Epilepsia Open

Background: People of childbearing potential with epilepsy in regions endemic for Taenia solium, where neurocysticercosis (NCC) is highly prevalent, represent a vulnerable population due to the elevated burden of epilepsy and resource limitations. Clinical practice in these settings remains poorly characterized. This study characterized anti-seizure medication (ASM) prescribing patterns by medication risk profiles among people of childbearing potential with epilepsy in Northern Peru, a region highly endemic for T. solium. Methods: Participants were drawn from a prospective, population-based epilepsy cohort in Tumbes, Peru (2006 to 2020). The analytic population included females with epilepsy aged 15 to 49 years. The primary outcome was pregnancy-associated ASM risk of congenital malformations and adverse neurodevelopmental outcomes. ASMs were classified as ''Established Low Risk'' (lamotrigine, levetiracetam), ''Possible Risk/Inadequate Data'' (carbamazepine, phenobarbital, phenytoin), and ''Established High Risk'' (valproic acid). Prescription patterns were examined in relation to demographic and clinical characteristics. Results: Among 1,975 individuals with epilepsy, 685 were people of childbearing potential. Approximately 34.9% met criteria for probable or definite NCC. Most ASM prescriptions were in the ''Possible Risk/Inadequate Data'' category (87.0%), and 12.8% received ''Established High Risk'' medications. In multivariable analysis, high-risk prescribing was associated with prior ASM use and polytherapy. Discussion: People of childbearing potential with epilepsy were predominantly treated with carbamazepine, phenytoin, phenobarbital, and valproate, reflecting local ASM availability. Despite evidence supporting lamotrigine and levetiracetam in pregnancy, prescribing patterns reflect local formulary constraints. These findings highlight a gap between guideline recommendations and real-world prescribing in resource-limited settings, underscoring the need for context-specific treatment strategies.

Early acquired brain injury is a major risk factor for infantile epileptic spasms syndrome (IESS), which may impair cognitive development, especially if diagnosis and treatment are delayed. However, individual-level prediction of which infants will develop IESS is currently not possible. We assessed whether high-frequency oscillations (HFOs) in scalp EEG or recurrent interictal epileptiform discharges (IED) during the first months of life could predict forthcoming IESS. Our population-based cohort included 36 infants with cortical injury due to infarction, haemorrhage, infection or trauma involving a large cortical area ([&ge;] anterior/posterior cerebral artery territory or [&ge;] half of the middle cerebral artery territory), or hypoxic-ischaemic encephalopathy with cortical and deep grey matter involvement. The infants underwent repeated EEGs during the first year of life until 12 months of age or until IESS diagnosis. HFOs during sleep were scored both visually and automatically, whereas IEDs were assessed visually only. We tested whether HFO rate increased during the first year of life using a mixed-effects model with within- and between-subject random effects. Using only EEGs recorded prior to IESS diagnosis, we evaluated whether HFO rate or recurrent IEDs could predict IESS development by training a ridge-regularized logistic regression model with exhaustive leave-2-subjects-out cross-validation. Eleven infants (31%) developed IESS. HFO rate increased with age in both groups but more steeply in the IESS group [within person slope {beta} = 2.43 (IESS) vs. 0.06 (no-IESS) units/month, P < 0.001]. The logistic regression model showed that both HFO rate [AUC 0.801 (95% CI 0.668, 0.936)] and recurrent IEDs [AUC 0.826 (95% CI 0.720, 0.932)] were able to predict forthcoming IESS. However, in a multivariable model, only recurrent IEDs remained independently associated with IESS, and HFO rate did not add predictive value. The marked increase in HFO rate toward IESS diagnosis supports their role as a biomarker of epileptogenesis. During the first months of life, HFOs and recurrent IEDs performed equally well in predicting subsequent IESS. However, IEDs are easier to apply to clinical practice.

