David G. Vossler

Objective: This randomized, double‐blind, phase 1b/2a clinical trial was designed to evaluate the safety, tolerability, and efficacy of oral bexicaserin versus placebo for the treatment of seizures in adolescents and adults with developmental and epileptic encephalopathies (DEEs). Methods: Eligible participants had a DEE diagnosis, were aged 12–65 years, and were taking 1–4 concomitant antiseizure medications. Randomization to treatment groups (4:1 bexicaserin:placebo) was stratified by type of DEE (Dravet syndrome [DS], Lennox–Gastaut syndrome [LGS], or DEE Other). Following a 28‐day baseline period, the treatment period consisted of a 15‐day flexible uptitration period (6, 9, or 12 mg three times daily, 5 days each) and a 60‐day maintenance period on the highest tolerated dose. Primary end points were safety (adverse events) and change from baseline in countable motor seizure frequency. Results: Forty‐three and nine participants were assigned to bexicaserin treatment and placebo, respectively, and received ≥1 dose (safety set); 35 bexicaserin and nine placebo participants completed titration, entered the maintenance period, and had ≥1 seizure measurement during the maintenance period (full analysis set). Twenty‐eight of 43 bexicaserin‐treated participants (65.1%) and three of nine (33.3%) in the placebo group reported drug‐related treatment‐emergent adverse events (TEAEs); seven of 43 participants (16.3%) discontinued bexicaserin due to a TEAE during titration and two of 43 (4.7%) during maintenance, most frequently due to somnolence. Median reductions in countable motor seizure frequencies were −59.8% with bexicaserin and −17.4% with placebo; reductions with bexicaserin were observed across DEEs (DS, −74.6%; LGS, −50.8%; DEE Other, −65.5%). The proportion of participants achieving ≥50% reductions during the treatment period (responder analysis) was 60.0% with bexicaserin versus 33.3% with placebo. Significance: Bexicaserin was well tolerated and associated with clinically relevant reductions in countable motor seizure frequencies in participants with a variety of DEEs. This novel trial design may expand treatment access to patients previously excluded from clinical trials.

OBJECTIVE: This article provides current evidence on how and when to treat unprovoked first seizures in children and adults, guides intervention with appropriate doses and types of modern and effective therapies for acute repetitive (cluster) seizures, and reviews evidence for the diagnosis and management of established, refractory and super-refractory status epilepticus. LATEST DEVELOPMENTS: Artificial intelligence shows promise as a clinical assistant in decision making after a first seizure. For nonanoxic convulsive refractory status epilepticus third-phase treatment, equipoise exists regarding whether it is better to add a second IV nonsedating antiseizure medication given via loading dose (eg, brivaracetam, lacosamide, levetiracetam, fosphenytoin or valproic acid) or to start an anesthetizing continuous IV infusion antiseizure medication such as ketamine, midazolam, propofol or pentobarbital. ESSENTIAL POINTS: After a first seizure, the risk of a second seizure is about 36% at 2 years and 46% after 5 years. The risk is doubled in the presence of EEG epileptiform discharges, a brain imaging abnormality, a nocturnal first seizure, or prior brain trauma. For acute repetitive seizures, providers should give a proper dose of benzodiazepines based on the patient’s weight and needs. First-phase treatment for convulsive established status epilepticus is the immediate administration of full doses of benzodiazepines. Second-phase treatment for convulsive established status epilepticus is a full loading dose of IV fosphenytoin, levetiracetam, valproic acid, or if necessary, phenobarbital.

Objectives: The Phase 3 Study 338 (NCT02834793) assessed long‐term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox–Gastaut syndrome (LGS).Methods: Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18‐week double‐blind, randomized, placebo‐controlled Core Study and ≥52‐week open‐label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure‐freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.Results: Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs −.7%, respectively, p = .001) or all countable motor seizures (44.0% vs −.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment‐emergent adverse events occurred in 85.3% of perampanel‐treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo‐treated patients.Significance: This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long‐term efficacy and safety of perampanel in the LGS population.

Objective: This study was undertaken to assess long‐term safety, tolerability, and efficacy of lacosamide (LCM) as adjunctive therapy for generalized onset tonic–clonic seizures (GTCS) in patients aged ≥4 years with idiopathic generalized epilepsy (IGE).Methods: EP0012 (NCT02408549) was a phase 3, multicenter, open‐label extension (OLE) trial. Patients were enrolled from SP0982 (NCT02408523). Trial duration was ≥2 years (adults) and ≤5 years (children). The trial consisted of a treatment period, ≤4‐week taper period, and 30‐day safety follow‐up. Safety (primary) variables were incidence of treatment‐emergent adverse events (TEAEs), discontinuations due to TEAEs, incidence of onset of absence or myoclonic seizures, and increase in days with absence or myoclonic seizures per 28 days. Efficacy (secondary) variable was percent change in GTCS frequency per 28 days. Kaplan–Meier estimated retention rates and analyses by number of lifetime antiseizure medications (ASMs) were performed post hoc.Results: Overall, 239 patients (mean age = 27.9 years, 56.1% female, 18.4% children) were enrolled and received ≥1 dose of LCM in this OLE (median treatment duration = 3.2 years); 157 (65.7%) completed the trial, and 82 (34.3%) discontinued. The most common reason for discontinuation (≥10%) was withdrawn consent (30 [12.6%]). Kaplan–Meier estimated retention rate was 87%, 72%, and 60% at 1, 3, and 5 years, respectively. Overall, 222 (92.9%) patients reported TEAEs; 19 (7.9%) discontinued due to TEAEs. Few patients had an increase in number of days with absence or myoclonic seizures, or incidence of new absence or myoclonic seizures. Median percent change in GTCS frequency per 28 days from the combined baseline was −88.6% (range = −100.0 to 465.4, n = 238). Post hoc analyses demonstrated small numerical differences between patients with 1, 2, and ≥3 lifetime ASMs.Significance: The results support the use of long‐term adjunctive LCM for GTCS in patients with IGE. Long‐term adjunctive LCM was efficacious and well tolerated independent of the number of ASMs used before LCM initiation.Clinical trial registration: ClinicalTrials.gov: NCT02408549.

