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11 Vestibular Migraine
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205
Pathophysiology
The pathophysiology for vestibular migraine is not currently fully understood. It
seems logical that any pathophysiologic model should explain all of the following:
(1) Why there is an association between migraine and vertigo/dizziness; (2) Why
some patients with migraine headaches get vertigo, and some do not; (3) Why some
patients can have vertigo/dizziness without a prior headache history; (4) Why acute
attacks of minutes to hours of spinning vertigo can occur; (5) Why variable amounts
of symptoms can occur between episodes, including motion sensitivity, disequilibrium, dizziness, aural pressure, tinnitus, visual vertigo, and motion sickness; (6)
Why vestibular migraine is linked to other vestibular diseases, including Meniere’s
disease, BPPV, vestibular neuritis, and bilateral vestibular loss; (7) Why there is
frequently, but not always a family history of migraine. To date, no complete explanation is available.
Much of the current researches on the mechanisms that underlie vestibular
migraine use the framework of classical migraine research. Migraine headache was
originally thought to involve arterial spasm and dilation. Therefore, it was hypothesized that alterations of the labyrinthine artery could explain the pathophysiology
of VM.However, this theory does not explain the wide range of clinical manifestations that are seen in those that suffer from vestibular migraine [48, 49], or the
prolonged duration of vestibular symptoms both during and between acute migraine
episodes. Furthermore, it’s been shown that migraines do not just involve arterial
spasm, but instead a complex interplay of neurologic events in susceptible patients.
One theory is that vestibular migraine is really a vestibular aura. Migraine with
aura includes neurologic symptoms which are most frequent visual but can also be
other sensory or central nervous system symptoms such as paresthesias. These aura
symptoms gradually progress over several minutes to an hour and are often accompanied by or shortly followed by headache. Currently, migraine aura is thought to
be a result of spreading cortical depolarization—which is an expanding wave of
neuronal depolarization in the brain. This wave suppresses electrical activity and
leads to a delayed restoration of transmembrane concentration gradients. Cortical
spreading depolarization, in addition to aura, is thought to be responsible for the
disorientation and brain fog that occur in migraine. A similar pathway has been
investigated as a potential mechanism for VM if this cortical spreading depression
reaches central vestibular centers. It’s possible that spreading depression may reach
the vestibular brainstem nuclei, thalamus or other higher order vestibular centers
including multisensory integrative areas, or other vestibular processing centers,
leading to vertigo [13]. This explanation could potentially explain acute vertigo lasting minutes to hours, but may not be sufcient to explain the interictal symptoms.
Another migraine mechanism that has been investigated as a potential cause for
VM is the trigeminovascular inammatory system. Headache and facial pain in
migraine are caused by aberrant activation of the nociceptive sensory portion of the
trigeminal nerve. These nerve efferents innervate the dura and intracranial blood
vessels leading to the classic headache symptoms [50]. Trigeminal efferents also
provide sensory input for the face and sinuses which may explain some of the other
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D. M. Gillard and J. D. Sharon
otolaryngological symptoms that can be associated with migraine. It is thought that
trigeminovascular inammatory peptides that are released may also affect the inner
ear, leading to vestibular symptoms [51]. Animal models of guinea pigs have shown
that electrical stimulation of the trigeminal nerve leads to plasma extravasation in
the spiral modiolar artery within the cochlea [52]. Therefore this activation of the
trigeminal nerve may lead to vascular changes and release of inammatory peptides
within the ear, possibly explaining the vestibular symptoms in VM.
Once the trigeminal-vascular system is sensitized it releases a host of vasoactive
and inammatory peptides, including substance P, calcitonin gene-related peptide
(CGRP), and neurokinin A. These peptides lead to vasodilation, mast cell degranulation, and neurogenic inammation [53]. CGRP released by the trigeminal system
leads to vasodilation and plasma extravasation [50] creating a positive feedback
loop that furthers inammation in the migraine state. Infusions of CGRP in humans
have been shown to precipitate acute migraine attacks in both patients who have
migraine with [54] and without aura [55]. There are multiple anti-CGRP antibodies
that bind to the CGRP receptor or ligand including, galcanezumab (Eli Lilly and
Company), fremanezumab (Teva Pharmaceuticals), and erenumab (Amgen/
Novartis) that have been approved for the treatment of migraine [56], highlighting
the important role of the trigeminovascular inammatory system in the pathophysiology of migraine. CGRP has been studied extensively in classical migraine and
researchers have been looking into its role in vestibular migraine.
