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Objective: Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate., Methods: A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration., Results: The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period., Significance: Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load., Plain Language Summary: Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies., Methods: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE])., Results: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively., Conclusions: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE., (© 2024. The Author(s).)

This analysis assessed the effectiveness and tolerability of brivaracetam (BRV) in older (≥65 years of age) and younger (≥16 to <65 years of age) adults with epilepsy. This was a subgroup analysis from EXPERIENCE/EPD332, a pooled analysis of individual patient records from multiple independent, non-interventional studies of patients with epilepsy starting BRV in Australia, Europe, and the United States. Included patients had ≥6 months of follow-up data. Outcomes included responders (≥50 % reduction from baseline in seizure frequency), seizure freedom (no seizures within 3 months before the time point), and continuous seizure freedom (no seizures from baseline) at 12 months; BRV discontinuation during the whole study follow-up; and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were deemed non-responders/not seizure-free. Analysis populations included the Full Analysis Set (FAS; patients who received ≥1 BRV dose and had seizure type and age documented at baseline) and the modified FAS (FAS patients who had ≥1 seizure recorded during baseline). The FAS was used for all outcomes except seizure reduction. The FAS included 147 (8.9 %) patients aged ≥65 years and 1497 (91.1 %) aged ≥16 to <65 years. Compared with the younger subgroup, patients aged ≥65 years had a longer median epilepsy duration (33.0 years [n = 144] vs 17.0 years [n = 1460]) and lower median seizure frequency at index (2.0 seizures/28 days [n = 129] vs 4.0 seizures/28 days [n = 1256]), and less commonly had >1 prior antiseizure medication (106/141 [75.2 %] vs 1265/1479 [85.5 %]). At 12 months, a numerically higher percentage of patients aged ≥65 years versus the younger subgroup achieved ≥50 % seizure reduction (46.5 % [n = 71] vs 36.0 % [n = 751]), seizure freedom (26.0 % [n = 100] vs 13.9 % [n = 1011]), and continuous seizure freedom (22.0 % [n = 100] vs 10.7 % [n = 1011]). During the whole study follow-up, 43/147 (29.3 %) patients aged ≥65 years and 508/1492 (34.0 %) aged ≥16 to <65 years discontinued BRV. The incidence of TEAEs since the prior visit was similar in both subgroups at 3 months (≥65 years vs ≥16 to <65 years: 38/138 [27.5 %] vs 356/1404 [25.4 %]), 6 months (19/119 [16.0 %] vs 176/1257 [14.0 %]), and 12 months (8/104 [7.7 %] vs 107/1128 [9.5 %]). This real-world analysis suggests BRV was effective in patients aged ≥65 years and ≥16 to <65 years, with numerically higher effectiveness in the older subgroup. BRV was well tolerated in both subgroups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E. Faught has received research funding from Xenon and UCB Pharma, and consulting fees from Aucta, Azurity, Biogen, the Centers for Disease Control and Prevention, LivaNova, Neurelis the State of Georgia, SK Life Science and Trevena, is on the editorial board of the Annals of Neurology and the executive board of The Epilepsy Consortium H. Besson, D. Bourikas, T. Daniels, F. Floricel, and C. Laloyaux are employees of UCB Pharma. W. D’Souza’s salary is part-funded by The University of Melbourne; he has received travel, investigator-initiated, scientific advisory board, and speaker’s honoraria from UCB Pharma Australia & Global; investigator-initiated, scientific advisory board, travel, and speaker’s honoraria from Eisai Australia & Global; advisory board honoraria from LivaNova and Tilray; educational grants from Novartis, Pfizer, and Sanofi-Synthélabo; educational, travel, and fellowship grants from GSK Neurology Australia; and honoraria from SciGen Pharmaceuticals; he has an equity interest in the device company EpiMinder. P. Klein has served as a consultant for Abbott, Arvelle Therapeutics, Neurelis, and SK Life Science; as a consultant, advisory board member, and speaker for Aquestive, Eisai, Sunovion, and UCB Pharma; is a member of the medical advisory board of Stratus and the scientific advisory board of OB Pharma; is the CEO of PrevEp; and has received research support from CURE and Department of Defense/Lundbeck. M. Reuber receives payment from Elsevier as editor-in-chief of Seizure; and has received research grants and speaker’s fees from Eisai, LivaNova, and UCB Pharma. F. Rosenow reports personal fees from Angelini Pharma, Arvelle Therapeutics, Eisai GmbH, and GW Pharmaceuticals; personal fees and other from Novartis; personal fees and grants from UCB Pharma; and grants from the Detlev-Wrobel-Fonds for Epilepsy Research Frankfurt, Deutsche Forschungsgemeinschaft, the European Union, and the State of Hessen outside the submitted work. J. Salas-Puig has received grants from Bial and UCB Pharma; and reports personal fees from Bial, Eisai, Esteve, Sanofi, and UCB Pharma outside the submitted work. V. Soto Insuga has received speaker honoraria from Bial, Eisai, and UCB Pharma. B.J. Steinhoff has received speaker’s honoraria from Al-Jazeera, Desitin, Eisai, GW Pharmaceuticals, Hikma, Novartis, Sandoz, and UCB Pharma; and has served as a consultant for Arvelle Therapeutics, B. Braun, Bial, Desitin, Eisai, GW Pharmaceuticals, and UCB Pharma. A. Strzelczyk reports personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, GW/Jazz Pharmaceuticals, Marinus Pharma, Precisis, Takeda, UCB Pharma, UNEEG medical, and Zogenix. He is editor-in-chief of Clinical Epileptology and section editor of Neurological Research and Practice. J.P. Szaflarski has received research funding from Biogen, the Department of Defense, Eisai, GW Pharmaceuticals companies, National Institutes of Health, National Science Foundation, NeuroPace, Serina Therapeutics, Shor Foundation for Epilepsy Research, State of Alabama General Funds, and UCB Pharma; has served as a consultant or advisory board member for Elite Medical Experts, GW Pharmaceuticals, LivaNova, Lundbeck, Medical Association of the State of Alabama, NeuroPace, Serina Therapeutics, SK Life Science, and UCB Pharma; has served as an investigator on GW Research Ltd trials; and is an editorial board member for Epilepsy & Behavior, Epilepsy & Behavior Reports (associate editor), Epilepsy Currents (contributing editor), Folia Medica Copernicana, Journal of Epileptology (associate editor), and Journal of Medical Science. D. Friesen is an independent contractor for UCB Pharma. V. Villanueva has served as a consultant or on an advisory board for Arvelle Therapeutics, Bial, Eisai, Esteve, GW Pharmaceuticals, Novartis, and UCB Pharma; has received research grants from Bial, Eisai, and UCB Pharma; and has received speaker’s honoraria from Bial, Eisai, Esteve, GW Pharmaceuticals, Novartis, and UCB Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim was to examine the effect of polytherapy (i.e., the number of administered anti-seizure medications (ASMs)) on memory, and whether the interaction between the number of ASMs and attentional/executive functioning affect presurgical memory functioning and postsurgical memory changes in patients with drug-resistant epilepsy., Methods: Two studies were carried out. Study 1 consisted of a presurgical assessment of 125 adult patients, in which attention/executive function (EpiTrack screening tool) and memory were assessed (cross-sectional study). Of them, 72 patients underwent a second postsurgical evaluation, in which memory was assessed (Study 2). Patients were distributed into groups based on EpiTrack performance and number of ASMs., Results: The interaction between the number of ASMs and the attentional/executive functioning significantly affected presurgical memory, with patients with impaired EpiTrack performance taking three-four ASMs having poorer scores than patients with intact EpiTrack performance taking three-four ASMs (for all, p < .0001). This interaction also affected postsurgical memory changes, with patients with impaired Epitrack performance taking three-four ASMs having higher postsurgical decline than those with intact Epitrack performance taking three-four ASMs (for all, p < .005). No differences were found in patients taking two ASMs. Furthermore, the number of ASMs was associated with presurgical memory performance and postsurgical memory changes only in patients with impaired EpiTrack performance (for all, p < .05)., Conclusions: Our findings underline the utility of EpiTrack, together with the clinical information on the number of prescribed ASMs, to corroborate the impact of polytherapy on memory and to optimize the prediction of postsurgical memory changes., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit [last observation carried forward) and tolerability (adverse events [AEs]). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER's known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP)., Method: This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation., Results: The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness., Significance: In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency., Purpose: This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE., Methods: The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option., Results: In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose., Conclusions: Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VV has participated in advisory boards and industry-sponsored symposia by Angelini, Bial, Eisai Inc, Jazz Pharmaceuticals, Novartis, Takeda, UCB Pharma, and Zogenix. JMS has received research grants or honoraria as speaker or participant in advisory boards from Angelini, BIAL, Eisai Inc, Esteve, Ferrer, Jazz Pharmaceuticals, GW Pharmaceuticals, Sanofi, UCB Pharma, and Zogenix for participation in advisory boards or pharmaceutical industry-sponsored symposia. MT has participated in DRE clinical trials with different ASMs development and reports receiving consulting fees from Angelini, Bial, Eisai Inc, GSK, GW Pharmaceuticals, and UCB Pharma. MAC has received honoraria for participating in advisory boards/consultancy from Angelini, Amgen, Janssen, Pfizer, Roche, Novartis, Alexion, Lilly, Bayer, AstraZeneca, Galápagos, BMS, Almirall, UCB, MSD, Abbvie, Mylan, Sanofi, Teva. AN has received honoraria for presentations and advisory boards from Angelini, GSK, Bristol, MSD, Pfizer, and ASTRA and a congresses registration fee from Janssen. JS, PPD, and EAB are employees of Angelini. SS and AG are employees of Omakase Consulting S.L. which receive funding from Angelini to develop this study., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Up to 10% of people living to 80 years of age have one or more seizures; and many will not require anti-seizure medication (ASMs). In 85% of patients, the diagnosis comes from the history of the index event. One-third of patients with an apparent "first seizure" have previous events, changing their diagnosis to epilepsy. Targeted investigations are important for classification and risk prediction. Patients with a low risk of seizure recurrence are not usually offered ASM treatment. High-risk patients have multiple seizures, neurological deficits, intellectual disability and/or relevant abnormal investigations; and are offered ASMs. Individual factors modulate this decision-making. Future integrated technologies offer the game-changing potential for seizure monitoring and prediction, but are not yet robust, convenient or affordable. Therapeutic drug monitoring in patients taking ASMs may confirm ASM toxicity, or when non-adherence, malabsorption, or rapid metabolism are suspected causes of breakthrough seizures. They are less useful when these factors are intermittent or irregular. Current evidence does not favour routine monitoring of serum levels, as it neither reliably predicts control, relapse, or adverse effects. The decision to discontinue ASM should follow a full discussion with the patient of risks and benefits. Along with population risk factors for seizure recurrence, the patient's lifestyle and preferences must be considered. ASM are usually discontinued in a slow step-wise fashion, one at a time, after at least two years of remission. Seizure recurrence risk plateaus only after 2 years following ASM discontinuation, and patients need access to specialist follow-up over that period., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS)., Methods: Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts., Results: The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment., Conclusions: This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J Eric Piña-Garza has served as an advisor and speaker for Aquestive, Eisai, Jazz/Greenwich Biosciences, Neurelis, SK Life Science, Sunovion, Supernus, and UCB Pharma. Vicente Villanueva has participated in advisory boards and pharmaceutical-industry–sponsored symposia for Angellini, Arvelle, Bial, Eisai, Esteve, GW Pharmaceuticals, Novartis, Pfizer, Takeda, UCB Pharma, and Zogenix. William Rosenfeld has served on the speaker’s bureau for Eisai, Greenwich Biosciences, SK Life Science, Sunovion, and UCB Pharma, has received research support from GW Pharmaceuticals, Marinus, Medtronic, SK Life Science, Takeda, UCB Pharma, and Upsher-Smith, and is a consultant for SK Life Science. Kazunori Saeki is an employee of Eisai Co., Ltd. Harumi Yoshinaga has served as the chairman of the appropriate use committee for Sabril; as a consultant for Sanofi; and as a speaker for Eisai, Takeda, and UCB Japan. Anna Patten is an employee of Eisai Europe Ltd. Manoj Malhotra is a former employee of Eisai Inc., (Copyright © 2022. Published by Elsevier Inc.)

