ObjectivesTo assess first clinical experiences with brivaracetam (BRV) in the treatment of epilepsies.MethodsData on patients treated with BRV from February to December 2016 and with at least one clinical follow-up were collected from electronic patient records. Data on safety and efficacy were evaluated retrospectively.ResultsIn total, 93 patients were analyzed; 12 (12.9%) received BRV in monotherapy. The mean duration to follow-up was 4.85 months (MD = 4 months; SD = 3.63). Fifty-seven patients had more than one seizure per month at baseline and had a follow-up of more than 4 weeks; the rate of ≥50% responders was 35.1% (n = 20) in this group, of which five (8.8%) patients were newly seizure-free. In 50.5% (47/93), patients were switched from levetiracetam (LEV) to BRV, of which 43 (46.2%) were switched immediately. Adverse events (AE) occurred in 39.8%, with 22.6% experiencing behavioral and 25.8% experiencing non-behavioral AE. LEV-related AE (LEV-AE) were significantly reduced by switching to BRV. The discontinuation of BRV was reported in 26/93 patients (28%); 10 of those were switched back to LEV with an observed reduction of AE in 70%. For clinical reasons, 12 patients received BRV in monotherapy, 75% were seizure–free, and previous LEV-AE improved in 6/9 patients. BRV-related AE occurred in 5/12 cases, and five patients discontinued BRV.ConclusionBRV seems to be a safe, easy, and effective option in the treatment of patients with epilepsy, especially in the treatment of patients who have psychiatric comorbidities and might not be good candidates for LEV treatment. BRV broadens the therapeutic spectrum and facilitates personalized treatment.

Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

ObjectivesBrivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting.DesignRetrospective, observational multicentre study.SettingWe retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist.ParticipantsData of 615 epilepsy patients treated with BRV were included in the study.Primary and secondary outcome measuresEfficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X2 contingency tests and effect sizes were performed.ResultsOverall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV.ConclusionsThe present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.