Background and ObjectivesDevelopmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort.MethodsWe retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up.ResultsPathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype.DiscussionThis large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

BACKGROUND:Stereoelectroencephalography (SEEG) is a well-established technique for localizing epileptogenic zones in patients with drug-resistant epilepsy, including children. While considered safe, rare but serious complications can occur. CASE PRESENTATION:We report the case of a girl with tuberous sclerosis complex and drug-resistant epilepsy who underwent SEEG implantation as part of pre-surgical evaluation. Electrode placement was uneventful. However, during SEEG monitoring, the signal was lost on two electrodes, raising suspicion of fracture. During explantation, these electrodes were not retrieved, as the distal ends were not visible. The removal of the remaining electrodes proceeded without complication. Nearly 3 years later, the patient developed progressive gait instability. Imaging revealed migration of one electrode fragment into the spinal canal at the L4-L5 level, in contact with the cauda equina, and another fragment into the left temporal horn of the lateral ventricle. The spinal fragment was successfully removed surgically without complication. CONCLUSION:To the best of our knowledge, this is the first reported case of brain and spinal migration of a retained fragment of a SEEG electrode. This case highlights a rare but potentially significant complication of SEEG implantation and discuss the management of electrode fragments.

BACKGROUND AND OBJECTIVES:Developmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort. METHODS:We retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up. RESULTS:Pathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype. DISCUSSION:This large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

Background: Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. Methods: We leveraged a large, multicentre international cohort comprising 282 individuals with KCNQ2 pathogenic variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed. Results: SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, early SCB initiation within the first month of life was associated with significantly more favourable neurodevelopmental trajectories, including higher rates of achievement of major motor milestones. Early seizure freedom itself was a strong predictor of improved neurodevelopment, with the positive effect of SCBs likely mediated by their ability to control seizures. However, considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation. Variant severity and possible genetic modifiers likely contribute to this heterogeneity, underscoring the need for precision therapies beyond nonspecific ASM approaches. Conclusion: Our results strongly support the use of SCBs as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE due to their high effectiveness. Moreover, SCBs appear most beneficial when initiated during the neonatal period, with earlier treatment linked to earlier seizure offset and better developmental outcomes. These results highlight the importance of early genetic diagnosis and timely SCB therapy, and support CBZ or OXC as first-line agents. We however emphasise that early treatment is not universally transformative, and further work, including exploration of targeted therapies but also standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population. ### Competing Interest Statement S.W. received consultancy fees from UCB, Xenon Pharmaceuticals, Lundbeck, Knopp Biosciences, Encoded Therapeutics, Angelini Pharma, and Roche. C.F. has served on scientific advisory board for longboard pharmaceuticals and biocodex and has received speaker honoraria from Nutricia, UCB, and Jazz Pharmaceuticals. S.A. is Deputy Editor for Epilepsia. He has received personal fees for lectures or advice from: Biocodex, Eisai, Encoded, GRIN therapeutics, Jazz Pharmaceuticals, Longboard, Lundbeck, Neuraxpharm, Nutricia, Mosaica, Proveca, Servier, Stoke, Stream neuroscience, UCB Pharma. He has been investigators for: Eisai, Lundbeck, Proveca, Takeda, UCB Pharma. I.E.S. has served on scientific advisory boards for Biocodex, BioMarin, CAMP4 Therapeutics, Chiesi, Eisai, Encoded Therapeutics, Knopp Biosciences, Longboard Pharmaceuticals, Mosaica Therapeutics, Takeda Pharmaceuticals, UCB; has received speaker honoraria from Akumentis, Biocodex, BioMarin, Chiesi, Eisai, GlaxoSmithKline, Liva Nova, Nutricia, Stoke Therapeutics, Zuellig Pharma; has received funding for travel from Biocodex, BioMarin, Eisai, Encoded Therapeutics, GlaxoSmithKline, Stoke Therapeutics, UCB; has served as an investigator for Anavex Life Sciences, Biohaven Ltd, Bright Minds Biosciences, Cerebral Therapeutics, Cerecin Inc, Cereval Therapeutics, Encoded Therapeutics, EpiMinder Inc, ES-Therapeutics, GW Pharma, Longboard Pharmaceuticals, Marinus, Neuren Pharmaceuticals, Neurocrine BioSciences, Ovid Therapeutics, Praxis Precision Medicines, Shanghai Zhimeng Biopharma, SK Life Science, Supernus Pharmaceuticals, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, Zynerba; and has consulted for Atheneum Partners, Biohaven Pharmaceuticals, Care Beyond Diagnosis, Cerecin Inc, Eisai, Epilepsy Consortium, Longboard Pharmaceuticals, Praxis, Stoke Therapeutics, UCB, Zynerba Pharmaceuticals; 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 pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). The remaining authors report no competing interests. ### Funding Statement C.M. received funding from University of Antwerp-BOF (FFB200262). S.W. received funding from Fonds Wetenschappelijk Onderzoek (FWO 1861424N), GSKE - UCB Award, European Partnership for Personalized Medicine (EPPerMed BEATKCNQ), KCNQ2e.v. L.V. and S.W. received funding from the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ). L.V. recieved funding from the Agence Nationale de la Recherche (ANR 19-CE17-0018-02). M.M. was supported by Aix Marseille Univ, Agence Nationale de la Recherche (ANR 19‐CE17‐0018‐02). A.T.G.C received funding from the National Health and Medical Research Council (NHMRC) Postgraduate Scholarship, Australia. E.C.C. received funding from the Jack Pribaz Foundation, the KCNQ2 Cure Alliance, the Miles Family Fund, and the parents of Raz Fisher. This work was supported by funding from the Australian National Health and Medical Research Council (GNT1091593, GNT1172897, GNT2006841, GNT2010562, GNT2033247) and Medical Research Future Fund Australia (GNT2007707). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Informed consent for participation and publication was obtained from all parents or legal guardians according to the Declaration of Helsinki. The study was approved by the Human Research Ethics Committees of the University Hospital of Antwerp (Belgium, number: 20/50/683) and the Committee for the Protection of Persons (Comite de Protection des Personnes Sud-Est III, France, IDRCB: 2020-A01363-36). Data are reported in line with the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) statement. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data supporting the findings of this study are available to those eligible upon request to the corresponding author.

