Arabic verbal fluency in mesial temporal and generalized epilepsy: evidence from letter and category tasks with healthy controls.

Screening for serum antineuronal antibodies in pediatric epilepsy.

Cognitive phenotypes in adults with temporal lobe epilepsy from South Africa - A contribution to the international classification of cognitive disorders in epilepsy (IC-CoDE).

Mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS) is a leading cause of drug-resistant epilepsy. Surgical resection, particularly anterior temporal lobectomy (ATL), achieves high rates of seizure freedom, but outcomes vary. Identifying reliable preoperative predictors may optimize patient selection and surgical success.To systematically evaluate preoperative clinical, neuroimaging, and neuropsychological factors associated with postoperative seizure outcomes in MTLE.A systematic review was conducted according to PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science were searched for cohort studies (2010-2025) reporting predictors of seizure freedom after MTLE-HS surgery. Eligible studies assessed one or more preoperative factors (clinical, EEG, imaging, neuropsychological) in relation to postoperative outcomes. Data were extracted for qualitative synthesis, and methodological quality was assessed with the Newcastle-Ottawa Scale (NOS).From 615 records, 24 studies were included, encompassing patients treated with ATL, selective amygdalohippocampectomy (SAHE), or stereotactic laser ablation. Seizure freedom rates (Engel I/ILAE 1) ranged from 50% to 75%, with ATL achieving ~ 70% at 1-2 years. Multimodal concordance-MRI-visible HS, unilateral seizure onset on EEG, and concordant PET hypometabolism-was the strongest predictor of seizure freedom. Bilateral EEG/PET abnormalities consistently predicted poorer outcomes, whereas structural measures, such as hippocampal subfield volumes and HS subtypes, showed little prognostic value.Multimodal presurgical concordance is a robust predictor of favorable outcomes in MTLE-HS surgery, whereas bilateral or discordant findings indicate a higher risk of failure. Comprehensive presurgical evaluation remains essential to optimize surgical decision-making.

Is temporal lobe epilepsy a progressive disease? Insights from a 5-HT1A receptor partial volume correction study.

Objective. Temporal lobe epilepsy (TLE) is frequently accompanied by hippocampal sclerosis (HS) and involves widespread alterations in brain structure and function. However, most neuroimaging studies rely on single-modality data and provide limited insight into the microscale neural mechanisms underlying these changes. The relationship between structural connectivity (SC) and functional connectivity also remains insufficiently understood. This study aims to integrate structural and functional data to investigate microscale neural dynamic alterations in TLE.Approach. A biophysically informed relaxed mean-field model was employed to estimate region-specific microscale parameters, including recurrent connection weightwand subcortical driveI, in healthy controls (HCs) and left HS (LHS) or right HS (RHS) patients. Individual SC derived from diffusion magnetic resonance imaging was used as anatomical constraints to simulate resting-state neural dynamics. Group differences in model-derived parameters were evaluated. In addition, graph-theoretical analyses were conducted to characterize alterations in structural and functional network topology and to examine associations between network metrics, microscale parameters, and clinical measures.Main results. Compared with the HC group, both LHS and RHS groups showed observable differences in recurrent connection weightwand subcortical driveIacross multiple brain regions, including the superior parietal lobule, temporal pole, and insula cortex. These changes suggest disrupted local recurrent dynamics and altered subcortical modulation, potentially impairing large-scale network integration. Furthermore, microscale parameter alterations were significantly associated with changes in network topology, indicating that local circuit dysfunction can propagate to macroscopic network reorganization.Significance. This study provides mechanistic evidence for multiscale brain network remodeling in TLE and demonstrates the utility of biophysical modeling in linking structural architecture with functional dynamics, offering new insights into the pathophysiology of epilepsy.