Objective: Pediatric epilepsy patients undergoing stereo-electroencephalography (sEEG) for ictal onset evaluation provide a rare window to study the developing brain. While methodological frameworks for task-based sEEG research are well-established in adults, pediatric-specific guidance remains underdeveloped. Furthermore, many pediatric epilepsy patients have comorbidities that might typically exclude them from participating in research. We examine factors that influence research participation and discuss considerations for conducting sEEG research in children. Methods: Here, we present a retrospective analysis of task-based research participation patterns from an NIH-funded study of speech and language representations (1R01DC018579) in 66 patients (ages 4-24) undergoing sEEG monitoring at Texas Children's Hospital to determine whether specific comorbidities influenced research participation. Results: Eighty-nine percent (n=66) of patients approached for consent agreed to participate in the study. Despite high rates of comorbidities including neurocognitive disorder (66.67%), language delay (31.75%), global developmental delay (23.81%), mood disorders (33.33%), ADHD (46.03%), autism spectrum disorder (14.29%) or other cognitive/intellectual disabilities (36.51%), all participants engaged in at least one task. While the majority of these diagnoses did not appear to influence subject participation, global developmental delay was associated with a significant reduction in time spent on active tasks. Discussion: Despite high prevalence of neuropsychological comorbidities among participants, our evidence suggests that these participants contribute meaningfully to studies investigating important developmental questions. We suggest strategies for tailoring task-based research to accommodate the unique needs of individuals in this population. Such practices are important for ensuring that research studies reflect the true diversity of the population.

Background and Objectives: Genetic causes of epilepsy are well-established in children, but the genetics of adult-onset epilepsy is not well understood. There are few studies of epilepsy genetics in older adults, U.S. military Veterans, and people with acquired causes of epilepsy like traumatic brain injury (TBI) and stroke. To test if rare gene variants that cause pediatric epilepsy are associated with adult-onset epilepsy, we determined the prevalence of pathogenic germline variants (PGVs) in epilepsy-associated genes in an ancestrally diverse cohort of older Veterans and examined the penetrance of epilepsy among PGV carriers. We evaluated the effect of mode of inheritance (MOI), variant selection, single gene-level factors, and gene-disease relationship validity on prevalence and penetrance estimates. Methods: This retrospective cohort study used electronic health record (EHR) data from Veterans enrolled in the Million Veteran Program (MVP) biobank who had whole genome sequencing (WGS) data available. We identified Veterans with one or more rare (variant allele frequency [VAF] <0.01) pathogenic/likely pathogenic single nucleotide variants (SNVs) within one or more of 165 expert-curated epilepsy genes. Epilepsy phenotype was defined using a validated algorithm, and penetrance estimates were calculated using Bayes theorem and compared to civilian cohorts. Results: There were 102,624 MVP participants with WGS data. Mean age at censorship or death was 74.6 years, 6.1% were female and 6.3% had epilepsy. Among participants, 1.9% (n=1,955) carried at least 1 rare PGVs and 1.0% (n=1,041) carried ultrarare PGVs. Most carriers of autosomal dominant (AD) PGVs (89.7%) were not diagnosed with epilepsy, though carriers of both AD and autosomal recessive (AR) ultrarare PGVs had increased odds of epilepsy (odds ratios of 1.72 and 1.45, respectively) compared to non-carriers. Penetrance estimates were low for AD PGVs (8.2%), but similar to estimates from civilian biobanks. Discussion: Veterans carrying PGVs in AD-labeled epilepsy genes had increased risk for epilepsy, but only 10.3% were diagnosed. Unexpectedly, Veterans heterozygous for AR-labeled PGVs also had increased risk of epilepsy. Potential reasons for this include latent compound heterozygosity, misclassification of variant pathogenicity or gene MOI, or the possibility that PGVs in AR genes may be risk alleles for adult-onset epilepsy.

The gene most commonly implicated in epilepsy, SCN1A, encodes the neuronal voltage-gated sodium channel subunit NaV1.1. SCN1A variants that reduce sodium current ("loss of function" variants) cause Dravet syndrome, a neurodevelopmental disorder defined by treatment-resistant temperature-sensitive epilepsy with onset at/around 5 months of age, developmental delay/intellectual disability, and features of or formal diagnosis autism. However, an emerging group of variants cause "gain of function" (GoF) effects on NaV1.1 and result in a distinct presentation with earlier onset than Dravet syndrome and prominent movement disorder but without temperature sensitivity. We developed the first mouse model of SCN1A GoF epilepsy with heterozygous Cre-dependent expression of the recurrent patient variant Scn1a-p.R1636Q. Global expression of this variant causes premature mortality in 100% (64/64) of mutant mice between postnatal day 12-18 due to spontaneous, convulsive seizures. Activation of the mutant allele in parvalbumin interneurons (Dlx5/6-Cre or PV-Cre), but not excitatory neurons (Slc17a7-Cre) or other interneuron subtypes (VIP-Cre or Sst-Cre), recapitulates the premature mortality and epilepsy phenotypes. Treatment of Scn1a-p.R1636Q mutant mice with the sodium channel blocker GS967 markedly prolongs lifespan. This work is the first study of SCN1A GoF epilepsy in a preclinical model in vivo. Further investigation in the Scn1aflox(R1636Q)mouse will yield new mechanistic insights into disease mechanisms to drive advances in the treatment of SCN1A GoF epilepsy.

