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 (26). Longer attacks, up to 7 days, are rare. Nearly one third of patients with amaurosis fugax and internal carotid stenosis greater than 75% had prolonged course or “positive” visual phenomena such as scintillations, making it difficult to differentiate from retinal migraine (39).

Amaurosis fugax triggered by exposure to bright light suggests severe internal carotid artery stenosis or occlusion (32). This unusual form of ocular ischemic syndrome is associated with more than 90% of internal carotid artery stenosis, resulting in various degrees of visual impairment ranging from total blindness to blurring or dimming of vision or visual field defect (93). Binocular vision impairment may be caused by bilateral carotid severe stenosis or occlusion (102).

Although rarely associated with focal neurologic deficits, MRI performed in patients with amaurosis fugax may reveal asymptomatic cerebral infarcts.

If associated with pain, Horner syndrome and scintillations often related to postural changes or exposure to bright light, carotid artery dissection should be suspected (12). The association with dysgeusia should also prompt investigation for dissection (07).

Stenosis of the central retinal artery may present with recurrent amaurosis fugax worse while bending down. Fluorescent angiography reveals retinal hypoperfusion (21).

Nonembolic amaurosis fugax is perceived as grey, white, black, or phosphenes, is most frequently patchy, occurs in some patients with migraine, and tends to recover in the reverse order of appearance. Some patients may respond to nifedipine, suggesting a vasospasm component (76; 77).

Internal carotid artery occlusion may cause pupillary dilatation with poor reaction to light, neovascularization of the iris, (rubeosis iridis), elevated intraocular pressure with secondary glaucoma, proliferative retinopathy with microaneurysms, scattered flame-shaped hemorrhages, and prominent venous stasis may be seen (28; 116).

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

Alternating amaurosis fugax in presence of high D-dimer may be a manifestation of a malignancy. Resection may stop recurrence of symptoms (58).

Embolic material in the retina was reported in the late 1800s (40). 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 (33).

Table 1. Retinal Emboli

The embolus may not be seen during an attack of central retinal arterial ischemia (90). Venous tortuosity and midperipheral hemorrhages suggest impaired ocular perfusion (ie, ocular ischemic syndrome).

A bruit over the ipsilateral carotid bifurcation is found in approximately one half to two thirds of patients.

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 1 or both eyes, lasts for several seconds to minutes, and reflects preexisting optic nerve demyelination (95).

Prognosis and complications

Recurrence of amaurosis is highest in the first month, then it decreases thereafter (06). After amaurosis fugax, the risk of stroke increases with the degree of stenosis but is 3 times lower than in patients who had the first hemispheric transient ischemic attack (97). However, 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 3 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% (109).

The risk of stroke is highest during the first few days after the initial event, approximately 6.4% in the first 3 days, and increases to 26% at 14 days (104). 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 (99).

The long-term prognosis of amaurosis fugax is benign in most young patients even after multiple episodes, if they have no residual deficits and no underlying systemic, cardiac, or carotid disease (101). The risk of permanent visual impairment following a retinal transient ischemic attack is approximately 1% per year (57).

Mortality rate after amaurosis fugax is similar to that of transient ischemic attack but 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 (44).

Clinical vignette

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

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 an 80% to 99% stenosis of the left internal carotid artery, whereas the right internal carotid was normal.

The vascular surgeon performed endarterectomy on the left internal carotid artery on the basis of the ultrasound alone. She received aspirin and high dose statin and remained neurologically asymptomatic.

Biological basis

Etiology and pathogenesis

Visual loss in amaurosis fugax is due to retinal, choroidal, or optic nerve hypoperfusion. Positive visual phenomena may be triggered by decreased ocular perfusion pressure during postural changes or an increase in retinal oxygen demand by exposure to bright light (32; 86).

Ocular ischemia is caused by large artery occlusive disease, cardioembolism, small artery occlusive disease (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, dissection, or inflammation. Atherosclerosis occurs typically at the carotid bifurcation or 2 cm above it. 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). Neck or facial pain or Horner syndrome suggest internal carotid artery dissection (11).

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 (117). Retinal artery embolization from calcific aortic stenosis or cardiac valve disease is rare (106).

