Chapter 118 – Ocular Ischemic Syndrome
MATTHEW T.S. TENNANT
GREGORY M. FOX
GARY C. BROWN
• Ocular signs and symptoms secondary to severe, chronic arterial hypoperfusion.
• Visual loss.
• Blot retinal hemorrhages.
• Dilated, beaded retinal veins.
• Decreased ocular perfusion pressure.
• Ocular neovascularization.
• Severe ipsilateral or bilateral carotid artery obstruction.
• Pain or ocular angina.
• Neovascular glaucoma.
• Corneal edema and striae.
• Mild anterior uveitis.
• Cherry-red spot in macula.
• Cotton-wool spots.
• Spontaneous pulsations of retinal arteries.
• Ischemic optic neuropathy.
Ocular ischemic syndrome is a condition that has a variable spectrum of signs and symptoms that result from chronic ocular hypoperfusion, usually secondary to severe carotid artery obstruction. Ocular signs and symptoms secondary to severe carotid artery obstruction, described in 1963 by Kearns and Hollenhorst, initially was called venous stasis retinopathy. Because other authors employed same the term to describe nonischemic central retinal vein occlusion, an entirely different condition, this nomenclature is best avoided. Additional names given to this condition include hypoperfusion retinopathy, hypotensive retinopathy, ischemic ocular inflammation, and ischemic oculopathy.
EPIDEMIOLOGY AND PATHOGENESIS
The ocular ischemic syndrome occurs at a mean age of 65 years and generally does not develop before 50 years of age. Men who have this condition outnumber affected women by a ratio of 2:1, which reflects the higher incidence of atherosclerotic cardiovascular disease in men. No racial predilection exists. Bilateral involvement occurs in 20% of cases. The incidence of ocular ischemic syndrome is not known precisely but is estimated at 7.5 cases per million population annually based on the work of Sturrock and Mueller.  Approximately 5% of patients who have hemodynamically significant carotid artery disease develop ocular ischemic syndrome.
The pathogenesis of the syndrome is decreased arterial inflow on a chronic basis. The period and extent of the impaired blood flow necessary to develop this syndrome still is not clear. Using color Doppler imaging, Ho et al. were able to study blood flow velocity and vascular resistance in the ocular circulation. Reversal of ophthalmic artery flow was demonstrated in 12 of 16 eyes studied, and all the studied eyes that had ocular ischemic syndrome had decreased peak systolic flow velocities of the central retinal artery. Reversal of flow within the ophthalmic artery represents collateralization through the external carotid artery system in response to obstructions in the internal carotid artery system. Moreover, Ho et al. were able to show that eyes that have significant visual loss demonstrate posterior ciliary artery hypoperfusion. Therefore, secondary ischemia of the optic nerve, choroid, retinal pigment epithelium, and outer segments of the photoreceptors is likely to result in the visual loss seen in ocular ischemic syndrome. Experimental blood flow studies of McFadzean et al. corroborate these findings, which suggest that posterior ciliary arterial hypoperfusion results in visual loss in ocular ischemic syndrome. In rare cases, color Doppler imaging detects isolated ophthalmic artery stenosis in patients who have ocular ischemic syndrome but no carotid artery disease.
Loss of vision is present in over 90% of affected patients at the time of evaluation. The visual loss generally occurs gradually, over a period of weeks to months, but can occur abruptly. Approximately 5% of patients have a previous history of amaurosis fugax.
The severity of the visual loss is variable. About 35% of affected eyes at the time of evaluation have a visual acuity of 20/40 (6/12) or better, while 30% range from 20/50 (6/15) to 20/400 (6/120). In the remaining 35%, acuity is sufficient to count fingers or worse. The absence of light perception is an uncommon finding initially but may develop as a sequela of severe posterior segment ischemia, often in combination with neovascular glaucoma. A prolonged time for recovery of vision after exposure to bright lights may occur in patients who have posterior segment ischemia.
