Central vestibular disorders

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1 J Neurol (2007) 254: DOI /s REVIEW Marianne Dieterich Central vestibular disorders Received: 1 June 2006 Received in revised form: 26 June 2006 Published online: 6 April 2007 Prof. Dr. M. Dieterich, MD (&) Dept. of Neurology Johannes Gutenberg-University Mainz Langenbeckstrasse Mainz, Germany Tel.: / Fax: / dieterich@neurologie.klinik.unimainz.de j Abstract Dizziness or vertigo is an erroneous perception of selfmotion or object-motion as well as an unpleasant distortion of static gravitational orientation. It is caused by a mismatch between the vestibular, visual, and somatosensory systems. Thanks to their functional overlap, the three systems are able to compensate, in part, for each other s deficiencies. Thus, vertigo is not a well-defined disease entity, but rather a multisensory syndrome that results when there is a pathological dysfunction of any of the stabilizing sensory systems (e.g., central vestibular disorders, peripheral vestibular diseases with asymmetric input into the vestibular nuclei). This article provides an overview of the most important and frequent forms of central vestibular vertigo syndromes, including basilar/vestibular migraine, which are characterized by ocular motor, postural, and perceptual signs. In a simple clinical classification they can be separated according to the three major planes of action of the vestibulo-ocular reflex: yaw, roll, and pitch. A tonic imbalance in yaw is characterized by horizontal nystagmus, lateropulsion of the eyes, past-pointing, rotational and lateral body falls, and lateral deviation of the perceived straight-ahead. A tonic imbalance in roll is defined by torsional nystagmus, skew deviation, ocular torsion, tilts of head, body, and the perceived vertical. Finally, a tonic imbalance in pitch can be characterized by some forms of upbeat or downbeat nystagmus, fore-aft tilts and falls, and vertical deviation of the perceived straight ahead. The thus defined syndromes allow for a precise topographic diagnosis as regards their level and side. j Key words central vestibular syndrome Æ vestibulo-ocular reflex Æ eye movements Æ vertical nystagmus Æ vertigo Æ vestibular migraine Introduction Central vestibular forms of vertigo are caused by lesions along the vestibular pathways, which extend from the vestibular nuclei in the medulla oblongata to the ocular motor nuclei and integration centers in the pons and rostral midbrain, and to the vestibulocerebellum, the thalamus, and multisensory vestibular cortex areas in the temporoparietal cortex [1, 2]. These forms of vertigo are often clearly defined clinical syndromes of various etiologies, with typical ocular motor, perceptual, and postural manifestations

2 560 that permit a topographic brainstem diagnosis. The analysis of nystagmus can also be helpful for localizing the lesion site [3]. Depending on the size of the lesion, central vestibular syndromes can occur in isolation or as part of a complex infratentorial syndrome. Additional symptoms of supranuclear or nuclear ocular motor disorders and/or other neurological brainstem deficits can also occur (e.g., Wallenberg s syndrome with ocular tilt reaction as well as Horner s syndrome, sensory deficits, ataxia, dysarthria, and dysphagia). The most important structures for central vestibular forms of vertigo are the neuronal pathways for mediating the vestibulo-ocular reflex (VOR)[4]. They travel from the peripheral labyrinth over the vestibular nuclei in the medullary brainstem to the ocular motor nuclei (III, IV, VI) and the supranuclear integration centers in the pons and midbrain (interstitial nucleus of Cajal, INC; and rostral interstitial nuclei of the medial longitudinal fasciculus, rimlf) (Fig. 1). This three-neuronal reflex arc makes compensatory eye movements possible