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The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on patients with one or more electrode contacts in the piriform cortex. Primary objectives included determining piriform cortex involvement within the electrophysiologically defined epileptogenic network and assessing the effects of electrical stimulation. Twenty-two patients were included in the study. Notably, only one patient exhibited piriform cortex involvement at seizure onset, associated with an olfactory aura. Two patients showed early piriform cortex involvement, while others displayed late or no involvement. Electrical stimulation of the piriform cortex induced after-discharges in three patients and replicated a habitual seizure in one. These findings present a contrast to surgical outcome studies, suggesting that the piriform cortex may not typically play a significant role in the epileptogenic network among patients with non-lesional temporal lobe epilepsy.

Objective Methods Results Interpretation Hippocampal sclerosis (HS), the most common pathology associated with temporal lobe epilepsy (TLE), is not always visible on magnetic resonance imaging (MRI), causing surgical delays and reduced postsurgical seizure‐freedom. We developed an open‐source software to characterize and localize HS to aid the presurgical evaluation of children and adults with suspected TLE.We included a multicenter cohort of 365 participants (154 HS; 90 disease controls; 121 healthy controls). HippUnfold was used to extract morphological surface‐based features and volumes of the hippocampus from T1‐weighted MRI scans. We characterized pathological hippocampi in patients by comparing them to normative growth charts and analyzing within‐subject feature asymmetries. Feature asymmetry scores were used to train a logistic regression classifier to detect and lateralize HS. The classifier was validated on an independent multicenter cohort of 275 patients with HS and 161 healthy and disease controls.HS was characterized by decreased volume, thickness, and gyrification alongside increased mean and intrinsic curvature. The classifier detected 90.1% of unilateral HS patients and lateralized lesions in 97.4%. In patients with MRI‐negative histopathologically‐confirmed HS, the classifier detected 79.2% (19/24) and lateralized 91.7% (22/24). The model achieved similar performances on the independent cohort, demonstrating its ability to generalize to new data. Individual patient reports contextualize a patient's hippocampal features in relation to normative growth trajectories, visualise feature asymmetries, and report classifier predictions.Automated and Interpretable Detection of Hippocampal Sclerosis (AID‐HS) is an open‐source pipeline for detecting and lateralizing HS and outputting clinically‐relevant reports. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)‐AS‐1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.(R)‐AS‐1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)‐AS‐1 on glutamate uptake was assessed in COS‐7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)‐AS‐1 on GLT‐1 expression in mice.(R)‐AS‐1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock‐ and 6 Hz‐induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine‐resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)‐AS‐1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)‐AS‐1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT‐1 expression in vivo was observed after repeated treatment.Collectively, our results show that (R)‐AS‐1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy (mTLE) is a debilitating disease characterized by recurrent seizures originating from temporal lobe structures such as the hippocampus. The pathogenic mechanisms underlying mTLE are incompletely understood but include changes in the expression of non-coding RNAs in affected brain regions. Previous work indicates that some of these changes may be selective to specific sub-cellular compartments, but the full extent of these changes and how these sub-cellular compartments themselves are affected remains largely unknown. Here, we performed small RNA sequencing (RNA-seq) of sub-cellular fractions of hippocampal tissue from mTLE patients and controls to determine nuclear and cytoplasmic expression levels of microRNAs (miRNAs). This showed differential expression of miRNAs and isomiRs, several of which displayed enriched nuclear expression in mTLE. Subsequent analysis of miR-92b, the most strongly deregulated miRNA in the nucleus, showed accumulation of this miRNA in the nucleolus in mTLE and association with snoRNAs. This prompted us to further study the nucleolus in human mTLE which uncovered several defects, such as altered nucleolar size or shape, mis-localization of nucleolar proteins, and deregulation of snoRNAs, indicative of nucleolar stress. In a rat model of epilepsy, nucleolar phenotypes were detected in the latency period before the onset of spontaneous seizures, suggesting that nucleolar changes may contribute to the development of seizures and mTLE. Overall, these data for the first time implicate nucleolar defects in the pathogenesis of mTLE and provide a valuable framework for further defining the functional consequences of altered sub-cellular RNA profiles in this disease. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Anterior temporal lobe resection (ATLR) is an effective treatment for drug‐resistant temporal lobe epilepsy (TLE), although language deficits may occur after both left and right ATLR. Functional reorganization of the language network has been observed in the ipsilateral and contralateral hemispheres within 12 months after ATLR, but little is known of longer‐term plasticity effects. Our aim was to examine the plasticity of language functions up to a decade after ATLR, in relation to cognitive profiles.We examined 24 TLE patients (12 left [LTLE]) and 10 controls across four time points: pre‐surgery, 4 months, 12 months, and ~9 years post‐ATLR. Participants underwent standard neuropsychological assessments (naming, phonemic, and categorical fluency tests) and a verbal fluency functional magnetic resonance imaging (fMRI) task. Using a flexible factorial design, we analyzed longitudinal fMRI activations from 12 months to ~9 years post‐ATLR, relative to controls, with separate analyses for people with hippocampal sclerosis (HS). Change in cognitive profiles was correlated with the long‐term change in fMRI activations to determine the “efficiency” of reorganized networks.LTLE patients had increased long‐term engagement of the left extra‐temporal and contralateral temporal regions, with better language performance linked to bilateral activation. Those with HS exhibited more widespread bilateral activations. RTLE patients showed plasticity in the left extra‐temporal regions, with better language outcomes associated with these areas. Both groups of patients achieved cognitive stability over 9 years, with more than 50% of LTLE patients improving. Older age, longer epilepsy duration, and lower pre‐operative cognitive reserve negatively affected long‐term language performance.Neuroplasticity continues for up to ~9 years post‐epilepsy surgery in LTLE and RTLE, with effective language recovery linked to bilateral engagement of temporal and extra‐temporal regions. This adaptive reorganization is associated with improved cognitive outcomes, challenging the traditional view of localized surgery effects. These findings emphasize the need for early intervention, tailored pre‐operative counseling, and the potential for continued cognitive gains with extended post‐ATLR rehabilitation. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance This study was undertaken to analyze the histology underlying increased T2 signal intensity (iT2SI) in anterior temporal lobe white matter (aTLWM) epilepsy due to hippocampal sclerosis (TLE/HS).Twenty‐three patients were included: 16 with increased T2 signal in the aTLWM and seven with HS only. Magnetic resonance imaging (MRI) findings were consistent across two neuroradiologists (kappa = .89, p < .001). Quantification of neuronal cells, astrocytes, oligodendrocytes, and vacuolization in the white matter of temporal lobe specimens was performed by immunohistochemistry (neuronal nuclear antigen, glial fibrillary acidic protein, oligodendrocyte transcription factor, and basic myelin protein, respectively). Surgical specimens from TLE/HS patients with and without iT2SI in the aTLWM were compared. Samples of aTLWM were divided into three groups, according to MRI features: G1 = samples of iT2SI, G2 = samples with normal T2 signal intensity from patients without white matter imaging abnormalities, and G3 = samples with normal T2 signal intensity adjacent to areas with iT2SI.Patients with increased T2 signal had a significantly younger age at epilepsy onset (p < .035). Histological analysis revealed a higher percentage of vacuolar area in these patients (p < .004) along with a lower number of ectopic neurons (p = .042). No significant differences were found in astrocyte or oligodendrocyte counts among groups.A higher proportion of vacuoles in regions with iT2SI may be the histopathologic substrate of this signal alteration in the white matter of the temporal lobe in patients with TLE/HS. This method of quantifying vacuoles using digital image analysis proved reliable and cost‐effective. [ABSTRACT FROM AUTHOR]

Background Objectives Animals Methods Results Conclusions and Clinical Importance Lesions causing refractory epilepsy, often associated with temporal lobe epilepsy (TLE), can be undetectable on standard magnetic resonance imaging (MRI) in dogs. Automated brain volumetry, widely used in human medicine, can now be applied in veterinary medicine because of the availability of brain atlases.This study aimed to develop an automatic volumetry method, translate the outcomes into the assessment of temporal lobe volumes in dogs with idiopathic epilepsy, and correlate the results with the electroencephalography (EEG) data of epileptiform discharges (EDs).Thirty‐one dogs of various breeds with dominant temporal lobe discharge.Retrospective, observational study. The MRI and EEG examination results of dogs referred for neurological diagnosis data between 2016 and 2021 were retrospectively analyzed. An automated volumetry method was developed, which allowed the evaluation of temporal lobe volumes of the dogs. The asymmetric ratio (AR) was then estimated, and the results were correlated with the EEG EDs.12/31 (38%; 95% CI: 21.8%‐57.8%) dogs had an asymmetric ratio >6%. Among them, reduction in temporal lobe volumes correlated with the side of the EEG EDs in 7 cases. There was no statistical correlation between temporal lobe volume changes and ED location.Preliminary volumetric analysis of the temporal lobes indicates the presence of volume differences between the lobes in some dogs with idiopathic epilepsy. Diagnosis of TLE in dogs based on MRI volumetry in correlation with EEG examination, especially for dogs with drug‐resistant epilepsy, can influence the development of new therapeutic options, such as surgery. [ABSTRACT FROM AUTHOR]

Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, whereas semantic memory houses context-independent knowledge. Behavioural and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions such as the hippocampus and distributed neocortices. Here, we explored declarative memory system reorganization in patients with unilateral temporal lobe epilepsy (TLE) as a human disease model to test the impact of variable degrees of MTL pathology on memory function. Our cohort included 31 patients with TLE and 60 age- and sex-matched healthy controls, and all participants underwent episodic and semantic retrieval tasks during a multimodal MRI session. The functional MRI tasks were closely matched in terms of stimuli and trial design. Capitalizing on non-linear connectome gradient-mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, in both the MTL and neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed a marked topographic reorganization of both neocortical and MTL systems during episodic memory states. Neocortical alterations were characterized by reduced functional differentiation in TLE across lateral temporal and midline parietal cortices in both hemispheres. In the MTL, in contrast, patients presented with a more marked functional differentiation of posterior and anterior hippocampal segments ipsilateral to the seizure focus and pathological core, indicating perturbed intrahippocampal connectivity. Semantic memory reorganization was also found in bilateral lateral temporal and ipsilateral angular regions, whereas hippocampal functional topographies were unaffected. Furthermore, leveraging MRI proxies of MTL pathology, we observed alterations in hippocampal microstructure and morphology that were associated with TLE-related functional reorganization during episodic memory. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioural deficits in episodic memory, but again not in semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, whereas episodic processes are supported by a network involving both the hippocampus and the neocortex. Alterations of such networks can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage, such as TLE. [ABSTRACT FROM AUTHOR]

Temporal Lobe Epilepsy (TLE) is a severe neurological condition characterized by recurrent seizures that often do not respond well to available anti-seizure medications. TLE has been associated with epileptogenesis, a process that starts during the latent period following a neurologic insult and is followed by chronic phase. Recent research has linked canonical Wnt signaling to the pathophysiology of epileptogenesis and TLE. Our previous study demonstrated differential regulation of canonical Wnt signaling during early and late stage post status epilepticus (SE) induction. Building on these findings, our current study utilized Wnt modulators: GSK-3β inhibitor 6-bromoindirubin-3'-oxime (6-Bio) and disheveled inhibitor niclosamide and investigated their impact on canonical Wnt signaling during the early (30 days) and later stages (60 days) following SE induction. We assessed several parameters, including seizure frequency, astrogliosis, synaptic density, and neuronal counts in hippocampal tissue. We used immunohistochemistry and Nissl staining to evaluate gliosis, synaptic density, and neuronal counts in micro-dissected hippocampi. Western blotting was used to examine the expression of proteins involved in canonical Wnt/β-catenin signaling, and real-time PCR was conducted to analyze their relative mRNA expression. Wnt modulators, 6-Bio and Niclosamide were found to reduce seizure frequency and various other parameters including behavioral parameters, hippocampal morphology, astrogliosis and synaptic density at different stages of TLE. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE). Methods: This study retrospectively included 38 patients with unilateral TLE and 26 age- and gender-matched healthy controls (HCs). The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), and cognitive assessment were obtained for each participant. Neuropsychological test batteries included Montreal Cognitive Assessment (MoCA), Minimum Mental State Examination, Arithmetic Test (AT), Digit Symbol Substitution Test (DSST), Digit Span Test (DST), Boston Naming Test, Block design, Phonological Fluency Test (PFT), and Semantic Verbal Fluency (SVF). Results: Compared to HCs, TLE patients had lower scores of MoCA, AT, DSST, DST, Block design, PFT and SVF (all p < 0.05) and lower values of mean DTI-ALPS index (1.491 ± 0.142 vs. 1.642 ± 0.123, p < 0.001). Significantly lower DTI-ALPS index values were observed in the ipsilateral hemisphere than in the contralateral hemisphere (1.466 ± 0.129 vs. 1.517 ± 0.175, p = 0.013) for patients with unilateral TLE. Correlation analyses found that SVF performance was significantly or borderline significantly associated with glymphatic function (FDR-corrected p < 0.05 for all DTI-ALPS index and FDR-corrected p = 0.057 for CPV) in TLE patients. Linear regression analyses showed that increased CPV and