Epilepsy Foundation

The modified Atkins diet is increasingly used as an adjunctive therapy for drug-resistant epilepsy. Recent evidence suggests that such dietary interventions may affect the pharmacokinetics of antiseizure medications and induce DNA methylation changes. However, it remains unclear whether epigenetic regulation of drug-metabolizing enzymes contributes to variability in medication serum levels. We analyzed 58 adults with drug-resistant epilepsy treated with a modified Atkins diet for 12 weeks. DNA methylation was profiled in peripheral blood before diet initiation (baseline) and after 4 weeks and 12 weeks using a genome-wide array. A total of 131 cytosine-phosphate-guanine (CpG) sites mapped to 13 candidate genes involved in antiseizure medication metabolism were assessed. One CpG in the CES1 gene showed significant methylation changes from baseline to 4 weeks, 12 weeks, and across all timepoints (FDR = 0.0018), indicating consistent longitudinal effects. Repeated measures correlation analyses were used to evaluate within-individual associations between DNA methylation and antiseizure medication serum concentrations. Two CpG–drug associations showed strong positive intra-individual correlations: CYP3A5 methylation was significantly associated with carbamazepine serum levels (repeated measures correlation coefficient = 0.81, FDR = 0.023), whereas CYP3A4 methylation showed a similarly strong but borderline association with topiramate (correlation coefficient = 0.76, FDR = 0.051). This study finds that a modified Atkins diet may be associated with DNA methylation variation at genes involved in drug metabolism. Furthermore, DNA methylation levels were strongly associated with individual serum concentrations of certain antiseizure medications. These findings are consistent with the concept of a diet–epigenome–drug metabolism axis and warrant further investigation in larger studies to assess clinical implications for personalized dietary and pharmacological management in epilepsy.

To evaluate clinical outcomes, treatment response and predictors of seizure freedom after vagus nerve stimulation in patients with drug-resistant epilepsy in a Mexican cohort. We conducted a retrospective multicenter cohort across 13 epilepsy centers in Mexico (2003-2024) including patients aged ≥4 years with drug-resistant epilepsy or epileptic encephalopathy. Treatment response was defined as at least 50% seizure reduction and Engel outcomes. Logistic regression identified predictors of seizure freedom. Model performance was assessed with receiver operating characteristic analysis, area under the curve, Hosmer-Lemeshow test, and a confusion matrix. Ninety-three patients (51 children, 42 adults) were included. At 1 year, median monthly seizure frequency decreased by 82.5% (40-7; p < .001). The incidence of status epilepticus declined by 92.8%, acute prolonged seizures by 80.9%, the burden of antiseizure medications by 25%, and epilepsy-related hospitalizations by 100% (all p < .001). Overall, 68.8% achieved ≥50% reduction and 11.8% became seizure-free. On univariate analysis, comorbidities, multiple seizure types, higher baseline seizure frequency, greater number of antiseizure medications, and magnet use were inversely related to seizure freedom, while normal brain MRI showed a direct relationship. On multivariable analysis, only baseline seizure frequency ≥30/month independently predicted seizure freedom (p = .047), corresponding to 97.7% lower odds. A predictive model incorporating comorbidities and number of antiseizure medications improved discrimination (p < .001) with 86.6% sensitivity and 81.8% specificity. Vagus nerve stimulation was associated with substantial seizure frequency reduction, lower morbidity, and less healthcare utilization, with a favorable safety profile. Baseline seizure burden emerged as the key predictor of seizure freedom and may guide patient selection, supporting earlier vagus nerve stimulation consideration in drug-resistant epilepsy.

