Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types and high resistance to antiseizure medication (ASM), often necessitating nonpharmacologic therapies, including neuromodulation. Responsive neurostimulation (RNS), a closed-loop brain-responsive neuromodulation device, has emerged as an adjunctive treatment option for drug-resistant epilepsy (DRE), but evidence on its safety and effectiveness in LGS remains limited. This study examines real-world outcomes of RNS therapy in patients with LGS-associated DRE. This retrospective multicenter study included patients with LGS who underwent RNS implantation before December 2024 across four Level 4 National Association of Epilepsy Centers (NAEC) in the United States. Demographic, clinical, surgical, and outcome data were systematically collected using a standardized case report form and analyzed. Thirty-seven patients met inclusion criteria. At the time of RNS implantation, 95% of patients were pediatric (mean age 12.9 years, range 3.6-28.8) with a median follow-up of 24.5 months. All patients had generalized tonic seizures; additional seizure types included tonic-clonic (62%), atonic (50%), atypical absence (19%), and other (54%). The pooled responder rate (≥50% seizure reduction) was 62%, including 10% with ≥90% reduction. Thalamic-only stimulation of the bilateral centromedian nucleus (CMN) was the most common electrode configuration (76%), followed by cortico-thalamic targeting to the CMN and bi-frontal regions (18%). Among responders, 83% received thalamic-only CMN stimulation. ASM reduction occurred in 10% of patients. Adverse events were reported in 13%, primarily implant-related infections, with 4 patients requiring explantation. Stimulation-related side effects occurred in 27% and resolved with programming adjustments in 80%. RNS targeting thalamic and cortico-thalamic networks resulted in seizure reduction in the majority of this predominantly pediatric LGS cohort. Therapy was generally well-tolerated with few serious adverse events, supporting its potential role as an adjunctive treatment option for DRE in LGS. Lennox-Gastaut syndrome is a severe form of epilepsy that is often hard to control with medications. This study evaluated responsive neurostimulation (RNS), an implanted device that monitors brain activity and delivers electrical stimulation to help stop seizures before they spread. In 37 mostly pediatric patients, about 60% had their seizures reduced by at least half, and some improved even more. The treatment was generally safe, and most side effects could be managed by adjusting the device.

Cenobamate (CNB) is an effective antiseizure medication, though its mechanisms of efficacy remain incompletely understood. We assessed changes in cortical responses to transcranial magnetic stimulation (TMS) following CNB treatment. We recruited people with drug-resistant focal epilepsy scheduled to start add-on CNB in a tertiary epilepsy center. We performed TMS coupled with electromyography (EMG) and electroencephalography (EEG) at baseline, at 100 mg/day and at the maximum tolerated or minimum effective dose. Participants were categorized as responders (≥50% seizure reduction) or nonresponders. We used linear mixed models and cluster-based permutation tests to assess CNB effects on resting motor thresholds (rMTs), intracortical inhibition and the amplitude, mean field power and event-related spectral perturbation of TMS-evoked EEG potentials (TEPs). For TMS measures that were significantly affected by CNB dose (p < 0.05), we assessed differences between responders and non-responders and correlations with seizure frequency. Twenty-eight participants completed the study (16 females; median age, 50 years). rMT (p < 0.01) increased and cortical silent period (CSP) lengthened (p = 0.03) with increasing CNB dose. These changes did not differ between responders and nonresponders, nor did they correlate with reduced seizure frequency. Short- and long-interval intracortical inhibition, as well as all TEP parameters, remained unchanged. While CSP lengthening may merely reflect higher stimulation intensities, rMT increases align with CNB's suggested modulation of sodium channels. rMT changes that are independent of clinical response suggest that sodium channel effects do not fully account for the therapeutic efficacy of CNB. We used magnetic brain stimulation in people with epilepsy to find out how the antiseizure medication cenobamate affects brain activity. As its dose increased, cenobamate raised the stimulation strength required to activate a muscle, known as the resting motor threshold (rMT). These changes did not predict a reduction in seizures. This suggests that cenobamate's effectiveness involves more than its effects on mechanisms linked to the rMT.

