Clinical manifestations

Presentation and course

Migraine with brainstem aura is an episodic disorder and occurs in 1.5% of patients with headache (80). More than one third of subjects have their first attack in the second decade of life, and two thirds in the second or third decade (67). The condition also occurs frequently in children (36), and a small number of cases may present for the first time after age 50. The condition may occur in combination with other types of migraine, but migraine with brainstem aura remains the dominant form in more than 75% of cases (67). At first, Bickerstaff noted predominance of teenage girls in his basilar artery migraine population, but subsequent experience revealed a female incidence similar to other types of migraine (08). The highest female-to-male ratio (approximately 3:1) is found when migraine with brainstem aura first presents in the second decade of life (67). Not uncommonly, when basilar artery migraine begins in the teens, the frequency of attacks diminishes in adult life and is replaced by other forms of migraine (09; 11).

Patients who suffer from migraine with brainstem aura identify precipitating factors similar to those of other forms of migraine. Precipitating factors were identified by 71% of subjects in one series (67). Intense emotional stimuli (74%) and sleep disorders (65%) were the most common trigger factors, followed by change in weather, sunshine, cold wind, acute stress, alcohol, and fatigue (80).

Migraine with brainstem aura occurred in 23 out of 348 patients (6.6%) with migraine with nonhemiplegic aura. Mean age at onset was 20.3 ± 11.7 years (range 6 to 49 years). Among these patients, 15 out of 23 patients (65%) reported bilateral pain, and 8 out of 23 patients (35%) reported unilateral pain. The basilar-type aura comprised diplopia (52%), vertigo (43%), tinnitus (43%), bilateral visual symptoms (39%), hypacusia (26%), ataxia (26%), dysarthria (22%), bilateral paresthesias (13%), and decreased level of consciousness (13%) (80).

The aura lasts from 5 minutes to 60 minutes in the majority of cases, but it can extend up to 3 days. Visual symptoms commonly occur first, predominantly in the temporal and nasal fields of vision. The visual disturbance may consist of blurred vision, teichopsia, scintillating scotoma, and graying or total loss of vision. The features may start in one visual field and then spread to become bilateral. Hallucinations of body magnification, especially that of the head and hands corresponding to the dominance of these regions in the sensory cerebral cortex, are also seen (62). Bickerstaff pointed out that when vision is not completely obscured, diplopia might occur, usually as a sixth nerve weakness (11). Some forms of diplopia may appear in as many as 16% of cases (67). Visual symptoms are typically followed by bilateral paresthesias of arms and legs and are frequently associated with a combination of the aforementioned “brainstem symptoms” (12).

Tingling and numbness occur in more than 60% of cases in a typical cheiro-oral spreading pattern seen in migraine with aura. This condition is usually bilateral and symmetrical but may alternate sides in a hemi-distribution pattern. Occasionally, dysesthesia will extend to the trunk.

Vertigo is the most common brainstem symptom, occurring in 61% to 63% of patients (67; 41). Higher frequencies of vertigo attacks, neurologic symptoms, and saccadic dysmetria occurred in patients with migraine with brainstem aura as compared to those with migrainous vertigo (74). The ataxia and tinnitus may accompany or be independent of vertigo. Dysarthria is as frequent as vertigo.

Impairment of consciousness is common (67). Patients may enter into a state of impaired consciousness that resembles sleep from which they may be easily aroused by stimulation, only to return to the same state (09). Rarely, this progresses to stupor and prolonged coma (47; 24; 52). Other forms of altered consciousness include amnesia, syncope, and drop attacks with transient loss of consciousness.

Seizures have been observed in association with migraine with brainstem aura (10; 06). EEG changes without clinical seizures during attacks of typical basilar artery migraine have also been described (44), and these cases are said to have a good response to anticonvulsants (44; 14; 45; 68). De Romanis and colleagues did a long-term follow-up study in seven children with migraine with brainstem aura who had EEG findings of occipital spike-wave complexes and found that the EEG normalized once the migraine with brainstem aura resolved (20). Three of his patients developed seizures, and four developed migraine with aura.