Awake craniotomy (AC) with functional brain mapping is the standard approach for the resection of brain tumors in eloquent areas. Two main anesthetic techniques are commonly used: "Asleep-Awake-Asleep" (SAS) and "Monitored Anesthesia Care" (MAC). SAS involves general anesthesia during nonawake phases, while MAC utilizes conscious sedation, allowing for spontaneous ventilation without invasive airway devices. Both are effective and safe, but information on patient-reported intraoperative experiences is lacking. Here, we compare the subjective experience, postoperative quality of life, and operating room time of patients managed by SAS versus MAC. We performed a postoperative telephone survey of all consecutive patients who underwent AC for eloquent brain tumors at the University Medical Center Freiburg, Germany, between October 2018 and April 2024. SAS was used until November 2023, while MAC was used thereafter. The third part of the Beez interview protocol and the EuroQol EQ-5D-5L (including the EQ Visual Analog Scale) were delivered to assess patient-reported intraoperative experience and current health-related quality of life. Patient-reported outcomes and operating room time were compared between the 2 groups. Thirty-four of 40 patients (17 in each group) were available for telephone interview with more female patients in the SAS group compared with the MAC group (82% vs. 12%, P<0.001). Other baseline parameters were balanced. Patient-reported intraoperative experience and quality of life were similar between the SAS and MAC groups. Operating room times were significantly shorter for MAC (366±107min) than for SAS (453±81min) (P=0.011). Our institutional protocols for SAS and MAC resulted in similar intraoperative experience and postoperative QoL, while MAC procedures had shorter operating room times. Larger studies are required to confirm these findings.

Patients with leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) encephalitis are typically elderly men that often carry human leucocyte antigen (HLA)-DRB1*07:01 (≈90%). Herein, we aimed to investigate whether patients with atypical demographic profiles or not carrying DRB1*07:01 have distinct clinical manifestations and outcome. Retrospective chart review of LGI1-Ab patients diagnosed at the French Reference Centre and three other European centres. Among 238 patients included, median age at onset was 66 years (IQR: 60-73), 65% were male, 89% carried DRB1*07:01 and 10% DRB1*04:02, another known secondary HLA association. We identified three age groups (young, typical, old) based on percentiles of age distribution. Young (≤51 years) patients were less commonly male (35%, p=0.004), while faciobrachial dystonic seizures (FBDS; 65%, p=0.047) and hyponatraemia (64%, p=0.046) were more frequent in old (≥79 years) patients. Old patients experienced poor outcome (modified Rankin Scale [mRS] >2 at last follow-up) more frequently (64%, p<0.001). There were no significant differences between males and females. DRB1*07:01 non-carriers were younger (p=0.005) and less frequently male (47%, p=0.044), while non-carriers of both DRB1*07:01 and DRB1*04:02 experienced poor outcome more commonly (64%, p=0.005). Older age (adjusted OR: 1.08, 95% CI [1.02 to 1.14], p=0.008), higher mRS at nadir (4.22 [2.46-7.24], p<0.001) and DRB1*07:01 non-carrier status (8.39 [1.88-37.44], p=0.005) were independently associated with poor outcome. Moreover, older age (1.08 [1.04-1.11], p<0.001), FBDS (2.20 [1.17-4.13], p=0.014) and hyponatraemia (2.30 [1.22-4.34], p=0.010) were associated with severe encephalitis (mRS >3 at nadir). Age appears to be the main driver of clinical presentation, severity and outcome in LGI1-Ab encephalitis. Remarkably, DRB1*07:01 non-carriers are younger, more commonly female and experience poorer prognosis, reflecting a distinct pathophysiology.

While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping. snRNA-seq showed similar cell identities and proportions between cases and controls, suggesting that mosaic pathogenic variants in PI3K-mTOR pathway genes in FCD exert their effect by disrupting transcription in conserved cell types. GO-TEN and ResolveOME analyses confirmed that pathogenic variant-carrying cells have well-differentiated neuronal or glial identities, with enrichment of variants in cells of the neuroectodermal lineage, pointing to cortical neural progenitors as possible loci of somatic mutation. Within FCD type 2 lesions, we identified upregulation of PI3K-mTOR signaling and related pathways in variant-carrying neurons, downregulation of these pathways in non-variant-carrying neurons, as well as associated changes in microglial activation, cellular metabolism, synaptic homeostasis, and neuronal connectivity, all potentially contributing to epileptogenesis. These genotype-specific changes in mosaic lesions highlight potential disease mechanisms and therapeutic targets.