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Abstract

Background

Migraine with brainstem aura is defined as a migraine with aura including at least two of the following symptoms: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and/or decreased level of consciousness.

Aim

The aim of this study is to review data coming from clinical observations and functional mapping that support the role of the cerebral cortex in the initiation of brainstem aura symptoms.

Results

Vertigo can result from a vestibular cortex dysfunction, while tinnitus and hypacusis can originate within the auditory cortex. Diplopia can reflect a parieto-occipital involvement. Dysarthria can be caused by dysfunctions located in precentral gyri. Ataxia can reflect abnormal processing of vestibular, sensory, or visual inputs by the parietal lobe. Alteration of consciousness can be caused by abnormal neural activation within specific consciousness networks that include prefrontal and posterior parietal cortices.

Conclusion

Any symptom of so-called brainstem aura can originate within the cortex. Based on these data, we suggest that brainstem aura could have a cortical origin. This hypothesis would explain the co-occurrence of typical and brainstem aura during attacks and would fit with the theory of cortical spreading depression. We propose that migraine with brainstem aura should be classified as a typical migraine aura.

Keywords

Migraine with brainstem aura basilar cortex spreading depression functional mapping

Introduction

Migraine with brainstem aura is defined as a migraine with aura including at least two of the following brainstem symptoms: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and/or decreased level of consciousness (1). This form of migraine was described in 1961 by Bickerstaff, who reported 34 patients with migraine attacks starting with visual manifestations followed by vertigo, ataxia, dysarthria and occasionally tinnitus, lasting from two to 45 minutes and followed by a migraine headache (2). At that time, the vasospastic theory supposed that ischemia was the cause of migraine aura symptoms. Migraine with aura including vertigo, ataxia, dysarthria and tinnitus was thus interpreted as a “migrainous disturbance affecting the basilar artery system” and was called “basilar artery migraine” (2). Later on, because the ischaemic hypothesis and the involvement of the basilar artery were questioned, basilar artery migraine was called “basilar-type migraine” (3) and then “migraine with brainstem aura” (1).

Since the original description of migraine with brainstem aura, significant advances have been made in the knowledge of migraine aura pathophysiology. Nowadays, typical migraine aura symptoms are thought to be the clinical consequence of a transient cortical dysfunction caused by a cortical spreading depression (CSD) (4). However, the underlying mechanisms of migraine with brainstem aura remain unclear and debated. One hypothesis could be that “brainstem” aura does not originate in the brainstem but has a cortical origin. Even though any symptom of brainstem aura can be observed in patients with brainstem lesions, numerous clinical observations and functional mapping data show that these latter symptoms can also originate within the cortex. A potential cortical origin of “brainstem” aura would explain the frequent association between symptoms of brainstem and of typical aura during attacks (5). This hypothesis would also explain the frequency of “brainstem” aura symptoms in hemiplegic migraine (6). Moreover, a cortical origin of any aura symptom (e.g. typical, brainstem-like and hemiplegic) would fit with the theory of cortical spreading depression as the underlying mechanism of migraine aura.

The aim of this study is to review data coming from clinical observations and functional mapping that support the role of the cerebral cortex in the initiation of clinical symptoms of migraine with brainstem aura.

Methods

This review was initiated with a PubMed search of the US National Library of Medicine with the following key words: [dysarthria] OR [vertigo] OR [tinnitus] OR [hypacusis] OR [diplopia] OR [ataxia] OR [decreased level of consciousness] AND ([migraine with basilar aura] OR [basilar-type migraine] OR [basilar artery migraine] OR [functional mapping] OR [stereo-electroencephalography] OR [cortical electrical stimulation] OR [epilepsy]).