Vasospasm. Vasospasm of the retinal vessels that responds to calcium channel blockers was described (110).

Anterior ischemic optic neuropathy. Anterior ischemic optic neuropathy results from short posterior ciliary artery ischemia and presents as acute, painless unilateral visual loss with a swollen optic disc. Anterior ischemic optic neuropathy is not typically associated with carotid stenosis (31).

Internal jugular stenosis. Internal jugular stenosis may be seen on contrast-enhanced MRI and MRA in patients with normal carotid arteries (19). Moderate to severe internal jugular stenosis may alter the ocular hemodynamics and cause flow reversal in the superior ophthalmic vein (48), dilatation of the retinal venules (23), and increased resistance in the retrobulbar arteries (16). Multiple etiologies underlie the venous insufficiency, like external compression from bone, muscle structures, embryological defect, and infectious or inflammatory disorders (23).

Severe hypotension. Severe hypotension may cause ischemic anterior or posterior optic neuropathy with or without concurrent cerebral watershed ischemia (50). Hypoperfusion of the occipital lobes may cause bilateral visual loss. The diagnosis is often suggested by symptoms triggered by posture. This phenomenon is more commonly associated with carotid occlusive disease.

Thrombophilia. Thrombophilia may cause amaurosis fugax (36). Family history of thromboembolism, personal history of thrombosis, miscarriage, skin rash, false positive test for syphilis, and abnormal coagulation parameters should raise the suspicion of antiphospholipid antibody syndrome or congenital coagulopathy. Among the drugs promoting thrombosis is testosterone (37).

Orbital mass lesions. Orbital mass lesions may manifest as gaze-evoked amaurosis. Proptosis, globe indentation, and papilledema may be seen in these patients (91).

Migraine. Migraine causes transient visual loss by cortical spreading depression. Retinal migraine is very rare (46). Some patients developed permanent visual loss during migraine; unfortunately, the mechanism in most cases was not specified (41).

Other causes. Other causes of amaurosis fugax are giant cell arteritis (27), Takayasu arteritis (30), moyamoya disease (72), neurosarcoidosis (55), neurocysticercosis (94), visual seizures (89), cervical rib causing thoracic outlet syndrome (52), dental procedures, infiltration of the inferior alveolar nerve block (108), glaucoma, blowing of the nose, intraocular hemorrhages, and malaria (75). Preeclampsia is associated with a multitude of visual disturbances, including amaurosis fugax (83).

Epidemiology

Amaurosis may occur in any adult age group. 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 (101). Carotid artery dissection may occur in any age group and can cause amaurosis fugax.

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).

Despite the lack of high-quality epidemiologic data, treating the common vascular risk factors may prevent amaurosis fugax due to large artery occlusive disease and some forms of cardiac embolism in addition to reduction of the risk of cortical stroke.

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, all processes posterior to the optic chiasm, are suggested by transient binocular visual loss. Seizures may cause transient binocular visual loss often associated with altered consciousness or eye deviation. They are typically maximal at onset and, in contrast to migraine, have no build-up or evolution of symptoms over time.

Idiopathic intracranial hypertension (pseudotumor cerebri). Idiopathic intracranial hypertension is suggested by 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 often consists of positive visual phenomena and homonymous hemianopia, usually accompanied by brainstem dysfunction like dysarthria, dysphagia, vertigo, and diplopia; in less than 1% of cases, it may be isolated (14). 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. Slowly spreading amaurosis fugax with positive phenomena visible with the eyes closed suggests a central etiology, most likely but not always migraine (46). There should be at least 2 attacks with symptoms that evolve over at least 5 minutes, last up to 1 hour, and are fully reversible.

Retinal migraine. Retinal migraine is characterized by monocular visual symptoms followed by migraine without aura. Cases without headache were described, but the migraine origin of the symptoms cannot be confirmed, and other causes should be ruled out first (45). The majority of cases of retinal migraine were found to have other causes than migraine (46). In most cases, visual loss was more likely caused by retinal vasospasm and ocular hypoperfusion observed during fundus examination or with retinal angiography (49).

