Recent advances in central acute vestibular syndrome of a vascular cause

Acute vestibular syndrome (AVS) is characterized by acute onset of spontaneous prolonged vertigo (lasting days), spontaneous nystagmus, postural instability, and autonomic symptoms. Peripheral AVS commonly presents as vestibular neuritis, but may also include other disorders such as Meniere's disease. Vertigo in central AVS due to vertebrobasilar ischemic stroke is usually accompanied by other neurological dysfunction. However it can occur in isolation and mimicking peripheral AVS, particularly with cerebellar strokes. Recent large prospective studies have demonstrated that approximately 11% of patients with isolated cerebellar infarction presented with isolated vertigo mimicking peripheral AVS, and the bedside head impulse test is the most useful tool for differentiating central from peripheral AVS. Herein we review the keys to the diagnosis of central AVS of a vascular cause presenting with isolated vertigo or audiovestibular loss.     

Inferior vestibular neuritis

Vestibular neuritis (VN) mostly involves the superior portion of the vestibular nerve and labyrinth. This study aimed to describe the clinical features of VN involving the inferior vestibular labyrinth and its afferents only. Of the 703 patients with a diagnosis of VN or labyrinthitis at Seoul National University Bundang Hospital from 2004 to 2010, we retrospectively recruited 9 patients (6 women, age range 15-75) with a diagnosis of isolated inferior VN. Diagnosis of isolated inferior VN was based on torsional downbeating spontaneous nystagmus, abnormal head-impulse test (HIT) for the posterior semicircular canal (PC), and abnormal cervical vestibular-evoked myogenic potentials (VEMP) in the presence of normally functioning horizontal and anterior semicircular canals, as determined by normal HIT and bithermal caloric tests. All patients presented with acute vertigo with nausea, vomiting, and imbalance. Three patients also had tinnitus and hearing loss in the involved side. The rotation axis of torsional downbeating spontaneous nystagmus was best aligned with that of the involved PC. HIT was also positive only for the involved PC. Cervical VEMP was abnormal in seven patients, and ocular VEMP was normal in all four patients tested. Ocular torsion and subjective visual vertical tests were mostly within the normal range. Since isolated inferior VN lacks the typical findings of much more prevalent superior VN, it may be mistaken for a central vestibular disorder. Recognition of this rare disorder may help avoid unnecessary workups in patients with acute vestibulopathy.     

Vestibular responses in Wernicke's encephalopathy

Two patients with Wernicke's encephalopathy were evaluated with quantitative vestibulo-ocular reflex and ocular motor testing. Vestibulo-ocular reflex testing included caloric irrigation, earth vertical axis rotational sinusoids, and rotational impulses. Both patients demonstrated hypoactive vestibular responses to both caloric and rotational stimuli at the time of presentation. One patient had unbeating nystagmus that diminished with upgaze, downgaze, or convergence. Following treatment with thiamine, both patients' vestibular responses improved but remained abnormal, with a short vestibulo-ocular reflex time constant and increased low-frequency rotational phase lead. Impairment of the velocity storage element attributable to damage to the vestibular nucleus and nucleus prepositus hypoglossi may account for this permanent effect on the vestibulo-ocular reflex.     

Pharmacotherapy of vestibular and ocular motor disorders,including nystagmus

We review current pharmacological treatments for peripheral and central vestibular disorders, and ocular motor disorders that impair vision, especially pathological nystagmus. The prerequisites for successful pharmacotherapy of vertigo, dizziness, and abnormal eye movements are the “4 D’s”: correct diagnosis, correct drug, appropriate dosage, and sufficient duration. There are seven groups of drugs (the “7 A’s”) that can be used: antiemetics; anti-inflammatory, anti-Ménière’s, and anti-migrainous medications; anti-depressants, anti-convulsants, and aminopyridines. A recovery from acute vestibular neuritis can be promoted by treatment with oral corticosteroids. Betahistine may reduce the frequency of attacks of Ménière’s disease. The aminopyridines constitute a novel treatment approach for downbeat and upbeat nystagmus, as well as episodic ataxia type 2 (EA 2); these drugs may restore normal “pacemaker” activity to the Purkinje cells that govern vestibular and cerebellar nuclei. A limited number of trials indicate that baclofen improves periodic alternating nystagmus, and that gabapentin and memantine improve acquired pendular and infantile (congenital) nystagmus. Preliminary reports suggest suppression of square-wave saccadic intrusions by memantine, and ocular flutter by beta-blockers. Thus, although progress has been made in the treatment of vestibular neuritis, some forms of pathological nystagmus, and EA 2, controlled, masked trials are still needed to evaluate treatments for many vestibular and ocular motor disorders, including betahistine for Ménière’s disease, oxcarbazepine for vestibular paroxysmia, or metoprolol for vestibular migraine.     