We aimed to create practical recommendations to support healthcare teams starting ketogenic diet therapy (KDT) for children with super-refractory status epilepticus in intensive care settings. A literature review was conducted to extract published data on patient selection, diet prescription, diet initiation, monitoring, fine-tuning, and discontinuation of KDT for super-refractory status epilepticus. Statements were formulated within each subtopic, and an online survey was distributed to gauge the extent of international agreement with these statements to inform consensus-based recommendations for initiation and maintenance of KDT in pediatric intensive care settings, with a focus on enteral nutrition. Consensus on a statement for inclusion in the core recommendations was reached if ≥75% of respondents "Agreed" or "Strongly Agreed". Recommendations from relevant published guidelines or studies were also included. Twenty-two relevant manuscripts were identified, and 25 statements were formulated. Seventy-two healthcare professionals responded to the survey, including dietitians, medics, nurses, intensivists, and a neurophysiologist. Clinical recommendations were made across the following areas, using evidence from published literature, survey agreement, or the clinical expertise of the authors: patient selection and timing of start, preparation for treatment, dietary prescription, diet initiation, monitoring adverse effects, fine tuning, and weaning of KDT. Thirty statements met the criteria for core recommendations. These are the first international multidisciplinary recommendations for use of KDT for children with super-refractory status epilepticus, intended as a sensical guide for dietitians, neurologists, intensivists, and associated healthcare professionals. The majority of the recommendations are based on survey agreement due to a paucity of published evidence. Children with very severe seizures that do not stop despite medication often need care in intensive care units. This study brings together published evidence and international expert consensus to provide clear guidance on when and how a high-fat, low-carbohydrate ketogenic diet can be started safely in this setting. The recommendations highlight early diet initiation, close monitoring, and strong teamwork between doctors, dietitians, nurses, and pharmacists while recognizing that more high-quality research is still needed.

The presence or absence of sleep spindles in patients with infantile epileptic spasms syndrome (IESS) has been proposed as a potential predictor of cognitive outcome; however, the validity of this predictor remains uncertain. This study aimed to establish the utility of sleep spindle characteristics as prognostic markers of developmental outcomes in patients with IESS. We retrospectively analyzed 26 patients with IESS who underwent longitudinal electroencephalography (465 recordings) to assess the presence, frequency, duration, and location of spindles. Patients were divided into two groups based on their developmental outcomes. The good outcome group consisted of patients with a developmental quotient (DQ) of ≥50, whereas the poor outcome group comprised patients with a DQ of <50. We compared the clinical and spindle characteristics between these two groups. The good and poor outcome groups comprised 11 and 15 patients, respectively. In the univariate analysis, known etiology, developmental delay (DQ < 70) at spasm onset, and the absence of fast spindles (≥13 Hz) within 3 months after spasm onset were significantly more common in the poor outcome group than in the good outcome group. Multivariate Firth logistic regression analysis showed that only the absence of fast spindles within 3 months after spasm onset was significantly associated with poor developmental outcomes. The absence of fast sleep spindles may be a valuable predictor of developmental outcomes in IESS compared with the established developmental prognostic factors reported by previous studies. Our results show the importance of the early organization of fast spindles to obtain favorable developmental outcomes in patients with IESS. We studied electroencephalography during sleep in 26 children with infantile epileptic spasms syndrome (IESS) to see if certain patterns, called sleep spindles, relate to later development. Children who did not show fast sleep spindles (≥13 Hz) within 3 months after spasm onset were more likely to have poor developmental outcomes. This finding suggests that the early appearance of fast sleep spindles may be an important marker of better brain development in children with IESS.

