Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients: Post Hoc Analysis of a Phase III, Multicenter, Open-Label Study.

BACKGROUND: Cenobamate is an antiseizure medication (ASM) approved in the US and Europe for the treatment of uncontrolled focal seizures. OBJECTIVE: This post hoc analysis of a phase III, open-label safety study assessed the safety and efficacy of adjunctive cenobamate in older adults versus the overall study population. METHODS: Adults aged 18-70 years with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled in the phase III, open-label safety study; adults aged 65-70 years from that study were included in our safety analysis. Discontinuations due to adverse events and treatment-emergent adverse events (TEAEs) were assessed throughout the study in all patients who received one or more doses of cenobamate (safety study population). Efficacy was assessed post hoc in patients who had adequate seizure data available (post hoc efficacy population); we assessed patients aged 65-70 years from that population. Overall, 100% responder rates were assessed in the post hoc efficacy maintenance-phase population in 3-month intervals. Concomitant ASM drug load changes were also measured. For each ASM, drug load was defined as the ratio of actual drug dose/day to the World Health Organization defined daily dose (DDD). RESULTS: Of 1340 patients (mean age 39.7 years) in the safety study population, 42 were ≥ 65 years of age (mean age 67.0 years, 52.4% female). Median duration of exposure was 36.1 and 36.9 months for overall patients and older patients, respectively, and mean epilepsy duration was 22.9 and 38.5 years, respectively. At 1, 2, and 3 years, 80%, 72%, and 68% of patients overall, and 76%, 71%, and 69% of older patients, respectively, remained on cenobamate. Common TEAEs (≥ 20%) were somnolence and dizziness in overall patients, and somnolence, dizziness, fall, fatigue, balance disorder, and upper respiratory tract infection in older patients. Falls in older patients occurred after a mean 452.1 days of adjunctive cenobamate treatment (mean dose 262.5 mg/day; mean concomitant ASM drug load 2.46). Of 240 patients in the post hoc efficacy population, 18 were ≥ 65 years of age. Mean seizure frequency at baseline was 18.1 seizures/28 days for the efficacy population and 3.1 seizures/28 days for older patients. Rates of 100% seizure reduction within 3-month intervals during the maintenance phase increased over time for the overall population (n = 214) and older adults (n = 15), reaching 51.9% and 78.6%, respectively, by 24 months. Mean percentage change in concomitant ASM drug load, not including cenobamate, was reduced in the overall efficacy population (31.8%) and older patients (36.3%) after 24 months of treatment. CONCLUSIONS: Results from this post hoc analysis showed notable rates of efficacy in older patients taking adjunctive cenobamate. Rates of several individual TEAEs occurred more frequently in older patients. Further reductions in concomitant ASMs may be needed in older patients when starting cenobamate to avoid adverse effects such as somnolence, dizziness, and falls. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT02535091.

Effectiveness of Anti-Calcitonin Gene-Related Peptide Medication in Vestibular Migraine: A Retrospective Cohort Study in an Asian Population.

BACKGROUND: Migraine and dizziness often coexist, with vestibular migraine (VM) presenting with vestibular symptoms and headaches. Calcitonin gene-related peptide (CGRP) may be involved in motion-induced symptoms; however, studies on the use of anti-CGRP monoclonal antibodies (mAbs) for the treatment of VM have yielded conflicting results. This study aimed to clarify the effectiveness of anti-CGRP mAbs in VM treatment. METHODS: This retrospective observational cohort study, conducted between 1 January 2021 and 31 March 2023, assessed 12 Japanese patients with VM who were treated with anti-CGRP mAbs (CGRP group) for 6 months and 11 Japanese patients who received standard of care for VM and served as controls. Clinical questionnaires and equilibrium tests were administered, with primary outcomes including changes in Dizziness Handicap Inventory (DHI) scores compared with baseline values. Objective variables included the DHI score and explanatory variables included demographic data, balance test results, head-up tilt (HUT) test results, vestibular test results and questionnaire survey results. Analysis of variance was used to assess the treatment effects of anti-CGRP mAbs, and multivariate regression analysis was performed to identify mAb responders. RESULTS: After 6 months, the CGRP group showed significant improvements in DHI scores [0 versus 6 months, odds ratio (95% confidence interval): 22.01 (0.13-43.88)] and number of vertigo/dizziness attacks per month [0 versus 6 months: 10.28 (2.80-17.76)]. No significant difference was observed in the control group [DHI scores, 0 versus 6 months: 0.65 (-26.84 to 28.14); number of vertigo/dizziness attacks per month, 0 versus 6 months: - 8.07 (- 23.77 to 7.62)]. Multivariate regression analysis showed that autonomic function at baseline was associated with mAb response in patients [ß estimates (95% confidence interval): 3.63 (0.21-7.06)]. CONCLUSIONS: Treatment with anti-CGRP mAbs was more effective than conventional treatment in preventing migraine in patients with VM. While the identified factors associated with treatment responsiveness offer valuable insights into personalised treatment approaches, further prospective studies are warranted to validate the findings due to our study's retrospective design and limited sample size.