during rapid head and body movements. It is thus crucially responsible for regulating the ocular motor system. Another branch of the VOR system runs over the posterolateral thalamus up to the multisensory vestibular areas in the parietotemporal cortex, such as the parietoinsular vestibular cortex (PIVC), retroinsular areas, areas in the superior temporal gyrus and in the inferior parietal lobe which are primarily responsible for perception of selfmotion and orientation. Descending pathways lead from the vestibular nuclei along the medial and lateral vestibulospinal tract into the spinal cord to mediate postural control. In addition, there are also pathways to the vestibulocerebellum and to the hippocampus. Thus, disorders of the VOR are not only characterized by ocular motor deficits, but also by disorders of perception due to impaired vestibulocortical projections of the VOR and by disorders of postural control due to impaired vestibulospinal projections of the VOR (Fig. 1). Central vestibular syndromes are the result of lesions of these pathways caused by infarction, hemorrhage, tumor, or degenerative processes, by multiple sclerosis plaques, or, more rarely, by pathological irritations such as paroxysmal brainstem attacks (with ataxia and dysarthria) as occur in basilar/vestibular migraine, multiple sclerosis or in vestibular epilepsy. They are not rare, but the third and fourth most frequent forms of vertigo in a neurological dizziness unit [2](Table 1). The differential diagnosis of peripheral labyrinthine and central vestibular disorders is guided by auditory signs (Ménière s disease, perilymphatic fistula, neurovascular cross-compression), brainstem signs (central positional vertigo, vertebro-basilar ischemia, basilar PERCEPTION VESTIBULO OCULAR REFLEX A H UT P VESTIBULO SPINAL REFLEX OS VIII IV III Brainstem RI lateral medial vestibulo- vestibulospinal spinal tract tract Fig. 1 Schematic drawing representing the vestibulo-ocular reflex (VOR) with its 3-neuron reflex arc and its mediation of ocular motor, perceptual, and postural functions; as well as an ocular tilt reaction with ocular torsion and vertical divergence of the eyes due to a tonic imbalance of the graviceptive pathways (III, IV, VII Cranial nerve nuclei; OS superior oblique muscle; RI inferior rectus muscle; A, P, H anterior, posterior, horizontal semicircular canal, UT utricle) Table 1 The frequency of different vertigo-/dizziness syndromes in patients seen in a neurological dizziness unit [36] Diagnosis Frequency n % 1. Benign paroxysmal positional vertigo Phobic postural vertigo (PPV) Central vestibular vertigo Vestibular migraine Menière s disease Vestibular neuritis Bilateral vestibulopathy Psychogenic vertigo (without PPV) Vestibular paroxysmia Perilymph fistula Unknown vertigo syndromes Other disorders

3 561 migraine, paroxysmal ataxia/dysarthria), certain provoking factors such as head motion (benign paroxysmal positioning vertigo, central positional vertigo, neurovascular cross-compression, bilateral vestibulopathy), or family history (congenital vertigo). Since the central nervous system has a strong impulse to become habituated to a persisting sensory mismatch, all therapy for vertigo should avoid disturbing these naturally compensatory mechanisms, which are centered within the vestibular nuclei. It is important to note that the prerequisite for this habituation and compensation is the stimulus of a sensory mismatch. Adequate therapy for vertigo must consider that antivertiginous drugs suppress such mechanisms, because most of these drugs are vestibular sedatives. Therefore, vestibular suppressants should only be administered when vertigo is accompanied by distressing nausea and vomiting, i.e., in acute peripheral vestibulopathy and in acute brainstem and cerebellar lesions (near the vestibular nuclei), or to prevent motion