Introduction Identifier les meilleurs candidats pour la SNV reste difficile : il n’y a à l’heure actuelle que peu d’études portant sur de larges cohortes et avec un long follow-up. Objectifs Notre objectif est d’analyser la réponse à la SNV chez les patients avec épilepsie généralisée pharmacorésistante et de rechercher des facteurs pronostiques favorables de réponse. Méthodes Cette étude monocentrique rétrospective a collecté des données de juillet 2000 jusqu’à juin 2024 parmi les patients avec épilepsie généralisée pharmacorésistante et qui ont bénéficié d’une implantation de la stimulation du nerf vague avec un follow-up d’au moins un an. Des analyses univariées, multivariées, une régression logistique univariée, ainsi que des régressions logistiques par étapes et pénalisées (LASSO) ont été réalisées. Résultats Dans notre population de patients avec épilepsie généralisée pharmacorésistante ayant eu l’implantation d’un stimulateur du nerf vague à Marseille (n=129), 82 avaient un syndrome de Lennox Gastaut et 27 une épilepsie généralisée idiopathique. Le suivi post-implantation moyen était de 8 ans et 9 mois (1–21) ; 40 % des patients étaient répondeurs ; 15 % avaient une amélioration>75 %, et certains étaient libres de crises (recul 1,5–12 ans) ; d’autres ont présenté une franche amélioration, très précoce, mais suivie d’un échappement. Les variables associées à un meilleur résultat SNV étaient le sexe masculin et un âge plus élevé à l’implantation et à la dernière observation, quel que soit le sous-type d’épilepsie. Discussion Dans notre étude, nous avons observé un bon taux de répondeurs à la SNV malgré un très long follow-up, des patients très améliorés voire libres de crise, et d’autres très améliorés mais seulement de manière transitoire. Un âge plus élevé est un facteur pronostique positif (déjà retrouvé dans quelques autres études), ainsi le sexe masculin, ce qui par contre n’avait encore jamais été retrouvé à ce jour. Conclusion Cette étude permet de définir de potentiels nouveaux facteurs prédictifs de bonne réponse à la SNV, et de mieux caractériser certains profils de réponse.

