Methods to quantify cortical hyperexcitability are of enormous interest for mapping epileptic networks in patients with focal epilepsy. We hypothesize that, in the resting state, cortical hyperexcitability increases firing-rate correlations between neuronal populations within seizure onset zones (SOZs). This hypothesis predicts that in the gamma frequency band (40-200 Hz), amplitude envelope correlations (AECs), a relatively straightforward measure of functional connectivity, should be elevated within SOZs compared to other areas. To test this prediction, we analyzed archived samples of interictal electrocorticographic (ECoG) signals recorded from patients who became seizure-free after surgery targeting SOZs identified by multiday intracranial recordings. We show that in the gamma band, AECs between nodes within SOZs are markedly elevated relative to those elsewhere. AEC-based node strength, eigencentrality, and clustering coefficient are also robustly increased within the SOZ with maxima in the low-gamma band (permutation test Z-scores > 8) and yield moderate discriminability of the SOZ using ROC analysis (maximal mean AUC ~ 0.73). By contrast to AECs, phase locking values (PLVs), a measure of narrow-band phase coupling across sites, and PLV-based graph metrics discriminate the seizure onset nodes weakly. Our results suggest that gamma band AECs may provide a clinically useful marker of cortical hyperexcitability in focal epilepsy.

UNASSIGNED: Disheveled, EGL-10, and pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a component of GTPase-activating protein (GAP) activity toward the RAG complex 1 (GATOR1) protein, which is an inhibitor of the amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). With the wide application of whole exome sequencing (WES), more and more variations in DEPDC5 were uncovered in FFEVF families.
UNASSIGNED: A family with a proband diagnosed with familial focal epilepsy with variable foci (FFEVF) was involved in this study. Whole exome sequencing (WES) was performed in the proband, and Sanger sequencing was used to confirm the variation carrying status of the family members. Mini-gene splicing assay was performed to validate the effect on the alternative splicing of the variation.
UNASSIGNED: A novel variant, c.1217 + 2T>A, in DEPDC5 was identified by WES in the proband. This splicing variant that occurred at the 5\' end of intron 17 was confirmed by mini-gene splicing assays, which impacted alternative splicing and led to the inclusion of an intron fragment. The analysis of the transcribed mRNA sequence indicates that the translation of the protein is terminated prematurely, which is very likely to result in the loss of function of the protein and lead to the occurrence of FFEVF.
UNASSIGNED: The results suggest that c.1217 + 2T>A variations in DEPDC5 might be the genetic etiology for FFEVF in this pedigree. This finding expands the genotype spectrum of FFEVF and provides new etiological information for FFEVF.

UNASSIGNED: Although previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy.
UNASSIGNED: The single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy\'s GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted.
UNASSIGNED: In the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038-1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162-1.546, P = 5.70 × 10-5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS.
UNASSIGNED: This Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

An epilepsy diagnosis reduces a patient\'s quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma by injury, malformations, inflammation, or a prolonged (febrile) seizure. Although extensive research has been conducted to understand the process of epileptogenesis, a therapeutic approach to stop its manifestation or to reliably cure the disease has yet to be developed. In this review, we briefly summarize the current literature predominately based on data from excitotoxic rodent models on the cellular events proposed to drive epileptogenesis and thoroughly discuss the major molecular pathways involved, with a focus on neurogenesis-related processes and transcription factors. Furthermore, recent investigations emphasized the role of the genetic background for the acquisition of epilepsy, including variants of neurodevelopmental genes. Mutations in associated transcription factors may have the potential to innately increase the vulnerability of the hippocampus to develop epilepsy following an injury-an emerging perspective on the epileptogenic process in acquired forms of epilepsy.