CGRP has been demonstrated within vestibular brainstem efferents and in terminals that make synaptic contact with vestibular end organs in rat and chinchilla
models [57–59]. More recently, CGRP has also been demonstrated in the human
vestibular system, validating these earlier animal models [60, 61]. CGRP positive
neurons located near the vestibular nuclei project directly to the vestibular endorgans [62, 63] as well as the vestibular nucleus and vestibular cerebellum [59, 64].
CGRP is expressed in peripheral vestibular organs as well, where it is co-located
with choline acetyl-transferase, which makes acetylcholine, the primary neurotransmitter of the efferent vestibular system.
In animal models CGRP infusion has been shown to cause photophobia [65], so
there is some thought that CGRP release could also be responsible for hypersensitivity in the ear which may lead to some of the vestibular phenomena seen in
VM. CGRP knockout mice have reductions in sound-evoked activity in the cochlear
nerve [66], which implies a roll for CGRP in the response to external stimulus in the
ear as well as the eye. Additionally, loss of CGRP has been shown to cause perturbations of the vestibular system. CGRP receptor knockout mice had a reduced
vestibulo- ocular reex (VOR) gain, with no effect in VOR phase [67]. CGRP negative mouse models also show reduced otolith activation timing and impaired balance [68]. The connection between the trigeminovascular inammatory peptide
CGRP, migraine and the vestibular system remains an exciting pathway for further
investigations into the underlying pathophysiology of VM.
The central sensory sensitization theory has been utilized to help explain the
chronic symptoms in patients with VM, and help provide insights as to why they can
have vertigo and motion sensitivity that is prominent even in between acute migraine
episodes. It is thought that VM sufferers have lower thresholds for sensory stimuli,
including motion. This process is thought to be responsible for some of the chronic
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symptoms of VM, such as dizziness and motion sickness that is present between
acute migraine episodes. Functional MRI studies of classical migraine show that
migraine sufferers have atypical responses to visual, olfactory and painful cutaneous stimuli [69] and it is thought that this relationship may hold true for vestibular
inputs in patients with VM.
Sensory hypersensitivity to light, sound and motion is thought to be caused by
alteration of circuitry in the thalamus which leads to an overall altered multisensory
integration. Patients with VM often report that their vertigo is associated with headaches movements and this dizziness occurs even outside of acute vertigo attacks
highlighting that they also share this abnormal sensory integration. The ventral posterior lateral and ventral posterior medial nuclei of the thalamus are relay nuclei for
somatosensory information, which includes vestibular inputs [70]. The thalamus
has increased activation in vestibular migraine [71] which highlights this as an
important pathway for sensory sensitization in VM sufferers.
Testing in patients with VM has provided some support for this theory of abnormal multisensory integration. Although there are a variety of papers that show minor
abnormalities on vestibular testing alone (see section “Work-Up”) results across
studies have been inconsistent and neither sensitive nor specic for VM.However,
there is some thought that the true decits can be seen in multisensory information
processing and that these may point to possible mechanisms for VM.In a study of
the effects of static head tilt on upright perception on VM patients and healthy controls perception of head tilt was measured in a dark room using a subjective visual
vertical paradigm at three head tilt positions. Interestingly, patients with VM showed
larger subjective visual vertical errors with head tilt to the right, but not with upright
head position or head tilt to the left. On head tilt to the right VM patients tended to
overestimate the tilt magnitude compared to controls suggesting these patients have
abnormal sensory integration for spatial orientation processing [72].
Additional evidence to support that multisensory integration abnormalities cause
central sensory sensitization is that VM sufferers have abnormal sensitivity to rolltilt testing. In a study of the VOR and perception of self-motion in VM patients and
healthy controls, researchers found that VM patients were abnormally sensitive to
roll tilt. This test involves both semicircular canal and otolith activity. They were not
more sensitive to tests that activated the canals or the otoliths in isolation [73].
Again, these results show that investigation of multisensory inputs reveals abnormalities which could be used to elucidate the mechanisms behind VM.
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Functional Neuroimaging
Functional imaging studies of VM patients are providing new clues to the mechanisms that may underlie the pathophysiology of VM.In a small study of two patients,
regional brain metabolism of VM was recently assessed [74]. During a migraine
attack, 18F-uorodeoxy glucose-PET studies showed that compared to the interictal
period there was increased activation in the temporo-parietal-insular areas and bilateral thalami and decreased activation of the occipital cortex. It was thought that this
pattern of metabolism represents activation of the vestibulo-thalamo-cortical
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pathway and inhibition between the vestibular and visual systems which may
explain some of the vestibular symptoms of VM.
