Epilepsia最新文献

Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug-resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood.

Methods: The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A+ DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI-IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3), Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P), and Pediatric Evaluation of Disability Inventory (PEDI).

Results: Fifty-eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age-appropriate milestones. Mean BSID-III Cognitive raw scores increased minimally, with age-equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: -11.0, 95% confidence interval [CI]: -15.3 to -6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF-P Global Executive Composite T-scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS-3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: -9.0, 95% CI: -11.9 to -6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it.

Significance: Infants and young children with SCN1A+ DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

Objective: Genetic generalized epilepsies (GGEs) comprise the most common genetically determined epilepsy syndromes, following a complex mode of inheritance. Although many important common and rare genetic factors causing or contributing to these epilepsies have been identified in the past decades, many features of the genetic architecture are still insufficiently understood. This study integrates genome-wide association study (GWAS) data from the International League Against Epilepsy Consortium on Complex Epilepsies with transcriptome-wide association studies to identify genes whose genetically regulated expression levels are associated with epilepsy.

Methods: To achieve this, we used multiple computational approaches, including MAGMA, a tool for gene analysis of GWAS data, and its derivatives E-MAGMA and H-MAGMA, to improve gene mapping accuracy by utilizing tissue-specific expression and chromatin interaction data. Furthermore, we developed ME-MAGMA to incorporate methylation quantitative trait loci data, providing insights into epigenetic factors.

Results: We identified a total of 897 false discovery rate-corrected (<.05) candidates. These include voltage-gated calcium channels, voltage-gated potassium channels, and other genes such as NPRL2, CACNB2, and KCNT1 associated with epilepsy pathogenesis that act as key players in neuronal communication and signaling in the brain.

Significance: In this study, we propose new candidate genes to expand the dataset of potential epilepsy-causing genes. Further research on these genes may enhance our understanding of the complex regulatory mechanisms underlying GGE and other types of epilepsy, potentially revealing targets for therapeutic intervention.

Objective: In epilepsy, daily treatment provides only symptomatic seizure control, leaving a significant unmet need for a treatment that affects the underlying predisposition to seizures. Here, in a first-of-its-kind study, we test the hypothesis that intermittent treatment of seizure clusters with diazepam in the kainic acid post-status epilepticus rat model of acquired epilepsy has an enduring effect on the seizure cluster phenotype, suggestive of potential disease modification.

Methods: Following kainic acid-induced status epilepticus, rats with epilepsy were monitored for occurrence of seizure clusters (≥2 seizures in 24 h) for a 3-week baseline period before entering a 6-week treatment period using a previously established multidose regimen of diazepam (n = 7) or vehicle (n = 9) upon identification of a seizure cluster. In a subsequent 2-week outcome period during which no rats received diazepam, we evaluated changes in seizure cluster size, burden (cluster size × severity), duration, and other phenotype parameters.

Results: A total of 3396 seizures and 216 seizure clusters were included for analysis. During the outcome period, time between seizures in a cluster (also interseizure interval [ISI]) was significantly longer in the diazepam group (log ISI = .25 longer, SE = .08, p < .0001), and the proportion of clustered seizures with an ISI of ≤30 min increased in the outcome period in the vehicle group (p = .023) but was stable in the diazepam group. Despite the occurrence of rebound seizures during the treatment period, improvement in several phenotypical parameters, including severity and proportion of seizures in a cluster, supported a positive impact of intermittent diazepam treatment on seizure cluster biology.

Significance: Changes in several seizure cluster phenotypical parameters were suggestive of an enduring disease-modifying effect of diazepam, despite an apparent rebound effect of intermittent diazepam treatment on seizure frequency. Further study is warranted using a model incorporating a background antiseizure medication regimen to potentially attenuate the unexpected rebound seizures.

Objective: Epilepsy is the most common chronic neurological disorder in children, and approximately one third of patients develop drug-resistant seizures. Reliable biomarkers are needed to improve diagnosis, prognostic assessment, and treatment monitoring. This study evaluated four circulating microRNAs-miR-15a-5p, miR-106b-5p, miR-146a-5p, and miR-152-3p-as potential diagnostic and prognostic biomarkers in pediatric epilepsy.

