限局性皮質異形成

OBJECTIVE: Surgical intervention is frequently considered for drug-resistant focal structural epilepsy. However, the impact of early surgery on seizure control, cognitive performance, and quality of life (QoL) across drug-sensitive and drug-resistant patients remains incompletely characterized. METHODS: We conducted a prospective-retrospective study on 214 patients with age > 6 years with focal structural epilepsy (focal cortical dysplasia type II, hippocampal sclerosis, low-grade epilepsy-associated tumors) stratified as: drug-sensitive (DS, n = 72) and drug-resistant (DR, n = 112) patients undergoing surgery, and drug-resistant patients on pharmacological treatment (DRT, n = 30). Cognitive function (including language, verbal and visuospatial memory, attention/executive functions) and QoL (using the Quality of Life in Epilepsy Inventory [QOLIE] and 36-Item Short Form Survey [SF-36] questionnaires) were assessed at baseline and 1-year follow-up in patient subgroups. Statistical analyses included chi-square tests, t tests, analysis of variance (ANOVA), and multivariable regression models; p < .05 was considered statistically significant. RESULTS: The DS patients demonstrated superior rates of complete seizure freedom (86%) compared with DR patients (69%, p = .009). At baseline, DS patients exhibited significantly fewer cognitive deficits compared with DR and DRT patients (p < .05). At the 1-year follow-up, no significant changes in neuropsychological performance were observed in any group, although a mild decline in verbal and/or visuospatial memory performance was observed in DRT patients. In a subset of patients (n = 59 adults) at baseline, DR and DRT patients reported significantly worse overall subjective QoL compared with DS patients (p = .047 and p = .036, respectively). Longitudinal analysis revealed significant improvements in QoL among surgically treated patients. SIGNIFICANCE: Early epilepsy surgery in symptomatic focal epilepsy yields excellent seizure outcomes, particularly in DS patients. Baseline preservation of cognitive function and QoL, together with the stability of these measures after surgery, suggests that timely surgery may help prevent deterioration in cognitive and psychosocial functioning. These findings support early referral for surgical evaluation in selected patients and highlight the need for larger studies with extended follow-up, to confirm surgical outcome, long-term neuropsychological, and patient-reported benefits.

Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new potential FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 6 new genes in which loss of function significantly increases pS6 levels: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. Further analysis of the mTOR pathway showed that only two of the genes, PIK3R3 and HIP1, caused hyperphosphorylation throughout the AKT/mTOR/S6 signaling pathway. Importantly, potential pathogenic variants in these two genes have been reported in resected brain tissue from a single FCD patient each, supporting the predictive validity of our screen. Knocking down each of the 6 genes in iNeurons made mTOR signaling resistant to the loss of neurotrophic factor signaling, specifically GDNF; even without GDNF, pS6 levels remained comparable to GDNF-stimulated controls. Thus, we have identified negative regulators of neuronal mTOR signaling in the context of lost neurotrophic factor support. Our data expand the set of genes that are likely to regulate mTOR pathway signaling in neurons, provide biological confirmation for candidate genes identified in human tissue, and suggest additional targets for investigating somatic gene variants in resected FCD tissues. The identification of novel mTOR regulators using iNeurons also highlights the importance of genetic screening in disease-related cell types.

OBJECTIVE: Selecting patients for surgery for drug resistant epilepsy (DRE) with malformations of cortical development (MCD) by non-invasive evaluation is challenging. Optimizing surgical strategy and predicting seizure outcomes are also difficult. We analyzed the data of patients with DRE and MCD over a 12-year period at a single institution to assess the role of non-invasive pre-surgical evaluation, surgical strategy, and predictors of seizure outcome. METHODS: Between April 2011 and March 2022, 584 patients with DRE underwent pre-surgical evaluation and surgery at our institution. During the study period, a total of 93 patients underwent surgery for DRE and MCD. Six patients who underwent invasive evaluation, and another six patients with incomplete data were excluded from the study. We have analyzed the clinical profile, pre-surgical evaluation data, surgical strategy, histopathology, and seizure outcome and have identified the predictors of the seizure outcome. RESULTS: The cohort consists of 81 patients (males = 47) with a mean age of seizure onset of 6.85 years and mean age at surgery of 16.54 years. The mean duration of epilepsy before surgery was 9.75 years. The mean follow-up period was 8.66 years. In this study, 63 patients achieved international league against epilepsy (ILAE) class 1 outcome and 18 patients achieved class 2-6 outcome. Of the patients who had complete resection of the lesion, 86.2% had ILAE class 1 outcome, and those with incomplete resection had 55.17%. We found that factors such as fewer anti-seizure medications and complete resection of the lesion were associated with a favorable outcome on multivariable analysis. CONCLUSIONS: Based upon these predictors, we conclude that patients with stereotypical habitual seizures, who were on fewer anti seizure medications (ASM) preoperatively and who have undergone complete resection of the lesion can expect a favorable post-operative seizure outcome. Lack of concordant findings on pre-surgical evaluation did not independently predict poor outcome in this study, suggesting that discordant findings should not per se exclude patients with MCD from undergoing epilepsy surgery.

INTRODUCTION: Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy and has predominantly been associated with impaired inhibitory signaling. However, recent ultrastructural studies have identified morphological alterations in excitatory synapses, suggesting that structural changes in excitatory connectivity may also contribute to cortical hyperexcitability. METHODS: We used biophysically grounded computational models of human cortical pyramidal neurons to investigate how disease-associated alterations in dendritic spine architecture affect neuronal excitability. Spine density and spine geometry were independently manipulated based on quantitative volume electron microscopy measurements, allowing us to distinguish the contributions of individual structural features of excitatory synapses. RESULTS: Reduced spine density and altered spine neck geometry increased neuronal excitability through complementary mechanisms, whereas variations in spine head size had comparatively minor effects. These structural alterations differentially influenced synaptic signal propagation and spike initiation. Their combined effects substantially increased neuronal output, particularly under conditions of sparse synaptic input. DISCUSSION: These findings identify excitatory synaptic microstructure as an independent and mechanistically distinct contributor to hyperexcitability in FCD Type I. By linking ultrastructural abnormalities to altered neuronal input-output function, this study supports a potential contribution of excitatory synaptic alterations to the pathophysiology of FCD.

[This corrects the article DOI: 10.3389/fnins.2026.1915535.].