Epilepsia最新文献

Objective: Although vagus nerve stimulation (VNS) is a well-established neuromodulation therapy for drug-resistant epilepsy, treatment outcomes remain heterogeneous. One possible source of variability lies in differing interpretations of seizure frequency ratings (SFRs). This study examined interrater reliability (IRR) in SFRs between (1) retrospective clinician-clinician chart reviews and (2) prospective caregiver-clinician reports, and explored sources of disagreement.

Methods: Data were collected from the CONNECTiVOS database. In the retrospective cohort (n = 254), two clinicians independently reviewed medical records and rated seizure frequency across multiple timepoints. In the prospective cohort (n = 214), caregivers and clinicians independently reported SFR in children treated with VNS. IRR was assessed across different measurement thresholds, and potential causes of disagreement were analyzed.

Results: Clinician-clinician agreement in retrospective chart reviews was excellent (intraclass correlation coefficient [ICC] > .90, Cohen κ > .80), with 18.8% divergent ratings and 4.8% exceeding the reliable change index. Disagreement was significantly associated with higher mean seizure frequency at baseline (p = .004) and at postoperative timepoints (p < .001). In the prospective caregiver-clinician comparison, agreement for absolute seizure frequency was poor (ICC < .50), with discrepancies in 86.5% of cases, although only 1.8% were statistically significant. When rating pairs diverged, clinicians more often reported lower absolute seizure frequencies (p = .002) and greater relative seizure reductions (p = .023) and were more likely to classify patients as achieving a 90% reduction (p = .043).

Significance: This study highlights interrater variability in both retrospective and prospective SFR assessments, a finding systematically related to baseline seizure frequency. Coarser classifications (e.g., 50% or 90% seizure reduction) may improve agreement but reduce clinical nuance. Future efforts should focus on structured, patient-centered documentation and the development of objective outcome measures in VNS evaluation, particularly for children with high seizure burden.

Objective: This study investigated whether scalp high-frequency activity (HFA) rates in neonates with seizures predict postneonatal epilepsy (PNE). It also assessed whether HFA rates differentiate neonates with seizures from healthy neonates and whether they vary by seizure etiology, therapeutic hypothermia, and electroencephalographic (EEG) background activity.

Methods: We included 47 neonates with EEG-confirmed seizures (nine with neonatal mortality, three lost to follow-up, 35 with 1-year follow-up), and eight healthy neonates. Scalp HFA rates during sleep were determined using an automated detector.

Results: Neonatal seizure etiologies included hypoxic-ischemic encephalopathy (HIE, n = 16), structural vascular lesions (SVL, n = 14), and neonatal onset genetic epilepsies (n = 14). Scalp HFA rates were significantly higher in neonates with seizures (.16 ± .15 HFA/min/channel [ch]) than in healthy neonates (.03 ± .02 HFA/min/ch), with a threshold of .06 HFA/min/ch best differentiating these groups. Among neonates with seizures, those with genetic etiologies had significantly higher HFA rates (.24 ± .19 HFA/min/ch) than those with SVL (.07 ± .05 HFA/min/ch). HFA rates were not associated with EEG background activity and were unaffected by therapeutic hypothermia in neonates with HIE. Of the 35 surviving neonates with seizures, 11 developed PNE, whereas 16 had normal development at follow-up. Neonates who developed PNE had significantly higher HFA rates (.27 ± .18 HFA/min/ch) than those with normal development (.11 ± .09 HFA/min/ch), with a threshold of .12 HFA/min/ch best differentiating these groups.

Significance: Scalp HFA differentiates neonates with seizures from healthy neonates and may help identify those at higher risk for PNE. These findings support the potential use of scalp HFA as a potential biomarker for seizure monitoring and epilepsy risk stratification in neonates.

Objective: In children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE), magnetic resonance imaging-guided stereotactic laser ablation (SLA) therapy offers less-invasive treatment compared to craniotomy and resection. Our study seeks to further expand on the long-term outcomes in patients with TSC-related DRE who have undergone SLA.