BACKGROUND:Epileptic disorders are a heterogeneous group of neurological conditions, with many cases linked to monogenic causes, particularly in developmental and epileptic encephalopathies (DEE). Identifying pathogenic variants aids treatment, prognosis, and family planning. In France, genetic testing is coordinated through the EpiGene network. METHODS:We analyzed clinical and genetic data from 2563 epilepsy patients referred to four diagnostic labs (2016-2023). Epilepsy syndromes were classified via pre-test questionnaires, and genotyping used various gene panels, including a 68-gene core panel. Multivariate logistic regression assessed diagnostic rates and genotype-phenotype correlations. RESULTS:Overall, 27.0% of patients had pathogenic/likely pathogenic variants, mainly within the core panel (24%). SCN1A and KCNQ2 were the most frequently mutated genes. Diagnostic yield varied by syndrome, with Dravet Syndrome Spectrum (DSS) and early-infantile DEE (EIDEE) showing the highest rates (41% and 34%, respectively). Genetic heterogeneity differed across syndromes, from DSS (predominantly SCN1A) to Infantile Epileptic Spasms Syndrome (IESS, 12%), involving ≥ 26 genes. Outside DEE, self-limited neonatal epilepsy (SeLNE) had the highest yield (50%). Earlier seizure onset was associated with a higher likelihood of a positive molecular diagnosis, whereas intellectual disability severity and drug resistance were not independently predictive of diagnostic outcome. Genotype-phenotype correlations highlighted that objective clinical data (e.g., age of onset) can outperform syndrome labels (e.g., EIDEE) in predicting diagnosis. CONCLUSION:This large cohort study refines the genetic landscape of epilepsy, informs classification challenges, and enhances genetic testing strategies, ultimately improving patient care and future research directions.

OBJECTIVE:Lennox-Gastaut syndrome (LGS) is typically characterized by drug-resistant epilepsy and subsequent cognitive deterioration. Surgery is a rare but viable option for the control of seizures in a subset of patients with LGS. This study aimed to describe the organization of the epileptogenic zone network (EZN) in patients with LGS using stereoelectroencephalography (SEEG) and to report the outcome of post-SEEG treatment. METHODS:A quantitative SEEG signal analysis was conducted in 14 consecutive patients with LGS, in whom a potentially localized EZN was suggested based on a comprehensive noninvasive evaluation. The EZN and the irritative zone network were identified using relevant biomarkers during ictal (epileptogenicity index and connectivity epileptogenicity index) and interictal (spikes and high-frequency oscillations) recordings. The applied post-SEEG treatments were assessed, including SEEG-guided radiofrequency thermocoagulation (RF-TC), surgery, and neurostimulation. RESULTS:The seizure onset patterns showed some specificity by seizure type, with 84% of tonic seizures involving low-voltage fast activity. The EZN of patients with LGS was often, but not always, complex and extensive, involving two or more lobes (79%) and both hemispheres (64%). The lateral neocortical structures, particularly the lateral premotor and dorsolateral prefrontal cortices, were identified as being most frequently involved in the EZN. Among the explored subcortical structures, only the pulvinar, central-lateral thalamic nucleus, and hypothalamic hamartoma belonged to the EZN. Twelve patients (86%) underwent SEEG-guided RF-TC, with 50% experiencing a >50% reduction in baseline seizure frequency. Four patients (29%) underwent curative surgery for significant involvement of a lesion in the EZN, and one case achieved an Engel class I outcome. SIGNIFICANCE:This is the first quantitative SEEG study in patients with LGS to demonstrate the utility of SEEG in identifying patients who may benefit from surgery and to perform SEEG-guided RF-TC. Nevertheless, the indications for SEEG should be carefully assessed, as localized EZN is uncommon in LGS.

Background: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease. Methods: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR-Cas9 editing and standard cell biology techniques. Findings: Between Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of <125 x 10:sup>-6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1-8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. Interpretation: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population.

OBJECTIVE:Neonatal seizures initiate the onset of epilepsy in less than 20% of cases. Establishing accurate and prompt diagnosis for precision medicine, offering tailored care, and informing families about neurodevelopmental prognosis represents a significant challenge. We aim to describe the natural history of drug-resistant epilepsy and negative brain MRI with neonatal onset, and to identify predictors of neurodevelopmental outcomes. METHODS:We retrospectively analyzed demographic, clinical, electroencephalogram (EEG), and genetic data from neonates with epilepsy onset before 1 month of age, with no provoked cause, and a normal brain MRI, followed at a tertiary center from 2000 to 2020. Neonates with self-limited epilepsy (SLE) or those responding to phenobarbital without later epilepsy were excluded. RESULTS:Among 56 patients, 60% had a genetic etiology (KCNQ2, STXBP1, KCNT1, others). Most (96%) developed intellectual disability (ID); moderate ID without cerebral palsy (CP) was recorded in 11, and profound intellectual and multiple disabilities (PIMD) in 42. Only two patients had a favorable neurodevelopmental outcome without intellectual disability. An abnormal neurological exam at epilepsy onset was the sole risk factor for future PIMD. SIGNIFICANCE:Neonatal-onset pharmacoresistant epilepsies with a normal brain MRI are predominantly monogenic and lead to poor neurodevelopmental outcomes. An abnormal initial neurodevelopmental assessment predicts future PIMD. PLAIN LANGUAGE SUMMARY:Our study found that epilepsy starting in the neonatal period is often linked to a strong genetic component. The prognosis is generally poor, with frequent neurodevelopmental delays. An abnormal neurological examination during the neonatal period is a predictor of worse outcomes.

