Treatment of Vasospastic Amaurosis Fugax with Calcium-Channel Blockers

Table 1. Table 1. Characteristics of Nine Patients with Amaurosis Fugax.

The characteristics of the nine patients are summarized in Table 1. The four women ranged in age from 25 to 65 years, and the five men from 34 to 79 years. Each of these patients had multiple episodes of monocular visual loss that recurred over a period of days, weeks, or months. Patient 1 reported daily attacks in which vision dimmed “like a rheostat” to the point of temporary monocular blindness. Patient 2 had several episodes of periorbital ache each day, followed by monocular blindness that lasted 10 to 15 minutes and then cleared spontaneously. Patient 3 reported feeling as though a “gray shield” had been placed in front of her eye for 15 minutes. Patient 4 reported having an uncomfortable ocular sensation followed by the impression that a white curtain was descending to cover her left eye and, on one occasion that a black curtain was covering her right eye. Patient 5 described a peculiar ocular “awareness” followed either by a brief period of blurred vision or by total monocular visual loss. Patient 6 had four to six attacks per day, beginning with a retro-orbital ache, after which his vision dimmed to the point that he could not perceive hand movement 30 cm (1 ft) ahead of him. Patient 7 had four episodes of visual blurring in a two-day period that progressed to total monocular blindness and lasted from five minutes to two hours. Patient 8 had had attacks of amaurosis fugax for several years, initially presenting with occlusion of the superior branch of the retinal artery. Patient 9 had a “whiteout” of the entire field of his right eye that lasted from 5 to 60 minutes and occurred every three days.

Each patient had been treated unsuccessfully for amaurosis fugax with one or more anticoagulants: aspirin, another nonsteroidal antiinflammatory agent (naproxen [Naprosyn]), warfarin, and heparin. Three of the patients had been treated with prednisone for systemic lupus erythematosus or possible vasculitis. Patient 9 had undergone a right carotid endarterectomy for a 95 percent stenosis of the internal carotid artery, without relief of the visual episodes.

Figure 1. Figure 1. Retina of Patient 7 during an Attack of Amaurosis Fugax, Showing Disk Pallor, Constriction of Retinal Arterioles, and Rouleaux Formation in Venules, Indicating Sluggish Blood Flow.

Figure 2. Figure 2. Retina of Patient 7 after 18 Months of Treatment with a Calcium-Channel Blocker, Showing Reperfusion of Arterioles and Veins with Normal Blood Flow.

Intraretinal microvascular abnormalities related to the patient's diabetes mellitus are present near the macula.

Three of the patients had an episode of visual loss during a neuro-ophthalmic examination, so that the retina was directly observed. In each case, visual acuity in the affected eye was found to be reduced to the point that only light perception remained -- and in some instances there was no light perception -- and the pupil was unreactive to direct light stimulation. Figure 1 shows the retina of Patient 7 during an episode of amaurosis fugax. The optic disk was slightly pale; the arterioles were narrow, threadlike, and nonperfused; and the veins were segmentally constricted with a discontinuous blood column (described as “boxcarring” or rouleaux formation), indicating sluggish or absent blood flow. Between attacks, visual acuity, color vision, visual fields, pupils, ocular motility, intraocular pressure, ophthalmodynamometric findings, and ophthalmoscopic appearance were normal. No emboli were visualized at any time (Figure 2).

The medical evaluation of each patient to exclude embolism or carotid occlusive disease consisted of echocardiography (transesophageal in two patients), carotid duplex scanning (in two patients transcranial Doppler ultrasonography was also done to confirm the absence of intracavernous carotid disease), and Holter monitoring (one patient also had 24-hour monitoring of blood pressure to rule out episodic hypotension). Blood tests routinely included a complete blood count; blood chemical analyses; thyroid-function tests; measurement of the Westergren erythrocyte sedimentation rate; tests for antinuclear antibodies, syphilis, Lyme disease, and anticardiolipin antibody; calculation of the partial-thromboplastin time; and measurements of protein C, protein S, factor VIII, and antibodies against antiphosphatidylcholine and phosphatidylserine.

Five patients were evaluated with neurologic imaging techniques: computed tomography in one patient and magnetic resonance imaging in four patients, three of whom also underwent magnetic resonance angiography. Cerebral angiography was performed in four patients. Fluorescein angiography of the retina in four patients did not reveal a delayed circulation time. Temporal-artery biopsies in Patients 6 and 9 were negative. All results proved normal, except as indicated in Table 1.

After informed consent was obtained from each patient, treatment with calcium-channel blockers was initiated. When the initial dose was inadequate, the attacks continued but were less frequent and less severe. The dose was increased until an effective therapeutic dose was achieved (20 mg of nifedipine three times daily, 60 mg of a long-acting preparation of nifedipine a day, or 120 mg of a long-acting preparation of verapamil a day); thereafter, no patient had further attacks. Two patients stopped taking the calcium-channel blocker soon after they became free of symptoms, and two other patients skipped several doses of medication while traveling. In each of these four patients, the attacks of amaurosis fugax resumed within a few days and persisted until treatment with nifedipine was reinstated. More than one year after treatment was begun, all patients were still taking calcium-channel blockers, with no further recurrence of amaurosis fugax.