Methods: Patients with TSC and DRE treated with SLA, between July 1, 2016 and January 1, 2022, at our institution were identified retrospectively. Reduction in number of anti-seizure medications (ASMs), developmental improvement as reported by the patients' families, seizure frequency measured in surgically targeted seizure type and total seizures per day, and Engel classification were evaluated at 6 months, 1 year, 2 years, and thereafter at the most recent follow-up visit if available.

Results: Forty patients (ages 11 months to 23 years, median age 3.6 years) with TSC underwent SLA. Total follow-up was on average 2.9 years post-surgery. Significant (>50%) reduction in total seizure frequency occurred in 80% of patients (n = 32), with 63% of patients reporting a >90% reduction in seizure frequency (n = 25) at last follow-up. Fifty-eight percent had complete freedom from their surgically targeted seizure type (n = 23). At last follow up, perceived developmental gains occurred in 63% (n = 25), reduction in ASM occurred in 40% (n = 16), and Engel class was III or less in 93% of patients (n = 37).

Significance: SLA was safe and effective for most patients, even the very young. A majority of patients achieved improvement in seizure frequency, including the surgically targeted seizure type, but less than half were able to reduce medications. Reported developmental improvement was related to Engel outcomes. Future studies utilizing neuropsychological testing in the full cohort will be required to offer objective insights into post-operative development profiles.

Objective: Transmembrane proteins play essential roles in neuronal function, yet many remain poorly characterized. Transmembrane protein 151A (TMEM151A) was identified in 2021 as a disease-associated gene linked to paroxysmal neurological disorders. Despite its broad expression in the central nervous system, its role in neuronal network activity remains unclear. This study aims to determine the cell type-specific expression pattern of Tmem151a and to investigate its functional involvement in seizure pathophysiology.

Methods: Cell-type specific expression of Tmem151a was examined using RNAscope in situ hybridization combined with immunohistochemistry. Seizure susceptibility was assessed by pentylenetetrazol (PTZ) challenge and cortical electrostimulation in Tmem151a-knockout mice on a C57BL/6J background, with electroencephalographic recordings confirming seizure activity. The hippocampal kindling model was used to evaluate epileptogenesis in Tmem151a-knockout, CaMKIIa-conditional knockout, and Olig2-conditional knockout mice. TMEM151A overexpression in forebrain was achieved by intravenous delivery of adeno-associated virus (AAV-PHP.eB) in Emx1-Cre mice, followed by hippocampal kindling analysis.

Results: In mice, Tmem151a was predominantly expressed in glutamatergic excitatory neurons and oligodendroglia, with lower expression in γ-aminobutyric acidergic neurons and minimal expression in astrocytes and microglia. Tmem151a-knockout mice exhibited heightened susceptibility to both PTZ- and electrostimulation-induced seizures, along with accelerated epileptogenesis in a hippocampal kindling model. Conditional deletion of Tmem151a in forebrain excitatory neurons, but not in oligodendrocytes, similarly promoted epileptogenesis. Conversely, AAV-mediated overexpression of TMEM151A in Emx1-positive cell populations effectively suppressed seizure progression during hippocampal kindling.

Significance: Cell type-specific knockout and overexpression experiments reveal that TMEM151A in forebrain excitatory neurons functions as a key regulator of seizure susceptibility. These results identify TMEM151A as a critical molecular determinant of neuronal network excitability and a potential therapeutic target for epilepsy.

Spreading depolarization (SD) is a transient disruption of electrographic activity that slowly propagates through the gray matter by chemical contiguity, and it is characterized by a large depolarization of neurons and glial cells. SD, which is associated with massive changes in ion homeostasis, including extreme increases in [K⁺]_o, was shown to occur in various neurological diseases such as migraine and traumatic brain injury. It is hypothesized to also occur in epilepsy. We review here the cellular and pharmacological features of SD that was mainly induced in vitro by different pharmacological manipulations as well as its relationship to focal seizures that can concomitantly occur in these in vitro and in vivo preparations. Recent experimental evidence points to SD playing a role in controlling seizure generation, but other studies have reported that SD facilitates ictogenesis. We conclude that further work is needed to firmly identify the role of SD in modulating focal seizure generation. These future experiments should also help in clearly defining the role played by SD in the manifestation of sudden unexpected death in epilepsy.