Background and Objectives: To evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate (CNB) in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study., Methods: Patients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n = 360) could enter the OLE, where they underwent a 2-week blinded conversion to CNB (target dose, 300 mg/d; min/max, 50/400 mg/d)., Results: Three hundred fifty-five patients were included in the OLE safety population (265 originally randomized to CNB, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% of patients (209/355) were continuing CNB treatment and 141 had discontinued, including 16.6% (59/355) because of lack of efficacy, 8.7% (31/355) because of withdrawal by patient, and 7.6% (27/355) because of adverse events. The median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE modified intent-to-treat population, 10.2% of patients (36/354) achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% of patients (72/355)., Discussion: Long-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of CNB treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of CNB., Classification of Evidence: This study provides Class IV evidence that oral CNB 50-400 mg/d is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1-3 ASMs., Trial Registration Information: ClinicalTrials.gov NCT01866111 (clinicaltrials.gov/ct2/show/results/NCT01866111)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study., Methods: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs., Results: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months., Conclusion: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice., (Copyright © 2022. Published by Elsevier Ltd.)

The PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study was a pooled analysis of data from 44 real-world studies from 17 countries, in which people with epilepsy (PWE; focal and generalized) were treated with perampanel (PER). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness assessments included 50% responder rate (≥ 50% reduction in seizure frequency from baseline) and seizure freedom rate (no seizures since at least the prior visit); in PWE with status epilepticus, response was defined as seizures under control. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. The Full Analysis Set included 5193 PWE. Retention, effectiveness and safety/tolerability were assessed in 4721, 4392 and 4617, respectively. Retention on PER treatment at 3, 6, and 12 months was 90.5%, 79.8%, and 64.2%, respectively. Mean retention time on PER treatment was 10.8 months. The 50% responder rate was 58.3% at 12 months and 50.0% at the last visit, and the corresponding seizure freedom rates were 23.2% and 20.5%, respectively; 52.7% of PWE with status epilepticus responded to PER treatment. Overall, 49.9% of PWE reported AEs and the most frequently reported AEs (≥ 5% of PWE) were dizziness/vertigo (15.2%), somnolence (10.6%), irritability (8.4%), and behavioral disorders (5.4%). At 12 months, 17.6% of PWEs had discontinued due to AEs. PERMIT demonstrated that PER is effective and generally well tolerated when used to treat people with focal and/or generalized epilepsy in everyday clinical practice., (© 2021. The Author(s).)

