Real-life evidence about the use of intravenous brivaracetam in urgent seizures: The BRIV-IV study.

PURPOSE: Urgent seizures are a medical emergency for which new therapies are still needed. This study evaluated the use of intravenous brivaracetam (IV-BRV) in an emergency setting in clinical practice. METHODS: BRIV-IV was a retrospective, multicenter, observational study. It included patients ≥18 years old who were diagnosed with urgent seizures (including status epilepticus (SE), acute repetitive seizures, and high-risk seizures) and who were treated with IV-BRV according to clinical practice in 14 hospital centers. Information was extracted from clinical charts and included in an electronic database. Primary effectiveness endpoints included the rate of IV-BRV responder patients, the rate of patients with a sustained response without seizure relapse in 12 h, and the time between IV-BRV administration and clinical response. Primary safety endpoints were comprised the percentage of patients with adverse events and those with adverse events leading to discontinuation. RESULTS: A total of 156 patients were included in this study. The mean age was 57.7 ± 21.5 years old with a prior diagnosis of epilepsy for 57.1% of patients. The most frequent etiologies were brain tumor-related (18.1%) and vascular (11.2%) epilepsy. SE was diagnosed in 55.3% of patients. The median time from urgent seizure onset to IV treatment administration was 60.0 min (range: 15.0-360.0), and the median time from IV treatment to IV-BRV was 90.0 min (range: 30.0-2400.0). Regarding dosage, the mean bolus infusion was 163.0 ± 73.0 mg and the mean daily dosage was 195.0 ± 87.0 mg. A total of 77.6% of patients responded to IV-BRV (66.3% with SE vs. 91% other urgent seizures) with a median response time of 30.0 min (range: 10.0-60.0). A sustained response was achieved in 62.8% of patients. However, adverse events were reported in 14.7%, which were predominantly somnolence and fatigue, with 4.5% leading to discontinuation. Eighty-six percent of patients were discharged with oral brivaracetam. CONCLUSION: IV-BRV in emergency settings was effective, and tolerability was good for most patients. However, a larger series is needed to confirm the outcomes.

Onset of efficacy and adverse events during Cenobamate titration period.

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

Therapy delay in status epilepticus extends its duration and worsens its prognosis.

BACKGROUND: Timing in status epilepticus (SE) attention is probably the most relevant modifiable prognostic factor and may influence SE duration and prognosis. We aimed to describe the precise relationship between management timing, duration, and prognosis of SE. METHODS: Observational longitudinal prospective study on a cohort of all patients diagnosed with SE admitted to our tertiary hospital from September 2017 to August 2019, with a 3-month follow-up. Univariate and multivariable analyses were performed to identify clinical and timing variables associated with SE duration and prognosis. RESULTS: Eighty-three SE affecting 76 patients were included. Median age was 73 years, 61.4% were women, median baseline modified Rankin Scale (mRS) was 2, and 55.4% had prior epilepsy. In the out-of-hospital group (n = 50), median time to emergencies was 1.3 h and to hospital admission 2.8 h. In the global series, median time to neurologist was 4.3 h, and median time to therapy initiation was 4.5 h. These four times positively correlated with SE duration (all Spearman's rho coefficient >0.5, all p < .001). SE median duration was 24 h and was extended 1.2 h for each hour of treatment delay. A longer SE duration was associated with increased mortality and morbidity, both at hospital discharge and at 3-month follow-up (both p < .05). After 3 months, mortality was 30.1%, while recovery to baseline mRS occurred in 39.5%, with an overall median mRS of 4. CONCLUSIONS: There were pervasive delays in all phases of SE attention, which conditioned a longer SE duration, and this led to increased long-term morbimortality.

Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort.

OBJECTIVE: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. METHODS: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. RESULTS: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. CONCLUSIONS: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy.

Epidaily, a scale for comprehensive functional assessment of patients with epilepsy.

OBJECTIVE: To develop and validate an epilepsy-specific scale for comprehensive functional assessment of patients with epilepsy, named Epidaily. METHODS: The multidisciplinary research group created through brainstorming a list of 47 items to explore the cognitive, social, basic and instrumental functionality of the patient. A group of epilepsy experts independent of the research group evaluated the suitability of all the items, which then were selected and reviewed by the research group to conform the Epidaily scale. On a sample of 102 patients, a reliability analysis was performed, as well as a validation one using as reference scale the score on the Activities of Daily Living Questionnaire (ADLQ), which evaluates basic and instrumental functionality. RESULTS: Epidaily consisted of 10 items distributed in four dimensions, with a possible score from 0 to 100 (perfect functionality). Inter-observer reliability was excellent, with an intraclass correlation coefficient of 0.98 (95% confidence interval 0.97-0.99). Criterion validity was demonstrated by the high positive correlation of the Epidaily score with the ADLQ score (Spearman's rho coefficient 0.85, p < 0.001). Significant relation was found between ADLQ and Epidaily in the linear regression analysis (p < 001), which reported that Epidaily explains 85.5% of the variability of ADLQ (R-squared 0.85). Discriminant validity was also proved, as Epidaily allowed to classify epilepsy severity based on Cramer et al epilepsy severity classification. The median time to obtain the Epidaily score was 5 min (interquartile range 4-6). SIGNIFICANCE: Epidaily is a brief and versatile scale, with excellent inter-observer reliability, which has been validated for comprehensive functional assessment of patients with epilepsy.