sickness. These drugs are not indicated for patients with chronic dizziness or positioning vertigo. If possible, specific therapies should be directed at the underlying cause. In some cases it is best to recommend rehabilitation, although the lesioned function will be compensated for over time. In particular, vestibular rehabilitation is often needed to speed up recovery and central compensation. j Central vestibular syndromes Clinical aspects, course of disease, pathophysiology, and therapeutic principles To differentiate central vestibular forms of vertigo from other forms, it is helpful to refer to the duration of the symptoms [2]: Syndrome of the VOR Horizontal plane (yaw) Sagittal plane (pitch) Frontal plane (roll) Clinical symptoms - vestibular pseudoneuritis, spontaneous horizontal nystagmus, - horizontal past-pointing to the right/left (subjective straight-ahead), - postural instability, falling tendency to one side, turning in the Unterberger-step test - downbeat nystagmus, upbeat nystagmus, deviation of the subjective horizontal upwards or downwards, - postural instability with a falling tendency forward or backward - ocular tilt reaction, skew deviation, ocular torsion, head tilt, - deviation of the subjective visual vertical (SVV) clockwise or counterclockwise, - postural instability with a falling tendency to one side short, rotatory or postural vertigo attacks lasting seconds to minutes or for a few hours are caused by transient ischemic attacks within the vertebrobasilar territory, basilar migraine/vestibular migraine, paroxysmal brainstem attacks with ataxia/dysarthria in multiple sclerosis, and the rare vestibular epilepsy. hours to several days long persisting rotatory and postural vertigo attacks, generally with additional brainstem deficits, can be caused by an infarction, hemorrhage, or MS plaque in the brainstem, seldom by a long-lasting basilar migraine attack. several days to weeks of permanent postural vertigo (seldom permanent rotatory vertigo) combined with a tendency to fall and usually caused by persisting damage to the brainstem or the cerebellum bilaterally, e.g., downbeat nystagmus syndrome due to Arnold-Chiari malformation or upbeat nystagmus syndrome due to paramedian pontomedullary or pontomesencephalic damage (infarction, hemorrhage, tumor). Central vestibular syndromes in the 3 major planes of action of the VOR The central vestibular brainstem syndromes can be classified for a simple clinical overview according to the three major planes of action of the VOR [2, 5]: Vestibular syndromes in the horizontal (yaw) plane These are rare, for example, horizontal benign paroxysmal positioning vertigo due to a canalolithiasis in the horizontal canal of the labyrinth [6]. As far as we know nowadays, central syndromes in yaw are caused only by lesions in the area of the entry zone of the vestibular nerve in the medulla oblongata, the medial and/or superior vestibular nuclei, and the neighboring integration centers for horizontal eye movements (nucleus praepositus hypoglossi and paramedian pontine reticular formation). Other clinical signs are ipsilateral caloric hyporesponsiveness, horizontal gaze deviation, falling tendency to the affected side, and a past-pointing corresponding to a deviation of the subjective straight-ahead. The clinical symptoms are similar to those of an acute peripheral vestibular lesion as occurs in vestibular neuritis and thus is also called vestibular pseudoneuritis. In most cases there is a horizontal rotatory nystagmus. A purely central yaw plane syndrome is rare, because the area of a lesion that can theoretically cause a pure tone imbalance in the yaw plane adjoins and in part overlaps with structures in the vestibular nuclei, which are also responsible for vestibular function in the roll plane. For this reason mixed patterns are found more frequently.