Corpora amylacea (CA), now called wasteosomes, are basophilic inclusions associated with aging, neurodegeneration, and impaired glymphatic waste clearance. Their presence is well described in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and related to hippocampal neuronal loss and longer epilepsy duration. Here, we assessed CA deposition in TLE patients submitted to epilepsy surgery with any histological diagnosis and explored its relationship with clinical and neuropsychological variables. Histological signs of the glymphatic system were evaluated. Qualitative and quantitative evaluation of CA was performed on neocortical and hippocampal surgical specimens and correlated with age at onset, duration of epilepsy, type of seizure at surgery, antecedents, psychiatric symptoms, and seizure outcome. Podoplanin (PDPN) expression was assessed in a subgroup of patients with high and low CA presence as a histological marker of lymphatic elements. Comparison with nonepileptic tissues was also performed. Fifty consecutive patients were included with the following histological diagnosis: 18 patients with HS only, 10 patients with HS and associated focal cortical dysplasia (type IIIa), seven patients with encephalocele, five cryptogenic patients with no abnormalities on resected brain specimens (no lesion), and 10 patients with other histological findings. Patients with HS were vulnerable to CA accumulation compared to other etiologies. There was a significant association between CA density and duration of epilepsy, independent of age at surgery or other clinical parameters, and the presence of CA was associated with a worse preoperative cognitive profile. Preliminary histological observations from a few cases suggested enlarged perivascular spaces and altered PDPN vascular expression in patients with higher deposition of CA. These findings provide evidence that CA accumulation correlates with epilepsy duration and suggest a contribution of altered brain clearance mediated by the glymphatic system to cortical dysfunction and cognitive deficits. Future research on glymphatic alterations and their therapeutic modulation may improve management of TLE and other epileptic or neurodegenerative conditions.

The diagnosis of neurogenetic disorders is often prolonged due to clinical variability and significant genetic heterogeneity, making molecular diagnosis challenging. This study aimed to investigate the molecular basis of rare inherited neurological conditions in three consanguineous Moroccan families. We performed Whole exome sequencing (WES) on probands from three unrelated consanguineous Moroccan families (NP 69, NP 84, NP 89). Candidate variants were validated by Sanger sequencing and segregated within the families. Pathogenicity was assessed through in silico prediction tools. Molecular modeling and molecular dynamics simulations were applied to assess the structural impact of selected variants. Whole exome sequencing revealed likely disease-causing variants in all three families. In Family NP 69, we found compound heterozygous missense variants in RYR3 gene (p.Gly2168Arg and p.Val854Ile) in a proband presenting with developmental delay and hippocampal sclerosis. In Family NP 84, a homozygous missense variant (p.Trp671Arg) in POLR3A gene, was associated with classic hypomyelinating leukodystrophy and ataxia, but with atypical features including preserved cognition, myoclonus, and oligodontia, consistent with recurrence of a previously reported variant in North Africa and suggestive of a possible founder effect. In Family NP 89, a homozygous splice-site mutation in LAMA2 gene (c.8244 + 1G > A) was confirmed in a proband with severe congenital muscular dystrophy. This study reports a novel compound heterozygous configuration in RYR3, confirms a previously reported bi-allelic variant in POLR3A, and validates a recurrent LAMA2 variant. Together, these findings add new insights into the genotype-phenotype spectrum of neurogenetic disorders in consanguineous North African populations, all consistent with a shared autosomal recessive inheritance pattern.

Hippocampal sclerosis (HS) represents a higher proportion of surgical pathology in adult epilepsy patients compared to pediatric surgical cohorts. We hypothesized that while HS may serve as an initial pathological substrate, hippocampal abnormalities in epilepsy may also represent a duration-related structural change process that evolves with disease progression. To test this duration-dependent hypothesis, we investigated associations between disease duration and hippocampal morphological features using advanced neuroimaging in a large multicenter cohort. This study included 705 patients with unilateral focal epilepsy (age 25.4 ± 14.9 years, disease duration 14.8 ± 13.6 years) and 424 healthy controls from three centers in China. Global hippocampal features (volume, thickness, gyrification, mean curvature, intrinsic curvature) and subfield volumes were extracted using HippUnfold and AID-HS. Z-scores were calculated using normative models controlling for age, sex, total intracranial volume, and site. Associations between disease duration and hippocampal features were assessed using Spearman correlations and duration-stratified group comparisons. Longitudinal changes were evaluated in 80 patients with serial MRI scans using linear mixed-effects models. Patients with epilepsy showed significant bilateral hippocampal abnormalities compared to controls, with more severe changes ipsilateral to the seizure focus. Disease duration significantly correlated with all ipsilateral hippocampal metrics: negatively with volume (ρ = -0.181, p < 0.001), thickness (ρ = -0.135, p < 0.001), and gyrification (ρ = -0.141, p < 0.001), and positively with mean curvature (ρ = 0.121, p = 0.003) and intrinsic curvature (ρ = 0.171, p < 0.001). Contralateral associations were observed for volume (ρ = -0.085, p = 0.044), thickness (ρ = -0.082, p = 0.049), and intrinsic curvature (ρ = 0.080, p = 0.049). Longitudinal analysis revealed significant annual decline in ipsilateral hippocampal volume (β = -0.21 Z-score units/year, p = 0.042). We provide novel neuroimaging evidence supporting the duration-related structural alteration hypothesis of hippocampal structural changes in focal epilepsy. These findings may help explain the higher proportion of HS observed in adult surgical cohorts compared to pediatric surgical cohorts and enhance understanding of epilepsy pathophysiology, suggesting that disease duration is significantly associated with hippocampal structural abnormalities, indicating that it may serve as an important reference indicator for clinical monitoring and therapeutic decision-making.