Mnemonic discrimination in patients with unilateral mesial temporal lobe epilepsy relates to similarity and number of events stored in memory.

Mesial temporal lobe epilepsy (mTLE) is a neurological disorder associated with histopathological changes in different subfields of the hippocampus. These alterations have been associated with memory difficulties. In this study, we tested the hypothesis that these difficulties stem on mnemonic discrimination impairment due to a reduced ability to make similar representations more distinct, leading to an increased susceptibility to interference. With this aim, we used a visual mnemonic discrimination task and evaluated the ability of a group of patients with unilateral mTLE, relative to controls, to discriminate between a studied item and a new foil item, as a function of the similarity between them, and of the number of exemplars from a category stored in memory. We found that patients performed worse than controls when the studied item had to be discriminated from a physically similar new object from the same basic-level category. Crucially, reliable differences between groups were observable in the conditions in which more exemplars from a category were held in memory. In the conditions in which the studied item had to be discriminated from a foil from a different basic-level category, there were no differences between groups, with one exception. Neither a general cognitive impairment nor a general memory impairment could account for this pattern of results. Current findings indicate that patients found more difficulties in conditions with higher interference, which poses greater demands for pattern separation. A disruption of pattern separation processes resulting from hippocampal damage provides a reasonable interpretation for these results. Future studies should explore the causal relationship between hippocampal subfields integrity and mnemonic discrimination capacity in mTLE patients.

Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.

OBJECTIVE: To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS). METHODS: This multicenter, retrospective, observational study was conducted in patients aged ≥12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up. RESULTS: A total of 98 patients (mean age = 49.6 ± 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046). SIGNIFICANCE: PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.

Consensus statement for the management of generalized tonic-clonic seizures in Spain.

OBJECTIVE: To develop recommendations for the management of patients with primary or secondary generalized tonic-clonic seizures (GTCS) based on best evidence and experience. METHODS: The Delphi methodology was followed. A multidisciplinary panel of 10 experts was established, who defined the scope, users and preliminary recommendations. Systematic and narrative reviews of the current literature were performed to assess data on the risk of sudden unexpected death in epilepsy and the efficacy and safety of add-on therapy in patients with GTCS. Twenty-five definitive recommendations were generated which were then graded on a scale of 1 (totally disagree) to 10 (totally agree) by the experts and 45 neurologists. Consensus was reached if at least 70% of the participants applied a score of ≥7. Each recommendation was then assigned a level of evidence, a grade of agreement and a grade of recommendation. The entire process was supervised by an expert methodologist. RESULTS: Overall, 24 out of 25 recommendations achieved consensus. These included specific recommendations on diagnosis, evaluation and treatment. The recommendations also emphasized the importance of proper psychological evaluation and effective communication between patients and health professionals, and the importance of patient and family education and support. SIGNIFICANCE: The recommendations generated by this consensus can be used as a guide for the diagnosis and management of patients with GTCS.

Praxis induction and its relationship with cognition in genetic generalized epilepsy.

INTRODUCTION: Praxis induction (PI) is a reflex trait defined as the precipitation of epileptic discharges (ED) or seizures by cognition-guided tasks that often involve visuomotor coordination and decision-making. This is a characteristic of genetic generalized epilepsy (GGE), and especially of juvenile myoclonic epilepsy (JME). Additionally, several studies have described dysexecutive traits in these patients. Our objective was to analyze PI in the different syndromes of GGE and explore the relationship between PI and cognitive performance. METHODS: Sixty-one adult patients with GGE underwent video-electroencephalograph (EEG) during which a neuropsychological activation protocol (NPAP) was performed: reading, writing, calculations, crosswords, and tangram. Praxis induction was defined by the presence of ED during the NPAP with a persistence of at least twice seen on the basal EEG. All patients also underwent a comprehensive cognitive evaluation. RESULTS: We observed PI in 22 out of 61 patients (36%). Grouped by syndrome, PI was more frequent in adult patients with persistent childhood or juvenile absence epilepsy (JAE, 60%), followed by JME (42.1%) and in a lesser grade in patients with only tonic-clonic generalized seizures (9%). Patients classified as having PI did not obtain worse results in the cognitive evaluation. The presence of ED during the performance of a test was associated with a trend to lower results in that specific test. SIGNIFICANCE: Our study showed a relevant presence of PI in patients whose absence epilepsy persists into adulthood, and not only in JME, the syndrome classically associated with PI. According to our results, PI as a reflex trait does not imply necessarily a poorer cognitive phenotype, but the induction of frequent ED during the tasks could be associated with transient cognitive impairment.

Diagnostic gap in genetic epilepsies: A matter of age.

OBJECTIVE: This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and intellectual disability, with special focus on genetics. METHODS: Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit of two hospitals in Madrid, Spain were included. The main inclusion criterion was an undetermined etiological diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG). RESULTS: Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling the inclusion criteria (mean age: 33.9 years). Regarding the etiological workup, advanced neuroimaging, prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An etiological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age and seizure freedom. CONCLUSIONS: Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older age and seizure freedom seem to be associated with the highest diagnostic gap.