Emilio Perucca

Objective: Aside from congenital malformations and impaired postnatal neurodevelopment, risks associated with antiseizure medication (ASM) use during pregnancy have been sparsely investigated, particularly outside of epilepsy. We aimed to assess these risks through a systematic literature review and meta-analysis, including ASM exposure for any indication. Methods: We searched MEDLINE, EMBASE, and Cochrane for studies including pregnant women on ASMs for any indication and untreated pregnant women, investigating obstetric complications and fetal/neonatal complications other than congenital malformations and impaired neurodevelopment. Differences in outcomes between groups were estimated using odds ratios (ORs) with 95% CIs. Results: Of 20,416 references identified, 75 studies amassing 16,941,373 pregnancies or live births (14,437,221 pregnancies with maternal outcome data and 14,938,972 live births with fetal/neonatal outcome data) were included. Forty-nine studies had low risk of bias, and 26 had medium risk. Compared with pregnancies in unaffected women (women without the conditions indicating prescription of ASMs), those exposed to ASMs had increased odds of several adverse outcomes including preterm birth (OR 1.30, 95% CI 1.09-1.54), cesarean section (OR 1.43, 95% CI 1.13-1.81), gestational diabetes (OR 1.44, 95% CI 1.07-1.94), induction of labor (OR 1.46, 95% CI 1.15-1.86), preeclampsia (OR 1.33, 95% CI 1.02-1.72), spontaneous miscarriage (OR 1.42, 95% CI 1.01-2.01), and spontaneous fetal loss (OR 2.54, 95% CI 1.04-6.24). Comparison of outcomes between untreated women with the same ASM indications and unaffected women showed that some differences (preterm birth, cesarean section, gestational diabetes, and preeclampsia) were largely attributable to the underlying condition, particularly epilepsy. The odds of spontaneous miscarriage, spontaneous fetal loss, elective cesarean section, 5-minute APGAR score <7, and admission to the neonatal intensive care unit were significantly greater in ASM-exposed than in unexposed pregnancies in women with the same indications, but the possible confounding effect of between-group differences in disease severity could not be assessed. The odds of small-for-gestational age differed across ASMs, with signals pointing to an association with clonazepam, oxcarbazepine, topiramate, and zonisamide. Conclusions: Pregnancies exposed to ASMs are at increased risk of numerous obstetrical and perinatal complications. Although some of these adverse outcomes are attributable to the underlying condition, particularly epilepsy, exposure to ASMs seems to be associated with additional risks. These findings can be incorporated into routine patient counseling.

By targeting the underlying etiology, precision therapies offer an exciting paradigm shift to improve the stagnant outcomes of drug-resistant epilepsies, including developmental and epileptic encephalopathies. Unlike conventional antiseizure medications (ASMs) which only treat the symptoms (seizures) but have no effect on the underlying disease, precision therapies have the potential to suppress not only the seizures but also disabling comorbidities, including cognitive and behavioral abnormalities, which share the same causative mechanisms. Monogenic epilepsies are an attractive target for precision therapies because of their well-defined molecular mechanisms which can be tested in vitro and can be counteracted by specific drugs. Unfortunately, however, for the vast majority of proposed precision therapies, the evidence for their clinical efficacy is either non-existent or limited to uncontrolled observational accounts. Everolimus is the sole precision therapy with a seizure-related indication with class I evidence of efficacy, highlighting the practical and ethical challenges in obtaining high-level evidence. Here, we review the evidence landscape for candidate precision therapies, including repurposed and innovative treatments currently in development, discuss lessons learned from their use, and highlight strategies to improve their application and evaluation in the clinical setting. PLAIN LANGUAGE SUMMARY: Precision therapies offer a new approach to treat drug-resistant monogenic epilepsies, that is, epilepsies caused by a defect in a single gene. Unlike traditional antiseizure medications, precision therapies target the cause of the disease and have the potential to improve not only seizure control but also concomitant conditions such as cognitive and behavioral disorders. To date, the evidence derived from the clinical use of most proposed precision therapies is limited. This review explores current evidence and strategies to advance their development.

