Diagnostic MRI evaluation of temporal lobe epilepsy (TLE) depends on the subjective visual interpretation of MRI images. These interpretations could be enhanced by quantitative artificial intelligence (AI) support tools. Humans often make sequential and conditional decisions during their radiological interpretations, such as whether an abnormality is present and, if present, characterizing the abnormality. It is not known whether it is superior to train AI to treat every decision separately in a similar step-wise manner or to train a model holistically on all decisions simultaneously. Here, we analysed three large epilepsy MRI datasets [n = 3676, 2320 people with epilepsy and 1356 healthy controls (HC)] to perform two tasks: (i) establish the presence of a TLE pattern on MRI and (ii) determine TLE pattern lateralization. We compared Step-wise models that independently classify TLE versus HC and lateralize patients as left TLE (L-TLE) or right TLE (R-TLE), against a simultaneous model trained to distinguish all three classes in a single step. To do this, 3D volumetric T1-weighted images were input into an EfficientNetV2 model multiple times to ensure reproducibility of results. Class prediction, model classification confidence and saliency maps were output for interpretability. Step-wise models outperformed the Simultaneous model on both tasks (both Ps < 0.001), with an average ∼2.8% accuracy increase for discriminating HC from TLE and an average 12.7% accuracy increase for distinguishing L-TLE from R-TLE. For both the Step-wise and Simultaneous models, important features discriminating TLE from HC included the known TLE limbic pattern involving the hippocampus, parahippocampal cortical regions, cingulate cortex and lateral temporal regions. However, there was less concordance between the Step-wise and Simultaneous models for the L-TLE versus R-TLE task (all Fisher's Zs > 10.5, Ps < 0.001); the Step-wise model focused less on subcortical regions such as the thalamus and hippocampus and focused more on distributed cortical pathology. Across the two Step-wise models, 95.1% of TLE patients had accurate classifications in either HC versus TLE and/or L-TLE versus R-TLE tasks. These results included 69.6% of patients being both correctly labelled as TLE and lateralized, 13.9% being correctly labelled TLE but lateralized incorrectly and 11.6% being lateralized correctly but not detected as TLE. These findings provide evidence that diagnostic tasks with simpler, Step-wise AI models may enhance diagnostic performance and interpretability in clinical workflows. Future AI clinical support tools can leverage this step-wise approach in the early identification of TLE-related structural patterns, supporting timely diagnosis and treatment decisions.

Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.

Background and Objectives:Pathogenic variants in the SCN2A gene, encoding the α-subunit type 2 of the voltage-gated sodium channel NaV1.2, cause a phenotypic spectrum including 4 major disorders as benign familial infantile seizures, developmental and epileptic encephalopathy, intellectual disability, and autism. Gain-of-function variants resulting phenotypes may be treated with sodium channel blockers, while loss-of-function (LoF) conditions are non-respondent. We focused on the effects of the pathogenic SCN2A variant c.4976C>T (p.A1659V) found in heterozygosity in 3 patients affected by DEE non responsive to SCB. We functionally investigated this previously uncharacterized SCN2A variant. Methods:Three individuals with the SCN2A c.4976C>T (p.A1659V) variant were studied. This variant was detected by next-generation sequencing (NGS). The nucleotide substitution was inserted by site-directed mutagenesis in a stabilized SCN2A plasmid encoding NaV1.2. Expression and functional characterization of the NaV1.2 A1659V variant was performed in HEK293 cells by western blotting, confocal microscopy, and patch clamp electrophysiology. Results:The same de novo pathogenic SCN2A variant was detected in 3 patients with DEE characterized by early onset, severe ID, and seizures unresponsive to SCB. In 2 patients, the variant is in a mosaic state. The NaV1.2 A1659V variant did not affect channel protein expression while exhibiting significant effects on its function as shown by the reduced Na+ currents, a shift of the activation curve toward more negative potentials, a shift of the inactivation curve to more negative voltages, and slower kinetics of inactivation compared with native NaV1.2 in HEK293 cells. Simulations suggested that the variant increases excitability in neurons. Discussion:These results revealed the multifaceted functional effect of A1659V variant on channel activity and highlighted the complex genotype-phenotype correlation underlying significant clinical and pharmacological variability in SCN2A-related encephalopathies.