Methods: A total of 122 pediatric patients with epilepsy and 29 age- and sex-matched healthy controls were prospectively enrolled at Bambino Gesù Children's Hospital (Rome) between 2022 and 2025. Clinical variables included epilepsy type, etiology, seizure frequency, electroencephalography, magnetic resonance imaging, and comorbidities. Serum miRNAs were measured by reverse transcription quantitative polymerase chain reaction and normalized using the 2^-ΔΔCt method, accounting for hemolysis. Nonparametric tests (Mann-Whitney, Kruskal-Wallis, Wilcoxon) were used for comparisons. Forty-three patients were reevaluated after ≥12 months to assess longitudinal expression.

Results: All four miRNAs were significantly upregulated in children with epilepsy compared to controls (p < .05). miR-146a-5p expression differed among etiological groups, being higher in structural compared with genetic or unknown etiologies (p = .014). Both miR-15a-5p and miR-106b-5p correlated with seizure frequency, showing greater expression in patients with monthly-to-daily seizures than in those with sporadic seizures or seizure-free patterns (p = .004 and p = .017). No association was found with antiseizure medications, intellectual disability, or psychiatric comorbidities. Longitudinal analysis showed a significant increase in miR-15a-5p and miR-106b-5p at follow-up (p < .01), independent of clinical outcome, whereas miR-146a-5p remained stable over time. These findings suggest that miR-15a-5p and miR-106b-5p reflect ongoing epileptic activity, whereas miR-146a-5p may relate to underlying pathophysiology rather than seizure dynamics.

Significance: Circulating miRNAs represent promising, minimally invasive biomarkers in pediatric epilepsy. miR-146a-5p may aid etiologic classification, whereas miR-15a-5p and miR-106b-5p could serve as dynamic indicators of disease burden and treatment response, supporting biomarker-driven precision approaches in epilepsy care.

Objective: Temporal lobe epilepsy (TLE) is the most common focal epilepsy but remains highly heterogeneous across hemispheric and structural etiology. This study aimed to characterize microstate-based network dynamics in TLE and evaluate their diagnostic value for seizure lateralization and structural etiology using machine learning.

Methods: Resting-state electroencephalography (EEG) recordings from 150 patients with unilateral TLE (71 right, 79 left) and 65 healthy controls (HCs) were analyzed. EEG signals were segmented into canonical microstates (A, B, C, D), and microstate-specific spatial, and temporal dynamic functional connectivity (dFC) variability metrics were extracted using phase lag index analysis. After two-step feature selection, the appropriate number of features were derived and input into Random Forest, XGBoost, and Support Vector Machine (SVM) classifiers to distinguish: TLE vs HCs, left vs right TLE, and magnetic resonance imaging (MRI)-negative (MRI-neg) vs hippocampal sclerosis (HS) TLE subtypes (TLE-HS). Model performance was evaluated on independent hold-out validation set using receiver operating characteristic analyses.

Results: Compared with HCs, patients with TLE exhibited increased duration and occurrence of microstate D and reduced expression microstate B, reflecting maladaptive attentional overactivation and visual suppression. Spatial variability was globally decreased, most prominently in left TLE. SVM achieved excellent performance for TLE detection (area under the curve [AUC] = .98) and lateralization (AUC = .97), whereas classification between MRI-neg TLE and TLE-HS was limited (AUC = .58).

Significance: EEG microstate-derived dFC metrics provide reliable, non-invasive biomarkers for identifying and lateralizing TLE using short duration resting-state EEG recordings. This framework advances understanding of TLE heterogeneity and supports the development of individualized electrophysiological tools for precision diagnosis.