Results

Characteristics of brainstem aura symptoms

According to the ICHD-3 β, symptoms of brainstem aura clearly originate from the brainstem and exclude motor weakness (1). Vertigo is one of the most common symptoms, reported by 43–63% of patients (5,7–8). It is described as rotational (65%), illusory self or object motion (43%), positional (22%) or as head motion intolerance (65%) (5). Auditory symptoms manifest as tinnitus (43–45%) or hypacusis (21–26%) (5,7). Diplopia is reported by 45–52% of patients (5,7) but, to the best of our knowledge, its precise clinical characteristics – monocular or binocular or bilateral monocular – remain to be described. Dysarthria is encountered in 22–57% of patients (5,7–8). Data regarding the prevalence of ataxia are more heterogeneous, ranging from 5–63% (5,7–8). These discrepant figures may be related to the fact that the assessment of ataxia can be challenging in migraineurs who suffer from concomitant visual, somatosensitive and/or vertigo aura. The interrelationships between these clinical features have already been suggested by Bickerstaff (2) in his descriptions: “Each attack is preceded by severe rotational vertigo, during which her gait becomes so ataxic that she has to lie down”; or, “the vision was failing in both eyes, and within fifteen seconds he was blind. At the same time, he had rotational vertigo and became extremely ataxic”. The last brainstem aura symptom is altered consciousness, which is reported by 13–24 % of patients (5 –7). However, the term “altered consciousness” may be ambiguous since it refers to loss of consciousness, confusion or amnesia in the descriptions of migraine with brainstem aura (5 –8).

Why not a cortical origin for brainstem aura symptoms?

The suspected origin of aura symptoms has long been based on “lesion mapping”, that is, the understanding of a regional brain function by studying deficits that result from focal brain lesions (9). Further studies have suggested that typical migraine aura symptoms are rather the clinical consequence of a transient neuronal dysfunction caused by a cortical spreading depression (CSD) than that of an exclusive loss of neuronal function caused by cerebral hypoxia (10). CSD is characterized by a propagating wave of neuronal hyperexcitability followed by a transient depression of cortical excitability that spreads at a characteristic rate of 3 to 5 mm per minute (11). The wave of neuronal excitation was proposed to cause positive migraine aura features and the prolonged depolarization to cause negative features (12). However, both positive and negative symptoms of migraine aura may also reflect a transient dysfunction of specific brain areas through which CSD is traveling (13), emphasizing the importance of functional mapping in the understanding of clinico-anatomical correlations of aura symptoms.

Several functional mapping tools, such as functional neuroimaging and electrical cortical stimulations, can be used to identify eloquent brain areas that are involved in physiological functions such as motor function, language, or memory. Direct cortical electrical stimulation performed in awake patients during surgical procedures or in patients with drug-resistant epilepsy undergoing stereo-electroencephalography (stereo-EEG or SEEG) leads to reproducible changes in neurological function including transient positive and negative features (14).

Several clinical observations obtained in epileptic patients, or in patients with brain lesions, as well as functional mapping data obtained in epileptic patients, might help us to better understand the clinico-anatomical correlations of aura symptoms.

Cortical origin of vertigo

Vertigo is not specific for brainstem dysfunction, but is also described in diseases affecting the vestibular cortex such as epilepsy. The link between vertigo and epilepsy had already been described more than 100 years ago (see Hewett and Bartolomei for a review) (15). Vertigo may either occur at seizure onset, or later in the development of seizures, or as the main ictal symptom of epileptic seizures (15). In patients with refractory epilepsy, SEEG recordings provided evidence that ictal vertigo can originate from several cortical regions including the superior parietal region (16) and the temporo-parieto-occipital junction (17). Transient vertigo is rare in vestibular cortex lesions, such as stroke, even though a few cases have been reported in patients with infarcts affecting the parieto-insular vestibular cortex (18). The reason why unilateral cortical infarcts rarely cause vertigo might be that the intact hemisphere, where vestibular and visual inputs are in agreement, determines the global perception of orientation and motion by suppressing the misleading information coming from the damaged hemisphere through trans-callosal connections (19).

Contrary to other sensory cortices, such as the visual cortex, the vestibular cortex refers to a multisensory cortical network that integrates pure vestibular, visual, and proprioceptive inputs (20). The parieto-insular vestibular cortex has been proposed as the core vestibular region (21). Recently, diffusion tensor imaging and functional connectivity magnetic resonance imaging showed a congruent functional and structural link between the vestibular nuclei located in the ponto-medullary brainstem and the ipsilateral and contralateral parieto-insular vestibular cortex (22). Direct electrical stimulations performed during SEEG elicit subjective vestibular sensations described as a feeling of bodily motion or rotation illusion (23) when applied to the precuneus, the inferior parietal lobule, the anterior part of the intraparietal sulcus, the posterior cingulate gyrus (14,23), the first and second temporal gyrus (20 –23) and the posterior part of the insula (24).