Another study conducted in between acute attacks showed similar activation of
the bilateral insular cortex, thalamus, cerebellum and brainstem during caloric testing [71]. The thalamus continues to be examined in VM, as it is involved in pain
processing and cortical excitability. It is posited that dysfunction in the integration
and processing of vestibular and pain information through vestibulo-thalamo- cortical
pathways that lead to the symptomatic attacks in VM.Whole brain imaging in
migraine sufferers has also shown grey matter changes in regions of the brain important in pain and vestibular processing implying that VM may lead to permanent
structural changes in the brain in relation to pain and vestibular inputs which may
help explain the vestibular hypersensitivity present during and between episodes [75].
In another imaging study of VM patients, 12 patients with VM underwent wholebrain blood oxygen level-dependent fMRI during cold water calorics and results
were compared with patients with migraine without aura and healthy controls. VM
patients had increased thalamic activation compared to the other groups, providing
additional support for the abnormal thalamic activation theory of VM [71]. Although
there are not many functional neuroimaging studies the current body of research
shows that in VM has structural and functional abnormalities that are similar to
those seen in classical migraine. They also have additional abnormalities in vestibular systems which may show a connection between classic migraine mechanisms
and vestibular symptoms. More neuroimaging studies will be needed to further elucidate these structural and functional changes.
D. M. Gillard and J. D. Sharon
Genetics ofVestibular Migraine
Genetic analysis in VM has been done to help guide theories on the pathophysiology
of the disease. There does appear to be some genetic component to VM, as patients
with VM often have a positive family history [76]. Genetic variations in ion channels
and membrane transporters have been investigated in the pathophysiology of migraine
[77] and could potentially present a common pathway for the VM variant. Ionic
homeostasis in the inner ear is important for the maintenance of endocochlear potential and alterations could lead to a variety of vestibular and cochlear symptoms. In
addition, ion channel dysfunction in the cerebellum is also thought to lead to imbalance, incoordination and nystagmus. Familial hemiplegic migraine, a rare form of
migraine that presents with motor weakness, aura, paresthesias and sensory changes
and aphasia can also present with a variety of otolaryngologic symptoms including
vertigo, tinnitus and imbalance [78]. Genetic analyses of familial hemiplegic migraine
have identied mutations in CACNA1A, a calcium channel gain of function mutation
[79], ATP1A2, a loss of function mutation in the sodium potassium-ATPase trans-
porter [80] and SCN1A, a gain of function mutation in a voltage gated sodium channel
[81]. These ion channelopathies present in familial hemiplegic migraine are being
investigated as potential mechanisms for classical migraine. These mutations in the
voltage-gated calcium channel CaV2.1 promote cortical spreading depression in
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migraine as well as in vestibular migraine [82]. Unfortunately, a link between these
ion channelopathies discovered in familial hemiplegic migraine and VM has not been
discovered [83]. However, a recent variant of ATP1A2 has been identied in a family
with progressive hearing loss and migraine [84]. In a genome-wide association study
(GWAS) of 38 loci involved in migraine, two genes were identied that are involved
in the notch pathway for hair cell development which could provide an underlying
genetic connection between classical migraine and vestibular symptoms. Additional
genetic analyses of migraine have not identied specic genetic mutations in
VM.Despite this lack of ndings genetic analyses of VM and calcium channelopathies represent a possible area for future research on the pathophysiology of VM.
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Presentation
The hallmark symptoms of vestibular migraine (VM) are vertigo (a subjective sense
of motion when there is none occurring, or altered sense of motion when motion is
occurring) and/or dizziness (an altered sense of spatial orientation without vertigo)
[85]. This helps to distinguish vestibular migraine from migraine headaches occurring with vertigo. If the predominant symptom that causes the patient to seek medical attention is vertigo, then we prefer the label vestibular migraine. The presentation
of VM is highly variable, not only between individuals, but also between different
attacks in the same individual. Symptoms can even uctuate within a single attack.
The vestibular symptoms can often be difcult to describe for patients and thus hard
for the practitioner to interpret in the ofce. The vertigo in VM is often worsened by
head movement and position changes. The duration of an acute vertigo episode is
highly variable and can last anywhere from minutes to days, or even longer.
As covered in the diagnostic criteria below, there are different forms of vestibular
migraine. In the author’s clinic, they are equally divided. Some patients have a history of migraine headaches, and then develop episodic vertigo, with or without
migrainous symptoms (photophobia or phonophobia or aura). Other patients do not
have a history of migraine headache, but develop episodic vertigo with migrainous
symptoms.