Objective: To determine whether paradoxical relief, feeling unusually better after a seizure compared to before it, is more common after functional/dissociative seizures (FDS) than epileptic seizures (ES), quantify its diagnostic accuracy, and explore its relationship with preictal symptoms. Methods: Consecutive patients admitted to a tertiary epilepsy unit for prolonged inpatient EEG monitoring underwent a structured clinical interview on admission, before final multidisciplinary diagnostic classification. Preictal dissociative and autonomic/somatic symptom burden was assessed using items adapted from established questionnaires. Diagnostic classification incorporated clinical history, seizure semiology, video electroencephalography findings, and collateral information. Patients with dual or indeterminate diagnoses were excluded. Associations with paradoxical relief were examined using logistic regression, followed by an exploratory mediation analysis. Results: Of 176 patients assessed, 66 with FDS and 65 with ES were included. Paradoxical relief was reported by 46/66 patients with FDS (69.7%) and 10/65 with ES (15.4%; unadjusted odds ratio [OR] 12.65, 95% confidence interval [CI] 5.57 to 31.09). As a diagnostic signal for FDS, paradoxical relief had 69.7% sensitivity (95% CI 57.1 to 80.4), 84.6% specificity (95% CI 73.5 to 92.4), a positive likelihood ratio of 4.53 (2.51 to 8.19), and a negative likelihood ratio of 0.36 (0.24 to 0.52). FDS diagnosis remained independently associated with paradoxical relief after adjustment (OR 10.59, 95% CI 3.42 to 38.06). In a parallel mediation analysis, dissociative symptom burden showed a significant indirect effect, accounting for 19.5% of the association between diagnostic group and relief, whereas the indirect effect through somatic/autonomic symptom burden was not significant. Significance: Paradoxical relief is substantially more common after FDS than ES and may provide a simple, clinically useful diagnostic signal. Its absence does not exclude FDS, and the finding requires external validation. The association with dissociative symptoms is exploratory and supports prospective investigation of whether relief reflects transient resolution of a disturbed, disembodied preictal state.

Introduction[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) frequently reveals hypometabolism extending beyond the epileptogenic zone in focal cortical dysplasia (FCD). However, it is unclear whether these peripheral hypometabolic areas harbour pathological cells potentially contributing to seizure generation. This study characterized histopathology in the lesion epicentre vs borders of the FDG-PET hypometabolism-informed resections in pediatric patients undergoing epilepsy surgery. MethodsFourteen children with intractable, extra-temporal focal epilepsy (mean age 9.0{+/-}5.0 years; 9 female) were retrospectively reviewed. FDG-PET contributed significantly to surgical planning in all cases, with the resection encompassing the visually-apparent MRI signal abnormalities as well as areas of surrounding hypometabolism when safely feasible. Multiple pathological specimens were obtained from the epicentre and surrounding hypometabolic areas. Overall, 136 specimens were analyzed: 64 epicentre (mean 4.6{+/-}3.2/patient) and 72 border (mean 5.1{+/-}3.5/patient). ResultsPathology was identified in 75% of epicentre specimens (59% with frank FCD (fFCD) IIa/b, 16% with dysmorphic neurons only (DNO)). Border specimens showed pathology in 62% (31% fFCD IIa/b, 31% DNO). We fitted a Bayesian logistic mixed model with pathology as outcome variable, location as predictor, and subject as a random effect. Compared to negative pathology, the log-odds of fFCD in the epicentre was 1.00 (confidence interval (CI) 0.32, 1.77) and -1.25 in the border (CI -2.17, -0.40). The log-odds of DNO vs negative pathology was non-significant in both locations. All patients achieved Engel Ia status at one-year follow-up with no long-term neurological deficits. ConclusionThese findings suggest a gradient of histopathology, with fFCD concentrated in the epicentre and DNO present in both the epicentre and hypometabolic borders. Thus, FDG-PET may be used to better detect the histopathological borders of FCD type II, and the high seizure-freedom rate presented here supports the inclusion of these surrounding hypometabolic regions in the surgical resection (when safe to do so), potentially improving the likelihood of removing epileptogenic cells. Key PointsO_LIPathological cells are present not only in the MRI signal abnormality in FCD but also in the periphery of the FDG-PET hypometabolism. C_LIO_LIWe observe a gradient of histopathology, with frank FCD concentrated in the epicentre and dysmorphic neurons spread throughout the area of hypometabolism. C_LIO_LIMaximal safe resection of the area of hypometabolism may increase likelihood of removing epileptogenic cells, thus improving surgical outcome. C_LI

