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 (24). The visual manifestations range from total blindness to blurring or dimming of vision or visual field defect (91). Nearly one third of patients with amaurosis fugax and internal carotid stenosis greater than 75% experience long attacks and scintillations similar to retinal migraine (37). A bruit over the ipsilateral carotid bifurcation is found in approximately one half to two thirds of patients.

Binocular vision impairment suggests bilateral carotid disease (100). Alternating amaurosis fugax in the presence of high D-dimer may be seen in malignancy. Tumor resection may stop the recurrence of symptoms (57).

If amaurosis is triggered by bright light, internal carotid artery stenosis more than 90% or occlusion may be responsible (30). 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 (26; 112).

Retinal hypoperfusion caused by central retinal artery stenosis is aggravated by bending down and is diagnosed by fluorescent angiography (19). Pain, Horner syndrome, dysgeusia, and scintillations triggered by postural changes or exposure to bright light suggest carotid artery dissection (12; 07).

Nonembolic 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 (76; 77).

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 in 1875 (38). Hollenhorst described cholesterol crystals in the retinal circulation. The characteristics of the plaque may suggest a proximal source, although in practice these distinctions are often difficult to make. However, retinal vessels typically look normal during an episode of amaurosis fugax, even if the central retinal artery is occluded (31).

Table 1. Retinal Emboli

The embolus may not be visible during an attack of central retinal arterial ischemia (88). 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. The symptoms resolved after carotid endarterectomy (62).

Uhthoff phenomenon is a 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 several seconds to minutes, and reveals preexisting optic nerve demyelination (93).

Prognosis and complications

Recurrence of amaurosis is highest in the first month (06). The risk of stroke following amaurosis fugax increases with severity of stenosis but is three times lower than after the first transient ischemic attack (95). Nevertheless, silent acute cerebral infarctions were detected by brain MRI in 23% of patients with retinal artery occlusion and amaurosis fugax (59).

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% (105).

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 (101). Another study on patients with symptomatic internal carotid artery stenosis of greater than 70% diagnosed between 2004 and 2012 have a risk of stroke of 2% at day 2 and 7.5% at day 30, lower than earlier reported (96).

Permanent visual impairment occurs in approximately 1% per year (56). In young patients, even recurrent amaurosis fugax has a benign prognosis in the absence of stroke or underlying systemic, cardiac, or carotid disease (99).

Mortality after amaurosis fugax is similar to that of 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 (42).

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 past 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. Unenhanced 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 (30; 84).

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 (63).

Carotid artery dissection. Carotid artery dissection may occur in any age group and presents as neck or facial pain, Horner syndrome, and artery-to-artery embolism (11). Recurrent episodes may be triggered by an elongated styloid process (111)

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 (113). Retinal artery embolization from calcific aortic stenosis or cardiac valve disease is rare (102).

Vasospasm. Vasospasm of the retinal vessels that responds to calcium channel blockers was described (106).

Anterior ischemic optic neuropathy. This condition results from short posterior ciliary artery ischemia. It presents as acute, painless unilateral visual loss with a swollen optic disc. Anterior ischemic optic neuropathy is not typically associated with carotid stenosis (29).

Internal jugular vein stenosis. Internal jugular stenosis may be seen on contrast-enhanced MRI and MRA in patients with normal carotid arteries (17). 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 (21) and increased resistance in the retrobulbar arteries (14).

Severe hypotension. Severe hypotension may cause ischemic anterior or posterior optic neuropathy with or without concurrent cerebral watershed ischemia (47). 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 (34). 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. Among the drugs promoting thrombosis is testosterone (35).

Orbital mass lesions. An orbital mass is suggested by gaze-evoked amaurosis, proptosis, globe indentation, and papilledema (89).

Migraine. Migraine causes transient visual loss by cortical spreading depression. Retinal migraine is very rare (44). Some patients developed permanent visual loss during migraine; unfortunately, the mechanism in most cases was not specified (39).

Other causes. Other causes of amaurosis fugax include giant cell arteritis (25), Takayasu arteritis (28), Tolosa-Hunt syndrome (52), moyamoya disease (72), neurosarcoidosis (53), neurocysticercosis (92), visual seizures (87), cervical rib causing thoracic outlet syndrome (49), inferior alveolar nerve block during dental procedures (104), glaucoma, blowing of the nose, intraocular hemorrhages, and malaria (75). Preeclampsia is associated with a multitude of visual disturbances, including amaurosis fugax (82). Recurrent hypnic amaurosis fugax may occur on awakening, with full recovery of vision (98).

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 (99).

Prevention

Amaurosis fugax shares risk factors with internal carotid artery disease, such as old age, history of diabetes mellitus, myocardial infarction, hypertension, and smoking (10).

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 (55).

NASCET showed superiority of carotid endarterectomy to medical therapy alone in symptomatic patients with internal carotid stenosis greater than 70% (73). 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 (83).

Carotid endarterectomy mostly helped patients who had three or more of the following risk factors: older than 75 years, male sex, history of transient ischemic attack or stroke, history of intermittent claudication, ipsilateral stenosis of 80% to 94%, or absent collaterals on angiography (09). 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 (16).

Initially reserved for high-risk patients, carotid artery stenting has been proven to have a similar outcome as carotid endarterectomy. Carotid endarterectomy was associated with a higher risk of myocardial infarction, whereas carotid artery stenting was associated with a higher risk of stroke (65).