Cortical origin of auditory symptoms

Tinnitus is a conscious perception of sound in the absence of a corresponding external source (25). It may arise as an elementary auditory hallucination generated by the neocortical temporal lobe, notably within Heschl’s gyrus (26). Epileptic acoustic elementary hallucinations originating from the auditory cortex are described as like “hearing a tone, sound, noise, buzzing, humming” (27 –29). Less commonly, transient elementary auditory hallucinations can be symptomatic of a cortical lesion (30), mostly a temporal lobe infarction (31).

Hypacusia is reported during focal epileptic seizures and described as “ictal deafness” (32–33), as a feeling of “entering a soundproof room (see Florindo Bisulli et al., 2006 for review) (34) or a “fading of environment sounds” (28). Such symptoms are usually associated with epileptic discharges within the primary auditory cortex (34).

The auditory cortex is located within the posterior part of the superior temporal cortex including Heschl’s gyrus, the planum temporale, and some portion of the posterior superior temporal gyrus (35). Direct electrical stimulations performed during SEEG within Heschl’s gyrus produce tinnitus described as “whistle, puff, ringing, roar, musical tone” coming from the contralateral ear (36). Elementary auditory hallucinations can also be elicited during electrical stimulation within the inferior part of insular cortex (37–38).

Stimulations of the posterior part of the superior temporal gyrus produce auditory illusions such as “hearing sounds less clear or distant or suppressed”, while stimulations of the posterior part of the middle temporal gyrus induce “auditory illusion such as sounds getting distant” (39). Auditory dysfunction such as hypacusis or hearing suppression or deafness has also been observed during stimulation of the auditory cortex within the anterior lateral Heschl’s gyrus and posterior lateral superior temporal gyrus (40).

Cortical origin of diplopia

Monocular diplopia is classically the result of ophthalmic diseases, while binocular diplopia is associated with lesions affecting extraocular muscles, the neuromuscular junction, or oculomotor nerves. Less commonly, patients may describe bilateral monocular diplopia that persists whatever eye is closed (41). This rare type of cerebral diplopia, also called polyopia, manifests by seeing two or more images arranged in ordered rows and columns (42). Cerebral diplopia or polyopia is associated with a dysfunction of the primary or secondary visual cortex (41). Transient cerebral diplopia has been reported during focal epileptic seizures involving the parietal and/or the occipital cortex (43 –45). Cerebral diplopia has also been reported in a few patients with occipital ischemic lesions (46,47). According to Ffytche et al. (48), polyopia and palinopsia reflect an abnormal processing of visual inputs through the “dorsal stream” connections between the visual cortex and the parietal lobe coordinate systems.

Visual phenomena evoked by cortical stimulation are classified as elementary hallucinations (like a spot or a blob); intermediary hallucinations defined as geometric forms (kaleidoscope, star,); and complex hallucinations (49). Cerebral diplopia has been reported during the electrical stimulation of the posterior temporal gyrus (39) and the temporo-peri-sylvian vestibular cortex (23).

Cortical origin of dysarthria

Dysarthria is a speech disorder characterized by “the dysfunction in the initiation, control or coordination of the articulatory structures involved in speech output” (50). Dysarthria is a classical symptom of opercular syndrome. Paroxystic dysarthric speech may occur in opercular and insular-opercular seizures (51,52) while chronic dysarthria is a frequent manifestation of ischemic lesions affecting the lower opercular motor cortex (50 –53).