A dull ache over the eye or brow is reported by up to 40% of patients who have ocular ischemic syndrome. The pain results from either ischemia of the globe or elevated intraocular pressure (IOP) caused by neovascular glaucoma. The pain associated with ocular ischemic syndrome, especially when IOP is normal, has been called ocular angina.
Anterior segment findings in ocular ischemic syndrome are common. Corneal edema and striae may not be present unless an increased pressure from neovascular glaucoma also is present. Approximately two thirds of eyes that have ocular ischemic syndrome have neovascularization of the iris at the time of initial examination by the ophthalmologist. However, this percentage may be deceptively high, because those who have asymptomatic milder involvement may not visit the ophthalmologist. In severe cases, ectropion uvea may develop. Flare in the anterior chamber commonly accompanies iris neovascularization. Iris neovascularization
Figure 118-1 Retinal vascular changes in ocular ischemic syndrome. Narrowed retinal arteries; dilated, minimally tortuous retinal veins; and blot retinal hemorrhages are present in an eye that is affected by ocular ischemic syndrome.
in the eye of a nondiabetic, with no evidence of venous occlusive disease or other predisposing cause, is suggestive of ocular ischemic syndrome.
Neovascular glaucoma, defined as neovascularization of the iris and an IOP greater than 22?mmHg, is seen in only one half of the patients with ocular ischemia who have neovascularization of the iris. Some patients who have neovascularization of the iris may develop complete closure of the anterior chamber angle with fibrovascular tissue, but the IOP remains normal. This phenomenon probably results from impaired ciliary body perfusion and decreased aqueous humor production as a consequence of carotid stenosis.
Anterior uveitis in eyes that have ocular ischemic syndrome has been described well. Iritis, present in 20% of these eyes, is generally mild. Flare is a more prominent feature than the cellular response, and keratitic precipitates are seen infrequently. In patients over 50 years of age who have new-onset iritis, the possibility of ocular ischemic syndrome must be considered.
Lens opacification, even formation of a mature cataract, may occur in the end stages of ocular ischemic syndrome. However, often at the time of evaluation little difference exists in the incidence of cataract between affected eyes and fellow eyes.
Signs in the posterior segment provide important clinical clues that suggest this diagnosis. Numerous signs can be seen in the fundus, which include the following:
• Retinal arterial narrowing
• Retinal venous dilation without tortuosity
• Retinal hemorrhages and microaneurysms
• Neovascularization of the optic disc or retina
• Cherry-red spot
• Cotton-wool spots
• Spontaneous pulsations of the retinal arteries
Retinal arterial narrowing and straightening, commonly associated with areas of focal constriction, are seen in eyes that have ocular ischemic syndrome. These signs can be difficult to differentiate from the narrowed vessels commonly seen in the elderly. Dilated retinal veins are seen frequently in eyes that display ocular ischemic syndrome. In ocular ischemic syndrome retinal veins also may have significant beading, similar to eyes that have preproliferative or proliferative diabetic retinopathy. In contrast to eyes that have central retinal venous occlusion, retinal venous tortuosity is not a prominent feature ( Fig. 118-1 ). Retinal hemorrhages are seen in 80% of eyes, most characteristically of a dot and blot variety located in the midperiphery, but they can extend into the posterior pole ( Fig. 118-2 ). Microaneurysms also
Figure 118-2 Retinal hemorrhages in ocular ischemic syndrome. Dot and blot hemorrhages, as well as microaneurysms, are seen commonly in the midperiphery of eyes that are affected by ocular ischemic syndrome.
are seen in the same locations. Neovascularization, which ranges from mild to severe, may occur on the optic disc in over one third of patients who have ocular ischemic syndrome. Retinal neovascularization has been described in 8% of eyes.
During examination, a cherry-red spot is seen in 12% of eyes that display ocular ischemic syndrome. This finding most commonly occurs as the IOP from neovascular glaucoma exceeds the central retinal artery’s perfusion pressure. Cotton-wool spots and spontaneous pulsations of the retinal arteries are each found in 5% of eyes that have the syndrome. When not present spontaneously, retinal arterial pulsations can be elicited easily by minimal pressure on the globe, because of the severe diminution in ocular perfusion pressure. In contrast, eyes that have nonischemic central retinal venous occlusion require a normal amount of digital pressure to induce retinal arterial pulsations.  In the past, ocular plethysmography was performed to assess ocular perfusion pressure quantitatively. It rarely is used now.
