Ellis CA, Copeland J, Velez I
… +25 more, Oliver KL, Shalaby H, Baldwin A, Armstrong C, Back A, Berlin B, Cohen S, Cuddapah VA, deCampo D, Dubbs H, Ginn N, Harrison AG, Lewin N, Lusk L, Marsh ED, Massey SL, McDonnell PP, McKee JL, Ortiz-Gonzalez X, Prentice AJ, Sullivan KR, Ruggiero SM, Fitzgerald MP, Goldberg EM, Helbig I
OBJECTIVE: Genetic testing has become a routine part of clinical epilepsy care. Family history is an indication for genetic testing, but the diagnostic yield, predictors of a genetic diagnosis, and association with famil...OBJECTIVE: Genetic testing has become a routine part of clinical epilepsy care. Family history is an indication for genetic testing, but the diagnostic yield, predictors of a genetic diagnosis, and association with familial patterns are not well understood. METHODS: This was a retrospective cohort study of genetic testing performed at pediatric and adult epilepsy genetics clinics. Eligible patients (probands) had epilepsy and one or more first-degree relatives or two or more other relatives with epilepsy. Genetic testing strategies were patient specific, reflecting real-world clinical practice. Familial patterns were classified based on affected relatives of the proband. Diagnostic variants were tested in the proband's parents when possible. RESULTS: We studied 484 probands and their families. A genetic diagnosis was identified in 99 of 484 (20%). Predictors of a genetic diagnosis were presence of neurodevelopmental disorder (X(1) = 9.6, p = .002) and earlier age at seizure onset (Mann-Whitney U test, p < .001). The likelihood of a genetic diagnosis was not associated with epilepsy type, drug resistance, brain magnetic resonance imaging (MRI) findings, number of affected first-degree relatives, total number of affected relatives, or having an affected parent with epilepsy. Among those with genetic diagnoses, variant segregation matched the familial pattern of affected individuals in 79%. The other 21% of families had unexpected segregation, including de novo variants in patients with affected ancestors and inherited variants in patients with no known affected ancestors. SIGNIFICANCE: Familial epilepsy has a substantial rate of genetic diagnosis and is an appropriate indication for genetic testing. Pedigree-related factors did not influence the likelihood of genetic diagnosis, suggesting that all families can be considered for genetic testing, independent of inheritance patterns and number of affected relatives. Familial patterns can help interpret genetic test results, while also revealing the complexities of incomplete penetrance and independent epilepsy etiologies in families.
OBJECTIVE: Systematic reviews and meta-analyses (SRMAs) are critical for synthesizing evidence and guiding clinical and public health decision-making. This study aims to evaluate the reliability, validity and reproducibi...OBJECTIVE: Systematic reviews and meta-analyses (SRMAs) are critical for synthesizing evidence and guiding clinical and public health decision-making. This study aims to evaluate the reliability, validity and reproducibility of the International League Against Epilepsy (ILAE) Commission on Epidemiology Risk of Bias Tool by comparing it against the Newcastle-Ottawa Scale (NOS) to inform whether the ILAE tool may serve as a valid alternative in epilepsy-focused evidence syntheses. METHODS: This study was planned a priori on three consecutive SRMAs. We assessed 54 observational studies included in these SRMAs focused on psychiatric comorbidities in persons with epilepsy. Eligible studies had ≥30 participants per group and validated criteria for diagnosing epilepsy and psychiatric conditions. Two independent raters scored all studies using both tools. The ILAE tool comprises six specific domains: (1) Source of Study Population; (2) Completeness (Sensitivity) of Epilepsy Case-Finding; (3) Sensitivity of Comorbidity Determination; (4) Accuracy of Epilepsy Diagnosis; (5) Accuracy of Comorbidity Diagnosis; and (6) Representativeness of Study Sample. Test-retest reproducibility used intraclass correlation coefficient (ICC). Correlation used Spearman's rho. Agreement used weighted kappa. Bland-Altman analysis reported mean difference. RESULTS: There was a strong positive correlation between NOS scores and ILAE ratings (Spearman's rho = 0.80, 95% confidence interval [CI] 0.68-89, p < 0.001). Cohen's weighted kappa was 0.68 (95% CI 0.37-0.92, p < 0.001). Bland-Altman mean difference was 0.09 with limits from -0.48 to 0.67, showing good agreement between tools. The ILAE tool showed excellent test-retest reproducibility (ICC 0.90, 95% CI 0.83-0.94). SIGNIFICANCE: The ILAE tool demonstrated strong reliability and substantial agreement with the NOS while offering epilepsy specific rigor in diagnostic accuracy, sensitivity, case finding and representativeness. The ILAE tool offers a reliable, conceptually relevant, field-specific alternative for quality assessment in epilepsy SRMAs.