decreased DTI-ALPS index were independent risk factors for semantic fluency impairment (all p < 0.05). Furthermore, mediation analyses found the mediator role of the mean DTI-ALPS index in the relationship between choroid plexus enlargement and semantic fluency impairment (indirect effect: β = -0.182, 95%CI = -0.486 to -0.037). Conclusion: These findings reveal the important role of the DTI-ALPS index and CPV in SVF performance in unilateral TLE. Decreased DTI-ALPS index and increased CPV are the independent risk factors for semantic fluency impairment. The DTI-ALPS index may fully mediate the relationship between CP enlargement and SVF performance. These insights provide a radiological foundation for further investigations into the mechanism of the glymphatic system in TLE pathophysiology. [ABSTRACT FROM AUTHOR]

Background: P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB. Methods: Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2). Results: DRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%). Conclusions: [11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases. Trial registration: EudraCT 2019-003137-42. Registered 28 February 2020. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy （TLE） is a common type of epilepsy. It may lead to cognitive impairment when it becomes recurrent. However, how it happens remains unclear. Recently, noninvasive resting-state functional magnetic resonance imaging （rs-fMRI） has been used comprehensively in the clinical diagnosis of temporal lobe epilepsy-associated cognitive impairment for its high temporal and spatial resolution. To better understand the effectiveness of rs-fMRI in the diagnosis, his paper reviews the relevant literature, comprehensively analyzing the epileptogenic foci localization and neural network alterations displayed by rs-fMRI and exploring the insight to the mechanism of temporal lobe epilepsy-associated cognitive impairment. Moreover, the paper has discussed the rs-fMRI's potential in predicting surgical outcomes and machine learning applications. This review is hoped to be conducive to improving treatment outcomes and providing novel approaches for more precise and intelligent interventions in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: People with epilepsy (PWE) have been hypothesized to have higher prevalence of personality disorders and cognitive disorders. The objective of this study was to investigate the controversial notion of “epileptic personality,” a series of supposedly specific personality traits of people with epilepsy (PWE). Methods: For this purpose, 29 individuals with Mesial Temporal lobe Epilepsy (MTLE) and 23 with Juvenile myoclonic epilepsy (JME) as confirmed by electroencephalography (EEG), MRI scans and clinical examination, underwent a thorough neuropsychological and personality assessment. The resulting neuropsychological profiles were statistically analyzed considering possible personality disorders, character traits, cognitive and linguistic deviations from 20 healthy controls (HC). Results: Our findings suggest accumulative cognitive and linguistic deficits in individuals with epilepsy compared to controls. It is possible that these might be misinterpreted as personality disorders. Specifically, personality traits (p  =  0.049) and verbal fluency (p  =  0.013), were significantly different between PWEs and controls. Also, the type of epilepsy and lateralization seem to affect executive function (p  =  0.049) and pragmatology scores (p  <  0.001), exhibiting differences in subgroup analysis. Discussion: Different theories are considered as plausible pathophysiological explanations for the aforementioned differences. This research might serve as a basis to further investigate the cognitive aspects of epilepsy and possible pharmacological interventions, which are currently lacking. [ABSTRACT FROM AUTHOR]

Central and systemic inflammation play pivotal roles in epileptogenesis and proepileptogenesis in temporal lobe epilepsy (TLE). The interplay between peripheral CD4+ T cells and central microglia orchestrates the "systemic‐central" immune response in TLE. However, the precise molecular mechanisms linking central and systemic inflammation in TLE remain unknown. This preliminary findings revealed an imbalance in Th1/Th2 subsets in the periphery，accompanied by related cytokines release in TLE patients. they proposed that this peripheral Th1/Th2 imbalance may influence central inflammation by mediating microglial state dynamics within epileptic foci and distant brain regions. In Li‐pilocarpine‐induced TLE rats, a peripheral Th1/Th2 imbalance and observed corresponding central and systemic responses is confirmed. Notably, CD4+ T cells infiltrated through the compromised blood‐brain barrierand are spatially close to microglia around epileptic foci. Intravenous depletion and reinfusion of CD4+ T cells modulated microglia state dynamics and altered neuroinflammatory cytokines secretion. Moreover, mRNA sequencing of the human hippocampus identified Notch1 as a key regulator of Th1/Th2 differentiation, CD4+ T cell recruitment to brain infiltration sites, and the regulation of microglial responses, seizure frequency, and cognition. This study underscores the significance of Th1/Th2 imbalance in modulating the "systemic‐central" response in TLE, highlighting Notch1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Epilepsy, a