Effects of Prochlorperazine on Normal Vestibular Ocular and Perceptual Responses: A Randomised, Double-Blind, Crossover, Placebo-Controlled Study

Background: The present study investigated whether prochlorperazine affects vestibular-ocular reflex (VOR) and vestibulo-perceptual function. Methods: We studied 12 healthy naïve subjects 3 hours after a single dose of oral prochlorperazine 5mg in a randomised, placebo-controlled, double-blind, cross-over study in healthy young subjects. Two rotational tests in yaw were used: 1) a Threshold task investigating perceptual motion detection and nystagmic thresholds (acceleration steps of 0.5deg/s/s) and 2) Suprathreshold responses to velocity steps of 90deg/s in which vestibulo-ocular (VO) and vestibulo-perceptual (VP) time constants of decay, as well as VOR gain, were measured. Results: Prochlorperazine had no effect upon any measure of nystagmic or perceptual vestibular function compared to placebo. This lack of effects on vestibular-mediated motion perception suggests that the drug is likely to act more as an antiemetic than as an anti-vertiginous agent

Intratympanic methylprednisolone versus gentamicin in patients with unilateral Ménière's disease: a randomised, double-blind, comparative effectiveness trial

Background Ménière’s disease is characterised by severe vertigo attacks and hearing loss. Intratympanic gentamicin,the standard treatment for refractory Ménière’s disease, reduces vertigo, but damages vestibular function and can worsen hearing. We aimed to assess whether intratympanic administration of the corticosteroid methylprednisolone reduces vertigo compared with gentamicin. Methods In this double-blind comparative eff ectiveness trial, patients aged 18–70 years with refractory unilateral Ménière’s disease were enrolled at Charing Cross Hospital (London, UK) and Leicester Royal Infirmary (Leicester, UK). Patients were randomly assigned (1:1) by a block design to two intratympanic methylprednisolone(62·5 mg/mL) or gentamicin (40 mg/mL) injections given 2 weeks apart, and were followed up for 2 years. All investigators and patients were masked to treatment allocation. The primary outcome was vertigo frequency over the final 6 months (18–24 months after injection) compared with the 6 months before the first injection. Analyses were done in the intention-to-treat population, and then per protocol. This trial is registered with ClinicalTrials.gov, number NCT00802529. Findings Between June 19, 2009, and April 15, 2013, 256 patients with Ménière’s disease were screened, 60 of whom were enrolled and randomly assigned: 30 to gentamicin and 30 to methylprednisolone. In the intention-to-treat analysis (ie, all 60 patients), the mean number of vertigo attacks in the fi nal 6 months compared with the 6 months before the fi rst injection (primary outcome) decreased from 19·9 (SD 16·7) to 2·5 (5·8) in the gentamicin group (87% reduction) and from 16·4 (12·5) to 1·6 (3·4) in the methylprednisolone group (90% reduction; mean diff erence –0·9,95% CI –3·4 to 1·6). Patients whose vertigo did not improve after injection (ie, non-responders) after being assessed by an unmasked clinician were eligible for additional injections given by a masked clinician (eight patients in the gentamicin group vs 15 in the methylprednisolone group). Two non-responders switched from methylprednisolone to gentamicin. Both drugs were well tolerated with no safety concerns. Six patients reported one adverse event each: three in the gentamicin group and three in the methylprednisolone group. The most common adverse event was minor ear infections, which was experienced by one patient in the gentamicin group and two in the methylprednisolone group. Interpretation Methylprednisolone injections are a non-ablative, effective treatment for refractory Ménière’s disease. The choice between methylprednisolone and gentamicin should be made based on clinical knowledge and patient circumstances

Abnormal Visuo-vestibular Interactions in Vestibular Migraine: a Cross Sectional Study

Vestibular migraine is amongst the commonest causes of episodic vertigo. Chronically, patients with vestibular migraine develop abnormal responsiveness to both vestibular and visual stimuli characterised by heightened self-motion sensitivity and visually-induced dizziness. Yet, the neural mechanisms mediating such symptoms remain unknown. We postulate that such symptoms are attributable to impaired visuo-vestibular cortical interactions, which in-turn disrupts normal vestibular function. To assess this, we investigated whether prolonged, full-field visual motion exposure, which has previously been shown to modulate visual cortical excitability in both healthy individuals and avestibular patients, could disrupt vestibular ocular reflex (VOR) and vestibular-perceptual thresholds of self-motion during rotations. Our findings reveal that vestibular migraine patients exhibited abnormally elevated reflexive and perceptual vestibular thresholds at baseline. Following visual motion exposure, both reflex and perceptual thresholds were significantly further increased in vestibular migraine patients relative to healthy controls, migraineurs without vestibular symptoms and patients with episodic vertigo due to a peripheral inner-ear disorder. Our results provide support for the notion of altered visuo-vestibular cortical interactions in vestibular migraine, as evidenced by vestibular threshold elevation following visual motion exposure

REPLY TO ADRION ET AL. ON PATEL ET AL. Letter to the Editor, British Medical Journal