Migraine with brainstem aura associated with conversion symptoms (abnormal movements, pseudo-epileptic fits, or motor, sensation, or sensory deficits) was also reported, and shaking was the most common symptom (58.1%) (27).

Migrainous stroke in a 56-year-old man has been reported (54). He presented with symptoms of a left cerebellar infarct and underwent a thorough evaluation for all possible causes, and none were found. He had an NIH Stroke Scale score of 3 on hospital admission that was reduced to a score of 1 on follow-up 3 months later. Interestingly, his migraines in the left occipital region decreased in frequency (from two per month to one per year) and severity (from 6 or 7 out of 10, to 2 out of 10) after stroke. This may be due to the impairment of vasodilatory responses of the cerebral arteries after a stroke.

In most patients, headache is located in the occipital region. The headache is of a throbbing, pounding nature and is accompanied by severe nausea and vomiting. It is unusual for the headache to be unilateral or localized to the more anterior parts of the cranium. Photophobia and phonophobia occur in one third to one half of the patients. As with other forms of migraine, the symptoms may occur without headache, but this is seen in no more than 4% of cases (67).

Whether migraine with brainstem aura is an independent disease or only a specific form of migraine with typical aura has been explored. In one study, the clinical features of 38 patients with migraine with brainstem aura were analyzed (41). The median duration of aura was 60 minutes (range of 2 minutes to 72 hours), and symptoms included vertigo (61%), dysarthria (53%), tinnitus (45%), diplopia (45%), bilateral visual symptoms (40%), bilateral paresthesias (24%), decreased level of consciousness (21%), hypacusia (21%), and ataxia (5%). Besides the basilar-type aura, all patients described visual aura symptoms during the attacks of migraine with brainstem aura, 61% had a unilateral or bilateral sensory aura, and 40% had aphasic aura. Overall, 95% of the patients with migraine with brainstem aura (36 out of 38) also reported attacks of migraine with typical aura at other times. The study concluded that there was no firm evidence to establish migraine with brainstem aura as an independent disease.

One study suggests that any symptom of so-called brainstem aura may have a cortical origin based on the latest data from functional mapping and clinical observation studies (19). Vertigo, tinnitus or hypacusis, diplopia, dysarthria, and ataxia can originate from a vestibular cortex, auditory cortex, parieto-occipital, precentral gyri, and parietal lobe, respectively. Alteration of consciousness can reflect abnormal neural activation within specific consciousness networks including posterior parietal or prefrontal and cortices. This hypothesis would probably explain the co-occurrence of typical and brain-stem aura during attacks, and these two types of aura fit clinical consequence of a transient cortical dysfunction caused by a cortical spreading depression. The authors further propose that migraine with brainstem aura should be classified as one kind of typical migraine aura.

In addition to brainstem aura, symptoms may originate within the cortex; Yamani and colleagues analyzed all patients with migraine with brainstem aura from the Danish Headache Center (DHC) and a large sample of telephone-interviewed patients with migraine with aura (79). The telephone-interviewed cohort included 1781 subjects with a diagnosis of migraine with aura or probable migraine with aura. Of these, 228 fulfilled the diagnostic criteria for migraine with brainstem aura of the ICHD-3. However, after the face-to-face interview, neurologic examination, and imaging studies, 4 of 293 cases with migraine with brainstem aura (1.37%) were found, corresponding to 0.04% of the general population. They concluded that telephone interview based on the ICHD-3 diagnostic criteria for migraine with brainstem aura is too open and suggested developing tighter criteria of a core syndrome caused by brainstem dysfunction.

Prognosis and complications

The prognosis for migraine with brainstem aura is generally good. Most frequently, patients had their first attacks between the ages of 11 and 20 years (80). The disorder declines in frequency as the patients enter their 20s and 30s. One study demonstrated the favorable long-term outcome of migraine with brainstem aura in children or adolescence: the headache remission rate was 38.5% in migraine with brainstem aura, compared to 23.4% of all patients with migraine with aura (70).