Objective: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome., Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated., Results: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients., Significance: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: To understand the currently available post-marketing real-world evidence of the incidences of and discontinuations due to the BAEs of irritability, anger, and aggression in people with epilepsy (PWE) treated with the anti-seizure medications (ASMs) brivaracetam (BRV), levetiracetam (LEV), perampanel (PER), and topiramate (TPM), as well as behavioral adverse events (BAEs) in PWE switching from LEV to BRV., Methods: A systematic review of published literature using the Cochrane Library, PubMed/MEDLINE, and Embase was performed to identify retrospective and prospective observational studies reporting the incidence of irritability, anger, or aggression with BRV, LEV, PER, or TPM in PWE. The incidences of these BAEs and the rates of discontinuation due to each were categorized by ASM, and where possible, weighted means were calculated but not statistically assessed. Behavioral and psychiatric adverse events in PWE switching from LEV to BRV were summarized descriptively., Results: A total of 1500 records were identified in the searches. Of these, 44 published articles reporting 42 studies met the study criteria and were included in the data synthesis, 7 studies were identified in the clinical trial database, and 5 studies included PWE switching from LEV to BRV. Studies included a variety of methods, study populations, and definitions of BAEs. While a wide range of results was reported across studies, weighted mean incidences were 5.6% for BRV, 9.9% for LEV, 12.3% for PER, and 3.1% for TPM for irritability; 3.3%* for BRV, 2.5% for LEV, 2.0% for PER, and 0.2%* for TPM for anger; and 2.5% for BRV, 2.6% for LEV, 4.4% for PER, and 0.5%* for TPM for aggression. Weighted mean discontinuation rates were 0.8%* for BRV, 3.4% for LEV, 3.0% for PER, and 2.2% for TPM for irritability and 0.8%* for BRV, 2.4% for LEV, 9.2% for PER, and 1.2%* for TPM for aggression. There were no discontinuations for anger. Switching from LEV to BRV led to improvement in BAEs in 33.3% to 83.0% of patients (weighted mean, 66.6%). *Denotes only 1 study., Conclusions: This systematic review characterizes the incidences of irritability, anger, and aggression with BRV, LEV, PER, and TPM, and it provides robust real-world evidence demonstrating that switching from LEV to BRV may improve BAEs. While additional data remain valuable due to differences in methodology (which make comparisons difficult), these results improve understanding of the real-world incidences of discontinuations due to these BAEs in clinical practice and can aid in discussions and treatment decision-making with PWE., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Following publication in 2014 of the International League Against Epilepsy (ILAE) official report changing the definition of epilepsy, a number of questions remain unresolved in regard to deciding when to start treatment and to the choice of a particular antiseizure medication (ASM). This study uses a Delphi method to update consensus among a panel of experts on the initiation of epilepsy treatment in order to provide insight regarding those questions. The study was undertaken in four phases. Firstly, a multi-center steering committee met to review relevant bibliography and to draft a questionnaire. Secondly, a panel of neurologists specialized in epilepsy was selected and convened. Thirdly, an online survey was carried out in two rounds. Fourthly, the final results were discussed at a face-to-face meeting of the steering committee to draw conclusions. The final questionnaire focused on three independent sections: the decision to commence ASM in different clinical situations, the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex (including childbearing potential), and the choice of initial monotherapy depending on comorbidity. In these two latter sections, fourteen ASMs approved for monotherapy use by the EMA and available in Spain were considered. Regarding the decision as to when to commence treatment, the results show agreement exists to initiate treatment following a first generalized tonic-clonic seizure or a focal seizure if the electroencephalography (EEG) reveals epileptiform activity, if the MRI reveals a lesion, or when it occurs in elderly patients. With respect to the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex profile, it is agreed to avoid valproic acid (VPA) in women with childbearing potential, with levetiracetam (LEV) and lamotrigine (LTG) being the preferable options in generalized epilepsy. In focal epilepsy, the options are broader, particularly in men, and include the most recent ASMs approved for monotherapy. In the elderly, LEV, lacosamide (LCM), eslicarbazepine acetate (ESL) and LTG are considered the most suitable drugs for initiating treatment. With regard to comorbidities, the recommendation is to avoid enzyme inducing ASMs, with LEV, the most recent ASMs approved for monotherapy and LTG being the preferred options. In conclusion, as the ILAE definition states, there are different situations that lead to treatment initiation after a first seizure. When choosing the first ASM, the type of epilepsy, childbearing potential and drug-drug interaction are key factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients included in the Euro-Esli study who had focal seizures associated with post-stroke epilepsy (PSE)., Materials and Methods: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments (evaluated after 3, 6 and 12 months of ESL treatment and at final follow-up ["last visit"]) included rates of response (≥50% seizure frequency reduction), seizure freedom (no seizures since at least the prior visit) and retention. Safety/tolerability was assessed throughout ESL treatment by evaluating adverse events (AEs) and discontinuation due to AEs. A post hoc analysis was conducted of patients with PSE versus patients without PSE ("non-PSE")., Results: Of 1656 patients included in the analysis, 76 (4.6%) had PSE and 1580 (95.4%) had non-PSE. Compared with non-PSE patients, PSE patients were significantly older, had significantly shorter epilepsy duration, significantly lower total baseline seizure frequency, and were treated with significantly fewer prior and concomitant antiepileptic drugs (P < .001 for all). At the last visit, the responder rate was significantly higher in PSE versus non-PSE patients (72.9% vs 60.6%; P = .040), as was the seizure freedom rate (48.6% vs 31.7%; P = .003). After 12 months, retention was significantly higher in PSE versus non-PSE patients (87.8% vs 77.4%; P = .035). The incidence of AEs was similar for PSE versus non-PSE patients (36.0% vs 35.8%; P = .966)., Conclusions: These findings suggest that ESL may be an effective and well-tolerated treatment option for patients with focal seizures due to PSE., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This post hoc analysis of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2-12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic-clonic (PGTC) seizures., Methods: Adolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs)., Results: The Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients., Conclusions: Adjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy., Competing Interests: Declaration of competing interest J Eric Piña-Garza has served as an advisor for Sunovion and UCB Pharma, as a speaker for Aquestive, Eisai, Greenwich Biosciences, Supernus, Sunovion, and UCB Pharma, and as an advisor and speaker for Eisai, Lundbeck, and Supernus. William Rosenfeld has served on the speaker's bureau for Eisai, Greenwich Biosciences, Sunovion, and UCB Pharma, has received research support from GW Pharmaceuticals, Marinus, Medtronic, SK Life Science, Takeda, UCB Pharma (near completion), and Upsher-Smith, and is a consultant for SK Life Science. Kazunori Saeki is an employee of Eisai Co., Ltd. Vicente Villanueva has participated in advisory boards and pharmaceutical-industry–sponsored symposia for Bial, Eisai, Esteve, GlaxoSmithKline, GW Pharmaceuticals, Medtronic, Novartis, Pfizer, and UCB Pharma. Harumi Yoshinaga has no disclosures to make in relation to this work. Anna Patten is an employee of Eisai Ltd. Betsy Williams is a former employee of Eisai Inc. and has carried out consultancy work for Eisai Inc. Manoj Malhotra is an employee of Eisai Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the efficacy, safety and tolerability of eslicarbazepine acetate (ESL) in patients transitioning from carbamazepine or oxcarbazepine to ESL in clinical practice, by analysing data from the Euro-Esli study., Methods: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness assessments included responder rate (≥50 % seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit), assessed after 3, 6 and 12 months of ESL treatment, and at the last visit. Safety and tolerability were assessed throughout follow-up by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Data were analysed for cohorts of patients who transitioned from carbamazepine and oxcarbazepine to ESL either due to lack of efficacy or poor tolerability., Results: Euro-Esli included 2058 patients, of whom 233 (11.3 %) transitioned from carbamazepine to ESL and 134 (6.5 %) transitioned from oxcarbazepine to ESL. After 12 months of ESL treatment, responder and seizure freedom rates for patients transitioning from carbamazepine due to lack of efficacy (n = 163) were 70.0 % and 30.9 %, respectively. Corresponding values for patients transitioning from oxcarbazepine due to lack of efficacy (n = 90) were 57.1 % and 25.0 %, respectively. Among patients who transitioned from carbamazepine and oxcarbazepine to ESL due to poor tolerability (n = 64 and n = 61, respectively), 26.6 % and 39.5 % experienced AEs, and 8.3 % and 6.8 % discontinued ESL due to AEs, respectively., Conclusion: ESL was efficacious and generally well tolerated in patients transitioning from carbamazepine or oxcarbazepine in clinical practice due to inadequate seizure control or intolerable AEs with these agents., Competing Interests: Declaration of Competing Interest RR is a consultant for Eisai, Bial, UCB, GlaxoSmithKline and Shire, and receives grant and research support from Bial, Eisai, and UCB. JP has participated in clinical trials for Eisai, UCB, and Bial; received research grants from Eisai, Medtronic, UCB, and Cyberonics; received speaker honoraria from Cyberonics, Eisai, Medtronic, Orion Pharma, and UCB; received support for travel to congresses from Cyberonics, Eisai, Medtronic, and UCB; and participated in advisory boards for Cyberonics, Eisai, Medtronic, UCB, and Pfizer. GA has no conflicts of interest. RM is a current employee of Eisai Europe Ltd. VV has participated in advisory boards and pharmaceutical industry-sponsored symposia for Eisai, UCB Pharma, Bial, Pfizer, GSK, Esteve, Novartis and GW Pharma., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: The aim of the study was to evaluate the effectiveness and tolerability of eslicarbazepine acetate (ESL) when used as monotherapy for 1 year or more in routine clinical use in patients with focal seizures in epilepsy clinics in Spain., Methods: This is a retrospective, observational, noninterventional study. Eligible patients were aged ≥18 years, had focal seizures, and started on ESL ≥1 year before database closure. Primary endpoint was the following: proportion seizure-free for ≥6 months at 1 and 2 years. Secondary endpoints included retention on ESL monotherapy at 1 and 2 years, seizure frequency change, seizure worsening, and side effects. Other analyses included seizure freedom from baseline to 1 and 2 years and outcomes in special populations., Results: Four hundred thirty-five patients were included (127 on first-line monotherapy and 308 converting to ESL monotherapy): median daily dose was 800 mg at all time points; 63.2% were seizure-free at 1 year, 65.1% at 2 years, and 50.3% for the entire follow-up. Mean duration of ESL monotherapy was 66.7 months; retention was 88.0% at 1 year and 81.9% at 2 years. Mean reduction in seizure frequency was 75.5% at last visit. Over the entire follow-up, seizure worsening was seen in 22 patients (5.1%), side effects in 28.0%, considered severe in 1.8%, and leading to discontinuation in 5.7%. Dizziness, hyponatremia (sodium <135 mEq/l), and somnolence were the most frequent side effects. Outcomes in special populations (patients aged ≥65 years and those with psychiatric history or learning difficulty) were consistent with the overall population., Conclusions: Patients with focal seizures taking ESL monotherapy had excellent retention, high seizure-free rates, and good tolerability up to 2 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Psychiatric and intellectual comorbidities are common in patients with epilepsy. However, data on the use of antiepileptic drugs in these patients are still lacking. This study assessed the real-world effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) in patients with intellectual disability and psychiatric comorbidities, including a separate analysis specifically in those with depression, using data from the Euro-Esli study. Effectiveness measures included responder and seizure freedom rates. Safety and tolerability were assessed by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Of the 2058 patients initially included in the Euro-Esli study, 952 patients had intellectual disability data available, 1138 had psychiatric comorbidity data available and 1134 had depression data available. Of those who had intellectual or psychiatric comorbidity data available, 11.3% (108/952) suffered from intellectual disability, 24.9% (283/1138) had a psychiatric disorder, including depression, and 12.4% (141/1134) specifically had depression. Responder and seizure freedom rates were generally comparable between patients with psychiatric comorbidity and those without, and patients with depression and those without. However, responder and seizure freedom rates were significantly lower in patients with intellectual disability compared with those without. Overall, patients with psychiatric and intellectual comorbidities experienced more AEs and AEs leading to ESL discontinuation than patients without these comorbidities. The incidence of psychiatric AEs was not significantly different for patients with psychiatric comorbidities or depression than those without, and the incidence of cognitive AEs was not significantly different for patients with intellectual disability than those without. These findings suggest that ESL is effective in patients with psychiatric and intellectual comorbidities and that its use in these patients is unlikely to exacerbate existing psychiatric or cognitive disturbances., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Evaluate long-term effectiveness and tolerability of brivaracetam in clinical practice in patients with focal epilepsy., Materials and Methods: This was a multicenter retrospective study. Patients aged ≥16 years were started on brivaracetam from November 2016 to June 2017 and followed over 1 year. Data were obtained from medical records at 3, 6 and 12 months after treatment initiation for evaluation of safety- and seizure-related outcomes., Results: A total of 575 patients were included in analyses; most had been treated with ≥4 lifetime antiepileptic drugs. Target dosage was achieved by 30.6% of patients on the first day. Analysis of primary variables at 12 months revealed that mean reduction in seizure frequency was 36.0%, 39.7% of patients were ≥50% responders and 17.5% were seizure-free. Seizure-freedom was achieved by 37.5% of patients aged ≥65 years. Incidence of adverse events (AEs) and psychiatric AEs (PAEs) was 39.8% and 14.3%, respectively, and discontinuation due to these was 8.9% and 3.7%, respectively. Somnolence, irritability, and dizziness were the most frequently reported AEs. At baseline, 228 (39.7%) patients were being treated with levetiracetam; most switched to brivaracetam (dose ratio 1:10-15). Among those who switched because of PAEs (n = 53), 9 (17%) reported PAEs on brivaracetam, and 3 (5.7%) discontinued because of PAEs. Tolerability was not highly affected among patients with learning disability or psychiatric comorbidity., Conclusions: In a large population of patients with predominantly drug-resistant epilepsy, brivaracetam was effective and well-tolerated; no unexpected AEs occurred over 1 year, and the incidence of PAEs was lower compared with levetiracetam., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe., Materials and Methods: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy., Results: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue., Conclusions: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal-onset seizures, complementing evidence from clinical trials., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To pool observational data on the routine use of perampanel to obtain information on real-world outcomes and data in populations typically underrepresented in clinical trials., Methods: Individual-level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1-year retention rate, 1-year seizure freedom rate (duration ≥6 months), and incidence of treatment-emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses., Results: The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27 years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One-year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46-50%), and 1-year seizure-free rate (≥6-month duration) was 9.2% (74/803; 95% CI 7-11%). Median treatment duration was 11.3 months (1832 patient-years); median dose was 8 mg. In 388 individuals with available data at 3, 6, and 12 months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66-70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure-free rate, and higher number of prior AEDs with lower seizure-free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65 years, 1-year retention rate was 48% and seizure-free rate was 28%., Significance: Across a large, treatment-resistant population, add-on perampanel was retained for ≥1 year by 48% of individuals, and 9% were seizure-free for ≥6 months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE)., Methods: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included., Results: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent., Significance: In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: The aim of this study was to evaluate long-term effects of adjunctive perampanel on cognition, efficacy, growth, safety, and tolerability in adolescents with inadequately controlled partial seizures., Methods: Study 235, a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II study with an open-label extension phase (NCT01161524), was primarily designed to assess the effects of adjunctive perampanel on cognition. Patients (aged ≥12 to <18years) had a diagnosis of epilepsy with inadequately controlled partial seizures, with or without secondary generalization, despite receiving 1-3 antiepileptic drugs. During the double-blind phase, adjunctive perampanel or placebo was administered over a 6-week titration period and a 13-week maintenance period up to 12mg/day. During the extension phase, all patients received perampanel. Data from the extension phase are presented here. Study endpoints included change from baseline in Cognitive Drug Research (CDR) measures of cognition, seizure frequency, growth, development, the occurrence of treatment-emergent adverse events (TEAEs), and laboratory values., Results: A total of 114 patients entered the extension phase (prior double-blind treatment: placebo, n=41; perampanel, n=73). Perampanel had no effect on the CDR system global cognition score, continuity of attention, quality of episodic memory, quality of working memory, or speed of memory but was associated with a significant decline in power of attention at end of treatment compared with baseline (p=0.03). There were no effects on language skills or manual dexterity from baseline to end of treatment. At Weeks 40-52, median reduction in seizure frequency was 74.1%, and 50% responder rate was 66.0%. There were no clinically relevant effects of perampanel on growth or development at end of treatment compared with baseline. Overall, 84.2% of patients experienced at least one TEAE and 70.2% experienced at least one treatment-related TEAE. The most common TEAEs were dizziness (29.8%) and somnolence (19.3%). The TEAEs resulted in the discontinuation of treatment in 6.1% of patients., Conclusions: In keeping with the 19-week double-blind phase, long-term adjunctive treatment with perampanel did not have any significant overall effects on the CDR system global cognition score in adolescent patients with inadequately controlled partial seizures. Similar trends were observed across the individual CDR system domains. Adjunctive perampanel showed sustained long-term seizure control and had a safety and tolerability profile similar to that observed in prior clinical studies., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy., Methods: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period., Results: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations., Conclusions: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).

