Epilepsy affects over 50 million people worldwide. Drug-resistant epilepsy (DRE) accounts for up to a third of these cases, and neuro-inflammation is thought to play a role in such cases. Despite being a long-debated issue in the field of DRE, the mechanisms underlying neuroinflammation have yet to be fully elucidated. The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics. Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes, such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis. The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems. We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application. We hope to provide an insightful overview to advance the quest for better DRE treatments.

Objective: Stereo‐electroencephalography‐guided three‐dimensional radiofrequency thermocoagulation (SEEG‐3D RFTC) is a minimally invasive treatment for mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE‐HS). This study aimed to investigate the long‐term prognosis after SEEG‐3D RFTC treatment in patients with MTLE‐HS.Methods: This single‐center retrospective study included 28 patients with MTLE‐HS treated with SEEG‐3D RFTC from January 2016 to May 2018. Postoperative curative effects were evaluated using the Engel classification, and the patients were followed up for 5 years.Results: The proportions of patients categorized as Engel I between 1 and 5 years after surgery were 72.41% (12 months after surgery), 67.86% (18 months after surgery), 62.07% (24 months after surgery), 50.00% (36 months after surgery), 42.86% (48 months after surgery), and 42.86% (60 months after surgery), respectively. Regarding long‐term efficacy, based on the Engel classification, SEEG‐3D RFTC showed room for improvement.Significance: This was the first study to evaluate the efficacy of SEEG‐3D RFTC for MTLE‐HS with long‐term follow‐up. SEEG‐3D RFTC is a promising alternative for patients with MTLE‐HS.Plain Language Summary: This study explored the potential of stereoelectroencephalography‐guided three‐dimensional radiofrequency thermocoagulation, a minimally invasive approach, for treating medial temporal lobe epilepsy with hippocampal sclerosis. Involving 28 patients, the research tracked the treatment’s success over five years using the Engel classification. Initial results were promising, with 72.41% of patients achieving the most favorable outcome (Engel I) at one year. While there was a gradual decrease in this proportion over time, 42.86% of patients maintained this positive outcome at five years, highlighting the treatment's potential for long‐term efficacy.

Temporal lobe epilepsy (TLE), the most common form of epilepsy, is primarily characterized by hippocampal sclerosis (HS). Microglia reactivity is a critical component of TLE pathogenesis, and apolipoprotein E (APOE) may be a potential mediator of these processes. However, its role in TLE progression remains unclear. Bioinformatics approaches with biomarker validation are integrated to elucidate APOE's role and hippocampal microglia in the mechanisms underlying TLE. APOE expression is significantly elevated in the hippocampal tissues of patients with TLE‐HS and in TLE mouse models. Single‐cell RNA sequencing reveals a subset of microglia with high APOE gene expression, which serves as the principal carrier of increased APOE during disease progression. Bioinformatic analyses, in vitro studies, and in vivo functional experiments utilizing TLE mouse models implicate these APOE ‐expressing microglia in regulating microglial differentiation, promoting neuroinflammation, neuronal apoptosis, and enhancing neuronal excitability. Genetic knockout of APOE mitigates gliosis, neuronal cell death, and seizure frequency in the hippocampus of epileptic mice. Additionally, APOE expression primarily induces significant alterations in glycerophospholipid metabolism and its associated metabolic derivatives within the epileptic microenvironment. Overall, APOE ‐expressing microglia are pivotal drivers of HS and TLE progression, positioning APOE and its downstream signaling pathways as promising therapeutic TLE targets.

