Progress in protecting vestibular hair cells.

Vestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and coordinate their movement. Vestibular hair cells are susceptible to ototoxic drugs, aging, and genetic factors that can lead to permanent vestibular dysfunction. Vestibular dysfunction mainly results from the injury of hair cells, which are located in the vestibular sensory epithelium. This review summarizes the mechanisms of different factors causing vestibular hair cell damage and therapeutic strategies to protect vestibular hair cells.

Analysis of the effectiveness of the prophylaxis of vestibular migraine depending on the diagnostic category and the prescribed drug.

INTRODUCTION: Vestibular migraine (VM) consists of recurrent episodes of vestibular symptoms that are accompanied by migraine in at least 50% of the episodes. The criteria of the Bárány Society include two diagnostic categories: "actual" vestibular migraine and probable vestibular migraine. There is a wide range of drugs that can be prescribed for the prophylactic treatment of VM, but recommendations for the selection of the most appropriate drug are currently lacking. OBJECTIVE: To measure the extent to which the prophylactic treatment of VM reduces vestibular symptoms, headache and the number of crises depending on the diagnostic category of the Bárány Society and the drug used for prophylaxis. MATERIAL AND METHODS: This is a multicenter prospective study. Patients with VM who presented to any of the participating centers and who subsequently met the VM criteria were prescribed one of the following types of prophylaxis: acetazolamide, amitriptyline, flunarizine, propranolol or topiramate. Patients were called back for a follow-up visit 5 weeks later. This allowed the intensity of vestibular symptoms, headache and the number of crises before and during treatment to be compared. RESULTS: 31 Patients met the inclusion criteria. During the treatment, all the measured variables decreased significantly. In a visual analogue scale, the intensity of vestibular symptoms decreased by 45.8 points, the intensity of headache decreased by 47.8 points and patients suffered from 15.6 less monthly crises compared to the period before the treatment. No significant between-group differences were found when patients were divided based on their diagnostic category or the choice of prophylaxis prescribed to them. CONCLUSION: The treatment of VM produces a reduction of symptoms and crises with no significant differences based on patients' diagnostic categories or the choice of prophylaxis prescribed to them.

Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome.

Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function of RAP1A, a RAF1 regulator, can activate the RAS/MAPK pathway and cause KS, an observation recapitulated in other genetic models of the disorder. These data suggested that suppression of this signaling cascade might be of therapeutic benefit for some features of KS. To pursue this possibility, we performed a focused small molecule screen of a series of RAS/MAPK pathway inhibitors, where we tested their ability to rescue disease-relevant phenotypes in a zebrafish model of the most common KS locus, kmt2d. Consistent with a pathway-driven screening paradigm, two of 27 compounds showed reproducible rescue of early developmental pathologies. Further analyses showed that one compound, desmethyl-Dabrafenib (dmDf), induced no overt pathologies in zebrafish embryos but could rescue MEK hyperactivation in vivo and, concomitantly, structural KS-relevant phenotypes in all KS zebrafish models (kmt2d, kmd6a and rap1). Mass spectrometry quantitation suggested that a 100 nM dose resulted in sub-nanomolar exposure of this inhibitor and was sufficient to rescue both mandibular and neurodevelopmental defects. Crucially, germline kmt2d mutants recapitulated the gastrulation movement defects, micrognathia and neurogenesis phenotypes of transient models; treatment with dmDf ameliorated all of them significantly. Taken together, our data reinforce a causal link between MEK hyperactivation and KS and suggest that chemical suppression of BRAF might be of potential clinical utility for some features of this disorder.

Prophylactic treatment of vestibular migraine / Tratamento profilático da migrânea vestibular