Most therapies for drug-resistant epilepsy (DRE) focus on focal-onset seizures, the most common seizure types. Studying primary generalized tonic-clonic seizures (PGTCS) is more challenging due to diagnostic and recruitment difficulties. While vagus nerve stimulation (VNS) therapy is globally established in DRE with focal-onset seizures, approved indications vary by region. This study assesses the safety and effectiveness of VNS therapy in individuals with drug-resistant PGTCS. Data from five studies were included in the analysis. The PGTCS group included 170 participants with reported PGTCS who received VNS therapy and completed 24 months of follow-up. Outcomes included observed and Bayesian-estimated PGTCS responder rates (≥50% seizure reduction) and seizure frequency changes. Observed rates were determined from clinical studies, while Bayesian responder rates were estimated using a hierarchical model. The Bayesian hierarchical model estimated the 24-month PGTCS responder rate for patients in CORE-VNS to be 65.2% (95% credible interval: 55.1%-75.1%). The Bayesian estimate at 24 months for responder rates across all studies was 65.5%. Most responders (91.7%) maintained their response from 6 and 12 months to 24 months. Median seizure frequency decreased by 71.4% for PGTCS and 62.5% for all seizures at 24 months. Treatment-emergent adverse events (TEAEs) were low and consistent with those seen in people with focal-onset seizures treated with VNS therapy. No new safety concerns were identified, including no increased risk of Status Epilepticus (SE) or death. These findings support VNS therapy as a safe and effective treatment for reducing PGTCS in participants with DRE. Primary generalized tonic-clonic seizures (PGTCS) carry higher risks of complications and death than focal-onset seizures. Vagus nerve stimulation (VNS therapy) is approved for drug-resistant PGTCS outside the USA. Data from five LivaNova-sponsored clinical studies show that VNS therapy is safe and effective in adults and children. Among 170 participants, about 66% had a ≥50% reduction in PGTCS at 24 months, and 92% of early responders maintained improvement. Among 149 participants, median PGTCS frequency fell by 71%. Treatment-emergent adverse events were low, with no new safety concerns identified.

Atypical absence status epilepticus (AASE) is a rare subtype of nonconvulsive status epilepticus (NCSE), characterized by clouding of consciousness and continuous or fluctuating epileptiform activity, generally at a frequency below 3 Hz. Only sparse literature exists on the genetic conditions associated with it. We performed a systematic review to identify the genetic diagnoses in which AASE has been described, and examined the available clinical, EEG, treatment and outcome details. The protocol was registered in PROSPERO and reporting followed PRISMA guidelines. We searched public databases for combinations of the terms: "atypical absence status epilepticus," "status epilepticus," "non convulsive status epilepticus," and "gene," "genetics," "epileptic encephalopathy," "developmental and epileptic encephalopathy," "DEE." Only original articles in English were included. We identified 34 publications reporting 97 patients with AASE and an underlying genetic condition. Most patients had a chromosomal abnormality (88%), in particular ring chromosome 20 (53% of the total patients) and Angelman syndrome caused by a 15q11-q13 deletion (31%). Seven epilepsy genes (UBE3A, CNKSR2, TRPM3, KCNH2, NEXMIF, SYNGAP1, GABRB1) were found in which a clinical and electrographic picture consistent with AASE was described. Therefore, in the context of a possible genetic diagnosis, AASE has been reported mainly in chromosomal disorders. However, this condition is likely underrecognized and underreported, particularly in monogenic epilepsies. Therefore, a deeper phenotyping and a more standardized use of classification terms would be necessary both for clinical and research purposes. PLAIN LANGUAGE SUMMARY: We reviewed the scientific literature to find out in which genetic conditions a rare EEG and clinical pattern, called atypical absence status epilepticus, has been described. We found that this pattern is mainly reported in patients with changes in chromosome structure, such as ring chromosome 20 and Angelman syndrome. Among single-gene (monogenic) forms of epilepsy, it has been described in association with seven genes (UBE3A, CNKSR2, TRPM3, KCNH2, NEXMIF, SYNGAP1, GABRB1). When clinicians suspect a genetic cause of epilepsy and this finding is present, they should consider checking also for chromosomal changes.

