Clinical manifestations

Presentation and course

Over the last two decades, several definitions of retinal migraine have been proposed. Troost defined retinal migraine as a transient or permanent monocular visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migrainous episodes (85). Several years later, the first edition of the International Classification of Headache Disorders (ICHD-1), developed by the International Headache Society, established more rigid criteria, requiring at least two attacks of fully reversible monocular scotoma or blindness lasting less than 60 minutes associated with headache (type unspecified) (41). Criteria for the diagnosis of retinal migraine were revised in the 2013 ICHD-3 beta edition to include: (A) at least two attacks fulfilling criteria B and C; (B) aura consisting of fully reversible monocular positive and/or negative visual phenomena (eg, scintillations, scotomata, or blindness) confirmed during an attack by either or both of the following: (1) clinical visual field examination, (2) the patient's drawing (made after clear instruction) of a monocular field defect; (C) at least two of the following three characteristics: (1) the aura spreads gradually over greater than five minutes, (2) aura symptoms last five to 60 minutes, (3) the aura is accompanied, or followed within 60 minutes, by headache; (D) not better accounted for by another ICHD-3 diagnosis, and other causes of amaurosis fugax have been excluded (42).

A review of the literature included positive and negative visual phenomena as symptoms of retinal migraine (37; 35a; 34). Typical descriptions of positive visual phenomena included flashing rays or flickers of light, zigzag lightning, and other teichopsia, whereas perceptions of bright colored streaks, halos, or diagonal lines were less commonly experienced (40; 83; 72). The negative visual losses included blurring, “gray-outs,” and “black-outs,” causing partial or complete blindness (77; 28; 61; 65). Elementary forms of scotoma were perceived as blank areas, black dots, or spots in the field of vision (50; 38). Visual field defects can be altitudinal, quadrantic, central, or arcuate. Complex patterns of monocular visual impairment, such as the appearance of “black paint dripping down from the upper corner of my left eye,” the coalescence of peripherally located spots, a “bluish stain,” and tunnel vision were noted rarely (12; 36; 31).

In most cases, the migraine headache was ipsilateral to the visual loss. Nearly 50% of patients with monocular visual loss had a history of migraine with conventional visual aura. Rare cases of transient monocular visual loss have also been reported with cluster headache, idiopathic stabbing headache, chronic daily headache, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and an unspecified headache type (21; 56; 02; 19; 78).

Recurrent monocular visual disturbances were strictly unilateral and without side shift in most patients, although some experienced side-alternating attacks. The temporal relationship between the visual loss and the headache was variable. Usually, the onset of visual loss preceded or accompanied the headache; less often, the visual loss followed an attack of migraine. By definition, the visual symptoms occurred within one hour of the attack. The duration of transient monocular visual loss varied widely between patients and within individual patients. The duration of the visual symptoms was as short as a few seconds but usually lasted many minutes to one hour. Prolonged but fully reversible monocular visual loss rarely occurred, sometimes lasting hours, days, or even weeks (21; 25; 53; 48; 84; 36; 51; 61). Only a few patients had ophthalmologic examinations during an attack. Examinations, when performed, were usually normal, suggesting retrobulbar involvement. One self-reported case of retinal migraine cited multiple ophthalmologic examinations during attacks, as well as one performed by a retinal specialist (80). This patient was a 71-year-old male ophthalmologist who had suffered from attacks of migraine with and without aura since the age of 16. His conventional visual aura consisted of homonymous scintillating scotomas lasting 15 to 20 minutes. Beginning at the age of 56, he experienced recurrent monocular visual events, which were stereotypic, short-lived, and mostly isolated in nature. The patient reproduced the scotomas of some of these events using Amsler grids. With the exception of one episode, all of these events involved his left eye, lasted 10 to 11 minutes, and were not associated with headache. During one of these episodes, a retinal specialist examined him six to seven minutes into the ictus. No evidence of retinal vasospasm, embolic phenomena, or other abnormalities was found. Ota and colleagues described a 29-year-old woman with a 10-year history of headaches for several hours (74). She experienced recurrent bouts of transient monocular visual impairment that were stereotypic, lasting two to five minutes in the right eye. During one of these episodes ophthalmologic examination revealed retinal vasospasm and severely impaired visual activity (reduced from 20/15 to light perception) of the right eye. Lee and colleagues described a 26-year-old woman with a 4-year history of migraine with aura who experienced complete monocular visual loss of the left eye lasting 20 hours (61). During this episode, automated static perimetry revealed complete monocular blindness in the left eye, yet fundus photography revealed normal findings without steno-occlusion or vasoconstriction. Gonzalez-Martin-Moro and colleagues described a 27-year-old man with a 13-year history of migraine with aura who experienced a bluish stain in the center of his right eye lasting 48 hours (31). During this episode, optical coherence tomography angiography revealed the presence of an extensive area of hypoperfusion in his right retina, particularly the superficial retinal plexus, yet central visual fields were normal. Paracentral acute middle maculopathy was identified in a patient with migraine with aura experiencing a central scotoma lasting days by a finding of hyperreflective bands within the inner nuclear layer of the retina on optical coherence tomography (70).