Advances in stereo-electroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RFTC) have led to the development of cross-electrode RFTC, which has been shown to result in significantly larger lesions and higher seizure-freedom rates compared to standard RFTC methods. Given the novelty of cross-electrode RFTC, herein we review the reported surgical techniques and treatment-related outcomes to date to identify current research gaps and future directions. Ten articles were identified for review including 187 participants who underwent cross-electrode RFTC. Hypothalamic hamartoma (HH) and hippocampal sclerosis (HS) accounted for 52% and 26% of all cases, respectively. The proportion of cases with seizure freedom at last follow-up was 71%, including 84% of the HH cases, 54% of all temporal lobe cases, and 56% of the HS cases. Long-term efficacy in one HS study dropped from 72% at 12 months to 43% at 5 years post-treatment. Most (94%) reported complications resolved. One study reported favorable neuropsychological outcomes in HS cross-electrode RFTC compared to standard resective epilepsy surgery; however, it did not use memory tasks known to be reliable proximal markers of mesial temporal dysfunction/disease. In conclusion, extending RFTC boundaries through cross-electrode methods may improve RFTC efficacy and produce seizure-freedom rates comparable to established epilepsy surgical interventions in the treatment of HH and HS at 12 months, with a low risk of postoperative complications. There is limited research exploring efficacy in non-lesional epilepsy despite these cases often undergoing SEEG for diagnostic purposes and being well placed for cross-electrode RFTC. In addition, there is a lack of research exploring the neurocognitive and psychiatric risks of cross-electrode RFTC.

Feline hippocampal necrosis and temporal lobe epilepsy: A review of current literature and definitions.

Multi-omics identifies RNF149 as a key molecular marker mediating neuron-glia interaction in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common focal epilepsy but remains highly heterogeneous across hemispheric and structural etiology. This study aimed to characterize microstate-based network dynamics in TLE and evaluate their diagnostic value for seizure lateralization and structural etiology using machine learning. Resting-state electroencephalography (EEG) recordings from 150 patients with unilateral TLE (71 right, 79 left) and 65 healthy controls (HCs) were analyzed. EEG signals were segmented into canonical microstates (A, B, C, D), and microstate-specific spatial, and temporal dynamic functional connectivity (dFC) variability metrics were extracted using phase lag index analysis. After two-step feature selection, the appropriate number of features were derived and input into Random Forest, XGBoost, and Support Vector Machine (SVM) classifiers to distinguish: TLE vs HCs, left vs right TLE, and magnetic resonance imaging (MRI)-negative (MRI-neg) vs hippocampal sclerosis (HS) TLE subtypes (TLE-HS). Model performance was evaluated on independent hold-out validation set using receiver operating characteristic analyses. Compared with HCs, patients with TLE exhibited increased duration and occurrence of microstate D and reduced expression microstate B, reflecting maladaptive attentional overactivation and visual suppression. Spatial variability was globally decreased, most prominently in left TLE. SVM achieved excellent performance for TLE detection (area under the curve [AUC] = .98) and lateralization (AUC = .97), whereas classification between MRI-neg TLE and TLE-HS was limited (AUC = .58). EEG microstate-derived dFC metrics provide reliable, non-invasive biomarkers for identifying and lateralizing TLE using short duration resting-state EEG recordings. This framework advances understanding of TLE heterogeneity and supports the development of individualized electrophysiological tools for precision diagnosis.