Progress in neuro-otology research in the last year

Herein, we summarize articles in the field of neuro-otology published in the Journal of Neurology over the last year. Topics included acute and chronic vertigo as well as auditory and ocular motor disorders. Characteristic lesion locations in Pusher syndrome are reported and the usefulness of bedside ocular motor tests in vertebrobasilar stroke is revisited. Probing the vestibular system and its value in predicting the outcome in vegetative state is discussed. Several articles address new diagnostic and therapeutic approaches in different disorders associated with chronic vestibular, auditory or gait deficits. In a series of case reports, we focus on different eye movement disorders in the vertical plane, which are often difficult to assess.     

血管源性中枢急性前庭综合征及其眼震形式

急性前庭综合征（acute vestibular syndrome,AVS）是以急性持续性眩晕起病,伴有恶心、呕吐,自发眼震,步态不稳,头动不能耐受等症状的临床综合征,持续时间超过24?h,大多为数天或数周。中枢性AVS以血管源性常见,其中大多数为后循环缺血性卒中,尤其部分脑干、小脑梗死常表现为急性孤立性眩晕,这类患者的诊断极具挑战性。随着前庭及眼动生理机制研究的深入,基于前庭、眼动及姿势平衡系统等方面的床旁检查重要性也日益凸显。眩晕患者的床旁检查,除了常规的神经科及耳科查体外,基于前庭-眼反射的各类眼震的评价极有助于快速诊断、识别中枢性AVS。本文对血管源性中枢性AVS的神经血管解剖基础、脑干和小脑卒中所致AVS的眼震特点等进行了综述归纳。     

A dynamic model for eye‐position‐dependence of spontaneous nystagmus in acute unilateral vestibular deficit (Alexander's Law)

Spontaneous nystagmus (SN) is a symptom of acute vestibular tone asymmetry. Alexander's Law (AL) states that slow‐phase velocity of SN is higher when looking in the direction of fast‐phases of nystagmus and lower in the slow‐phase direction. Earlier explanations for AL predict that during SN, slow‐phase eye velocity is a linear function of eye position, increasing linearly as eye deviates towards the fast‐phase direction. Recent observations, however, show that this is often not the case; eye velocity does not vary linearly with eye position. Such new findings necessitate a re‐evaluation of our understanding of AL. As AL may be an adaptive response of the vestibular system to peripheral lesions, understanding its mechanism could shed light on early adaptation strategies of the brain. Here, we propose a physiologically plausible mechanism for AL that explains recent experimental data. We use a dynamic control system model to simulate this mechanism and make testable predictions. This mechanism is based on the known effects of unilateral vestibular deficit on the response of the ipsi‐ and contralesional vestibular nuclei (VN) of the brainstem. This hypothesis is based on the silencing of the majority of ipsilesional VN units, which creates an asymmetry between the responses of the ipsi‐ and contralesional VN. Unlike former explanations, the new hypothesis does not rely on lesion detection strategies or signals originating in higher brain structures. The proposed model demonstrates possible consequences of acute peripheral deficits for the function of the velocity‐to‐position neural integrator of the ocular motor system and the vestibulo‐ocular reflex.     

General vestibular testing.