Rarely, migraine with brainstem aura is complicated by stroke, most often in the posterior cerebral artery (11; 76) but also other terminal arteries (65). Migraine is associated with cardiovascular risk factors, and the risk of stroke is increased at least twofold in those with migraine with aura, smoking habit, and oral contraceptive use (23; 43; 66). However, there is no evidence that patients with migraine with brainstem aura have higher risk of stroke than patients with migraine with typical aura. Nevertheless, one case report showed a patient who developed ventricular tachycardia during migraine with brainstem aura attack, which is believed to be related to autonomic dysregulation (61).

Clinical vignette

A 33-year-old, right-handed Caucasian female presented with a history of headaches that began at 18 years of age and were accompanied by spells of visual disturbances and syncope. The headaches improved when the patient was pregnant, but in the postnatal period her visual symptoms and syncope became worse. The headaches were mostly in the left occipital, frontal, and periorbital regions and were reported to be throbbing, accompanied by nausea and vomiting, and lasting as long as 3 days. About an hour prior to the onset of the headaches, the patient would get visual auras consisting of zigzag lines, blurry vision, tunnel vision, left hemianopsia, and palinopsia; the auras would last up to 15 minutes. About once a week, she would have a syncopal spell with loss of consciousness for up to 5 minutes that may or may not have been followed by a headache. EEG, MRI, and MRA were performed and were all normal. She was started on verapamil, and her syncopal episodes promptly ceased. However, she continued to have visual auras, and her headaches increased in frequency. The dose of verapamil was increased, but this caused her to have expressive and receptive aphasic spells. She also experienced blindness and vertigo; these symptoms lasted up to 10 minutes. The dose of verapamil was then reduced, and she was put on lamotrigine and coenzyme Q10; her visual auras and vertigo ceased, and she did not have further aphasic episodes.

Biological basis

Etiology and pathogenesis

Migraine with brainstem aura is considered a variant of migraine, with the aura symptoms arising from the brainstem or bilateral occipital hemispheres.

Genetics. There were reports that migraine with brainstem aura could be associated with CACNA1A non-sense mutation at codon position 583 (63) and ATA1A2 gene (R548H) (02). However, no causative mutations of these two genes were identified in three other reports (41; 17; 18).

Migraine is currently considered a neurovascular disorder related to primary dysfunction of brainstem nuclei involved in nociceptive modulation. The pain of migraine probably arises from complex interactions of (1) the pain-sensitive cranial blood vessels, (2) the trigeminal nerve fibers that innervate them, and (3) the cranial parasympathetic outflow (30). Neurogenic inflammation, produced by the antidromic release of neuropeptides by trigeminal nerve endings, induces the vasodilatation and extravasation of plasma proteins, as well as the sensitization of trigeminal nociceptive nerve endings. Cytokines and chemokines play a role in migraine pain as mediators in neurovascular inflammation and activators of the trigeminal nerve (25).

The brainstem nuclei of the locus ceruleus, the dorsal raphe nuclei, and the periaqueductal gray may be important to the pathogenesis of migraine in general and migraine with brainstem aura in particular. These nuclei regulate cerebral blood flow, influence cortical neuron excitability, and modulate endogenous pain control mechanisms. PET scans taken during acute migraine attacks have demonstrated that brainstem structures are important in the genesis of migraine. These scans have consistently shown increased activation (indicating increases in regional cerebral blood flow values) in median brainstem structures (including periaqueductal gray, midbrain reticular formation, dorsal raphe nuclei, and locus ceruleus) contralateral to the headache side (75; 04). Stimulation of the locus ceruleus reduces cerebral blood flow while causing extracerebral vasodilatation. It is possible that activation of the locus ceruleus causes a vasoconstriction of the basilar artery resulting in brainstem symptoms typical for migraine with brainstem aura, but further studies are needed.

A study with vestibular evoked myogenic potential (VEMP) testing evaluated the sacculo-collic reflex in 20 patients with basilar artery migraine. Absent or delayed VEMPs were detected in some of them, suggesting the descending pathway from the saccule through the brainstem to cranial nerve XI is interrupted, which the authors attributed to hypoperfusion in the territory of the basilar artery. After relief of headache and vertigo following 3 months of medication, 10 asymptomatic patients with either absent or delayed VEMPs before treatment underwent follow-up VEMP testing, and nine of the patients (90%) displayed normal VEMPs bilaterally, suggesting reversible ischemia in the territory of the basilar artery (53).