Objective: This systematic review synthesizes evidence on multimodal machine learning (ML) decision support systems for epilepsy surgery focusing on postsurgical outcome prediction, with emphasis on methodological quality and implications for clinical practice.

Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched PubMed, Scopus, and Web of Science using predefined keywords. Seventy records were screened; 10 studies met inclusion/exclusion criteria, reporting ML-based prediction of surgical outcomes in drug-resistant epilepsy (DRE) and using ≥2 data modalities. Extracted items included study design, population, data sources, algorithms, validation strategy, performance metrics, and outcome definitions. Two reviewers independently screened records.

Results: Nine studies were retrospective and one prospective; seven were single-center and two multicenter. Most integrated neuroimaging (9/10), electroencephalography (8/10), and clinical variables (7/10); two included neuropsychology, and one added ablation parameters for magnetic resonance-guided laser interstitial thermal therapy. Sample sizes ranged from 15 to 11 067. Performance varied; best results (area under the curve [AUC] ≈ .95) were reported with multimodal gradient boosting, whereas ablation-based models achieved lower discrimination (AUC ≈ .67). The oldest neural-network study reported 98% accuracy on a small, nonstandard dataset. Cross-validation predominated; only two studies assumed prospective validation. Outcome definitions were heterogeneous, and time points were inconsistently specified. Despite variability, several clinically relevant findings emerged; multimodal ML improved, but not universally, prediction of seizure freedom, supported epileptogenic-zone localization, and in one large multicenter study, enabled earlier identification of surgical candidates compared with routine referral pathways.

Significance: ML shows promise for outcome prediction and presurgical decision support in DRE, particularly when integrating multimodal data. Translation is currently constrained by limited external and prospective validation, inconsistent outcome frameworks, and insufficient interpretability. Future research should prioritize harmonized endpoints, multicenter external validation (including federated approaches), and explainable models capable of informing both patient selection and surgical strategy.

The recent International League Against Epilepsy (ILAE) official and updated classification of focal cortical dysplasia (FCD) includes a third type-FCD type 3-characterized by architectural abnormalities (cortical dyslamination) associated with another "principal" lesion: hippocampal sclerosis (HS), developmental tumors, vascular malformations, or gliotic scars. We posit that the clinical relevance of FCD type 3 is not established, as dyslamination cannot be reliably identified preoperatively and (although unproven, because unidentifiable) persistence of cortical tissue with putative dyslamination after resective surgery does not preclude seizure control. Here we discuss these issues from the epileptologist's perspective and stimulate the debate on whether the FCD type 3 construct impacts decision-making in the epilepsy surgery field-or else is of little practical significance.

Objective: To examine whether initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with seizure recurrence and related outcomes in adults with epilepsy and type 2 diabetes.

Methods: We conducted a retrospective cohort study using de-identified electronic health records from the TriNetX Research Network (January 2003-August 2025), including adults ≥18 years with ≥3 epilepsy or recurrent seizure diagnoses. Patients initiating a GLP-1 RA (exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, or tirzepatide) without prior comparator therapy were compared with those initiating other glucose-lowering agents (sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase 4 inhibitors, sulfonylureas, or insulin) without GLP-1 RA exposure. Propensity score matching (1:1) was performed on 82 covariates, yielding 8688 matched pairs. Outcomes were assessed using Cox proportional hazards models.

Results: After matching, the mean age was 52.6 years, and 67.6% were female. Median follow-up was 514 days (interquartile range [IQR] 671) for GLP-1 RA initiators and 415 days (IQR 769) for comparators. GLP-1 RA initiation was associated with lower risk of seizure recurrence (HR .82, 95% confidence interval [CI] .78-.86; RD -2.1%), hospitalization (HR .35, 95% CI .29-.43; RD -2.6%), and all-cause mortality (HR .40, 95% CI .34-.47; RD -4.8%). Associations with status epilepticus (HR .75, 95% CI .66-.85; RD -.7%) and ICU admission (HR .82, 95% CI .69-.96; RD -.3%) were smaller; the latter was not statistically significant.