Since amaurosis fugax is usually ascribed to embolism, thrombosis, or chronic carotid arterial hypoperfusion, treatment has usually consisted of anticoagulation with warfarin, antiplatelet therapy with aspirin, or carotid endarterectomy^2,3. These treatments, however, may be inappropriate or unsuccessful in patients whose attacks of amaurosis fugax are caused primarily by vasospasm. No prospective study has reported the incidence of vasospasm, but any estimate that is based on the number of patients referred for neuro-ophthalmic evaluation because their amaurosis was unresponsive to aspirin and other usual therapeutic measures would be biased. Although vasospasm tends to be underreported and thus unappreciated as a cause of amaurosis fugax,^4-6 it has been implicated as the mechanism underlying migraine,^7-11 Raynaud's phenomenon,¹² and Prinzmetal's angina¹³. Vasospasm may not only be a primary cause of amaurosis fugax, but can also occur as a result of platelet aggregation, leading to the release of serotonin in damaged vessels, or in inflammatory syndromes such as vasculitis or giant-cell arteritis^14,15.

The patients described here are representative of a diverse group in whom amaurosis suspected to be of vasospastic origin was successfully treated with a calcium-channel blocker. Vasospasm was considered to be the cause of amaurosis fugax in these patients after other causes had been excluded by a thorough evaluation. Therapy with a calcium-channel blocker was instituted only after other medications failed to stop the attacks. The response to the calcium-channel blocker seemed to be specific, since the attacks resumed when the medication was withdrawn, and the degree of relief from amaurosis fugax appeared to be related to the dose of calcium-channel blocker administered. Low doses resulted in mild or infrequent attacks, and adequate doses completely stopped the attacks.

Unless retinal vasospasm is observed by clinicians, patients with vasospastic amaurosis fugax may be difficult to differentiate from patients with amaurosis fugax from other causes. Ophthalmoscopic examination may substantiate vasospasm as the cause if it reveals the presence of arteriolar narrowing and venular rouleaux formation during a symptomatic episode, or exclude it if evidence of emboli or optic-nerve disease is found.

The patients in this study seemed to have few distinctive clinical characteristics. Their attacks of visual loss tended to be frequent, recurring many times a day. They often had temporary complete monocular blindness rather than loss restricted to the inferior or superior altitudinal visual field. Several of the patients experienced a prodromal ocular sensation or ache before losing their vision.

The medical histories of these patients included migraine, Raynaud's disease, systemic lupus erythematosus, and other conditions causing hypercoagulability. Patients with vasospastic amaurosis fugax may comprise two groups: younger patients (nearly half of our patients were under 50 years of age) with a history of migraine or autoimmune diathesis, and older patients with no history of migraine. Although migraine with monocular visual disturbance is an uncommon phenomenon,^10,11 vasospasm has been implicated as the cause of amaurosis that occurs in young patients with migraine^10,11 and has been documented by photography of the fundus¹⁶.

Vasomotor instability may underlie a tendency toward migraine, but primary vasospasm is now considered too simplistic an explanation for migraine, and current theories emphasize the complexities of the regulation of vasomotor tone by neurotransmitters, especially serotonin (5-hydroxytryptamine), and prostaglandins⁹. Migraine-like phenomena are well described in patients with systemic lupus erythematosus,^8,17,18 and retinal vasospasm has been observed in a young woman with amaurosis fugax whose medical evaluation revealed underlying lupus¹⁸. In that patient, amaurosis ceased when the lupus flare was treated with prednisone. Both migraine headache and amaurosis fugax have been treated successfully with nifedipine in patients with lupus⁸. The addition of nifedipine was effective therapy in Patient 1, in whom amaurosis fugax developed during long-term treatment with prednisone for lupus.

Migraine-like transient visual phenomena can develop in older patients with no history of migraine,^19,20 and these visual disturbances have often been attributed to vertebrobasilar insufficiency²⁰. In such patients, cerebrovascular disease in the ocular as well as the posterior circulation could provide the substrate for the aggregation of platelets, with the resultant release of neurotransmitters precipitating vasospasm¹⁵. Conventional antiplatelet therapy with aspirin, however, was not effective in the patients described here. Although calcium-channel blockers have been hypothesized to have a minor role in inhibiting platelet aggregation,²¹ that role remains in doubt²². The primary action of the calcium-channel blockers on calcium flux in vessel walls suggests that, in our patients, they acted to prevent occlusive vasospasm in already narrowed vessels. Calcium-channel blockers have previously been used successfully to stabilize the vasomotor tone of patients with Raynaud's disease,^12,23 coronary-artery spasm,¹³ cortical migraine,^8,9 and cerebral-artery vasospasm after subarachnoid hemorrhage²⁴.

Retinal- or ophthalmic-artery vasospasm should be considered as the cause of amaurosis fugax when thromboembolic disease and carotid-artery hypoperfusion have been carefully excluded as causes. In such cases, a calcium-channel blocker may be effective treatment.