A randomized double-blind, placebo-controlled, cross-over trial (Vestparoxy) of the treatment of vestibular paroxysmia with oxcarbazepine.

OBJECTIVE: Vestibular paroxysmia (VP) is characterized by short, often oligosymptomatic attacks of vertigo which occur spontaneously or are sometimes provoked by turning the head. Despite the description of the disease almost 40 years ago (first termed "disabling positional vertigo"), no controlled treatment trial has been published to date. The Vestparoxy trial was designed as a randomized, placebo-controlled, double-blind cross-over trial to examine the therapeutic effect of oxcarbazepine (OXA) in patients with definite or probable VP. METHODS: Patients were recruited from August 2005 to December 2011 in the outpatient Dizziness Unit of the Department of Neurology of the Munich University Hospital, and randomized to receive OXA (first week: 300 mg once per day, second week: 300 mg b.i.d., third week: 300 mg t.i.d. until the end of the third month), followed by placebo or vice versa with a 1-month wash-out period in between. The primary endpoint was the number of days with one or more attacks. Secondary endpoints were the number of attacks during the observed days, and the median (for each day) duration of attacks. All these endpoints were assessed using standardized diaries collected at the end of each treatment phase. RESULTS: Forty-three patients were randomized, 18 patients provided usable data (2525 patient days) for at least one treatment phase and were included in the main (intention-to-treat) analysis. The most common reasons for discontinuation documented were adverse events. The risk of experiencing a day with at least one attack was 0.41 under OXA, and 0.62 under placebo treatment, yielding a relative risk of 0.67 (95% CI 0.47-0.95, p = 0.025). The number of attacks during the observed days ratio was 0.53 (95% CI 0.42-0.68, p < 0.001) under OXA compared to placebo. Median attack duration was 4 s (Q25: 2 s, Q75: 120 s) under OXA, and 3 s (Q25: 2 s, Q75: 60 s) under placebo treatment. When days with no attacks, i.e., duration = 0, were included in the analysis, these figures changed to 0 (Q25: 0, Q75: 3 s), and 2 (Q25: 0, Q75: 6 s). No serious adverse events or new safety findings were identified during the trial. CONCLUSIONS: The Vestparoxy trial showed a significant reduction of VP attacks under OXA compared to placebo treatment, confirming the known and revealing no new side effects.

Vestibular function in patients with Niemann-Pick type C disease.

We investigated whether vestibular dysfunction may cause or contribute to postural imbalance and falls in patients with Niemann-Pick type C disease (NP-C). Eight patients with NP-C disease and 20 healthy controls were examined using the video-based head impulse test (vHIT) and caloric irrigation to investigate horizontal canal function as well as ocular- and cervical vestibular evoked myogenic potentials (o- and cVEMP), and binocular subjective visual vertical estimation (SVV) for otolith function, and static posturography. There were no significant differences in vestibulo-ocular gain, caloric excitability, o-/cVEMP measures or SVV between the two groups. Posturographic total sway path (tSP) and root mean square (RMS) were significantly higher in NP-C than in controls in 3 out of 4 conditions. The Romberg quotient (RQ) to assess the amount of visual stabilization was significantly lower in the NP-C than in the HC group. In contrast to other inherited metabolic disorders, such as Morbus Gaucher type 3, we did not find any evidence for an impairment of canal or otolith function in patients with NP-C as their cause of postural imbalance. Since RQ was low in NP-C patients, indicating proper sensory input, the observed increased postural sway is most likely due to a cerebellar dysfunction in NP-C, which may therefore, explain postural imbalance.

Comparison of linear motion perception thresholds in vestibular migraine and Menière's disease.