OBJECTIVE: Executive dysfunction, affective symptoms, and unemployment are prevalent in patients with epilepsy, yet the relation between these variables remains poorly understood. The present study examined: (1) The rela...OBJECTIVE: Executive dysfunction, affective symptoms, and unemployment are prevalent in patients with epilepsy, yet the relation between these variables remains poorly understood. The present study examined: (1) The relationship between epilepsy-related variables, affective symptoms, and executive functions (EFs); and (2) how these variables may be associated with participation in employment or education. METHODS: Retrospective study including 559 patients admitted to the Norwegian National Centre for Epilepsy. EFs was assessed using EpiTrack, and affective symptoms were evaluated with the 7-item Generalized Anxiety Disorder (GAD-7) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). RESULTS: Impaired EFs were observed in half of the patients, and were associated with a higher antiseizure medication (ASM) load, even after adjusting for variables related to disease severity. Approximately 36% of the patients reported symptoms indicating major depression and 19% reported symptoms indicating generalized anxiety. Half of the sample was unemployed, and these patients showed poorer EFs than those engaged in employment or education (F(3, 530) = 12.29, p < .001, ηp = .07), with no group differences in seizure frequency, anxiety, or depressive symptoms. SIGNIFICANCE: In patients at a tertiary epilepsy center, executive dysfunction is prevalent along with heightened symptoms of depression and anxiety. Executive dysfunction is associated with a higher ASM load as well as increased likelihood of unemployment. Our findings suggest that job retention may depend on more than the burden of epilepsy alone, with executive functioning playing a critical role. These findings emphasize the importance of monitoring EF during treatment adjustments and support minimizing total ASM load whenever possible to promote better functional outcomes.
OBJECTIVE: Epileptic seizures are generated in cerebral networks that propagate ictal and interictal activity. The structure of cerebral networks underpinning epileptic activity can be inferred from diffusion-weighted ma...OBJECTIVE: Epileptic seizures are generated in cerebral networks that propagate ictal and interictal activity. The structure of cerebral networks underpinning epileptic activity can be inferred from diffusion-weighted magnetic resonance imaging (DWI). However, publicly available DWI data in individuals with epilepsy are scarce, and processing is technically challenging due to scan-specific artifacts, limiting research progress. METHODS: Here, we release raw DWI data from 216 individuals with epilepsy and 98 healthy controls. Subject identifiers align with our previous data release (IDEAS), which includes T1-weighted and FLAIR magnetic resonance imaging, surgical details, and long-term seizure outcomes after surgery. Preprocessing reduced distortions and artifacts, and fully processed data include diffusion metric maps in native and template space. We also provide parcellated structural connectomes using multiple atlases and connectivity measures. RESULTS: To illustrate the utility of these IDEAS II data, we replicated ENIGMA consortium findings, observing widespread reductions of fractional anisotropy, particularly ipsilateral to the area of seizure onset. We further demonstrate localized abnormality, and network connectivity using streamline tractography in a patient who subsequently underwent temporal lobe resection. SIGNIFICANCE: This open dataset offers a comprehensive resource to advance research on structural connectivity and surgical outcomes in epilepsy.
