhage secondary to a ruptured retinal arterial macroaneurysm. The visual acuity was counting fingers. B: The fluorescein angiogram obtained 20 seconds after injection reveals prominent retinal vessels in the region of the subretinal blood, but the vessels are obscured in the area of preretinal blood. A small focus of hyperfluorescence along the course of a retinal artery corresponds to the macroaneurysm. C: Five weeks later, visual acuity had improved to 20/50 after reabsorption of much of the blood. D: The fluorescein angiogram of the eye in (C), obtained 34 seconds after injection, demonstrates that the macroaneurysm remains hyperfluorescent.

Fluorescein angiography typically reveals hyperfluorescence of the aneurysm that begins early and increases throughout the study (Fig. 5.75B). It can help to identify an aneurysm located along the course of a retinal artery when blood obscures the surrounding retina.

Figure 5.75. A: Retinal arterial macroaneurysm, with retinal edema and hard exudate involving the fovea. The visual acuity was 20/40. B: The fluorescein angiogram of the eye in (A), obtained 90 seconds after injection, reveals hyperfluorescence of the aneurysm.

Most retinal arterial macroaneurysms are 100 to 300 m in diameter, the size of some cerebral aneurysms. It is unknown whether people with retinal arterial macroaneurysms have a higher incidence of aneurysms elsewhere in the body.

Figure 5.76. Branch retinal arterial obstruction distal to a spontaneously thrombosed retinal arterial macroaneurysm.

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Disorders that can mimic a retinal arterial microaneurysm include macular branch retinal vein obstruction, choroidal neovascularization, and causes of posterior segment neovascularization that could lead to preretinal hemorrhage, such as diabetic retinopathy.

Arterial and venous macroaneurysms can occur within the retinal vasculature in the distribution of a previous branch retinal vein obstruction. They can also be seen in cases of Coats' disease, Eales disease, and angiomatosis retinae.

Management

Treatment is generally not indicated for hemorrhages that occur secondary to retinal arterial macroaneurysms, particularly because bleeding is a one-time event and the aneurysm often autothromboses after the hemorrhage.

Although a large prospective study on the natural course of the disease when retinal edema involves the central fovea is lacking, most clinicians consider performing laser therapy in this setting to facilitate resolution of the edema. Light gray burns using 200- to 500- m spots with the argon green laser can be applied to the aneurysm itself, although some prefer to surround the lesion. The major complication of treatment is obstruction of the retinal artery distal to the microaneurysm, which occurs in about one sixth of treated cases. However, retinal arterial obstruction can occur spontaneously (Fig. 5.76).

Parafoveal Telangiectasis

In 1956, Reese used the term retinal telangiectasis to describe a retinal vascular abnormality characterized by ectatic, incompetent retinal capillaries occurring in the macular or peripheral retina. In 1982, Gass and Oyakawa applied the term idiopathic juxtafoveolar retinal telangiectasis to the disorder, but it has since become more commonly referred to as parafoveal telangiectasis.

Clinical Features

It is thought that parafoveal telangiectasis can take two forms: congenital and acquired. Gass divided the condition into group 1 (A and B subgroups), group 2, and group 3.

Figure 5.77. Group 1A parafoveal telangiectasis. An area of circinate exudate is present in the temporal macula.

Group 1A is congenital unilateral parafoveal telangiectasis. This form typically presents in middle-aged men, and it produces macular edema and hard exudates that can extend as far as 2 or 3 disc diameters from the central fovea (Fig. 5.77). The entity may be a variant of Coats' disease. The median vision at the time of presentation is 20/40, but this can drop to 20/200.

Group 1B is acquired unilateral parafoveal telangiectasis. This subtle form also affects middle-aged men, usually involving only a single clock hour of the perifoveolar retina. Visual loss is minimal.

Group 2 is the most common form of parafoveal telangiectasis. This variant affects both sexes and is seen primarily during the sixth and seventh decades of life. It is typically bilateral and tends to involve the temporal fovea in each eye (Fig. 5.78). The retinal capillaries can be subtly dilated, and the retina in the involved area appears slightly gray. Retinal pigment epithelial hyperplasia develops with time. Choroidal neovascularization is found in about 14% of eyes at the time of presentation and can develop later in others (Fig. 5.79). The median visual acuity in eyes without choroidal neovascularization is 20/40. Rarely, a familial variant can be seen.