Abstract Importance: Drug-resistant focal epilepsy affects approximately 30% of children with epilepsy and carries excess mortality, impaired neurodevelopment, and substantial costs. Epilepsy surgery is underutilized despite proven superiority over medical management. MRI-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to open resection, but comparative evidence to guide procedure selection is limited. Objective: To estimate lifetime outcomes and costs of epilepsy surgery versus medical management for pediatric drug-resistant focal epilepsy, and to provide etiology-informed guidance for choosing between open resection and MRgLITT. Design: Markov decision analytic model with a lifetime horizon, parameterized from published systematic reviews, meta-analyses, and cohort studies. Setting: United States, healthcare payer perspective. Participants: Hypothetical cohort of 10-year-old children with drug-resistant focal epilepsy and a seizure focus <3 cm3. Interventions: Best medical management, open resective surgery, or MRgLITT. Main Outcomes and Measures: Quality-adjusted life years (QALYs), lifetime direct medical costs, incremental cost-effectiveness ratios, and lifetime survival. Seizure outcomes were classified as seizure freedom or disabling seizures. Cost-effectiveness was assessed at $100,000/QALY. Results: Both surgical strategies were associated with a 4.6-year survival advantage, 3.6 additional lifetime QALYs, and lower costs than medical management. MRgLITT yielded 22.64 QALYs at $120,943; open resection yielded 22.62 QALYs at $121,650; medical management yielded 19.00 QALYs at $127,471. The difference between MRgLITT and open resection was 0.015 QALYs, reflecting near-equivalent effectiveness; in probabilistic sensitivity analysis, MRgLITT was optimal in 50.3% of iterations and open resection in 38.3%, with neither showing clear superiority. Etiology-specific analyses favored MRgLITT for focal cortical dysplasia and mesial temporal sclerosis, and open resection for tumor-related and cavernoma-related epilepsy. Conclusions and Relevance: Both open resection and MRgLITT were associated with substantially better lifetime outcomes and lower costs than medical management, supporting early surgical referral. Overall effectiveness between surgical approaches was clinically similar, with neither demonstrating clear superiority; the model suggests epilepsy etiology, rather than expected effectiveness alone, should guide procedure selection between MRgLITT and open resection.