UNASSIGNED: An important challenge in epilepsy is to define biomarkers of response to treatment. Many electroencephalography (EEG) methods and indices have been developed mainly using linear methods, e.g., spectral power and individual alpha frequency peak (IAF). However, brain activity is complex and non-linear, hence there is a need to explore EEG neurodynamics using nonlinear approaches. Here, we use the Fractal Dimension (FD), a measure of whole brain signal complexity, to measure the response to anti-seizure therapy in patients with Focal Epilepsy (FE) and compare it with linear methods.
UNASSIGNED: Twenty-five drug-responder (DR) patients with focal epilepsy were studied before (t1, named DR-t1) and after (t2, named DR-t2) the introduction of the anti-seizure medications (ASMs). DR-t1 and DR-t2 EEG results were compared against 40 age-matched healthy controls (HC).
UNASSIGNED: EEG data were investigated from two different angles: frequency domain-spectral properties in δ, θ, α, β, and γ bands and the IAF peak, and time-domain-FD as a signature of the nonlinear complexity of the EEG signals. Those features were compared among the three groups.
UNASSIGNED: The δ power differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The θ power differed between DR-t1 and DR-t2 (p = 0.015) and between DR-t1 and HC (p = 0.01). The α power, similar to the δ, differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The IAF value was lower for DR-t1 than DR-t2 (p = 0.048) and HC (p = 0.042). The FD value was lower in DR-t1 than in DR-t2 (p = 0.015) and HC (p = 0.011). Finally, Bayes Factor analysis showed that FD was 195 times more likely to separate DR-t1 from DR-t2 than IAF and 231 times than θ.
UNASSIGNED: FD measured in baseline EEG signals is a non-linear brain measure of complexity more sensitive than EEG power or IAF in detecting a response to ASMs. This likely reflects the non-oscillatory nature of neural activity, which FD better describes.
UNASSIGNED: Our work suggests that FD is a promising measure to monitor the response to ASMs in FE.

OBJECTIVE: Several antiseizure medications (ASMs) have been approved for the treatment of focal epilepsy. However, there is a paucity of evidence on direct comparison of ASMs. We evaluated the comparative efficacy and safety of all approved add-on ASMs for the treatment of focal epilepsy using network meta-analysis.
METHODS: Data through extensive literature search was retrieved from PubMed, Embase, Cochrane, and ClinicalTrial.gov databases using predefined search terms from inception through March 2023. PRISMA reporting guidelines (CRD42023403450) were followed in this study. Efficacy outcomes assessed were ≥50%, ≥75%, and 100% responder rates. Patient retention rate and safety outcomes such as overall treatment-emergent adverse events (TEAEs) and individual TEAEs were assessed. \"Gemtc\" 4.0.4 package was used to perform Bayesian analysis. Outcomes are reported as relative risks (RRs) and 95% confidence interval (CI).
RESULTS: Literature search retrieved 5807 studies of which, 75 studies were included in the analysis. All ASMs showed significantly higher ≥50% responder rate compared with placebo. Except the ≥75% seizure frequency reduction for zonisamide (2.23; 95% CI: 1.00-5.70) and 100% for rufinamide (2.03; 95% CI: 0.54-11.00), all other interventions showed significantly higher ≥75% and 100% responder rates compared with placebo. Among treatments, significantly higher 100% responder rate was observed with cenobamate compared to eslicarbazepine (10.71; 95% CI: 1.56-323.9) and zonisamide (10.63; 95% CI: 1.37-261.2). All ASMs showed a lower patient retention rate compared to placebo, with the least significant value observed for oxcarbazepine (0.77; 95% CI: 0.7-0.84). Levetiracetam showed a lower risk of incidence (1.0; 95%CI: 0.94-1.1; SUCRA: 0.885067) for overall TEAE compared with other medications.
CONCLUSIONS: All approved ASMs were effective as add-on treatment for focal epilepsy. Of the ASMs included, cenobamate had the greatest likelihood of allowing patients to attain seizure freedom.
CONCLUSIONS: This article compares the efficacy and safety of antiseizure medications (ASMs) currently available to neurologists in the treatment of epileptic patients. Several newer generation ASMs that have been developed may be as effective or better than the older medications. We included 75 studies in the analysis. In comparison, all drugs improved ≥50%, ≥75% and 100% responder rates compared to control, except for Zonisamide and Rufinamide in the ≥75% and 100% responder rate categories. Retention of patients undergoing treatment was lower in drugs than placebo. All drugs were tolerated, the levetiracetam showed the best tolerability. Cenobamate more likely help completely to reduce seizures.