Group 3 includes patients with bilateral telangiectasis and retinal capillary nonperfusion. Some cases may represent a variant of cerebroretinal vasculopathy, as described by Grand and associates.

Included in the differential diagnosis of parafoveal telangiectasis are diabetic retinopathy, radiation retinopathy, Coats' disease, and age-related macular degeneration if retinal pigment hyperplasia or choroidal neovascularization is present.

The association of parafoveal telangiectasis and diabetes mellitus deserves special mention. Among parafoveal telangiectasis patients with normal fasting blood glucose levels, Millay and colleagues found that the glucose tolerance test was abnormal in 35% of those with unilateral disease and in

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more than 60% of those affected bilaterally. Green and associates demonstrated histopathologic accumulations of basement membrane in the retinal capillary walls, similar to the findings seen in eyes with diabetic retinopathy.

Figure 5.78. A: Group 2 parafoveal telangiectasis. Retinal thickening is present, predominantly in the temporal fovea, in this bilateral condition. B: The fluorescein angiogram obtained 25 seconds after injection reveals more discrete leakage of dye in the temporal fovea. C: Diffuse intraretinal leakage of dye within approximately 4 minutes after injection. (Courtesy of William Benson, M.D.)

Figure 5.79. A: Gray-black pigmentation in an area of choroidal neovascularization in an eye with parafoveal telangiectasis. B: The fluorescein angiogram obtained 45 seconds after injection reveals marked hyperfluorescence centrally, corresponding to the choroidal neovascularization, and less intense hyperfluorescence surrounding the neovascular membrane, reflecting a disturbance in the retinal pigment epithelium. (Courtesy of William Benson, M.D.)

Management

Laser therapy may benefit group 1A cases that are likely a variant of Coats' disease. It is probably of minimal benefit for the other variants. Treatment of associated choroidal neovascularization may also be necessary in selected cases. The relation between diabetes mellitus and parafoveal telangiectasis should not be forgotten, because some of these patients may eventually develop frank diabetes.

Radiation Retinopathy

Radiation retinopathy appears to occur primarily as a result of retinal vascular damage. Radiation optic neuropathy is a variant that can also be seen with radiation retinopathy, and choroidopathy can occur as well. The abnormality can occur secondary to external beam irradiation (i.e., teletherapy) or localized plaque therapy (i.e., brachytherapy).

Although many clinicians are familiar with the term rad to quantify radiation doses, the term centigray (cGy) has supplanted it; 1 rad equals 1 cGy.

Figure 5.80. A: Radiation retinopathy occurring after external beam irradiation (i.e., teletherapy) is manifested by peripapillary cotton-wool spots and retinal hemorrhages. B: The fluorescein angiogram reveals peripapillary retinal capillary nonperfusion. C: Same fundus as in A, several months later. D: A repeat fluorescein angiogram reveals extensive retinal capillary nonperfusion. The eye eventually developed iris neovascularization and neovascular glaucoma.

Figure 5.81. Hard exudation, retinal sheathing, retinal hemorrhages, and telangiectases occurred in an eye with radiation retinopathy.

Clinical Features

The posterior segment signs seen with radiation retinopathy include cotton-wool spots, retinal hemorrhages, hard exudates, microaneurysms, retinal vascular telangiectasias, vascular sheathing, macular edema, and neovascularization of the optic disc or retina (Fig. 5.80). Hard exudation appears to be more pronounced after brachytherapy than teletherapy (Figs. 5.81 and 5.82).

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Retinal pigment epithelial changes are commonly seen, and central retinal artery obstruction and central retinal vein obstruction have rarely been reported.

Figure 5.82. Equator-plus photograph of an eye with radiation retinopathy resulting from cobalt plaque irradiation (brachytherapy) for a choroidal melanoma. The hard exudation is extensive.

Radiation retinopathy is related to the radiation dose and the fraction size. Tissue damage appears to increase with dose fractions greater than 250 cGy/day of extreme beam irradiation. Retinopathy has been reported after as little as 1,100 cGy of external beam irradiation, but 3,000 to 3,500 cGy usually are necessary to induce changes. The mean dose given in cases of radiation retinopathy occurring after teletherapy is about 5,000 cGy. After 7,000 to 8,000 cGy, 85% of patients demonstrate posterior segment changes within several months. The administration of chemotherapy may exacerbate radiation retinopathy, even when not given concomitantly with the irradiation. Patients with a preexisting microangiopathy, such as from diabetes mellitus, appear to be more prone to vascular damage from irradiation.