Monogenic epilepsies are 1.6 times more likely to be treatment-resistant compared to other epilepsies, emphasizing the need for additional therapeutic strategies. Sleep dysfunction beyond sleep-related breathing disorders is common yet insufficiently characterized and treated in monogenic epilepsies. We therefore sought to study sleep phenotypes across these epilepsies, examine associations with seizure severity, and assess the diagnostic rate of sleep disorders. From 2,519 individuals enrolled in the Epilepsy Genetics Research Project at Children's Hospital of Philadelphia, we identified the monogenic epilepsies most frequently associated with sleep-related diagnoses, yielding 252 individuals across nine genetic diagnoses (STXBP1, n = 79; SCN1A, n = 57; SCN2A, n = 34; KCNQ2, n = 21; SLC6A1, n = 14; SYNGAP1, n = 13; WDR45, n = 13; KCNT1, n = 11; PCDH19, n = 10). Monogenic epilepsies exhibited distinct sleep endophenotypes, including insomnia, parasomnia, and sleep-related movement disorders in SCN1A-related disorders; frequent epileptiform discharges in sleep with insomnia symptoms in SCN2A-related disorders; sleep dysfunction restricted to the developmental and epileptic encephalopathy subtype in KCNQ2-related disorders; and insomnia without nocturnal seizure involvement in SYNGAP1-related disorders. Formal sleep diagnoses were present in only 25% of individuals (63/252), yet 58% (145/252) reported sleep difficulties, suggesting substantial underdiagnosis. Persistent seizures were associated with higher odds of sleep disorder diagnoses (OR 2.87, 95% CrI 1.57-5.36), disrupted sleep architecture (OR 2.06, 95% CrI 1.08-4.16), nocturnal seizures (OR 4.47, 95% CrI 2.50-8.28), hypersomnolence (OR 2.38, 95% CrI 1.27-4.58) and insomnia (OR 1.80, 95% CrI 1.06-3.05). Neuropsychiatric comorbidities were independently associated with sleep burden after adjustment for seizure severity (OR 2.49, 95% CrI 1.40-4.49). We find that monogenic epilepsies exhibit distinct, gene-specific sleep endophenotypes that are underdiagnosed. Treating sleep difficulties beyond obstructive sleep apnoea may improve seizure control and developmental outcomes, highlighting the need for timely diagnosis of co-occurring sleep disorders.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Background and Objectives: In persons with epilepsy, seizure risk is tightly linked to the health of sleep and circadian rhythms. Rest-activity rhythms (RARs), derived from continuously worn activity monitors, can provide objective assessments of diurnal patterns of activity. Compared with healthy controls, adults with epilepsy have been shown to display weak and unstable RARs. In this study, we aimed to directly measure RARs in patients with infantile epileptic spasms syndrome (IESS), a potentially devastating developmental and epileptic encephalopathy. As a comparator, we similarly examined identically measured RARs from a cohort of healthy infants. Methods: For this cross-sectional case-control comparison, we obtained multiday actograms in a sample of infants with IESS using ankle-worn Actiwatch-2 devices deployed during overnight follow-up EEG evaluations designed to assess initial treatment efficacy. Control actograms (similarly obtained via Actiwatch-2 devices) from the Rise & SHINE study (Sleep Health in Infancy and Early Childhood) were downloaded from the National Sleep Research Resource. We computed a series of parametric and non-parametric measures to depict the maturation of RARs over this developmental window and compared RARs from each IESS subject against up to 4 age-matched controls. Results: In 891 actigraphy recordings obtained from 333 SHINE subjects, age-dependent increases in body length and weight were associated with progressive increases in RAR height (amplitude/mesor/M10), regularity (interdaily stability), entropy and fractal complexity, together with progressive declines in RAR fragmentation (intradaily variability). Compared with age-matched controls, multiday actograms from IESS subjects (n = 11, 9 males) displayed marked reductions in RAR height (amplitude/mesor/M10) and interdaily stability, together with reductions in entropy and fractal complexity. Conclusions: During infancy, rest-activity rhythms display a stereotyped maturation in height, complexity and day to day consistency, revealing a developmental "growth curve" of RAR maturation. Severe RAR disruptions in infants with IESS may relate to the encephalopathy imposed by the underlying genetic/metabolic condition, structural lesion, and/or the psychomotor retardation imparted by antiseizure medications. Actigraphy recordings may offer a scalable, noninvasive approach to objectively and longitudinally assess circadian health in patients with IESS.

Background: Temporal lobe epilepsy surgery (TLS) is an effective treatment for drug-resistant focal epilepsy but is often associated with cognitive decline. A key unresolved question is how to distinguish average from severe memory loss and how these levels differentially affect everyday life. We addressed this question applying patient-derived norms of memory decline and conducting qualitative inter-views with patients experiencing expected or unexpectedly severe memory loss. Methods: Regression-based normative change criteria for postoperative verbal memory loss were derived from a single-center cohort of 806 patients. Two matched groups of four patients each were selected from the severe memory de-cline (SMD; below the 5th percentile) and average memory decline (AMD; 20th - 75th percentile) ranges. In-depth, semi-structured narrative interviews were analyzed using qualitative content analysis with a combined deductive-inductive ap-proach. Results: AMD narratives emphasized recovery, with surgery integrated into a con-tinuing sense of self. In contrast, SMD descriptions focused on persistent symp-toms, continued treatment, and illness despite meaningful seizure reduction. Pa-tients with SMD also reported limited information, insufficient psychological preparation or postoperative cognitive rehabilitation. Conclusions: Whereas AMD was generally manageable and successfully integrat-ed into everyday life, SMD disrupted identity, autonomy, and expected life trajecto-ries. Current surgical pathways appear to address these cognitive sequelae insufficiently. Improved expectation management, together with structured preoperative counseling and postoperative rehabilitation, may facilitate adaption to memory de-cline and improve long-term functioning and quality of life after surgery.

