The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day - 1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over >= 1 time points for all eye conditions. Partial suppression was a >= 3-point reduction over >= 3 testing times vs the same time points on day - 1 in >= 1 eye condition. In addition, pharmacokinetics and safety were assessed. Of 27 evaluable patients, 9 reentered to receive a 2nd dosing 1-6 months later, providing a total of 36 individual exposures. At all doses administered - even the lowest -, several subjects reached a complete abolishment of PPR, with a rapid onset of effect. Overall, complete abolishment of PPR was obtained in 40-71 % of the patients; the effect increasing with the dose. In terms of effective doses to suppress PPR, SEL was at least 1,500 times more potent than levetiracetam and 10-20 times more potent than brivaracetam. Adverse events of SEL, including dizziness and somnolence, were mild to moderate. Pharmacokinetics of SEL demonstrated rapid absorption and a linear dose:plasma level relationship. This proof-of-principle study demonstrates that - based on our own experience - SEL is the most potent compound ever tested in the photosensitivity model.

OBJECTIVE:Evaluating the efficacy of an opioid antagonist, naloxone (NLX), to reduce the severity of post-ictal hypoxemia and immobility after focal to bilateral tonic-clonic seizures (FBTCS). METHODS:ENALEPSY is a double-blind placebo (PCB)-controlled trial conducted in patients with focal epilepsy undergoing long-term video-EEG monitoring (LTM). Patients with a FBTCS during LTM were randomized 1:1 to receive intravenous NLX or PCB within the 2 min following the end of FBTCS. After database lock, a discrepancy between the allocated arm and the received treatment was detected, resulting in a 4:1 NLX:PCB ratio. To further explore the efficacy of NLX, we used historical control (HC) data collected in patients included in the REPO2MSE study whose characteristics matched those of patients randomized in ENALEPSY. The efficacy of NLX was then assessed versus PCB and versus HC. The primary endpoint was the delay between the end of the seizure and recovery of SpO2 ≥ 90%. Secondary efficacy outcomes included desaturation nadir and duration of the post-ictal immobility. RESULTS:33 patients contributed to the NLX group, 7 to the PCB group, and 43 to the HC group. The proportion of FBTCS type 1 or 3 was 84% in NLX, 100% in PCB, and 84% in HC. NLX did not improve the delay of recovery of SpO2 ≥ 90% or the desaturation nadir. By contrast, the duration of the post-ictal immobility differed across groups. The time to mobility recovery within the first 5 min post-ictal was very similar in the PCB (200.3 ± 215.8 s) and HC (194.4 ± 192.0 s) groups, and significantly shorter in the NLX group (128.9 ± 151.1 s) when compared to HC (Hazard Ratio, 1.84; 95% CI, 1.11-3.05; p = 0.021). SIGNIFICANCE:NLX did not prevent post-ictal respiratory dysfunction but might reduce the duration of post-ictal immobility. Confirmation of this effect and its impact on SUDEP risk will require additional studies. PLAIN LANGUAGE SUMMARY:Release of endogenous opioids might participate in the severity of post-ictal hypoxemia and immobility after focal to bilateral tonic-clonic seizures (FBTCS). We conducted a multicenter double-blind randomized placebo-controlled trial evaluating the efficacy of an opioid antagonist, naloxone (NLX), administered within 2 min following the end of FBTCS. The efficacy of NLX was further explored with a comparison with historical control. NLX did not improve the delay of recovery or the severity of post-ictal hypoxemia. Post-ictal immobility was significantly shorter in the NLX group when compared to historical control. The impact of these results on SUDEP prevention will require additional studies.