The goal of epilepsy treatment is seizure freedom, typically with antiseizure medication (ASM). If patients fail to attain seizure control despite two trials of appropriately chosen ASMs at adequate doses, they are classified as having drug-resistant epilepsy (DRE). Adverse events (AEs) commonly occur in people with DRE because they are typically on ⩾2 ASMs, increasing the potential for drug-drug interactions. Early emerging AEs may impact adherence, decrease quality of life, and delay achieving optimal treatment dosages. Cenobamate is an oral ASM with a long half-life which has proven to be highly effective in clinical trials. An international Delphi panel of expert epileptologists experienced in the clinical use of cenobamate and other ASMs was convened to develop consensus best practices for managing patients during and after cenobamate titration, with consideration for its known pharmacokinetic and pharmacodynamic interactions, to allow patients to reach the most appropriate cenobamate dose while limiting tolerability issues. The modified Delphi process included one open-ended questionnaire and one virtual face-to-face meeting. Participants agreed that cenobamate can be prescribed for most patients experiencing focal-onset seizures. Patients initiating cenobamate therapy should have access to healthcare professionals as needed and their treatment response should be evaluated at the 100-mg dose. Patients with intellectual disabilities may need additional support to navigate the titration period. Proactive down-titration or withdrawal of sodium channel blockers (SCBs) is recommended when concomitant ASM regimens include ⩾2 SCBs. When applicable, maintaining a concomitant clobazam dose at ~5-10 mg may be beneficial. Patients taking oral contraceptives, newer oral anticoagulants, or HIV antiretroviral medications should be monitored for potential interactions. Because clinical evidence informing treatment decisions is limited, guidance regarding dose adjustments of non-ASM drugs was not developed beyond specific recommendations presented in the Summary of Product Characteristics.

Lamotrigine, a widely utilized broad-spectrum anticonvulsant, is commonly prescribed for epilepsy management and bipolar mood disorders. Despite its extensive clinical usage, instances of lamotrigine overdose are underreported. Here, we present a case involving acute encephalopathy and seizure onset following an intentional lamotrigine overdose. This case underscores the importance of recognizing the potential clinical manifestations of lamotrigine toxicity, such as encephalopathy and seizures, emphasizing the necessity for vigilant management of patients receiving this medication.

Epilepsy surgery may be a curative therapy for patients with drug-resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug-resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work-up and ruled out surgery in 7 of them. We observed that the co-existence of some recurrent clinical characteristics as early seizures\' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome. PLAINE LANGUAGE ABSTRACT: Genetic testing is not yet systematically included in the pre-surgical assessment of patients with drug-resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.

OBJECTIVE: This study aimed to explore the impact of co-antiseizure medication (co-ASM) optimization on the effectiveness and tolerability of adjunctive cenobamate (CNB) in patients with drug-resistant epilepsy in a real-world setting.
METHODS: This unicentric, retrospective, observational study included adults with focal-onset seizures who had received ≥2 previous ASMs. The main effectiveness endpoints included responder rates and seizure frequency reduction at 3, 6, and 12-month visits. The number of co-ASMs and defined daily dose (DDD) were analyzed at every visit. Safety endpoints included adverse drug reactions (ADRs).
RESULTS: Thirty-four patients with a median epilepsy duration of 22 years and a median of 15.5 seizures/month were analyzed. The median number of prior ASMs was 12, and the mean number of co-ASMs was 2.9 (SD 1). There was a reduction in seizure frequency/month from baseline to the last visit (p < 0.0001). Between baseline and the end of the study, the mean number of co-ASMs in the per-protocol (PP) population was reduced from 2.9 to 1.6 (p < 0.0001), and DDD was reduced from 3.6 to 1.4 (p < 0.0001). Sodium channel blockers (carbamazepine and lacosamide) and GABAergic drugs (clobazam) were the agents with the most significant reductions in DDD after 12 months. The percentage of patients in the PP population with ≥3 co-ASMs was reduced from 61.8% at baseline to 14.3% at 12 months; 1 patient was receiving CNB as monotherapy at the last visit. At the last visit, 85.7% of the PP population were ≥50% responders, and 33.3% were seizure-free. The percentage of patients with ADRs in the PP population was 71.9% at 3 months and 52.3% at 12 months.
CONCLUSIONS: Following rational polytherapy, optimization of co-ASM management during CNB treatment allowed high seizure freedom rates despite meaningful reductions in co-medication, while also achieving both good tolerability and patient satisfaction scores in a highly drug-resistant population.
CONCLUSIONS: Many patients with epilepsy still have seizures, even after being treated with several different epilepsy drugs. In this study of 34 patients from a Spanish clinic, we show that the epilepsy drug cenobamate can reduce the number of seizures in these patients, even after many other epilepsy drugs have failed. We also show that patients treated with cenobamate can reduce the dose or even stop taking certain other epilepsy drugs. This allows them to simplify their treatment and reduce adverse effects while still keeping control of their epilepsy.