Betahistine alleviates benign paroxysmal positional vertigo (BPPV) through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway

BACKGROUND: Betahistine is a clinical medication for the treatment of benign paroxysmal positional vertigo (BPPV). Otolin, a secreted glycoprotein with a C-terminal globular domain homologous to the immune complement C1q, has been identified as a biomarker for BPPV. However, the role of complement C1q/TNF-related proteins (CTRPs) with a C-terminal globular domain in BPPV is unclear, so we explored the change of CTRPs in betahistine treated BPPV. METHODS: We treated BPPV patients with Betahistine (12 mg/time, 3 times/day) for 4 weeks and observed the clinical efficacy and the expression of CTRP family members in BPPV patients. Then, we constructed a vertigo mice model of vestibular dysfunction with gentamicin (150 mg/Kg) and a BPPV model of Slc26a4loop/loop mutant mice. Adenoviral vectors for CTRP expression vector and small interfering RNA were injected via the intratympanic injection into mice and detected the expression of CTRP family members, phosphorylation levels of ERK and AKT and the expression of PPARγ. In addition, we treated mice of vestibular dysfunction with Betahistine (10 mg/Kg) and/or ERK inhibitor of SCH772984 (12 mg/Kg) and/or and PPARγ antagonist GW9662 (1 mg/Kg) for 15 days, and evaluated the accuracy of air righting reflex, the time of contact righting reflex and the scores of head tilt and swimming behavior. RESULTS: After treatment with Betahistine, the residual dizziness duration and the score of the evaluation were reduced, and the expression of CTRP1, 3, 6, 9 and 12 were significantly increased in BPPV patients. We also found that Betahistine improved the accuracy of air righting reflex, reduced the time of contact righting reflex and the scores of head tilt and swimming behavior in gentamicin-treated mice and Slc26a4loop/loop mutant mice. The expression levels of CTRP1, 3, 6, 9 and 12, phosphorylation levels of ERK and AKT, and PPARγ expression were significantly increased, and the scores of head tilt and swimming behavior were decreased in vestibular dysfunction mice with overexpression of CTRPs. Silencing CTRPs has the opposite effect. SCH772984 reversed the effect of Betahistine in mice with vestibular dysfunction. CONCLUSION: Betahistine alleviates BPPV through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.

Intervention strategies for residual dizziness after successful repositioning maneuvers in benign paroxysmal positional vertigo: a single center randomized controlled trial / 中华耳鼻咽喉头颈外科杂志

Objective: To compare the effects of different intervention strategies for the management of residual dizziness following successful canalith repositioning procedure (CRP) in patients with benign paroxysmal positional vertigo (BPPV). Methods: A total of 129 BPPV patients with residual dizziness following successful CRP were recruited during January 2019 and July 2019. They were randomly assigned into three groups with 43 cases in each group: the vestibular rehabilitation group received rehabilitation training for four weeks; betahistine group was given orally 12 mg betahistine three times a day for four weeks; and the control group had no specific treatment. The primary outcomes were daily activities and social participation assessed by the Vestibular Activities and Participation measure (VAP). Secondary outcomes includedbalance function assessed by sensory organization test (SOT) and the duration of residual symptoms. Stata15.0 software was used for statistical analysis. Results: The scores of VAP in the three groups decreased over time, but a more significant decrease was found in vestibular rehabilitation group. Further paired comparison showed that the difference between the vestibular rehabilitation group and the control group was of statistical significance (B=-3.88, χ2=18.29, P<0.01), while the difference between the betahistine group and the control group was not statistically significant (B=-0.96, χ2=1.16, P=0.28). The balance function of the three groups showed a trend of recovery over time, with no significant differences between groups (χ2=1.37, df=2, P>0.05). The median duration of residual dizziness for both vestibular rehabilitation and betahistine groups was 14 days, while that of control group was 19 days, with no significant difference between three groups[Log-rank (Mantel-Cox) test; χ2=1.82, df=2, P=0.40]. Conclusion: Vestibular rehabilitation can significantly improve the daily activities and social participation function in BPPV patients with residual symptoms following successful CRP, but its effects on shortening the duration of residual symptoms and promoting the recovery of balance function remain uncertain.