4 562 Fig. 2 Schematic drawing of the brainstem and cerebellum with the typical sites of lesions that induce vestibular syndromes in the pitch plane of the VOR, i.e., downbeat (down) and upbeat (up) nystagmus syndromes, and in the roll plane (III, IV, VI, VII cranial nerve nuclei, MLF medial longitudinal fasciculus, rimlf rostral interstitial nucleus of the medial longitudinal fasciculus, INC interstitial nucleus of Cajal) The most common causes include MS plaques or ischemic infarctions within the vestibular nuclei or fascicles. If the lesion extends beyond the vestibular nuclei, other accompanying brainstem symptoms can be detected. Since a unilateral medullary ischemic or inflammatory brainstem lesion is generally present, the prognosis is favorable because central compensation takes place over the opposite side. The symptoms can be expected to resolve slowly within days to weeks. Thus, central compensation together with simultaneous treatment of the underlying illness can be promoted by early balance training. Vestibular syndromes in the sagittal (pitch) plane These have so far been attributed to lesions in the following three places: paramedian bilateral in the medullary and pontomedullary brainstem, the pontomesencephalic brainstem with the adjacent cerebellar peduncle, or the cerebellar flocculus bilaterally (Fig. 2). In spite of many clinical reports of downbeat nystagmus (DBN) and upbeat nystagmus (UBN) and multiple hypotheses about possible mechanisms, the pathophysiology is still under discussion [7 9]. In the light of several clinical findings and experimental data, a current general concept is that asymmetries in the cerebello-brainstem network that normally stabilizes vertical gaze could lead to an imbalance in structures such as (a) the vertical cerebello-vestibular Ôneural integrator, (b) the central connections of the vertical VOR including both the semicircular canal and the otolith responses, or (c) the vertical smooth pursuit system. In a recent review by Pierrot-Deseilligny and Milea [10] DBN is explained by a floccular lesion that results in a disinhibition of the pathway from the superior vestibular nucleus via the ventral tegmental tract and thereby in a relative hyperactivity of the elevator muscles inducing an upward slow phase. The crucial role of the flocculus in DBN was confirmed only recently in an FDG-PET study: a glucose hypometabolism was found in the cerebellar flocculus/paraflocculus and tonsil that could be improved by effective medical therapy with 4-aminopyridine [11](Fig. 3). The downbeat nystagmus syndrome (DBN) is characterized by a fixational nystagmus, frequently acquired, which beats downward in primary gaze position, is exacerbated on lateral gaze and in headhanging position, may have a rotatory component, and is accompanied by a combination of visual and vestibulocerebellar ataxia with a tendency to fall backward and past-pointing upward as well as vertical smooth pursuit deficits [2, 4, 12, 13]. The syndrome is frequently persistent. The individual components can differ, since there are obviously other pathogeneses besides the vestibular one with imbalance in the graviceptive VOR (impairment in the projection of otolithic information), e.g., imbalance of dysfunction of the neuronal ocular motor integrator and of the saccade-burst generator and of the vertical smooth pursuit system [7, 14]. DBN is often the result of a bilateral lesion of the flocculus or the paraflocculus (e.g., intoxication due to anticonvulsant drugs) or caused by a lesion at the bottom of the 4 th ventricle [15, 16]. Accordingly it is mostly a drug-induced dysfunction or congenital: 25% of patients have craniocervical junction anomalies (Chiari malformation), 20% have cerebellar degeneration, and about 50% are of unknown etiology. It can also be caused by a paramedian lesion of the medulla oblongata [17], more rarely by, e.g., multiple sclerosis, hemorrhage, infarction, or tumor. A DBN due to a lesion in the upper medulla at the level of the rostral nucleus praepositus hypoglossi has so far only been reported in monkeys, not in humans [18]. Upbeat nystagmus (UBN) is rarer than downbeat nystagmus. It is also a fixation-induced nystagmus that beats upward in primary gaze position, and is combined with a disorder of the vertical smooth pursuit eye movements, a visual and vestibulospinal ataxia with a tendency to fall backward, and pastpointing downward [2, 4, 13, 19]. On the one hand, the pathoanatomical location of most acute lesions is near the median plane in the medulla oblongata in

