Clinical manifestations

Presentation and course

Although amaurosis fugax is classically described as a “curtain” or “shade” descending over the eye(s), patients complain more often of a blur, cloud, or fog over their vision. The episodes may be monocular or binocular, depending on the etiology. A homonymous visual field defect indicates a lesion involving the posterior visual pathways.

Rapid onset of painless altitudinal visual loss lasting 10 minutes or less suggests high-grade carotid stenosis (28). The visual manifestations range from total blindness to blurring or dimming of vision or visual field defect (98). Nearly one third of patients with amaurosis fugax and internal carotid stenosis greater than 75% experience prolonged attacks and scintillations resembling retinal migraine (42). A bruit over the ipsilateral carotid bifurcation occurs in up to two thirds of patients.

Binocular vision impairment suggests bilateral carotid disease (107). Alternating amaurosis fugax associated with high D-dimer may be seen in malignancy and stops after tumor resection (62).

Amaurosis triggered by bright light was seen with internal carotid artery stenosis greater than 90% (34). Internal carotid artery occlusion may cause pupillary dilatation that is poorly reactive to light, neovascularization of the iris, proliferative retinopathy, microaneurysms, scattered flame-shaped hemorrhages, prominent venous stasis, and secondary glaucoma (30; 120).

Hypoperfusion caused by central retinal artery stenosis is aggravated by bending down and diagnosed by fluorescent angiography (23). Pain, Horner syndrome, dysgeusia, and scintillations triggered by postural changes or exposure to bright light suggest carotid artery dissection (13; 07).

Non-embolic amaurosis fugax is perceived as grey, white, black, or phosphenes. It is usually patchy, occasionally associated with migraine, and tends to recover in the reverse order of appearance. A response to nifedipine suggests vasospasm (83; 84).

Bilateral optic disc swelling usually reflects elevated intracranial pressure, whereas unilateral papilledema suggests ischemia, inflammation, or infiltration. Optic disc atrophy is seen in patients with residual visual impairment.

Retinal embolism was reported by Gowers (43). Hollenhorst described cholesterol crystals in the retinal circulation. However, retinal vessels typically look normal during an episode of amaurosis fugax, even if the central retinal artery is occluded (36).

Table 1. Retinal Emboli

Retinal embolism correlates poorly with the severity of carotid artery stenosis and should prompt further investigations (95). Venous tortuosity and midperipheral hemorrhages suggest impaired ocular perfusion (ie, ocular ischemic syndrome).

One case of recurrent amaurosis fugax associated with choreiform movements of the contralateral side was described as limb shaking transient ischemic attack that resolved after carotid endarterectomy (67).

Uhthoff phenomenon is the worsening of neurologic symptoms, including vision, in patients with multiple sclerosis after exercise, or with elevation of core body temperature. It may affect one or both eyes, lasts for seconds to minutes, and reveals preexisting optic nerve demyelination (100).

Prognosis and complications

Recurrence of amaurosis fugax is highest in the first month (06). The risk of stroke increases with severity of stenosis but is three times lower than after the first transient ischemic attack (102). Nevertheless, brain MRI detected silent acute cerebral infarctions in 23% of patients with retinal artery occlusion and amaurosis fugax (64).

Stroke, myocardial infarction, or vascular death were predicted by occurrence of more than three attacks, involvement of the peripheral visual field, constricting visual field, downward progression of visual loss, or upwards resolution of visual loss. The annual incidence of these vascular events was 4.4% (112).

The risk of stroke is highest shortly after the initial event, approximately 6.4% in the first 3 days, and increases to 26% at 14 days (108). In another study, patients with symptomatic internal carotid artery stenosis greater than 70% had a risk of stroke of 2% at day 2 and 7.5% at day 30, lower than earlier reported (103).

Permanent visual impairment occurs in approximately 1% per year (61). In young patients without stroke or systemic, cardiac, or carotid disease, even recurrent amaurosis fugax has a benign prognosis (106).