The latency period from the administration of external beam irradiation to the development of radiation changes is approximately 18 months, with a range of 6 to 36 months. For brachytherapy, the mean time is about 15 months, with a range of 4 to 32 months.

Figure 5.83. Radiation optic neuropathy in a left eye occurred after brachytherapy for a superotemporal choroidal melanoma.

Figure 5.84. Acute radiation optic neuropathy is characterized by marked swelling of the optic disc and peripapillary hard exudate.

Fluorescein angiography may reveal areas of retinal capillary nonperfusion. In approximately 25% of eyes receiving external beam irradiation, the nonperfusion becomes so severe that iris neovascularization develops.

Radiation optic neuropathy can develop if the treatment is directed toward the anterior optic nerve (Fig. 5.83). Disc swelling can range from mild to severe, with striking peripapillary exudation in some cases (Fig. 5.84). The decrease in vision may be mild to severe, with approximately 20% of eyes demonstrating spontaneous improvement over several months.

The condition most likely to be confused with radiation retinopathy is diabetic retinopathy. Ophthalmoscopically, the two can be indistinguishable in some cases. Typically, there are more microaneurysms with diabetic retinopathy than with radiation retinopathy. Hypertensive retinopathy and central retinal vein obstruction can also present with a similar appearance.

The patient's history is essential for making the diagnosis of radiation retinopathy. Because of the latency, particularly when external beam irradiation is administered for neoplasms unassociated with the eye (e.g., oropharynx, brain), patients do not associate the radiotherapy with subsequent ocular changes.

Management

It has been suggested that focal grid laser therapy is of benefit in decreasing visual loss secondary to macular edema. Panretinal photocoagulation has been advocated when posterior segment neovascularization or iris neovascularization develops. Therapies such as hyperbaric oxygen and systemic corticosteroid treatment have not been shown to be consistently effective.

Retinopathy of Prematurity

Our knowledge of ROP began in 1942 with the work of Terry, who referred to the condition as retrolental fibroplasia. In the early 1950s, Campbell's observations implicated the use of oxygen in the newborn nursery as playing a role in the

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pathogenesis of the disease; these concerns were delineated in the reports of the Cooperative Study of Retrolental Fibroplasia. Insights into this potentially blinding disease continued to be published. It seems clear that the two primary risk factors for the development of ROP are low birth weight and prematurity. Babies weighing less than 1,500 g at birth and born at approximately 26 to 28 weeks of gestation are most likely to manifest ROP. Some degree of ROP is seen in 25% to 30% of infants weighing less than 1,500 g and in 65% of infants weighing less than 1,250 g at birth. Those weighing less than 800 g run the greatest risk of needing treatment.

A major advance toward better understanding and managing ROP occurred with the development of the International Classification of ROP. This classification divided the retina into zones 1, 2, and 3, with the optic nerve as the central focal point for each of the concentric circles that define the three zones. The acute or active phases of the disease itself was divided into five stages. Stage 1 is defined as a thin structure within the plane of the retina that separates vascularized from avascular retina. Stage 2 represents an elevated ridge that has extended beyond the plane of the retina. In stage 3, there is extraretinal fibrovascular proliferation or neovascularization at the ridge. In stage 4, there is a partial traction-like retinal detachment; stage 4A indicates extramacular retinal detachment, and stage 4B indicates macular involvement. Stage 5 is defined as a total retinal detachment in an open or closed funnel configuration.

The term plus disease denotes significantly dilated and tortuous retinal vessels in the posterior pole. It indicates extensive vascular incompetence, and can be associated with vitreous haze, iris vessel engorgement, and poor pupillary dilation. Plus disease is a poor prognostic sign.

The classification scheme also specified the extent of disease in terms of clock hours. Overall, the farther posterior and the more quadrants involved with neovascularization, the worse the prognosis.

Clinical Features

Critical for the ophthalmologist examining premature infants is the ability to recognize threshold disease, a term used to indicate the presence of plus disease (Fig. 5.85) with stage 3 changes greater than or equal to 5 contiguous or 8 cumulative clock hours (Fig. 5.86) in zone 1 or 2.