The evolution from nocturnal paroxysmal dystonia (NPD) to sleep-related hypermotor epilepsy (SHE) is a complex and fascinating journey, marked by numerous twists and discoveries.1 This topic was recently reviewed by Fotedar and Luders,2 who erroneously concluded that SHE is not an identifiable focal epilepsy syndrome as they believed that it is based on weak evidence. We wish to address errors in their analysis and offer a more balanced understanding of this important form of epilepsy. The authors2review more than 40 years of history largely through a lens based on electrophysiology and pre-surgical evaluation. They challenge the epileptic origin of SHE, previously termed nocturnal frontal lobe epilepsy (NFLE), now recognized as a well-characterized entity 3. Their chronological reconstruction, more comprehensively addressed in previous works,1, 4 seems arbitrary and incomplete, omitting key studies that have contributed significantly to the understanding of the epileptic origin of the syndrome. In particular, even before the debates on the true nature of NPD began, others had observed episodes similar to NPD in patients with confirmed epilepsy. From the 1970s, authorities in North America began to define frontal lobe epilepsy (nocturnal and diurnal), often misdiagnosed as psychiatric in origin (Figure 1).3, 5-18 The historical reconstruction presented in the review2 is also incomplete in its identification of three eras marked by landmark studies (1972–1993, 1994–1998, 1999 to present), paying cursory attention to a crucial event: the Consensus Conference in Bologna,17 which established diagnostic criteria for the syndrome (Table 1). The syndrome was subsequently accepted by the International League Against Epilepsy (ILAE) Commission on Terminology.3 The consensus conference method is recommended for addressing important clinical questions in the face of limited high-quality evidence. The main outcome, a consensus statement, represents the collective opinions of an expert panel, derived from systematic review and discussion of available evidence.19 The Bologna Consensus Conference was planned and completed between November 2013 and September 2014, using rigorous methods addressing conditions with limited evidence, such as rare diseases (see online appendix in Tinuper et al.17 for details). The final definition of the condition was reached through a transparent process that included predefined research questions, a systematic review for each question, an independent systematic mapping of the evidence,20 an assessment of the literature's quality with reliable tools,21, 22 and an open, structured debate of 2 days involving a workgroup of experts for each the three main topics (clinical history; electro-clinical features; etiologic and pathogenic background) and a multidisciplinary international panel jury including specialists in child and adult epilepsy, sleep medicine, neurosurgery, genetics, epidemiology, and research methodology. The analysis explicitly covered all controversies and gray areas highlighted by Fotedar and Luders2 (e.g., absence of a clear ictal rhythm does not exclude an epileptic origin, not all seizures in SHE are frontal in origin, and so on). Fotedar and Luders correctly delineate the change in terminology over decades but failed to note that terms such as paroxysmal arousal (PA),23 epileptic nocturnal wandering (ENW),24 and minor motor episodes or events (MMEs)25, 26 – have been long since abandoned.3, 17 We agree that not all episodes previously reported under the term "NPD" are unequivocally epileptic. However, there is robust evidence for an epileptic basis in many cases, based on consistent hypermotor seizure semiology observed in the same patient, both within the same night and over the years, supported by anatomo-electro-clinical data in some. The evolution of seizures with the same semiological onset but varying duration has led to seemingly distinct descriptors, ranging from very brief motor attacks (brief) to hypermotor seizures sometimes followed by prolonged complex ambulatory behavior (long). These have been subsequently recognized as part of the clinical spectrum of seizures in SHE, both within and between patients.1 Fotedar and Luders express frustration that influential neurologists in the mid-1990s led the community to believe that epilepsy was the basis for most sleep-related paroxysmal motor episodes.14-16 They argued that all of these episodes were automatically assumed to be seizures and alternative diagnoses were often dismissed. This was never the case. Indeed, it is essential to recognize the extensive work that was done to clarify the differential diagnosis between sleep-related seizures and other sleep disorders (e.g., parasomnias), which remains a challenging but critical distinction. In that period, in addition to further