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.

Suplementação de zinco para cocleovestibulopatias: sinopse baseada em evidências / Zinc supplementation for cochleovestibulopathies: evidence-based synopsis

Contexto: O zinco é um elemento-traço que age no sistema auditivo, atuando em sinapses auditivas e na cóclea, sobretudo junto à enzima superóxido dismutase. Objetivo: Avaliar a efetividade da suplementação de zinco para o tratamento de cocleovestibulopatias. Material e Métodos: Trata-se de sinopse baseada em evidências. Procedeu-se à busca por estudos que associavam zinco à perda auditiva, tontura e zumbido em três bases eletrônicas de dados: Cochrane - Central de Registros de Ensaios Clínicos - CENTRAL (2022), PubMed (1966- 2022) e Portal BVS (1982-2022). Dois pesquisadores independentemente extraíram os dados e avaliaram a qualidade dos estudos para a síntese. Os desfechos de análise envolveram melhora de perda auditiva, tontura e zumbido. Resultados: Foram encontrados 231 estudos. Cinco estudos (quatro ensaios clínicos randomizados e uma revisão sistemática) envolvendo um total de 249 pacientes. Discussão: A literatura mundial apresenta poucos estudos relacionando zinco e cocleovestibulopatias. A maioria trata-se de estudos in vitro ou de experimentação animal. Os estudos em humanos são ensaios clínicos de baixa amostragem e elevada heterogeneidade, que avaliaram melhora de perda auditiva e melhora de zumbido. Nenhum estudo avaliou melhora da tontura. O nível de evidência é muito baixo e não permite, nesse momento, aferir a efetividade do zinco para tratamento de cocleovestibulopatias em humanos, sendo sua utilização clínica baseada na experiência de cada profissional. Conclusões: Não há evidência de efetividade da suplementação de zinco no tratamento de cocleovestibulopatias, sendo recomendada a realização de novos estudos de boa qualidade metodológica. PALAVRAS-CHAVE: Zinco, perda auditiva, tontura, zumbido, prática clínica baseada em evidências

Clinical characteristics of patients with persistent postural-perceptual dizziness / Caracterização clínica dos pacientes com tontura postural-perceptual persistente (TPPP)

INTRODUCTION: Persistent postural-perceptual dizziness is the dizziness that lasts for over three months with no clinical explanation for its persistence. The patient's motor response pattern presents changes and most patients manifest significant anxiety. OBJECTIVE: To evaluate the clinical characteristics of patients with persistent postural and perceptual dizziness. METHODS: statistical analysis of clinical aspects of patients with persistent postural-perceptual dizziness. RESULTS: 81 patients, average age: 50.06 ± 12.16 years; female/male ratio: 5.7/1; main reasons for dizziness: visual stimuli (74%), body movements (52%), and sleep deprivation (38%). The most prevalent comorbidities were hypercholesterolemia (31%), migraine headaches (26%), carbohydrate metabolism disorders (22%) and cervical syndrome (21%). DHI, State-Trait Anxiety Inventory - Trait, Beck Depression Inventory, and Hospital Anxiety and Depression Scale questionnaires were statistically different (p < 0.05) when compared to controls. 68% demonstrated clinical improvement after treatment with serotonin reuptake inhibitors. CONCLUSION: Persistent postural-perceptual dizziness affects more women than men, with a high associated prevalence of metabolic disorders and migraine. Questionnaires help to identify the predisposition to persistent postural-perceptual dizziness. The prognosis is good with adequate treatment. .