5 563 Fig. 3 Results of the 18F-fluorodeoxyglucose positron emission tomography (PET) scanning without and with 4-aminopyridine treatment in a patient with downbeat nystagmus (DBN). Both show a glucose hypometabolism but only in the region of the cerebellar flocculus/paraflocculus and tonsil bilaterally when compared with a normal database of the whole brain. On treatment the DBN had improved significantly. This finding supports the view that the cerebellar (para-) flocculus and tonsil play a crucial role in DBN. The hypometabolism might reflect reduced inhibition or even disinhibition of the circuits to the vestibular nuclei, thus causing DBN. (adopted from [11] ) A) B) without treatment sagittal on treatment coronal transversal 0 z-score 6 neurons of the paramedian tract (PMT), close to the caudal part of the perihypoglossal nucleus [15, 19, 20], which are responsible for vertical gaze-holding [21](Fig. 2). On the other, lesions have been reported near the median plane in the tegmentum of the pontomesencephalic junction, the brachium conjunctivum, and probably in the anterior vermis [22, 23]. Only recently a lesion of the paramedian pontine brainstem was described affecting the central ventral tegmental tract [24]. The symptoms of UBN persist as a rule for several weeks but are usually not permanent. Because the eye movements generally have larger amplitudes, oscillopsia in UBN is very distressing and impairs vision significantly. UBN due to damage to the pontomesencephalic brainstem is frequently combined with a unilateral or bilateral internuclear ophthalmoplegia (INO), indicating that the MLF is affected. The main etiologies are bilateral lesions in MS, brainstem ischemia or tumor, Wernicke s encephalopathy, cerebellar degeneration, and dysfunction of the cerebellum due to intoxication. The course and prognosis depend on the underlying illness. It is therapeutically expedient to attempt treatment of the symptoms of persisting DBN or UBN by administering gabapentin (3 200 mg/day p.o.), baclofen ( mg/day p.o.), or clonazepam (3 0.5 mg/day p.o.) [25, 26]. Recently, the potassium channel blockers 3,4-diaminopyridine and 4-aminopyridine have been shown to be effective in reducing DBN in some but not all patients with DBN and UBN [27, 28]. Potassium channels are abundant on cerebellar Purkinje cells the output neurons from cerebellar cortex and the related agent, 4-aminopyridine, is reported to increase the discharge of these neurons by affecting the slow depolarizing potential [29]. Such an enhancement of Purkinje cell activity could restore the inhibitory influence of the cerebellar cortex upon vertical vestibular eye movements to normal levels [30]. From these studies it was concluded that (a) 4-aminopyridine reduces the downward drift in UBN by augmenting smooth pursuit commands, and (b) 3,4-diaminopyridine minimizes the gravity independent velocity bias and improves deficient inhibitory cerebellar control on overacting otolith-ocular reflexes. Vestibular syndromes in the vertical (roll) plane These syndromes indicate an acute unilateral deficit of the graviceptive vestibular pathways, which run from the vertical canals and otoliths over the ipsilateral (medial and superior) vestibular nuclei and the contralateral medial longitudinal fasciculus (MLF) to the ocular motor nuclei and integration centers for vertical and torsional eye

6 564 movements (INC and rimlf) in the rostral midbrain [5, 31, 32](Fig. 2). More rostral to the midbrain, only the vestibular projection of the VOR for perception in the roll plane (determination of the subjective visual vertical, SVV) runs over the vestibular subnuclei in the posterolateral thalamus [33] to the parietoinsular vestibular cortex (PIVC) in the posterior insula [31, 34]. The crossing of these pathways at pontine level is especially important for topographic diagnosis of the brainstem. All signs of lesions in the roll plane a single or a complete ocular tilt reaction (i.e., head tilt, vertical divergence of the eyes, ocular torsion, SVV deviation) represent an ipsiversive tilt (ipsilateral eye lowermost) in both the very rare, unilateral peripheral vestibular lesion or the frequent pontomedullary lesion (medial and superior vestibular nuclei) below the pyramidal decussation in the brainstem [5]. All signs in the roll plane ocular motor, perceptual, and postural exhibit contraversive deviations (contralateral eye lowermost) for unilateral pontomesencephalic lesions of the brainstem above the pyramidal decussation and indicate a deficit of the MLF or of the supranuclear nucleus of the INC [5]. Unilateral lesions of vestibular structures located rostral from the INC manifest with perceptual deficits only (deviation of the SVV) without accompanying ocular motor