electroclinical studies, diagnostic tools such as questionnaires and algorithms were developed, to aid clinicians in minimizing diagnostic errors in either direction, assessing the diagnostic accuracy of semiological patterns observed on video27 or reported on clinical history.28-33 Fotedar and Luders emphasize that the frequency of definitive interictal epileptiform changes on the electroencephalography (EEG) recordings of pre-surgical SHE cases is considerably higher than that seen in familial cases of SHE and even in a series of sporadic cases. We agree with this observation, which is likely an artifact of ascertainment bias, EEG recording time, and etiology. Pre-surgical cases are studied because they are drug resistant and typically have days or weeks of day and night video-EEG monitoring, and may have lesions. Milder cases, especially those in families, may have a single routine EEG and may be in remission at the time they are evaluated and are typically non-lesional.15 The absence of ictal and interictal epileptiform abnormalities does not exclude a diagnosis of SHE, in severe cases (concentrated in surgical series) or milder ones. In surgical series, it is widely recognized that co-registration of the scalp and stereo EEG (SEEG) can show surprisingly little abnormality on scalp EEG even when SEEG is very active (Figure 2). The authors cite (Figure 2 in ref.2) a case with PAs16 to support their criticism that many of the published NPD cases lacked definitive ictal/interictal epileptiform changes. PAs, frequently occurring in patients with SHE, are characterized by abrupt trunk and limb movements that can resemble simple motor sleep phenomena and exhibit a pseudoperiodic pattern linked to K-complex bursts or Cyclic Alternating Pattern (CAP) recurrence.1 However, the Consensus Conference deemed PAs insufficient for diagnosing SHE due to their controversial nature, inconsistent nomenclature across SHE study groups, and the risk of unreliable clinical diagnosis when only minor motor events or few episodes are captured.1, 17 We also note the attempts by Fotedar and Luders to reinterpret EEG tracings from older publications, especially given the challenges of analyzing published figures, rather than the whole recording. We do not wish to address every critique related to interpretations of EEG records from the 1990s, but we want to highlight one specific case—figure 42 – which the authors cited as a paradigmatic example of "overreading." Although we will not delve into the objections about this EEG tracing (whose quality understandably falls short of 2024 standards), we would like to point out that the patient in question carried a pathogenic KCNT1 variant (Figure 2, Family B, subject III.2 in Heron et al.34). This patient subsequently underwent epilepsy surgery involving resection of the right mesiolateral frontal region, with histopathology confirming the presence of focal cortical dysplasia (Figure 1, Family B, subject III.2).35 Furthermore, the authors propose that epileptic sleep-related paroxysmal motor events require the presence of a magnetic resonance imaging (MRI) lesion (table 1 in ref.2). However, even with advances in MRI techniques, 40%–50% of patients with SHE have negative MRIs in surgical series of drug-resistant patients.18, 36 Fotedar and Luders point out that many of the cases of SHE may have originated outside the frontal lobe. This has been well recognized by many groups and emphasized at the Consensus Conference and, precisely for this reason, led to the change of name from NFLE to SHE.17 It is well established that up to 30% of patients with hypermotor seizures, once categorized as the hallmark of NFLE, actually have seizures originating from extrafrontal regions.17 Seizures may arise in areas including the insula,37 midline parietal cortex,38 and other regions.18, 39 Therefore, revisiting this well-established point adds little value to their article. In the initial part of their "critical review," Fotedar and Luders disingenuously imply that the finding of CHRNA4 pathogenic variants was not replicated. Their review of molecular genetics is outdated, incomplete, and inaccurate. For CHRNA4, its pathogenic role in SHE is cemented by identification in both families and de novo cases, in individuals of European, Lebanese, and Japanese ethnicities.40-42 Multiple groups over the last three decades have confirmed the presence of autosomal dominant pathogenic variants in a range of genes including those encoding nicotinic subunits (CHRNA4, CHRNB2, and CHRNA2), mechanistic target of rapamycin (mTOR) pathway proteins (DEPDC5, NPRL2, and NPRL3) and potassium sodium-activated channel subunit (KCNT1) (Table 2).34, 43-47 In a series of 103 SHE cases, 19% of familial and 7% of sporadic cases had a pathogenic variant in an established SHE gene.48 The mTOR