In nearly half of reported cases of retinal migraine, patients ultimately experienced permanent monocular visual defects, but no consistent pattern of visual field loss was noted. Severe narrowing or occlusion of retinal arteries and veins was observed rarely (26; 20; 10; 57; 76; 21; 81; 04; 05; 33; 53; 46; 14; 30; 03; 55; 08; 18; 06). The diagnoses of anterior or posterior ischemic optic neuropathy were reported in a dozen or so cases (44; McDonald and Sanders 1971; 17; 13; 90; 12; 73; 52; 54; 60; 47; 32; 06). Other findings included cotton wool spots (49; 93), retinal pigmentary change (10), central retinal venous occlusion (24; 11; 39), central serous retinopathy (85), optic nerve atrophy (24; 09), optic disc edema (44), paracentral acute middle maculopathy (71), and hemorrhages of the optic nerve, retina, or vitreous (26; 16; 27).

Prognosis and complications

Although retinal migraine has traditionally been viewed as a benign condition, it appears that patients with migraine may have subclinical precortical visual dysfunction and permanent attacks of partial or complete monocular visual loss occur more often than generally appreciated. Studies with automated perimetry have demonstrated subclinical visual field defects in some asymptomatic patients with migraine (63). There was a correlation between these findings and duration of disease and advancing age.

Some patients with retinal migraine who experience transient monocular visual loss may present with considerable variation in phenotype (either continuing to have transient visual loss or experiencing new attacks of permanent visual loss), whereas others only experience permanent monocular visual loss without a preexisting history of transient visual loss. No specific factor has been identified to account for this variation in phenotype or for the heterogeneity of this condition (34). Just as migraine aura sometimes gives rise to migrainous infarction, the authors believe that irreversible visual loss is part of the spectrum of retinal migraine and perhaps a form of migrainous infarction. Patients with retinal migraine appear to have prolonged and permanent monocular visual loss much more commonly than do those with conventional migraine who experience prolonged typical aura or migrainous infarction. The high number of patients with transient monocular visual loss who eventually develop permanent monocular visual loss makes retinal migraine a less benign condition than migraine with conventional visual aura. Therefore, although no data determine the efficacy of preventive treatment for this entity, prophylactic drug therapy seems prudent even if attacks are infrequent (35).

Clinical vignette

A 44-year-old woman suffered from attacks of migraine without aura since the age of 30. The headaches began in the right nuchal and temple regions, typically lasted one to two days, and occurred an average of one to two times per month, usually in association with her menses. Associated features included photophobia, phonophobia, osmophobia, nausea, vomiting, facial pallor, and dysarthria. One year before presentation, the patient experienced one to two attacks per week of her otherwise typical migraine headache associated with recurrent bouts of monocular visual loss ipsilateral to the headache. Complete blindness of the right eye always began 30 minutes into the headache. Alternately covering each eye during attacks confirmed that the visual changes were limited to the right eye. The monocular visual loss lasted the entire duration of the headache, ranging from eight hours to three days, and then fully resolved. There was a strong family history of migraine. Past history included asthma and abnormal uterine bleeding. The patient drank alcoholic beverages occasionally but denied cigarette smoking and illicit drug use.

Her general medical, ophthalmologic, and neurologic examinations were normal. Investigations included a CT scan of the brain, MRI and angiogram of the brain, MR angiogram of the neck, echocardiography, and extensive hematologic tests, all of which were within normal limits. The patient was treated with topiramate 300 mg daily with complete cessation of her recurrent bouts of monocular visual loss as well as a reduction of headaches (one per month).