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 (18; 79). The declining stroke recurrence over the past decades is attributed to better hypertension control and antithrombotic medications and has important implications in trial design (45). 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 (80). Progressive or fluctuating symptoms were associated with worse outcome after urgent carotid endarterectomy (81; 08).

If internal carotid artery stenosis is intracranial, aspirin and warfarin have similar efficacy in preventing stroke (70). 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 (18; 22).

Atherosclerotic internal carotid artery occlusion does not benefit from surgical bypass between the external and internal carotid arteries despite excellent cerebral reperfusion (79; 40). An alternative intervention for symptomatic internal carotid artery occlusion is stenting of the external carotid artery if stenotic (110). 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 (55).

Internal carotid artery dissection treatment with anticoagulation was not superior to antiplatelet administration alone (68; 51).

Initially, 50 to 325 mg/day of aspirin is commonly used. Clopidogrel, which inhibits platelets in a manner distinct from aspirin, has been shown to be slightly more effective in preventing recurrent stroke than aspirin (71). Low-dose aspirin combined with extended-release dipyridamole may be more effective than aspirin alone in secondary stroke prevention (15). 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 a cerebral ischemic event (23).

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% (69). 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 (50).

It is unclear if the prophylactic and abortive treatments available for migraine headache prevent 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 (106).

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 (75).

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 lasts 20 to 30 minutes. It manifests as homonymous hemianopia and is occasionally associated with scintillating scotomas and brainstem dysfunction, like dysarthria, dysphagia, vertigo, and diplopia; in less than 1% of cases, it may be isolated (13). 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 (44). 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.

Retinal migraine. In retinal migraine, the monocular visual loss is followed by migraine without aura. In the absence of headache, other etiologies should be ruled out first (43). Most cases labeled as retinal migraine have other causes for visual loss. No permanent visual loss has been due to retinal migraine (44). Retinal vasospasm and ocular hypoperfusion were observed during fundus examination or with retinal angiography (46).

Giant cell arteritis. Giant cell arteritis often causes transient visual loss and diplopia. It mostly occurs in elderly patients with temporal artery induration and 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 (20).

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 (94). 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 (60).

Diagnostic workup

Carotid ultrasonography. Carotid ultrasonography is noninvasive and can determine the degree of extracranial artery stenosis from blood flow velocity as well as provide information about the vessel wall configuration and plaque morphology. The use of intravenous contrast may help in differentiating thrombosis from dissection (97; 41). Stroke risk depends on the severity of stenosis and atherosclerotic plaque morphology, such as echodensity (85; 66), juxtaluminal hypoechoic area (48), and enhancement, by using late-phase contrast with microbubbles ultrasound (74). 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 was a better predictor of major neurologic events compared to the percent of diameter stenosis (58).

Computed tomography angiography. Computed tomography angiography can accurately measure the degree of carotid stenosis and evaluate the plaque morphology (107). Three-dimensional reconstruction (3D-CTA) may be beneficial in selecting patients prior to carotid interventions (109).

Magnetic resonance angiography of the neck. This is another noninvasive method of measuring the arterial diameter. Its tendency to overestimate the degree of stenosis can be corrected by use of contrast. Some preliminary studies suggest that either a high-quality noninvasive test alone or in combination with angiography may be adequate (36).

In absence of internal carotid artery stenosis, contrast enhanced MRI and MRA may detect moderate to severe jugular vein stenosis (17). Molecular MRI imaging, which is still in the experimental stage, may greatly improve our understanding of plaque behavior and risk stratification (64).

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 (90). Color Doppler of the orbit can evaluate these distal vessels and may demonstrate ophthalmic artery stenosis, retrolaminar emboli, and reversal of direction of ophthalmic artery flow in ocular ischemic syndrome (67).

Cardiac evaluation. Cardiac evaluation is accomplished with electrocardiography as well as transthoracic or transesophageal echocardiography. Transesophageal echocardiography is more sensitive than transthoracic echocardiography at finding emboligenic lesions (108). Prolonged cardiac monitoring with portable or insertable monitors may improve detection of atrial fibrillation (61; 33; 54; 86).

Inflammatory systemic and hypercoagulable disorders. 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 should be considered in elderly patients with headache, jaw claudication, scalp tenderness, elevated ESR or CRP, or thrombocytosis.

Management

Amaurosis fugax is a transient event that 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 outcomes of both angioplasty stenting and endarterectomy. Stroke and transient ischemic attack predict higher rates of periprocedural complications. Following amaurosis fugax, the periprocedural risk is similar to that of asymptomatic carotid stenosis (32). Nevertheless, even in patients with an insignificant risk for stroke judged by the degree of stenosis, plaque hemorrhage and microembolic signals are associated with an increased 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 may produce a hypercoagulable state leading to stroke, but these are not commonly preceded by transient ischemic attacks in general, or amaurosis fugax. However, thrombotic events, in particular venous sinus thrombosis, may indirectly affect the visual system.

In a review of visual disturbances reported in association with preeclampsia, amaurosis fugax is cited as a transient symptom that rarely leads to permanent vision loss (82). However, as visual symptoms are common in preeclampsia and indeed can be the initial manifestation, physicians are advised to recognize the clinical significance of an episode of amaurosis fugax.

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 (103).