pathway genes are sometimes associated with structural malformations visible on MRI and may be included in surgical series.49, 50 nAChRs genes43 CHRNA4 CHRNB2 CHRNA2 Cholinergic Receptor Nicotinic Alpha 4 Subunit Cholinergic Receptor Nicotinic Beta 2 Subunit Cholinergic Receptor Nicotinic Alpha 2 Subunit 20q13.33 1q21.3 8p21.2 AD AD AD MIM*118504 MIM*118507 MIM*118502 GATOR-1 genes DEPDC5 44, 45 NPRL2 46 NPRL3 47 DEP Domain Containing 5 NPR2- like Protein Nitrogen Permease Regulator-like 3 22q12.2-q12.3 3p21.31 16p13.3 AD AD AD MIM*614191 MIM*607072 MIM*600928 The authors later try to disconnect the molecular findings from the epileptology, implying that these validated genetic variants are associated with non-specific sleep-related paroxysmal motor episodes, rather than with SHE. The clinical relationship of SHE to parasomnias remains poorly understood but, at this time, there is no evidence associating these genes with other familial sleep disorders.51 There are several reports of patients with pathogenic variants in CHRNA4, clinical features of SHE, and ictal epileptiform changes48 including one case with SEEG documenting a widespread epileptogenic network (case 352). The same findings have been reported for a few patients with germ-line pathogenic variants in the mTOR pathway genes.53 Overlooking this well-supported evidence disregards significant advancements in understanding the genetic underpinnings of epilepsy. The authors proposed a four-dimensional classification system for paroxysmal motor sleep episodes based on semiology, naming the new entity "sleep-related paroxysmal motor episodes" (SPME). We believe that this definition lacks both clarity and utility in the terms required by current scientific standards for defining new diagnostic criteria (e.g., prognostic ability, reproducibility, accuracy, and favorable balance between benefits and harms in applying the new definition).54 The implications of not differentiating epileptic seizures from other sleep-related motor phenomena, resulting in incorrect diagnosis and management, are potentially dangerous in terms of morbidity, mortality risk, and impact on quality of life. In conclusion, although we certainly welcome continued discourse on SHE, it is important that these discussions be grounded in comprehensive, up-to-date evidence and not a rehash of debates that have long been resolved. We thank Dr. Lorenzo Ferri and Giulia Bruschi for their assistance in preparing the figures and Dr. Anna Scarabello and Dr. Lorenzo Muccioli for their contributions to the editing of the manuscript and the bibliographic review. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Francesca Bisulli has served on scientific advisory boards for Jazz, Takeda Pharmaceuticals, Ethypharm, and UCB; has received speaker honoraria from Angelini, UCB, Jazz, and Eisai; has received funding for travel from Jazz, Eisai, Angelini, and UCB; has served as an investigator for UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; and has consulted for Xenon Pharmaceuticals and Takeda Pharmaceuticals. Samuel F. Berkovic has received unrestricted educational grants to his institution from UCB Pharma, Eisai, SEER, Chiesi, and LivaNova. He has served as a consultant for Praxis Precision Medicines and has received personal honoraria for lectures and presentations from Eisai and DeltaMed. He holds a patent on methods of treatment and diagnosis of epilepsy by detecting mutations in the SCN1A gene, which is held by Bionomics Inc. and licensed to Athena Diagnostics and Genetics Technologies Ltd., with institutional royalties. He serves as Chief Medical Officer for the Epilepsy Foundation (Victoria). Ingrid Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, and Longboard Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, LivaNova, Nutricia, Zuellig Pharma, Stoke Therapeutics, Eisai, Akumentis, and Praxis; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, Stoke Therapeutics, Eisai, and Longboard Pharmaceuticals; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc., Epygenyx, ES-Therapeutics, GW Pharma, Longboard Pharmaceuticals, Marinus, Neurocrine BioSciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, Biohaven Pharmaceuticals, Stoke Therapeutics, Praxis; and is a Non-Executive Director of Bellberry Ltd. and a Director of the Australian Academy of Health and Medical Sciences. She may accrue future revenue on a pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc. and licensed to various diagnostic companies; and has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2 012 900 190 and PCT/AU2012/001321 (TECH ID:2012–009). Eduard Hirsch, Lino Nobili, Federica Provini, Paolo Tinuper, and Luca Vignatelli declare no disclosures related to this paper. Data sharing is not applicable to this article as no datasets were generated or analyzed.

