Ocular ischemic syndrome (OIS) is a rare eye disease caused by chronic hypoperfusion of the common or internal carotid artery.
Ocular ischemic syndrome encompasses the ocular signs and symptoms that result from chronic vascular insufficiency. Common anterior segment findings include advanced cataract, anterior-chamber cell and flare, and iris neovascularization. Posterior segment signs include narrowed retinal arteries, dilated but nontortuous retinal veins, midperipheral dot-and-blot retinal hemorrhages, cotton-wool spots, and optic nerve/retinal neovascularization. Most patients with ocular ischemic syndrome present with gradual vision loss or pain.[1, 2, 3, 4, 5, 6, 7]
The most common etiology of ocular ischemic syndrome is severe unilateral or bilateral atherosclerotic disease of the internal carotid artery or marked stenosis at the bifurcation of the common carotid artery. It is postulated that the decreased vascular perfusion results in tissue hypoxia and increased ocular ischemia, leading to neovascularization.[3, 8, 9] Ocular ischemic syndrome is more likely to develop in patients with poor collateral circulation between the two internal carotid arteries or between the internal and external carotid arteries. Patients with adequate collateral circulation may not develop ocular ischemic syndrome even if the internal carotid artery is totally occluded.[10]
Patients with ocular ischemic syndrome may show decreased blood flow in the retrobulbar vessels. They may also have reversal of blood flow in the ophthalmic artery because blood is shunted away from the ophthalmic artery and into the lower-resistance intracranial blood vessels.[10]
The incidence of ocular ischemic syndrome is estimated to be 7.5 cases per 1 million population per year but is likely underdiagnosed.[11] Among individuals with carotid occlusive disease, approximately 4%have ocular ischemic syndrome.[12] Ocular ischemic syndrome is bilateral in around 20% of cases.
Patients with ocular ischemic syndrome have a significantly higher rate of vascular disease than the general population; 73% have hypertension, 56% have diabetes, 48% have a history of ischemic heart disease, 27% have had a prior stroke, and 19% have peripheral vascular disease.[13]
Males are affected more frequently than females, by a ratio of approximately 2:1, because of a higher rate of cardiovascular disease in men.[14]
Ocular ischemic syndrome mainly affects elderly patients, with a mean age of 65 years. Ocular ischemic syndrome is uncommon in patients younger than 50 years.[10]
Patients with ocular ischemic syndrome have an overall poor visual prognosis. However, patients with better visual acuity at presentation are more likely to retain good final vision. The presence of iris neovascularization is associated with significantly lower vision, with 97% of cases resulting in a final visual acuity of count fingers or worse.[15, 13, 16]
Smoking cessation, a diet low in fat and sugar, and regular exercise can decrease the rate of vascular disease and potentially lower the likelihood of developing ocular ischemic syndrome.
Decreased vision is the most common symptom associated with ocular ischemic syndrome, occurring in 91% of patients. In one study, most patients (67%) noted gradual vision loss over weeks to months, while 12% had decreased vision over days, and another 12% noted decreased vision over seconds to minutes. A history of transient vision loss is present in 10%-15% of patients with ocular ischemic syndrome (OIS).[1]
Patients with ocular ischemic syndrome can present with variable degrees of visual loss. Up to two thirds of patients can present with visual acuities of 20/60 or worse. One third of patients will have visual acuities of counting fingers or worse.[1, 17]
Visual fields are variable and may show no defect, central scotoma, nasal defect, cecocentral defects, or presence of only a central or temporal island.[6]
About 40% of patients with ocular ischemic syndrome have eye pain. Pain secondary to ischemia is characteristically described as a dull ache over the brow, which begins gradually over a period of hours to days. Lying supine may decrease pain since blood flow is increased. Pain can also result from elevated intraocular pressure in the presence of neovascular glaucoma.
Anterior segment
Corneal abnormalities: Descemet folds and corneal edema may be present secondary to ocular hypotony, increased intraocular pressure, or endothelial dysfunction due to ischemia.[1, 3]
Iris neovascularization: Iris neovascularization is encountered in 67-87% of affected eyes and can be caused by retinal ischemia, choroidal ischemia, or both.