Biological basis

Etiology and pathogenesis

The underlying pathophysiology of retinal migraine remains largely unknown. Bouts of transient monocular visual loss lasting less than 1 hour, transient monocular visual loss of prolonged duration, and transient monocular visual loss that later becomes permanent correspond clinically to the conventional auras of migraine, prolonged auras, and migrainous infarction, respectively. Perhaps these three phenomena affecting the cerebrum (especially the cortex) or the eye (especially the retina) share common pathophysiologic mechanisms (35). Spreading depression of cortical neurons is the accepted concept of the typical aura of migraine and perhaps a similar mechanism affects the retina. This phenomenon has been noted in the retina of the chicken (86). The expression of major NMDA receptor subtypes, NR1, NR2A, and NR2B, and calcitonin-gene related peptide (CGRP) receptors (89) in the chick retina makes them pertinent targets for pharmacologic inhibition of spreading depression (88). One patient who described her transient monocular visual loss as black paint slowly dripping down from the corner of her monocular visual field may well be describing spreading depression of the retina (36).

Primary vascular dysregulation is associated with retinal vascular disease and is comorbid with migraine. Theoretically, it could be a factor in the pathogenesis of retinal migraine (22). Ischemia is the other mechanism commonly invoked to explain permanent monocular visual loss in the setting of migraine. Vasospasm of retinal arterioles and veins has been demonstrated in cases of transient monocular visual loss where no other predisposition to vascular disease was discovered (23; 01). Vasospasm during migraine headaches has also been angiographically documented (82). Although vasospasm is no longer considered the primary cause of the focal neurologic deficits of migraine, this older concept of migraine may account for a shared pathophysiology in some cases (35).

Some studies, such as kinetic arc perimetry (15), measurements with flickering light stimuli (68), motion coherence perimetry (66), and measurements of contrast thresholds for static and moving stimuli (69), implicated both cortical and precortical visual sites. A reduction in nerve fiber layer thickness has been found in migraine patients in contrast to control subjects (29). The significance of these findings to retinal migraine is uncertain.

Minor risk factors for vascular disease were identified in only a few patients with transient and permanent monocular visual loss. They included hypertension, hyperthyroidism, pregnancy, diabetes, oral contraceptive use, smoking, and increased levels of factor VIII. These conditions were not thought to be the main cause of the visual loss.

Epidemiology

Retinal migraine is thought to be a rare disorder, but its true prevalence and incidence are unknown (07). In a review of the literature, Hill and associates applied strict International Headache Society, 2nd edition, criteria in a broad-based review of the reported cases of transient monocular visual loss, finding only five of 142 cases that met definite criteria for retinal migraine. The authors attributed the other cases of transient monocular visual loss to retinal vasospasm (43; 91). Using strict International Headache Society, 3rd edition, criteria, Maher and colleagues identified only 12 cases of retinal migraine in a literature review between 2006 and 2020 (65). In another review, nearly two thirds of patients with retinal migraine were found to be female (35). More than half of the patients experienced only transient monocular visual loss, whereas the remainder later developed permanent monocular visual loss in association with otherwise typical attacks of migraine. Men and women were equally affected in the transient group, whereas the permanent group showed a female preponderance, with a female-to-male ratio of 2.5:1. Age at onset of retinal migraine ranged from seven to 54 years. Mean age at onset was similar in both groups (24.7 years for the transient group, 23 years for the permanent group). The duration of retinal migraine before diagnosis ranged from days to several decades. Similarly, the evolution from transient to permanent attacks of monocular visual loss in the permanent group was variable, occurring within the same year of retinal migraine onset and up to 52 years later. With the exception of one case, in which attacks of transient monocular visual loss ceased after oral contraceptives were discontinued, no specific precipitating events were identified. Thirty percent of patients had a documented family history of migraine. Because many cases did not include information on family history, this number may be underestimated. Only two patients had familial retinal migraine (62).

Prevention

One treatment approach focuses on the avoidance of potential migraine triggers (ie, stress, use of oral contraceptives, smoking) by patients with infrequent attacks. It has been suggested that prophylactic therapy should be deferred when patients have infrequent attacks, ie, less than one attack per month (45). However, this course of action may not be prudent because episodes of permanent monocular visual loss can occur in migraineurs with and without prior attacks of transient monocular visual loss (34).