Introduction: Stimulation-evoked focal to bilateral tonic-clonic seizure (FBTCS) can be a stressful and possibly harmful adverse event for patients during cortical stimulation (CS). We evaluated if drug load reduction of antiepileptic drugs (AEDs) during CS increases the risk of stimulation-evoked FBTCS., Material and Methods: In this retrospective cohort study, we searched our local database for patients with drug-resistant epilepsy who underwent invasive video-EEG monitoring and CS in the University Hospital la Fe Valencia from January 2006 to November 2016. The AED drug load was calculated with the defined daily dose. We applied a uni- and multivariate logistic regression model to estimate the risk of stimulation-evoked FBTCS and evaluate possible influencing factors. Furthermore, we compared patients whose AEDs were completely withdrawn with those whose AEDs were not., Results: Fifty-eight patients met the inclusion criteria and were included in the analysis. Stimulating 3806 electrode contact pairs, 152 seizures were evoked in 28 patients (48.3%). Ten seizures (6.6%) in seven patients (12.1%) evolved to FBTCS. In the univariate and multivariate analysis, a 10% reduction in drug load was associated with an increase of the odds ratio (OR) of stimulation-evoked FBTCS by 1.9 (95%-CI 1.2, 4.0, p-value=0.04) and 1.9 (95%-CI 1.2, 4.6, p-value=0.04), respectively. In patients, whose AEDs were completely withdrawn the OR of FBTCS increased by 9.1 (95%CI 1.7, 69.9, p-value=0.01) compared with patients whose AEDs were not completely withdrawn. No other factor (implantation type, maximum stimulus intensity, number of stimulated contacts, history of FBTCS, age, gender, or epilepsy type) appears to have a significant effect on the risk of stimulation-evoked FBTCS., Conclusions: The overall risk of stimulation-evoked FBTCS during CS is relatively low. However, a stronger reduction and, especially, a complete withdrawal of AEDs are associated with an increased risk of stimulation-evoked FBTCS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Pooled evaluation of the key efficacy and safety profile of eslicarbazepine acetate (ESL) added-on to stable antiepileptic therapy in adults with focal-onset seizures., Methods: Data from 1703 patients enrolled in four phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2 week titration period, ESL was administered at 400 mg, 800 mg, and 1200 mg once-daily doses for 12 weeks (maintenance period). Pooled efficacy variable was standardized (/4 weeks) seizure frequency (SSF) analyzed over the maintenance period as reduction in absolute and relative SSF and proportion of responders (≥50% reduction in SSF). Pooled safety was analyzed by means of adverse events and clinical laboratory assessments., Results: SSF was significantly reduced with ESL 800 mg (P < 0.0001) and 1200 mg (P < 0.0001) compared to placebo. Median relative reduction in SSF was 33.4% for ESL 800 mg and 37.8% for 1200 mg (placebo: 17.6%), and responder rate was 33.8% and 43.1% (placebo: 22.2%). ESL was more efficacious than placebo regardless of gender, geographical region, epilepsy duration, age at time of diagnosis, seizure type, and type of concomitant antiepileptic drugs (AED). Incidence of adverse events (AEs) and AEs leading to discontinuation was dose dependent. Most common AEs (>10% patients) were dizziness, somnolence, and nausea. The incidence of treatment-emergent AEs (dizziness, somnolence, ataxia, vomiting, and nausea) was lower in patients who began taking ESL 400 mg (followed by 400 mg increments to 800 or 1200 mg) than in those who began taking ESL 600 mg or 800 mg., Conclusions: Once-daily ESL 800 mg and 1200 mg showed consistent results across all efficacy and safety endpoints, independent of study population characteristics and type of concomitant AEDs. Treatment initiated with ESL 400 mg followed by 400 mg increments to 800 or 1200 mg provides optimal balance of efficacy and tolerability., (© 2017 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