Vass and colleagues proposed that inner ear symptoms like phonophobia, tinnitus, fluctuation in hearing perception, and increased noise sensitivity provide indirect evidence that cochlear blood vessels are also affected by basilar artery migraine. They examined neuronally mediated permeability changes in the cochlea and basilar artery by colloidal silver and Evans Blue extravasation, following orthodromic and antidromic stimulation of the trigeminal ganglion innervating the cochlea. Capsaicin and electrical stimulation induced both dose- and time-dependent plasma extravasation of colloidal silver and Evans Blue from the basilar artery and anterior inferior cerebellar artery. Both orthodromic and antidromic activation of trigeminal sensory fibers also induced cochlear vascular permeability changes and significant quantitative differences between the treated and control groups in spectrophotometric assays. These results characterize a vasoactive connection between the cochlea and vertebrobasilar system through the trigeminal sensory neurons. Thus, they proposed that vertigo, tinnitus, and hearing deficits associated with migraine with brainstem aura could arise by excitation of the trigeminal nerve fibers in the cochlea, resulting in local plasma extravasation. In addition, cochlear “dysfunction” may also trigger basilar and cluster headache by afferent input to the trigeminal system (73).

Lodi and colleagues studied 78 patients with migraine in attack-free periods, of whom 37 had migraine with typical aura or migraine with brainstem aura, and found that in the occipital lobes of all subgroups of migraine, cytosolic free Mg2+ as well as the free energy released by the reaction of ATP hydrolysis were significantly reduced (55). Among patients with migraine, the level of free energy released by the reaction of ATP hydrolysis and the cytosolic free Mg2+ showed a trend in keeping with the severity of clinical phenotype, both showing the lowest values in patients with migraine stroke and the highest in patients with migraine without aura. These suggest that the reduction in free Mg2+ in tissues with mitochondrial dysfunction is secondary to the bioenergetics deficit and are against a primary role of low brain cytosolic free Mg2+ in causing the bioenergetics deficit in headache. There may, therefore, be little role for magnesium supplementation as a treatment modality in these patients.

One study with stimulation single-fiber EMG on a group of migraineurs revealed that single-fiber EMG abnormalities were almost exclusively seen in patients with migraine with aura, especially if they had prolonged auras or multiple aura types (03). As single-fiber EMG abnormalities are also seen in patients with familial hemiplegic migraine, they postulate that the CACNA1A gene may also be involved in common forms of migraine with aura with resulting P/Q calcium channel dysfunction.

Epidemiology

No population-based epidemiologic surveys have been conducted on migraine with brainstem aura. Migraine with brainstem aura is a rare migraine subtype that accounts for approximately 1.5% of headaches (41; 80). In a Danish clinic-based sample, migraine with brainstem aura occurred in 10% of patients with migraine with aura (38 out of 362) (41).

Prevention

Migraine with brainstem aura may be prevented by non-pharmacologic and pharmacologic management.

Differential diagnosis

The differential diagnoses of migraine with brainstem aura include cerebrovascular diseases, seizure, and hereditary disorders. The accuracy of the clinical diagnosis can be significantly improved by carefully considering the symptoms that present, the timeline of their course, their relationship to other symptoms, and by actively looking for potential causes (57).

Cerebrovascular diseases are the most serious differential diagnosis of migraine with brainstem aura (59). Transient ischemic attacks involving any part of the vertebrobasilar territory must be considered, particularly if migraine with brainstem aura presents for the first time in the later life. The features of posterior cerebral artery ischemia include photopsia with single and formed visual hallucinations, hemianopic visual loss, transient numbness, episodic light-headedness, confusional spells, tinnitus, and headache (10; 26; 76). Thus, posterior cerebral artery ischemia alone can mimic migraine with brainstem aura. Patients with primary brainstem hemorrhage or subarachnoid hemorrhage commonly present with headache and neurologic deficits, but these will rarely figure into the differential diagnosis unless the symptoms are presenting for the first time. Cerebral arteriovenous malformations of the occipital cortex may present with attacks of migraine with visual aura, complicated by seizures and brainstem neurologic deficits (42). Antiphospholipid antibody syndrome (49) and thrombotic thrombocytopenic purpura can present with transient ischemic attacks and headache.