BACKGROUND AND OBJECTIVES:Anti-NMDAR encephalitis (NMDARE) is a severe neurologic condition, and recently, the NMDAR Encephalitis One-Year Functional Status (NEOS) score has emerged as a 1-year prognostic tool. This study aimed to evaluate NEOS score and biomarker (neurofilament light chains [NfL], total-Tau protein, glial fibrillary acidic protein, and serum cytokines) correlation with modified Rankin Scale (mRS), cognitive impairment, and clinical recovery in pediatric NMDARE over 2 years. METHODS:In this French multicenter observational study, 104 pediatric patients with NMDARE were followed for a minimum of 2 years. Clinical data and serum/plasma samples were collected. Biomarker levels, measured using electroluminescence mesoscale discovery (MSD) S-PLEX, were compared between patients and controls and assessed for correlations with disease activity, mRS, cognitive/language impairment, and recovery status at 2 years. RESULTS:At a median follow-up of 39.5 months, 68 percent of patients had unfavorable recovery and 54% had significant cognitive impairment. Both outcomes were strongly associated with younger age at diagnosis (OR 6.10 [1.91-27.3] p < 0.01 and 5.69 [1.46-27.7] p = 0.02, respectively). A higher NEOS score was significantly correlated with increased cognitive impairment (OR 2.53 [1.52-4.21], p < 0.001), higher mRS scores (OR 2.12 [1.34-3.57], p < 0.01), and unfavorable recovery at 2 years (OR 2.00 [1.30-3.06], p = 0.015). Elevated NfL levels were significantly associated with unfavorable recovery (OR 3.62 [1.29-10.9] p = 0.012) and severe cognitive impairment (OR 3.77 [1.38-10.9] p = 0.012) at 2 years. The combined area under the curve (AUC) for NfL and NEOS was significantly higher than the AUCs of NEOS and NfL alone (p = 0.01). DISCUSSION:The NEOS score strongly predicts long-term outcomes in NMDARE, with its predictive value extending beyond the first-year mR prediction. NfL levels at disease onset seem to improve accuracy in predicting poor outcomes, providing valuable information for treatment decisions and future clinical trials.

Recent studies in adults suggested that extended-interval dosing of rituximab/ocrelizumab (RTX/OCR) larger than 12 months was safe and could improve safety. This was an observational cohort study of very active pediatric-onset multiple sclerosis (PoMS) (median (range) age, 16 (12-17) years) treated with RTX/OCR with 6 month standard-interval dosing (n = 9) or early extended-interval dosing (n = 12, median (range) interval 18 months (12-25)). Within a median (range) follow-up of 31 (12-63) months after RTX/OCR onset, one patient (standard-interval) experienced relapse and no patient showed disability worsening or new T2-weighted lesions. This study suggests that the effectiveness of RTX/OCR is maintained with a median extended-interval dosing of 18 months in patients with very active PoMS.

BackgroundPrevious studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex.MethodsWe identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected.ResultsForty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery.ConclusionDespite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na +/ K + ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3 -negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 ( n = 3), ATP1A2 ( n = 3), ANK3 ( n = 1), SCN2A ( n = 1), and CHD2 ( n = 1). In follow-up investigations, two additional ATP1A3 -negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A , lead to AHC or AHC-like presentation. Still, the majority of ATP1A3 -negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.

Objective Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) creates an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence there is an urgent need for novel therapies. Previously we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. Methods We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. Results Here we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated Interictal-like Epileptiform Discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti- grik2 miRNA was designed to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. Interpretation Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients.

Abstract We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/mL oral solution). In our cohort, 26 patients had associated epilepsy (26/46 [56%]), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow‐up was 15 mg/kg/day. The median treatment duration was 13 months (range: 1–32 months). CBD reduced the incidence of seizures in seven out of 10 patients (70%) with one seizure‐free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug‐resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.

To study long‐term clinical and cognitive outcomes of patients with anti‐N‐methyl‐d‐aspartate receptor encephalitis (NMDAR‐E), an acute autoimmune neurological disease with severe acute presentations.