Vestibular Migraine Treatment: A Comprehensive Practical Review

Duncan Smyth; Zelie Britton; Louisa Murdin; Qadeer Arshad; Diego Kaski

Brain. 2022;145(11):3741-3754.

Abstract and Introduction

Abstract

Vestibular migraine is an underdiagnosed but increasingly recognized neurological condition that causes episodic vertigo associated with other features of migraine. It is now thought to be the most common cause of spontaneous (non-positional) episodic vertigo, affecting up to 1% of the population. A meta-analysis of preventative treatments for vestibular migraine was published in 2021, but the authors were unable to establish a preferred treatment strategy due to low quality of evidence and heterogeneity of study design and outcome reporting. Therefore, there remains a clinical need for pragmatic management guidelines specific to vestibular migraine using the available evidence. Here, we provide a practical review utilizing a systematic qualitative assessment of the evidence for abortive and preventative interventions in adults. The overall evidence base for vestibular migraine treatment is of low quality. Nevertheless, we provide practical treatment recommendations based on the available evidence and our experience to help guide clinicians treating patients with vestibular migraine. We also discuss how future clinical trials could be designed to improve the quality of evidence in this condition.

Introduction

Vestibular migraine (VM) is an underdiagnosed but increasingly recognized condition that causes episodic vertigo, often accompanied by headache. A condition first clearly described by Boenheim in 1917,^[1] it is now thought to be the most common cause of spontaneous (non-positional) episodic vertigo, affecting between 1% and 2.7% of the general population,^[2,3] 11% of patients in specialized dizziness clinics^[4] and 13% of patients in headache clinics.^[5] Previously known variously as 'migrainous vertigo', 'migraine-associated vertigo', 'migraine-associated dizziness', 'migraine-anxiety-associated dizziness' and 'migraine-related vestibulopathy', vestibular migraine has been accepted by the International Classification of Headache Disorders (ICHD) as the unifying term that identifies both the vestibular and migrainous symptoms.

The clinical presentation of vestibular migraine is diverse. Episodes of dizziness usually last between 5 min and 72 h, although shorter and longer episodes have been reported.^[6] Vestibular symptoms can mimic benign paroxysmal positional vertigo,^[7] and prominent auditory symptoms with overlap with Ménière's disease have been reported.^[8,9] Episodes are often, but not invariably, accompanied by other symptoms of migraine, including migrainous headache, photophobia, phonophobia and visual aura. Neurological examination is classically unremarkable, but during acute attacks can reveal spontaneous or positional nystagmus in the majority of patients,^[7,10–13] and some studies have reported mild abnormalities of semicircular canal function and eye movements interictally.^{[7,10,14–18]} The current diagnostic criteria, first proposed by Neuhauser et al.^[4] and ratified by the International Headache Society and the committee for the International Classification of Vestibular Disorders (ICVD) of the Bárány Society,^[6] mandate a history of migraine and the temporal overlap of vestibular and migrainous symptoms in at least 50% of episodes, and allow for the possibility of probable vestibular migraine (see Table 1). Importantly for a disease without an objective diagnostic gold standard, these criteria have been shown to be reliable on repeated assessments over a 9-year period.^[9]

The pathophysiology of vestibular migraine is incompletely understood. As with migraine, there is a significant female preponderance^[4,19] for reasons not well explained. Both environmental and genetic factors are likely to be important,^[20,21] and recent familial studies have suggested possible loci of interest at 5q35,^[22] 11q (with reduced penetrance in men)^[23] and 22q12.^[24] One proposed mechanism for episodes is hypoperfusion of the inner ear during migrainous attacks secondary to vasospasm resulting in vertiginous symptoms, a theory that is supported by the occasional association of migraine with sudden sensorineural hearing loss^[25] and the observation that migraine is a risk factor for stroke;^[26,27] however, cochlear symptoms are certainly not a universal feature. Alternatively, episodes may be due to sensitization and activation of the trigeminovascular system leading to release of the pro-inflammatory neuropeptides substance P and calcitonin gene-related peptide (CGRP), which has connections with brain areas associated with processing of nociceptive information as well as thalamic and vestibular-associated cortices.^[28] Neuroimaging studies support the hypothesis that there are specific abnormalities in the structure and activity of the vestibulo-thalamo-cortical pathway in vestibular migraine.^[29,30]

