Clinical manifestations

Presentation and course

Historically, an aura without migraine headache was described as slowly evolving patterns of scintillating scotomas that have precisely the same range of patterns and duration of evolution. On reaching middle age, patients with typical migraine preceded by aura can continue to have auras without the succeeding headache. It can be preceded by hunger, tiredness, or increased micturition frequency, similar to the prodromes of migraine attacks, and it can be followed by lassitude and photophobia, which are frequent migraine postdromal symptoms. Precipitants of migraine aura without headache (ie, hunger, bright lights, insufficient sleep, and anoxia) are also triggers of migraine with and without aura.

Fisher has published a personal account of life with migrainous auras without headache (23). He described 41 episodes of scintillating zigzags that occurred when he was between 59 and 85 years of age. The spells occurred irregularly and were unrelated to season of the year, time of day, activity at onset, diet, or temperamental state. The characteristic appearance was a flickering zigzag line that began centrally and migrated to the periphery. The display, which was stereotyped, was achromatic. The average duration was 15 minutes. Both visual fields were equally involved, though never at the same time.

A multicenter study in patients with migraine with aura showed that visual aura symptoms were variable and often overlapping, and approximately half of the patients reported nonvisual aura symptoms, with sensory and speech symptoms being the most common (35). Of note, prospective recordings for 861 aura attacks in this study showed that 27% of the aura attacks were not followed by headache, in contrast to 4% to 10% in previous studies.

The International Classification of Headache Disorders, 3rd edition, proposed the diagnostic criteria for typical aura without headache (code 1.2.1.2), which allows the aura symptoms to be one or more of the following: visual, sensory, speech, and/or language, with the exclusion of motor, brainstem, and retinal symptoms (38). In the beta version of the 3rd edition, the diagnostic criteria for 1.2 migraine with aura have been substituted in the definitive classification by the appendix A1.2 migraine with aura criteria. Indeed, the latter performed better in distinguishing migraine with aura from transient ischemic attacks. The typical aura symptoms to fulfill the 1.2. typical aura without headache diagnosis should demonstrate, during two attacks, at least three of the following characteristics (criterion C of 1.2 migraine with aura diagnostic criteria, if the aura is not accompanied, nor followed within 60 minutes, by headache): (1) at least one aura symptom spreads gradually over 5 minutes; (2) two or more aura symptoms occur in succession; (3) each individual aura symptom lasts 5 to 60 minutes; (4) at least one aura symptom is unilateral; and (5) at least one aura symptom is positive. In a systematic review, however, it was found that a nonhemiplegic migraine aura could last longer than 1 hour in a significant proportion of migraineurs, especially in patients with nonvisual aura symptoms (66). A prospective study also showed that 14% of visual aura symptoms, 21% of sensory symptoms, and 17% of dysphasic symptoms last for more than 1 hour (68). The term “prolonged aura” has been abandoned because it is not rare that the aura lasts for more than 1 hour but, in such cases, patients have to show at least two of the other typical characteristics of 1.2 migraine with aura criterion C during the same attack or at least in their usual attacks to fulfill criteria for one of the recognized subtypes or subforms of 1.2 migraine with aura. The classification recommends coding the cases that do not have these characteristics as 1.5.2 probable migraine with aura, specifying, the atypical feature in parenthesis (eg, prolonged aura).

Prognosis and complications

Unlike migraine headache, which frequently lessens or even disappears after 55 years of age, migraine aura without headache often persists without permanent deficit into the 70s and 80s. Current guidelines state that female migraineurs without aura who develop an aura while on combined oral contraceptives must stop this mode of contraception, as they are at risk for developing strokes (49). Combined hormonal contraceptives are contraindicated based on data from the 1960s and 1970s, with higher doses of estrogen than current drugs. In fact, ischemic stroke risk might not be significantly increased with low-dose estrogen, and ultra-low-dose formulations may conversely reduce the frequency of aura (12; 31); however, a metanalysis pointed out that oral contraceptives could account for a slightly increased risk of subarachnoid hemorrhage (73). Further studies are needed to assess the stroke risk, and precautionary suspension of oral contraceptives is still recommended in migraine with aura. A report suggested that patients suffering from migraine with aura and having more than one migraine attack a month have a greater risk of having a subclinical infarct in the cerebellar area as seen on MRI (45). Some meta-analyses have shown the increased long-term risk of cardiovascular and cerebrovascular events, particularly in patients with aura (41; 50). The implications of these data for patients having migraine aura without headache are not clear, with a lack of data to recommend preventive therapy. Although solid data are still lacking, controlling traditional vascular risk factors is believed to be the mainstay in preventing these complications.