Differential diagnosis

Patients often have difficulty distinguishing between the loss of vision in one homonymous hemifield and the loss of vision in one eye. To accurately make this distinction, the patient must alternately cover each eye and compare their views. The description of hemifield loss with both eyes open is characteristic of a homonymous hemianopia rather than monocular visual loss. If uniocular visual loss is confirmed, one must attempt to exclude other causes of transient or permanent monocular visual loss. The differential diagnosis of retinal migraine includes amaurosis fugax. In retinal migraine, visual loss typically evolves slowly and often lasts longer than amaurosis fugax of carotid artery origin. The “shade dropping over a visual field,” typical of microembolization, was not reported by patients with retinal migraine. Other causes of transient monocular visual loss include atherosclerosis; thrombus originating from the carotid artery, heart, or great vessels; giant cell arteritis; other arteritides with or without autoimmune diseases; primary vascular disease of the central retinal artery or vein; illicit drug use; demyelinating disease; and hypercoagulable states, such as macroglobulinemia, polycythemia, anticardiolipin antibody syndrome, and sickle cell disease. Less common causes are transseptal cardiac catheterization and orbital diseases, including mass lesions, retinal detachment, orbital vasculitis, and intermittent angle-closure glaucoma (64; 35; 75; 79).

Diagnostic workup

The clinician needs to identify or exclude secondary causes of transient monocular blindness because retinal migraine is a diagnosis of exclusion. If a patient’s history or general physical, ophthalmologic, or neurologic examination includes atypical features, imaging studies or other diagnostic testing is warranted. Features that should prompt concern for an underlying secondary cause of headache with transient monocular blindness include absence of a typical migraine history, onset after the age of 50, incomplete resolution of monocular visual loss, concomitant medical problems that can precipitate attacks of transient monocular blindness, and the presence of atypical neurologic signs or symptoms. All cases with persistent monocular visual loss should be fully investigated. To exclude the possibility of a cardioembolic source, investigations such as electrocardiography, echocardiography, and Holter monitoring need to be performed. Diagnostic testing of patients with suspected ischemic disease of the eye or brain should include duplex scanning, CT, high-resolution MRI and angiography, fluorescein angiography, and, in uncertain cases, conventional angiography. Neuroimaging can exclude an orbital or intracranial mass. Other diagnostic possibilities, such as vasculitis, hypercoagulable states, illicit drug use, and rheumatologic disorders, require a complete laboratory evaluation, consisting of a complete blood count with differential and platelet count, prothrombin time, partial thromboplastin time, toxic drug screen, lupus anticoagulant and anticardiolipin antibody levels, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody titer, antiphospholipid antibodies, protein C and S, antithrombin III levels, and serum protein electrophoresis (34; 75).

Management

No clear guidelines exist regarding the management of patients with retinal migraine. In an attempt to prevent irreversible ocular damage, early medical management with daily aspirin and a migraine preventive agent may be advisable (34). Prophylactic medications that anecdotally have benefit include calcium channel blockers (ie, verapamil, nifedipine, nimodipine), tricyclic antidepressants (ie, nortriptyline), beta-blockers (ie, propranolol), and neuromodulators (ie, divalproex sodium, topiramate). Aspirin is a logical agent because of its antiplatelet activity. In a few cases, simple monotherapy reduced the frequency of migraine with and without monocular visual defects. The authors favor antiepileptic drugs (ie, topiramate or divalproex sodium) and tricyclic antidepressants (ie, amitriptyline or nortriptyline). Though some patients respond to beta-blockers, we do not usually recommend beta-blockers because of their theoretical potential for arteriolar constriction. Although episodes of vasospastic amaurosis fugax appear to have been successfully treated with calcium channel blockers (92), they were not effective in the few patients the authors treated. Several patients unfortunately were refractory to many migraine preventives given as monotherapy or in combination.

There is currently insufficient clinical information to support specific recommendations for acute medical therapy in the treatment of retinal migraine. Given the potential risk of worsening any underlying vasospasm, medications with vasoconstrictive properties (ie, ergotamine, triptans) should not be used (34). Only a few patients were treated with acute medication during the attack of retinal migraine. Inhaled carbon dioxide improved vision “slightly” in one patient during one attack, whereas amyl nitrate and isoproterenol via inhaler showed “good efficacy” in improving the visual loss in a few patients. None of these medications helped relieve the headache (58; 59). Patients who experienced permanent monocular visual loss showed no consistent benefit from calcium channel blockers, oral and intravenous corticosteroids, or vasodilators (35).