Neovascular glaucoma: This is elevated intraocular pressure in the presence of angle neovascularization. Neovascular glaucoma is seen in about one third of patients with ocular ischemic syndrome. Lower arterial perfusion to the ciliary body may induce hypotony or normal intraocular pressure despite significant anterior chamber angle neovascularization due to decreased production of aqueous fluid.
Anterior chamber inflammation: Uveitis, characterized by the presence of cells and flare in the anterior chamber, was estimated to occur in up to 20% of eyes. In most cases, the inflammatory reaction is only mild and flare is more prominent than cell.
Cataract: Advanced degrees of lens opacities may be seen in patients with ocular ischemic syndrome. Asymmetric cataract may help support the diagnosis of ocular ischemic syndrome.
Posterior segment
Retinal vessels: Retinal arteries are typically narrow in eyes with ocular ischemic syndrome. The veins are usually irregularly dilated but not tortuous, which can help differentiate ocular ischemic syndrome from central retinal vein occlusion (CRVO).[1, 3, 18]
Retinal hemorrhages: Midperipheral dot-and-blot retinal hemorrhages are observed in 24-80% of eyes with ocular ischemic syndrome. Microaneurysms can also be seen.
Cotton-wool spots: These are seen in approximately 5% of eyes with ocular ischemic syndrome and are typically located in the posterior pole.
Neovascularization: Neovascularization of the optic nerve is seen in 13-35% of eyes with ocular ischemic syndrome. Retinal neovascularization is less common, and occurs in 3-8% of cases. Neovascularization of the optic nerve can be mild, or it can progress into extensive fibrous proliferation, causing secondary vitreous hemorrhage and tractional retinal detachment.
Cherry-red spot: The cherry-red spot appears as a result of ischemia involving the inner layers of the retina, as typically seen in cases of central retinal artery occlusion. It is noted in 12% of eyes with ocular ischemic syndrome.
Optic disc: Optic disc pallor, cupping, or edema is also noted in patients with ocular ischemic syndrome.
The most common cause of ocular ischemic syndrome is atherosclerosis of the carotid artery. In most cases, stenosis must be 90% or greater to cause ocular ischemic syndrome.
Other causes include the following:
Potential complications include the following:
Although there are no specific blood tests that are required in the workup of ocular ischemic syndrome (OIS), it is essential to evaluate the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels in patients with suspected giant cell arteritis.[19, 20]
Referral to a primary care physician or cardiologist is recommended to evaluate vascular risk factors. Cholesterol levels and hemoglobin A1c may be evaluated.
Ocular Imaging Studies
Fluorescein angiography
The most sensitive angiographic sign of ocular ischemic syndrome is prolonged retinal arteriovenous time, present in more than 95% of cases; however, this is not specific for ocular ischemic syndrome. Prolonged arm-to-choroid and arm-to-retina time, staining of the retinal vessels (arteries more than veins), leakage from retinal vessels, and retinal capillary nonperfusion may also be seen.[1, 14]
Indocyanine green (ICG) angiography
ICG angiography helps visualize choroidal abnormalities. Arm-to-choroid may be increased, patchy choroidal filling or choroidal filling defects may be seen, or there may be slow filling of the watershed zone (areas between zones supplied by two different vessels).[14]
Ocular coherence tomography (OCT)
In one study, average choroidal thickness was reduced in patients with ocular ischemic syndrome; however, the retinal macular thickness did not differ between patients with ocular ischemic syndrome and age-matched controls.[21] OCT can be also be used to identify macular edema.
Optical coherence tomography angiography (OCT-A)
OCT-A has shown increased foveal avascular zone (FAZ) and decreased retinal vessel density in a case of ocular ischemic syndrome that improved after carotid artery stenting.[22]
Carotid duplex ultrasonography
This is the most commonly used test to diagnose carotid disease. It is a noninvasive method that shows both anatomical imaging of the vessel and flow velocity information.[23, 24, 25]
Magnetic resonance angiography (MRA) and computed tomographic angiography (CTA)
MRA and CTA are second-line noninvasive methods for the evaluation of arterial vessels. These studies can provide accurate anatomical details about intracranial vessels and are often helpful if carotid ultrasonography is not diagnostic or to aid surgical planning.