Subjective benign paroxysmal positional vertigo in patients with osteoporosis or migraine / Vertigem posicional paroxística benigna subjetiva em pacientes com osteoporose ou migrânea

Abstract Introduction Subjective benign paroxysmal positional vertigo is a form of benign paroxysmal positional vertigo in which during the diagnostic positional maneuvers patients only present vertigo symptoms with no nystagmus. Objective To study the characteristics of subjects with subjective benign paroxysmal positional vertigo. Methods Prospective multicenter case-control study. All patients presenting with vertigo in the Dix-Hallpike test that presented to the participating hospitals were included. The patients were separated into two groups depending on whether nystagmus was present or not. An Epley Maneuver of the affected side was performed. In the follow-up visit, patients were checked to see if nystagmus and vertigo were present. Both groups of patients were compared to assess the success rate of the Epley maneuver and also to compare the presence of 19 variables. Results 259 patients were recruited, of which 64 belonged to the subjective group. Nystagmus was eliminated in 67.2% of the patients with benign paroxysmal positional vertigo. 89.1% of the patients with subjective benign paroxysmal positional vertigo remained unaffected by nystagmus, thus showing a significant difference (p = 0.001). Osteoporosis and migraine were the variables which reached the closest to the significance level. In those patients who were taking vestibular suppressors, the percentage of subjective benign paroxysmal positional vertigo was not significantly higher. Conclusions Subjective benign paroxysmal positional vertigo should be treated using the Epley maneuver. More studies are needed to establish a relationship between osteoporosis, migraine and subjective benign paroxysmal positional vertigo. The use of vestibular suppressants does not affect the detection of nystagmus.

Resumo Introdução A vertigem posicional paroxística benigna subjetiva é um tipo de vertigem posicional paroxística benigna na qual, durante as manobras posicionais diagnósticas, os pacientes apresentam apenas sintomas vertiginosos sem nistagmo. Objetivo Estudar as características de indivíduos com vertigem posicional paroxística benigna subjetiva. Método Estudo prospectivo multicêntrico de caso-controle. Foram incluídos todos os pacientes com vertigem no teste de Dix-Hallpike, que se apresentaram nos hospitais participantes. Os pacientes foram separados em dois grupos, dependeu da presença ou não do nistagmo. Uma manobra de Epley foi realizada no lado afetado. Na consulta de seguimento, os pacientes foram avaliados para verificar a presença ou não do nistagmo e da vertigem. Ambos os grupos de pacientes foram comparados para avaliar a taxa de sucesso da manobra de Epley e também para comparar a presença de 19 variáveis. Resultados Foram recrutados 259 pacientes, dos quais 64 pertenciam ao grupo subjetivo. O nistagmo foi eliminado em 67,2% dos pacientes com vertigem posicional paroxística benigna. Em 89,1% dos casos, os pacientes com vertigem posicional paroxística benigna subjetiva mantiveram-se não afetados pelo nistagmo, mostraram uma diferença significativa (p = 0,001). Osteoporose e enxaqueca foram as variáveis que atingiram o nível mais próximo ao de significância. Nos pacientes que tomavam supressores vestibulares, a porcentagem de vertigem posicional paroxística benigna subjetiva não foi significativamente maior. Conclusões A vertigem posicional paroxística benigna subjetiva deve ser tratada com a manobra de Epley. Mais estudos são necessários para estabelecer uma relação entre osteoporose, enxaqueca e vertigem posicional paroxística benigna subjetiva. O uso de supressores vestibulares não afeta a detecção do nistagmo.

Hearing function after betahistine therapy in patients with Ménière's disease / Função auditiva após terapia com beta-histina em pacientes com doença de Ménière

ABSTRACT INTRODUCTION: Preventing or reversing hearing loss is challenging in Ménière's disease. Betahistine, as a histamine agonist, has been tried in controlling vertigo in patients with Ménière's disease, but its effectiveness on hearing problems is not known. OBJECTIVE: To examine the effect of betahistine on hearing function in not-previously-treated patients with Ménière's disease and to define possible contributors in this regard. METHODS: A total of 200 not-previously-treated patients with definite unilateral Ménière's disease received betahistine by mouth (initial dose, 16 mg three times a day; maintenance dose, 24-48 mg daily in divided doses). Changes in indicators of hearing status before and six months after treatment were documented. Hearing loss was considered as the mean hearing level >25 dB HL at five frequencies. RESULTS: The mean duration of disease was 3.37 years. Six months after treatment the mean hearing level decreased by 6.35 dB compared to that at the baseline (p < 0.001). Both patients' age and the duration of disease correlated negatively with the improvement in hearing function. Post treatment hearing loss was independently associated with age, the initial hearing level and the chronicity of disease. The corresponding optimal cut-off points for predicating a persistent hearing loss 6 months after treatment were 47 years, 38 dB HL, and 1.4 years, respectively. CONCLUSION: Oral betahistine was significantly effective in preventing/reversing hearing deterioration in patients with Ménière's disease. Age, the hearing level on admission, and the disease duration were independent predictors of hearing status after treatment.