deficits or head tilt [33, 34]. Ocular tilt reaction in unilateral infarctions of the paramedian thalamus (in 50%) is caused by a simultaneous lesion in the paramedian rostral midbrain (INC)[33]. Unilateral lesions of the posterolateral thalamus can cause thalamic astasia with moderate ipsiversive or contraversive SVV tilts, which indicate involvement of the vestibular thalamic subnuclei. This generally resolves within a matter of days or a few weeks [33]. Perceptual deficits in the sense of pathological deviations of the SVV occur during unilateral deficits along the entire VOR projection and are one of the most sensitive signs of acute brainstem lesions (in ca. 90% of cases of acute unilateral infarctions)[5]. If instead of a functional deficit due to a lesion, there is an excitation of the VOR projection on one side, the same effects will be triggered, but in the opposite direction. If a torsional nystagmus occurs in the acute phase, the rapid nystagmus phase will be in the opposite direction of the tonic skew deviation and the ocular torsion [35]. The etiology of these unilateral lesions is frequently an infarction of the brainstem or the paramedian thalamus, which extends into the rostral midbrain. Course and prognosis depend also here on the etiology of the underlying illness. One can count on a significant, generally complete recovery from the symptoms in the roll plane within days to weeks due to the central compensation over the opposite side. j Basilar migraine / vestibular migraine Classification Migraine is an episodic disorder that has headache as its most prominent feature and occurs in various combinations with autonomic, gastrointestinal and neurological symptoms [2, 36]. The incidence of vertigo in association with migraine has been reported to range between 50% and 70%, if one includes under the heading of vertigo sensations of dizziness, light-headedness, and unsteadiness [37 39]. This surprisingly high incidence rate does not, however, reflect the clinical importance of vertigo in relation to other more characteristic and distressing symptoms of migraine, since only one-third of these patients describe vestibular vertigo. According to Kayan and Hood [40] and Müri and Meienberg [41], vertigo appears to be either the major symptom or a severe complication of migraine in only 5 8% of cases. It is important to note that thus afflicted patients contact dizziness specialists first and foremost and not headache specialists, since their prevailing complaint is distressing vertigo/dizziness. Over the last two decades those who manage dizzy patients have increasingly realized that migraine is an important cause of various forms of episodic vertigo. Although it is one of the most frequent neurological syndromes diagnosed in neurological dizziness units (Table 1), it is still certainly underdiagnosed, especially if the vertigo attacks lack a temporal relationship with typical migraine symptoms [36, 42 45]. In a first approach one is tempted to attribute migrainous vestibular vertigo to basilar-type migraine, since vertigo is most often caused by dysfunction of the peripheral (labyrinth, vestibular nerve) or central (brainstem, cerebellum) vestibular circuitry dysfunction, both of which territories are supplied by the basilar artery. If the attacks of vertigo are associated with other brainstem symptoms, more rarely also disturbances of consciousness, psychomotor deficits, or changes of mood, one speaks of basilar migraine. The attacks can, however, also be monosymptomatic, manifesting with only vertigo and perhaps also with a hearing disorder; they are called vestibular migraine. However, there is to date a problem with the correct classification. The International Headache Society [46] requires an aura with two or more symptoms originating from the brain-

7 565 stem and/or from both hemispheres simultaneously, usually developing over 5 20 min and lasting no longer than 60 min to qualify as criteria for basilartype migraine. Thus, by definition purely monosymptomatic attacks with rotational vertigo for seconds to a few minutes or for hours to days cannot be termed basilar-type migraine [42]. The latter diagnosis is considered even less appropriate if the attacks are not followed by headache [42, 44, 45]. Some authors propose the term migrainous vertigo, to emphasize the particular etiology of these vertigo attacks [47]. Others have proposed the term vestibular migraine to stress the particular manifestitation of migraine with vertigo as the prevailing or sole symptom, often even without associated headache [2, 42]. The latter term is more oriented to the existing classification of the