Epilepsia最新文献

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.

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 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.

Objective: The identification of pathogenic variants in developmental epileptic encephalopathy (DEE) genes can be vital for counseling and individualized treatment. Penetrance is usually considered to be high or full, although this has never been studied in population cohorts. Recent evidence shows that common polygenic risk factors (polygenic risk score [PRS]) are increased in DEE cases, suggesting they might modify risk.

Methods: We calculated the penetrance of autosomal dominant epilepsy variants that have previously been classified as (likely) pathogenic in ClinVar, in two large cohorts (n = 42 863 and n = 386 306) using whole genome sequencing data. Next, we calculated PRS to assess whether common variants could modify epilepsy risk among people carrying pathogenic variants.

Results: Most people carrying pathogenic DEE variants did not have epilepsy. Penetrance estimates suggested that the probability of epilepsy in pathogenic variant carriers ranges between 4.1% and 9.8%. Among people carrying epilepsy variants, PRS was predictive of an epilepsy diagnosis. A high PRS was associated with increased risk of severe epilepsy, whereas a low PRS seems protective in people carrying a pathogenic variant.

Significance: Our results suggest that average variant penetrance is lower than expected and modified by PRS. A high PRS combined with a pathogenic variant may be necessary to develop a severe epilepsy phenotype like DEE. Reconsidering penetrance assumptions could improve variant classification and diagnostic yield. Our findings may enhance genetic counseling by refining risk estimates and could extend to other diseases.

Objectives: This study explored the safety and effectiveness of adjunctive cenobamate (CNB) in patients with different levels of drug-resistant epilepsy (DRE) in a real-world setting, including its impact on the use of co-antiseizure medication (co-ASM).

Methods: This was a single-center, retrospective, observational study. Adults with refractory seizures who had received ≥2 previous ASMs and had been treated with CNB for at least a year were included. Effectiveness and safety endpoints were assessed at 3, 6, 12, and 24 months after CNB was initiated. Co-ASM use was assessed at every visit.

Results: Ninety-four patients were included; 23 of 94 (24.5%) had received ≤4 previous ASMs and 70 of 94 (74.5%) had received ≥5 previous ASMs. Patients with ≥5 previous ASMs had a younger age at onset (mean 12 vs 25.9 years) and a longer duration of epilepsy (mean 28.1 vs 16.7 years) compared with patients with ≤4 previous ASMs. The mean CNB daily dose was 310 ± 76.7 mg at 2 years. The mean number of co-ASMs received by patients was reduced significantly between baseline and all time points (p ≤ .01). The mean defined daily dose (DDD) per patient (not including CNB) was also reduced significantly across all time points (p < .01), falling from 3.2 ± 2.3 at baseline to 1.2 ± 1.9 at the 2-year follow-up. At 1 and 2 years after initiation of CNB, 79.6% and 80% of patients had a ≥50% reduction in seizure frequency and 36.6% and 30.9% were seizure-free, respectively. At 2 years, 73.2% of patients reported their condition to be "Very much better" or "Much better" compared with baseline; 37.5% reported treatment-related adverse drug reactions at 2 years.

Significance: In patients with DRE, CNB treatment allowed long-term high seizure-freedom rates and significant reductions in co-ASM use, while also achieving both good tolerability and high patient satisfaction scores.

Objective: This work was undertaken to describe the level of evidence for co-occurring epileptic seizures in patients with known functional/dissociative seizures (FDS) using stratification criteria analogous to the International League Against Epilepsy criteria for functional seizures.

Methods: Adult patients (age $\ge$ 18 years) with "documented" or "clinically established" FDS seen in a health system with a multidisciplinary FDS clinic were manually evaluated by retrospective chart review to identify their risk of co-occurring epilepsy. They were grouped into five mutually exclusive categories based on "red flags" for co-occurring epilepsy in the clinical history, semiology of unobserved seizures, and neurodiagnostic data. The categories of concern for co-occurring epilepsy were as follows: unlikely, possible, probable, clinically established, and documented.

Results: We identified 460 patients with FDS (median age = 34 years, interquartile range = 24-46 years, 78% female). The majority (62.6%, 95% confidence interval = 58%-67%) had "unlikely" co-occurring epilepsy due to no "red flags." Some (11.5%) patients had high likelihood of co-occurring epilepsy: 10.2% electroencephalographically "documented" and 1.3% "clinically established." There were 74 (16.5%) patients with neurodiagnostic "red flags" indicating "probable" co-occurring epilepsy. The remaining 9.3% had historical reports of "red flags" indicating "possible" co-occurring epilepsy.

Significance: The majority (62.6%) of people with FDS were "unlikely" to have co-occurring epilepsy due to the lack of "red flags." Conversely, 11.5% of patients with FDS had a high level of certainty of co-occurring epileptic seizures (clinically established and documented). In patients with intermediate concern, patient-centered decision-making can guide the next steps of diagnosis and treatment.

Objective: Stereoelectroencephalography (sEEG) is commonly employed in the workup for epilepsy surgery in patients with focal drug-resistant epilepsy (DRE). Intracranial hemorrhage is a known complication, with reported incidence rates ranging from .9% to 19.1%. Rarely, pseudoaneurysms have been reported in literature as a potential cause. This retrospective cohort study aims to describe the occurrence, clinical characteristics, and management of iatrogenic pseudoaneurysms following sEEG and the clinical outcome of the described cases.

Methods: A cohort of 395 patients (4067 depth electrodes) with DRE who underwent sEEG was retrospectively analyzed. The identified patients with pseudoaneurysms were analyzed in detail, focusing on timing of detection and location of the aneurysms, clinical characteristics, management strategies, and clinical outcome.

Results: A symptomatic iatrogenic pseudoaneurysm was identified in six of 395 cases (1.5%), with a per-electrode risk of .15% (6/4067); all occurred at the M2/M3 branches of the middle cerebral artery. All six cases presented with intracerebral or subarachnoid hemorrhage. Aneurysms were detected with combined cerebral computed tomographic angiography (CTA) and digital subtraction angiography (DSA) and treated without complications by surgical clipping or endovascular embolization. The depth electrode implantation and planned sEEG recording had to be either prematurely discontinued or canceled in four of six cases. No patients died; five experienced neurological symptoms and required prolonged hospitalization, with four needing additional rehabilitation.

Significance: Pseudoaneurysms following sEEG represent a serious complication with significant clinical consequences and warrant early detection and intervention. Occurrence is underreported in literature. It is recommended to use CTA and DSA when a pseudoaneurysm is suspected, particularly in cases of intraparenchymal or subarachnoid hemorrhage, and especially when depth electrodes are in close proximity to a blood vessel.