Orsini A, Marini L, Bergonzini L
… +16 more, D'Angelo F, Lelli S, Foiadelli T, Spreafico E, Santi V, Mencaroni E, Verrotti A, Ferretti A, Parisi P, Morganti R, De Lorenzo B, Küppers B, Bonuccelli A, Battini R, Peroni D, Cordelli DM
Seizures, when prolonged or repeated, leading to status epilepticus (SE), represent a medical emergency, requiring prompt treatment. In these conditions, the use of continuous midazolam (MDZ) infusion is often reserved f...Seizures, when prolonged or repeated, leading to status epilepticus (SE), represent a medical emergency, requiring prompt treatment. In these conditions, the use of continuous midazolam (MDZ) infusion is often reserved for established or refractory SE and considered an anesthesiologic treatment, while evidence on its early use in non-intensive settings is still limited. To verify this approach in daily practice, we retrospectively collected data on about 42 episodes of pediatric SE or acute repetitive seizures (ARSs), treated with continuous MDZ infusion in non-intensive setting. Collected data include demographical information, previous history of epilepsy, instrumental examinations (electroencephalography [EEG] and brain magnetic resonance imaging [MRI]), comorbidities, anti-seizure medications (ASMs), information about the event, other treatments (first- and second-line), information about MDZ infusion, and need for other third-line treatment and/or intensive care unit (ICU) transfer. Infusion durations and rates varied widely, but in most cases (38/42) low dose (<.23 mg/kg/h) were employed. The treatment was effective in 84.2% of cases, achieving both clinical and EEG response. No adverse events (AEs) were reported. The need for a second-line treatment (particularly levetiracetam [LEV] and phenobarbital [PB]) was associated with a worse outcome. Another third-line treatment was needed in 9.5% of cases. Patients (21.4%) were transferred to ICU; a higher risk of ICU admission was reported in patients with precipitating factors (infection, surgery, hypertension and suboptimal anti-seizure medication [ASM] serum levels), and those receiving MDZ infusion at higher rates and/or co-treated with PB. Overall, our study suggests that low-dose continuous MDZ infusion is an effective and safe strategy for treatment of pediatric SE and ARSs in non-intensive settings.
Sullivan J, Valente K, Villanueva V
… +12 more, Strzelczyk A, Nabbout R, Nakagawa E, Zhang Y, Zolnowska M, Khan Y, Dong C, Hsiao S, Sheikh SI, von Rosenstiel P, Asgharnejad M, Murthy V
OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in children and young adults with Dravet syndrome (DS). METHODS: SKYLINE (NCT04940624) was a multicenter, random...OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in children and young adults with Dravet syndrome (DS). METHODS: SKYLINE (NCT04940624) was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that enrolled patients with DS aged 2-21 years with uncontrolled convulsive seizures (≥4/month despite adequate treatment). Participants received oral soticlestat 300 mg (weight adjusted) or matching placebo twice daily. The total study duration was 16 weeks, comprising 4-week dose titration and 12-week maintenance treatment periods. The primary endpoint was a comparison of monthly convulsive seizure frequency between baseline and the titration/maintenance periods. Key secondary endpoints included several modified Caregiver and Clinical Global Impression of Improvement (GI-I) scales for DS. RESULTS: One hundred forty-four participants were randomized (71 placebo, 73 soticlestat) with a mean (SD) age of 10.3 (5.0) years; 72 (50%) were male, and 117 (81.3%) were receiving ≥3 antiseizure medications. Median change from baseline in convulsive seizure frequency over the full treatment period was -8.64% with placebo (n = 71) and -22.16% with soticlestat (n = 73), a difference of -15.64% (p = .061); in the maintenance treatment period, these changes were -11.99% with placebo and -23.29% with soticlestat, a difference of -14.29% (p = .089). The proportion of participants with ≥50% reduction in convulsive seizures was 9.9% with placebo and 27.4% with soticlestat (nominal p = .008). Soticlestat showed clinically meaningful results in the Caregiver and Clinical GI-I, and Clinical GI-I Seizure Intensity and Duration scales over the 16-week treatment period (all nominal p-values ≤ .004). The most commonly reported treatment-emergent adverse events related to study drug were somnolence, change in seizure presentation, decreased appetite, and insomnia. SIGNIFICANCE: Although statistical significance was narrowly missed, soticlestat showed a numerical benefit over placebo for convulsive seizure decrease. Clinically meaningful benefits across multiple secondary endpoints were observed. No new safety concerns emerged.