Abstract This multicenter retrospective study evaluated the effectiveness and safety of highly purified cannabidiol (CBD) in 22 patients with 15q11.2‐q13.1 duplication or deletion syndromes (15q‐DDS), including 12 with 15q duplication syndrome (dup15q) and 10 with Angelman syndrome (AS). Median (interquartile range [IQR]) age at CBD initiation was 14.5 (10–22.5) years, with a median (IQR) follow‐up of 21 (14–33) months. All dup15q and two AS patients presented with a Lennox–Gastaut phenotype. At last observation, mean seizure reduction was 55.7% (95% confidence interval 38.7–72.7), with 63.6% patients achieving ≥50% reduction, 40.9% achieving ≥75% reduction, and 18.2% achieving seizure freedom. Tonic seizures in dup15q and myoclonic seizures in AS showed the most notable reductions. EEG improvement was observed in 7/16 patients, with marked improvement observed in two dup15q patients. Clinical improvement on the Clinical Global Impression‐Improvement scale was reported in 72.7%, alongside nonseizure benefits such as improved sleep, behavior, and attention in a subset of patients. CBD was well tolerated; no patient discontinued CBD due to side effects alone, and retention at last visit was 81.8%. These findings suggest that CBD may provide clinically meaningful benefit in patients with 15q‐DDS, including seizure reduction and improvements in sleep, behavior, and attention in selected cases. Plain Language Summary Epilepsy secondary to 15q11.2‐q13.1 duplication or deletion syndromes (15q‐DDS) is often severe, making daily life difficult for patients and their families. In this study, treatment with highly purified cannabidiol (CBD) reduced seizures in many patients with 15q‐DDS. CBD was generally well tolerated, and caregivers also reported improvements in sleep, behavior, and attention in a number of cases. Overall, these findings suggest that CBD may be a helpful treatment option for people with 15q‐DDS.

OBJECTIVE:The polygenic risk score (PRS) for individuals with genetic generalized epilepsy (GGE) quantifies the common risk variants in genes identified in genome-wide association studies. We hypothesized that the phenotype of GGE patients differs based on their GGE PRS. METHODS:We identified participants with highest (n = 59) versus lowest (n = 48) PRS from the GGE patients (n = 2256) recruited through the Epi25 Collaborative for comparison. Detailed clinical data were acquired retrospectively for the 59 high PRS and 48 low PRS individuals with GGE from the Epi25 database and from the contributing centers. For validation, we accessed a larger cohort (n = 1175) of patients with GGE included in the Epi25 Collaborative. RESULTS:This study found no difference in phenotypic features of patients between the high-PRS GGE and low-PRS GGE subgroups, including age at onset, family history, and specific GGE syndrome. However, more patients from the lowest compared to the highest PRS subgroup were pharmacoresistant (31.7% vs. 8.9%, p = .01). On validation in a larger cohort, the PRS did not differ in the group of pharmacoresistant compared to nonpharmacoresistant patients. SIGNIFICANCE:No meaningful association between PRS and age at onset, history of febrile seizures, pre-/perinatal complications, epilepsy syndromes, seizure types, co-occurrence of functional/dissociative (nonepileptic) seizures, psychiatric comorbidities, electroencephalographic/magnetic resonance imaging findings, or drug response could be demonstrated in this study of people with GGE.