Linear motion perceptual thresholds (PTs) were compared between patients with Menière's disease (MD) and vestibular migraine (VM). Twenty patients with VM, 27 patients with MD and 34 healthy controls (HC) were examined. PTs for linear motion along the inter-aural (IA), naso-occipital axes (NO), and head-vertical (HV) axis were measured using a multi-axis motion platform. Ocular and cervical vestibular evoked myogenic potentials (o/c VEMP) were performed and the dizziness handicap inventory (DHI) administered. In order to discriminate between VM and MD, we also evaluated the diagnostic accuracy of applied methods. PTs depended significantly on the group tested (VM, MD and HC), as revealed by ANCOVA with group as the factor and age as the covariate. This was true for all motion axes (IA, HV and NO). Thresholds were highest for MD patients, significantly higher than for all other groups for all motion axes, except for the IA axis when compared with HC group suggesting decreased otolith sensitivity in MD patients. VM patients had thresholds that were not different from those of HC, but were significantly lower than those of the MD group for all motion axes. The cVEMP p13 latencies differed significantly across groups being lowest in VM. There was a statistically significant association between HV and NO thresholds and cVEMP PP amplitudes. Diagnostic accuracy was highest for the IA axis, followed by cVEMP PP amplitudes, NO and HV axes. To conclude, patients with MD had significantly higher linear motion perception thresholds compared to patients with VM and controls. Except for reduced cVEMP latency, there were no differences in c/oVEMP between MD, VM and controls.

Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus.

Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT).

Acetyl-dl-leucine in Niemann-Pick type C: A case series.

OBJECTIVE: To assess the effects of the modified amino acid acetyl-dl-leucine (AL) on cerebellar ataxia, eye movements, and quality of life of patients with Niemann-Pick type C (NP-C) disease. METHODS: Twelve patients with NP-C disease were treated with AL 3 g/d for 1 week and then with 5 g/d for 3 weeks with a subsequent washout period of 1 month. The Scale for the Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L, and the visual analog scale (VAS) were administered. Measurements took place at baseline, after 1 month of therapy, and after 1 month of washout. RESULTS: The SARA score changed from the baseline (median [±SD, interquartile range]) of 10.8 (11.2, 8-24.6) to 7.0 (10.7, 5.6-19.6) on medication (difference: 3.8 points) and 10.5 (11.5, 7.1-23.9) after washout (difference: 3.5 points) (p = 0.000412; post hoc p = 0.003 between baseline and on medication, and on medication and washout p = 0.005). The SCAFI subscore 9-Hole Peg Test for dominant hand, mDRS score, and VAS score also improved on medication. No side effects except transient dizziness in one patient were reported. CONCLUSIONS: Treatment with AL improved ataxic symptoms in patients with NP-C without relevant side effects, thus showing a reasonable risk-benefit profile. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that AL improves cerebellar symptoms and quality of life in patients with NP-C.

Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials?

Downbeat nystagmus (DBN) is caused by an impairment of Purkinje cells in the flocculus. The decreased cerebellar inhibitory input affects otolith pathways. Since ocular and cervical vestibular evoked myogenic potentials (o-/cVEMP) test the otoliths, the VEMP were measured in DBN patients and in controls. Sixteen patients with DBN, 14 cerebellar oculomotor disorder patients without DBN (COMD), and 16 healthy controls were examined with o-/cVEMP. Computational modeling was used to predict VEMP differences between groups. DBN patients had significantly higher oVEMP peak-to-peak (PP) amplitudes than COMD patients without DBN and controls. Cervical VEMP did not differ. The computational model of DBN predicted a twofold oVEMP increase for DBN patients. These findings suggest an enhancement of the utriculo-ocular response. The unchanged cVEMP indicate no effect on the otolith-cervical reflex in DBN. Computational modeling suggests that the utriculo-ocular enhancement is caused by an impaired vertical neural integrator resulting in the increased influence of utricular signals. This also explains the gravitational dependence of DBN.

Pharmacotherapy of vestibular and cerebellar disorders and downbeat nystagmus: translational and back-translational research.

There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl-DL-leucine ("the eight A's"). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière's disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl-dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT).

Ocular VEMPs indicate repositioning of otoconia to the utricle after successful liberatory maneuvers in benign paroxysmal positioning vertigo.