Mortality after amaurosis fugax is the same as after transient ischemic attack and lower compared to stroke (Poole and Ross 1985). The risk of vascular death in patients with amaurosis and atheromatous carotid disease is 3.5% per year and is largely due to cardiac death (47).

Clinical vignette

A 66-year-old woman presented with a 3-week history of visual spells. The spells had no clear precipitants and consisted of sudden darkening of vision in her left eye. There were no other neurologic symptoms, eye pain, or headache. The spells lasted between 30 seconds and several minutes and abated as suddenly as they began. During the last spell, she covered the left eye and noticed normal vision in the right eye. She had a history of hypertension and noninsulin-dependent diabetes mellitus. Her medical history was negative for eye problems, head pain, jaw pain, weight loss, migraine, and cardiac disease.

Her blood pressure was 136/80 mmHg with a regular heart rate of 76. The funduscopic and the rest of neurologic examination were normal.

Electrocardiogram revealed normal sinus rhythm. CT scan of the brain was normal. Carotid Doppler revealed 80% to 99% stenosis of the left internal carotid artery and normal right internal carotid artery.

After endarterectomy of the left internal carotid artery, she received aspirin and a high-dose statin and remained asymptomatic.

Biological basis

Etiology and pathogenesis

Visual loss in amaurosis fugax is due to retinal, choroidal, or optic nerve hypoperfusion. Positive visual phenomena result from decreased ocular perfusion pressure during postural changes or increased retinal oxygen demand by exposure to bright light (34; 91).

Ocular ischemia is caused by carotid artery disease, cardioembolism, small artery occlusion (anterior ischemic optic neuropathy, vasculitis), vasospasm, venous disease, systemic and hypercoagulable disorders (hyperviscosity, antiphospholipid antibody syndrome), and systemic hypoperfusion. In one study, amaurosis fugax was more often associated with carotid stenosis than atrial fibrillation (05).

Internal carotid artery stenosis. Internal carotid artery stenosis may be caused by atherosclerosis or inflammation. Atherosclerosis typically occurs at the level of carotid bifurcation. A moderate size plaque may become symptomatic due to intraplaque hemorrhage or superimposed thrombosis. Amaurosis fugax was associated with male sex, hypertension, dyslipidemia, and tobacco use (68).

Carotid artery dissection. Dissection may occur in any age group and presents as neck or facial pain, Horner syndrome, and artery-to-artery embolism (12). Recurrent episodes may be triggered by an elongated styloid process (119)

Nonvalvular atrial fibrillation. Nonvalvular atrial fibrillation, the most common cardioembolic etiology of amaurosis fugax, may be underreported. Out of 400 patients with transient or permanent monocular vision loss, of which only 53% underwent prolonged cardiac monitoring, 9% had atrial fibrillation (121). Embolism from calcified aortic stenosis or cardiac valve disease is rare (109).

Vasospasm. Vasospasm of the retinal vessels responds to calcium channel blockers (114).

Anterior ischemic optic neuropathy. Caused by short posterior ciliary artery ischemia, anterior ischemic optic neuropathy is not typically associated with carotid stenosis. Anterior ischemic optic neuropathy presents as acute, painless unilateral visual loss with a swollen optic disc (33).

Internal jugular vein stenosis. This condition may be seen on contrast-enhanced MRI and MRA in patients with normal carotid arteries (21). Moderate to severe internal jugular stenosis may alter the ocular hemodynamics and cause flow reversal dilatation of the retinal venules. Multiple etiologies underlie the venous insufficiency, like external compression from bone muscle structures, embryological defect, and infectious or inflammatory disorders (25) and increased resistance in the retrobulbar arteries (18).

Severe hypotension. Ischemic anterior or posterior optic neuropathy may be associated with cerebral watershed ischemia (52). Hypoperfusion of the occipital lobes may cause bilateral visual loss. The symptoms are triggered by posture, especially in presence of carotid stenosis.

