Treatment simplification to optimize cenobamate effectiveness and tolerability: A real-world retrospective study in Spain.

OBJECTIVE: This study aimed to explore the impact of co-antiseizure medication (co-ASM) optimization on the effectiveness and tolerability of adjunctive cenobamate (CNB) in patients with drug-resistant epilepsy in a real-world setting. METHODS: This unicentric, retrospective, observational study included adults with focal-onset seizures who had received ≥2 previous ASMs. The main effectiveness endpoints included responder rates and seizure frequency reduction at 3, 6, and 12-month visits. The number of co-ASMs and defined daily dose (DDD) were analyzed at every visit. Safety endpoints included adverse drug reactions (ADRs). RESULTS: Thirty-four patients with a median epilepsy duration of 22 years and a median of 15.5 seizures/month were analyzed. The median number of prior ASMs was 12, and the mean number of co-ASMs was 2.9 (SD 1). There was a reduction in seizure frequency/month from baseline to the last visit (p < 0.0001). Between baseline and the end of the study, the mean number of co-ASMs in the per-protocol (PP) population was reduced from 2.9 to 1.6 (p < 0.0001), and DDD was reduced from 3.6 to 1.4 (p < 0.0001). Sodium channel blockers (carbamazepine and lacosamide) and GABAergic drugs (clobazam) were the agents with the most significant reductions in DDD after 12 months. The percentage of patients in the PP population with ≥3 co-ASMs was reduced from 61.8% at baseline to 14.3% at 12 months; 1 patient was receiving CNB as monotherapy at the last visit. At the last visit, 85.7% of the PP population were ≥50% responders, and 33.3% were seizure-free. The percentage of patients with ADRs in the PP population was 71.9% at 3 months and 52.3% at 12 months. SIGNIFICANCE: Following rational polytherapy, optimization of co-ASM management during CNB treatment allowed high seizure freedom rates despite meaningful reductions in co-medication, while also achieving both good tolerability and patient satisfaction scores in a highly drug-resistant population. PLAIN LANGUAGE SUMMARY: Many patients with epilepsy still have seizures, even after being treated with several different epilepsy drugs. In this study of 34 patients from a Spanish clinic, we show that the epilepsy drug cenobamate can reduce the number of seizures in these patients, even after many other epilepsy drugs have failed. We also show that patients treated with cenobamate can reduce the dose or even stop taking certain other epilepsy drugs. This allows them to simplify their treatment and reduce adverse effects while still keeping control of their epilepsy.

Transient Focal Neurological Events in Cerebral Amyloid Angiopathy and the Long-term Risk of Intracerebral Hemorrhage and Death: A Systematic Review and Meta-analysis.

Importance: Transient focal neurological episodes (TFNEs) are a frequently overlooked presentation of cerebral amyloid angiopathy (CAA), a condition with prognostic implications that are still not well described. Objective: To perform a systematic review and meta-analysis to examine the factors associated with incident lobar intracerebral hemorrhage (ICH) and death in patients with CAA presenting with TFNEs. Data Sources: A systematic review and individual participant meta-analysis including (1) a hospital-based cohort and (2) the results obtained from a systematic search performed in MEDLINE and Embase completed in December 2019. Study Selection: Included studies were observational reports of TFNEs. Patient-level clinical, imaging, and prognostic data were required for inclusion. For aggregate data studies, patient-level data were requested. Disagreements were resolved by consensus. Data Extraction and Synthesis: Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines by 4 independent reviewers. The quality of reports was determined based on the modified Pearson Case Report Quality Scale. Main Outcomes and Measures: The clinical characteristics of TFNEs, neuroimaging features, and use of antithrombotics during follow-up were considered exposures. The predefined main outcomes were lobar ICH and risk of death during follow-up. Results: Forty-two studies and 222 CAA-associated TFNE cases were included from the initial 1612 records produced by the systematic search; 26 additional patients (11 men [42.3%]; mean [SD] age, 77 [8] years) were provided by the hospital-based cohort. A total of 108 TFNEs (43.5%) consisted of motor symptoms. Convexity subarachnoid hemorrhage and cortical superficial siderosis were detected in 193 individuals (77.8%) and 156 individuals (62.9%) in the systematic search and hospital-based cohort, respectively. Follow-up duration could be obtained in 185 patients (median duration, 1 year [IQR, 0.8-2.5 years]). During follow-up, symptomatic lobar ICH occurred in 76 patients (39.4%). Motor symptoms (odds ratio, 2.08 [95% CI, 1.16-3.70]) at baseline and antithrombotic use during follow-up (odds ratio, 3.61 [95% CI, 1.67-7.84]) were associated with an increase in risk of lobar ICH. A total of 31 patients (16.5%) died during follow-up; lobar ICH during follow-up and cortical superficial siderosis were the main risk factors for death (odds ratio, 3.01 [95% CI, 1.36-6.69]; odds ratio, 3.20 [95% CI, 1.16-8.91], respectively). Conclusions and Relevance: Patients presenting with CAA-associated TFNEs are at high risk of lobar ICH and death. Motor TFNEs and use of antithrombotics after a TFNE, in many cases because of misdiagnosis, are risk factors for ICH, and therefore accurate diagnosis and distinguishing this condition from transient ischemic attacks is critical.

Bassoon-disruption slows vesicle replenishment and induces homeostatic plasticity at a CNS synapse.

Endbulb of Held terminals of auditory nerve fibers (ANF) transmit auditory information at hundreds per second to bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN). Here, we studied the structure and function of endbulb synapses in mice that lack the presynaptic scaffold bassoon and exhibit reduced ANF input into the AVCN. Endbulb terminals and active zones were normal in number and vesicle complement. Postsynaptic densities, quantal size and vesicular release probability were increased while vesicle replenishment and the standing pool of readily releasable vesicles were reduced. These opposing effects canceled each other out for the first evoked EPSC, which showed unaltered amplitude. We propose that ANF activity deprivation drives homeostatic plasticity in the AVCN involving synaptic upscaling and increased intrinsic BC excitability. In vivo recordings from individual mutant BCs demonstrated a slightly improved response at sound onset compared to ANF, likely reflecting the combined effects of ANF convergence and homeostatic plasticity. Further, we conclude that bassoon promotes vesicular replenishment and, consequently, a large standing pool of readily releasable synaptic vesicles at the endbulb synapse.