Clinical vignette

A 69-year-old man reported his first attack of migraine aura without headache 4 years earlier. While reading the morning paper, the patient noticed that the print looked a little unclear in the center of his vision. A bright dot appeared 2 to 3 minutes later; this gradually spread into his upper left visual field, making an arc-shaped zigzag. It took about 5 minutes to develop to its full extent; it lasted another 10 minutes and then disappeared suddenly. There was no ensuing headache. The man had three more attacks in the next 2 years without any trigger being identified.

He emphasized that he was retired and under no stress. He had never experienced any migrainous symptoms prior to the first attack.

Biological basis

Etiology and pathogenesis

Migraine aura without headache is considered a migraine-associated phenomenon, although typical aura symptoms could be an isolated phenomenon or accompany other conditions or other primary headaches, being described in about 25% of cluster headache patients (18). The connection between aura and headache, particularly migraine pathophysiology, has been largely discussed (10). Both vascular and neurogenic causes that have been proposed are tightly intertwined. The following are some of the prevailing theories:

Cortical spreading depression. The cortical spreading depression of Leao, a primary brain phenomenon, may account for the clinical symptoms of migraine with aura (07). Although there are some arguments against its role, cortical spreading depression is still recognized as the most likely pathophysiological mechanism of migraine aura (11; 38). A number of studies have shown that the aura phase of migraine is associated with a reduction of cerebral blood flow, moving across the cortex at a rate of 3 to 6 mm/min in the gray matter of the posterior part of the hemisphere contralateral to the affected visual field, paresthesia, or other focal neurologic symptoms, preceded by a phase of hyperperfusion (54; 17; 13). These phenomena were also demonstrated by using neuroimaging of the cerebral cortex, particularly functional MRI, with the analysis of blood oxygenation level-dependent signal changes within extrastriate cortex (area V3A) recorded during visual aura attacks that exhibit the characteristics of the cortical spreading depression and follow the retinotopic progression of the visual percept (32). Combined PET/MRI imaging showed glial activation in migraineurs with aura in areas possibly involved in cortical spreading depression generation (primary visual cortex, visual areas V3A, and Broca area), as well as with areas involved in pain processing (thalamus and primary/secondary somatosensory and insular cortices) (32). Many studies have explored the role of innate immunity in neuroinflammation in migraine pathophysiology (09). According to a study, the NLRP3 inflammasome assembly happened within 15 minutes of cortical spreading depression, and inhibiting NLRP3 or Panx1 through genetic or pharmacological methods reduced cortical spreading depression-induced neuronal inflammation and related symptoms (14). This raises the possibility that an aberrant NRLP3 pathway could prevent the progression of an aura to the subsequent headache episode. However, further studies are required to validate this likely mechanism in specific patient groups.

Genetic basis. Studies using transgenic mice carrying the human familial hemiplegic migraine gene and newly developed optogenetics methods largely advanced the understanding of pathophysiology of migraine aura and cortical spreading depression (36).

Except for rare monogenic subtypes such as familial hemiplegic migraine, no genetic or molecular markers for migraine had been convincingly established until the first genome-wide association study in 2010 (06). Later, a huge amount of genetic data was analyzed, with partially consistent results. One meta-analysis combined 22 genome-wide association studies from the International Headache Genetics Consortium comprising 59,674 migraine cases with a confirmed number of 44 independent single nucleotide polymorphisms significantly associated with migraine and 38 distinct genomic loci (including the X chromosome for the first time) (29). Most of the migraine loci involved in vascular development and pain processing were implicated in migraine with or without aura. Seven genomic loci (TSPAN2, TRPM8, PHACTR1, FHL5, ASTN2, near FGF6 and LRP1) were significantly associated with migraine without aura (06), but none with migraine with aura, probably reflecting the smaller sample size.