A dysfunction of the vestibular system is commonly characterized by a combination of phenomena involving perceptual, ocular motor, postural, and autonomic manifestations: vertigo/dizziness, nystagmus, ataxia, and nausea. These 4 manifestations correlate with different aspects of vestibular function and emanate from different sites within the central nervous system. The diagnosis of vestibular syndromes always requires interdisciplinary thinking. A detailed history allows early differentiation into 9 categories that serve as a practical guide for differential diagnosis: (1) dizziness and lightheadedness; (2) single or recurrent attacks of vertigo; (3) sustained vertigo; (4) positional/positioning vertigo; (5) oscillopsia; (6) vertigo associated with auditory dysfunction; (7) vertigo associated with brainstem or cerebellar symptoms; (8) vertigo associated with headache; and (9) dizziness or to-and-fro vertigo with postural imbalance. A careful and systematic neuro-ophthalmological and neuro-otological examination is also mandatory, especially to differentiate between central and peripheral vestibular disorders. Important signs are nystagmus, ocular tilt reaction, other central or peripheral ocular motor dysfunctions, or a unilateral or bilateral peripheral vestibular deficit. This deficit can be easily detected by the head-impulse test, the most relevant bedside test for the vestibulo-ocular reflex. Laboratory examinations are used to measure eye movements, to test semicircular canal, otolith, and spatial perceptional function and to determine postural control. It must, however, be kept in mind that all signs and ocular motor and vestibular findings have to be interpreted within the context of the patient's history and a complete neurological examination.     

Separating posterior-circulation stroke from vestibular neuritis with quantitative vestibular testing

ObjectiveTo separate vestibular neuritis (VN) from posteriorcirculation stroke (PCS) using quantitative tests of canal and otolith function.MethodsVideo Head-Impulse tests (vHIT) were used to assess all three semicircular canal pairs; vestibulo-ocular reflex (VOR) gain and saccade metrics were examined. Cervical and ocular-Vestibular-Evoked Myogenic Potentials (c- and oVEMP) and Subjective Visual Horizontal (SVH) were used to assess otolith function.ResultsFor controls (n = 40), PCS (n = 22), and VN (n = 22), mean horizontal-canal VOR-gains were 0.96 ± 0.1, 0.85 ± 0.3 and 0.40 ± 0.2, refixation-saccade prevalence was 71.9 ± 41, 90.7 ± 57, 209.2 ± 62 per 100 impulses and cumulative-saccade amplitudes were 0.9 ± 0.4°, 2.4 ± 2.2°, 8.0 ± 3.5°. Abnormality-rates for cVEMP, oVEMP and SVH were 38%, 9%, 72% for PCS, and 43%, 50%, 91% for VN.A gain ≤0.68, refixation-saccade prevalence of ≥135% and cumulative-saccade amplitudes ≥5.3° separated VN from PCS with sensitivities of 95.5%, 95.5%, and 81.8%, and specificities of 68.2%, 86.4% and 95.5%. VOR-gain and saccade prevalence when combined, separated VN from PCS with a sensitivity and specificity of 90.9%. Abnormal oVEMP asymmetry-ratios were of low sensitivity (50%) but high specificity (90.9%) for separating VN from PCS.ConclusionvHIT provided the best separation of VN from PCS. VOR-gain, refixation-saccade prevalence and amplitude were effective discriminators of VN from PCS.SignificancevHIT and oVEMP could assist early identification of the aetiology of Acute Vestibular Syndrome in the Emergency Room.     

Cervical and ocular vestibular-evoked myogenic potentials in acute vestibular neuritis

ObjectivesTo clarify the origin and afferent pathways of short-latency ocular vestibular-evoked myogenic potential (oVEMP) in response to air-conducted sound (ACS), we evaluated cervical (cVEMP) and ocular VEMPs in patients with vestibular neuritis (VN).MethodsIn response to air-conducted tone burst, the oVEMP and cVEMP were measured in 60 healthy controls and in 41 patients with acute VN. The VN selectively involved the superior vestibular nerve (superior VN) in 30 patients, affected the inferior vestibular nerve only (inferior VN) in three and damaged both superior and inferior vestibular nerve branches in eight.ResultsAll 30 patients with superior VN presented normal cVEMPs, indicating preservation of the saccular receptors and their afferents in the inferior vestibular nerve. However, the oVEMP was abnormal in all patients with superior VN. By contrast, the patients with inferior VN showed normal oVEMP and abnormal cVEMP.ConclusionThese dissociations in the abnormalities of cVEMP and oVEMP in patients with VN selectively involving the superior or inferior vestibular nerve suggest that the origin of the vestibular nerve afferents of oVEMP differ from those of cVEMP.SignificanceThe oVEMP in response to ACS may be mediated by the superior vestibular nerve, probably due to an activation of the utricular receptors.     