Thrombophilia. Thrombophilia may cause amaurosis fugax (39). Personal or family history of thromboembolism, miscarriage, skin rash, false positive test for syphilis, and coagulopathy should raise the suspicion of antiphospholipid antibody syndrome or congenital coagulopathy. Testosterone is prothrombotic (40).

Orbit mass lesions. Suggested by gaze-evoked amaurosis, orbit tumors also cause proptosis, globe indentation, and papilledema (96).

Migraine. Transient visual loss during migraine is caused by cortical spreading depression. Retinal migraine is very rare (49). Some patients developed permanent visual loss during migraine; unfortunately, the mechanism in most cases was not specified (44).

Other causes. Other causes of amaurosis fugax include giant cell arteritis (29), Takayasu arteritis (32; 09), Tolosa-Hunt syndrome (57), moyamoya disease (78), neurosarcoidosis (58), neurocysticercosis (99), visual seizures (94), cervical rib causing thoracic outlet syndrome (54), inferior alveolar nerve block during dental procedures (111), glaucoma, blowing of the nose, intraocular hemorrhages, and malaria (82). Preeclampsia is associated with a multitude of visual disturbances, including amaurosis fugax (89). Recurrent hypnic amaurosis fugax may occur on awakening, with full recovery of vision (105).

Epidemiology

Amaurosis occurs in all adult age groups. A Danish prospective study in a community aged between 25 and 84 years found a pooled annual incidence of 13.7 per 100,000 men and 9.4 per 100,000 women. The peak incidence rate occurs in the seventh decade, at 38 per 100,000 men and 26.6 per 100,000 women (04).

Patients older than 50 years of age typically have ischemic causes of amaurosis fugax, whereas younger patients may have migraine or no discernible etiology (106).

Prevention

Amaurosis fugax shares risk factors with internal carotid artery disease, such as old age, history of diabetes mellitus, myocardial infarction, hypertension, and smoking (11).

Management of the vascular risk factors is key to secondary stroke prevention, including diabetes, smoking cessation, lipids, and, especially, hypertension. Lifestyle modification by promoting low-salt and Mediterranean diets, physical activity, and medication compliance is important for preventing stroke (60).

NASCET demonstrated superiority of carotid endarterectomy to medical therapy alone in symptomatic patients with internal carotid stenosis greater than 70% (79). However, the perioperative stroke and death rates are substantially lower in patients presenting with amaurosis fugax compared to those presenting with hemispheric transient ischemic attack or minor stroke (90).

Carotid endarterectomy helped if three or more of the following risk factors were present: male sex older than 75 years, history of transient ischemic attack or stroke, history of intermittent claudication, ipsilateral stenosis of 80% to 94%, or absent collaterals on angiography (10). Carotid endarterectomy should only be offered to high-risk patients with a minimum life expectancy of 5 years. The procedure should only be performed in a center with acceptable morbidity and mortality (20).

Initially reserved for high-risk patients, carotid artery stenting has been proven to have a similar outcome as carotid endarterectomy. Although the perioperative risk was low, endarterectomy was associated with more cases of myocardial infarction, whereas carotid artery stenting was associated with more strokes (70).

The patients enrolled in NASCET did not benefit from the current intensive medical therapy. Several interventional trials failed to show a significant advantage over medical therapy due to the lower-than-expected rate of stroke in the medical arm (22; 86). The declining stroke recurrence over the past decades is attributed to better hypertension control and antithrombotic medications and has important implications in trial design (50). The question of whether surgical intervention is still the optimal therapeutic approach in patients with symptomatic carotid stenosis can be addressed by a new trial.

The optimal timing of carotid endarterectomy is between 48 hours and 7 days if early revascularization is not contraindicated (87). Progressive or fluctuating symptoms were associated with worse outcome after urgent carotid endarterectomy (88; 08).

