This study aimed to determine the patterns of changes in structure, function, and cognitive ability in early-onset and late-onset older adults with focal epilepsy (OFE). This study first utilized the deformation-based morphometry analysis to identify structural abnormalities, which were used as the seed region to investigate the functional connectivity with the whole brain. Next, a correlation analysis was performed between the altered imaging findings and neuropsychiatry assessments. Finally, the potential role of structural-functional abnormalities in the diagnosis of epilepsy was further explored by using mediation analysis. Compared with healthy controls (n = 28), the area of reduced structural volume was concentrated in the bilateral cerebellum, right thalamus, and right middle cingulate cortex, with frontal, temporal, and occipital lobes also affected in early-onset focal epilepsy (n = 26), while late-onset patients (n = 31) displayed cerebellar, thalamic, and cingulate atrophy. Furthermore, correlation analyses suggest an association between structural abnormalities and cognitive assessments. Dysfunctional connectivity in the cerebellum, cingulate cortex, and frontal gyrus partially mediates the relationship between structural abnormalities and the diagnosis of early-onset focal epilepsy. This study identified structural and functional abnormalities in early-onset and late-onset focal epilepsy and explored characters in cognitive performance. Structural-functional coupling may play a potential role in the diagnosis of 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.

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.

OBJECTIVE: DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients.
METHODS: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies.
RESULTS: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335).
CONCLUSIONS: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.

BACKGROUND: Adjunctive cenobamate was effective and safe for the treatment of uncontrolled focal onset seizures in a randomized, double-blind, placebo-controlled, phase 2 study (YKP3089C017; NCT01866111). This post-hoc analysis assessed the efficacy of adjunctive cenobamate in the treatment of patients with different epileptic etiologies during the study.
METHODS: Adult patients with uncontrolled focal seizures who previously received 1 to 3 antiseizure medications (ASMs) were randomly assigned in a ratio of 1:1:1:1 to receive placebo or cenobamate 100, 200 or 400 mg/day. Patients were further stratified based on their etiologic causes as genetic/presumed genetic, unknown cause, structural cause, and not reported (NR) groups. The frequency per 28 days for an 18-week double-blind treatment period, responder rates (≥50 %, ≥75 %, ≥90 %, and 100 %) during the maintenance phase (12 weeks), and safety were assessed.
RESULTS: A total of 394 patients were categorized into the genetic/presumed genetic (n = 9; 2.28 %), unknown cause (n = 199; 50.51 %), structural cause (n = 177; 44.92 %), and NR (n = 13; 3.30 %) groups, with 4 patients were classified into either of the two etiological causes each. The baseline characteristics were comparable. The percentage of reduction in seizure frequency per 28 days was significantly higher in the cenobamate-treated structural (p = 0.01) and unknown cause (p = 0.0003) groups compared with the placebo group. Responder rates of ≥50 %, ≥75 %, ≥90 %, and 100 % were also higher with cenobamate therapy. Notably, no serious treatment-emergent adverse events (TEAEs) were observed in the genetic/presumed genetic group treated with cenobamate. The most common TEAEs (≥10 %) occurring in patients treated with cenobamate were nervous system disorders by system organ class, and somnolence was the most commonly reported TEAE.
CONCLUSIONS: Cenobamate reduces seizures in adult patients previously treated with ASMs, with high responder rates and acceptable safety, regardless of underlying causes.

UNASSIGNED: Neuregulin-1 (NRG-1) appears to play a role in the pathogenesis of several neuropsychiatric disorders, including epilepsy. We conducted a study to investigate the effect of anti-seizure medication on NRG-1 mRNA and NRG-1 protein levels in patients with first-episode focal epilepsy.
UNASSIGNED: The levels of NRG-1 mRNA isoforms (type I, II, III, and IV) in peripheral blood mononuclear cells (PBMCs) of 39 healthy controls, 39 first-episode focal epilepsy patients before anti-seizure medication (ASM) therapy and four weeks after administration of ASM were measured by RT-qPCR, and the levels of NRG-1 protein in the serum of samples of each group were determined using ELISA. In addition the relationship between efficacy, NRG-1 mRNA expression, and NRG-1 protein expression was analyzed.
UNASSIGNED: The levels of NRG-1 mRNA progressively increased in patients with first-episode focal epilepsy treated with ASM and were distinctly different from those before medication, but remained lower than in healthy controls (all P < 0.001). Before and after drug administration, NRG-1 protein levels were substantially higher in epileptic patients than in healthy controls, and no significant changes were detected with prolonged follow-up (P < 0.001). Patients with epilepsy who utilized ASM were able to control seizures with an overall efficacy of 97.4%. There was a negative correlation between NRG-1 mRNA levels and efficacy: as NRG-1 mRNA levels increased, seizures reduced (all P < 0.05).
UNASSIGNED: Our research indicated that NRG-1 may play a role in the pathophysiology of epilepsy. NRG-1 mRNA may provide ideas for the discovery of novel epilepsy therapeutic markers and therapeutic targets for novel ASM.