Magnetic resonance imaging (MRI) abnormalities have been reported in individuals who later die from sudden unexpected death in epilepsy (SUDEP), but their specificity and predictive value remain uncertain. Postmortem MRI (PM-MRI) offers a unique opportunity to distinguish structural features associated with SUDEP from changes related to epilepsy, comorbid illness, or the postmortem interval. We performed PM-MRI in nine individuals: five with suspected SUDEP, two with epilepsy who died from non-seizure-related causes, and two without epilepsy who died from sudden cardiac death. Hippocampal, amygdala, and subcortical volumes were quantified using validated segmentation methods and compared with 70 healthy invivo controls. Compared with non-SUDEP cases, SUDEP cases showed significantly larger hippocampal (p = 0.014) and amygdala (p = 0.023) volumes, with most exceeding the healthy control mean, whereas non-SUDEP cases consistently demonstrated volume reductions. These findings parallel invivo MRI observations in individuals at high risk of SUDEP and are consistent with transient peri- or postictal structural changes. In the context of recent large-scale studies showing few validated clinical SUDEP biomarkers beyond frequent generalized tonic-clonic seizures and sleeping alone, PM-MRI may provide an objective approach to positively identifying individuals who died from SUDEP. PLAIN LANGUAGE SUMMARY: We used magnetic resonance imaging (MRI) scans taken after death to study brain changes in people who died from sudden unexpected death in epilepsy (SUDEP). We found that certain brain areas involved in seizure control and automatic body functions, such as breathing and heart rate, were larger in people who died from SUDEP than in people who died from other causes. These changes were similar to those previously seen on brain scans of people with epilepsy who are known to be at higher risk of SUDEP while they were still alive. Our findings suggest that postmortem MRI may help identify brain changes linked to SUDEP.

This review examines how recent genetic and technological advances have transformed our understanding and treatment of genetic epilepsies (GEs), with a focus on disorders involving GABAA receptors (GABRs) and the GABA transporter 1 (GAT-1) encoded by SLC6A1. About 1000 genes are associated with epilepsy, including ~100 directly linked to defined epilepsy syndromes. Many disease-causing variants affect ion channels and transporters, disrupting protein structure, trafficking, and synaptic function. These defects often underlie developmental and epileptic encephalopathies (DEEs). A key insight from recent studies is that endoplasmic reticulum (ER)-related pathology-such as protein misfolding, ER retention, and accelerated degradation, which are common consequences of those pathogenic variants. For example, mutations in SLC6A1 or GABRG2 lead to impaired trafficking and reduced surface expression of GAT-1 or GABR subunits, resulting in deficient inhibitory neurotransmission. These mechanisms have been validated using advanced cellular assays and mouse models, although such experimental approaches remain costly and labor-intensive. Artificial intelligence (AI) is emerging as a powerful complement to experimental studies. Computational approaches, including generative AI and protein language models, can predict mutation-induced changes in protein structure, stability, and interactions, aided by tools such as AlphaFold. These methods enable large-scale, system-level analysis of variants and hold promise for accelerating drug discovery. However, current AI models are limited by fragmented datasets and the inherent complexity of biological systems. Integrating AI with experimental research offers a scalable strategy to translate mechanistic insights across genetic epilepsies (GEs). For instance, 4-phenylbutyrate (PBA), tested in SLC6A1 and GABRG2 epilepsy mouse models and now in clinical trials (NCT04937062), shows promise for treating GEs and DEEs caused by ER-retained mutant proteins. AI-based prediction could help identify additional GEs likely to respond to similar therapeutic approaches. Overall, combining experimental and AI-driven methods represents a new frontier for advancing the diagnosis and treatment of GEs and DEEs. PLAIN LANGUAGE SUMMARY: Mutations in almost 1000 genes have been linked to epilepsies, including those affecting GABA signaling such as GABAA receptors and the GABA transporter. Using cell and mouse studies, we found that many of these gene mutations cause similar problems inside cells. Specifically, the mutant proteins get stuck inside the cell in a structure called the endoplasmic reticulum (ER) and cause ER stress. Importantly, an FDA-approved drug 4-phenylbutyrate (PBA) can reduce these problems. We propose using artificial intelligence (AI) to predict how different gene mutations affect protein function and to identify which patients are likely to benefit from PBA treatment.