Objective: Primidone (PMD) is a first-line treatment option for essential tremor (ET) but its use involves a risk of acute neurotoxic manifestations after the first dose. Our aim was to assess the prevalence of acute PMD intolerance in patients with ET and the potential protective effect of phenobarbital (PB) pre-treatment. Methods: This retrospective study compared the frequency and severity of acute intolerance after a first dose of PMD (62.5 mg) in ET patients started on treatment without previous exposure to PB or after PB pre-treatment (10 mg/day for 2-3 weeks). Intolerance manifestations and their severity were assessed on a visual analogue scale. Results: Twenty-five patients reported symptoms of acute intolerance to PMD, particularly somnolence, ataxia/unsteadiness, confusion, dizziness and nausea/vomiting. The prevalence of neurotoxic symptoms was 82% (23/28) among patients unexposed to PB compared with 17% (2/12) among those pre-treated with PB (p = 0.0002). Compared with no previous PB exposure, pre-treatment with PB was also associated with fewer number of adverse effects per patient (p = 0.0003) and lower severity scores (p = 0.0004). Two patients who could not tolerate PMD when administered without previous PB exposure reported no adverse effects when re-challenged after PB pre-treatment. Conclusions: Pre-treatment with PB minimizes the occurrence of acute intolerance to PMD, most likely due to functional cross-tolerance. The option of receiving low-dose PB for a short period before starting on PMD should be offered to ET patients in whom PMD therapy is indicated. PB-pre-treatment should also be considered whenever occurrence of acute intolerance prevented continuation of PMD therapy.

Objective: The in vivo effects of fenfluramine result from the combined actions of four active molecular entities (l-fenfluramine, d-fenfluramine, and the corresponding enantiomers of the primary metabolite norfenfluramine). Each of these compounds has different properties, with cardiovascular toxicity risk being ascribed primarily to the d-enantiomers. To determine whether l-fenfluramine or l-norfenfluramine is a better candidate for development as an enantiomerically pure antiseizure medication, we investigated dose-response and brain/plasma concentration-response relationships for each of the four individual enantiomers in mice. Methods: Antiseizure activity was evaluated in the maximal electroshock (MES) model at the time of peak effect. Neurotoxicity was assessed by determining minimal motor impairment (MMI) in the rotarod test. Median effective dose (ED50), median toxic dose (TD50), median effective concentration (EC50), and median toxic concentration (TC50) in plasma and brain were estimated from dose- and concentration-response curves after administration of each individual enantiomer. Protective indexes (PIs) were estimated based on dose (TD50/ED50) and plasma/brain concentrations (TC50/EC50). Results: The four enantiomers differed in antiseizure potency and neurotoxic activity. d-Norfenfluramine had the highest potency, but it also had the highest toxicity and the lowest PI. Differences in antiseizure potency and toxicity estimated from plasma and brain concentrations were more prominent than those estimated based on dose. l-Fenfluramine had greater potency than d-fenfluramine and l-norfenfluramine, and was overall the compound with the highest PI (6.3 based on dose, 41.6 based on plasma concentrations, and 39.2 based on brain concentrations). Conclusions: These findings are relevant in determining which enantiomer is most suitable for clinical development as a stereoselectively pure follow-up compound to the marketed racemic fenfluramine, and indicate that l-fenfluramine has superior antiseizure activity over l-norfenfluramine in the MES model. This study also illustrates the limitations of relying solely on dose-response curves, and the added value of assessing concentration-response relationships.

Objective: To report interim data from an ongoing, open-label extension (OLE) of a Phase 2b study (X-TOLE) of azetukalner in adults with focal onset seizures (FOS) receiving 1-3 antiseizure medications. Methods: Eligible participants enrolled in the 7-year OLE at 20 mg azetukalner once daily with food. Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of ≥50%, ≥75%, ≥90%, and 100% seizure reductions. Results: 285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the 24-month interim analysis (September 5, 2023), 182 participants had been treated for ≥12 months and 165 for ≥24 months; 152 (55.3%) continued in the study. The median (range) treatment duration in the OLE was 26.3 (0.1-46.6) months. MPC reduction was 83.2% at 24 months in the OLE vs. DBP baseline. For all participants who entered the OLE, 56.4% (155/275) and 44.4% (122/275) achieved a ≥50% seizure reduction, 28.4% (78/275) and 19.6% (54/275) achieved a ≥90% seizure reduction, and 22.2% (61/275) and 14.9% (41/275) achieved seizure freedom (100% seizure reduction) for any consecutive ≥6- and ≥12-month period, respectively. For those who reached ≥24 months in the OLE, seizure freedom was achieved by 34.5% (57/165) and 23.6% (39/165) for any consecutive ≥6- and ≥12-month period, respectively. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Serious AEs were reported in 35 (12.7%) participants. Conclusions: The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis. Azetukalner was generally well tolerated, with no new safety signals compared to the DBP. These data suggest sustained long-term efficacy and safety of azetukalner in a difficult-to-treat population. Conclusions: This long-term study assessed the safety and efficacy of azetukalner to treat focal seizures. Patients taking azetukalner daily with food for about 2 years had far fewer focal seizures with azetukalner than before taking the medication. For those who had been treated for 24 months, about a third were seizure-free for a consecutive 6-month period, and about a quarter were seizure-free for a consecutive 12-month period. Most side effects were mild or moderate, and these included dizziness, headache, and somnolence (sleepiness).