Interictal epileptiform discharges (IEDs) often co-occur across spatially-separated cortical regions, forming IED networks. However, the factors prompting IED propagation remain unelucidated. We hypothesized that slow oscillations (SOs) might facilitate IED propagation. Here, the amplitude and phase synchronization of SOs preceding propagating and non-propagating IEDs were compared in 22 patients with focal epilepsy undergoing intracranial electroencephalography (EEG) evaluation. Intracranial channels were categorized into the irritative zone (IZ) and normal zone (NOZ) regarding the presence of IEDs. During wakefulness, we found that pre-IED SOs within the IZ exhibited higher amplitudes for propagating IEDs than non-propagating IEDs (delta band: p = 0.001, theta band: p < 0.001). This increase in SOs was also concurrently observed in the NOZ (delta band: p = 0.04). Similarly, the inter-channel phase synchronization of SOs prior to propagating IEDs was higher than those preceding non-propagating IEDs in the IZ (delta band: p = 0.04). Through sliding window analysis, we observed that SOs preceding propagating IEDs progressively increased in amplitude and phase synchronization, while those preceding non-propagating IEDs remained relatively stable. Significant differences in amplitude occurred approximately 1150 ms before IEDs. During non-rapid eye movement (NREM) sleep, SOs on scalp recordings also showed higher amplitudes before intracranial propagating IEDs than before non-propagating IEDs (delta band: p = 0.006). Furthermore, the analysis of IED density around sleep SOs revealed that only high-amplitude sleep SOs demonstrated correlation with IED propagation. Overall, our study highlights that transient but widely distributed SOs are associated with IED propagation as well as generation in focal epilepsy during sleep and wakefulness, providing new insight into the EEG substrate supporting IED networks.

Nitrogen permease regulator-like 3 (NPRL3) has been reported to play a role in seizure onset. The principal manifestation of NPRL3-related epilepsy is a range of epilepsy-associated syndromes, such as familial focal epilepsy with variable foci (FFEVF), sleep-related hypermotor epilepsy (SHE), and temporal lobe epilepsy (TLE). The association between phenotype and genotype of NPRL3 mutations remains inadequately described. This study aimed to explore the phenotypic and genotypic spectra of NPRL3-related epilepsy. We reported two novel NPRL3 variants in two unrelated epilepsy cases, including a nonsense (c.1174C > T, p.Gln392*) and a missense variant (c.1322C > T, p.Thr441Met). Following a review of the literature, a total of 116 cases of NPRL3-related epilepsy were assessed, mostly with nonsense and frameshift mutations. Our findings suggest that patients harboring various NPRL3 variants exhibit variable clinical manifestations. In addition, it may be worthwhile to consider the existence of NPRL3 mutations in epilepsy patients with a family history. This study provides useful information for the treatment and prognosis by expanding the phenotypic and genotypic spectrum of NPRL3-related epilepsy. PLAIN LANGUAGE SUMMARY: This study expands the phenotypic and genotypic spectra of NPRL3-related epilepsy by reporting two cases with different novel variants. Following a review of the literature, it was observed that patients harboring various NPRL3 variants exhibited a variability of clinical manifestations. Also, patients carrying nonsense mutations are frequently prone to drug resistance and other severe comorbidities such as developmental delay, but more cases need to be collected to confirm these findings.

The neonatal and infantile period is the age group with the highest incidence of epilepsy, in which gene variants in sodium and potassium channels are an important etiology, so the sodium channel blocker class of antiseizure medications may be effective in the treatment of early onset epilepsy. This study aimed to summarize the efficacy and tolerability of oxcarbazepine (OXC) in the treatment of focal epilepsy in neonates and infants under 3 months of age.
A retrospective analysis of children with focal epilepsy onset within 3 months of age and treated with OXC in a tertiary pediatric epilepsy center in China was conducted. The efficacy, tolerability and influencing factors of OXC were evaluated.
A total of 50 patients were enrolled, with a median age of epilepsy onset of 11.5 (2, 42) days. There were 32 cases of early infantile developmental and epileptic encephalopathy, 10 cases of self-limited neonatal or neonatal-infantile epilepsy, and 8 cases of focal epilepsy that could not be classified as epileptic syndrome. The median age of application of OXC was 47 (31, 66) days. The median follow-up time was 16.5 (10, 25) months, with 7 deaths. Thirty-eight cases (76.0 %) were effective with OXC treatment, including 28 cases (56.0 %) achieved seizure freedom. Of the 34 cases whose pathogenesis involved genetic factors, 19 cases with sodium/ potassium channel gene variants had higher effective and seizure-free rates than those with other gene variants. The most common adverse event was transient hyponatremia. 2 cases had rash and 2 cases had abnormal electrocardiogram, 3 of which discontinued OXC.
This single-center retrospective study suggests that OXC is effective and tolerable for the treatment of focal epilepsy in neonates and infants under 3 months of age. The efficacy of OXC is better in patients with sodium/ potassium channel gene variants.