Due to a paucity of data on the management of vestibular migraine specifically, treatment recommendations have generally been extrapolated from studies on other forms of migraine. Pharmacological options for acute migraine include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics and triptans.^[31] Prophylactic treatment options include beta-blockers (propranolol, metoprolol), calcium channel blockers (for example, flunarizine), antiepileptic drugs (topiramate, sodium valproate), antidepressants (amitriptyline, nortriptyline, venlafaxine), antiserotonergic drugs (pizotifen), antihypertensives (candesartan, lisinopril) and monoclonal antibodies against CGRP (erenumab, fremanezumab, galcanezumab). Supplements (co-enzyme Q10, magnesium and riboflavin), greater occipital nerve block, botulinum toxin, external trigeminal nerve stimulation (eTNS), single transcranial magnetic stimulation and non-invasive vagus nerve stimulation (nVNS) are recommended by the British Association for the Study of Headache.^[31] Acupuncture may be helpful for some patients.^[32] A Cochrane review in 2015 that set out to identify effective pharmacological agents for the prevention of vestibular migraine failed to identify any completed study that met the strict inclusion criteria required for Cochrane reviews.^[33] A review and meta-analysis of preventive treatments for vestibular migraine was published in 2021,^[34] but the authors were unable to establish a preferred treatment strategy due to low quality of evidence and heterogeneity of study design and outcome reporting.

As current migraine treatment guidelines are based on work that did not assess the efficacy of interventions to control vestibular symptoms, there remains a clinical need for pragmatic management guidelines specific to vestibular migraine using the available evidence. Considering this, we felt that performing another meta-analysis would not be of practical utility given such a small number of appropriate studies. Equally, a narrative review would likely include publications at risk of serious bias due to poor study quality and significant heterogeneity. Thus, while others have provided comprehensive systematic reviews and meta-analyses of vestibular migraine treatment,^[33,34] here we sought to offer a practical, clinically oriented review utilizing a systematic qualitative assessment of the evidence for each treatment option, upon which we offer treatment recommendations.

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Table 1. Bárány Society/International Headache Society criteria for vestibular migraine
Vestibular Migraine	Probable Vestibular Migraine
A. At least 5 episodes with vestibular symptoms of moderate or severe intensity, lasting 5 min to 72 h B. Current or previous history of migraine with or without aura according to the International Classification of Headache Disorders (ICHD) C. One or more migraine features with at least 50% of the vestibular episodes: • headache with at least two of the following characteristics: one-sided location, pulsating quality, moderate or severe pain intensity, aggravation by routine physical activity • photophobia and phonophobia • visual aura D. Not better accounted for by another vestibular or ICHD diagnosis	A. At least five episodes with vestibular symptoms of moderate or severe intensity, lasting 5 min to 72 h B. Only one of the criteria B and C for vestibular migraine is fulfilled (migraine history or migraine features during the episode) C. Not better accounted for by another vestibular or ICHD diagnosis