In another international collaborative study, a dominant-negative mutation in the gene encoding the 2-pore domain potassium channel TRESK (TWIK-related spinal cord potassium channel) was the first ever described discovered causative gene for a common hereditary form of migraine with aura (46). Although further studies are required to explore whether these findings are generalizable, these studies provided direct evidence of genetic predisposition of migraine aura and implicated potential therapeutic targets.

Endothelial dysfunction and microemboli. A clinic-based study considered young women (125 patients with migraine with and without aura) for changes in coagulatory, inflammatory, and oxidative stress parameters and reported a strong association between biomarkers of endothelial activation and migraine, especially for migraine with aura (64).

One study demonstrated that microemboli could cause cortical spreading depression in a mouse model, providing a link between cardiac or extracardiac right-to-left shunt and migraine aura (53). In young patients with cryptogenic stroke and frequent migraine with aura, there is an outstanding prevalence of patent foramen ovale (93%) (70). The higher prevalence of patent foramen ovale in migraineurs, especially with aura, with respect to the general population, and positive results of nonrandomized studies of patent foramen ovale closure, led to randomized clinical trials that failed their primary endpoints and, although registering modest reduction in headache frequencies, the trials were burdened by procedural complications (26). However, migraine aura physiopathology seems to be related to right-left shunt and atrial septal aneurysms as syndromic comorbidities, possibly affecting disease history (04). This finding strengthens the link between cardiovascular development and the aura conundrum.

Gap junction theory. Gap junctions that provide communication between astrocytes and neurons were recognized to be important in the pathogenesis of cortical spreading depression, and a gap-junction inhibitor, tonabersat, was found to be effective in inhibiting cortical spreading depression and reducing migraine aura (37).

The link between cortical spreading depression and trigeminovascular system. Cortical spreading depression somehow triggers the trigeminovascular complex with the release of neuropeptides (eg, neurokinin A, substance P, and calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide), which causes a sterile neurogenic inflammation and sensitizes the sensory nerve fibers surrounding the meningeal arteries (27). These nociceptive inputs are carried into the trigeminal nucleus caudalis and then to the contralateral ventrobasal and medial thalamus and finally to the cortex via the quintothalamic tract. The spreading depression-induced activation of the trigeminal meningeal nociceptors might be mediated by activation of pannexin-1 channel (44). Moreover, it was demonstrated in an animal model that calcitonin gene-related peptide receptor antagonist MK-8825 attenuated pain induced by trigeminal nerve activation without altering cortical spreading depression (21).

In migraine aura without headache, there is no progression from the aura to the headache phase. Therefore, the cortical spreading depression is not followed by activation of the trigeminal vascular complex. A study analyzing the detailed drawings of a patient’s visual percept of more than 1000 attacks of migraine aura without headache over 18 years revealed the distinctive anatomical and physiological features of migraine aura (33). Another study analyzed 216 auras in 72 patients and reported inconstant temporal succession between aura and headache and a high inter- and intravariability of aura characteristics (67). These studies found that auras in a given individual can initiate from multiple distinct sites, can propagate nonconcentrically with a variable extent in the occipital cortex, and can sometimes be clinically “silent.”

Epidemiology

The Global Burden of Disease Study showed that the worldwide prevalence of migraine is two to three times more prevalent in women than in men, with peaks in prevalence in both sexes between 30 to 39 years of age (25). However, the ratio of migraine prevalence between men and women is not consistent across all age ranges. Longitudinal studies evaluating aura symptoms are not very common.

In the Framingham cohort study (71), 2110 subjects were questioned biannually from 1971 to 1989 about visual symptoms. Twenty-six (1.23%) had migrainous visual episodes; the majority (77%) began after the age of 50 years; they were stereotypic in 65%. The episodes lasted 15 to 60 minutes in 50% of subjects; 58% never had headaches accompanying the episodes; and 42% had no headache history. The authors concluded that late-life onset transient visual phenomena similar to the visual migraine aura are not rare and often occur in the absence of headache. Such symptoms appear not to be associated with an increased risk of stroke, and invasive diagnostic procedures or therapeutic measures are generally not indicated.