Carotid angiography
Carotid angiography is an invasive procedure with a 1.2% risk of cerebral infarction. It is typically used only if ultrasonography, MRA, or CTA shows inconclusive or contradictory results.[1, 10]
Electroretinography (ERG) can help distinguish ocular ischemic syndrome from central retinal vein occlusion (CRVO) or central retinal artery occlusion (CRAO). In ocular ischemic syndrome, both the inner and outer retina are ischemic. Therefore, ERG in ocular ischemic syndrome shows a reduction in both a-waves (which correspond to photoreceptors) and b-waves (which correspond to bipolar and Muller cells). Eyes with CRVO or CRAO typically have an electronegative ERG result because the inner retina is ischemic but the outer retina is unaffected.[10]
Both of these tests can indirectly measure carotid disease by evaluating ophthalmic artery pressure and ocular pulsations. These methods have been replaced by carotid imaging studies.
Topical steroids, such as prednisolone, and cycloplegics are used to treat anterior-segment inflammation and pain.
Panretinal photocoagulation (PRP) is used to treat neovascularization of the iris, optic nerve, or retina. PRP was reported to cause regression of neovascularization in about one third of patients with ocular ischemic syndrome. The low rate of regression after PRP is attributed to the fact that choroidal ischemia alone (rather than retinal ischemia) is sufficient to cause neovascularization in some patients with ocular ischemic syndrome. PRP is most beneficial prior to development of neovascular glaucoma, as the visual prognosis is poor once this has developed.[2, 16, 26, 14]
If neovascular glaucoma develops, intraocular pressure-lowering drops are used. Prostaglandin analogues and pilocarpine are generally avoided to prevent worsening of inflammation. Glaucoma surgery may be needed if medical therapy does not control IOP.
If cystoid macular edema is present, intravitreal steroids and or intravitreal anti-VEGF agents can be used; however, multiple injections may be needed, and vision may be significantly limited by ischemia.[27]
Carotid endarterectomy is recommended for symptomatic stenosis of 50%-99% if the perioperative risk of stroke or death is less than 6%.[28] A small number of publications have reported on the ophthalmic outcome of carotid endarterectomy in patients with ocular ischemic syndrome, and the data presented are inconclusive.[29] Visual acuity is stabilized or improved in about 25% of eyes following endarterectomy. Endarterectomy is likely more beneficial for visual prognosis if performed prior to the development of neovascularization.[30]
Carotid artery stenting, an alternative to endarterectomy, is used in patients who are at high risk for complications after endarterectomy, such as patients with previous neck radiation or radical neck surgery, patients with high carotid stenosis, or patients with congestive heart failure, unstable angina, or recent myocardial infarction.[10]
Bypass procedures, such as superficial temporal artery to middle cerebral artery anastomoses (STA-MCA), have been tried in patients with 100% carotid obstruction in whom endarterectomy is precluded.
For the treatment of neovascular glaucoma, implantation of glaucoma drainage valves may be needed. In cases with poor visual prognosis, diode cyclophotocoagulation (dCPC) is an option.
Limited dietary fat, salt, and sugar can help control vascular risk factors such as atherosclerosis, hypertension, and diabetes.
For patients with suspected ocular ischemic syndrome (OIS), carotid Doppler is the first-line test to confirm the diagnosis. Referral to a primary care doctor or cardiologist is recommended, since ocular ischemic syndrome is the first manifestation of carotid disease in 69% of patients, and early identification can prevent heart attack, stroke, or death.[6]
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Prednisolone is used to treat acute inflammation following eye surgery or other insults to the eye. It decreases inflammation and corneal neovascularization, suppresses migration of polymorphonuclear leukocytes, and reverses increased capillary permeability.
Clinical Context: Dexamethasone is used for various allergic and inflammatory diseases. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Clinical Context: This agent suppresses the migration of polymorphonuclear leukocytes and reverses capillary permeability.
Clinical Context: Triamcinolone is used to treat inflammatory reactions that are responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. May be used intravitreally to treat cystoid macular edema.
Ophthalmic steroids are used to treat pain and anterior segment inflammation.
Clinical Context: Atropine acts at parasympathetic sites in smooth muscle to block response of sphincter muscle of iris and muscle of ciliary body to acetylcholine, causing mydriasis and cycloplegia.
Clinical Context: Cyclopentolate is the anticholinergic drug of choice in the treatment of cornea abrasions. It prevents the muscle of ciliary body and sphincter muscle of the iris from responding to cholinergic stimulation, causing mydriasis and cycloplegia.