VM patients may have nystagmus present during their VM episodes. The nystagmus can be quite variable between patients and even within the same patient. One
study using a vestibular event monitor found that VM patients had spontaneous
horizontal upbeating or downbeating nystagmus, positional nystagmus, or no nystagmus. In this study spontaneous vertical nystagmus was shown to be highly specic for VM.Their positional nystagmus was also persistent and did not extinguish
with time [86].This is important to note, because not all positional vertigo is BPPV;
vestibular migraine can cause identical symptoms. Around 60% of patients with
VM have evidence of central ocular motor disorders between acute VM attacks
including gaze-evoked nystagmus with saccadic smooth pursuit, horizontal or vertical spontaneous nystagmus and central positional nystagmus [13].
Patients with VM may have other associated otolaryngologic symptoms in addition to their vestibular symptoms. These include tinnitus, which can be pulsatile,
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D. M. Gillard and J. D. Sharon
aural fullness and subjective hearing loss [87]. Neck stiffness, facial numbness, and
facial pressure can all occur as well.
Cognitive dysfunction is a frequent complaint for patients with VM.One study
looked at the Cognitive Failures Questionnaire, which is an indicator of cognitive
dysfunction measured by the frequency of everyday cognitive slips (e.g., forgetting
names, or what you were trying to do). Subjects with VM patients had elevated
scores compared to normative controls, Meniere’s disease patients, and those with
BPPV [88–90]. They also have increased rates of reported brain fog and fatigue [89].
VM triggers are generally the same as for regular migraine triggers, including
stress, skipped meals, specic foods or beverages, bright lights, allergies, barometric pressure changes, loud sounds or busy visual scenes. They are also shown to
have hormonal triggers, for example hormonal changes at menopause may be a
trigger for an initial episode of VM, much like for migraine in women [91].
Patients with VM will often have a positive family history for migraine. In the
author’s clinic, 45% have a rst-degree family member with a history of migraine.
Therefore, this can be an important diagnostic clue for VM.
The vertigo and motion sensitivity seen in VM patients is often long-standing
and can even be present between migraine attacks. In general, patients with VM are
hypersensitive to movement and suffer from motion sickness at high rates [10]. This
may help explain some of the chronic symptoms of VM.In addition, it can be more
difcult to treat those with motion sensitivity, as physical therapy may paradoxically worsen symptoms.
VM signicantly reduces the quality of life for sufferers. Using 2008 NIHS data,
60% of VM patients had missed work or school because of their diagnosis, 37%
called their diagnosis at least a moderate problem, and 52% had a fall [20].
Comparatively, the rate of falls in the non VM population was only 17%. In the
author’s practice, the rate of comorbid depression is 48% and anxiety is 45%.
In clinical practice we often nd that patients have a lot of hesitation and mistrust
toward this diagnosis. Patients often do not think vestibular attacks are migraines and
see them as distinct symptoms from their usual migraines. We also nd several common myths about migraines within the VM population. Many patients and providers
believe that migraines have to cause headache, although we now know that there are
several known migraine variants that do not cause headache including acephalgic or
ocular migraine, abdominal migraine and hemiplegic migraine. It is also thought that
migraines are episodic and can’t be continuous so the persistent vestibular symptoms
between episodes cannot represent migraines. However, chronic migraine is diagnosed when migraines occur 14 or more days per month, and status migrainosus
refers to a migraine lasting 72h or longer, proving that migraine attacks and symptoms can last longer than the classic teaching of 72 h. Patients often think that
migraine is an obvious diagnosis and that since other providers did not give them a
migraine diagnosis that it cannot be the cause of their vestibular symptoms. Although
as demonstrated previously, VM is likely highly underdiagnosed. Many patients also
share the belief that migraines cannot possibly be as severe or life altering as their
symptoms, which prior research shows is false. VM can be a very severe diagnosis
causing signicant morbidity for patients.
Tr iggers
migraine
Percentage
a
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11 Vestibular Migraine
211
In a UCSF cohort of 67 patients who presented to the UCSF Balance and Falls
Center with dizziness, a plurality of subjects felt neutral as to whether or not their
provider would gure out the cause of their dizziness, 31% were neutral as to
whether or not treatment would help. About one third of patients who met ICHD-3
criteria for migraine did not believe that migraines could cause dizziness. Finally a
majority of subjects did not believe that migraines could be chronic [92].
Figure 11.1 shows vertigo triggers, associated symptoms, episode length, episode frequency, and secondary vestibular diagnoses for a cohort of 51 VM patients
in the author’s practice.