A French 1-year prospective study enrolled 3773 migraine patients. Migraine with aura was reported in 26% of patients, with 6% of them (57 of 978) over 50 years of age. Prevalence of first-time migraine aura after 50 was 1.8%, and typical aura without headache was reported by 61% of them (11 of 18). Occurrence of aura exclusively without headache was reported by 17% (3 of 18) (20).

In a further prospective population-based study from Italy with 574 patients, the lifetime prevalence for typical aura without headache was 0.9% (men 1.6%; women 0.3%) (60). The incidence of migraine aura without headache has not been well documented in the pediatric population. However, a single university-based pediatric neurologist performed a retrospective review of pediatric migraine patients. Shevell identified 14 patients (nine girls, five boys) who had migraine aura without headache, representing 2% of all patients with a primary diagnosis of migraine. Thirteen patients had a strong family history of migraine. Age of symptom onset ranged from 5 to 12 years, with a mean of 8 years. Symptoms were episodic in all patients, varying in frequency from weekly to (more typically) monthly and generally lasting less than 10 minutes (61).

In Alabama, a questionnaire survey of 1000 patients presenting for a comprehensive eye examination revealed that 6.5% reported experiencing visual sensations consistent with migraine aura without headache. The prevalence in males was 2.9%, and in females, 8.6%. A multivariate analysis revealed that female gender (odds ratio [OR] = 2.3), a history of migraine headaches (OR = 3.2), and a history of childhood motion sickness (OR = 2.7) were significantly related to migraine aura without headache (24). A Japanese study demonstrated that 35 out of 1063 patients (3.2%; 1.1% males and 2.1% females) in general ophthalmologic clinics had typical aura without headache. The age of patients with typical aura without headache showed a biphasic distribution: 20 to 39 years and 60 to 69 years (02).

Patients with late-onset aura (≥ 45 years of age at aura onset) shared identical clinical features, risk factors, and comorbidities with patients with early-onset aura, except that patients with late-onset aura were more likely to not fulfill all ICHD-II aura criteria and to lack headache (52).

Prevention

There are no relevant data showing how typical aura can be prevented or mitigated by means of lifestyle or dietary elements.

An open preliminary study to evaluate the efficacy of ginkgolide B in migraine reported a reduction of both duration and frequency of aura (03).

Differential diagnosis

The major differential diagnosis is transient ischemic attack. The updated diagnostic criteria of International Classification of Headache Disorders, 3rd edition, perform better in distinguishing between aura and transient ischemic attack. Although transient ischemic attacks develop abruptly with a sudden onset of symptoms, the onset of symptoms in migraine aura without headache is generally gradual and spreads or intensifies over minutes or hours. Dennis and colleagues examined 50 cases prospectively and compared them with 50 age-matched patients who had suffered from transient ischemic attack (19). Although the results are not conclusive, they do suggest that patients with the clinical characteristics of migraine aura without headache have a low risk of subsequent vascular events than those with transient ischemic attacks, despite having a similar prevalence of vascular risk factors (19).

Epilepsy may also be associated with auras, but these auras are characteristic. The epileptic aura is momentary, lasts seconds and not minutes, and usually consists of big blotches of light, figures, faces, or scenes rather than geometric patterns (30). A systemic study of visual phenomena and headache in occipital epilepsy as well as differentiation from migraine (55) supports Gower's views.

“Visual snow” is a persistent disturbance in the entire visual field, resembling the “static” or “snow” noises of analogue television. Patients with visual snow are commonly comorbid with migraine and have been given various diagnoses historically, including persistent migraine aura, post-hallucinogen flashback, or psychogenic disorder, etc. Some studies suggest that visual snow is a unique visual disturbance distinct from persistent migraine aura (58); however, there might be a pathophysiological overlap of visual snow and typical migraine aura (59).

Hypoglycemic episodes in diabetes may rarely cause visual disturbances that resemble migraine aura, but systemic symptoms are usual, and headache often follows the episode (51).