BACKGROUND:Novel biomarkers of the risk of sudden unexpected death in epilepsy (SUDEP) are needed to better inform people with epilepsy of their individual risk and identify those at a high risk. The aim of this study was to identify such biomarkers, particularly with the exploration of seizures characteristics that have not been previously investigated, including peri-ictal peripheral oxygen saturation (SpO2) and site of seizure onset. METHODS:We conducted a nested case-control study of SUDEP within a dedicated nationwide prospective cohort. Eligible participants were adults with drug-resistant focal epilepsy undergoing in-hospital seizure monitoring at 16 epilepsy monitoring units in France. Clinical data, results from presurgical investigations, and raw recordings from video EEG, electrocardiogram (ECG), and SpO2 were collected until the end of the recruitment period. The French National Directory of Natural Persons Identification was queried annually to identify deaths. SUDEP cases were adjudicated on the basis of medical records and interviews documenting the circumstances of death. Each SUDEP case was matched to four controls on the basis of study centre and date of inclusion. SUDEP risk factors were identified using LASSO-penalised conditional logistic regression. FINDINGS:From May 18, 2010, to Aug 23, 2015, we enrolled a total of 1074 participants and followed their vital status until the end of 2018, yielding a total of 6828 patient-years of follow-up. 42 participants died during follow-up, including 18 cases of definite or probable SUDEP, resulting in a SUDEP rate of 2·64/1000 patient-years (95% CI 1·36-3·92). Four risk factors were significantly associated with the risk of SUDEP: an extratemporal epileptogenic zone (OR 37·8, 95% CI 3·21-446·2, p=0·0039), a BMI of 30 or higher (26·0, 2·0-339·6, p=0·013), male sex (12·6, 1·5-106·8, p=0·0201), and predominantly nocturnal seizures (6·0, 1·2-28·7, p=0·026). In contrast, the presence of peri-ictal SpO2 of less than 80% during focal seizures, the frequency of focal-to-bilateral tonic-clonic seizures, heart rate variability, age at epilepsy onset, number of antiseizure medications, and history of depression were not significantly associated with SUDEP. INTERPRETATION:Extratemporal epilepsies involving the perisylvian region or frontal lobe appear to be associated with an increased risk of SUDEP. This finding warrants confirmation in larger cohorts and underscores the need to improve the diagnosis and surgical management of extratemporal epilepsies, which might contribute to improved SUDEP risk stratification and prevention. FUNDING:French Ministry of Health (Programme Hospitalier de Recherche Clinique National 2009).

OBJECTIVE:Investigate real-world outcomes in drug-resistant epilepsy (DRE) patients treated with cenobamate as adjunctive treatment to other antiseizure medications (ASMs) within the Early Access Programs (EAP) in Germany, France, and the United Kingdom. METHODS:DRE adults with uncontrolled focal-onset seizures were included from 19 hospitals participating in the EAP in this retrospective study. Data were sourced from clinical records. Participants were evaluated at baseline, 1 months, and 3 months from cenobamate start, and 3, 6, and 12 months after maintenance. The primary effectiveness endpoint was the 50% responder rate, defined as the reduction in seizure frequency ≥50%. RESULTS:Data were collected from 298 patients who received at least one dose of cenobamate; efficacy was evaluated on 216 patients with seizure data available. At baseline, the median epilepsy duration was 22.2 years, and 41.9% of patients had previous epilepsy surgery, including vagus nerve stimulation, with a median of nine previously failed ASMs. The median number of seizures/month was 8.8. After 3 months of maintenance, the 50% responder rate (primary endpoint) was 49.3%; the median percentage seizure reduction from baseline was 49.1%. A total of 100%, ≥90%, and ≥75% seizures reduction were reported in 13.6%, 20.0%, and 33.6% of patients, respectively. Both the responder rate and the median percentage seizure reduction steadily increased during the observation period. At 6-month maintenance, the seizure-free rate was 24.2%. The retention rate assessed by Kaplan-Meier decreased from 96.6% at 1-month cenobamate start to 69.7% at 12-month maintenance. Adverse Drug Reactions (ADRs) to cenobamate occurred in 30.9% of patients, with asthenia, dizziness, and somnolence being the most frequent; the majority were mild-to-moderate and resolved during the observation period; three patients (1.0%) experienced a total of seven serious ADRs, all during titration. SIGNIFICANCE:In this study, cenobamate demonstrated to be an effective option for people with uncontrolled epilepsy even after multiple failed ASMs or failure of epilepsy surgery. PLAIN LANGUAGE SUMMARY:This study involved patients with drug-resistant epilepsy, who had continued seizures despite using at least two antiseizure medications (ASMs). Patients received cenobamate (Ontozry) as epilepsy treatment during the Early Access Program (EAP) in France, Germany, and the United Kingdom. An EAP allows patients to receive promising new drugs under clinical supervision before they are commercially available. After 6 months from cenobamate start, 49.3% of patients had their seizures cut by half or more, and 13.6% became seizure-free. A total of 30.9% of patients had an undesirable reaction to cenobamate, mostly mild-to-moderate and resolved; the most frequent were asthenia, dizziness, and somnolence.