INTRODUCTION:Neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD), Fragile X syndrome (FXS), and Rett Syndrome (RTT), share impairments in cognitive and behavioral functioning and may involve an altered excitatory/inhibitory balance modulated by the endocannabinoid system. This systematic review evaluated the safety and efficacy of cannabinoid-based products (CBPs) in these pediatric NDDs. METHODS:We conducted a systematic review according to Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) 2020, including randomized and nonrandomized studies of patients under 18 years treated with cannabidiol (CBD), cannabidivarin (CBDV), tetrahydrocannabinol (THC), or their combinations. Outcomes were adverse events (AEs) and treatment discontinuation, seizure reduction, and behavioral and cognitive changes. Study quality and certainty of evidence were assessed using design-specific risk-of-bias tools and the GRADE approach. RESULTS:Seventeen studies (two randomized controlled trials, observational studies, and case series) met the inclusion criteria. Across diagnoses, CBPs were generally associated with mild-to-moderate AEs and low discontinuation rates. Descriptive pooled proportions suggested behavioral improvements in ASD and FXS and seizure reduction in RTT, with exploratory analyses indicating differential effects of CBD versus CBD + THC on behavioral and cognitive outcomes in ASD. CONCLUSION:CBPs may offer potential benefits for selected behavioral symptoms and comorbid epilepsy in pediatric NDDs, but current evidence is insufficient to support routine clinical use. High-quality randomized controlled trials with standardized outcome measures and long-term follow-up are needed to clarify efficacy, safety, and syndrome-specific effects.

OBJECTIVE:Drug-resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short-chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti-inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease-modifying effects in a preclinical model of DRE. METHODS:Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE. RESULTS:SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3-fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut-brain axis dysfunction to disease progression. INTERPRETATION:These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance. ANN NEUROL 2026;100:613-627.

Extensive neuroimaging research in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) has identified brain atrophy as a disease phenotype. While it is also related to a complex genetic architecture, the transition from genetic risk factors to brain vulnerabilities remains unclear. Using a population-based approach, we examined the associations between epilepsy-related polygenic risk for HS (PRS-HS) and brain structure in healthy developing children, assessed their relation to brain network architecture, and evaluated its correspondence with case-control findings in TLE-HS diagnosed patients relative to healthy individuals. We used genome-wide genotyping and structural T1-weighted MRI of 3826 neurotypical children from the Adolescent Brain Cognitive Development (ABCD) study. Surface-based linear models related PRS-HS to cortical thickness measures, and subsequently contextualized findings with structural and functional network architecture based on epicentre mapping approaches. Imaging-genetic associations were then correlated to atrophy and disease epicentres in 785 patients with TLE-HS relative to 1512 healthy controls aggregated across multiple sites. Higher PRS-HS was associated with decreases in cortical thickness across temporo-parietal as well as fronto-central regions of neurotypical children. These imaging-genetic effects were anchored to the connectivity profiles of distinct functional and structural epicentres. Compared with disease-related alterations from a separate epilepsy cohort, regional and network correlates of PRS-HS strongly mirrored cortical atrophy and disease epicentres observed in patients with TLE-HS and were highly replicable across different studies. Findings were consistent when using statistical models controlling for spatial autocorrelations and robust to variations in analytic methods. Capitalizing on recent imaging-genetic initiatives, our study provides novel insights into the genetic underpinnings of structural alterations in TLE-HS, revealing common morphological and network pathways between genetic vulnerability and disease mechanisms. These signatures offer a foundation for early risk stratification and personalized interventions targeting genetic profiles in epilepsy.

Dravet syndrome (DS), a severe developmental and epileptic encephalopathy often linked to SCN1A mutations, is defined by a profound thermosensitivity, making fever and hyperthermia potent seizure triggers. This review synthesizes evidence-based strategies and expert consensus for the management of fever and vaccination in children with DS. Management diverges from standard pediatrics, prioritizing aggressive pyrexia control through early antipyretics, physical cooling, and prophylactic benzodiazepines. Proactive strategies are also crucial for non-febrile hyperthermia from triggers like hot baths and overexertion. Although vaccinations can precipitate an initial seizure, they neither cause DS nor worsen its prognosis. Immunization remains strongly recommended, with prophylactic antipyretics advised as a key risk-mitigation measure. Importantly, current management strategies are based primarily on expert consensus rather than controlled clinical trials. Bridging expert consensus with clinical evidence is essential to reduce morbidity and improve long-term quality of life in DS.

