Citations

Abstract Objective To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status. Methods In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2–18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1–3; 4–6; ≥7), and SCN1A pathogenic variant status ( SCN1A +; SCN1A −). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure‐free interval, and Clinical Global Impression–Improvement [CGI–I] scale scores rated by parents/caregivers and investigators), and safety (treatment‐emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved). Results Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure‐free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement (“Much Improved”, “Very Much Improved”) on CGI–I scores across all stratified groups. CGI–I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator‐rated CGI–I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end‐of‐study. Significance Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well‐tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted. Plain Language Summary Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2–18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A . They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

Abstract Objective Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)‐negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. Results A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG‐guided radiofrequency thermocoagulation (RF‐TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). Significance This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG‐guided RF‐TC. The high proportion of MRI‐negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.

Abstract Objective Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Task Force study provides an updated overview of current trends and regional differences. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) across 29 countries and six continents, identified through ILAE networks, and included all children and adolescents treated in 2023 who underwent presurgical evaluation/epilepsy surgery. Results Group‐level data were available for 2427 patients. Mean age at surgery was 9.1 ± 4.9 years; mean epilepsy duration was 5.3. At surgery, 3.2% were <1 year old (highest in Oceania: 5.1%), and 6.1% were nonpharmacoresistant (highest in Europe: 15.0%). Prior neurosurgery was reported in 14.2% (highest in North America: 28.8%), including 8.0% resections (6.1% for epilepsy, 1.5% for tumors; highest in Oceania: 16.5%), 2.3% disconnections (1.3% corpus callosotomy; highest in South America: 4.7%), and 4.2% neuromodulation (3.7% vagal nerve stimulation, .2% responsive neurostimulation, one deep brain stimulation; highest in North America: 12.2%). Developmental and epileptic encephalopathies (DEEs) at surgery included Lennox–Gastaut syndrome (7.4%), infantile epileptic spasms syndrome (5.1%), and DEE with spike–wave activation in sleep (1.5%). Presurgical investigations included fluorodeoxyglucose positron emission tomography (52.6%; highest in Oceania: 79.7%), genetic testing (46.8%; highest in Asia: 54.3%), magnetic resonance imaging (MRI) postprocessing (32.4%; highest in South America: 53.0%), functional MRI (fMRI; 15.2%; highest in North America: 40.3%), magnetoencephalography (11.9%; highest in North America: 39.3%), single photon emission computed tomography (9.6%; highest in North America: 22.2%), high‐density electroencephalography (EEG; 1.9%; highest in Europe: 4.7%), source localization (1.6%; highest in Oceania: 7.6%), Wada test (1.2%; highest in North America: 3.5%), and EEG‐fMRI (.5%; highest in Europe: 1.1%). Significance Despite some early surgeries, including in infancy and before pharmacoresistance, mean epilepsy duration before surgery remains >5 years. Reoperations are common, with resection more frequent than neuromodulation. Genetic testing in nearly half of patients reflects its growing relevance, and the high rate of DEEs underscores the complexity of surgical candidates.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Abstract The International League Against Epilepsy (ILAE) is a global organization dedicated to improving the lives of people with epilepsy through education, research, and advocacy. Recognizing the need for broader engagement and multidisciplinary collaboration, the ILAE has established five sections: Young Epilepsy Section (YES), Nursing, Social Work and Social Services (SWSSS), Neurotechnology, and Pharmacy. These sections aim to strengthen professional networks, enhance education, and promote innovation in epilepsy care. YES fosters leadership and participation among early‐career professionals, whereas the Nursing Section addresses gaps in epilepsy‐specific training and competency development. SWSSS emphasizes psychosocial care, advocacy, and health equity, supporting Intersectoral Global Action Plan (IGAP) objectives through culturally sensitive interventions. The Neurotechnology section advances the integration and development of innovative tools for diagnosis and treatment, and the Pharmacy section focuses on optimizing medication management and access to antiseizure medications globally. Collectively, these sections contribute to the WHO IGAP by improving policy, care delivery, research, and public health responses. Looking ahead, ILAE seeks to expand multidisciplinary participation, encourage cross‐sectional collaboration, and maintain its role as a leading force in global epilepsy care. Through these initiatives, ILAE continues to build capacity, foster inclusivity, and drive progress toward equitable, comprehensive epilepsy services worldwide. Plain Language Summary The International League Against Epilepsy (ILAE) is the global organization responsible for all healthcare professionals involved in the care of those with epilepsy. Recognizing the increasing number of different disciplines now contributing to epilepsy care, and the need to develop professionals of the future, the ILAE has recognized “sections” of like‐minded individuals to encourage networking and communication. Together, these sections contribute to the WHO Intersectoral Global Action Plan (IGAP) by improving policy, care delivery, research, and public health responses. Moving forward, the ILAE seeks to expand multidisciplinary participation, encourage collaboration, and maintain its role as a leading force in global epilepsy care.

Abstract Objectives Dravet syndrome (DS) is a drug‐resistant developmental and epileptic encephalopathy, often requiring three or more antiseizure medications (ASMs). Consequently, the therapeutic landscape is highly complex, combining DS‐specific agents (stiripentol, STP; cannabidiol, CBD; fenfluramine, FFA), non‐specific ASMs, and non‐pharmacologic options such as dietary therapy or neuromodulation. In addition, recognition of patients' changing needs across the lifespan, together with the essential contribution of caregiver education to effective treatment oversight—including awareness of potential drug–drug interactions and adverse events—emphasizes the value of an integrated and forward‐looking approach. A consensus initiative was developed to guide clinicians in the management of patients with DS, with a particular focus on STP‐containing regimens. Methods Based on a literature review and clinical vignette discussions, a nominal group of five international DS experts developed 38 statements across six themes: (i) general principles, (ii) guiding physicians to empower families, (iii) STP as add‐on to specific and non‐specific Dravet ASMs, (iv) FFA in regimens containing STP, (v) CBD in regimens containing STP, and (vi) patient follow‐up during treatment initiation. Statements were scored on a 9‐point Likert scale (1 = strongly disagree, 9 = strongly agree) first by the nominal group and then by an international panel of 59 DS clinicians. Consensus was defined as ≥75% rating ≥7 and/or a median ≥8. Results Thirty‐four of the 38 statements (89%) reached consensus among both the nominal group and the international panel; one did not reach consensus in either, and three reached consensus only among the nominal group. Both panels agreed on the importance of involving families in treatment decisions and follow‐up, as well as on key aspects of polytherapy management, including ASM initiation, treatment adjustments, and adverse event management. Significance This international consensus integrates evidence and clinical expertise to establish shared principles that address a long‐standing gap in the polytherapeutic management of Dravet syndrome. Plain Language Summary Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood, with seizures that often persist throughout life. Because the disease is highly drug resistant, most patients are treated with polytherapy, making clinical management complex for clinicians. This consensus brings together published evidence and expert experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.