Pharmacological advances in the treatment of neuro-otological and eye movement disorders

PURPOSE OF REVIEW: First, to describe the current pharmacological treatment options for peripheral and central vestibular, cerebellar, and ocular motor disorders. Second, to identify vestibular and ocular motor disorders in which treatment trials are warranted. RECENT FINDINGS: Peripheral vestibular disorders: In vestibular neuritis recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Ménière's disease treatment strategies range from low-salt diet, diuretics, and betahistine, to intratympanic injection of corticosteroids or gentamicin. Unfortunately most of the trials on Ménière's disease do not have an up-to-date design. In bilateral vestibulopathy steroids do not seem to improve vestibular function.Central vestibular, cerebellar, and ocular motor disorders: The use of aminopyridines introduced a new therapeutic principle in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA2). These potassium channel blockers presumably increase the activity and excitability of cerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells on vestibular and cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus, and gabapentin and memantine, pendular nystagmus. Many other eye movement disorders, however, such as ocular flutter, opsoclonus, central positioning, or see-saw nystagmus are still difficult to treat. SUMMARY: Although progress has been made in the treatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA2, state-of-the-art trials must still be performed on many vestibular and ocular motor disorders, namely Ménière's disease, bilateral vestibulopathy, vestibular paroxysmia, vestibular migraine, and many forms of central eye movement disorders.     

Effect of 4-aminopyridine on gravity dependence and neural integrator function in patients with idiopathic downbeat nystagmus

Downbeat nystagmus (DBN) is a frequent sign in patients with cerebellar degeneration. It consists of an upward drift of the eye that does not depend on vertical head position (spontaneous drift, SD), a gravity-dependent component (GD), and a gaze-evoked drift reflecting gaze-holding impairment (deficient neural integrator function). The potassium-channel blocker 4-aminopyridine (4-AP) is reported to reduce DBN in patients with cerebellar atrophy but with little or no effect in patients with idiopathic DBN. We prospectively studied the effect of 4-AP on all three components in a large (n = 24) group of the clinically frequent idiopathic DBN. DBN was reduced by 22–31% when the head was off the head erect position. In contrast, there was no effect on vertical gaze-evoked drift. This indicates the therapeutic efficacy of 4-AP not only in patients with cerebellar atrophy but also in idiopathic DBN patients. This beneficial effect, which might be missed when gravity-dependent head positions are not tested, was not related to an improvement of gaze-holding deficit. We suggest it may be related to the restored inhibition of the overacting otolith−ocular reflex.     

Vestibular dysfunction in migraine: effects of associated vertigo and motion sickness

The mechanisms of vestibular migraine and motion sickness remain unknown. The aims of this study were to determine interictal vestibular dysfunction in migraineurs according to associated dizziness/vertigo and motion sickness, and to find out whether impaired uvulonodular inhibition over the vestibular system underlies the vestibular symptoms and signs by measuring tilt suppression of the vestibulo-ocular reflex (VOR). One hundred and thirty-one patients with migraine [65 with vestibular migraine (MV), 41 with migrainous dizziness (MD), and 25 with migraine only (MO)] and 50 normal controls underwent evaluation of vestibular function. Motion sickness was assessed using the motion sickness susceptibility questionnaire (MSSQ) and subjective scale. Compared with normal controls and MO group, patients with MV/MD showed increased VOR time constant (TC) and greater suppression of the post-rotatory nystagmus with forward head tilt. The mean MSSQ score and subjective scale were highest in MV group, followed by MD, MO, and controls (p = 0.002, p < 0.001). Multiple linear regression model analyses revealed that motion sickness is an independent factor of TC prolongation (p = 0.024). Twenty-eight (21.4%) patients with migraine also showed perverted head shaking nystagmus and 12 (9.2%) had positional nystagmus. In view of the increased tilt suppression of the VOR, we speculate that dysfunction of the nodulus/uvula may not account for the prolonged TCs in MD/MV. Instead, innate hypersensitivity of the vestibular system may be an underlying mechanism of motion sickness and increased TC in MD/MV. The increased tilt suppression may be an adaptive cerebellar mechanism to suppress the hyperactive vestibular system in migraineurs.     

