MENIERES AND MIGRAINES
Neurotology of Migraine
Robert W. Baloh, MD
Neurotologic symptoms are common with migraine, yet relatively little is known about the pathophysiology of such symptoms. Motion sensitivity with bouts of motion sickness occurs in about two thirds of patients with migraine. Episodes of vertigo occur in about one fourth of patients and, in some, vertigo is the only symptom (so-called "migraine equivalent"). Phonophobia is the most common auditory symptom, but fluctuating hearing loss and acute permanent hearing loss occur in a small percentage. Migraine can mimic Meniere's disease and so-called "vestibular Meniere's disease" is usually associated with migraine. The recent discovery of a mutation in a brain calcium-channel gene in families with hemiplegic migraine and in families with episodic vertigo and ataxia suggests a possible mechanism for neurotologic symptoms in patients with more common varieties of migraine. A defective calcium channel, primarily expressed in the brain and inner ear, could lead to reversible hair cell depolarization and auditory and vestibular symptoms. This hypothesis is currently being investigated in other families with migraine headaches and neurotologic symptoms. Hopefully, such studies will lead to improved diagnosis and better treatments in the future.
Migraine is a disease characterized by periodic headaches, but patients often experience other symptoms including dizziness and hearing loss and, in some, these can be the only symptoms. Since most patients equate migraine with headache, it can be difficult to convince them that symptoms other than headache are due to migraine. Comments such as "But, doctor, I don't have a 'migraine' with my dizziness" or "I came to see you because of my dizziness. I haven't had a migraine for at least a year" are common in our Neurotology Clinic. Until we understand the pathophysiology of migraine, it will remain difficult to educate patients and their physicians on the relationship between migraine and neurotologic symptoms.
Furthermore, there is debate as to whether migraine with aura (MA) and migraine without aura (MO) are distinct syndromes, different manifestations of the same disorder, or part of a continuum. Patients can have both types of attacks (with and without aura), and not infrequently, both types of migraine run in the same family (see below). The headache phases of both types of migraine are almost identical, and the same treatments are usually effective for both types of migraine. Conversely, certain epidemiological characteristics, overall familial aggregation, and varying pathophysiologic findings suggest that these two types of migraine may be separate entities.
NEUROTOLOGIC SYMPTOMS AND MIGRAINE
Vestibular Symptoms.--The association of migraine and dizziness extends back to the 19th century when Liveing mentioned their connection in his "On Megrim: Sick Headaches and Some Allied Health Disorders." Overall, episodic vertigo occurs in about 25% of unselected migraine patients (about as frequent as the visual aura). Episodes typically come on abruptly, often without any precipitating factor, and can last from minutes to days at a time. The vertigo attacks can occur during the headache, but most often the attacks occur during the headache-free interval. In addition, patients with migraine frequently report a long history of sensitivity to motion, with bouts of car sickness as a child and motion sickness as an adult. A small subset are so sensitive to their own motion and motion of the environment that they curtail many routine activities including riding in an automobile.
Kayan and Hood compared the incidence of nonspecific dizziness (a giddy sensation) and vertigo (an illusion of rotation) in 200 patients with migraine and 166 patients with tension headache. The headache sufferers were taken in sequence as they presented to a large outpatient headache clinic. Although the incidence of nonspecific dizziness was about the same in the migraine and tension headache groups (28% and 22%, respectively), the migraine patients had a much higher incidence of vertigo than the tension headache patients (27% compared with 8%, a difference significant at P < 0.001 level). In 10 of the migraine patients, the vertigo was severe enough that the patients sought help for this symptom independent of the headache.
Auditory Symptoms.--Auditory symptoms are generally considered to be less common than vestibular symptoms with migraine. Phonophobia is probably the most common auditory symptom associated with migraine, occurring at some time in more than two thirds of patients, usually in association with headache. Several investigators have identified fluctuating low-frequency hearing levels in patients with migraine typical of those seen in patients with Meniere's disease. These changes are most commonly seen in young women around the time of their menstrual period. Migraine has also been identified as a cause of sudden hearing loss that persists. Such patients report the abrupt onset of a profound hearing loss and may show some gradual improvement, but they are often left with a severe unilateral sensorineural hearing loss. Some patients with sudden hearing loss report a prior history of fluctuating hearing in the same ear and many develop persistent tinnitus.