Neonatal hypoxic–ischemic encephalopathy (HIE) remains one of the leading causes of neonatal mortality and long-term neurodevelopmental disability despite therapeutic hypothermia, which provides only partial neuroprotection. Among adjunctive therapies, magnesium sulfate (MgSO4) has emerged as one of the most biologically plausible neuroprotective agents because of its ability to modulate glutamate-mediated excitotoxicity, intracellular calcium influx, oxidative stress, neuroinflammation, and apoptotic pathways. Nevertheless, encouraging molecular and preclinical findings have not translated into consistent clinical benefit. This narrative review critically examines the translational gap between the molecular mechanisms of magnesium sulfate and its clinical performance in neonatal HIE. Evidence from experimental models, clinical studies and recent meta-analyses was integrated to identify the biological and methodological factors potentially responsible for this discrepancy. We discuss the evolving pathophysiology of HIE across the primary, latent, secondary and tertiary phases of brain injury and analyze how the timing of intervention, lesion heterogeneity and inadequate biological stratification may influence therapeutic responsiveness. Current clinical research has largely evaluated broad neurological outcomes, particularly cerebral palsy, despite the heterogeneous neuropathological substrates underlying neonatal brain injury. We argue that this strategy may dilute genuine treatment effects by grouping together distinct lesion phenotypes with different biological mechanisms. Accordingly, we propose the “Neuroprotection per Effective Therapy (NET)” framework, a conceptual translational model integrating molecular targets, experimental evidence, MRI-defined lesion phenotypes, methodological quality, and advanced statistical approaches to improve patient stratification and outcome selection. Rather than questioning the biological efficacy of magnesium sulfate itself, this review suggests that future progress will depend on aligning molecular mechanisms with clinically meaningful phenotypes. Precision-based translational strategies may ultimately allow magnesium sulfate and other neuroprotective therapies to better reveal their therapeutic effects in biologically appropriate patient subgroups.

INTRODUCTION:Acquired demyelinating syndromes (ADS) of the central nervous system in children present a diagnostic challenge due to overlapping presentations. Differentiating monophasic from potentially recurrent conditions, such as pediatric-onset multiple sclerosis (POMS), myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other seronegative ADS, is essential for treatment and prognosis. This study aimed to characterize the initial presentation of pediatric ADS and evaluate the evolution of diagnosis over time to better guide treatment. METHODS:A retrospective study of 59 children with ADS diagnosed at a tertiary pediatric center in Italy (2012-2024) was conducted. Initial classifications included MS, acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS), optic neuritis (ON), neuromyelitis optica spectrum disorder (NMOSD), or "Indeterminate". Final diagnoses were categorized as MS, MOGAD, or "Other" demyelinating conditions. Demographic, clinical, MRI, CSF, and outcome were analyzed. Statistical comparisons among groups used Mann-Whitney U, Chi-square, or Fisher's exact tests (p < 0.05). RESULTS:At final diagnosis, older age at onset, absence of preceding infection and characteristic MRI findings (periventricular/callosal lesions, cerebellar involvement) were more frequent in MS group. Younger age, preceding infection, fever, irritability, and cortical involvement were associated with MOGAD. Nearly one-third of final MS cases (29%) were initially CIS or ON, while no ADEM cases converted to MS. "Other" ADS (non-MS/MOG-IgG antibody negative patients) showed more severe initial disability (p = 0.01). Transition to adult neurology was significantly higher in MS (p < 0.001). CONCLUSION:these findings underscore the heterogeneity of pediatric ADS at onset and the value of accurate acute management and longitudinal follow-up to refine diagnosis and guide treatment.