GATOR1 complex genes (DEPDC5, NPRL2, NPRL3) are associated with focal epilepsies, often without cortical malformations or intellectual disabilities. Our study focused on 10 children, with GATOR1 pathogenic variation and negative MRIs, all experiencing focal epilepsy onset between ages 1 and 7 years. Three were initially misdiagnosed with immune encephalitis, with seizure frequencies ranging from 2 per week to 40 per day. The seizures were monofocal and stereotyped in the same child. No recurrent brain localization was found in EEG, clinical data, or MRI. After achieving early developmental milestones, some patients developed cognitive or psychiatric challenges during active seizures. Over 1 to 14 years, three experienced recurrent status epilepticus, triggered by infections or medication changes. Currently, two patients are seizure-free on antiepileptic medications, while six continue to have frequent seizures. Notably, only half showed concordance between EEG and PET scan anomalies. Pathogenic variations included five in DEPDC5, four in NPRL3, and one in NPRL2, with six inherited from parents 3 of them being unaffected. The timeline for genetic analysis requests has significantly shortened over time. In cases of pharmacoresistant monofocal epilepsy with normal MRIs, in children with normal development-especially with a family history-testing for GATOR1 variations should be prioritized.

Introduction Les crises épileptiques sont classiquement considérées comme une complication des démences. Nous rapportons le cas d’un patient avec épilepsie focale de cause inconnue, développant ensuite des signes de synucléinopathie. Observation Un patient de 67 ans, droitier, a consulté le service de neurologie pour des épisodes stéréotypés de déjà-vus, suivis d’une désorientation temporo-spatiale avec amnésie antérograde. Chaque épisode durait 15minutes, survenant 10 fois par mois. Entre les épisodes, le patient rapportait un oubli accéléré. L’EEG a mis en évidence des pointes temporales gauches. Les biomarqueurs de la maladie d’Alzheimer dans le LCS étaient négatifs. On notait une atrophie insulaire droite. Le diagnostic d’épilepsie focale de cause inconnue a été posé, de type amnésie épileptique transitoire (AET) (Fig. 1). Du lacosamide 100mg a été introduit matin et soir. Trois ans après, alors que le patient était libre de crises, l’entourage témoignait d’une agitation nocturne. L’examen clinique objectivait un syndrome akinétohypertonique prédominant à droite. La polysomnographie a confirmé un trouble comportemental en sommeil paradoxal avec terreur nocturne, motivant un traitement par mélatonine à libération immédiate 20mg au coucher. Dans l’année, le bilan neuropsychologique a objectivé une majoration des déficits dysexécutifs et en mémoire verbale. Le DATSCAN a confirmé une dénervation dopaminergique. Une maladie à corps de Lewy (MCL) a finalement été évoquée (Fig. 2). Discussion Ce cas illustre que les crises épileptiques de début tardif sont un facteur de risque de démence et ne sont pas uniquement associées à la maladie d’Alzheimer. Au niveau syndromique, notre cas illustre que l’AET peut inaugurer une synucléionopathie, avec deux autres cas rapportés dans la littérature. Nous faisons l’hypothèse que l’alphasynucléine en elle-même pourrait induire une hyperexcitabilité neuronale. Conclusion Les neurologues, psychiatres et gériatres devraient connaître les présentations atypiques de synucléinopathies prodromales, ici avec crises focales précoces. Un suivi cognitif rapproché peut être bénéfique pour ces patients.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Introduction Le cénobamate, un nouvel antiépileptique disponible depuis 2020, présente des résultats très encourageants en termes d’efficacité chez des patients épileptiques pharmacorésistants. Cependant, ils sont issus d’une population étroitement sélectionnée. Objectifs L’objectif de notre travail est d’analyser l’efficacité, la tolérance et les adaptations thérapeutiques dans une cohorte de patients traitée par cénobamate en vie réelle. Méthodes Une étude rétrospective monocentrique a été conduite, incluant l’ensemble des patients traités par cénobamate de novembre 2020 à mars 2023. L’efficacité à 6 et 12 mois, les effets indésirables et les modifications thérapeutiques ont été évalués à partir des comptes rendus de consultations trimestrielles. Le traitement était efficace s’il réduisait d’au moins 50 % la fréquence des crises mensuelles. Résultats Au total, 81 patients ont été inclus. À 6 et 12 mois (n=71 et n=57), 33 % des patients étaient répondeurs aux traitements. Quatorze pour cent étaient libres de crises à un an. Vingt-cinq pour cent des patients ont arrêté le traitement, principalement pour inefficacité. Les effets indésirables les plus fréquents étaient : asthénie (52 %), troubles de l’équilibre (25 %), sensations vertigineuses (14 %). Le lacosamide et le clobazam étaient les traitements les plus modifiés au cours du suivi du fait d’effet indésirables. Discussion Dans notre cohorte, 40 % des patients ne répondaient pas aux critères d’inclusions des études princeps ; cependant, nos résultats concordent avec ceux obtenus dans les essais cliniques en termes d’efficacité et de tolérance. Les effets indésirables résultaient en majorité d’interactions pharmacologiques. Conclusion Le cénobamate montre une efficacité inédite dans une population épileptique pharmacorésistante à court de ressources thérapeutiques, au prix d’effets indésirables fréquents dont la prise en charge reste à codifier.