Resumo Introdução: Prevenir ou reverter a perda auditiva é um desafio na doença de Ménière. A betahistina, um agonista de histamina, tem sido testada no controle de vertigem em pacientes com doença de Ménière, mas sua eficácia em problemas de audição ainda não é conhecida. Objetivo: Analisar o efeito da betahistina na função auditiva em pacientes com doença de Ménière não tratados previamente, e definir possíveis contribuintes a esse respeito. Método: Um total de 200 pacientes sem tratamento prévio, e com diagnóstico definido de doença de Ménière unilateral, recebeu beta-histina por via oral (dose inicial de 16 mg três vezes ao dia; dose de manutenção de 24-48 mg por dia, em doses divididas). Alterações dolimiar auditivo antes e após seis meses de tratamento foram documentadas. Considerou-se como perda auditiva uma média do nível de audição > 25 dB NA em cinco frequências. Resultados: A média de duração da doença foi de 3,37 anos. Seis meses após o tratamento, a média do limiar auditivo diminuiu em 6,35 dB, em comparação com o valor da linha de base (p < 0,001). Tanto a idade dos pacientes quanto a duração da doença apresentaram correlação negativa com a melhora da função auditiva. A perda auditiva após o tratamento foi independentemente associada à idade, ao nível inicial de audição e à cronicidade da doença. Os pontos de corte ótimos correspondentes para prever uma perda auditiva persistente seis meses após o tratamento foram 47 anos, 38 dB HL e 1,4 ano, respectivamente. Conclusão: A betahistina oral foi significantemente eficaz na prevenção/reversão da deterioração auditiva em pacientes com doença de Ménière. Idade, nível de audição na admissão e duração da doença foram fatores preditivos independentes da condição auditiva após o tratamento.

Reabilitação vestibular com realidade virtual na doença de Ménière / Vestibular rehabilitation with virtual reality in Ménière's disease

A tecnologia de realidade virtual fornece uma grande variedade de estímulos que geram conflitos sensoriais em diferentes níveis de dificuldades e em ambiente seguro. OBJETIVO: Verificar o efeito de um programa de reabilitação vestibular do equilíbrio corporal com estímulos de realidade virtual em pacientes com doença de Ménière. Forma de estudo: Estudo clínico observacional. MÉTODO: Quarenta e quatro pacientes, com idade entre 18 e 60 anos e doença de Ménière definida, distribuídos em dois grupos - experimental (GE) e controle (GC) - fizeram uso de betaistina e dieta alimentar; o grupo experimental foi submetido adicionalmente a 12 sessões de reabilitação com realidade virtual da BRU TM. Os pacientes responderam ao Dizziness Handicap Inventory (DHI), à escala analógica de tontura e realizaram a posturografia com realidade virtual antes e após a intervenção. RESULTADOS: Após a intervenção, o GE apresentou valores significantemente menores do DHI (p < 0,001) e da escala analógica de tontura (p = 0,012) e valores significantemente maiores da área do limite de estabilidade (p = 0,016), em comparação com o GC. CONCLUSÃO: A reabilitação do equilíbrio corporal com estímulos de realidade virtual é eficaz na melhora da tontura, da qualidade de vida e do limite de estabilidade de pacientes com doença de Ménière.

Virtual reality technology can provide a wide range of sensory stimuli to generate conflicts of varying degrees of complexity in a safe environment. OBJECTIVE: To verify the effect of a virtual realitybased balance rehabilitation program for patients with Menière's disease. METHOD: This observational clinical study included 44 patients aged between 18 and 60 years diagnosed with Menière's disease submitted to a controlled randomized therapeutic intervention. The case and control groups took betahistine and followed a diet. Case group subjects underwent 12 rehabilitation sessions with virtual reality stimuli in a Balance Rehabilitation Unit (BRU TM). Patients were assessed based on DHI scores, the dizziness visual analogue scale, and underwent posturography with virtual reality before and after the intervention. RESULTS: After the intervention, the case group showed significantly lower scores in DHI (p < 0,001) and in the dizziness visual analog scale (p = 0.012), and had significantly greater limit of stability areas (p = 0.016) than controls. CONCLUSION: Virtual reality-based balance rehabilitation effectively improved dizziness, quality of life, and limit of stability of patients with Menière's disease.

Betahistine in the treatment of tinnitus in patients with vestibular disorders / Betaistina no tratamento do zumbido em pacientes com distúrbios vestibulares

Betahistine is a medicine used to treat vestibular disorders that has also been used to treat tinnitus. AIM: To assess the effects of betahistine on tinnitus in patients with vestibular disorders. MATERIAL AND METHOD: Retrospective data were collected from patient records for individuals presenting with vestibular dysfunction and tinnitus. Patients included had received betahistine 48 mg/day and clinical outcomes were compared with a control group comprising individuals who were unable to receive betahistine due to gastritis, ulcers, pregnancy, asthma or hypersensitivity to the drug. Patients underwent control of any aggravating factors and also standard vestibular exercises as a basis for treatment. The intensity, frequency and duration of tinnitus were assessed on the first day of dosing and after 120 days of treatment. Clinical improvement was defined as a total or partial reduction of tinnitus after treatment. RESULTS: Clinical improvement was observed in 80/262 (30. 5 percent) of patients treated with betahistine and 43/252 (17. 1 percent) of control patients. Betahistine significantly (p<0. 0001) improved tinnitus in treated individuals. CONCLUSIONS: The daily dosage of 48 mg of betahistine during 120 consecutive days is useful to reduce or eliminate tinnitus in patients with vestibular disorders.

