Epilepsy & Behavior

Background Psychiatric comorbidities commonly have a negative impact on epilepsy outcomes. However, they are continuously ignored in routine epilepsy care, with focus directed more towards seizure control. There is paucity of data on the burden of psychiatric morbidity among those living with epilepsy in Kenya. This study sought to determine the prevalence and associated factors of psychiatric morbidity among patients living with epilepsy at a tertiary referral hospital in Western Kenya. Methods This was a descriptive cross-sectional study. Consecutive sampling was used to recruit participants, with a sample size of 278. Data were collected using a structured pretested sociodemographic and clinical characteristics questionnaire, and the Mini International Neuropsychiatric Interview (MINI), and analyzed using STATA version 16. Pearson Chi-square test/Fishers Exact test and logistic regression were used to assess relationships at bivariate and multivariate levels respectively. Results The prevalence of psychiatric morbidity was 52.2%. Major depressive disorder was the most prevalent (36%), followed by anxiety disorders (26.2%), psychotic disorders (16.9%), and suicidality (15.1%). Casual/self-employment (aOR=2.590, p=0.020), seizure-related physical trauma (aOR=4.032, p=0.004), antiepileptic polytherapy (aOR=4.280, p=0.001), frequent seizures (aOR=3.801, p<0.001), and comorbid medical conditions (aOR=5.478, p=0.047) were independent predictors of psychiatric morbidity. Having attained a tertiary level of education was protective against psychiatric morbidity (aOR=0.221, p=0.036). Conclusion More than half of the patients living with epilepsy had at least one psychiatric comorbidity. Routine psychiatric screening and integration of mental health services in epilepsy care is essential to improve clinical outcomes.

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.

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.

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.

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.

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: Instrumental activities of daily living (IADLs) represent a critical but understudied measure of day-to-day function in persons with epilepsy(PWE). In the multicenter Brain Aging and Cognition in Epilepsy (BrACE) study of PWE aged greater than or equal to 55 years, we examined the proportion, clinical correlates, epilepsy-related predictors, and longitudinal trajectory of IADL impairment. Methods: IADLs were assessed using the Functional Activities Questionnaire (FAQ; range=0 to 30; higher=more impaired); a FAQ greater than or equal to 2 defines MCI-level impairment, and a FAQ greater than or equal to 5 defines dementia-level functional impairment. Multivariable logistic regression identified predictors of baseline function. Global cognition (Montreal Cognitive Assessment [MoCA]), individual cognitive measures, and quality of life (QOL) were compared between the impaired and unimpaired groups. Linear regression evaluated predictors of longitudinal functional decline. Results: Of 57 participants (mean age=66.6 years; female=52.6%), 38.6% (n=22) had MCI-level functional impairment and 17.5% (n=10) had dementia-level functional impairment. In univariate analyses, worse FAQ scores were associated with lower education, higher area deprivation index, early-onset epilepsy (EOE less than 60 years), antiseizure medication polytherapy, and epilepsy localization. In multivariable analysis, temporal lobe epilepsy (OR=4.46, 95% CI=1.09, 21.83,p=0.047), EOE(OR=7.14, 95% CI=1.16, 59.97, p=0.046), and lower education(OR=0.70,95% CI=0.49, 0.93, p=0.025) remained independently associated with baseline MCI-level functional-impairment. Lower education (OR=0.55,95% CI=0.29, 0.84, p=0.021) was the only factor associated with dementia-level IADL-impairment. IADL-impaired participants demonstrated lower verbal memory scores (adjusted p=0.041) and MoCA scores (adjusted p<0.001), particularly in the visuospatial/executive function, attention, and memory subscores, and worse QOL (adjusted p=0.041). IADL impairment was greatest in financially-mediated and memory-dependent tasks. Longitudinally, EOE (beta=7.51,95% CI=1.92, 13.10, p=0.017) and older age(beta=0.38,95% CI=0.12-0.65, p=0.012) predicted greater functional decline. Nearly one-third progressed to significantly worse function over a two-year period, with 15.4% progressing from MCI-level to dementia-level impairment and 15.4% from normal function to MCI-level IADL-impairment. Conclusions: Functional impairment affects ~40% of older PWE, with ~1-in-6 experiencing functional impairment comparable to overt dementias. Temporal lobe localization, EOE, lower education, and poorer cognition are important determinants of baseline functional status. EOE and older age predict accelerated functional decline, suggesting that cumulative disease burden and aging-related processes may drive functional deterioration. These findings provide one of the first epilepsy-specific longitudinal characterizations of IADL impairment and support routine functional assessment in PWE.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

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.

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: 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.

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.

Abstract Objective To validate a neonatal seizure detection algorithm that is based on extracted clinical features of the aEEG and CSA on a cohort of cooled neonatal patients with HIE. Methods A seizure detection algorithm was designed using aEEG margin features, CSA features, trained on a public dataset of 79 neonatal EEGs with three supervised machine learning classifiers. It was subsequently tested on an inhouse cohort of 23 neonates with asphyxia whose EEGs were collected during hypothermia therapy. Results The trained Random Forest Classifier, Support Vector Machines and Artificial Neural Network classifiers had an AUC of 0.76, 0.77, and 0.77 and an average accuracy of 0.85, 0.86, and 0.85 respectively. Finally, the average AUC across the 10 seizure patients included was 0.85. Conclusion A neonatal seizure detection algorithm that uses a combination of aEEG and CSA clinical features can capture seizures in HIE patients. Performance across seizure patients is not correlated with seizure duration.