Hydroxycarboxylic acid receptor 1 (HCAR1) is a G-protein-coupled lactate receptor expressed in the brain and plays a role in neuronal excitability and repair after injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of brain injury and seizures in term neonates. The goal of this study was to describe HCAR1 expression and function in the neonatal brain and understand its role in HIE-associated seizures. HCAR1 expression was measured using quantitative reverse transcriptase polymerase chain reaction in postnatal day (p)10-50 mice. Neuronal properties and spontaneous excitatory postsynaptic currents (sEPSCs) were measured in hippocampal principal neurons from HCAR1 knockout and wild-type mice when exposed to lactate. p10 HCAR1 knockout and wild-type mice were exposed to hypoxia-ischemia (HI) and underwent electroencephalography to compare seizure burden. HCAR1 was expressed at p10 at similar levels to adults. Lactate decreased amplitudes and sEPSC frequency in wild-type but not HCAR1 knockout mice. After HI, HCAR1 knockout mice had higher seizure burden and behavioral seizure scores than wild-type mice. HCAR1 is expressed on neurons and plays a role in neuronal excitability and seizures in the neonatal brain.

Objective: Surgical resection for epilepsy seeks to maximize seizure freedom while minimizing new neurocognitive impairments. Tailored resections guided by anatomoelectroclinical (AEC) hypotheses offer the possibility of sparing parts of the hippocampus. The relationship between the extent of hippocampal resection and postoperative neurocognitive outcomes in this context has not been studied and has important implications for clinical practice. We test this relationship in a series of left and right tailored anterior temporal lobectomy (ATL) surgeries.

Methods: We conducted a retrospective analysis of 34 adult patients with drug-resistant temporal lobe epilepsy (18 left, 16 right) who underwent tailored ATL based on individualized AEC hypotheses at the University of Pittsburgh Medical Center. All patients completed standardized pre- and postoperative neuropsychological testing, and 85.3% underwent preoperative stereoelectroencephalography to guide resection. Surgical extent was tailored through a multidisciplinary process integrating AEC correlations and intraoperative electrophysiology. Preoperative and postoperative hippocampal volumes were measured and correlated with changes in verbal and visual memory, as well as language performance.

Results: Greater extent of resection of the left hippocampus was significantly associated with worse postoperative outcomes in both verbal and visual recall. Extent of resection of the right hippocampus was not related to reductions in performance across any domain, with some indication of improvements in performance after right ATL surgery at the group level. Seizure outcomes (66.6% Engel I at 2 years) were consistent with the existing literature and did not vary with hippocampal resection extent.

Significance: These findings highlight the critical role of the left hippocampus in supporting both verbal and visual memory and underscore the importance of preserving hippocampal tissue during left ATL when feasible. Our results support the utility of AEC-guided tailored resections as a strategy to balance seizure control with cognitive preservation.

Objective: Interictal epileptiform discharges (IEDs) are transients observed on the electroencephalogram (EEG) of patients with epilepsy. IEDs have traditionally been recorded from scalp or intracranial EEG macrocontacts, which coarsely sample neural activity. Here, we investigated the use of flexible, high-resolution microelectrocorticographic (μECoG) arrays for measuring IEDs with greater spatiotemporal precision to test whether there exist microscale patterns of IED activity that may be missed on standard intracranial EEG.

Methods: We used liquid crystal polymer thin-film μECoG arrays with both high resolution (.76-1.72-mm spacing, 200-μm diameter) and large cortical coverage (144-1596 mm²) to record from seven patients undergoing surgical treatment of epilepsy. We identified IEDs by a combination of expert review and automated detection. We quantified the spatial extent of IEDs, mapped patterns of repeated IED activity, and quantified IED propagation direction using multilinear fit models. We also compared IED detection rates and propagation measurements between μECoG arrays and simulated macroarrays (10-mm spacing, 2.3-mm diameter).

Results: We demonstrated successful use of μECoG arrays to map intraoperative microscale patterns of IEDs. The majority of patients (5/7) exhibited elevated IED activity that was highly localized (subcentimeter localization). Across all patients, 40% of detected IEDs were observed within a 4-mm radius of cortex. μECoG arrays also mapped the direction of IED propagation. An average of 39% (range = 4.2%-96.5%, SD = ±36.8%) of the IED events captured by the μECoG arrays were not detectable by simulated macrocontacts.