The Euro-Esli study was an exploratory pooled analysis of data from 14 European clinical practice studies, which was conducted to audit the real-world effectiveness, safety, and tolerability of eslicarbazepine acetate (ESL) as an adjunctive treatment for partial-onset seizures. Retention and effectiveness were assessed after 3, 6, and 12 months of ESL treatment, and at the final visit. Safety and tolerability were assessed throughout ESL treatment by evaluating adverse events (AEs) and ESL discontinuation due to AEs. Data from 2058 patients (52.1% male; mean age 44.0 years) were included. All 2058 patients were assessed for safety and 1975 (96.0%) patients were assessed for effectiveness. After 12 months, retention, responder (≥50% seizure frequency reduction), and seizure freedom rates were 73.4, 75.6, and 41.3%, respectively. AEs were reported for 34.0% of patients and led to discontinuation in 13.6% of patients. The most frequently reported AEs were dizziness (6.7% of patients), fatigue (5.4%), and somnolence (5.1%). No unexpected safety signals emerged over a median duration of follow-up of >5 years. Subgroup analyses revealed that ESL was significantly more effective in patients aged ≥65 versus <65 years, in patients who were not receiving treatment with other sodium channel blockers versus those who were receiving treatment with other sodium channel blockers, and in patients who were receiving <2 versus ≥2 concomitant antiepileptic drugs at baseline. Euro-Esli is the largest ESL clinical practice study conducted to date. This study provides strong and reassuring evidence of ESL's safety profile, and complements the data from clinical trials.