OBJECTIVE: There is a growing synergy between the lines of research on cycles in epilepsy and seizure forecasting. It has been conjectured, for instance, that incorporating information about significant seizure cycles in...OBJECTIVE: There is a growing synergy between the lines of research on cycles in epilepsy and seizure forecasting. It has been conjectured, for instance, that incorporating information about significant seizure cycles into forecasting algorithms can lead to a better-than-chance forecasting performance. However, significance and better-than-chance are each typically evaluated against only a single null hypothesis, for example, that forecasts are generated by a Poisson process. We here argue that this should be considered only a first step. Our objective is to demonstrate the importance of testing complementary null hypotheses that represent alternative chance models. METHODS: To ensure controlled conditions, we use synthetic data generated from simple mathematical models. Samples drawn from gamma distributions are used to generate sequences of random seizure times and random forecasts. We then determine the strength of cycles as a function of the cycle duration and calculate the sensitivity and fraction of time under alarm obtained for the random forecasting algorithm. In both analyses, we apply numerical, surrogate-based null-hypothesis testing methods. In the latter case, this includes a straightforward approach to correcting for multiple testing on nonindependent data. RESULTS: Counterintuitively, the random seizure-time sequences contain multiple prominent cycles, which are judged highly significant by the Rayleigh test. Moreover, randomly forecasting random seizure times results in a sensitivity of 79% at a fraction of time under alarm of only 42%, clearly outperforming a Poisson-like predictor. In both cases, however, the flexibility and versatility of surrogate-based null-hypothesis tests allow us to successfully reveal that all results can be explained by chance models. SIGNIFICANCE: Before reaching conclusions on real cycles in epilepsy, the forecastability of seizures, and genuine capacity of forecasting algorithms, it is essential to test and reject several complementary null hypotheses. Many conclusions might not withstand such rigorous tests, allowing the community to focus on those that do.
Status epilepticus (SE) is a life-threatening neurological emergency with consensus-driven definitions for onset but no standardized criteria for its end point. This gap creates uncertainty in research and clinical pract...Status epilepticus (SE) is a life-threatening neurological emergency with consensus-driven definitions for onset but no standardized criteria for its end point. This gap creates uncertainty in research and clinical practice. We conducted a scoping review to evaluate how end points have been defined in SE research and to identify key areas of variability. Comprehensive searches of MEDLINE, Embase, and CENTRAL (Cochrane Central Registry of Controlled Trials; 1980-2025) yielded 3940 citations (1674 unique). After screening, 207 studies met the inclusion criteria and were charted using scoping review methodology (Preferred Reporting Items of Systematic Reviews and Meta-Analyses, extension for scoping reviews). Data were extracted on terminology, electroencephalography (EEG) use, temporal thresholds, and definitions of therapeutic success across retrospective and prospective designs. Five domains of heterogeneity were identified: (1) semantic terminology (e.g., "resolved," "controlled," "terminated," "cessation"); (2) EEG confirmation of the SE end point (reported in 54% of studies, with variable criteria); (3) whether time was included in defining the end point; (4) how quickly seizures were judged to have stopped, based on clinical signs, EEG findings, or both; and (5) how long seizure freedom had to be maintained to count as a successful end point. No consistent global or time-based patterns were identified, and overlapping terminology further limited comparison across studies. Despite established consensus definitions for SE onset, the end point remains variably defined, undermining methodological rigor and limiting cross-study synthesis. A unified, consensus-driven framework is urgently needed to standardize SE end points through the use of standard terminology and methodologies, thereby strengthening clinical trial design and facilitating regulatory evaluation of novel therapies.