Direct cortical stimulations performed in awake patients were the first procedures to evaluate cortical language functions (54) and to map dysarthria-related stimulation sites within the lateral precentral and postcentral gyri (55). Further functional neuroimaging studies showed that articulation activates a wide cortical and subcortical network including the motor cortex, the post-central gyrus, the superior temporal and the temporo-parietal cortices, the insula, the putamen, and the cerebellum (56). The activation of the left insula is associated with the articulatory planning of orofacial movements, while the initiation and execution of articulation activates the bilateral premotor and motor cortices, the pre-SMA and the left putamen (56). Dysarthria can be elicited by stimulation within the precentral gyrus, postcentral gyrus, the parietal operculum (14,55) and the insula (38).

Cortical origin of ataxia

Ataxia can result from disorders affecting cortical areas involved in integration of external and interoceptive inputs (vestibular, visual, somatosensory) and coordination of motor outputs in a multilevel sensorimotor network (22). Cortical vestibular disorders can manifest as vertigo, Pusher syndrome, room tilt illusion, spatial hemineglect, spatial memory deficits that cause balance disturbance and ataxia (57). Vestibular epilepsy (see above) can manifest by balance disturbance or falls (16). Ischemic lesion affecting the insula may also lead to dizziness and unsteadiness leading to marked gait difficulty (58). Lesions of the posterior parietal region lead to impairment in reaching and grasping objects presented in the visual field opposite to the affected hemisphere, known as optic ataxia.

Electrical stimulations of the vestibular cortex elicit subjective symptoms of vertigo such as sensation of body oscillation, feeling of levitation, sensation of falling flat, illusion of falling backward and objective manifestations described as the need to hold something to prevent falls (23–24,39,59). Electrical stimulations of the parietal posterior cortex result in the alteration of a visually-guided reaching task (optic ataxia) (60).

Cortical origin of decreased consciousness

Consciousness is difficult to define and can refer to wakefulness (the level of consciousness) and awareness of the external environment and of self (the content of consciousness) (61). Most studies come from clinical, neurophysiological, imaging and neuroimaging evaluations performed in patients during sleep, anesthesia, coma, vegetative state, minimally conscious state, and epilepsy. Even though specific consciousness networks are not fully understood, many neuroimaging and neurophysiology studies have shown that conscious states are linked to activity in specific cortico-cortical and cortico-thalamo-cortical pathways. One of the most studied networks is the default mode network (DMN), which encompasses the precuneus/posterior cingulate cortex, the medial prefrontal cortex and the medial parietal cortex (62 –64). Patients with disorders of consciousness such as coma show reduced activity within brain areas linked to the DMN (65 –67). Seizures are frequently associated with an alteration of the content or of the level of consciousness. Altered content of consciousness such as loss of consciousness but also neglect, agnosia or amnesia can be observed during focal seizures (68). The level of consciousness can be altered in focal temporal, parietal or frontal seizures. Intracranial EEG recordings suggest that the loss of consciousness (absence of interaction with the examiner) that occurs during parietal, temporal and frontal seizures is associated with an increase of the neural synchrony within cortico-cortical networks, especially the prefrontal and parietal associative cortices, and thalamo-cortical networks (69 –71).

Alteration of consciousness defined as a disrupted consciousness is exceptionally elicited by cortical electrical stimulations. Recently, a clinical study has reported that electrical stimulations of a small brain area that encompasses the anterior-dorsal insula and the neighboring claustrum elicited in a patient an “immediate impairment of consciousness with arrest of reading, onset of blank staring, unresponsiveness to auditory or visual commands” (72). Most often, cortical stimulations result in alteration of awareness of the environment or of the self but without loss of consciousness. Parietal electrical stimulations may result in the initiation of psychic phenomena such as “being in a parallel world” or “extraneousness of the environment” in the posterior cingulate gyrus, “feelings of extraneousness to the environment” “déja-vu” in the medial posterior parietal cortex, feeling of “being in a cartoon” in the precuneus (73), feeling of having had a gap, of having been disconnected (74). Confusion, which is also reported during migraine with brainstem aura, has been elicited after stimulation of the parietal lobe, especially the precuenus (73). Impairment of consciousness is also recorded during temporal lobe stimulations that can induce a feeling of unreality, déja vu, a dream-like state in the hippocampus and amygdala, and amnesia in the anterior superior temporal gyrus (39).