INTRODUÇÃO: A denominação tontura postural-perceptual persistente (TPPP) é atribuida à tontura que se mantém por mais de 3 meses em pacientes, sem que exista justificativa clínica para a sua persistência. A maioria dos pacientes possui perfil ansioso ou experimenta alto grau de ansiedade no início dos sintomas. O padrão de resposta motora apresenta-se alterado, com hipervigilância e hipersensibilidade a estímulos visuais e de movimento. OBJETIVO: Avaliar as características clínicas de pacientes com diagnóstico de TPPP. MÉTODO: Análise dos aspectos clínicos de pacientes do ambulatório de TPPP e quantificação do perfil ansioso ou depressivo. RESULTADOS: Foram avaliados 81 pacientes, com média de idade de 50,06 ± 12,16 anos; relação mulher/homem de 5,7/1; principais gatilhos para tontura: estímulos visuais (74%), movimentos corporais (52%) e privação de sono (38%). As comorbidades mais prevalentes foram hipercolesterolemia (31%), migrânea (26%), distúrbios do metabolismo do açúcar (22%) e síndrome cervical (21%). Os questionários DHI, STAI-Traço, Beck para depressão e HADS foram estatisticamente diferentes (P < 0,05) entre pacientes e controles. 68% de melhora clínica com o uso de inibidores da recaptação da serotonina. CONCLUSÃO: TPPP acomete principalmente as mulheres, sendo alta a associação com distúrbios metabólicos e migrânea. Os questionários auxiliam na identificação da predisposição à TPPP. Há bom prognóstico com o tratamento adequado. .

Imipramine for vestibular dysfunction in panic disorder: a prospective case series / Imipramina para disfunção vestibular em transtorno do pânico: uma série de casos prospectiva

OBJECTIVE: The purpose of this study was to evaluate the efficacy and effectiveness of imipramine on the treatment of comorbid chronic dizziness and panic disorder. METHOD: Nine patients with panic disorder and agoraphobia associated with chronic dizziness underwent otoneurological screening and were treated with a 3-months course of imipramine. Anxiety levels were measured with the Hamilton Anxiety Scale (HAM-A), dizziness levels were evaluated using the Dizziness Handicap Inventory (DHI), and panic severity and treatment outcome were assessed with the Clinical Global Impression Scale (CGI). RESULTS: At the baseline 33.3 percent (n=3) had a bilateral peripheral deficit vestibulopathy, the mean scores for HAM-A were 27.2±10.4, for DHI were 51.7±22.7, and for CGI-S were 4.8±0.9. All patients had a significant reduction in their HAM-A (11.1±5.5, p=0.008), DHI (11.5±8.1, p=0.008) and CGI-I (1.8±0.7, p=0.011) levels after 3-months imipramine treatment (mean=72.2±23.2 mg/day). CONCLUSION: This study found a decrease in anxiety levels and in the impact of dizziness in the patients' quality of life after a 3-months treatment course with imipramine.

OBJETIVO: O objetivo deste estudo foi avaliar a eficácia e efetividade da imipramina no tratamento da tontura crônica e do transtorno de pânico comórbidos. MÉTODO: Nove pacientes com transtorno do pânico e agorafobia associada com tontura crônica foram submetidos à avaliação otoneurológica e tratados durante 3 meses com imipramina. Os níveis de ansiedade foram medidos através da Escala Hamilton de Ansiedade (HAM-A); os de tontura foram avaliados usando o Dizziness Handicap Inventory (DHI), e a gravidade do pânico e sua resposta pela Escala de Impressão Clínica Global (CGI). RESULTADOS: Na avaliação inicial, 33,3 por cento (n=3) da amostra apresentavam vestibulopatia periférica deficitária bilateral; as médias foram: da HAM-A 27,2±10,4, do DHI 51,7±22,7 e do CGI-S 4,8±0,9. Todos tiveram uma redução significativa nos escores de HAM-A (11,1±5,5, p=0,008), DHI (11,5±8,1, p=0,008) e CGI-I (1,8±0,7, p=0,011), após 3 meses de tratamento com imipramina (média=72,2±23,2 mg/dia). CONCLUSÃO: Este estudo encontrou uma diminuição dos níveis de ansiedade e do impacto da tontura na qualidade de vida dos pacientes após um curso de 3 meses de tratamento com imipramina.

Cinarizina e as labirintopatias / Cinnarizine and labyrinth diseases

Uma revisäo dos resultados de vßrios estudos clÝnicos com a cinarizina no tratamento de diversos distúrbios vestibulares Ú apresentada. De acordo com estes resultados clÝnicos, o uso adequado de cinarizina Ú um procedimento terapÛutico seguro e muito eficaz na remissÒo da vertigem e outros tipos de tontura de variada etiologia e de origem vestibular perifÚrica ou central.