Migraine Aura Without Headache by Shih-Pin Chen MD Phd (Dr

Migraine aura without headache By Shih-Pin Chen MD PhD (Dr. Chen of the National Yang-Ming University School of Medicine has no relevant financial relationships to disclose.) Originally released December 30, 1993; last updated March 20, 2017; expires March 20, 2020

Introduction

This article includes discussion of migraine aura without headache and acephalgic migraine. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Migraine is a common neurologic disorder that is prevalent in the younger population. With age, migraine prevalence decreases, but some people continue to experience migraine auras without the subsequent or associated headache pain. In this article, the author reviews the clinical manifestations, prevalence, pathophysiology, therapeutic options, and prognosis for this selective group of patients. Breakthroughs in understanding the pathogenesis and clinical manifestations are highlighted.

Key points • Typical aura is consisted of visual, sensory, or speech symptoms with a mix of positive and negative features and complete reversibility. • Migraine aura could initiate from multiple distinct sites, propagate nonconcentrically with a variable extent in the occipital cortex, and can sometimes be clinically “silent”. • Differential diagnoses, including transient ischemic attack, should be considered when aura is late-onset with predominant negative features or is prolonged or of very short duration. • Cortical spreading depression, glutamatergic neurotransmission, channelopathies, neuronal-glial gap-junction communications, and microembolization might be important players in the pathogenesis of migraine aura. • Migraine with aura is associated with higher risks of subclinical brain lesions, ischemic or hemorrhagic strokes, and all cause mortalities; whether this remains true for “migraine aura without headache” requires further studies.

Historical note and terminology

Migrainous aura has been used to explain unusual visions, experiences, and perceptions that have been experienced by well-known personages. Lewis Carroll's pictorial descriptions in Alice in Wonderland and Alice Through the Looking Glass have been ascribed to his migrainous auras. His depiction of Alice may be a manifestation of the micropsia, macropsia, or metamorphopsia seen in migrainous auras of childhood.

There have also been suggestions that the painter Pablo Picasso may have had migrainous auras. His works feature illusory splitting in the vertical plane of his subjects' faces, and this has been compared to similar paintings by migraine patients depicting what they see during their aura phase (Podoll 2000). The absence of descriptions of the painter suffering from headaches may infer the presence of migraine aura without headache.

Fisher described a series of 120 patients: 25 had only visual symptoms; 18 had visual symptoms and paresthesias; 7 had visual symptoms and speech disturbances; 14 had visual and brainstem symptoms; 7 had visual symptoms, paresthesias, and speech disturbances; 25 had visual symptoms, paresthesias, speech disturbances, and paresis; 9 had recurrence of old stroke deficit; and 8 had miscellaneous symptoms (Fisher 1980). In 1986, a study of 85 cases demonstrated that 21 patients had visual symptoms; 6 had visual symptoms and paresthesias; 2 had visual symptoms and speech disturbances; 3 had visual symptoms, paresthesias and speech disturbances; 20 had visual symptoms, paresthesias, speech disturbances, and weakness; 3 had visual and brainstem symptoms; and 32 were without visual symptoms. Their ages ranged from 40 to 73 years. In only 40% of cases did headache occur in association with the episodes. These episodes have been coined ‘‘late-life migraine accompaniments,” “migraine equivalents,” “acephalic migraine,” or “migraine aura without headache.” 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 (Fisher 1999). 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.

Other migrainous auras unaccompanied by headache include paresthesias, speech disturbances, motor weakness, and brainstem symptoms, as depicted in Fisher's report (Fisher 1980). 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 (Hansen et al 2016). 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 (beta version), 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 followings: visual, sensory, speech and/or language, motor, brainstem, and retinal (Headache Classification Committee of the International Headache Society 2013). These aura symptoms should fulfill at least 2 of the following characteristics: 1.) At least 1 aura symptom spreads gradually over 5 minutes, or 2 or more symptoms occur in succession; 2.) Each individual aura symptom lasts 5 to 60 minutes; and 3.) At least 1 aura symptom is unilateral. In a systemic 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 (Viana et al 2016). 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 (Viana et al 2013). The term “prolonged aura” might be clinically useful for atypical cases.