Background: The choice of antiepileptic drug (AED) therapy in patients with brain tumor-related epilepsy (BTRE) is complicated, and there are a lack of robust clinical trial data to date., Methods: The NEOPLASM (Neuroncologic Patients treated with LAcoSaMide) study was a 6-month, multicenter, retrospective, observational study in patients with BTRE treated with lacosamide. Patients were started on lacosamide because of a lack of efficacy or adverse events (AEs) with prior AEDs or suitability versus other AEDs, according to clinical practice. The primary efficacy variable was the seizure-free rate at 6months. Safety variables included the proportion of patients with an AE and the proportion with an AE that led to discontinuation., Results: Overall, 105 patients from 14 hospital centers were included in the analysis. Treatment with lacosamide for 6months resulted in a 30.8% seizure-free rate, and 66.3% of patients had a ≥50% seizure reduction (responders). In the subset of patients included because of a lack of efficacy with prior AEDs, seizure-free rates were 28.0%, and 66.7% of patients were responders. No statistically significant differences in efficacy were observed according to the mechanism of action or enzyme-inducing properties of concomitant AEDs. Adverse events were reported by 41.9% of patients at 6months, and 4.7% of them led to discontinuation. The most common AEs were somnolence/fatigue and dizziness. Notably, 57.1% of the patients who were switched to lacosamide because of AEs with their previous therapy did not report any AE at 6-month follow-up., Conclusions: In this open-label, observational study, lacosamide appeared to be effective and well tolerated in a large population of patients with BTRE. Lacosamide may therefore be a promising option for the treatment of patients with BTRE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To characterize, in adolescents aged 12-17, the pharmacokinetic (PK) profile of perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between perampanel exposure and cognitive function, seizure frequency, and responder status., Methods: Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1-3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or perampanel (8-12mg/day) for 19 weeks, pooled with data from adolescent patients in perampanel Phase III studies 304, 305, 306. Exposure-cognition and exposure-efficacy relationships were modelled using data from study 235., Results: Population PK results from 152 adolescent patients revealed a perampanel apparent clearance of 0.729L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n=110) showed that increasing perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n=123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as perampanel concentration increased - both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent., Significance: Pharmacokinetics of perampanel are similar in adolescents to adults. Increasing perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel was shown in phase III trials to be an effective and well-tolerated adjunctive treatment for partial-onset seizures. In adolescents, it is necessary to characterize cognitive, neuropsychological, and behavioral side effects of antiepileptic drugs (AEDs). The current analysis focuses on behavioral outcomes, efficacy, and safety of perampanel in adolescents., Methods: Adolescents (12-17 years) on a stable regimen of 1-3 AEDs for partial-onset seizures were randomized (2:1 ratio) to receive up to 12 mg/day perampanel or placebo. Alongside efficacy, cognitive, and neuropsychological assessments, behavioral outcomes were measured with the Child Behavior Checklist (CBCL) before and after a 19-week titration and maintenance phase., Results: Of the randomized patients, 85 received perampanel and 48 received placebo. Median reduction in seizure frequency from baseline was 58.0% for perampanel and 24.0% for placebo (p = 0.079). More patients had seizure frequency reduced by 50% after perampanel (n = 49 [59.0%]) than placebo (n = 17 [37.0%]; p = 0.0144). Changes in behavior were minimal, and there were no differences between groups on competency (p = 0.619) or problems (p = 0.174). A greater proportion of placebo patients were classified in the CBCL "clinical" range for competency at end of treatment, whereas the number in the perampanel group remained unchanged. The overall safety profile was similar to that reported previously for perampanel; most frequently reported adverse events (AEs) were dizziness (26 patients [30.6% vs. 14.6% placebo]), somnolence (13 patients [15.3% vs. 4.2%]), and headache (nine patients [10.6% vs. 14.6%]). Aggression was reported in seven patients receiving perampanel (8.2% vs. 2.1% placebo); two of these were serious AEs, with neither requiring treatment discontinuation., Significance: Adjunctive perampanel is efficacious and well tolerated in adolescents with partial-onset seizures, and appears to have no clinically important impact on behavior measured using the CBCL., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background and Objectives: Many patients with epilepsy are treated with antiepileptic drug (AED) polytherapy. Several factors influence the choice of early add-on therapy, and deciding on the most appropriate drug can be difficult. This study aimed to assess the efficacy and tolerability of lacosamide as early add-on therapy in patients with partial-onset seizures., Methods: REALLY (REtrospective study of lAcosamide as earLy add-on aLong one Year) was a multicenter, retrospective, 1-year, real-life study. Patients included were aged older than 16 years, had partial-onset seizures, and were treated with lacosamide as add-on therapy after one or two prior AEDs. Data were collected retrospectively from clinical records. The primary study objective was to assess the efficacy of lacosamide over 12 months (seizure-free and responder rates), and the secondary objective was to assess the tolerability of lacosamide at 3, 6, and 12 months [adverse events (AEs) and discontinuation]., Results: One hundred and ninety-nine patients were enrolled in the study; 89 patients (44.7 %) had tried one AED and 110 patients (55.3 %) had tried two AEDs before lacosamide. At 12 months, the proportion of patients who were seizure free was 44.9 %, and 76 % of patients were responders. The seizure-free rate at 12 months for patients who had previously received one or two AEDs was 58 and 34.3 %, and the responder rate at 12 months was 83.0 and 70.4 %, respectively. The AE rate was 21.5 % at 3 months, 27.1 % at 6 months, and 31.2 % at 12 months, with 7.0 % of patients discontinuing treatment because of an AE. The most common AE reported was dizziness (11.6 %). Cryptogenic epilepsy, a higher number of prior AEDs, and the use of a sodium channel blocker at onset were associated with a worse outcome. The number of concomitant AEDs decreased over 1 year (Z = 5.89; p < 0.001). Twenty-two patients were converted to lacosamide monotherapy with at least one evaluation ≥6 months from the beginning of monotherapy conversion., Conclusions: Lacosamide was effective and well tolerated as early add-on treatment in patients who had received one or two previous AEDs.