If internal carotid artery stenosis is intracranial, aspirin and warfarin are equally effective in preventing stroke (76). Intensive medical therapy (antiplatelet, statin, strict blood pressure, and diabetes control coupled with smoking cessation) prevents more strokes, both in the short- and long-term, than angioplasty and stenting in patients with large intracranial arterial stenosis (22; 26).

Atherosclerotic internal carotid artery occlusion does not benefit from surgical bypass between the external and internal carotid arteries despite excellent cerebral reperfusion (86; 45). An alternative intervention for symptomatic internal carotid artery occlusion is stenting of the external carotid artery if stenotic (118). However, further studies are needed to validate this approach.

If cardiac embolism is due to atrial fibrillation, flutter, metallic valve, or intracardiac thrombus, anticoagulation with either coumadin or direct oral anticoagulation is recommended (60).

Internal carotid artery dissection treatment with anticoagulation was not superior to antiplatelet administration alone (73; 56).

Initially, 50 to 325 mg/day of aspirin is commonly used. Clopidogrel, a platelet inhibitor different from aspirin, has been shown to be slightly more effective in preventing recurrent stroke than aspirin (16). Low-dose aspirin combined with extended-release dipyridamole may be more effective than aspirin alone in secondary stroke prevention (19). A Cochrane review showed that the combination of 50 mg of aspirin and extended-release dipyridamole may prevent more recurrent events than aspirin alone, but only in patients who had cerebral ischemia (27).

In patients with symptomatic carotid stenosis waiting for revascularization, early statin therapy significantly reduces the 7-day risk of stroke after transient ischemic attack from 13.2% to 3.8% (74). In addition, high-dose statin therapy reduces the 5-year absolute risk for cardiovascular events by 3.5% (03).

The ocular ischemic syndrome due to internal carotid artery occlusion requires lowering of intraocular pressure to improve ocular perfusion and panretinal photocoagulation if fluorescein angiogram reveals retinal ischemia. Carotid artery revascularization improves not only the ocular perfusion but also visual acuity (55).

It is unclear if prophylaxis and treatment of migraine prevents migraine aura. A combination of aspirin and calcium channel blockers, beta-blockers, or anticonvulsants is used to prevent these symptoms; however, there is little evidence to guide such treatment (114).

Differential diagnosis

Amaurosis fugax may reflect a wide variety of pathologic processes. Because most patients present after the attack, the neurologic and ophthalmologic examination may be normal; therefore, obtaining a careful history is imperative. It is important to establish whether the visual loss was monocular or binocular.

Ipsilateral carotid artery stenosis. Ipsilateral carotid artery stenosis is suggested by monocular vision loss. Vision loss may be complete in 48% of patients; it may be sectorial or respect the horizontal meridian and suggests retinal artery branch occlusion (82).

Vertebrobasilar ischemia, migraine, and seizures are suggested by binocular visual loss. In addition, seizures may cause altered consciousness or eye deviation. They are typically maximal at onset and in contrast to migraine, which evolves gradually.

Idiopathic intracranial hypertension (pseudotumor cerebri). Idiopathic intracranial hypertension presents as visual obscurations lasting seconds during bending forward of the head.

Thromboembolism. Thromboembolism typically lasts 2 to 10 minutes and may be associated with hemispheric symptoms.

Migraine aura. Migraine aura manifests as homonymous hemianopia and lasts 20 to 30 minutes. It is occasionally associated with scintillating scotomas and brainstem dysfunction, like dysarthria, dysphagia, vertigo, and diplopia. Migraine aura is isolated in less than 1% of cases (15). There should be at least two attacks with symptoms that evolve over at least 5 minutes, last up to 1 hour, and are fully reversible. Migraine with aura, typical aura with non-migraine headache, and typical aura without headache may cause homonymous and unilateral visual symptoms, such as flickering lights or blurry vision. However, these symptoms are not always due to migraine (49).

Retinal migraine. During retinal migraine, the monocular visual loss is followed by migraine without aura. In the absence of headache, other etiologies should be ruled out first (48). Retinal migraine does not cause permanent visual loss (49). Arterial spasm and ocular hypoperfusion may be observed during fundus examination or with retinal angiography (51).