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. 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 (MacGregor and Guillebaud 1998). A few cases of patients with migraine headache without aura developing a retinal infarct have been recorded. A report suggested that patients suffering from migraine with aura and having more than 1 migraine attack a month have a greater risk of having a subclinical infarct in the cerebellar area as seen on MRI (Kruit et al 2004). Subsequent studies also demonstrated increased risks of transient ischemic attacks (Rist et al 2010), ischemic infarcts (Kurth et al 2011), hemorrhagic strokes (Kurth et al 2010), cardiovascular events (Gudmundsson et al 2010), and all-cause mortalities (Gudmundsson et al 2010) in patients with migraine with aura. This has implications for patients having migraine aura without headache, as they tend to be older with more risk factors for having stroke and, therefore, an argument may be made to treat these patients with 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 that his first attack of migraine aura without headache had appeared 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 3 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. Both vascular and neurogenic causes of migraine have been proposed, but it now appears that the 2 causes are tightly intertwined. Following are some of the prevailing theories:

Cortical spreading depression. The spreading cortical depression of Leao, a primary brain phenomenon, may account for the clinical symptoms of migraine with aura (Barkley et al 1990). A number of studies have shown that the aura phase of migraine is associated with a reduction of cerebral blood flow in the gray matter of the posterior part of the hemisphere contralateral to the affected visual field, paresthesia, or other focal neurologic symptoms (Olesen et al 1990; Cutrer et al 1998). The cerebral blood flow reduction appears to move across the cortex at a rate of 3 to 6 mm/min and is preceded by a phase of hyperperfusion consistent with that seen in cortical spreading depression (Cao et al 1999). By using high-field functional MRI, it was further demonstrated that blood oxygenation level-dependent (BOLD) signal changes recorded during visual aura attacks originate within extrastriate cortex (area V3A), exhibit characteristics of cortical spreading depression, and follow the retinotopic progression of the visual percept (Hadjikhani et al 2001). Interestingly, area V3A was found to have reduced connectivity with the salience network (the anterior insula) in patients with migraine with aura, but not in patients with migraine without aura, indicating an interictal brain pathology specific to migraine aura (Niddam et al 2016).

Genetic basis. Studies using transgenic mice carrying the human familial hemiplegic migraine gene largely advanced the understanding of pathophysiology of migraine aura and have implicated glutamatergic neurotransmission as a critical modulator of cortical spreading depression (Pietrobon 2010).

Except for rare monogenic subtypes such as familial hemiplegic migraine, no genetic or molecular markers for migraine had been convincingly established until 2010. The first genome-wide association study for migraine demonstrated that a common variant, r21835740 on 8q22.1, was associated with susceptibility of migraine, especially in migraine with aura (Anttila et al 2010). The study proposed that that the predisposing allele rs1835740 primarily affects glutamate metabolism, through regulating the expression of metadherin (MTDH, also called astrocyte elevated gene-1, AEG-1). However, this variant was not associated with the aura symptoms (visual, sensory, aphasic, and basilar type aura) or duration in a Danish population (Esserlind et al 2012). In addition, in subsequent genome-wide association studies or meta-analysis, this variant was not replicated in patients with either migraine with aura or migraine without aura (Chasman et al 2011; Freilinger et al 2012; Anttila et al 2013). 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) responsible for a common hereditary form of migraine with aura was identified (Lafreniere et al 2010). 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.

Microemboli. 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 (Nozari et al 2010). Two clinical studies also observed an increased prevalence of patent foramen ovale among patients with migraine aura without headache, and the closure of patent foramen ovale was correlated with improvement of the visual aura (Khessali et al 2012; Mojadidi et al 2012). Nonetheless, these observations need to be explored further because studies investigating patent foramen ovale in migraineurs have not reached consistent findings (Schwedt et al 2008; Garg et al 2010).