Cycloplegic drops are used to decrease pain and to stabilize the blood-aqueous barrier.
Clinical Context: Dorzolamide is a reversible carbonic anhydrase inhibitor that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably, it slows bicarbonate ion formation, producing a subsequent reduction in sodium and fluid transport. Systemic absorption can affect carbonic anhydrase in the kidney, reducing hydrogen ion secretion at the renal tubule and increasing renal excretion of sodium, potassium bicarbonate, and water. Dorzolamide is less stinging on instillation secondary to buffered pH.
Clinical Context: Brinzolamide catalyzes a reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. It may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than 1 topical ophthalmic drug is being used, administer them at least 10 minutes apart.
Clinical Context: Brimonidine is a relatively selective alpha2 adrenergic-receptor agonist that decreases IOP by dual mechanisms, reducing aqueous humor production and increasing uveoscleral outflow. Brimonidine has minimal effect on cardiovascular and pulmonary parameters. A moderate risk of allergic response to this drug exists. Caution should be used in individuals who have developed an allergy to Iopidine. IOP lowering of up to 27% has been reported.
Alphagan-P contains the preservative Purite and has been shown to be much better tolerated than its counterpart, Alphagan.
Clinical Context: Apraclonidine is a potent alpha adrenergic agent that is selective for alpha2 receptors, with minimal cross-reactivity with alpha1 receptors. It suppresses aqueous production and reduces elevated, as well as normal, IOP, whether accompanied by glaucoma or not. Apraclonidine does not have significant local anesthetic activity. It has minimal cardiovascular effects.
Clinical Context: Latanoprost may decrease IOP by increasing the outflow of aqueous humor. Patients should be informed about possible cosmetic effects to the eye/eyelashes, especially if uniocular therapy is to be initiated.
Clinical Context: This agent is a prostamide analogue with ocular hypotensive activity. It mimics the IOP-lowering activity of prostamides via the prostamide pathway. Bimatoprost ophthalmic solution is used to reduce IOP in open-angle glaucoma and ocular hypertension.
Clinical Context: This agent is a prostaglandin F2-alpha analogue. It is a selective FP prostanoid receptor agonist that is believed to reduce IOP by increasing uveoscleral outflow. Travoprost ophthalmic solution is used to treat open-angle glaucoma and ocular hypertension.
Clinical Context: This agent is a prostaglandin F2-alpha analogue. It is a selective FP prostanoid receptor agonist that is believed to reduce IOP by increasing uveoscleral outflow. Unoprostone ophthalmic solution is used to treat open-angle glaucoma and ocular hypertension.
Clinical Context: Tafluprost is a topical, preservative-free, ophthalmic prostaglandin analogue that is indicated for elevated IOP associated with open-angle glaucoma or ocular hypertension. The exact mechanism by which it reduces IOP is unknown, but it is thought to increase uveoscleral outflow.
Clinical Context: This agent selectively blocks beta1 adrenergic receptors, with little or no effect on beta2 receptors. It lowers IOP by reducing the production of aqueous humor. The drug may have less effect on the pulmonary system. Its IOP-lowering effect is slightly less than that of nonselective beta blockers. It may increase optic nerve perfusion and confer neuroprotection.
Clinical Context: Carteolol has an intrinsic sympathomimetic activity (partial agonist activity), with possibly less adverse effect on cardiac and lipid profiles.
Clinical Context: Timolol may reduce elevated and normal IOP, with or without glaucoma, by reducing the production of aqueous humor.
Clinical Context: Levobunolol is a nonselective beta adrenergic blocking agent that lowers IOP by reducing aqueous humor production and possibly increasing the outflow of aqueous humor.
Glaucoma eyedrops such as beta-blockers, alpha-2 agonists, prostaglandin analogs, and carbonic anhydrase inhibitors are frequently used to control intraocular pressure.
Clinical Context: This agent suppresses neovascularization and slows vision loss, resulting from macular degeneration, by binding to extracellular VEGF and selectively inhibiting VEGF from binding to its receptor.
Clinical Context: Used in the treatment of macular edema. This agent inhibits the activation of endothelial cell receptors, thereby suppressing neovascularization, which can slow vision loss due to macular degeneration.
Anti-VEGF injections can be used to treat cystoid macular edema or to promote (temporary) regression of neovascularization.