Ischemic optic neuropathy, which appears with acute, pale swelling of the disc, has been reported in an eye affected by ocular ischemic syndrome. Otherwise, the optic disc tends to be normal in appearance, unlike the disc edema seen with central retinal vein obstruction.
DIAGNOSIS AND ANCILLARY TESTING
In addition to clinical examination, fluorescein angiography can help to establish the diagnosis of ocular ischemic syndrome. Ideally, a delay in arm-to-choroid and arm-to-retina circulation times is demonstrated by fluorescein angiography, but variation in the location and speed of injection may make these times difficult to assess. However, demonstration of a well-demarcated leading edge of fluorescein dye within a retinal artery is very unusual for a normal eye and suggests ocular hypoperfusion ( Fig. 118-3 ). Patchy filling of the choroid that lasts more than 5 seconds is seen in about 60% of eyes affected by ocular ischemic syndrome ( Fig. 118-4 ).
Other findings on fluorescein angiography include an increased arteriovenous transit time, staining of the retinal vessels, macular edema, retinal capillary nonperfusion, and evidence of microaneurysms (especially in the periphery). The arteriovenous transit time exceeds 11 seconds in approximately 95% of affected eyes. Late staining of retinal vessels, more prominent in arterioles than in venules, is present in about 85% of cases ( Fig. 118-5 ).
Electroretinography demonstrates a decrease in both the a waves and b waves in eyes that are affected by ocular ischemic syndrome, in contrast to the sparing of the a wave found in central retinal artery occlusions. The choroidal and outer retinal ischemia of eyes that have ocular ischemic syndrome accounts for this difference.
Figure 118-3 Fluorescein angiography, ocular ischemic syndrome. A distinctly abnormal finding in a fluorescein angiogram of eyes that are affected by ocular ischemic syndrome is a well-demarcated leading edge of dye within the retinal arteries.
Color Doppler imaging is an excellent noninvasive means by which to assess the velocity of blood flow in the retrobulbar circulation. Diminution of blood flow velocities in the central retinal artery, choroidal vessels, and ophthalmic artery is typical. Reversal of flow in the ophthalmic artery is common, as well. Color Doppler imaging may be used to assess the carotid arteries simultaneously.
Carotid arteriography discloses generally a 90% or greater obstruction of the ipsilateral carotid artery in patients who have ocular ischemic syndrome. If noninvasive carotid artery evaluation is unremarkable in an eye that shows signs suggestive of ocular ischemia, conventional carotid arteriography or digital subtraction angiography may be required to demonstrate possible chronic obstruction of the ophthalmic artery.    Rarely, cases of ocular ischemia may be induced by a more distal obstruction in the ophthalmic artery itself.
Nonischemic central retinal venous occlusions and diabetic retinopathy are conditions most likely to be confused with ocular ischemic syndrome. Various ocular signs help to differentiate these conditions, as given in Table 118-1 . One particularly useful differentiating feature is a swollen optic disc, which typically is seen in nonischemic vein occlusions and not in ocular ischemic syndrome. In addition, central retinal vein occlusions typically have dilated and tortuous retinal veins. Although microaneurysms may occur in both diabetes and ocular ischemic syndrome, in diabetes they tend to involve the posterior pole preferentially. On rare occasions, giant cell arteritis may induce findings similar to those of ocular ischemic syndrome. In general, however, giant cell arteritis has a much more dramatic clinical picture, with ischemic optic neuropathy or retinal artery occlusion, or both.
Takayasu’s arteritis, also known as aortic arch syndrome or pulseless disease, is an idiopathic inflammation of larger elastic and muscular arteries—the aorta is affected in particular. It is primarily a disease of young adults, especially women, and is most prevalent in the Far East. Constitutional symptoms are common, including fever, fatigue, and weight loss.