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 (Hauge et al 2009). The link between cortical spreading depression and trigeminovascular system. Cortical spreading depression somehow triggers the trigeminovascular complex with release of neuropeptides (eg, neurokinin A, substance P, and calcitonin gene related peptide), which causes a sterile neurogenic inflammation and sensitizes the sensory nerve fibers surrounding the meningeal arteries (Strassman et al 1996; Bolay et al 2002). 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. Direct data showed that cortical spreading depression could activate meningeal nociceptors and central trigeminovascular neurons (Zhang et al 2010; Zhang et al 2011). The spreading depression- induced activation of the trigeminal meningeal nociceptors might be mediated by activation of pannexin-1 channel (Karatas et al 2013).

In migraine aura without headache, there is nonprogression from the aura to the headache phase. Therefore, the cortical spreading depression is not followed by activation of the trigeminal vascular complex. Why this is so is not known; it may be postulated that these patients have a higher activation threshold of the trigeminovascular 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 (Hansen et al 2013). The study 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"

In the Framingham cohort study (Wijman et al 1998), 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 increased risk of stroke, and invasive diagnostic procedures or therapeutic measures are generally not indicated.

Alvarez, a Mayo Clinic physician with a personal interest in 618 cases of migraine collected over 30 years, found that 12% of the men and 0.7% of the women had migraine aura without headache (Alvarez 1960). In another study the lifetime prevalences of migraine without aura, migraine with aura, migraine aura without headache, and migrainous disorder were found to be 8%, 4%, 1%, and 1%, respectively, in men and 16%, 7%, 3%, and 2%, respectively, in women (Russell et al 1995).

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 (9 girls, 5 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 migraines. 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. Nine patients described their aura as often colorful photopsias or scintillating scotomas. Two patients had micropsia, 1 had temporal distortion (time "speeded up"), 1 had hyperacusis, and 1 had a vague sense of disconnection from her surroundings. Only 2 patients had a headache occasionally associated with the described aura. Nine patients also had migraines with aura, with auras distinct from those observed during these patients' acephalic episodes. Neurologic examination, electrophysiologic investigation (EEG/evoked potentials), and neuroimaging were noncontributory in all instances (Shevell 1996).

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 (Fleming 2000). 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 (Aiba et al 2010).

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 (Martins et al 2012).

Prevention

A case report of migraine with prolonged aura prevented by propranolol 40 mg daily is noteworthy (Bento and Esperanca 2000). Some have suggested that the calcium channel antagonists and antiepileptic drugs may be useful in prevention (Silberstein et al 2001). Verapamil, flunarizine, divalproex, lamotrigine, and gabapentin have all been found to be effective (Lampl et al 2000). A study looking at treatment of migraines with aura with topiramate showed that it reduced migraine frequency, duration and intensity as expected but migraine aura frequency was unaffected (Lampl et al 2004).

Pascual and colleagues looked at the efficacy of lamotrigine in treating disturbing migraine auras. Of the 47 patients treated, 30 (68%) responded. Included in this group were 6 patients who had aura without headache. The mean monthly frequency of migraine auras in these 30 patients changed from 4.2 to 0.7. The response was considered excellent (more than 75% reduction) in 21 cases (70% of responders). Auras reappeared in 2 months in 9 of 13 patients where lamotrigine was stopped and ceased as soon as the drug was reintroduced (Pascual 2004). 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 among those therapeutic agents (Thissen et al 2014).

A case report found that lomerizine, a calcium channel blocker, is effective in reducing migraine with aura and visual aura without headache in an elderly patient, with concomitant restoration of cerebral hypoperfusion (Aoyagi et al 2011).

Differential diagnosis

The major differential diagnosis is 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. There were no significant differences in the prevalence of vascular risk factors and diseases in the 2 groups. Only 1 patient with migraine aura without headache suffered a subsequent vascular event (myocardial infarction). Three patients with transient ischemic attack had strokes, and 2 others died from vascular disease. 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.