To determine whether prompt genetic diagnosis in children with KCNQ2 neonatal epilepsy enabling targeted therapy is associated with improved outcomes, and identify early predictors of developmental outcomes. Thirty-seven children with KCNQ2 neonatal epilepsy were recruited from five pediatric centers. We reviewed demographic, clinical, EEG, and genetic data. We determined differences in outcomes between individuals with prompt (greater than 30 days from seizure onset) and later genetic diagnosis, and we identified neonatal factors associated with developmental outcome. Baseline characteristics were similar between children with prompt (n = 6, median age at genetic diagnosis 15 days) and later (n = 31, median age 309 days, p < .05) diagnosis. All with prompt diagnosis received sodium channel blocking (SCB) anti-seizure medication (ASM) in the neonatal period compared with 15/31 (48%) in the later diagnosis group. Children with prompt diagnosis had higher rates of seizure freedom at age 12 months than those with later diagnosis (6/6 [100%] vs. 17/31 [54%]; p .049], and lower number of emergency department representations (median 0 vs. 2), and hospital readmissions (median 0 vs. 1). Factors in the neonatal period associated with abnormal developmental outcome included neurological abnormalities (e.g., abnormal tone) and markedly abnormal neonatal EEG background (11/11 [100%] with markedly abnormal EEG vs. 11/24 [46%] with normal to moderately abnormal EEG). Prompt genetic diagnosis was associated with targeted therapy, resulting in improved seizure control and reduced hospital representation. Clinical features present in the neonate assist in predicting outcome severity, which is critically important in counselling families receiving a KCNQ2 diagnosis soon after seizure onset. In KCNQ2 neonatal epilepsy, sodium channel blocking antiseizure medicines are recommended, but the benefits of starting treatment early have been uncertain. Our findings show that prompt genetic diagnosis enabled early targeted treatment, with potential to improve outcomes. Specifically, prompt genetic diagnosis was associated with improved seizure control and reduced hospital visits compared with delayed diagnosis. However, a prospective, long-term study is needed to determine whether early treatment also improves developmental outcomes. Predicting outcome severity in newborns remains challenging, although abnormal neurological examination and markedly abnormal EEG in the newborn period were linked to abnormal developmental outcomes.

Children and adolescents with pharmacoresistant epilepsy (PRE) show marked individual cognitive and emotional variability not fully accounted for by demographic or clinical variables. This exploratory pilot study characterizes neuroanatomical abnormalities and their relationships with neuropsychological functioning in a pediatric patient cohort with PRE due to type II focal cortical dysplasia (FCD). Retrospective data were obtained from patients with histopathologically confirmed FCD II who completed presurgical evaluations including high-resolution 3T MRI and neuropsychological assessment. Voxel-based morphometric MRI postprocessing using the Morphometric Analysis Program (MAP18) provided age-adjusted quantitative characterizations of within-lesion MRI features [Junction (gray-white matter junction blurring), Extension (abnormal gyration), and Thickness (cortical thickening in the regional lesion)]. Associations between MRI feature z-scores and cognitive domain composite scores were evaluated using Pearson correlation coefficients and multivariable linear and logistic regression models, controlling for seizure side and site. Lesion ROI volumes were also analyzed to evaluate their associations with MRI feature z-scores and neuropsychological function. We included 24 patients [mean age = 13.8; 58% male] with FCD IIa (n = 8; 33%) or FCD IIb (n = 16; 67%). Patients with FCD IIb had higher mean and maximum Junction z-scores compared to those with FCD IIa (Cohen's d = 1.00 and 1.07). Mean and maximum Thickness z-scores were negatively associated with attention (r = -0.32; r = -0.47) and general cognitive ability (GCA; r = -0.46; r = -0.41). Mean Thickness z-scores were also negatively associated with visuospatial skills (r = -0.34). In regression models, higher mean and maximum Thickness were associated with poorer GCA scores (estimate (se): -14.98 (6.88), p = 0.042; -5.76 (2.41), p = 0.027, respectively), and higher maximum Thickness was associated with worse attention scores (estimate (se): -6.02 (2.60), p = 0.032). Lesion volumes were not associated with MRI feature z-scores, cognition, self-reported mood or anxiety. Our findings showed that lesional neuroanatomical abnormalities, particularly increased cortical thickness, were associated with poorer cognitive performance in pediatric patients with FCD II. Future research in larger, more diverse samples is needed to identify other factors contributing to neuropsychological variability in this population. We studied 24 pediatric patients with pharmacoresistant epilepsy (PRE) and a confirmed diagnosis of focal cortical dysplasia type II (FCD II) to examine how MRI findings relate to thinking abilities. Patients with FCD IIb showed more pronounced MRI abnormalities than FCD IIa. Greater cortical thickening within the lesion was associated with difficulties in overall cognitive ability, attention, and visuospatial skills. After adjusting for seizure side and site, the relationships between cortical thickness and reduced overall cognitive ability and attention performance remained significant. Findings suggest that specific MRI features may serve as imaging markers of cognition in pediatric patients with FCD II.