Acute vestibular syndrome: clinical head impulse test versus video head impulse test

HINTS battery involving head impulse test (HIT), nystagmus, and test of skew is the critical bedside examination to differentiate acute unilateral peripheral vestibulopathy from posterior circulation stroke (PCS) in acute vestibular syndrome (AVS). The highest sensitivity component of the battery has been reported to be the horizontal HIT, whereas skew deviation is defined as the most specific but non-sensitive sign for PCS. Video-oculography-based HIT (vHIT) may have an additional power in making the differentiation. If vHIT is undertaken, then both gain and gain asymmetry should be taken into account as anterior inferior cerebellar artery (AICA) strokes are at risk of being misclassified based on VOR gain alone. Further refinement in video technology, increased operator proficiency and incorporation with saccade analysis will increase the sensitivity of vHIT for PCS diagnosis. For the time being, clinical examination seems adequate in frontline diagnostic evaluation of AVS.     

Isolated vestibular nuclear infarction: report of two cases and review of the literature

Cerebral infarction presenting with isolated vertigo remains a diagnostic challenge. To define the clinical characteristics of unilateral infarctions restricted to the vestibular nuclei, two patients with isolated unilateral vestibular nuclear infarction had bedside and laboratory evaluation of the ocular motor and vestibular function, including video-oculography, bithermal caloric irrigation, the head impulse test (HIT) using magnetic scleral coils, and cervical and ocular vestibular-evoked myogenic potentials (VEMPs). We also reviewed the literature on isolated vertigo from lesions restricted to the vestibular nuclei, and analyzed the clinical features of seven additional patients. Both patients showed spontaneous torsional-horizontal nystagmus that beat away from the lesion side, and direction-changing gaze-evoked nystagmus. Recording of HIT using a magnetic search coil system documented decreased gains of the vestibular-ocular reflex for the horizontal and posterior semicircular canals on both sides, but more for the ipsilesional canals. Bithermal caloric tests showed ipsilesional canal paresis in both patients. Cervical and ocular VEMPs showed decreased or absent responses during stimulation of the ipsilesional ear. Initial MRIs including diffusion-weighted images were normal or equivocal, but follow-up imaging disclosed a circumscribed acute infarction in the area of the vestibular nuclei. Infarctions restricted to the vestibular nuclei may present with isolated vertigo with features of both peripheral and central vestibulopathies. Central signs should be sought even in patients with spontaneous horizontal–torsional nystagmus and positive HIT. In patients with combined peripheral and central vestibulopathy, a vestibular nuclear lesion should be considered especially when hearing is preserved.     

Cervical and ocular vestibular-evoked myogenic potentials in vestibular neuritis: comparison between air- and bone-conducted stimulation

To clarify the changes of cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials induced by air-conducted sound (ACS) and bone-conducted vibration (BCV) in patients with vestibular neuritis (VN), patients with VN (n = 30) and normal controls (n = 45) underwent recording of cVEMP and oVEMP in response to ACS (1,000 Hz, 5 ms, tone bursts) and BCV (500 Hz, short tone burst). Patients with VN showed a high proportion of oVEMP abnormalities in response to both ACS (80.0 %) and BCV at the forehead (Fz, 73.3 %) or the mastoid (76.7 %). In contrast, cVEMPs were mostly normal with both ACS and BCV in the patients. The dissociations in the abnormalities of cVEMP and oVEMP induced by ACS and BCV at the mastoids and at the forehead in patients with VN suggest that oVEMP reflects functions of the superior vestibular nerve and most likely the utricular function. The results of our study suggest that oVEMP induced by either ACS or BCV appears to depend on integrity of the superior vestibular nerve, possibly due to the utricular afferents travelling in it. In contrast, cVEMP elicited by either ACS or BCV may reflect function of the saccular afferents running in the inferior vestibular nerve.     