Box 1. Treatment options for management of vestibular migraine based on efficacy and side-effect profile data
All patients Lifestyle advice—discuss sleep, exercise, stress, avoidance of fasting, potential dietary triggers, alcohol, caffeine Abortive treatment—use less than 10 days per month (a) Simple analgesics/NSAIDs/triptans for headache (b) Vestibular sedatives (cyclizine, prochlorperazine, cinnarizine) for vertigo (c) Consider prochlorperazine, cyclizine, cinnarizine, or domperidone for nausea Preventative treatment—best efficacy evidence and lower rates of serious unwanted effects (a) Tricyclics (amitriptyline, nortriptyline)—consider if comorbid pain or insomnia. Start 10 mg at night and titrate up in 10 mg increments every 1–2 weeks. Usual dose range 10–150 mg at night. Lower doses are often effective for VM symptoms; higher doses (≥75 mg) may benefit patients with anxiety/depression, although in our experience patients with VM rarely tolerate this much. (b) Propranolol—generally well-tolerated in studies. Avoid in asthma, bradycardia, hypotension, and use with caution in type 1 diabetes mellitus. Start at 20 mg twice daily and titrate up every 1–2 weeks by 20–40 mg twice daily. Usual dose range 20–80 mg twice daily. (c) Flunarizine—consider if comorbid insomnia. Many patients report side effects (e.g. somnolence, weight gain) but rates of discontinuation are low. Need long-term monitoring to check for parkinsonism, so use with caution in elderly. Start at 10 mg at night (no need for dose titration) in younger patients, or 5 mg at night in older patients (>65 years). Preventative treatment—evidence of efficacy but risk of more serious unwanted effects (a) Topiramate—consider in obese patients. Avoid in underweight patients, women of childbearing potential (unless on reliable contraception) and those with uncontrolled low mood (risk of depressive symptoms/suicidality). Start at 25 mg at night and slowly titrate up by 25 mg every 2 weeks as effective/tolerated. Often poorly tolerated at higher doses. Usual dose range 25–100 mg twice daily. (b) Sodium valproate—avoid in obese patients. Contraindicated in women of childbearing potential. Start at 200 mg twice daily and titrate up by 200–400 mg every 1–2 weeks. Usual dose range 200–1000 mg twice daily. (c) Venlafaxine—consider if comorbid low mood. Note: can raise blood pressure and risk of withdrawal syndrome—essential to counsel patients to avoid sudden cessation. Start at 37.5 mg daily and titrate up by 37.5–75 mg every 2–4 weeks. Usual dose range 37.5–225 mg daily. Preventative treatment—limited efficacy evidence in VM—could be considered if failure of multiple other options (a) Lamotrigine—generally well tolerated. Very slow titration needed due to risk of rash/Stevens–Johnson syndrome. Note interaction with sodium valproate. Start at 12.5 mg daily (in patients not on sodium valproate). See British National Formulary (https://bnf.nice.org.uk/drug/lamotrigine.html) for titration instructions. Usual dose range 50–100 mg twice daily. (b) Candesartan—safe and well-tolerated. Consider if comorbid hypertension, although caution needed with respect to renal artery stenosis. No studies in VM. Start at 2 mg daily and titrate up by 2–4 mg every 4 weeks. Usual dose range 2–16 mg daily. (c) Nutraceuticals (riboflavin/coenzyme Q10/magnesium)—safe and well-tolerated. May be used separately or in combination. Useful in patients desiring 'natural' treatment. No studies in VM. Dose riboflavin 400 mg daily, coenzyme-Q10 150 mg daily, magnesium 400–600 mg daily (no need for dose titration). (d) Botulinum toxin A—likely to be more effective for headache than vestibular symptoms. Could be considered as a last resort in very refractory patients if available, if they have prominent headache and if other treatments have failed. Not funded for vestibular migraine in the UK. Preventative treatments currently undergoing evaluation Calcitonin gene-related peptide (CGRP) inhibitors Acupuncture Vestibular rehabilitation Consider in patients refractory or intolerant of pharmacological treatment and in patients desiring a non-pharmacological approach. Particularly useful if attacks are very frequent, concurrent persistent postural-perceptual dizziness (PPPD) or disabling avoidance behaviours. Availability and expertise may be limited in some centres so consider referring to tertiary centre.