CONCLUSIONS: This study showed a transient increase of ocular vestibular evoked myogenic potential (oVEMP) amplitudes in the affected ear after successful liberatory maneuvers and no changes in cervical VEMP (cVEMP) amplitudes. These findings support the hypothesis that successful liberatory maneuvers can lead to a repositioning of otoconia to the utricle. OBJECTIVES: To evaluate whether oVEMP amplitudes increase after successful liberatory maneuvers in patients with posterior semicircular canal benign paroxysmal positioning vertigo (pc-BPPV), while cVEMP amplitudes do not change. These findings may indicate a successful repositioning of dislodged otoconia to the utricular macula, but not to the saccular macula. METHODS: Thirty patients with unilateral pc-BPPV were prospectively examined with bone-conducted oVEMP and air-conducted cVEMP at four time points: before, after, 1 week after, and 1 month after the liberatory maneuvers (Sémont maneuvers). RESULTS: At the 1-week follow-up, 20 of 30 patients were asymptomatic (responders); BPPV could still be induced in the other 10 (non-responders). In responders the mean n10 amplitude on the affected side increased from 12 ± 6.5 µV at baseline (before the treatment) to 15.9 ± 7.1 µV at 1 week after treatment; this increase was significantly (p = 0.001) higher in responders than in non-responders. cVEMP did not differ significantly.

Clinical testing of otolith function: perceptual thresholds and myogenic potentials.

Cervical and ocular vestibular-evoked myogenic potential (cVEMP/oVEMP) tests are widely used clinical tests of otolith function. However, VEMP testing may not be the ideal measure of otolith function given the significant inter-individual variability in responses and given that the stimuli used to elicit VEMPs are not physiological. We therefore evaluated linear motion perceptual threshold testing compared with cVEMP and oVEMP testing as measures of saccular and utricular function, respectively. A multi-axis motion platform was used to measure horizontal (along the inter-aural and naso-occipital axes) and vertical motion perceptual thresholds. These findings were compared with the vibration-evoked oVEMP as a measure of utricular function and sound-evoked cVEMP as a measure of saccular function. We also considered how perceptual threshold and cVEMP/oVEMP testing are each associated with Dizziness Handicap Inventory (DHI) scores. We enrolled 33 patients with bilateral vestibulopathy of different severities and 42 controls to have sufficient variability in otolith function. Subjects with abnormal oVEMP amplitudes had significantly higher (poorer) perceptual thresholds in the inter-aural and naso-occipital axes in age-adjusted analyses; no significant associations were observed for vertical perceptual thresholds and cVEMP amplitudes. Both oVEMP amplitudes and naso-occipital axis perceptual thresholds were significantly associated with DHI scores. These data suggest that horizontal perceptual thresholds and oVEMPs may estimate the same underlying physiological construct: utricular function.

Semicircular canal, saccular and utricular function in patients with bilateral vestibulopathy: analysis based on etiology.

The diagnosis of bilateral vestibulopathy (BV) is typically established based on bilateral semicircular canal dysfunction. The degree to which both otolith organs-the saccule and utricle-are also impaired in BV is not well-established, particularly with respect to the etiology and severity of BV. The aim of this study was to evaluate semicircular canal, saccular and utricular function in patients with BV due to aminoglycoside ototoxicity and bilateral Menière's disease, and with different severities of BV. Caloric and head impulse testing were used as measures of canal function. Cervical vestibular-evoked myogenic potentials (cVEMP) and ocular VEMPs (oVEMP) were used as measures of saccular and utricular function, respectively. We enrolled 34 patients with BV and 55 controls in a prospective case-control study. Patients with BV were less likely to have saccular (61 %) or utricular (64 %) dysfunction relative to canal dysfunction (100 %). Utricular function differed significantly between patients by etiologic group: the poorest function was found in patients with BV due to aminoglycoside toxicity, and the best function in Menière's disease patients. Canal and saccular function did not vary according to etiology. Further, utricular but not saccular function was significantly correlated with canal function. Saccular and utricular function had the strongest association with Dizziness Handicap Inventory scores relative to canal function. These data suggest that when a patient with BV is identified in a clinical context, oVEMP testing is the most sensitive test in distinguishing between aminoglycoside toxicity and bilateral Menière's disease. Both cVEMP and oVEMP testing may be considered to evaluate the functional impact on the patient.