Discussion

Migraine with brainstem aura is classified as a distinct entity from typical migraine with aura, since symptoms are supposed to originate from the brainstem (1). However, in the light of the above data, we suggest that brainstem aura symptoms could reflect a transient cortical dysfunction. This hypothesis would explain the co-occurrence of typical and brainstem aura during attacks and the close clinical and epidemiological similarities observed between migraine with typical aura and migraine with brainstem aura (5). It would also fit with the theory of cortical spreading depression. Based on these findings, we propose that migraine with brainstem aura should be classified as a typical migraine aura.

Brainstem aura symptoms can reflect a cortical involvement

Data coming from clinical observations and functional mapping strongly suggest that any symptom of so-called brainstem aura can result from a cortical involvement. Vertigo can result from a parieto-insular vestibular cortex dysfunction. This posterior cortical origin would be consistent with the frequency of co-occurrence of both visual symptoms and vertigo during attacks. Tinnitus and hypacusis can originate within the temporal auditory cortex. Diplopia can reflect a parieto-occipital involvement and could be part of a visual aura, as could other complex visual hallucinations such as micropsia or macropsia. Dysarthria can be caused by dysfunctions of different brain areas such as the precentral gyrus. Ataxia can reflect vestibular, sensory, or optic alterations that affect mainly the parietal lobe. Alteration of consciousness may be the consequence of changes such as abnormal synchrony within specific consciousness networks that include precuneus/posterior cingulate cortex, the medial prefrontal cortex, and the medial parietal cortex.

In the light of the above data, we suggest that all the symptoms of migraine with typical or brainstem aura can originate in the cortex either uni- or bilaterally. Most of the symptoms reported in the so-called brainstem aura (vertigo, tinnitus, hypacusis, diplopia, dysarthria, ataxia) can result from a transient unilateral cortical dysfunction affecting mainly the parieto-temporo-insular areas.

A cortical origin of “brainstem” aura would explain the occurrence of typical aura symptoms during attacks of migraine with brainstem aura

During attacks, brainstem aura symptoms never occur alone but are always associated with typical aura symptoms consisting of visual, sensory and/or speech/language symptoms (1). A cortical initiation of brainstem aura would explain the simultaneous occurrence of “brainstem” and “typical” aura. As in migraine with typical aura, migraine with brainstem aura usually starts with visual symptoms. Visual symptoms, the most frequent aura symptoms, are reported by 65–100% of patients (2,5,7). They are described as transient amaurosis, diffuse reduction of vision, narrowed visual field, positive phenomena, or dysmorphia (8). They are bilateral in 40% of patients (5,7), as compared to 40% of patients with hemiplegic migraine (6) and 30% of patients with migraine with typical aura (75). In migraine with brainstem aura, aphasia is reported by 40% of patients while sensory aura, characterized by positive features (such as pins and needles) and/or negative features such as uni- or bilateral numbness, is reported by 30–61% of patients (5,7). Bilateral sensory symptoms affecting both hands and/or feet have long been interpreted as a characteristic manifestation of basilar-type aura, but have been removed from the latest classification. Indeed, bilateral sensory symptoms affect 13–37% of patients with brainstem aura (5,7) but 16% of patients with migraine with typical aura (75). Moreover, bilateral sensory symptoms may be caused by a bilateral involvement of the parietal cortex or a unilateral involvement of the SII area and insular cortex, where direct electric stimulations can evoke bilateral sensations (76).

The succession of aura symptoms and the associated headache also suggest that “brainstem” aura could be part of a typical aura. Indeed, the majority (90%) of “brainstem” aura symptoms occur in succession over more than 5 minutes (5). The “brainstem” aura has a median duration of 60 minutes. In the majority of patients (79%), “brainstem” aura is followed by a headache that fulfills the diagnosis criteria for migraine headache (5). Such similarities have been previously reported by Kirchmann and colleagues, who concluded that there was “no evidence that migraine with brainstem aura was a distinct disease entity different from typical migraine with aura” (5).