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.

Automated seizure detection devices are increasingly plausible tools for epilepsy trials, but no device is perfect. We used CHOCOLATES, a realistic seizure diary simulator, to examine how device sensitivity and false alarm rate (FAR) affect regression-to-the-mean (RTM) and placebo median percentage change (MPC) in a simulated randomized trial design. For each device condition, 100,000 potential participants were generated; eligibility was assessed during a 2-month baseline, followed by a 3-month test period. With FAR fixed at 0, reducing sensitivity from 100% to 10% increased the fraction of eligible participants exhibiting RTM from 38.2% to 64.8% and increased placebo MPC from 14.7% to 48.1%. With sensitivity fixed at 100% and expected FAR correction, increasing FAR from 0 to 1 alarm/day increased RTM from 38.2% to 53.2% and placebo MPC from 14.7% to 31.3%. Imperfect seizure detection can therefore change the apparent placebo response expected from RTM.

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.

Introduction Language functional MRI (fMRI) is a valuable tool for presurgical planning in epilepsy. Functional MRI can be challenging in children, and head motion can compromise its utility. The candidacy of patients with ADHD for fMRI is sometimes queried regarding concerns about possible head motion. In 2020, we implemented an fMRI task training program, via telehealth and/or mock MRI. We aimed to determine whether training increased language lateralisation success and/or reduced head motion in all patients, and in those with ADHD. We also aimed to determine whether patients with ADHD exhibited more head motion during fMRI than those without ADHD. Methods We retrospectively identified 223 epilepsy (85%) and other neurosurgery patients, (241 scans including repeats) with language fMRI at Royal Children's Hospital, Melbourne, Australia, 2016-2024. There were 24 individuals with ADHD listed in the Electronic Medical Record, five of whom had diagnoses of both ADHD and autism; and nine with autism. Language lateralisation success was determined by clinician description recorded as left/right/bilateral in the medical record. 99 patients were provided the training including fMRI task practise. Head motion was quantified by maximum Framewise Displacement (FDmax; mm). Results ADHD was associated with lower language lateralisation success. Training was associated with greater language lateralisation success, across all patients, and in those with ADHD. Regarding ADHD and head motion, outliers in FDmax were seen in 5 young patients with ADHD. Data were trimmed to allow separate investigation of FDmax for the sample with and without extremes of head motion. In untrimmed data, FDmax was significantly higher in patients with ADHD than in those without. In trimmed data, FDmax was on average lower in patients with ADHD than those without, however this was not statistically supported. Regarding training and head motion, across all patients, FDmax was significantly lower for scans with training than without. In patients with ADHD, FDmax was on average lower for scans with training, however training was not associated with FDmax. Conclusions Language fMRI training was associated with higher language lateralization success, particularly in patients with ADHD. Training was associated with reduced head motion across all patients. Although some young patients with ADHD had substantial head motion, most in our sample did not move more than those without ADHD. We conclude that the training program increases success of language fMRI, and that an ADHD diagnosis should not be a contraindication to language fMRI.

Temporal lobe epilepsy (TLE) is associated with dysregulation of transforming growth factor {beta} (TGF{beta}) signaling, a key contributor to epileptogenesis. SARA (Smad Anchor for Receptor Activation), a central regulator of this pathway, is controlled by the E3 ubiquitin ligase Smurf2 through ubiquitination. However, the role of the SARA-Smurf2 axis in regulating TGF{beta} signaling during TLE has not previously been described, and whether this pathway can be therapeutically targeted remains unknown. Using a pilocarpine-induced status epilepticus (SE) model and astrocytes derived from patients with refractory TLE, we identified dysregulation of the SARA-Smurf2 pathway in both experimental systems. In SE rats, SARA and Glial Fibrillary Acidic Protein (GFAP) levels were significantly increased, whereas Smurf2 induction was insufficient to prevent SARA accumulation. In TLE-derived astrocytes, increased SARA and GFAP immunoreactivity was accompanied by reduced Smurf2 immunoreactivity and altered Smurf2 subcellular distribution. Losartan treatment restored SARA and Smurf2 immunoreactivity toward a control-like pattern in both models and reduced seizure frequency and duration in SE animals. These findings point towards a dysregulation of the SARA-Smurf2 axis as a molecular signature of TLE, support SARA as a potential therapeutic target, providing experimental evidence for the repositioning of Losartan as a potential treatment alternative for drug-resistant epilepsy, warranting further translational and clinical investigation. KEY POINTSO_LIDysregulation of the SARA-Smurf2 axis is a molecular signature of experimental and human temporal lobe epilepsy. C_LIO_LIImpaired Smurf2-dependent regulation of SARA may sustain TGF{beta} signaling, astrocyte reactivity, and epileptogenesis. C_LIO_LILosartan restores the SARA-Smurf2 axis and reduces seizures, supporting a novel therapeutic strategy for TLE. C_LI