Perceived vertical and lateropulsion: clinical syndromes, localization, and prognosis

We present a clinical classification of central vestibular syndromes according to the three major planes of action of the vestibulo-ocular reflex: yaw, roll, and pitch. The plane-specific syndromes are determined by ocular motor, postural, and perceptual signs. Yaw plane signs are horizontal nystagmus, past pointing, rotational and lateral body falls, deviation of perceived straight-ahead to the left or right. Roll plane signs are torsional nystagmus, skew deviation, ocular torsion, tilts of head, body, and perceived vertical in a clockwise or counterclockwise direction. Pitch plane signs are upbeat/downbeat nystagmus, forward/backward tilts and falls, deviations of the perceived horizon. The thus defined vestibular syndromes allow a precise topographic analysis of brainstem lesions according to their level and side. Special emphasis is placed on the vestibular roll plane syndromes of ocular tilt reaction, lateropulsion in Wallenberg's syndrome, thalamic and cortical astasia and their association with roll plane tilt of perceived vertical. Recovery is based on a functionally significant central compensation of a vestibular tone imbalance, the mechanism of which is largely unknown. Physical therapy may facilitate this central compensation, but this has not yet been proven in prospective studies.     

Nystagmus and oscillopsia

The ocular motor system consists of several subsystems, including the vestibular ocular nystagmus saccade system, the pursuit system, the fixation and gaze-holding system and the vergence system. All these subsystems aid the stabilization of the images on the retina during eye and head movements and any kind of disturbance of one of the systems can cause instability of the eyes (e.g. nystagmus) or an inadequate eye movement causing a mismatch between head and eye movement (e.g. bilateral vestibular failure). In both situations, the subjects experience a movement of the world (oscillopsia) which is quite disturbing. New insights into the patho-physiology of some of the ocular motor disorders have helped to establish new treatment options, in particular in downbeat nystagmus, upbeat nystagmus, periodic alternating nystagmus, acquired pendular nystagmus and paroxysmal vestibular episodes/attacks. The discussed patho-physiology of these disorders and the current literature on treatment options are discussed and practical treatment recommendations are given in the paper.     

Primary Position Upbeat Nystagmus during an Acute Attack of Multiple Sclerosis

Background and Purpose

Ocular manifestation is one of the frequent signs of an acute attack in multiple sclerosis (MS), although primary position upbeat nystagmus (PPUN) is rare. The purpose of this study is to determine the incidence of PPUN in MS and to determine the lesions that are responsible for this sign.

Methods

The medical records of 120 MS patients with acute brain lesions were reviewed over a consecutive period of 9 years; of these, 6 patients were found to have PPUN. Other ocular motor abnormalities were analyzed in combination with upbeat nystagmus, video-oculographic findings, and lesions detected on brain MRI.

Results

Lesions in the pontine tegmentum involving the medial longitudinal fasciculus (MLF) and ventral tegmental tract (VTT) were the most common, being observed in three of the six patients with PPUN. One patient exhibited caudal medullary lesions bilaterally affecting the paramedian portion of the posterior tegmentum, and two patients exhibited multiple lesions involving the pons with the cerebral peduncle or medulla. In five patients, other ocular motor dysfunctions, such as gaze-evoked nystagmus (n=3) and internuclear ophthalmoplegia (n=1), were found in combination with upbeat nystagmus.

Conclusions

PPUN is an infrequent, ocular manifestation noted during an acute attack of MS, and was observed in 5% of the present cases. Brainstem lesions in these cases primarily involved the pontine tegmentum and the caudal medulla. These findings support the theory that upbeat nystagmus is attributable to damage to the upward vestibulo-ocular reflex pathway related to the vestibular nucleus, VTT, and interconnecting pathways.