Abstract Introduction: Vestibular migraine (VM) is now accepted as a common cause of episodic vertigo. Treatment of VM involves two situations: the vestibular symptom attacks and the period between attacks. For the latter, some prophylaxis methods can be used. The current recommendation is to use the same prophylactic drugs used for migraines, including β-blockers, antidepressants and anticonvulsants. The recent diagnostic definition of vestibular migraine makes the number of studies on its treatment scarce. Objective: To evaluate the efficacy of prophylactic treatment used in patients from a VM outpatient clinic. Methods: Review of medical records from patients with VM according to the criteria of the Bárány Society/International Headache Society of 2012 criteria. The drugs used in the treatment and treatment response obtained through the visual analog scale (VAS) for dizziness and headache were assessed. The pre and post-treatment VAS scores were compared (the improvement was evaluated together and individually, per drug used). Associations with clinical subgroups of patients were also assessed. Results: Of the 88 assessed records, 47 were eligible. We included patients that met the diagnostic criteria for VM and excluded those whose medical records were illegible and those of patients with other disorders causing dizziness and/or headache that did not meet the 2012 criteria for VM. 80.9% of the patients showed improvement with prophylaxis (p < 0.001). Amitriptyline, Flunarizine, Propranolol and Topiramate improved vestibular symptoms (p < 0.001) and headache (p < 0.015). The four drugs were effective in a statistically significant manner. There was a positive statistical association between the time of vestibular symptoms and clinical improvement. There was no additional benefit in hypertensive patients who used antihypertensive drugs as prophylaxis or depressed patients who used antidepressants in relation to other prophylactic drugs. Drug association did not show statistically significant results in relation to the use of a single drug. Conclusions: Prophylactic medications used to treat VM improve the symptoms of this disease, but there is no statistically significant difference between the responses of prophylactic drugs. The time of vestibular symptom seems to increase the benefit with prophylactic treatment.

Resumo Introdução: A migrânea vestibular (MV) é aceita atualmente como uma causa comum de vertigem episódica. O tratamento da MV envolve duas situações: as crises de sintomas vestibulares e o período intercrise. Para esse último, pode-se usar algum método de profilaxia. A recomendação atual é que se usem os mesmos medicamentos profiláticos usados para a enxaqueca, o que inclui os β-bloqueadores, antidepressivos e anticonvulsivantes. A recente definição diagnóstica da migrânea vestibular torna escasso o número de estudos sobre seu tratamento. Objetivo: Avaliar a eficácia do tratamento profilático usado em pacientes em um ambulatório de MV. Método: Revisão de prontuários de pacientes com MV pelos critérios da Bárány Society/International Headeache Society de 2012. Foram pesquisados os medicamentos usados e resposta ao tratamento obtida através da escala visual analógica (EVA) para tontura e cefaleia. Foram comparados os escores da EVA pré e pós-tratamento (a melhoria foi avaliada em conjunto e individualmente por droga usada). Também foram pesquisadas relações com subgrupos clínicos dos pacientes. Resultados: De 88 prontuários estudados, 47 foram elegíveis. Incluíram-se os pacientes que preenchiam os critérios diagnósticos para MV, foram excluídos os prontuários ilegíveis e aqueles de pacientes com outro distúrbio causador de tontura e/ou cefaleia que não preenchiam critérios de 2012 para MV. Apresentaram melhoria com a profilaxia 80,9% dos pacientes (p < 0,001). Amitriptilina, flunarizina, propranolol e topiramato apresentaram melhoria para sintomas vestibulares (p < 0,001) e para cefaleia (p < 0,015). Os quatro medicamentos foram eficazes de forma estatisticamente significante. Houve relação estatística positiva entre tempo de sintoma vestibular e melhoria clínica. Não houve benefício adicional para hipertensos que usaram anti-hipertensivos como profilaxia ou para os deprimidos que usaram antidepressivos em relação ao uso dos outros profiláticos. A associação de medicamentos não mostrou resultados estatisticamente significantes do uso de um medicamento isolado. Conclusões: Os medicamentos profiláticos usados para MV melhoram os sintomas dessa doença, porém não há diferença estatisticamente significante entre as respostas dos medicamentos profiláticos. O tempo de sintoma vestibular parece aumentar a melhoria obtida com o tratamento profilático.

Efficacy of microsurgical tumor removal for treatment of patients with intracanalicular vestibular schwannoma presenting with disabling vestibular symptoms.