Episodic seizures, particularly of temporal lobe origin, must be considered in the differential diagnosis of migraine with brainstem aura because of similar symptoms, eg, vertigo, imbalance, confusion, memory disturbance, disorders of consciousness, visual symptoms, and postictal headache (28). However, the visual aura of migraine develops slowly, within minutes, consisting of mainly achromatic and linear patterns, whereas the visual aura of occipital lobe seizure (idiopathic childhood occipital epilepsy of Gastaut) is short-lasting bright colors and circular shapes (58). On the contrary, migraine and seizure are common conditions, and a patient may have both migraine and seizure simultaneously.

Hereditary disorders that present with neurologic deficits similar to attacks of migraine with brainstem aura include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and mitochondrial encephalopathy with lactic acidosis and stroke (MELAS). CADASIL is an adult-onset inherited disease due to mutations in the Notch3 gene on chromosome 19p13. Recurrent attacks of severe migrainous headaches with aura, which include transient hemiparesis and brainstem symptoms, have been seen in patients with CADASIL (07; 72). MELAS is associated with several mutations in mitochondrial DNA. Multi-system involvement, lactic acidosis, and recurrent episodes of headache (mostly migraine) are part of the clinical spectrum (22).

Other disorders that may feature in the differential diagnosis include alternating hemiplegia of childhood, meningoencephalitis (82), neoplasia, compressive lesions of the cervicomedullary junction, multiple sclerosis, and Kleine-Levin syndrome (56).

Criteria based on the International Classification of Headache Disorders (ICHD-3) beta-version for 1.2 migraine with aura (MA), 1.2.1 migraine with typical aura (MTA), 1.2.3 hemiplegic migraine, 1.2.2 migraine with brainstem aura, and the alternative criteria A1.2 migraine with aura and A1.2.1 migraine with typical aura according to ICHD-2 were field tested in a cross-sectional study. This study showed that too many patients fulfilled ICHD-2 and ICHD-3 beta criteria for 1.2.2 migraine with brainstem aura, and it suggests that the criteria for 1.2.2 migraine with brainstem aura should be more restrictive (51).

Diagnostic workup

There are no specific diagnostic tests for migraine with brainstem aura. The methods of investigation depend on the clinical characteristics and findings. The patient history and the physical and neurologic examinations are the most important tools for diagnosing migraine with brainstem aura. Blood tests may include a complete blood count (to exclude anemia, polycythemia, and platelet dysfunction), electrolytes, drug screen, lactate, erythrocyte sedimentation rate, antiphospholipid antibody panel, and special coagulation profiles. EEG abnormalities are detected in less than one fifth of cases with migraine with brainstem aura (40) and are mostly independent of any clinical manifestation of the disorder. Ictal EEG may be indicated for migraine with brainstem aura, because it is helpful in the differential diagnosis of impaired consciousness and seizure (64). Brainstem and visual evoked responses are not needed unless a complex differential diagnosis is considered.

The seriousness of the neurologic deficit associated with migraine with brainstem aura and the gravity of the potential differential diagnosis are important reasons for an imaging study. MRI is the image of choice because of its sensitivity to focal ischemic lesions and posterior fossa structures. MRA may be helpful in detecting vasculopathies such as arteriovenous malformations, aneurysms, and arterial dissection. Transcranial Doppler studies can provide noninvasive information on basilar artery function (83; 46). When migraine with brainstem aura is associated with familial disorders in which seizures and stroke may figure (eg, MELAS), muscle biopsy and a lactate exercise test may be indicated.

As a final comment, it seems appropriate to quote Bickerstaff himself on the ideal approach to differential diagnosis. It is prudent to maintain the mindset that this should be a diagnosis of exclusion.