Diagnostic workup

A complete blood count and an erythrocyte sedimentation rate should be done to rule out anemia, polycythemia, thrombocytic abnormalities, systemic infections, and systemic arterial inflammation. When prolonged auras are present (especially in women with a personal or family history of deep venous thrombosis, miscarriages, or strokes), a coagulation workup, including prothrombin time, activated partial thromboplastin time, homocysteine, protein C and S, fibrinogen, antithrombin III, dosage, resistance to activated protein C (if the latter is positive, screening for the factor V Leiden mutation), Willebrand factor and tissue plasminogen activator antigens, and antiphospholipid antibodies, is prudent.

An MRI scan could show altered diffusion-weighted imaging sequences following transient ischemic attacks or epileptic discharges. An MRI with enhancement can reveal an arteriovenous malformation, cerebral venous thrombosis, or, rarely, a subdural hematoma that was missed on CT scan.

Carotid artery ultrasonography will show stenosis or a plaque, which may or may not be relevant.

Ophthalmic and cardiac opinions should be sought when a permanent visual defect or a change of pattern, whether cerebral or retinal, raises the possibility of a transient ischemic attack.

Management

The typical aura is transient, and acute treatment targeting this symptom should have an immediate effect to be considered in clinical practice.

In 1963 Wolff utilized inhalation therapy for migraine aura. Within 1 to 5 minutes of inhaling amyl nitrite or a carbon dioxide and air mixture, auras disappeared and then reappeared, whereas a carbon dioxide and oxygen mixture for 5 minutes completely cleared the aura. There was no recurrence, and the usual headache did not follow (72). Nifedipine has been found to be effective in terminating the aura but not headache phase of a migraine attack (28; 39). Other medications that are effective in treating prolonged auras include corticosteroids, neuroleptics, and intravenous magnesium and furosemide (57). A double-blind, randomized, controlled trial investigated the effect of intranasal ketamine versus intranasal midazolam in patients with prolonged aura and showed efficacy of ketamine in reducing severity of aura but not its duration; midazolam had no effect on aura (01). In a double-blind, placebo-controlled trial, 6 mg of sumatriptan injected subcutaneously neither shortened nor prolonged the visual aura in 17 patients with migraine aura without headache, and in those who had migraine aura followed by headache the ensuing headache ran its normal course (08). A post-hoc analysis from multiple randomized trials indicates that sumatriptan is less effective as acute treatment for attacks with aura (34).

There are no randomized, controlled trial studies for preventive treatment in typical aura without migraine. Commonly used medications for migraine prophylaxis showed efficacy inhibiting cortical spreading depression (62). Among antiepileptics, valproate, topiramate, levetiracetam, and mostly, lamotrigine are reported to effectively diminish both frequency and duration of aura symptoms (69). Beta-blockers, particularly metoprolol and propranolol, reduced auras in both open-label and randomized-controlled trials (43; 42). Tonabersat showed a preventive effect reducing the number of aura attacks but not headache days (37).

A review analyzing 47 cases with persistent migraine aura showed that most drugs have little effect in this special subset of patients; however, lamotrigine seems to be the most effective drug (63). In a small open-labeled pilot study, based on the role of the acid-sensing ion channel 1, the drug amiloride reduced aura and headache in four of seven patients with intractable aura (40).

Aspirin has been tested for aura prophylaxis; an observational case series of 49 patients with assumption of aspirin 80 mg daily reported aura frequency reduction in 93% of cases and the complete remission of auras in almost 50% (65). These data are corroborated by a retrospective study (05).

A small open-label clinical trial (18 patients, 22 auras) was performed to assess greater occipital nerve block for the acute treatment of prolonged or persistent migraine aura and showed promising results to be confirmed in randomized clinical trials (16).

Novel nonpharmacological treatments that deserve consideration are transcranial magnetic stimulation or vagus nerve stimulation. A systematic review on transcranial magnetic stimulation based on five studies concluded a possible effectiveness for migraine with aura treatment (47). Direct or transcutaneous vagus nerve stimulation was also found to be effective in suppressing cortical spreading depression (15), making it a potential therapeutic choice for migraine aura.

Special considerations

Pregnancy

Migraine aura seems to be related to increased levels of estradiol (eg, oral contraceptive, pregnancy), possibly related to a thrombophilic state with markers of endothelial activation (64).