Giant cell arteritis. Giant cell arteritis often causes transient visual loss and diplopia. It occurs in mostly elderly patients and is associated with temporal artery induration and scalp tenderness, jaw claudication, polymyalgia rheumatica, papilledema, and elevated erythrocyte sedimentation rate (ESR) and 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 is characterized by decreased peripheral pulses. Retinopathy is characterized by delayed arm-to-retina circulation time (22).

Rheumatoid arthritis. Rheumatoid arthritis may also affect the small and medium size blood vessels and may present 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. Recurrent angle closure glaucoma, impending central retinal vein occlusion, and congenital optic disc anomalies may also cause amaurosis but are readily detected on ophthalmologic examination. Microhyphema, which may be visualized by gonioscopy only, may cause a “snow globe” effect in the anterior chamber and cause vision loss triggered by bending over (60). Increased intraocular pressure may occur after vitreoretinal surgery and cause ipsilateral amaurosis fugax (96).

Diagnostic workup

Carotid ultrasonography. Carotid ultrasonography is noninvasive, can infer the degree of extracranial artery stenosis from blood flow velocity, and provide information about the vessel wall configuration and plaque morphology. Transoral carotid ultrasonography visualizes the superior portion of internal carotid artery, not accessible by the conventional ultrasonography (115). The use of intravenous contrast may help in differentiating thrombosis from dissection (100; 43).

High-resolution computed tomography angiography can also accurately measure the degree of carotid stenosis and evaluate the characteristics of atherosclerotic plaques (111). Three-dimensional reconstruction (3D-CTA) may be beneficial in selecting patients prior to carotid interventions (113).

Magnetic resonance angiography of the neck 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 (38).

In absence of internal carotid artery stenosis, contrast enhanced MRI and MRA may detect moderate to severe jugular vein stenosis (19).

The risk of stroke depends on the degree of stenosis and on the characteristics of the atherosclerotic plaque. Ultrasound can be used to identify the high risk plaque by looking at the echodensity (87), the size of the juxtaluminal hypoechoic area (51), echolucent plaques (66), and enhancement by using late-phase contrast with microbubbles US (74).

Molecular MRI imaging using various sequences and contrast agents targeting the plaque components or cells is still in experimental stage, but it may greatly improve our understanding of plaque behavior and risk stratification (64).

Conventional angiography may demonstrate the ophthalmic artery, but the smaller, distal vessels (short posterior ciliary and central retinal arteries) are not adequately visualized.

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

In patients with recurrent amaurosis fugax and normal noninvasive carotid imaging, digital subtraction 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 (92). 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 (112). Prolonged cardiac monitoring with portable or insertable monitors may improve detection of atrial fibrillation (61; 35; 56; 88).

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. In elderly patients with headache, jaw claudication, scalp tenderness, elevated ESR or CRP and/or thrombocytosis, temporal artery biopsy should be considered.

Management

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 (85). Also, the preoperative symptoms of carotid stenosis influence the periprocedural risk at 30 days, which in the case of amaurosis fugax is similar to that of asymptomatic carotid disease (34). Nevertheless, even in patients with insignificant stroke risk score by degree of stenosis, plaque hemorrhage and microembolic signals are associated with increased risk of recurrent cerebrovascular events (02). Because the risk of stroke is lower in patients with amaurosis fugax, carotid endarterectomy likely helped only patients who had 3 or more of the following risk factors: age above 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 patients with transient monocular visual loss who fall into a high-risk category and have at least a 5-year life expectancy. The procedure should only be performed in a center with acceptable morbidity and mortality (18).

Although initially reserved for patients at high surgical risk, carotid artery stenting has gained increased popularity as the operators’ skills, technique, and devices have improved. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed that in experienced hands, carotid endarterectomy and carotid artery stenting have similar short- and long-term outcomes. Carotid endarterectomy was associated with higher risk of myocardial infarction whereas carotid artery stenting with higher risk of stroke (65).

Since publication of NASCET, carotid endarterectomy was compared to carotid artery stenting only. The patients enrolled in NASCET did not benefit from aggressive medical therapy as recommended by the current guidelines. Several interventional trials failed to show significant advantage over medical therapy due to lower than expected rate of stroke in the medical arm (79; 20). The declining stroke recurrence over the past decades attributed to better hypertension control and antithrombotic medications has important implications in trial design (47). 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.