Since bromides were first used in 1857 to treat epilepsy, numerous antiseizure medications (ASM) have been developed. Many of these are available for the treatment of epilepsy and status epilepticus today. With so many ASM available, questions arise as to whether all of these medications are needed and when should they be used. As precision medicine begins to play a larger role in determining targeted treatments for specific types of epilepsy, a complete understanding of various medications is needed. Additionally, access to several of these medications can be limited in the United States and are especially limited globally. All these factors can make proper selection of ASM challenging and difficult for clinicians. This review highlights important aspects of older and newer medications, developments in precision medicine for epilepsy, increasing understanding of effective treatments for status epileptics, and a global perspective on ASM availability.

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Objective: In this post hoc analysis of a subset of patients from a long‐term, open‐label phase 3 study, we assessed ≥50%, ≥75%, ≥90%, and 100% seizure reduction and sustainability of these responses with cenobamate using a time‐to‐event analytical approach.Methods: Of 240 patients with uncontrolled focal seizures who had adequate seizure data available, 214 completed the 12‐week titration phase and received ≥1 dose of cenobamate in the maintenance phase (max dose 400 mg/day) and were included in this post hoc analysis. Among patients who met an initial given seizure‐reduction level (≥50%, ≥75%, ≥90%, or 100%), sustainability of that response was measured using a time‐to‐event methodology. An event was defined as the occurrence of a study visit at which the seizure frequency during the interval since the prior study visit exceeded the initially attained reduction level. Study visits during the maintenance phase occurred at 3‐month intervals.Results: Of the 214 patients analyzed, 188 (88%), 177 (83%), 160 (75%), and 145 (68%) met ≥50%, ≥75%, ≥90%, and 100% seizure‐reduction responses, respectively, for at least one study visit interval during the maintenance phase. The median (95% confidence interval [CI]) time to first visit without a ≥50% seizure reduction was not reached by 30 months of follow‐up (53% of patients maintained their initial ≥50% seizure reduction). Median (95% CI) time to first visit without sustaining the initial ≥75%, ≥90%, or 100% seizure reduction was 13.0 (7.5–21.9) months, 7.5 (5.4–11.6) months, and 7.0 (5.3–10.4) months, respectively. Among the 145 patients who had 100% seizure reduction during at least one study visit, 22% remained seizure‐free for at least 30 months and 63% had ≤3 study visits with seizures.Significance: Adjunctive treatment with cenobamate led to sustained seizure reductions during the maintenance phase of the phase 3 safety study.

Management of Refractory Status Epilepticus: An International Cohort Study (MORSE CODe) Analysis of Patients Managed in the ICU Chiu WT, Campozano V, Schiefecker A, Rodriguez DR, Ferreira D, Headlee A, Zeidan S, Grinea A, Huang YH, Doyle K, Shen Q, Gómez D, Hocker SE, Rohaut B, Sonneville R, Hong C-T, Demeret S, Kurtz P, Maldonado N, Helbok R, Fernandez T, Claassen J. Neurology. 2022;99(11):e1191-e1201. doi:10.1212/WNL.0000000000200818 Background and Objectives: Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings. Methods: Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge. Results: Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and >24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG <1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge. Discussion: Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE. Ketamine for Management of Neonatal and Pediatric Refractory Status Epilepticus Jacobwitz M, Mulvihill C, Kaufman MC, Gonzalez AK, Resendiz K, MacDonald JM, Francoeur C, Helbig I, Topjian AA, Abend NS. Neurology. 2022;99(12):e1227-e1238. doi:10.1212/WNL.0000000000200889 Background and Objectives: Few data are available regarding the use of anesthetic infusions for refractory status epilepticus (RSE) in children and neonates, and ketamine use is increasing despite limited data. We aimed to describe the impact of ketamine for RSE in children and neonates. Methods: Retrospective single-center cohort study of consecutive patients admitted to the intensive care units of a quaternary care children’s hospital treated with ketamine infusion for RSE. Results: Sixty-nine patients were treated with a ketamine infusion for RSE. The median age at onset of RSE was 0.7 years (interquartile range 0.15-7.2), and the cohort included 13 (19%) neonates. Three patients (4%) had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in 2 patients and delirium in 1 patient. Ketamine infusion was followed by seizure termination in 32 patients (46%), seizure reduction in 19 patients (28%), and no change in 18 patients (26%). Discussion: Ketamine administration was associated with few adverse events, and seizures often terminated or improved after ketamine administration. Further data are needed comparing first-line and subsequent anesthetic medications for treatment of pediatric and neonatal RSE.