Because the clinical picture produced by basilar artery disturbance can be so varied, it is perhaps a little too easy to include under the diagnosis of basilar artery migraine puzzling transient syndromes within this territory. Basilar artery migraine is a diagnosis which is unprovable and great care is required in labeling a patient with such a diagnosis, which, having been made, might be perpetuated without adequate attempts to further elucidate the cause (11).

Management

The management of migraine with brainstem aura consists of non-pharmacologic and pharmacologic therapy. The subjects must eat regular meals, obtain regular sleep, and avoid stress. They should deal with stress through relaxation or the use of coping strategies. They should attempt to identify the triggers of migraine and remove them from their everyday lives, because the incidence of triggers appears to be high in migraine with brainstem aura (67).

Although few randomized, controlled drug trials have been conducted for migraine with brainstem aura, the general principles of pharmacologic treatment of migraine can be applied with modifications. Acute attacks can be treated with analgesics such as aspirin or non-steroidal anti-inflammatory agents (NSAIDs) in combination with an antiemetic drug to improve gastrointestinal absorption. Triptans and ergotamines were excluded in the earlier trials because of potential vasoconstrictive properties and have not been well studied. Their safety profiles remain uncertain due to lack of clinical data, so the packages for all triptans continue to label this restriction. Greater occipital nerve blockade has been used to abort migraine with brainstem aura within minutes (05). If consciousness is persistently impaired or if seizure or coma occurs, hospital admission may be justified. A group of antimigraine drugs targeting 5-hydroxytryptamine1F (5-HT1F) receptors (lasmiditan), and gepants (rimegepant and ubrogepant), a group of calcitonin gene-related peptide (CGRP) receptor antagonists, have demonstrated efficacy and tolerability for the acute treatment of migraine in either phase 2 or phase 3 randomized clinical trials (37; 78). The lack of cardiovascular risks of these new classes of migraine-specific treatments may be used to relieve the acute symptoms of individuals with migraine with brainstem aura (77).

As for preventive therapy, a more aggressive approach is warranted even if the attacks occur only two to three times a year, because the attacks may be disabling or require hospitalization. All the prophylactic agents for migraine with or without aura could be used for migraine with brainstem aura. Calcium channel blockers such as verapamil and flunarizine are probably the drugs of choice, as both have been shown to be effective in the treatment of familial hemiplegic migraine (32; 81). Another calcium channel blocker, cinnarizine, is safe and effective in reducing both headache and vertigo aspects of migraine plus vertigo among the patients who suffer from either vestibular migraine or migraine with brainstem aura (69). The beta blockers and methysergide may be used with caution due to their potential vasoconstrictive properties (01). The tricyclic antidepressants might be avoided if EEG abnormalities are present, due to their propensity to promote seizure activity. In this circumstance, anticonvulsants such as sodium valproate, topiramate, and lamotrigine would be the drugs of choice. One small placebo-controlled trial confirmed the efficacy and safety of topiramate (25 mg and 100 mg) for prophylaxis of migraine with brainstem aura in children (50). There is also an anecdotal report that three women with a 5-year follow-up and one child with migraine with brainstem aura responded well to lamotrigine (21; 16; 38). CGRP monoclonal antibodies (CGRP mAbs) are now used for the prevention of migraine (15). Although there is no research on the treatment of migraine with brain stem aura, CGRP mAbs may be the most promising for future consideration.

Special considerations

Pregnancy

The subject of migraine and pregnancy has been reviewed (13). In general, the frequency of migraine is reduced during pregnancy, but there is no epidemiologic information specific to migraine with brainstem aura. One case report provided the association between migraine with brainstem aura and pregnancy (39). However, there are considerable diagnostic uncertainties in this case.

Anesthesia

Although there are no known special requirements for anesthesia, the perioperative period can predispose the patients to migraine attacks because of stress, bright lights, and the use of general anesthesia or opioids (71; 29). There is a reported case of “migraine with atypical aura” with symptoms and signs similar to migraine with brainstem aura that developed in the recovery room (60). The patients with migraine with brainstem aura should, therefore, receive appropriate preoperative evaluation and postoperative care.