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤ 24 h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose >200mg versus ≤ 200 mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage-titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required., (© 2013.)

Introduction: Zonisamide is an antiepileptic drug firstly approved in Europe as add-on therapy in adult patients with partial seizures and recently as monotherapy., Aim: To analyze the clinical development of zonisamide in Europe and USA., Development: It is a sulfonamide derivative that exerts its antiepileptic effect through different mechanisms, ion channels, neurotransmitters and free radicals. It has a lineal pharmacokinetic at usual doses, an hepatic metabolism without induction of other drugs and a half life of 60 hours. For his approval in USA and Europe four clinical randomized regulatory trials were performed. The efficacy of the drug was evaluated between 100 and 500 mg, showing a seizure reduction with respect to basal period between 24.7% (100 mg) and 52.5% (500 mg). The most frequent side effects were dizziness, fatigue, somnolence and weight loss. There is broad experience in conditions close to clinical practice in patients with partial epilepsy and different degree of refractoriness, pediatric population, monotherapy, generalized epilepsy and other special populations. Recently the results of a clinical trial in monotherapy have proved its efficacy in a no-inferiority design with carbamazepine. The seizure-free rate in the zonisamide group was 79.4%., Conclusions: At this moment, zonisamide represents a robust option in the treatment of a large number of patients with epilepsy, based on its multiple mechanism of action and efficacy in different situations.

A European observational cross-sectional study, ESPERA, was conducted in France and Spain in 2010. A random sample of neurologists, including specialists in epilepsy, prospectively enrolled adult patients treated for focal epilepsy with at least two antiepileptic drugs (AEDs) in combination. Investigators were asked to classify AED responsiveness of each enrolled patient according to the new 2009 ILAE criteria. These classifications were then reviewed by three experts. Potential factors of misclassification were then analyzed in order to evaluate the applicability of the new ILAE criteria for antiepileptic drug resistance in current clinical practice. Because of their complexity, use of the new ILAE criteria needs to be supported by relevant information and training to be adequately applied by neurologists in everyday practice., (Copyright © 2012 Elsevier Inc. All rights reserved.)

There has been little long-term success with polytherapy for patients with refractory partial-onset epilepsy. The rational combination of antiepileptic drugs based on their mechanism of action may help improve treatment efficacy and tolerability. Lacosamide, a novel sodium channel blocker (SCB), was investigated in 158 patients with partial-onset epilepsy in the prospective, multicenter, observational, RELACOVA cohort study conducted in Spain. After 12 months' treatment with lacosamide, 47% of patients were responders (≥50% reduction in seizure frequency) and 24% were seizure free. Lacosamide was well tolerated; dizziness was the most frequent adverse event. Efficacy was better (responder rate, 65% vs 38%; seizure free rate, 35% vs 17%) and there was a lower adverse event rate (33% vs 58%) in patients receiving non-SCBs (n=49) versus those receiving SCBs (n=104) as concomitant therapy at baseline. Further investigation of lacosamide combination therapy is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Treatment of status epilepticus (SE) has not changed in the last few decades, benzodiazepines plus phenytoin being the most common first line treatment. Intravenous levetiracetam (ivLEV) is a new antiepileptic drug with interesting properties for SE., Material and Methods: Efficacy and effectiveness of ivLEV in SE were assessed in an observational, multicentric and retrospective study. Efficacy was defined as cessation of seizures in the 24h subsequent to starting ivLEV, with no need of any further antiepileptic drug. All patients were treated following the standard protocol (benzodiazepines plus phenytoin or valproate). ivLEV was used as add-on therapy, except in those cases with contraindication for the standard protocol, when it was administered earlier., Results: 40 patients were included, 57% men, with a mean age of 63 years. The most common type of SE was partial convulsive (90%). ivLEV was effective in approximately half of the patients (57.5%), in a mean time of 14.4h. ivLEV was used as add-on treatment in 26 patients (after benzodiazepines plus phenytoin, valproate or both) with an efficacy of 46.1%, and as early treatment (pretreatment with benzodiazepines or nothing) in 14 patients with an efficacy of 78.5% (p 0.048). Adverse events were observed in 15% of patients., Conclusions: ivLEV was an effective antiepileptic drug for SE, but its efficacy depends on the timing of its administration, being more effective when used as early treatment, and less effective as add-on treatment., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective of this study is to evaluate the efficacy and safety of zonisamide (ZNS) for the treatment of idiopathic generalized epilepsies (IGEs)., Methods: Thirteen patients with different types of IGEs who were treated with ZNS between the years 2006 and 2008 were identified. Efficacy and tolerability were assessed at months 6 and 12 post-treatment. Response was defined as a 50% or greater reduction in seizure frequency., Results: Twelve patients (92.3%) continued with ZNS at month 6, and 11 (84.6%) at month 12. Mean daily dose was 319 mg (range 100-500 mg/d). Response was achieved at month 6 in eight of the 12 patients that continued with ZNS (66.6%), of which 7 were seizure-free (58.3%). At month 12, eight of the 11 patients that continued with ZNS were responders (72.7%) and 6 were seizure-free (63.6%). For different types of seizures, better responses were observed for absences and generalized tonic-clonic seizures. Four out of 13 patients (30.7%) experienced adverse events and in two (15.3%), these led to withdrawal., Conclusion: In this retrospective study, ZNS showed efficacy and tolerability for the treatment of different types of IGEs. Limitations include a small sample size and a relatively short period of follow-up. Our results are promising and justify the need for prospective controlled trials in IGE.

Objective: The goal of the study described here was to obtain psychometric validation of the Spanish version of the 38-item Side Effects and Life Satisfaction (SEALS) Inventory., Methods: A cross-cultural adaptation of the inventory was performed. A total of 595 patients with epilepsy were included in a multicenter cross-sectional study. The SEALS Inventory was completed, together with the Hospital Anxiety and Depression Scale and SF-12 Health Survey., Results: The mean SEALS score was 60.7. SEALS presented high internal consistency, with a Cronbach alpha coefficient of 0.93, and good test-retest reliability, with an intraclass correlation coefficient of 0.92. The pattern of correlations with the Hospital Anxiety and Depression Scale and SF-12 Health Survey indicated good convergent and divergent validity. SEALS scores discriminated patients according to epilepsy-related factors, emotional disturbances, and the generic quality of life., Conclusion: The Spanish version of the SEALS Inventory is a valid psychometric instrument. It may be used in routine clinical practice and in clinical trials in patients with epilepsy to capture the cognitive and behavioral aspects of quality of life.