Basilar migraine is a subtype of migraine characterized by recurrent headaches, usually localized to the occipital region, associated with multiple neurologic symptoms localized to the posterior fossa Since vertigo is one of the most common symptoms associated with basilar migraine, and since tinnitus and fluctuating hearing loss also occur, the differential diagnosis between basilar migraine and Meniere's disease can be difficult in some patients. Thought initially to occur primarily in adolescent girls, basilar migraine can occur in both sexes at any age. Bickerstaff postulated that the neurologic symptoms result from ischemia within the basilar artery distribution, presumably secondary to vasospasm. Harker and Rassekh and Olsson reported patients with basilar migraine and fluctuating low-frequency hearing loss indistinguishable from that seen with Meniere's disease. The hearing loss was often bilateral and reversible between attacks. These patients responded to migraine prophylactic medications such as beta-blockers or calcium-channel blockers.
MIGRAINE AND MENIERE'S DISEASE
Speculation on a relationship between migraine and Meniere's disease dates back to the initial description of the syndrome by Prosper Meniere in 1861. He noted that both conditions commonly manifested episodes of vertigo, fluctuating hearing levels, and recurring vomiting. Although many subsequent authors have also speculated on how migraine and Meniere's disease might be related, there is still no generally accepted mechanism to explain the relationship. There is no specific clinical diagnostic test for either disorder. Diagnostic criteria have been established for migraine and Meniere's disease, but some of the criteria overlap. For example, the key diagnostic feature for Meniere's disease is a fluctuating low-frequency sensorineural hearing loss which many clinicians consider pathognomonic for Meniere's disease. As noted above, however, fluctuating low-frequency hearing loss can occur in patients with migraine. Although headache is the most common symptom of migraine, visual aura or episodes of vertigo can occur without headache (so-called "migraine equivalents," see below). Therefore, even when using strict diagnostic criteria, it may not always be possible to separate the two conditions on clinical grounds alone.
Although most authors agree that there is an increased prevalence of migraine in patients with Meniere's disease compared with the general population, the overall percentage of Meniere's patients with migraine varies from study to study. Compared with a lifetime prevalence of migraine of any type in the general population of about 15%, it appears that the prevalence of migraine in patients with Meniere's disease is more than twice as high as that in the general population. However, these studies of the prevalence of migraine in Meniere's patients must be interpreted with caution since none of them used the current International Headache Society (IHS) criteria for the diagnosis of migraine and each used different criteria for the diagnosis of Meniere's disease. Kayan and Hood identified six cases of Meniere's disease among 80 patients referred to a headache clinic with the diagnosis of migraine (a prevalence of 7.5%). This is to be compared with a prevalence of Meniere's disease in the general population of approximately 0.05%.
Numerous studies have documented that migraine can lead to permanent auditory and vestibular deficits. Asymmetries on caloric examination occur with a higher frequency than in control populations.(4) Since endolymphatic hydrops can develop in an ear previously damaged by infection or trauma, another explanation for the association between migraine and Meniere's disease is the development of endolymphatic hydrops in an ear previously damaged by migraine. For example, the vasospasm could lead to ischemic damage to the endolymphatic duct and/or sac leading to impaired fluid circulation and the eventual development of hydrops. One would then expect a gradual progression of the disease typical of Meniere's disease of any cause.
Benign Paroxysmal Vertigo of Childhood. Is described as an episodic disorder in children under the age of 4 years that he called benign paroxysmal vertigo. A completely normal child suddenly becomes frightened, cries out, clings to the parent or staggers as though drunk, and exhibits pallor, diaphoresis, and often vomiting. Symptoms are accentuated by head movements and sometimes nystagmus and torticollis are observed. Some children report a true spinning sensation, but most have difficulty describing what they are experiencing. The spells typically last for several minutes. Afterward the child is immediately normal and can resume playing as though nothing had happened.
Vertigo spells typically begin before the age of 4 and occur up to several times a month. After a period of 2 to 3 years, they decrease in number and gradually disappear. Most children have no further spells after the age of 7 or 8. The cause of benign paroxysmal vertigo of childhood is unclear, although most authors suspect a vascular disturbance affecting the posterior circulation. Follow-up studies of patients with typical benign paroxysmal vertigo during childhood show that most eventually develop migraine.