BACKGROUND:Genetic epilepsy diagnosis is increasing due to technological advancements. Although the use of molecular diagnosis is increasing, chromosomal microarray analysis (CMA) remains an important diagnostic tool for many patients. We aim to explore the role and indications of CMA in epilepsy, given the current genomic advances. METHODS:We obtained data from 378 epileptic described patients, who underwent CMA between 2015 and 2021. Different types of syndromic or nonsyndromic epilepsy were represented. RESULTS:After excluding patients who were undertreated or had missing data, we included 250 patients with treated epilepsy and relevant clinical information. These patients mostly had focal epilepsy or developmental and epileptic encephalopathy, with a median start age of 2 years. Ninety percent of the patients had intellectual disability, more than two thirds had normal head size, and 60% had an abnormal magnetic resonance imaging. We also included 10 patients with epilepsy without comorbidities. In our cohort, we identified 35 pathogenic copy number variations (CNVs) explaining epilepsy with nine recurrent CNVs enriched in patients with epilepsy, 12 CNVs related to neurodevelopmental disorder phenotype with possible epilepsy, five CNVs including a gene already known in epilepsy, and nine CNVs based on size combined with de novo occurrence. The diagnosis rate in our study reached 14% (35 of 250) with first-line CMA, as previously reported. Although targeted gene panel sequencing could potentially diagnose some of the reported epilepsy CNVs (34% [12 of 35]). CONCLUSIONS:CMA remains a viable option as the first-line genetic test in cases where other genetic tests are not available and as a second-line diagnostic technique if gene panel or exome sequencing yields negative results.

Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.

Over the last few decades, deciphering the alteration of molecular pathways in brain tumors has led to impressive changes in diagnostic refinement. Among the molecular abnormalities triggering and/or driving gliomas, alterations in the MAPK pathway reign supreme in the pediatric population, as it is encountered in almost all low-grade pediatric gliomas. Activating abnormalities in the MAPK pathway are also present in both pediatric and adult high-grade gliomas. Across those alterations, BRAF p.V600E mutations seem to define homogeneous groups of tumors in terms of prognosis. The recent development of small molecules inhibiting this pathway retains the attention of neurooncologists on BRAF-altered tumors, as conventional therapies showed no significant effect, nor prolonged efficiency on the high-grade or low-grade unresectable forms. Nevertheless, tumoral heterogeneity and especially molecular alteration(s) associated with MAPK-pathway abnormalities are not fully understood with respect to how they might lead to the specific dismal prognosis of those gliomas and/or affect their response to targeted therapies. This review is an attempt to provide comprehensive information regarding molecular alterations related to the aggressiveness modulation in BRAF-mutated gliomas and the current knowledge on how to use those targeted therapies in such situations.

Familial adult myoclonus epilepsy (FAME) is a genetic condition characterized by the occurrence of cortical tremor, myoclonus, and epilepsy. To date, there is neither a curative nor a preventive treatment for FAME. Clinical management is essentially symptomatic and based on antiseizure medications (ASMs). The choice of the correct therapeutic option is limited to ASMs that have both an antiseizure and an antimyoclonic effect, such as valproate, levetiracetam, benzodiazepines, and perampanel. However, these medications control seizures well while having a limited effect on myoclonus and cortical tremor. In addition, many ASMs, including sodium channel blockers and gabapentin, are contraindicated in this condition. The ideal therapeutic option would be a precision treatment able to revert the genetic defect underlying it. Nevertheless, this does not seem to be an option that will be available soon.

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.