A cortical origin of brainstem aura would explain the occurrence of brainstem aura during attacks of migraine with typical aura

Clinical similarities between typical and brainstem aura are not only observed during migraine with brainstem aura, but also during attacks of migraine with typical aura. The closest interrelationship between both auras is observed in patients with hemiplegic migraine who fulfill frequently (69%) the ICHD criteria for migraine with brainstem aura (6). Hemiplegic migraine attacks consist of motor weakness associated with visual, sensory, and/or aphasic symptoms (1). These attacks frequently include symptoms of brainstem aura such as vertigo in 72%, dysarthria in 73%, tinnitus in 29%, hypacusis in 48%, diplopia in 51%, loss of balance in 72%, and decreased level of consciousness in 31% (6). Symptoms of brainstem aura are also reported during non-hemiplegic migraine with aura. For instance, dysarthria occurs in patients with typical aphasic aura. In the report of Russel and Olesen (75), 15 out of 29 patients with aphasic aura had dysarthria, while two patients of the study had dysarthria exclusively.

A cortical origin of the so-called brainstem aura would also explain the similar epidemiologic and genetic profile observed between migraine with typical aura and migraine with brainstem aura. Indeed, familial aggregation analysis shows that patients with basilar aura are equally distributed among families with typical aura (5). In hemiplegic migraine, more than two-thirds of the patients describe so-called brainstem symptoms (6,12). Attacks of migraine with brainstem aura may occur in patients with typical aura with or without hemiplegic symptoms, suggesting that genes involved in migraine with and without hemiplegic aura may trigger both typical and brainstem aura. For instance, a mutation in ATP1A2, a gene that is known to be involved in familial hemiplegic migraine, has been detected in a family comprising three patients with migraine with brainstem aura and three patients with typical aura (77).

A cortical origin of brainstem aura would fit with the theory of cortical spreading depression

Migraine aura is attributed to a transient neuronal dysfunction probably caused by a CSD. The pathophysiology of brainstem aura remains unknown, but is supposed to either reflect the propagation of CSD between brainstem and cortex or some parallel changes in each brain region (4). However, two factors argue against these hypotheses. Firstly, most animal studies have shown that CSD can be easily elicited in the cortex and the hippocampus but not in the brainstem (78). To our knowledge, CSD can be elicited in the brainstem of rats only under peculiar conditions highly different from those triggering CSD in the cortex (79). Moreover, repetitive depolarizations elicited in the brainstem don’t propagate into the cerebral cortex (80). Secondly, CSD is characterized by a slow propagation rate of 3–5 mm/min, so that the propagation of CSD between the brainstem and the cortex would not explain the co-occurrence of typical and brainstem aura symptoms during migraine with aura. In contrast, a transient dysfunction affecting cortical areas that generate dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and decreased level of consciousness would be consistent with the theory of cortical spreading depression.

Conclusion

Based on the data coming from functional mapping and from clinical observations studies, we suggest that migraine with brainstem aura can have a cortical origin. We propose that so-called brainstem aura should be classified as a migraine with typical aura.

Clinical implications

Brainstem aura symptoms can reflect a transient cortical dysfunction.

The hypothesis of a cortical origin of so-called brainstem aura would explain the co-occurrence of typical and brainstem aura during attacks and would fit with the theory of cortical spreading depression.

We propose that migraine with brainstem aura should be classified as a typical migraine aura.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Migraine with brainstem aura: Why not a cortical origin?

Abstract

Background

Aim

Results

Conclusion

Keywords

Introduction

Methods

Results

Characteristics of brainstem aura symptoms

Why not a cortical origin for brainstem aura symptoms?

Cortical origin of vertigo

Cortical origin of auditory symptoms

Cortical origin of diplopia

Cortical origin of dysarthria

Cortical origin of ataxia

Cortical origin of decreased consciousness

Discussion

Brainstem aura symptoms can reflect a cortical involvement

A cortical origin of “brainstem” aura would explain the occurrence of typical aura symptoms during attacks of migraine with brainstem aura

A cortical origin of brainstem aura would explain the occurrence of brainstem aura during attacks of migraine with typical aura

A cortical origin of brainstem aura would fit with the theory of cortical spreading depression

Conclusion

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

References