Vestibular Meniere's.--In their initial recommendations on criteria for the diagnosis of Meniere's disease, the American Academy of Ophthalmology and Otolaryngology Committee on Hearing and Equilibrium defined vestibular Meniere's disease as recurrent attacks of vertigo without associated auditory symptoms. It was assumed that most of these patients would progress to manifest all of the symptoms of classical Meniere's disease. However, because there are so many causes of recurrent episodes of vertigo other than Meniere's disease, more recently the American Academy of Otolaryngology Head and Neck Surgery Committee on Hearing and Equilibrium recommended discarding the term "vestibular Meniere's disease."A study followed up 38 patients with a diagnosis of vestibular Meniere's disease using a standard questionnaire. Seventeen of the 38 no longer fulfilled the criteria for the diagnosis of vestibular Meniere's disease at follow-up. Of these, 8 went on to develop unilateral Meniere's disease and 7 became asymptomatic. Of the 21 patients who continued to meet the criteria for vestibular Meniere's disease, 17 (81%) had migraine. Overall, this study suggests that only a small percentage of patients who present with recurrent episodes of vertigo typical of vestibular Meniere's disease go on to develop the classical symptom triad of Meniere's disease, whereas the majority are associated with migraine.
Benign Recurrent Vertigo of Adulthood. Is described in patients who between the ages of 7 and 55 years began to experience repeated episodes of vertigo, nausea, vomiting, and diaphoresis. The attacks often occurred on awakening in the morning, being particularly common around menstrual periods. Duration varied from a few minutes to as long as 3 to 4 days, with the vertigo becoming primarily positional toward the end of the spell. Nearly all patients were asymptomatic between spells. During the episodes there were no auditory symptoms, specifically no hearing loss, tinnitus, or ear pressure or fullness. Most patients either had migraine themselves or a strong family history of migraine. Furthermore, the episodes of vertigo had several features in common with migraine including precipitation by alcohol, lack of sleep, emotional stress, and a female preponderance.
INHERITED MIGRAINE SYNDROMES WITH NEUROTOLOGIC SYMPTOMS
Familial Hemiplegic Migraine (FHM).--Familial hemiplegic migraine is an autosomal dominant disease characterized by headache attacks preceded by, or accompanied by, episodes of hemiplegia, sometimes lasting days. Unlike MO and MA, the prevalence rate is the same in men and women. Within reported families with FHM, some affected members have interictal nystagmus, ataxia, and essential tremor. Migraine with aura and episodes of hemiplegia may alternate within individuals and co-occur within families. Based on this observation, Russell and Olesen concluded that the pathophysiology and etiology of FHM and uncomplicated migraine are probably the same. When questioned whether FHM was a hereditary form of basilar migraine. They studied aura symptoms in 83 patients from six unrelated families with FHM and found that 55 of the patients reported symptoms that met the IHS criteria for basilar migraine. Consistent with this interpretation, angiography performed during an FHM attack in a single patient showed vasospasm of the basilar artery.
The genetic defect in four families with hemiplegic migraine (two of which also had cerebellar ataxia) was linked to markers on chromosome 19p. However, other families with hemiplegic migraine were not linked to 19p, indicating genetic heterogeneity with FHM. They compared clinical characteristics in three families with FHM linked to chromosome 19p with those of two families not linked to 19p and found only minor differences. Patients from linked families had more frequent episodes of unconsciousness, and attacks were more often triggered by mild head trauma. This suggested a genetically determined lower threshold for external triggering of migraine attacks in the variety linked to 19p. Recently, four FHM families linked to 19p were found to have four different missense mutations in conserved functional domains of the gene coding for an alpha-1 sub-unit of a voltage-gated calcium channel (Figure).
Familial Episodic Ataxia With Interictal Nystagmus. This is a dominantly inherited neurologic disorder characterized by bouts of ataxia and vertigo with interictal nystagmus. Patients with EA-2 typically respond dramatically to treatment with acetazolamide. Migraine without aura occurs in about 50% of patients with EA-2, and there is overlap in the clinical features of EA-2 and FHM. Both EA-2 and FHM are associated with typical symptoms of basilar migraine, and both can have interictal nystagmus and progressive cerebellar ataxia.
Recently, two families with EA-2 were found to have mutations in the same voltage-gated calcium-channel gene on chromosome 19p that is defective in FHM (Figure). However, unlike the missense mutations in the calcium channel found with FHM, the mutations with EA-2 disrupt the reading frame and are predicted to yield a truncated alpha-1 subunit. This presumably leads to a decrease in the density of calcium channels normally heavily expressed in the cerebellum, possibly explaining the episodic and progressive ataxia seen with EA-2. How missense mutations in the same gene lead to episodes of hemiplegia in FHM is unclear. Although most heavily expressed in the cerebellum, the mutated calcium-channel subunit is also expressed in the brain stem and spinal cord.