Sinha N, Zhou DJ, Morgan VL
… +13 more, Englot DJ, Bonilha L, Brázdil M, He X, Masumoto R, Cao Q, O'Brien TJ, Wu C, Kaestner E, McDonald C, Gleichgerrcht E, McGonigal A, Davis KA
Intracranial electroencephalographic (iEEG) connectivity analysis is a promising method to localize epileptic networks and guide surgical planning in focal drug-resistant epilepsy. Despite numerous studies exploring its...Intracranial electroencephalographic (iEEG) connectivity analysis is a promising method to localize epileptic networks and guide surgical planning in focal drug-resistant epilepsy. Despite numerous studies exploring its utility, the added value of iEEG connectivity over standard clinical presurgical evaluation remains unclear. We assess the current evidence on the efficacy of iEEG connectivity analyses to improve seizure outcomes following epilepsy surgery through a systematic review and meta-analysis. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines, we searched PubMed and Embase for studies (2006-2024) of adult focal drug-resistant epilepsy patients who underwent surgical resection or ablation, reported outcomes at least 1 year postsurgery, and used iEEG connectivity analysis to localize networks. Reviews, nonhuman studies, and studies lacking iEEG connectivity analysis or network localization were excluded. We derived classification metrics (true/false positives/negatives) based on concordance between iEEG findings, clinical localization, and outcome. Subgroup meta-analyses and meta-regressions determined differences by seizure type, lesion status, and analysis approach. Of 2881 studies screened, 25 met criteria (n = 909). The pooled odds ratio comparing seizure outcome prediction using iEEG connectivity versus standard clinical evaluation was 1.36 (95% confidence interval = 1.10-1.69, p = .004), indicating a significant overall benefit. Subgroup analyses found no significant differences by directionality, modeling method (linear/nonlinear), or iEEG epoch (interictal/peri-ictal). Meta-regression revealed greater added value of iEEG connectivity in studies with higher proportions of non-seizure-free patients following surgery for temporal lobe or lesional epilepsy. However, no individual study achieved statistical significance on its own, reflecting limited power and lack of individual patient-level data. Power analysis confirmed that detecting a clinically meaningful effect requires substantially larger, potentially multicenter datasets. iEEG connectivity analysis offers modest but consistent increased value over standard clinical methods to predict seizure freedom in adult patients with focal drug-resistant epilepsy. For clinical translation, we propose recommendations for future studies to address sample size limitations, standardize reporting, and prioritize individual patient-level data sharing.
OBJECTIVE: This study was undertaken to investigate the molecular consequences of pathogenic variants in the SMC1A gene-particularly those associated with developmental and epileptic encephalopathy (DEE85)-and to evaluat...OBJECTIVE: This study was undertaken to investigate the molecular consequences of pathogenic variants in the SMC1A gene-particularly those associated with developmental and epileptic encephalopathy (DEE85)-and to evaluate the therapeutic potential of ataluren in restoring SMC1A function and mitigating disease-related transcriptomic and genomic alterations. METHODS: The study analyzed transcriptomic profiles from cell lines derived from individuals with DEE85 and Cornelia de Lange syndrome (CdLS), comparing the effects of different SMC1A variants. Particular focus was placed on nonsense variants and their impact on gene expression. Functional assays were conducted to assess the ability of ataluren to restore SMC1A protein expression, correct transcriptional defects, and reduce genomic instability. RESULTS: Transcriptomic alterations were strongly dependent on variant type, with nonsense variants causing the most profound gene expression changes. DEE85 and CdLS cell lines exhibited distinct transcriptional signatures. Treatment with ataluren led to successful restoration of SMC1A protein levels, partial correction of gene expression abnormalities, and a reduction in genomic instability in cells harboring nonsense variants. SIGNIFICANCE: These findings demonstrate that SMC1A-related epileptic encephalopathies are driven by variant-specific molecular mechanisms and highlight the therapeutic promise of ataluren for DEE85. The study supports further development of precision medicine strategies targeting nonsense variants in SMC1A, with potential implications for improving diagnosis, treatment, and quality of life in affected individuals.
Salimbene L, Mercier M, Spedaletti V
… +10 more, De Dominicis A, Calabrese C, Filosomi C, Angelucci E, Rosato V, Cappa M, Vigevano F, de Palma L, Trivisano M, Specchio N
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 a...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 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...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 mos...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...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.