A betaistina é um medicamento utilizado no tratamento de distúrbios da função vestibular, que também tem sido utilizado para tratar o zumbido. OBJETIVO: Avaliar o efeito da betaistina sobre o zumbido de pacientes com distúrbios vestibulares. MATERIAL E MÉTODO: Foram coletados dados retrospectivos de pacientes com vestibulopatia e zumbido. Os pacientes incluídos receberam 48 mg/dia de betaistina ao dia e os resultados clínicos foram comparados com os de um grupo controle, que incluiu indivíduos impossibilitados de receber betaistina devido à gastrite, úlceras, gravidez, asma ou hipersensibilidade ao medicamento. Os pacientes realizaram controle de fatores agravantes e exercícios de reabilitação vestibular, como tratamento de base para a vestibulopatia. A intensidade, frequência e duração do zumbido foram avaliadas no primeiro dia e após 120 dias de tratamento. A melhora clínica foi definida pela redução total ou parcial do zumbido após o tratamento. RESULTADOS: Observou-se melhora clínica do zumbido em 80/262 (30,5 por cento) dos pacientes tratados com a betaistina e em 43/252 (17,1 por cento) pacientes do grupo controle. A betaistina melhorou significativamente (p<0.0001) o zumbido nos indivíduos tratados. CONCLUSÃO: A dose de 48 mg/dia de betaistina durante 120 dias consecutivos é útil na redução ou eliminação do zumbido de pacientes com distúrbios vestibulares.

Otimizando o componente farmacológico da terapia integrada da vertigem / Optimizing the pharmacological component of integrated balance therapy

A farmacoterapia é opção importante no tratamento das vestibulopatias periféricas. OBJETIVO: Identificar a medicação que otimiza a terapia integrada da vertigem (TIV) na doença de Ménière e em outras vestibulopatias periféricas. MATERIAL E MÉTODO: Estudo de casos em que pacientes com doença de Ménière ou outras vestibulopatias periféricas receberam TIV com betaistina, cinarizina, clonazepam, flunarizina, Ginkgo biloba ou sem medicação durante 120 dias. RESULTADOS: Na doença de Ménière, TIV com qualquer um dos medicamentos foi mais eficaz do que TIV sem medicação, após 60 dias; a betaistina foi mais efetiva que todas as outras drogas, após 60 e 120 dias. Nas outras vestibulopatias periféricas, diferenças significantes foram observadas entre TIV com betaistina, cinarizina, clonazepam ou flunarizina e TIV sem medicação após 60 dias e todas as drogas foram mais efetivas que TIV sem medicação após 120 dias; betaistina, cinarizina ou clonazepam foram igualmente efetivos e betaistina foi mais efetiva que flunarizina e Ginkgo biloba. Os tratamentos foram bem tolerados. CONCLUSÕES: TIV incluindo medicação é mais efetiva que sem medicação na doença de Ménière ou em outras vestibulopatias periféricas. Betaistina foi o medicamento mais efetivo na doença de Ménière e tão eficaz quanto cinarizina ou clonazepam em outras vestibulopatias periféricas.

Drug treatment is an important option for the treatment of peripheral vestibular diseases. AIM: To identify the drug component associated with optimal integrated balance therapy (IBT) for MénièreÆs disease or other peripheral vestibular disorders. MATERIALS AND METHODS: Analysis of a series of patients with MénièreÆs disease patients or patients with other peripheral vestibular disorders that received IBT involving either no medication or betahistine, cinnarizine, clonazepam, flunarizine or Ginkgo biloba during 120 days. RESULTS: In MénièreÆs disease, significant differences were observed for all drug therapies (60 days) versus no medication; betahistine was significantly more effective than all other drugs at 60 and 120 days. For non-MénièreÆs disorders, significant differences were observed among betahistine, cinnarizine, clonazepam and flunarizine and no medication after 60 days; all drug therapies were significantly more effective than no medication after 120 days; betahistine, cinnarizine or clonazepam were equally effective and betahistine was more effective than flunarizine and EGb 761. All treatment options were well tolerated. CONCLUSIONS: Drug therapies were more effective than no medication in the IBT for patients with MénièreÆs disease or other peripheral vestibular disorders. Betahistine was the most effective medication for patients with MénièreÆs disease and was as effective as cinnarizine and clonazepam for other peripheral vestibular disorders.