Significance: These intraoperative data demonstrate that μECoG arrays can map the microscale spatiotemporal activity of IEDs. These patterns of IEDs may be poorly captured by standard, macroscale recording devices. Our findings support the use of high-resolution, large area coverage μECoG arrays for the presurgical and intraoperative mapping of epileptic cortex.

Objective: Epilepsy carries an increased risk of premature mortality. Although seizure freedom may reduce deaths, most population-based evidence originates from high-income countries. Data from low-income settings, such as rural China, remain scarce. We update mortality patterns and evaluate their associations with achieving 1-year seizure freedom among rural populations in China.

Methods: People with epilepsy living in rural Henan, China, were enrolled between 2010 and 2011 and followed up at three subsequent time points over 10 years. We collected demographic and clinical data, including survival outcomes. Seizure freedom was defined as a 12-month seizure-free interval recorded in any follow-up period. Causes of death were assessed using a structured verbal autopsy questionnaire and adjudicated by a multidisciplinary panel. We estimated mortality rates, standardized mortality ratios (SMRs), and cause-specific distributions, and used regression models to identify mortality predictors and associations with seizure freedom.

Results: Among the 610 participants enrolled (57.5% male), 67 had died over 10-year follow-up, yielding an all-cause mortality rate of 13.5/1000 person-years (95% confidence interval [CI] = 10.5-17.2) and an age- and sex-adjusted SMR of 2.4 (95% CI = 2.3-2.5). Epilepsy-related deaths accounted for 48% of deaths, with sudden unexpected death in epilepsy being predominant (33%). People who had ever achieved 12-month seizure freedom (n = 317) had significantly lower SMRs than those who never did (n = 293). Ever achieving seizure freedom was independently associated with a lower risk of all-cause mortality (odds ratio [OR] = .30, 95% CI = .17-.52) and epilepsy-related death (OR = .29, 95% CI = .12-.63). This protective effect was most pronounced in women, older adults, those with seizure onset during adulthood, and those without comorbidities.

Significance: Mortality in this cohort remains more than twice that of the general population, with sudden death accounting for one third of cases. Achieving 1-year seizure freedom even once during follow-up substantially reduced mortality risk and altered cause-of-death distributions. This finding underscores seizure control as a practical and encouraging treatment goal in resource-limited settings.

Objective: This study was undertaken to present the results of an exploratory phase 2 trial of stiripentol in Lennox-Gastaut syndrome (LGS).

Methods: This exploratory single-blind, single-arm, nonrandomized sequential-period phase 2 study was conducted at four centers in France between January 1989 and August 1993. Eligible patients were aged 2-20 years with LGS and experienced at least one seizure per week despite optimized therapy. After a 1-month baseline period under a stable treatment regimen, patients received placebo for 1 month followed by stiripentol for 2 months.

Results: Sixteen patients with LGS were enrolled, and efficacy was assessable in 14. The median [Q1-Q3] overall seizure frequency decreased from 31 [16-89] at baseline to 14 [8-21] after the first month of stiripentol (p = .044) and further to 4 [0-18] after the second month (p = .044). The reduction was consistent across seizure types. Eight patients (57%) were responders (≥50% reduction in overall seizure frequency) at the end of stiripentol treatment, including five (36%) who achieved complete seizure freedom and two with a ≥75% reduction in seizure frequency. All patients reported at least one adverse event during stiripentol treatment, most commonly somnolence, decreased appetite, and vomiting. These effects may be related to the high stiripentol doses administered (median = 91 mg/kg/day in the second month). Despite their frequency, no serious adverse events were reported during the stiripentol treatment period, and no clinically meaningful changes in hematological parameters or liver enzyme levels were observed.

Significance: Although this study was conducted before standardized clinical trial designs for LGS were established, a more comprehensive evaluation of stiripentol could have provided further insight into its potential benefits in this severe developmental and epileptic encephalopathy.