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 (Gowers 1906). A systemic study of visual phenomena and headache in occipital epilepsy as well as differentiation from migraine (Panayiotopoulos 1999) supports Gower's views.

“Visual snow” is a persistent disturbance in the entire visual field, resembling the “static” or “snow” noises of an 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 (Schankin et al 2014a); however, there might be a pathophysiological overlap of visual snow and typical migraine aura (Schankin et al 2014b).

Hypoglycemic episodes in diabetes may rarely cause visual disturbances that resemble migraine aura, but systemic symptoms are usual, and headache often follows the episode (Martins and Blau 1989).

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 antiphospholipid antibodies, protein C and S antibodies, and antithrombin III antibodies, is prudent.

An MRI scan with enhancement can reveal an arteriovenous malformation 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. Vertebral artery stenosis is currently not remediable and, therefore, uncovering it serves little purpose, although daily aspirin or anticoagulant therapy should be kept in mind.

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

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 (Wolff 1963). Wolff argued that these observations supported a vascular basis for both the aura and the headache, but dilated vessels could equally enable more oxygen or glucose to reach the brain from the circulation. In 25 trials, 15 patients inhaled a 10% carbon dioxide and 90% oxygen mixture. This cleared the auras completely; no headache followed in 5 instances (Wolff 1963). Nifedipine has been found to be effective in terminating the aura but not headache phase of a migraine attack (Goldner 1987; Hoffert 1992). Other medications that are effective in treating prolonged auras include corticosteroids, neuroleptics, and intravenous magnesium and furosemide (Rozen 2000). 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 (Bates et al 1994). In the same trial the aura duration was unaffected in those who had migraine aura followed by headache, and the ensuing headache ran its normal course (Bates et al 1994). However, a case was reported of a patient with prolonged visual migraine auras without headache, who successfully treated her auras with oral sumatriptan, reducing the duration of auras from 1.5 hours to 20 minutes (Kowacs et al 1999).

For prevention, calcium channel antagonists and anticonvulsants have been reported to be effective in preventing the occurrence of migraine aura without headache (Lampl 1999; Aoyagi et al 2011).

A gap-junction inhibitor, tonabersat, was found to be able to modulate cellular communication between nerve cells and glial cells in the trigeminal ganglion and, thus, to inhibit cortical spreading depression and neurogenic inflammation. A clinical trial demonstrated that tonabersat could reduce the median number of aura attacks (with or without headache) from 3.2 per 12 weeks to 1.0 per 12 weeks (p=0.01) and could be considered a specific therapy for patients with migraine aura (Hauge et al 2009).

Novel nonpharmacological treatments that deserve consideration are transcranial magnetic stimulation or vagus nerve stimulation. Using a hand-held device that delivers 2 pulses of transcranial magnetic stimulation to treat migraine in the aura phase, Lipton and colleagues demonstrated that 39% of the treatment group achieved a pain-free response 2 hours after treatment for the first attack compared with 22% in the sham stimulation group, resulting in a "therapeutic gain" of 17% (95% confidence interval, 3% to 31%; p=.0179) (Lipton et al 2010). This effect might be mediated through modulation of cortical spreading depression, as shown in animal studies (Andreou et al 2016). Direct or transcutaneous vagus nerve stimulation was also found to be effective in suppressing cortical spreading depression (Chen et al 2016), making it a potential therapeutic choice for migraine aura.

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Former authors

Joseph N Blau MD (original author) and Hua C Siow MD

ICD and OMIM codes

ICD codes

ICD-9: Migraine aura without headache: 346.1

ICD-10: Migraine aura without headache: G43.1

Profile

Age range of presentation

06-12 years 13-18 years 19-44 years 45-64 years 65+ years

Sex preponderance male>female, >2:1 male>female, >1:1

Family history none

Heredity none

Population groups selectively affected none selectively affected

Occupation groups selectively affected none selectively affected

Differential diagnosis list transient ischemic attack strokes vascular disease epilepsy occipital epilepsy hypoglycemic episodes diabetes

Associated disorders

Migraine aura Visual migraine