Introduction: Comorbidity between epilepsy and cancer is elevated. As a life-time condition, it is not impossible for a patient with epilepsy to have a cancer at some point. Besides, at least 30% of patients with primary brain tumors have epileptic seizures, but also in patients with metastatic infiltrating lesions of the central nervous system and with extracerebral tumors, epilepsy can be related. Seizures may also appear associated with paraneoplastic syndromes, such as limbic encephalitis and metabolic and infectious complications of chemotherapy and radiotherapy., Results: The precise mechanisms by which brain tumors and the other conditions mentioned above produce seizures are not fully understood, but are reviewed in this article, as well as the many different therapeutic options that may be used in the treatment of epileptic seizures. Pharmacological treatment poses various controversies, such as the utility of prophylactic treatment, interactions between antiepileptic drugs (AEDs) and chemotherapeutic drugs and the complications derived from the adverse effects of AEDs in this population. Finally, other treatments are proposed such as chemotherapy, radiotherapy and surgery, the rational application of which allows for an improvement in the patients' quality of life., Conclusion: In order to arrive at a diagnosis, the different causes that could condition the appearance of epileptic seizures in cancer patients must be known. After this, the most adequate treatment should be chosen, thus ensuring the comprehensive treatment of cancer and epilepsy.

The goal of epilepsy treatment is seizure freedom, typically with antiseizure medication (ASM). If patients fail to attain seizure control despite two trials of appropriately chosen ASMs at adequate doses, they are classified as having drug-resistant epilepsy (DRE). Adverse events (AEs) commonly occur in people with DRE because they are typically on ⩾2 ASMs, increasing the potential for drug–drug interactions. Early emerging AEs may impact adherence, decrease quality of life, and delay achieving optimal treatment dosages. Cenobamate is an oral ASM with a long half-life which has proven to be highly effective in clinical trials. An international Delphi panel of expert epileptologists experienced in the clinical use of cenobamate and other ASMs was convened to develop consensus best practices for managing patients during and after cenobamate titration, with consideration for its known pharmacokinetic and pharmacodynamic interactions, to allow patients to reach the most appropriate cenobamate dose while limiting tolerability issues. The modified Delphi process included one open-ended questionnaire and one virtual face-to-face meeting. Participants agreed that cenobamate can be prescribed for most patients experiencing focal-onset seizures. Patients initiating cenobamate therapy should have access to healthcare professionals as needed and their treatment response should be evaluated at the 100-mg dose. Patients with intellectual disabilities may need additional support to navigate the titration period. Proactive down-titration or withdrawal of sodium channel blockers (SCBs) is recommended when concomitant ASM regimens include ⩾2 SCBs. When applicable, maintaining a concomitant clobazam dose at ~5–10 mg may be beneficial. Patients taking oral contraceptives, newer oral anticoagulants, or HIV antiretroviral medications should be monitored for potential interactions. Because clinical evidence informing treatment decisions is limited, guidance regarding dose adjustments of non-ASM drugs was not developed beyond specific recommendations presented in the Summary of Product Characteristics. [ABSTRACT FROM AUTHOR]

Background: Anti‐seizure medications (ASMs) have been related to poor cognitive function, but their relationship with intracarotid amobarbital procedure (IAP) results remains unclear. Aims of the Study: To elucidate whether the number and drug load of ASMs are associated with memory scores of the IAP and the neuropsychological assessment. Methods: Fifty‐nine adult patients with drug‐resistant epilepsy (mean age = 36.1, SD = 11.6) underwent bilateral IAP (with drawings and words as memory items) and a neuropsychological assessment to assess the risk of post‐surgical memory decline. Total ASM drug load was calculated by summing the daily dose/defined daily dose ratio of every ASM of each patient. Pearson's correlations and hierarchical regressions were computed. Results: Total IAP memory score was associated with total ASM drug load (r = −0.30, p = 0.02) and seizure frequency (r = −0.25, p = 0.05). After controlling clinical variables, total ASM drug load explained 16% of the variance of total IAP memory score. This relationship was especially prominent in patients with left hemisphere focus (r = −0.33, p = 0.04). The number of current ASMs was not related to IAP memory score (r = −0.16, p = 0.24). The number or drug load of ASMs were not related to neuropsychological assessment results (for all, p > 0.07). Conclusions: Our findings suggest that total drug load can be a confounding variable in the IAP memory performance that could explain, at least in part, the reverse asymmetries reported in different studies. [ABSTRACT FROM AUTHOR]

Objective: We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). Methods: Patients received either plant‐derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14‐day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. Results: Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2–18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0–26) and were currently taking a median of three (range = 1–5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p =.02) and Day 13 for CBD10 (p =.03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD‐treated patients (56.3%–72.9%). Significance: The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week study period. [ABSTRACT FROM AUTHOR]

Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine acetate (ESL) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel blockers (SCBs). However, ESL is structurally distinct from CBZ and OXC, resulting in differences in metabolism, pharmacokinetics, and pharmacodynamics. Despite a lack of direct comparative data, evidence for potential differences in effectiveness and tolerability within the dibenzazepine family has emerged from studies in which patients being treated with one dibenzazepine agent have received adjunctive treatment with another (having achieved insufficient seizure control with the first) or have transitioned from one dibenzazepine agent to another because of lack of effectiveness or poor tolerability. Most of these studies have been conducted in the real-world clinical practice setting. ESL has been shown to be effective as adjunctive therapy in patients who have previously achieved inadequate seizure control with CBZ, indicating that the use of different dibenzazepine agents in combination can provide additive effectiveness benefits, which may reflect underlying differences in their mechanisms of action. Similarly, ESL monotherapy can be effective in patients who have switched from another dibenzazepine, such as CBZ or OXC, because of inadequate efficacy. There is also considerable evidence to demonstrate that patients transitioning from OXC or CBZ to ESL as a result of adverse events experience improvements in tolerability, which may also be associated with improvements in quality of life, alertness, and/or lipid profiles. Current evidence therefore demonstrates that ESL differs from other dibenzazepine agents in terms of effectiveness and tolerability.Funding: Eisai Ltd. [ABSTRACT FROM AUTHOR]

• Epitrack total score significantly contributes to better QOL composite score. • Epitrack total score contributes to perceived energy and cognitive self-rating. • The number of ASMs mediates the relationship between cognitive deficits and QOL. • The DDD of ASMs does not mediate the association between cognition and QOL. To assess whether cognitive performance predicts quality of life (QOL) in patients with drug-resistant temporal lobe epilepsy (TLE), using the Epitrack cognitive screening tool, while considering the mediating role of the number of anti-seizure medications (ASMs) and controlling for seizure-related, social, and emotional factors. Seventy-five adult patients with drug-resistant TLE (mean age = 39.76 years, SD = 11.66) underwent a presurgical neuropsychological assessment. Main Outcome Measures: Cognitive performance (Epitrack), depression (BDI-II), trait anxiety (STAI); and QOL (QOLIE-31) were assessed. Adjusting for seizure-related, social, and emotional factors, the Epitrack total score significantly contributed to QOL composite score, and energy and cognitive self-rating subscales. We found a significant indirect effect of the Epitrack total score on QOL composite score and seizure worry and social functioning subscales via the number of ASMs. Our findings underline the relevance of cognitive functioning on QOL and the clinical utility of Epitrack to track cognitive side effects of ASMs and, consequently, to predict and manage QOL in this population. [ABSTRACT FROM AUTHOR]

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel’s classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients. [ABSTRACT FROM AUTHOR]