International Headache Society. Both terms, however, are not included in the current 2nd edition of The International Classification of Headache Disorders. The term migrainous vertigo includes not only vestibular vertigo in a strict sense but also nonvestibular dizziness and light-headedness, dizziness associated with motion sensitivity, and head motion intolerance. In my opinion such a term would also apply to many patients who have a migraine without aura and who during their frequent headache attacks experience no rotational vertigo but only a lightheadedness or a mild head motion intolerance, i.e., an unspecific non-vestibular dizziness. Thus, I agree with Olesen s [48] recent comment that migrainous vertigo should not be proposed as a specific subtype of migraine similar to hemiplegic migraine, since the vestibular signs and symptoms are not specific enough and the vertiginous symptoms are just one of many manifestations of migraine. From our own experience [36, 42] we have found it helpful to focus on those patients who clearly experience audiovestibular attacks (with or without associated headache) in which vertigo is the leading complaint. These patients seem to represent, in the true sense of the word, the vestibular subgroup which has the syndrome in question. I would thus recommend a conservative approach: to concentrate on symptoms during the attacks which can be clearly localized to the vestibular system, e.g., rotational vertigo and/or to-and-fro vertigo (sometimes associated with concurrent nystagmus and ocular motor disorders or cochlear symptoms) and label them vestibular migraine, i.e., a form of migraine with a monosymptomatic vestibular aura. Clinical aspects and course In adults, migraine is the most common cause of spontaneous recurrent vertigo [47](see Table 1). Table 2 Vestibular migraine: frequency of central ocular motor signs in the attack-free interval in 90 patients [42] n % Normal Congenital strabismus Congenital nystagmus Central ocular motor signs Saccadic pursuit, vertical Saccadic pursuit, horizontal Gaze-evoked nystagmus Spontaneous nystagmus (>5 /sec) Positional nystagmus Dissociated gaze-evoked nystagmus 8 9 Downbeat nystagmus Upbeat nystagmus Impaired fixation suppression of VOR Nuclear oculomotor palsy Note: 1) Multiple quotations possible 2) In combination with other central ocular motor signs and/or a directional preponderance in caloric testing However, vestibular migraine is the chameleon among the episodic vertigo syndromes due to extreme variation of the manifestation, especially the duration, lasting from seconds to days, without associated headache in about one-third of the attacks, and the initial manifestation, occurring at any time throughout life [42, 44, 45, 49]. This broad spectrum poses a diagnostic problem. Differential diagnosis does not primarily encompass the spectrum of headache syndromes but the spectrum of vestibular disorders. Some other causes must be ruled out first, e.g., Menière s disease, which can mimic migraine [50] and vestibular paroxysmia due to neurovascular cross-compression of the eighth nerve [51]. Monosymptomatic audiovestibular attacks predominate in about 75% of such cases [42]. They are more difficult to recognize, especially if headache is missing (in about 30%). The diagnosis is simple, if the attacks are usually or always followed by occipital pressure in the head or a headache and if there is a positive family or personal history of other types of migraine (ca. 50%). It is easier to establish the diagnosis if the following symptoms occur: light and sound hypersensitivity, need for rest, tiredness after the attack, and urine surge. Contrary to other forms of migraine, more than 60% of persons with vestibular migraine also show mild central ocular motor disorders during attack-free intervals [42](Table 2). The surprisingly high incidence (65%) of subtle pathological ocular motor findings of central origin in the symptom-free interval agrees with a report by Kayan and Hood [52], who in reference to the attack described findings indicative of definite dysfunction of the vestibular and/or cochlear systems in 77.5% in their patients, half with central and half with peripheral pathology (18.8% central,