Preoperative systemic immune-inflammation index predicts seizure outcomes after anterior temporal lobectomy in drug-resistant temporal lobe epilepsy.

Face-name associative memory in temporal lobe epilepsy: Region-specific insights in right-hemisphere onset.

Neurocysticercosis (NCC) is a frequent cause of epilepsy in endemic regions. An association between NCC and hippocampal sclerosis (HS), a key pathological substrate of mesial temporal lobe epilepsy, has been increasingly reported but remains controversial. A literature search was conducted in PubMed, Scopus, and ScienceDirect focusing on publications describing epilepsy due to NCC with HS. Twenty-three original articles, published between 1998 and 2024, were identified from Brazil, Ecuador, India, Mexico, and Korea. The proposed relationships between NCC and HS include incidental coexistence, NCC as an initial precipitating injury, and the presence of a third variable. While multiple hypotheses have been discussed and reported cases compiled, the precise nature of this association remains unresolved. Although the mechanisms underlying the relationship between NCC and HS are not fully elucidated, evidence supports their coexistence in patients with epilepsy. Recognition of this association is important for clinical evaluation and may guide future research on pathogenesis and management.

Chronic Optogenetic Stimulation of Dentate Gyrus Granule Cells in Mouse Organotypic Slice Cultures Synaptically Drives Mossy Cell Degeneration Koretz CC, Schneider R, Jungenitz T, Drakew A, Roeper J, Deller T. Epilepsia . 2025;66:1734–1746. Objective: Degeneration of hilar mossy cells in the dentate gyrus is an important hallmark of hippocampal sclerosis and is often observed in patients with temporal lobe epilepsy. To understand the pathogenesis of hippocampal sclerosis and develop novel neuroprotective treatments, it is critical to determine the mechanistic processes of mossy cell degeneration and factors that influence cell vulnerability or resilience. However, suitable in vitro approaches are currently lacking. We have developed and validated an organotypic slice culture-based in vitro model that facilitates mechanistic studies of activity-dependent mossy cell vulnerability and resilience. Methods: A model was developed using entorhino-hippocampal slice cultures. Dentate gyrus granule cells were transduced with adeno-associated viruses to express channelrhodopsin2. Transduced cultures were chronically stimulated by light, and resulting cell damage was assessed by propidium iodide staining. Spontaneous synaptic activity before and after optical stimulation was recorded using whole-cell patch-clamp. Results: Selective and dose-dependent hilar neuron degeneration was observed following chronic optogenetic stimulation of organotypic slice cultures expressing channelrhodopsin-2 in granule cells. Treatment with the anticonvulsant retigabine reduced stimulation-induced hilar neuron loss in a dose-dependent manner. This demonstrates the suitability of our optogenetic in vitro model for drug screening. Patch-clamp recordings verified strong synaptic activation of mossy cells during optical stimulation and a reduction in spontaneous excitatory synaptic activity after stimulation. Significance: The role of mossy cells in the context of epileptic seizures has been a controversial topic of discussion. The presented in vitro model allows the study of mossy cell vulnerability on a single-cell level and provides the first evidence for changes in synaptic activity after stimulation. This model will facilitate our mechanistic understanding of temporal lobe epilepsy, providing a foundation for novel therapeutic interventions aimed at preserving mossy cell function in epilepsy patients.