Giant cell arteritis. Giant cell arteritis causes transient visual loss and diplopia, particularly in elderly patients with temporal artery induration, scalp tenderness, jaw claudication, polymyalgia rheumatica, papilledema, and elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). The most feared complication is blindness due to inflammatory occlusion of the ophthalmic and ciliary arteries branches. Temporal artery biopsy provides the definitive diagnosis.

Takayasu arteritis. Takayasu arteritis involves the large arteries and leads to decreased peripheral pulses. Retinopathy is characterized by delayed arm-to-retina circulation time (24).

Rheumatoid arthritis. Rheumatoid arthritis may affect the small and medium size blood vessels and presents as amaurosis fugax in patients with multiple proximal joint aches (01).

Table 2. Clinical Features and Common Causes of Transient Visual Loss

Dry eyes. Dry eyes may cause mild transient visual blurring relieved after a few seconds by blinking, rubbing the eyes, or using lubricating eye drops.

Other ophthalmologic conditions. Angle closure glaucoma, impending central retinal vein occlusion, and congenital optic disc anomalies may also cause amaurosis but are readily detected on ophthalmologic examination. Increased intraocular pressure after vitreoretinal surgery may cause ipsilateral amaurosis fugax (101). Microhyphema, which can only be visualized by gonioscopy, may cause a “snow globe” effect in the anterior chamber and cause vision loss triggered by bending over (65).

Diagnostic workup

The risk of stroke depends on the degree of arterial stenosis but also on the characteristics of the vulnerable atherosclerotic plaques. Embolic stroke of undetermined source (ESUS) may also occur in patients with nonstenotic (with < 50% stenosis) plaques. In a study of 138 patients with ESUS, 39.1% of patients had nonstenotic carotid plaques and 8.7% had bilateral carotid plaques; 60.6% of these plaques were ipsilateral to the side of the stroke, suggesting a causal relationship (80).

Carotid ultrasonography. This noninvasive method estimates the degree of arterial stenosis from blood flow velocity and characterizes the vessel wall configuration and plaque morphology. Intravenous contrast may help differentiate thrombosis from dissection (104; 46).

Carotid ultrasonography can reveal plaque morphology, such as echodensity (92; 71), juxtaluminal hypoechoic area (53), and enhancement, by using late-phase contrast with microbubbles ultrasound (81). In asymptomatic carotid stenosis of any severity, a combination of the plaque features (matrix, intraplaque hemorrhage, wall thickness, plaque burden), age, body mass index, and lipid profile is a better predictor of the major neurologic events compared to the severity of arterial stenosis alone (63).

Color Doppler. Color Doppler of the orbit can demonstrate ophthalmic artery stenosis, retrolaminar emboli, and reversal of direction of ophthalmic artery flow in ocular ischemic syndrome (72).

Computed tomography angiography. Computed tomography angiography can accurately measure the degree of carotid stenosis and evaluate plaque morphology (115). Three-dimensional reconstruction (3D-CTA) may be beneficial in selecting patients prior to carotid interventions (117).

Magnetic resonance angiography (MRA) of the neck. A noninvasive method of measuring the arterial diameter, MRA tends to overestimate the degree of stenosis. This can be corrected by the use of contrast. Either a high-quality noninvasive test alone or in combination with angiography may be adequate for patient evaluation (41). Jugular vein stenosis may be seen in the absence of internal carotid artery stenosis (21).

Discrimination of the vulnerable from the more stable plaques and risk stratification may be enhanced by using molecular MRI imaging (69). Dual-targeted microparticles of iron oxide (DT-MPIO) is such a molecular probe and is still in the experimental stage (17).

Fluorescein retinal angiography. Fluorescein retinal angiography is used to evaluate the retinal and choroidal circulation and may demonstrate occlusive disease, retinal edema, and hypoperfusion.