8 % peripheral, 30% inconclusive). Their study, however, provides no data on neuro-otological disturbance in the symptom-free interval. The frequency (21%) of persisting peripheral vestibular deficits in the study by Cutrer and Baloh [49] was less in our study (8.3%)[42]. Objectively measurable electronystagmographic ocular motor abnormalities (57 80%) were stressed earlier [40, 53, 54]. The patients are generally hypersensitive to movements and motion sickness, particularly during the migraine attack [49]. This is similar to phonophobia and photophobia during migraine attacks, which is induced by a neuronal sensory overexcitability, e.g., here of the inner-ear receptors. Originally basilar migraine was described by Bickerstaff in 1961 [55] as a typical illness of adolescence, which clearly predominated in females. Retrospective studies have, however, shown that basilar migraine with dizziness and vestibular migraine can develop throughout the patient s entire life, most often between the third and sixth decades [42, 44]. The ratio of women and men affected is 1.5 : 1. The frequency of basilar migraine with dizziness or a vestibular migraine amounts to 7 9% in special outpatient clinics for dizziness. The prevalence of basilar migraine with dizziness is not known; naturally that for migraine without aura is clearly higher and has a 1-year prevalence of 12 14% for women after puberty and 7 8% for men after puberty. Women are affected 2 3 times more often than men. If the attacks take a monosymptomatic course without headache, then they cannot be differentiated clinically from benign paroxysmal vertigo in childhood which has recently been shown to be linked to CAC- NA1A mutation [56]. A migrainous positional vertigo can mimic benign paroxysmal positional vertigo (BPPV)[57, 58] and migrainous vertigo episodes attacks of Menière s disease [50, 57]. Pathophysiology and therapeutic principles As regards the pathogenesis of basilar/vestibular migraine, it is interesting that the rare episodic ataxia type 2 (due to a mutation of a gene on chromosome 19p in the calcium channel) occurs in several families in combination with hemiplegic migraine, which is also located on chromosome 19 [59]. Moreover, the central findings in the ocular motor system during the symptom-free interval, as in episodic ataxia, also indicate that patients with vestibular migraine may have a hereditary neuronal disorder in the brainstem nuclei (channelopathy?). Neuronal deficits in the brainstem are also discussed as factors in the pathophysiology of migraine without aura. In this primarily neurovascular headache syndrome, in which the trigeminovascular system along with neurogenic inflammatory reactions plays a central role, animal studies have identified the nucleus locus coeruleus in the pontine brainstem as the modulator of the cerebral blood flow, the most important central nucleus of the noradrenergic system [60]. Furthermore, the serotonergic dorsal raphe nucleus in the midbrain seems to play an important role. PET studies have shown that this region and that of the dorsal pons with the nucleus coeruleus are also activated in patients during migraine attacks without aura [61]. These brainstem nuclei are, however, also activated immediately after successful treatment of a migraine attack but not during the symptom-free interval. Drug therapy acts at various sites within the trigeminovascular system and the neurogenic inflammatory cascade. Pragmatic therapy The same principles of therapy that have proven effective in migraine without aura are used, both for treating the attacks as well as for migraine prophylaxis, although the symptoms of dizziness and the accompanying headache can respond differently. To stop attacks lasting 45 minutes and longer, it is advisable to administer an antiemetic (e.g., metoclopramide, domperidon) early in combination with a non-steroidal antiphlogistic (e.g., ibuprofen, diclofenac), an analgesia (acetylsalicylic acid as soluble tablet or paracetamol as a suppository), or an ergotamine (ergotamine tartrate). The tryptanes, which are very effective against migraine attacks without aura and act at the 5- HT 1B/1D receptors of the vascular walls, are contraindicated for the treatment of migraine with aura because of the danger of a cerebral or cardiac infarction as a result of the vasoconstriction of the arteries. In individual cases, however, they have been reported to have positive effects in attacks of dizziness. The treatment of first choice for migraine prophylaxis is the administration of the beta-receptor blocker metoprolol retard (ca. 100 mg/day) for about 6 months. Alternatives are the calcium antagonist flunarizin (1 2 capsules, 10 mg per capsule, in the evening), valproic acid ( mg/day), lamotrigine ( mg/day), or topiramate (100 mg/day). j Acknowledgements This work has been supported by the German Research Foundation (DFG). This article is based on a talk given by the author at a teaching course at the European Neurological Society meeting in Lausanne on 29 May 2006.

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