This study aims to characterize the spatiotemporal dynamics of hippocampal atrophy and epileptogenicity in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS), and to investigate their relationship with disease duration. We conducted a cross-sectional study integrating structural magnetic resonance imagingandstereoelectroencephalographic (SEEG) data from 156 mTLE-HS patients. Hippocampal subfield volumetry was performed. In patients with SEEG (n = 67), interictal periodic and aperiodic components were quantified using the FOOOF ("fitting oscillations and one over f") algorithm, and ictal epileptogenicity index (EI) was calculated. Correlation analysis, along with linear statistical model and restricted cubic splines (RCS), were employed to examine the relationships between disease duration, hippocampal volumetry, and electrophysiological metrics, focusing on anterior versus posterior hippocampus. Hippocampal volume showed a negative correlation with disease duration in all subfields (head: r = -.185, p = .021; body: r = -.237, p = .003; tail: r = -.253, p = .001). RCS analysis indicated a nonlinear association, where the slope linking disease duration to volume loss appeared steeper (suggestive of accelerated atrophy) beyond approximately 15 years (p < .001). Electrophysiologically, the aperiodic exponent decreased significantly in both anterior (r = -.271, p = .012) and posterior hippocampus (r = -.323, p = .009). A significant positive correlation was found between disease duration and the EI specifically in the posterior hippocampus (r = .550, p < .001), and the group with high EI (≥.3) had a significantly longer disease duration compared to the low EI group (16.0 ± 8.0 vs. 11.3 ± 7.5 years, p = .015). mTLE-HS is characterized by a dual pattern of association with disease duration: a nonlinear (potentially accelerating) association with structural atrophy beyond ~15 years and an association between longer duration and higher epileptogenicity in posterior hippocampal regions. This spatiotemporal pattern provides a mechanistic basis for considering individualized extension of surgical resection in chronic cases, a strategy requiring prospective evaluation.

Hippocampal sclerosis is a frequent finding in pediatric epilepsy surgery and has traditionally been regarded as an acquired lesion. It commonly co-occurs with focal cortical dysplasia (FCD IIIa), yet whether hippocampal injury is secondary to seizures or reflects a shared underlying etiology remains unresolved. Here we identified somatic variants activating the RAS-MAPK pathway in 40% of patients with hippocampal sclerosis, but in none with non-sclerotic hippocampus. Gain-of-function variants in PTPN11 were the most common finding, with mutations present in both cortex and hippocampus and enriched in hippocampal neurons, consistent with a shared developmental origin. In mice, Ptpn11 D61Y mutants developed profound hippocampal degeneration and gliosis following subthreshold kainic acid exposure, whereas wild-type controls were unaffected. p38-dependent stress pathways were upregulated in patients and mice, suggesting a mechanism through which ERK-p38 crosstalk lowers the threshold for seizure-induced injury. These results provide a genetic explanation for FCD IIIa, elucidate the role of somatic mutations within the RAS-MAPK pathway in driving hippocampal sclerosis, and provide a target for pathway-specific interventions for intractable seizures.

Although intermediate/high Alzheimer's Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to examine health, lifestyle, and neuropathologic factors that distinguish older adults with dementia vs. normal cognition in the presence of intermediate/high ADNC. Participants were from The 90 + Study, a longitudinal study of aging in southern California. This cross-sectional analysis included participants with an intermediate/high ADNC on neuropathologic exam and normal cognition or dementia diagnosis on case conference. We analyzed 11 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent, and the total number of neuropathologies. To examine the association of health and lifestyle factors and neuropathologic changes (predictors) with cognitive diagnosis at consensus case conference, dementia vs. normal cognition, (outcome), we used logistic regression adjusted for demographics. Among 235 participants (mean age at death = 98years, 70% women), 33% maintained normal cognition. Participants with heart disease (OR = 0.45; 95% CI = 0.25, 0.81) and hypertension (OR = 0.53; 95% CI = 0.29, 0.95) had lower likelihood of dementia. In contrast, participants with a history of transient ischemic attacks (OR = 3.00; 95% CI = 1.46, 6.18), Lewy Body Disease (OR = 2.73; 95% CI = 1.14, 6.58), hippocampal sclerosis (OR = 2.70; 95% CI = 1.06, 6.86), Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic change (OR = 2.80; 95% CI = 1.53, 5.12), and a high number of non-ADNCs (OR = 4.46; 95% CI = 2.01, 9.92) had higher likelihood of dementia. Arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, and microvascular lesions were not associated with dementia. In this study, the presence of neurodegenerative neuropathologic changes other than ADNC and the absence of hypertension distinguish oldest old individuals with dementia from those with normal cognition. Understanding mechanisms underlying normal cognition in those with ADNC may provide important clues to prevention and resilience to the effects of AD neuropathology.