This seminar addresses the complexity of the management of epilepsy in adults with intellectual development disorders (IDD), advocating holistic and multidisciplinary care aligned with the learning objectives of the International League Against Epilepsy. Epilepsy is significantly more prevalent in people with IDD, presenting unique diagnostic, therapeutic, and psychosocial challenges. Accurate diagnosis is hampered by limitations in communication, necessitating reliance on caregivers' observations. In adults with IDD and epilepsy, utilization of diagnostic tools, e.g., video electroencephalograph (EEG) monitoring, is helpful but can be challenging. Management requires careful consideration of cognitive and behavioral comorbidities and the effects of antiseizure medications (ASMs) on cognitive function and quality of life (QoL). Personalized treatment plans should balance seizure control against ASM side effects, prioritizing therapeutic goals aligned with individual patient needs. Effective multidisciplinary care involves primary care physicians, neurologists, psychiatrists, psychologists, social workers, therapists, and specialized nursing staff. Transition periods, including from pediatric to adult care, and from the family home to professional care, represent critical phases requiring structured planning and collaboration among health and social-care providers, patients, and caregivers. Current gaps in integrated care include the need for targeted therapeutic approaches, more tailored cognitive and behavioral assessment tools, guidelines for managing pregnancy and hormonal considerations, management of commonly associated comorbidities, including non-epileptic paroxysmal events, and reduction of preventable morbidity and mortality, including sudden death. This seminar emphasizes the necessity of addressing these gaps to advance care standards, promote research, and ultimately improve patient outcomes. The manuscript includes two anonymized illustrative clinical case studies. Practical recommendations include systematic reassessment of underlying etiologies, including genetic counseling and testing, reviewing the electroclinical diagnosis, careful selection and titration of ASMs to minimize cognitive and behavioral impacts, and structured transition. Addressing these challenges and implementing an integrated care model could significantly enhance QoL for adults living with IDD and epilepsy.

Objective Fever can trigger seizures in several early-onset epilepsies. SCN1A-related epilepsies, including Dravet Syndrome, are the best characterised conditions in this spectrum, but a growing number of genes implicated in fever-sensitive epilepsies have emerged. We assessed the genetic heterogeneity of individuals who underwent testing because of seizures or epilepsy with fever sensitivity. In particular, we investigated the occurrence of ATP6V0C pathogenic variants and delineated its associated electroclinical features. Methods We retrospectively reviewed individuals tested with epilepsy-targeted Next Generation Sequencing (NGS) panels and/or Whole Exome Sequencing (WES) between 2022 and 2025, selecting those with documented fever sensitivity (defined as seizure occurrence or exacerbation temporally linked to febrile episodes in subjects who suffer from both febrile and afebrile seizures). Variants were filtered for frequency, evaluated through segregation and prediction tools, and classified according to ACMG guidelines. Results Among 721 individuals tested with NGS or WES for neurological indications, 418 (58%) had a history of seizures, including 53 (7.3%) with fever-sensitive epilepsy. Pathogenic or likely pathogenic variants were identified in 30% of these cases. Notably, ATP6V0C variants accounted for 2/16 (12.5%) of all pathogenic/likely pathogenic findings and were identified in 3.8% of tested fever-sensitive epilepsy patients, ranking among the most frequently implicated genes in this cohort. Significance Our findings support ATP6V0C as a relevant gene in the landscape of childhood epilepsies with fever sensitivity. The associated phenotype appears characterized by early febrile-triggered motor seizures, initially normal EEG followed by multifocal abnormalities, normal MRI and subsequent onset of neurodevelopmental impairment. These results highlight the importance of accurate molecular diagnosis in children presenting with fever-sensitive seizures, with potential implications for future precision therapies.