OBJECTIVE The aim of this study was to analyze the efficacy and risks of microsurgery via the hearing-preserving retrosigmoid approach in patients with intracanalicular vestibular schwannoma (VS) suffering from disabling vestibular symptoms, with special attention to vertigo. METHODS This is a retrospective analysis of 19 patients with intracanalicular VS and disabling vestibular dysfunction as the main or only symptom (Group A). All of the patients reported having had disabling vertigo attacks. Subjective evaluation of the impairment of patients was performed before surgery, 3 weeks after surgery, 3 months after surgery, and 1 year after surgery, using the Dizziness Handicap Inventory (DHI). The main outcome measures were improvement in quality of life as measured using the DHI, and general and functional outcomes, in particular facial function and hearing. Patient age, preoperative tumor size, preoperative DHI score, and preservation of the nontumorous vestibular nerve were tested using a multivariate regression analysis to determine factors affecting the postoperative DHI score. The Mann-Whitney U-test was used to compare the postoperative DHI score at 3 weeks, 3 months, and 1 year after surgery with a control group of 19 randomly selected patients with intracanalicular VSs, who presented without vestibular symptoms (Group B). The occurrence of early postoperative discrete vertigo attacks was also compared between groups. RESULTS The preoperative DHI score was ≥ 54 in all patients. All patients reported having had disabling rotational vertigo before surgery. The only significant factor to affect the DHI outcome 3 weeks and 3 months after surgery was the preoperative DHI score. The DHI outcome after 1 year was not affected by the preoperative DHI score. Compared with the control group, the DHI score at 3 weeks and 3 months after surgery was significantly worse. There was no significant difference between the groups after 1 year. Vertigo was improved in all patients and completely resolved after 1 year in 17 patients. CONCLUSIONS Disabling vestibular dysfunction that affects quality of life should be considered an indication for surgery, even in otherwise asymptomatic patients with intracanalicular VS. Surgical removal of the tumor is safe and very effective in regard to symptom relief. All patients had excellent facial nerve function within 1 year after surgery, with a very good chance of hearing preservation.

Assessment of D-methionine protecting cisplatin-induced otolith toxicity by vestibular-evoked myogenic potential tests, ATPase activities and oxidative state in guinea pigs.

To date, inadequate study has been devoted to the toxic vestibular effects caused by cisplatin. In addition, no electrophysiological examination has been conducted to assess cisplatin-induced otolith toxicity. The purposes of this study are thus two-fold: 1) to determine whether cervical vestibular-evoked myogenic potentials (VEMPs) and ocular VEMPs are practical electrophysiological methods of testing for cisplatin-induced otolith toxicity and 2) to examine if D-methionine (D-met) pre-injection would protect the otolith organs against cisplatin-induced changes in enzyme activities and/or oxidative status. Guinea pigs were intraperitoneally treated once daily with the following injections for seven consecutive days: sterile 0.9% saline control, cisplatin (5 mg/kg) only, D-met (300 mg/kg) only, or a combination of d-met (300 mg/kg) and cisplatin (5 mg/kg), respectively, with a 30 minute window in between. Each animal underwent the oVEMP and cVEMP tests before and after treatment. The changes in the biochemistry of the otolith organs, including membranous Na(+), K(+)-ATPase and Ca(2+)-ATPase, lipid peroxidation (LPO) levels and nitric oxide (NO) levels, were also evaluated. In the cisplatin-only treated guinea pigs, the mean amplitudes of the oVEMP tests were significantly (p<0.05) decreased when compared to the other three groups. In guinea pigs receiving both D-met and cisplatin, the amplitudes of their oVEMP tests were significantly larger (p<0.05) than those of the cisplatin-only group, but smaller (p<0.05) than those of the saline control or D-met-only group. However, no significant difference of the amplitudes of cVEMP tests was noted among the four groups. In comparison with the other three groups, the cisplatin-only group had the lowest (ps<0.05) mean Na(+), K(+)-ATPase and Ca(2+)-ATPase, and the highest (ps<0.05) LPO and NO levels. The oVEMP tests were feasible for the evaluation of cisplatin-related otolith dysfunction. D-Met attenuated the reduced ATPase activities and increased oxidative stress induced by cisplatin toxicity in the otolith organs.

[Application of platelet-enriched plasma for the prevention of cochleovestibular disorders associated with piston stapedoplasty].