If internal carotid artery stenosis is intracranial, warfarin does not protect more than aspirin against recurrent stroke (70). However, aggressive medical therapy (antiplatelet, statin, strict blood pressure and diabetes control coupled with smoking cessation) prevents more strokes both in short- and long-term compared to angioplasty and stenting in patients with large intracranial arterial stenosis (20; 24).

For patients with atherosclerotic internal carotid artery occlusion, surgical bypass between the external carotid artery and internal carotid artery did not provide an overall benefit compared to medical therapy, in spite of excellent cerebral reperfusion (79; 42).

An alternate intervention for symptomatic ipsilateral internal carotid artery occlusion may be stenting of the external carotid artery. In a small study of 12 patients with symptoms of ischemia (including amaurosis fugax) who were treated with external carotid artery stenting, there was preservation of neurologic status or complete resolution of symptoms (114).

In patients with internal carotid artery dissection, a retrospective study has failed to show that anticoagulation with heparin followed by warfarin with a target INR of 2 to 3 is superior to antiplatelet treatment alone (68; 54). However, a randomized clinical trial may be needed to determine which treatment is superior.

In absence of cardioembolism, antiplatelet agents are commonly used. Aspirin, in dosage of 50 to 325 mg/day is commonly used initially. 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).

Two large randomized trials, the Second European Stroke Prevention Study (ESPS-2) and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), have suggested that low-dose aspirin combined with extended-release dipyridamole may be more effective than aspirin alone in secondary stroke prevention (17). 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 (25).

In patients with symptomatic carotid stenosis waiting for revascularization, early statin therapy significantly reduces the 7-day risk of stroke after TIA, from 13.2% to 3.8% (69). In addition, aggressive statin therapy reduces the 5-year absolute risk for cardiovascular events by 3.5% (03).

Management of the ocular ischemic syndrome due to internal carotid artery occlusion remains difficult. Lowering intraocular pressure to improve ocular perfusion is critical. Panretinal photocoagulation may be indicated when fluorescein angiography shows evidence of retinal ischemia. Carotid artery revascularization by carotid endarterectomy or carotid artery stenting was found to improve the ocular circulation and visual acuity (53).

Many prophylactic and abortive treatments are available for migraine headache, but their efficacy for migraine aura remains unclear. Many neurologists use a combination of aspirin and calcium channel blockers, beta-blockers, or anticonvulsants to prevent these symptoms; however, there is little evidence to guide such treatment (110).

Outcomes

The optimal timing of carotid endarterectomy is important. Analysis of pooled data from the NASCET and the European Carotid Surgery Trial shows that the highest risk reduction of endarterectomy is within 14 days of the index event (84). Acceptable perioperative complications were reported within 14 days, and even at 2 days, from the index event (105). However, a prospective analysis of carotid endarterectomy in 2596 patients showed that the risk of stroke is significantly increased within the first 2 days and that it may be safer to operate from day 3 onward (98). Progressive or fluctuating symptoms was associated with worse outcome after urgent carotid endarterectomy (82; 08). In light of this data, the 2018 guidelines for management of acute ischemic stroke recommend performance of carotid revascularization between 48 hours and 7 days if early revascularization is not contraindicated (80). Finally, a German Statutory Quality Assurance Database has shown that carotid stenting up to day 7 is associated with an increased risk of stroke (103).

Several pooled analyses of clinical trials comparing carotid endarterectomy with carotid artery stenting, in which data from the CREST trial were not included, were done. The increased risk of stroke or death associated with carotid artery stenting is a measure of operator’s volume per year (10.1% if mean < 3.2 procedures/year vs. 5.1% if mean is > 5.6 procedures/year) (13). In contrast to carotid endarterectomy, early carotid artery stenting was associated with higher risk of periprocedural stroke or death, 9.4% for carotid artery stenting versus 2.8% for carotid endarterectomy (81). The risk of stroke was twice as high in elderly patients who underwent carotid artery stenting compared to endarterectomy; however, in patients younger than 70 years of age, carotid artery stenting and endarterectomy posed a similar risk (15).

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 in particular. 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 (83). 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 (107).