Digital subtraction cerebral angiogram. Digital subtraction cerebral angiogram may visualize the ophthalmic artery but not the smaller, distal vessels like short posterior ciliary and central retinal arteries. In patients with recurrent amaurosis fugax and normal noninvasive carotid imaging, cerebral angiogram may trigger diffuse vasospasm of the internal carotid and ophthalmic arteries. This may be confirmed by increased blood flow velocity on carotid Doppler (97).

Cardiac evaluation. Cardiac evaluation consists of electrocardiography, transthoracic echocardiography, or transesophageal echocardiography. Transesophageal echocardiography is more sensitive than transthoracic echocardiography at finding embolic sources (116). Prolonged cardiac monitoring with portable or insertable monitors may improve detection of atrial fibrillation (66; 38; 59; 93).

Positron emission scan (PET) scan. [(18)F]-fluorodeoxyglucose-PET (FDG-PET) imaging has emerged as a valuable tool targeting atherosclerotic plaque glycolysis, a marker for plaque inflammation and hypoxia (14). Evaluation of nonstenotic atherosclerotic plaques with FDG-PET-CT angiography found increased FDG uptake and more frequent as well as more extensive hypodense lesions on CTA ipsilateral to the stroke, suggesting a role in stroke etiology (75). In addition, measuring [(18)F]-fluorocholine uptake detects macrophage infiltration in a recently symptomatic vulnerable plaque (113).

Inflammatory systemic and hypercoagulable markers. Inflammatory systemic and hypercoagulable disorders, particularly those predisposing to arterial thrombosis, may affect selected patients: young, without vascular risk factors, family history of unexplained thrombosis. Testing for these includes anticardiolipin antibodies, lupus anticoagulant, erythrocyte sedimentation rate, ESR, CRP, sickle cell screen, and toxicology. Temporal artery biopsy is indicated if giant cell arteritis is suspected in elderly patients with headache, jaw claudication, scalp tenderness, elevated ESR or CRP, or thrombocytosis.

Uric acid metabolism. Xanthine oxidase, an enzyme involved in uric acid synthesis, is overexpressed in macrophages collected from the symptomatic plaques (35). Uric acid concentration within serum and carotid plaque is increased in patients with symptomatic carotid stenosis. This may be a useful marker for symptomatic carotid plaque (77).

Management

Amaurosis fugax is transient and does not cause tissue injury. Although there is no acute treatment for it, amaurosis fugax is a medical emergency as it may indicate a high risk for visual loss, stroke, or even death. All patients need urgent evaluation of the risk factors and prompt initiation of preventive medication or revascularization procedures.

Outcomes

The presenting symptom of carotid disease predicts the 30-day outcome of both angioplasty stenting and endarterectomy. Stroke and transient ischemic attack predict higher rates of periprocedural complications. The periprocedural risk after amaurosis fugax is similar to that of asymptomatic carotid stenosis (37). Nevertheless, even in patients with low-grade stenosis, plaque hemorrhage and microembolic signals increase the risk of recurrent cerebrovascular events (02).

The most common complications of preventive medications are abnormal bleeding, allergy, and gastric irritation. The revascularization procedures are associated with hyperperfusion syndrome, especially if multiple arterial occlusions or severe stenoses, hematoma at catheter insertion, cranial nerve injury after endarterectomy, infection, stroke, and myocardial infarction are present.

Special considerations

Pregnancy

Pregnancy results in a hypercoagulable state leading to stroke. However, stroke is not usually preceded by transient ischemic attacks or amaurosis fugax. Nevertheless, thromboembolism, in particular venous sinus thrombosis, may indirectly affect the visual system.

If associated with preeclampsia, amaurosis fugax rarely leads to permanent vision loss (89). However, amaurosis fugax should be differentiated from the visual manifestations of preeclampsia.

Anesthesia

There is no difference in the proportion of patients who had a stroke or died within 30 days of carotid endarterectomy between local versus general anesthesia (110).