Introduction: Seizures are the most frequent initial symptom of perinatal stroke. Apnea, a less commonly recognized neurological presentation, is a cessation of breathing lasting >15 seconds or shorter if associated with bradycardia. This study explores a monocentric cohort of newborns with perinatal stroke, emphasizing the role of Isolated Central Apnea (ICA) as a potential early indicator of cerebrovascular insult. Methods: A retrospective review was conducted on newborns (>= 36 weeks GA) diagnosed with MRI-confirmed perinatal stroke at our institution between March 2019 and March 2024. Infants with hypoxic-ischemic encephalopathy (HIE), congenital infections, meningoencephalitis, sepsis, or intrauterine stroke were excluded. Clinical data, neuroimaging findings, EEG/aEEG characteristics, and antiepileptic drug (AED) were analyzed. Results: Of 421 newborns who underwent brain MRI, 27 (6%) were diagnosed with perinatal stroke (16 males; median GA 38.5 weeks; mean BW 3137g). Seizures were the presenting symptom in 18 cases (67%), while 8 cases (30%) exhibited ICA as the first sign and an MRI revealing 5 arterial strokes (63%) and 3 venous strokes (37%). EEG abnormalities were detected in 7/8 (88%) cases, while brain ultrasound was abnormal in 5/8 (63%). AED therapy was required in 7/8 (88%) patients. Conclusions: ICA is an early sign of neonatal stroke in approximately one-third of cases. These findings underscore the importance of brain MRI in the diagnostic workup of persistent apnea in term and early-term neonates.

INTRODUCTION:Developmental and epileptic encephalopathies (DEEs), epilepsy-associated neurodevelopmental disorders (NDD), and epileptic syndromes with or without encephalopathy (ES±E) share overlapping genetic architectures where both etiology and seizures impair development. Despite genomic advances, many patients remain pharmacoresistant, and molecular diagnoses seldom translate into targeted treatments. This review connects mechanistic categories to precision therapies, providing a clinical decision-making framework. AREA COVERED:We outline pharmacological and investigational strategies-including antiseizure medications, dietary therapies, and disease-modifying approaches-across major mechanistic categories, including ion channel/receptor dysfunctions, synaptic/signaling defects, metabolic disorders, and neurodegenerative storage diseases. For each condition, potential therapeutic options are interpreted within a hierarchical precision-based framework, ranging from empiric seizure-type-driven treatments to gene-specific molecular interventions. A narrative literature search was conducted across major databases for English-language articles on DEEs, NDD, ES±E, and precision therapeutic approaches published up to early 2026. We categorized potential therapeutic interventions into five hierarchical tiers based on etiological specificity and evidence. Classification, achieved by expert consensus, distinguishes established (Tiers 1-3) from emerging strategies (Tiers 4-5). EXPERT OPINION:Progress depends on early etiological diagnosis and timely, mechanism-informed therapy. Future advances require expanded genomic testing, natural history studies, mechanism-based biomarkers, and innovative trial designs tailored to complex pediatric populations.

INTRODUCTION:Dravet syndrome (DS), a catastrophic developmental and epileptic encephalopathy primarily caused by SCN1A haploinsufficiency, remains largely refractory to current antiseizure medications. In recent years, gene-targeted therapies, including antisense oligonucleotides (ASOs)-and viral-based therapies, have emerged as promising disease-modifying strategies. AREAS COVERED:Preclinical in vitro and in vivo models demonstrated that ASO-mediated modulation of SCN1A can restore transcript and protein levels, normalize interneuron excitability, and extend survival. Key advances include the discovery of deep-intronic 'poison' exons expanding actionable ASO targets and the demonstration of long-term functional rescue after early-life administration. Complementary strategies, such as SCN8A modulation, SCN1A viral delivery, and tau suppression, further broadened therapeutic options. Clinically, the ASO STK-001 trial showed favorable safety, pharmacodynamic activity, and durable seizure reduction in Phase 1/2a and open-label extension trials, alongside improvements in adaptive behavior and cognition. EXPERT OPINION:ASO-based modulation of SCN1A represents a pivotal advance in DS therapy, translating robust preclinical efficacy into early clinical benefit. Optimization of dosing regimens, durability, and combinatorial approaches targeting parallel molecular pathways will be critical to realize precision gene therapy for DS. Viral gene therapy approaches constitute a promising therapeutic platform, but comprehensive validation will be essential to ascertain their immunogenic safety and demonstrate clinical efficacy.