Figure 5.85. Dilated and tortuous arterioles and veins are in the posterior pole characteristic of plus disease. Occasionally, iris engorgement may occur; this is an additional sign of significant plus disease.

Figure 5.86. Stage 3 retinopathy of prematurity with extraretinal fibrovascular proliferation.

Figure 5.87. Clinical photograph of the neovascular popcorn posterior to the ridge in stage 2 retinopathy of prematurity.

Prethreshold or regressing ROP can sometimes be confused with threshold disease when small neovascular lesions (i.e., popcorn) are seen posterior to the ridge (Figs. 5.87 and 5.88). The major complications during the active, proliferative

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phases of ROP include vitreous hemorrhage and traction retinal detachment.

Figure 5.88. Gross histopathologic specimen of the neovascular popcorn seen in Figure 5.87.

Figure 5.89. Temporal dragging of the retina in a 10-year-old boy with regressed retinopathy of prematurity.

In eyes with regressed ROP, one of the hallmark changes is dragging of the retina (Fig. 5.89). This usually occurs in the temporal retina and often causes some dragging or distortion in the macula. An accentuated form of dragging in regressed ROP is a falciform fold (Fig. 5.90). Such a fold through the macula, retinal detachment, and retrolental tissue were all considered unfavorable outcomes in the Cryotherapy for Retinopathy of Prematurity Cooperative Group study. Chorioretinal scarring may also occur in the fundus periphery or the posterior pole (Fig. 5.91). Another serious late occurrence in adult patients with ROP is exudative retinal detachment, which most likely results from vitreous traction (Fig. 5.92). The eyes affected by ROP tend to have high degrees of myopia and late rhegmatogenous retinal detachments.

The differential diagnosis for ROP includes dominant fam-ilial exudative vitreoretinopathy (FEVR), X-linked retinoschisis, incontinentia pigmenti, combined hamartoma of the retinal pigment epithelium, persistent posterior hyperplastic vitreous, Norrie's disease, and retinoblastoma. Of these, FEVR is the most frequently seen. Retinal changes may simulate those seen in ROP (Fig. 5.93), but there is usually a history of normal birth weight and full-term gestation. Because of the usual dominant inheritance pattern, examination of family members helps to establish the diagnosis.

Figure 5.90. Temporal retinal fold. Vision is less than 20/200. This was considered an unfavorable outcome in the Cryotherapy for Retinopathy of Prematurity Cooperative Group study.

Figure 5.91. Chorioretinal scar in the posterior pole of a 36-year-old woman with retinopathy of prematurity. These scars have been confused with those secondary to toxoplasmosis.

Management

Treatment of active ROP has included cryotherapy and laser photocoagulation. With either modality, treatment is applied to the entire peripheral avascular zone of retina. Cryotherapy creates large confluent scars, with a loss of retinal pigment epithelium and choroid (Fig. 5.94), but laser therapy produces more discrete scars (Fig. 5.95). Laser treatment, delivered with the indirect ophthalmoscope, is easier to deliver, and because of much less direct ocular manipulation, it appears less stressful to the infant. Comparable rates of regression have been reported for both types of treatment. Overall, the Cryotherapy for Retinopathy of Prematurity Cooperative Group study showed that unfavorable outcomes were reduced by almost half for eyes treated with threshold disease, as compared to those that were observed.

Figure 5.92. Exudative retinal detachment in a 23-year-old, one-eyed woman with retinopathy of prematurity. Because exudative detachments are probably caused by vitreous traction, a scleral buckle procedure was performed, which included cryotherapy to the abnormal peripheral vessels. This led to resolution of the exudative retinal detachment.

Figure 5.93. Temporal dragging of the retina in a patient with familial exudative vitreoretinopathy.

Figure 5.94. A large, confluent chorioretinal scar formed after cryotherapy. The retinal pigment epithelium and choroid have been destroyed.

Figure 5.95. Diode laser photocoagulation scars 1 year after treatment.

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Wills Eye Hospital Atlas of Clinical Ophthalmology
The Wills Eye Hospital Atlas of Clinical Ophthalmology
ISBN: 078172774X
EAN: 2147483647
Year: 2001
Pages: 17

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