The present study was designed to evaluate the influence of sealing the labyrinthine vestibule with platelet-enriched plasma (PEP) on the development of cochleovestibular complications following piston stapedoplasty. The platelet-rich plasma was prepared by single-step centrifugation of the whole venous blood. Analysis of the data obtained showed that the use of PEP for sealing the periprosthetic space after stapedoplasty reduces the risk of development of sensorineural hearing impairment compared with the application of fatty tissue for the same purpose or a freely positioned prosthesis. Moreover, the use of PEP decreases the probability of the development of tympanophonia and its intensity after piston stapedoplasty.

Cochlear implant and vestibular function.

OBJECTIVES: To document incidences of vestibular dysfunction after cochlear implantation and investigate why it occurs. This work was also motivated by a desire to provide the basis for better preoperative counseling and postoperative vestibular therapy to cochlear implant patients. SETTING: Melbourne Cochlear Implant Clinic at a tertiary referral hospital. STUDY DESIGN: Prospective observational study. PATIENTS: One hundred forty-six adult implant recipients, mean age, 60 years (range, 20-90 yr). MAIN OUTCOME MEASURES: Postoperative vestibular disturbance was defined as symptoms lasting for 1 week or longer after surgery. The differences in preoperative and postoperative vestibular function were measured from subjective assessments (Dizziness Handicap Inventory and Activity Balance Confidence questionnaires) and objective assessments (bithermal caloric tests). The position of the postoperative electrode was classified as "loose", "regular", or "tight" fitting. RESULTS: Thirty-two percent of patients reported vestibular disturbance and had poorer Dizziness Handicap Inventory, Activity Balance Confidence, and caloric results in the implanted ear after surgery. Patient age, cause, and preoperative caloric result did not predict postoperative vestibular symptoms. Recipients aged 70 years or older had significantly poorer caloric results on the implanted side after surgery that was not related to the intracochlear electrode position or surgical team. CONCLUSION: One-third of recipients can expect to experience a significant vestibular disturbance after surgery, regardless of age, cause, or preoperative caloric result. "Older" ears seem more prone to permanent injury after cochlear implantation.

Visual vestibular interaction in the dynamic visual acuity test during voluntary head rotation.

BACKGROUND: Although intact vestibular function is indispensable to maintaining spatial orientation, no good screening tests of vestibular function are implemented in the aviation community. High frequency voluntary head rotation was selected as a vestibular stimulus to isolate the vestibulo-ocular reflex (VOR) from visual influence. METHOD: A dynamic visual acuity test that incorporates voluntary head rotation was evaluated as a potential vestibular function screening tool: 27 normal subjects performed voluntary sinusoidal head rotation at frequencies from 0.7-4 Hz under 3 different visual conditions: visually-enhanced VOR, normal VOR, and visually suppressed VOR. Standardized Bailey-Lovie chart letters were presented on a computer monitor in front of the subject, who then was asked to read the letters while rotating his head horizontally. The electro-oculogram and dynamic visual acuity score were recorded and analyzed. RESULTS: There was no significant difference in gain or phase shift among 3 visual conditions in the frequency range 2.8-4 Hz. The dynamic visual acuity score shifted less than 0.3 log MAR at frequencies under 2.0 Hz. CONCLUSION: The dynamic visual acuity test at frequencies around 2 Hz can be recommended for evaluating vestibular function.

Preservation of auditory and vestibular function after surgical removal of bilateral vestibular schwannomas in a patient with neurofibromatosis type 2.

The outcome of acoustic neuroma (vestibular schwannoma) surgery continues to improve rapidly. Advances can be attributed to several fields, but the most important contributions have arisen from the identification of the genes responsible for the dominant inheritance of neurofibromatosis types 1 (NF1) and 2 (NF2) and the development of magnetic resonance imaging with gadolinium enhancement for the early anatomic confirmation of the pathognomonic, bilateral vestibular schwannomas in NF2. These advances enable early diagnosis and treatment when the tumors are small in virtually all subjects at risk for NF2. The authors suggest that advising young NF2 patients to wait until complications develop, especially hearing loss, before diagnosing and operating for bilateral eighth nerve schwannomas may not always be in the best interest of the patient. To the authors' knowledge, this is the first reported case of preservation of both auditory and vestibular function in a patient after bilateral vestibular schwannoma excision.