100
90
82
Motion
76
70 70
Stress
Bright lights
Busy visual scenes
Scrolling on a screen
68
64
60
Loud noises
Sleep disturbance
Barometric pressure changes
68
54
Dehydration
60
49
45 45
Air travel
58
43
31 31
Skipped meal
Hormonal changes
Certain foods or beverages
56
27
Allergies
Certain smells
21
80
70
60
50
40
30
20
10
0
b
80
70
60
50
40
Percentage
30
20
10
0
Light
sensitivity
Fig. 11.1 Clinical characteristics of vestibular migraine. Unpublished from a UCSF study of 51
subjects with VM. (a) Most common triggers of VM, (b) Associated symptoms during dizziness,
(c) Dizziness duration (d) Dizziness frequency per month, (e) Secondary vestibular diagnoses. MD
Meniere’s disease, BPPV benign paroxysmal positional vertigo, VH vestibular hypofunction,
PPPD persistent perceptual postural dizziness, MdDS mal débarquement syndrome
Sound
sensitivity
35
Ear pressure Head pressure HeadacheHeadache
meeting
criteria for
212
PercentagePercentage
<5 days 5–15 days >15 days
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Most Common Dizziness Duration
60
50
40
30
20
10
13
0
<5 min5 min–72 hrs >72 hrs
49
37
d
70
60
60
50
40
30
21
20
17
10
0
Fig. 11.1 (continued)
Po
Percentages
e
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60
50
40
30
20
15
10
0
MD
Fig. 11.1 (continued)
9
BPPV
333
VH
PPPD
st-Concussive Dizziness
MdDS
22
Other
58
None
Diagnostic Criteria
The rst diagnostic criteria for VM were described by Lempert and Neuhauser in
2001 [93–95]. They proposed four basic criteria for the diagnosis of VM were (1)
recurrent vestibular symptoms, (2) migraine based on the International Headache
Society (IHS) criteria, (3) migraine symptoms such as headache, photophobia, phonophobia or auras, during vertigo attacks, (4) other possible causes have been ruled out.
Currently, many clinicians use the newer but similar Barany Society Criteria for
Diagnosis to diagnose VM [96] (Table 11.1). Denite vestibular migraine can be
diagnosed with at least ve episodes of vestibular symptoms with migrainous features and history of migraine. Probable VM can be diagnosed even if the patient does
not have a positive history of classical migraine or consistent migrainous symptoms
along with their vestibular symptoms. In order to use the Barany society criteria, one
must be familiar with current ICHD criteria for the diagnosis of migraine headache.
The ICHD-3 criteria for migraine without aura are presented in Table11.2.
Work-Up
At the time of writing, there is no denitive diagnostic work-up for VM.Imaging
and routine laboratory testing in these individuals is generally normal. A variety
of vestibular tests have been used to evaluate patients with VM, with inconsistent
results. A meta-analysis by Furman in 2003 found that about one quarter of
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Table 11.1
criteria for the diagnosis of
vestibular migraine
Table 11.2
Classication of Headache
Disorders-3 Vestibular Migraine
Criteria
Barany Society
International
A.Vestibular migraine
(a) At least 5 episodes with vestibular symptoms
(i) Severity: moderate–severe
(ii) Timing: 5min–72h
(b) History of migraine±aura according to ICHD-3
(c) ≥1 of the following migraine features occurring with at
least 50% of vestibular episodes
(i) Headache with at least two of the following
characteristics: unilateral, pulsing, moderate or severe pain
intensity, aggravation by routine physical activity
(ii) Photophobia and phonophobia
(iii) Visual aura
(b) Not better accounted for by ICHD-3 diagnosis
B.Probable
(a) At least 5 episodes with vestibular symptoms
(i) Severity: moderate–severe
(ii) Timing: 5min–72h
(b) Has either (b) or (c) from “Denite” criteria but NOT
both
(c) Not better accounted for by ICHD-3 diagnosis
Diagnostic criteria for denite and probable vestibular migraine
from the Barany Society criteria [96]
A.At least ve episodes fullling criteria C and D
B.Current or past history of migraine without aura or
migraine with aura
C.Headache of moderate to severe intensity, lasting between
5min and 72h
D.At least half of episodes are associated with at least one of
the following three migrainous features:
(1) Headache with at least two of the following four
characteristics:
(a) Unilateral location
(b) Pulsating quality
(c) Moderate or severe intensity
(d) Aggravation by routine physical activity
(2) Photophobia and phonophobia
(3) Visual aura
E.Not better accounted for by another ICHD-3 diagnosis or
by another vestibular disorder.
Migraine without aura is the most common migraine disorder
presenting as a recurrent headache with migraine features as
described above. Available at https://ichd-3.org/
patients with migraine or migraine with signicant associated vestibular symptoms have abnormalities of the peripheral vestibular system, but these results
were inconsistent among studies [97]. In a study that directly compared migrainerelated dizziness with nonmigraine-related dizziness, there were no signicant
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