Background: Epilepsy has a genetic predisposition, yet causal factors and the dynamics of the immune environment in epilepsy are not fully understood.Methods: We analyzed peripheral blood samples from epilepsy patients, identifying key genes associated with epilepsy risk through Mendelian randomization, using eQTLGen and genome‐wide association studies. The peripheral immune environment's composition in epilepsy was explored using CIBERSORT. An epilepsy mouse model was established to validated the expression of key genes at the transcriptomic and proteomic levels through single‐cell analysis. Relevant pathways were verified. Finally, we developed a predictive model for antiepileptic drug response in epilepsy patients.Results: We found that CDC25B, DNMT1, GZMA, MTX1, and SSH2 expression decreases epilepsy risk, whereas FGD3, RAF1, and SH3BP5L increase it. Epilepsy patients exhibited an altered peripheral immune profile, notably with increased activated mast cells and decreased CD4 memory activated T cells and γδ T cells. Eight genes were significantly related to this immune environment. In the animal model, FGD3, SSH2, and DNMT1 were upregulated at both mRNA and protein levels in the hippocampus. FGD3 and SSH2 are specifically elevated in microglia and are primarily associated with actin regulation. The trained predictive model was deployed on an online platform.Conclusions: This study elucidates key genes linked to epilepsy, delineates the epilepsy immune landscape, and highlights the interaction between these domains, providing insights into potential epilepsy mechanisms and treatments.

Background: Focal cortical dysplasia Type II (FCD II) is a major cause of drug‐resistant epilepsy in children. Somatic mosaic variants affecting the PI3K–AKT–mTOR pathway are implicated in a substantial proportion of cases. The links between genotype, cellular pathology, epileptogenic networks, and clinical outcome remain incompletely defined. Methods: This review synthesizes evidence on somatic mTOR–pathway variants, lesion development, pathological cell populations, circuit mechanisms, single‐cell and spatial multi‐omics approaches in FCD II. Results: The developmental timing, lineage distribution, and local expansion of somatic variants influence lesion extent and phenotypic heterogeneity. Dysmorphic neurons may contribute to epileptogenicity through altered intrinsic excitability and synaptic function, whereas balloon cells may predominantly affect local circuits through secretory and microenvironmental mechanisms. mTOR hyperactivation may also alter interneuron development, subtype specification, and synaptic connectivity, thereby disrupting excitation‐inhibition balance. Single‐cell and spatial approaches, including RNA velocity, pseudotime analysis, chromatin‐age inference, and somatic genotyping, provide tools to resolve pathological cell states and lineage trajectories. Conclusions: FCD II should be considered a mosaic developmental disorder involving both cell‐autonomous and non‐cell‐autonomous mechanisms. Integrating somatic variant detection with cellular, spatial, electrophysiological, and surgical outcomes from matched patient tissue may enable biologically meaningful stratification and support the development of novel therapies.

Aims: Epilepsy is a common neurological disorder, often presenting with psychiatric comorbidities and cognitive impairment. Neuroimaging studies have suggested associations between epilepsy and subcortical volumetric abnormalities. The genetic basis between epilepsy and subcortical volume abnormalities is, however, poorly understood, particularly if they share a common genetic architecture. Methods: To investigate polygenic overlap, we employed the bivariate causal mixture model (MiXeR) to analyze genome‐wide association data from various epilepsy subtypes (genetic generalized epilepsy [GGE]: n = 49,388, all epilepsy [EP]: n = 69,995, focal epilepsy: n = 57,375) and 16 subcortical volumetric phenotypes ( n = 33,224). We identified shared genomic loci through conditional and conjunctional false discovery rate analyses (cond/conjFDR). Results: MiXeR results suggest substantial shared genetic variants between subcortical volume and common epilepsies. ConjFDR analysis identified 33 distinct shared loci between GGE and subcortical volumetric phenotypes. The shared loci were mapped to 322 protein‐coding genes. Among these, 49 genes showed significant expression‐trait associations with both GGE and subcortical volume phenotypes, and 12 of the 322 genes were also associated with cognitive, mental health, and personality‐related traits. Conclusion: We dissected the shared genetic architecture between common epilepsies and subcortical volumes. Expression‐trait association analyses further identified candidate genes associated with cognitive, mental health, and personality‐related phenotypes.