The ocular manifestations can mimic those of ocular ischemic syndrome. Retinal arterial narrowing, large arteriovenous anastomoses, and peripheral microaneurysms are common. Retinal neovascularization with vitreous hemorrhage may occur. Systemic corticosteroids are the treatment of choice.
Figure 118-4 Patchy choroidal filling, ocular ischemic syndrome. Patchy choroidal filling that lasts more than 5 seconds occurs in about 60% of eyes affected by ocular ischemic syndrome.
Figure 118-5 Staining of retinal arteries, ocular ischemic syndrome. Prominent staining of retinal arteries, rather than venules, can help to differentiate an eye that has ocular ischemic syndrome from an eye that is affected by a nonischemic central retinal vein occlusion (which shows more prominent staining of the venules).
The atherosclerosis that affects the carotid artery sufficiently to cause ocular ischemic syndrome generally is widespread. Of patients who have ocular ischemic syndrome, 50% show evidence of ischemic heart disease; and 25% have a history of previous cerebrovascular accidents.
Additional risk factors for both atherosclerosis and arteriosclerosis are found in these patients, such as systemic hypertension, which is found in two thirds of patients who have ocular ischemic syndrome, and diabetes mellitus, which is observed in more than 50% of these patients.
A 5-year mortality of 40% in patients who have ocular ischemic syndrome reflects the severity of their systemic vascular disease. The main cause of death in these patients is ischemic heart disease, with stroke the second most common cause.
In the early stage of the ocular ischemic syndrome, the neural retina shows coagulative necrosis of its inner layers, which are supplied by the retinal arterioles. If the area of coagulative necrosis is small and localized, it appears clinically as a cotton-wool spot, a microinfarct of the nerve fiber layer. Histologically, the
TABLE 118-1 — FEATURES THAT DISTINGUISH OCULAR ISCHEMIC SYNDROME
Ocular Ischemic Syndrome
Nonischemic Central Retinal Vein Occlusion
Retinal artery perfusion pressure
Mild to severe
Mild to moderate
Absent unless in association with diabetes
Arteriovenous transit time
Retinal vessel staining
Prominent arterial staining
Prominent venous staining
Clinical signs and fluorescein angiography that help differentiate ocular ischemic syndrome from nonischemic central retinal vein occlusions or diabetic retinopathy.
swollen end-bulbs of the infarcted nerve fiber layer superficially resemble cells, hence the term cytoid body. If the area of coagulative necrosis is extensive, it appears clinically as a gray neural retinal area, blotting out the background choroidal pattern. With complete coagulative necrosis of the posterior pole (e.g., after a central retinal artery occlusion), the red choroid shows through the central fovea as a cherry-red spot. The inner half of the neural retina becomes “homogenized” into a diffuse, relatively acellular zone. Generally, thick-walled retinal blood vessels are present.
TREATMENT, COURSE, AND OUTCOME
Patients who have mild ocular ischemic syndrome may maintain excellent vision, but the natural course of eyes that have the full-blown syndrome is quite poor. Assessment of carotid artery function in patients with ocular ischemic syndrome is of utmost importance. The North American Symptomatic Carotid Endarterectomy Trial demonstrated that carotid endarterectomy was beneficial for patients with carotid stenosis of 70–99% with a recent history of amaurosis fugax, a hemispheric transient ischemic attack, or a nondisabling stroke. The cumulative risk of ipsilateral stroke was 26% after 2 years for patients receiving antiplatelet treatment, while the cumulative risk of stroke was 9% 2 years after endarterectomy. The benefit of endarterectomy was tempered by a 2.1% risk of severe stroke or death during the immediate postoperative period in the patients who underwent surgery versus 0.9% in the antiplatelet group. In symptomatic patients with carotid artery stenosis of 50–69%, only a moderate reduction in risk of stroke was identified after carotid endarterectomy.