Significance: In this large multinational cohort, GLP-1 RA initiation was associated with reduced risks of seizure recurrence, hospitalization, and mortality compared with other glucose-lowering therapies. These hypothesis-generating findings warrant confirmation in prospective studies before translation into clinical practice.

Objective: To examine early responses to cenobamate therapy using prospective data from a dose-response study in Asian patients with focal seizures (YKP3089C035, C035) that employed a titration regimen starting at 12.5 mg/day.

Methods: In Study C035, adults 18-70 years of age with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications were randomized 1:1:1:1 to receive placebo or adjunctive cenobamate 100, 200, or 400 mg/day. The 24-week double-blind study included an 18-week titration and 6-week maintenance phase. During the first 8 weeks of titration ("early titration phase"), all cenobamate patients received the same dosing regimen: 12.5 mg/day for 2 weeks, 25 mg/day for 2 weeks, 50 mg/day for 2 weeks, and 100 mg/day for 2 weeks. Change in seizure frequency from baseline and responder rates were assessed at these 2-week intervals for combined cenobamate dose groups vs placebo. Analyses were performed on the modified intent-to-treat maintenance (MITT-M) population (≥1 study drug dose and seizure data in the maintenance phase); all patients completed early titration.

Results: Of 519 patients randomized, 446 were included in the MITT-M population (placebo n = 117, cenobamate n = 329). During Weeks 1-2, 3-4, 5-6, and 7-8 of titration, cenobamate patients experienced a median reduction in 28-day seizure frequency of 16.0% (vs 20.0% placebo, p = .81), 27.3% (vs 22.2% placebo, p = .42), 42.9% (vs 15.4% placebo, p = .002), and 55.6% (vs 20.0% placebo, p < .001), respectively. During Weeks 5-6 and 7-8, the 100% responder rates for cenobamate 50 and 100 mg/day were 17.0% (vs 12.8% placebo, p = .29) and 26.7% (vs 8.5% placebo, p < .001), respectively.

Significance: Statistically significant responses to cenobamate treatment occurred within the first 8 weeks of titration, including a 42.9% median reduction in 28-day seizure frequency (Weeks 5-6) and a seizure-free rate of 26.7% (Weeks 7-8). These data show that substantial seizure reductions occurred in many patients early during cenobamate titration.

Objective: Lamotrigine is one of the most widely prescribed antiseizure medication (ASM) and mood stabilizer in the United States due to its favorable side-effect profile, lower risk of teratogenicity, and minimal drug-drug interactions. This study aimed to examine age- and sex-associated variability in prescribing and pharmacokinetics, focusing on postmenopausal women.

Methods: Data were from electronic health records. Individuals were included if ≥18 years and received an ASM between January 1, 2015 and December 31, 2021. Lamotrigine prescriptions were compared based on age, sex, epilepsy diagnosis, and monotherapy/polytherapy. Statistical comparisons of proportions were conducted using two-proportion tests. To characterize age- and sex-related differences in LTG apparent oral clearance and assess the impact of covariates, linear mixed-effects modeling was employed.

Results: Records were available for 314 890 individuals, with 23 906 patients being prescribed lamotrigine at least once (as monotherapy or polytherapy) for both epilepsy and non-epilepsy diagnoses. The lamotrigine prescription rate was lower in postmenopausal women compared to younger women but higher than in older men, irrespective of diagnosis. Notably, lamotrigine was prescribed as monotherapy more frequently to patients without epilepsy than those with epilepsy, regardless of sex and age. The clearance of lamotrigine was 22% lower in postmenopausal women compared to younger women and 9% in older men. Lamotrigine clearance increased by 49% and 11% with co-administration of inducers or the presence of smoking, respectively. Lamotrigine clearance decreased by 51% in the presence of an inhibiting medication.

Significance: Prescription rates for lamotrigine varied between patients with epilepsy and those with non-epilepsy conditions. Age and sex differences in pharmacokinetics suggest the need for lamotrigine dose adjustments, highlighting the importance of therapeutic drug monitoring in personalized epilepsy care. Lamotrigine use was less frequent in postmenopausal women compared to younger women but higher compared to older men. Postmenopausal women were prescribed lamotrigine as monotherapy to a lesser extent than younger women and older men.