Objective Temporal lobe encephaloceles (ENC) are underdiagnosed causes of drug-resistant temporal lobe epilepsy (TLE), frequently associated with idiopathic intracranial hypertension (IIH). Emerging evidence suggests glymphatic system dysfunction in both IIH and TLE. We investigated glymphatic markers in TLE associated with ENC compared with seizure-free postoperative TLE controls of different aetiology. Methods Surgical specimens from 13 patients with TLE-ENC and 12 TLE-control patients were analyzed. Histological glymphatic markers included aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), podoplanin (PDPN), perivascular space (PVS) enlargement, and vessel density. High resolution MRI was used to assess a global PVS score. Results Compared with TLE-controls, TLE-ENC specimens showed increased white matter AQP4 expression and AQP4/GFAP ratio, whereas the AQP4/GFAP ratio was reduced in grey matter. PDPN expression was significantly elevated in both grey and white matter in TLE-ENC cases. MRI demonstrated greater supratentorial PVS enlargement in in ENC patients. Radiological features suggestive of IIH were identified in 46.1% of TLE-ENC patients. Compared with controls, TLE-ENC patients had shorter disease duration and lacked association with previous febrile seizures. Surgical treatment achieved seizure freedom in 70% of ENC patients at a median follow-up of 32 months. Interpretation This study provides the first characterization of glymphatic alterations in TLE-ENC-related epilepsy. Dysregulation of AQP4 and PDPN together with increased PVS burden suggests a distinct glymphatic dysfunction pattern in TLE-ENC, supporting a potential pathophysiological link among ENC formation, IIH, and epileptogenesis mediated by altered cerebrospinal fluid dynamics.

Background: Children with structural heart disease (SHD), particularly congenital heart disease (CHD), are increasingly recognised as being at risk of adverse neurological outcomes. Although advances in cardiac surgery and perioperative care have markedly improved survival, epilepsy has emerged as an important long-term complication. Reported prevalence estimates vary considerably across studies, and the overall burden remains uncertain. This systematic review and meta-analysis aimed to estimate the pooled prevalence of epilepsy among children with SHD and explore differences according to geographic region, lesion characteristics, and surgical exposure. Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 and MOOSE guidelines and registered in PROSPERO (CRD420261378572). PubMed/MEDLINE, Scopus, and ProQuest were searched for observational studies published between January 2000 and December 2025. Eligible studies included children aged 0-18 years with SHD or CHD reporting epilepsy prevalence or incidence. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies. A random-effects meta-analysis was performed to estimate pooled prevalence with 95% confidence intervals (CI). Results: Eight cohort studies comprising 21,731 children were included. Studies were conducted across North America, Europe, and Asia and predominantly involved surgically managed CHD populations. The pooled prevalence of epilepsy was 3.0% (95% CI 1.3%-4.8%), substantially higher than estimates reported in the general paediatric population. Heterogeneity was considerable (I{superscript 2} = 98.0%; p < 0.001). The 95% prediction interval ranged from 0% to 8.1%, indicating substantial variability across populations. Narrative subgroup synthesis suggested higher epilepsy prevalence among children with cyanotic and complex lesions and among surgically managed cohorts, particularly those exposed to cardiopulmonary bypass and perioperative neurological complications. Most studies were rated as having low risk of bias, and sensitivity analyses demonstrated stable findings. Conclusions: Children with SHD have a substantially increased burden of epilepsy compared with the general paediatric population. Complex lesions, perioperative neurological injury, and cardiac surgical exposure may contribute to epileptogenesis. Long-term neurological surveillance and multidisciplinary neurodevelopmental follow-up should be integrated into routine care for children with SHD.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy whose clinical and research representation requires integration of heterogeneous knowledge spanning seizures, development, behavior, SUDEP/autonomic risk, genetics, comorbidities, electrophysiology, pharmacology, and drug responsiveness. We report the development of a DS-focused ontology created by expert-guided specialization of a previously published epilepsy ontology. Scope expansion was defined through a scientific advisory board, structured review meetings, and iterative ontology curation in OWL. The resulting resource reorganized DS content across nine major domains and expanded the publicly released ontology from the pre-extension baseline to the current BioPortal version. Beyond structural growth, the ontology was assessed through expert-guided curation and downstream task-based reuse, including two published ontology-enabled LLM studies and an ongoing ontology-derived DS knowledge graph and AI assistant platform. These results suggest that disease-focused ontology specialization can provide durable infrastructure for DS data harmonization, knowledge representation, and AI-enabled translational informatics.

Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently recognized cause of drug-resistant focal epilepsy. It is often MRI-negative or shows imaging features mimicking focal cortical dysplasias, which makes recognition difficult and limits presurgical counseling. We aimed to identify an intracranial EEG (iEEG) biomarker that distinguishes MOGHE from other developmental brain lesions encountered in epilepsy surgery. In a retrospective multicenter test cohort of 38 patients (18 MOGHE, 20 non-MOGHE), we analyzed long-term stereo-EEG and subdural recordings. Only MOGHE patients showed highly stereotyped clusters of very brief low-voltage fast activity (LVFA) events, organized into status-like 3 to 12-minute episodes that often lacked clear clinical symptoms. LVFA clusters were present in 16/18 MOGHE and 0/22 non-MOGHE patients. We then tested diagnostic performance in an independent, blinded single-center validation cohort of 22 patients (11 MOGHE, 11 non-MOGHE), in which visual identification of LVFA clusters correctly classified 10/11 MOGHE and 10/11 non-MOGHE cases (Cohens kappa=0.82). Penalized logistic regression further confirmed MOGHE histology as the strongest predictor of LVFA clusters, independent of age and lobe localization. Because LVFA clusters can be recognized visually on routine intracranial EEG recordings without specialized software, this biomarker is readily applicable in clinical practice and may improve presurgical identification of MOGHE. Future prospective studies should determine whether its recognition influences surgical planning, improves outcome prediction, or facilitates selection of patients for mechanism-based therapies.

One-third of people with epilepsy continue to have seizures despite antiseizure medications (ASMs), and available therapies often fail to improve disabling cognitive comorbidities. Patients with drug resistant epilepsy report that the adverse effects of medications along with their comorbidities can have a greater negative impact on the quality of life than seizures. We previously identified recurrent JAK/STAT3 activation in chronic epilepsy and showed that transient treatment with the JAK inhibitor tofacitinib (CP690550) durably suppresses seizures and restores cognition in mice. Here, we tested CP690550 as an add-on therapy after failure of carbamazepine (CBZ), a common first line treatment for epilepsy, in a mouse model of multifocal temporal lobe epilepsy. In CBZ-resistant animals, dual therapy with CP690550 reduced median seizure frequency and time spent seizing by an order of magnitude; most dual therapy responders had no observed behavioral seizures during treatment. CP690550 also restored spatial working and short-term memory. We found that cognitive rescue was independent of seizure response. Our work suggests that JAK/STAT inhibition can overcome ASM nonresponse while independently improving epilepsy-associated cognitive dysfunction.

Objective: Cognitive impairment is a common comorbidity among people with epilepsy (PWE) and is associated with disability and reduced quality of life. We characterized the burden of cognitive impairment and identified factors associated with cognitive performance in a large, population-based cohort of PWE living in Northern Peru, a region highly endemic for Taenia solium where neurocysticercosis (NCC) is a common cause of acquired epilepsy. Methods: PWE enrolled in a population-based cohort in Northern Peru between 2007 and 2020 completed the Mini-Mental State Examination (MMSE) at enrollment. Cognitive impairment was defined as an MMSE score <24. Demographic and clinical data, including epilepsy characteristics and NCC status, were collected. Negative binomial regression was used to identify factors associated with the number of MMSE errors. Results: Among 764 participants, the mean MMSE score was 26.4 (SD 4.2), and 16.4% met criteria for cognitive impairment. Memory and attention were the most affected domains. In multivariable analysis, older age and lower educational attainment were independently associated with poorer cognitive performance. Conclusion: In this large, community-based cohort from Northern Peru, approximately 1 in 6 PWE had abnormal global cognition on the MMSE, with memory and attention most affected. These findings underscore the importance of incorporating cognitive evaluation and management into comprehensive epilepsy care, particularly in resource-limited settings where cognitive morbidity may be underrecognized. Given the potential for cognitive difficulties to compound disability and adversely affect quality of life, identifying and addressing cognitive morbidity may be especially important in populations already facing substantial barriers to epilepsy care.