We apologise for not having noticed earlier Adrion and colleagues’ comments on our study comparing the effectiveness of intratympanic Methylprednisolone to Gentamicin in refractory Ménière’s disease [1], covered by the BMJ [2]. Contrary to our expectations, both drugs were equally effective in controlling vertigo (primary outcome). Adrion’s main concerns were, (i) that negative studies pose the problem of “not knowing how to interpret the non-significant results in a clinically relevant way” and, (ii) the lack of a power calculation for the primary outcome. Regarding (i), our interpretation is that given the known ototoxic effects of gentamicin, ascertaining any minuscule difference between the two drugs is not justified and, very likely, unethical. A further comment was that “transforming the data to achieve a more symmetric distribution may have resulted in more power when an ANOVA or t-test is applied”. We agree that some of the data deviated from strict normality. There is always debate about the robustness of ANOVA in these cases, however this was addressed in the paper - non-parametric tests confirmed that there were no significant differences between Methylprednisolone and Gentamicin for vertigo outcomes ([1] Appendix, page 6). Adrion also recommended adjustment for baseline differences, but a crucial strength of our study was adherence to the CONSORT 2010 guidelines for transparent reporting of trials [3], which states that “Although proper random assignment prevents selection bias, it does not guarantee that the groups are equivalent at baseline. Any differences in baseline characteristics are, however, the result of chance rather than bias. The study groups should be compared at baseline for important demographic and clinical characteristics so that readers can assess how similar they were…….Adjustment for variables because they differ significantly at baseline is likely to bias the estimated treatment effect.” Nevertheless, to satisfy Adrion and colleagues’ concerns and for the benefit of readers, we reanalysed our primary outcome data with ANCOVA using baseline vertigo attack frequency over 6 months as covariate. As with ANOVAs and non-parametric tests, the re-analysis showed no difference between drugs (F=.527 df=1,57 p=.471). In other words, performing the ANCOVA does not change our results nor add any further information for the reader. Regarding (ii) the reason for the lack of power calculation for the primary outcome was clearly stated in our paper: “At the time of planning of our study, there were few published data on intratympanic gentamicin versus steroid treatment for Ménière’s disease”. Hence sample-size calculations were based on hearing outcomes where drug differences were better established [4]. However, we are now able to back-calculate our data. Depending on which outcome metric is chosen to resolve the small effects observed (vertigo attacks at 2 years, percentage reduction in vertigo attacks, absolute reduction in number of vertigo attacks, using intention to treat or per protocol), for conventional 80% power with p=.05 2-tailed the numbers of patients required is between 150 to over 400 per group, thus illustrating the minute differences, if any, for the primary outcome (vertigo). Finally, the comment “the primary endpoint may be biased since it was assessed by retrospective face-to-face interviews instead of event-oriented or daily symptom diaries”, was also addressed in the paper. It would be unethical to recruit patients with refractory Meniere’s disease experiencing more than one attack per week (Table 1,[1]) and require that they fill up a diary for the next 6 months before receiving treatment. Further, all the validated vestibular questionnaires used showed no differences between Methylprednisolone and Gentamicin either. In the same vein, it would be unethical to give patients a placebo when gentamicin is more effective than placebo for vertigo control (for Cochrane Review, see [5]) and it should be emphasised that a comparison between Gentamicin and Placebo led to the early termination of a randomised, double-blind, controlled trial in 2014 [6]. In view of our data [1], we believe that the initial treatment choice between an ototoxic drug (Gentamicin) and one that it is not (Methylprednisolone), will be simplified for most patients and doctors. References [1] Patel M, Agarwal K, Arshad Q et al. Intratympanic methylprednisolone versus gentamicin in patients with unilateral Meniere's disease: a randomised, double-blind, comparative effectiveness trial. Lancet 2016; 388(10061): 2753-62. [2]. Mayor S. Steroid injections through the eardrum reduce dizziness in Meniere’s disease, study finds. BMJ 2016; 355:i6185. [3] Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332. [4] Sennaroglu L, Sennaroglu G, Gursel B et al. Intratympanic dexamethasone, intratympanic gentamicin, and endolymphatic sac surgery for intractable vertigo in Meniere's disease. Otolaryngology--head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 2001; 125(5): 537-43. [5] Pullens B, van Benthem PP. Intratympanic gentamicin for Ménière's disease or syndrome. Cochrane Database Syst Rev. 2011;(3):CD008234. [6] Bremer HG, van Rooy I, Pullens B, et al. Intratympanic gentamicin treatment for Ménière's disease: a randomized, double-blind, placebo-controlled trial on dose efficacy - results of a prematurely ended study. Trials 2014;15:328. Competing Interests: None Competing interests: No competing interest

How imagery changes self-motion perception

AbstractImagery and perception are thought to be tightly linked, however, little is known about the interaction between imagery and the vestibular sense, in particular, self-motion perception. In this study, the observers were seated in the dark on a motorized chair that could rotate either to the right or to the left. Prior to the physical rotation, observers were asked to imagine themselves rotating leftward or rightward. We found that if the direction of imagined rotation was different to the physical rotation of the chair (incongruent trials), the velocity of the chair needed to be higher for observers to experience themselves rotating relative to when the imagined and the physical rotation matched (on congruent trials). Accordingly, the vividness of imagined rotations was reduced on incongruent relative to congruent trials. Notably, we found that similar effects of imagery were found at the earliest stages of vestibular processing, namely, the onset of the vestibular–ocular reflex was modulated by the congruency between physical and imagined rotations. Together, the results demonstrate that mental imagery influences self-motion perception by exerting top-down influences over the earliest vestibular response and subsequent perceptual decision-making