Stabilization or improvement in vision has been reported in about 25% of eyes after endarterectomy. Doppler color imaging has shown postoperative normalization of preoperative retrograde ophthalmic artery flow following endarterectomy. Electroretinogram a waves and b waves have improved with increased amplitude following endarterectomy. Occasionally, in eyes that have ciliary body hypoperfusion, complete angle closure, and normal IOP, carotid endarterectomy has resulted in severe glaucoma immediately after surgery. In cases in which 100% obstruction and distal propagation of a thrombus has occurred, bypass procedures, such as superficial temporal artery to middle cerebral artery, have been attempted. Although the vision improves transiently in 20% of such eyes, it usually deteriorates within 1 year of surgery.
In cases that have iris neovascularization in which the anterior chamber angle is open, panretinal photocoagulation may induce regression of the rubeosis. Unfortunately, the regression is not as prominent as that seen in patients who have iris neovascularization after central retinal vein occlusion. Elevated IOP from neovascular glaucoma may require cyclodestructive therapies or filtering procedures.
1. Kearns TP, Hollenhorst RW. Venous stasis retinopathy of occlusive disease of the carotid artery. Mayo Clin Proc. 1963;38:304–12.
2. Hayreh SS. So-called “central retinal vein occlusion.” Venous stasis retinopathy. Ophthalmologica. 1976;172:14–37.
3. Knox DL. Ischemic ocular inflammation. Am J Ophthalmol. 1965;60:995–1002.
4. Young LHY, Appen RE. Ischemic oculopathy: a manifestation of carotid artery disease. Arch Neurol. 1981;38:358–61.
5. Brown GC, Magargal LE. The ocular ischemic syndrome: clinical, fluorescein angiographic and carotid angiographic features. Int Ophthalmol. 1988;11:239–51.
6. Sturrock GD, Mueller HR. Chronic ocular ischaemia. Br J Ophthalmol. 1984;68:716–23.
7. Ho AC, Lieb WE, Flaharty PM, et al. Color Doppler imaging of the ocular ischemic syndrome. Ophthalmology. 1992;99:1453–62.
8. McFadzean RM, Graham DI, Lee WR, Mendelow AD. Ocular blood flow in unilateral carotid stenosis and hypotension. Invest Ophthalmol Vis Sci. 1989;30:487–90.
9. Kearns TP. Differential diagnosis of central retinal vein obstruction. Ophthalmology. 1983;90:475–80.
10. Brown GC. Anterior ischemic optic neuropathy occurring in association with carotid artery obstruction. J Clin Neurol Ophthalmol. 1986;6:39–42.
11. Brown GC, Magargal LE, Simeone FA, et al. Arterial obstruction and ocular neovascularization. Ophthalmology. 1982;89:139–46.
12. Bullock JD, Falter RT, Downing JE, Snyder HE. Ischemic ophthalmia secondary to ophthalmic artery occlusion. 1972;74:486–93.
13. Madsen PH. Venous-stasis retinopathy insufficiency of the ophthalmic artery. Acta Ophthalmol. 1966;44:940–7.
14. Sivalingham A, Brown GC, Magargal LE, Menduke H. The ocular ischemic syndrome. II. Mortality and systemic morbidity. Int Ophthalmol. 1990;13:187–91.
15. Sivalingham A, Brown GC, Magargal LE. The ocular ischemic syndrome. III. Visual prognosis and the effect of treatment. Int Ophthalmol. 1991;15:15–20.
16. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–53.
17. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998; 339:1415–25.
18. Kawaguchi S, Okuno S, Sakaki T, Nishikawa N. Effect of carotid endarterectomy on ocular ischemic syndrome due to internal carotid artery stenosis. Neurosurgery. 2001;48:328–33.
19. Story JL, Held KS, Harrison JM, et al. The ocular ischemic syndrome in carotid artery occlusive disease: ophthalmic color Doppler flow velocity and electroretinographic changes following carotid endarterectomy reconstruction. Surg Neurol. 1995;44:534–5.
20. Eggleston TF, Bohling CA, Eggleston HC, Hershey FB. Photocoagulation for ocular ischemia associated with carotid artery occlusion. Ann Ophthalmol. 1980;12:84–7.