Closed-loop neuromodulation via responsive neurostimulation (RNS) of the thalamus has emerged as a promising therapy for drug-resistant epilepsy (DRE), particularly in patients with broad or multifocal onset. However, response to thalamic RNS is inconsistent, and there is a crucial need to identify factors that distinguish responders from non-responders. Given the heterogeneous composition of the thalamus, the specific contributions of individual thalamic nuclei during seizures may explain the variability in outcomes between patients and could potentially serve as biomarkers for guiding target selection. We analyzed 129 seizures from 28 patients with DRE who underwent stereo-EEG monitoring with recordings of the centromedian (CM: n = 15) or pulvinar (PLV: n = 13) thalamic nuclei and were subsequently treated with RNS targeting the corresponding nucleus (CM: 11/15 [73%] responders; PLV: 7/13 [54%] responders). Patients were classified as responders (Engel class I-III) or non-responders (Engel class IV) based on reduction in seizure frequency. For each seizure, we constructed functional connectivity networks spanning seizure onset to termination and quantified the role of the thalamic nucleus by computing its total node strength. We also used an automated detection algorithm to measure the time of seizure spread to each thalamic nucleus relative to seizure onset. Connectivity and spread timing were then compared between responders and non-responders within each nucleus group. The timing of thalamic recruitment following seizure onset did not differ significantly between responders and non-responders in either nucleus, although CM responders showed a non-significant trend toward earlier recruitment. Analysis of functional connectivity revealed nucleus-specific patterns. CM responders exhibited significantly higher thalamic node strength than non-responders during the late-seizure phase, with no significant difference at early- or middle-seizure phases. PLV responders showed significantly higher thalamic node strength during the middle-seizure phase, but there was no significant difference at early- or late-seizure phases. These findings suggest that the degree and timing of thalamic involvement during seizures may serve as biomarkers for predicting response to thalamic RNS in DRE. CM involvement in responders was characterized by stronger connectivity that persisted through seizure termination, whereas PLV involvement in responders was reflected primarily in connectivity during seizure propagation and progression. Incorporating these nucleus-specific ictal network features into pre-surgical evaluation could improve patient selection and guide nucleus-specific targeting for thalamic RNS.

Objective To estimate the prevalence of epilepsy-associated malformations of cortical development (MCDs) in Eastern Denmark, and to validate whether epilepsy prevalence in the same population is consistent with national estimates. Methods A retrospective cohort study of people registered with ICD-10 code DG40* and/or DZ033A from 1998 up to 1 July 2023 was conducted. The study population was defined as all living residents in Eastern Denmark with at least one recorded hospital-patient contact within the year preceding 1 July 2023. Magnetic resonance imaging (MRI) availability was required to assess presence of any MCD. MRI radiology reports were manually reviewed or evaluated using a language model to identify MCDs, including encephalocele, focal cortical dysplasia (FCD), hemimegalencephaly, heterotopia, hypothalamic hamartoma, lissencephaly, polymicrogyria and schizencephaly. Prevalence estimates were calculated for each MCD subtype and for epilepsy overall, and compared with the available literature. Results On 1 July 2023, 28,739 people met inclusion criteria, and 14,434 had an available brain MRI, including radiological description of possible MCDs. The prevalence per 100,000 population was 1044.6 (95\% CI 1032.6 to 1056.6) for epilepsy and 32.1 (95\% CI 30.1 to 34.3) for any MCD associated with seizures. Reported MCD prevalence in the literature, when existent, was derived from pediatric age-ranged selected cohorts, except for FCD. No prevalence estimates for hemimegalencephaly and heterotopia were identified. Signifiance We presented the first population-based estimates of seizure-associated MCD prevalence in a large all-age cohort. Direct comparison with prior literature was prevented due to differences in study design and population structure, but epilepsy prevalence was consistent with previously reported national estimates.