Familial Migraine With Episodic Vertigo and Essential Tremor.--We recently reported a large family with migraine headache, episodic vertigo, and essential tremor consistent with an autosomal dominant pattern of inheritance. All affected members had the onset of symptoms before aged 25 years. Of the 15 subjects who met the IHS criteria for migraine headaches, 6 also had classical visual aura, 8 had recurrent episodes of vertigo, and 9 had essential tremor. The vertigo spells in affected members last seconds to hours and nearly always occur separately from the visual aura or headaches. Two siblings met the clinical criteria for the diagnosis of Meniere's disease. Essential tremor typically began in adolescence or early adulthood. All symptoms including headache, visual aura, vertigo, and essential tremor responded to treatment with acetazolamide. Within this pedigree, some members with MA gave rise to offspring with MO and some members with MO had offspring with MA. At least within this family, it seems that the same gene can result in migraine either with or without aura. Because of the response to acetazolamide, a mutation in a gene that codes for an ion channel subunit is suspected in this family. Linkage analysis ruled out the 19p locus linked to FHM and EA-2.
Familial Migraine With Bilateral Vestibulopathy.--In 1994, we reported three families with multiple members who experienced migraine headaches and brief episodes of vertigo (minutes), followed in later years by progressive loss of peripheral vestibular function. The episodes of vertigo were dramatically responsive to acetazolamide. In the late stages, when vertigo attacks had stopped, the patients noted imbalance and oscillopsia due to the bilateral vestibular loss. We have also ruled out linkage to the 19p locus of the FHM and EA-2 gene in these families. We suspect a mutation in a calcium-channel subunit that is expressed selectively in the vestibular hair cells to explain the episodic vertigo and progressive bilateral vestibulopathy with normal hearing. This probably represents an inner ear equivalent to EA-2 where episodes of vertigo and ataxia lead to a persistent ataxia, loss of cerebellar neurons, and cerebellar atrophy.
As with migraine headaches, treatment of vertigo due to migraine can be symptomatic or prophylactic. A wide range of antivertiginous and antiemetic drugs are useful for suppressing symptoms. Promethazine (25 or 50 mg orally or via suppository) is particularly effective because of its combined antivertiginous and antiemetic properties. The sedating effect of promethazine is usually acceptable in a sick patient who is eager to sleep. Less sedating drugs such as dimenhydrinate and meclizine are most useful for treating milder episodes of vertigo and for controlling motion sickness. Metoclopramide helps control the nausea and vomiting associated with both headache and vertigo. The decrease in gastric motility that often occurs during migraine attacks can decrease the absorption of oral drugs as well as contribute to the nausea and vomiting. Metoclopramide promotes normal gastric motility and may improve absorption of oral drugs. It is important to keep in mind that all of these drugs require a minimum of 20 to 30 minutes to enter the blood, and they do not reach peak levels for 1 to 2 hours. Specific treatments for headache, such as ergotamines or sumatriptan, are probably of little benefit for the treatment of migraine-associated vertigo, although there have been no reported treatment trials with these drugs.
Prophylactic treatments are appropriate when episodes of vertigo are occurring frequently or when the severity is not adequately controlled by symptomatic treatment. The same prophylactic medications used to treat headaches also control vertigo spells. These are the only drugs that might be useful for controlling migraine-associated hearing loss. Three main classes of drugs have been used: beta-blockers, calcium-channel blockers, and tricyclic amines. However, there have been no controlled trials of these medications in treating neurotologic symptoms with migraine. Also, the mechanism of action of these drugs for controlling migraine symptoms is unknown. Beta-blocker and calcium-channel blockers may prevent vasospasm of arteries to the inner ear just as they prevent vasospasm of retinal arteries in retinal migraine.
However, with the recent discovery of an abnormal calcium channel in patients with FHM and EA-2, these drugs may stabilize the basic underlying cellular metabolic defect. One typically begins with low doses and gradually works up to the therapeutic range. A trial of at least a month is required to assess efficacy. The first sign of effect is a decrease in the frequency and severity of attacks. Acetazolamide is a drug that deserves wider consideration as a migraine prophylactic. We have found it to be particularly effective in controlling vertigo and motion sickness in patients with migraine.(42) It is well known to suppress mountain sickness, a condition that commonly occurs in migraineurs. Its dramatic effect in EA-2 is presumably due to changes in cerebellar pH which helps stabilize the defective calcium channels. Assuming other migraine syndromes are due to ion channel defects in the brain and inner ear, then acetazolamide might be effective for a wide range of migraine disorders.