Box 2. Vestibular migraine representative case history 1
Case history: A 54-year-old female has had pulsating headaches approximately every 1–2 months since the age of 14 years, which improve if she lies in a dark room. She has no relevant comorbidities. About 2 years ago, the headaches became longer lasting (6–24 h) and more frequent (approximately weekly). Around the same time, she started to experience a 'swaying' sensation with the majority of headaches, sometimes preceding the headache but other times starting after the headache is established and lasting around 2–3 h. During these episodes she feels unsteady and often holds on to the wall when walking. She is also having occasional episodes of the swaying sensation without headache, although she still feels better in a dark room during these. She has been under significant stress and has been sleeping poorly, often taking several hours to get off to sleep. Her GP started her on propranolol for the headaches, as she had responded to this in her 30s during a period of increased headache severity. He also started her on betahistine to treat vertigo. Despite taking the prescribed treatments for 6 months and titrating propranolol up to 80 mg twice daily, she has not improved, and the vertigo episodes have become more frequent. Analysis and management: This patient presents a typical history and meets the Bárány Society criteria for definite vestibular migraine. Patients with vertigo are often prescribed betahistine (an H3-agonist); however, there is no role for this in vestibular migraine. It was reasonable to trial propranolol as her migraine responded to this in the past and she has trialled a reasonable dose for a good length of time. In this case, propranolol was weaned and stopped and amitriptyline was started, chosen due to poor sleep. She also acknowledged the stressors in her life and self-referred to counselling. The dose of amitriptyline was slowly increased to 60 mg nightly—she found 60 mg caused excessive sedation; however, she tolerated 50 mg well. Six weeks after returning to 50 mg she was reviewed and had only had one further headache, which was not associated with vertigo. She was no longer having difficulty sleeping and her sense of well-being was much improved. Learning points: • Choose preventative medications based on comorbidities/patient profile • Look for and address any triggers (e.g. sleep, stress, mood)

Box 3. Vestibular migraine representative case history 2
Case history: A 30-year-old female with a history of well-controlled asthma has had migraine headaches preceded by visual aura since age 18. These are only occasional but are severe and long-lasting (up to 48 h) and associated with vomiting and the need to be in a dark room. At age 27 she developed episodes of rotational vertigo of gradual onset, lasting hours at a time. The vertigo episodes were initially infrequent but by age 29 they were occurring 2–3 times per month. She does not have concurrent headache, hearing loss or tinnitus during the episodes, but recalls that during two of them she needed to be in a dark room and that noise from the street bothered her. She was referred to a neurologist and underwent a full neurological examination, MRI of the head, pure tone audiogram and bithermal caloric testing, which were all normal. She declined amitriptyline and was started on topiramate for probable vestibular migraine. She commenced 25 mg at night but experienced brain fog which interfered with her work, so stopped the medication. She was then started on flunarizine 5 mg at night which she found helpful—the episodes of vertigo reduced to monthly and were shorter duration. Six months later she is reviewed in clinic—she has gained 5 kg, which is affecting her self-esteem and making her feel anxious. The vertigo episodes have also become more frequent again and she says she feels worse than ever and is 'dizzy all the time'. She is noted to walk gingerly and holds onto the wall and is careful about moving her head. She is on long-term sick leave from her job and avoids seeing her friends as she is fearful of having vertigo. Analysis and management: This patient has episodic vertigo without headache, which requires careful evaluation. The normal examination and work-up has essentially excluded other conditions and she meets criteria for probable vestibular migraine. She initially responded to flunarizine; however, she developed weight gain and her symptoms worsened despite treatment. She has avoidant behaviour and is now markedly disabled. She was referred for vestibular rehabilitation and began a physiotherapist-supervised programme focused on balance, conditioning and confidence. Three months later she was reviewed in clinic again—she still had episodes of vertigo every few weeks, but her gait was better and she had returned to work part-time. At her next review a further 3 months later, she had only had one further episode of vertigo and her gait had normalized. She was able to work full-time and was no longer avoiding social situations. Learning point: Vestibular rehabilitation is a good option for patients refractory to pharmacological therapy. It is especially useful in patients with chronic symptoms and where symptoms are impacting upon emotional and/or social well-being.

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Vestibular Migraine Treatment: A Comprehensive Practical Review

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