common neurological disorder, has been increasingly associated with neuroinflammation, especially microglia activation. To gain insights into the research trends and patterns in this intersection, we conducted a bibliometric analysis of studies published between 2005 and 2024. Using the Web of Science Core Collection, we identified 1,229 relevant articles and reviews, focusing on the relationship between epilepsy and microglia. Methods: We employed the Bibliometrix R package and VOSviewer to analyze the data. Our search strategy combined epilepsy-related terms with microglia and microglial cell keywords. The analysis encompassed publication trends, country and institutional contributions, journal sources, authors, keywords, and thematic evolution. Results: The number of publications has steadily increased, particularly after 2019, indicating growing research interest. The United States, China, and Germany emerged as the most productive countries, with extensive collaboration between China and the United States. Epilepsia and Journal of Neuroinflammation were the most influential journals. Aronica E, Vezzani A, and Engel T were the most prolific authors. Thematic analysis revealed clusters focused on temporal lobe epilepsy, epilepsy-related disorders, and microglia activation. Over the past several years, research has shifted from fundamental brain function studies to in-vivo investigations of specific molecular mechanisms. The CSTB (-) mouse model and NF-κB signaling pathway both merit further in-depth investigation. Conclusion: In conclusion, this bibliometric study reveals a surge in epilepsymicroglia research, led by key countries, journals, and researchers. Temporal lobe epilepsy, epilepsy-related disorders, and microglia activation are focal themes. Future directions include exploring microglia activation mechanisms, utilizing animal models, and interdisciplinary approaches. [ABSTRACT FROM AUTHOR]

The article discusses a case report of a 36-year-old male with drug-resistant post-traumatic epilepsy who achieved seizure freedom without medication after stereoelectroencephalography (sEEG) implantation. The patient underwent sEEG monitoring, which captured a single event without sEEG correlate, prompting further investigation. Despite discontinuing all seizure medications, the patient remained seizure-free for over 3.5 years. The article highlights the potential benefits and risks of sEEG procedures in drug-resistant epilepsy cases, emphasizing the need for further research into potential tissue injury caused by depth electrode insertion. [Extracted from the article]

Objective Methods Results Significance Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear.Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic Kcna1‐null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE‐treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome.We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of Ligilactobacillus and Muribaculaceae, whereas SC injection decreased Bacteroides, Lactobacillus, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in Ascomycota and Saccharomyces. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of Lactobacillus (Spearman rho = .64, p = .03) and tended toward a negative correlation with Saccharomyces (Spearman rho = −.57, p = .057).Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Pathological amyloid‐β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1‐42 and p181‐tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug‐resistant temporal lobe epilepsy (TLE).In this cross‐sectional study, we enrolled individuals with drug‐resistant TLE who were 25–55 years old. Each participant underwent 18F‐flutemetamol PET, determination of CSF Aβ1‐42, p181‐tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET.Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4–24) years. Twenty‐six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z‐score = .90, 95% confidence interval [CI] = .60–1.20; contralateral: SUVR z‐score = .92, 95% CI = .57–1.27; p < .001), which was higher when compared to SUVR z‐scores in all the remaining regions (p < .001) and in the ipsilateral anterior cingulate (SUVR z‐score = .27, 95% CI = .04–.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1‐42 levels, and two (7%) had elevated p181‐tau levels in CSF. Higher p181‐tau levels correlated with poorer verbal fluency (R = −.427, p = .044).Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug‐resistant TLE. Additionally, abnormal CSF Aβ1‐42 levels were observed in a significant proportion of patients, and p181‐tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) has identified epilepsy as a significant public health issue that requires urgent attention. Epilepsy is a neurological disorder that affects millions of people worldwide and can lead to social, economic, and health challenges. The WHO emphasizes the need for improved awareness, diagnosis, treatment, and support for individuals with epilepsy. Neurosurgical interventions for epilepsy include removing or altering brain regions that generate seizures or implanting devices to regulate abnormal electrical activity. These interventions have advanced with technologies such as robotic assistance and neuromodulation devices. Neurosurgical treatment can significantly improve the quality of life for patients with drug-resistant epilepsy, even leading to complete seizure freedom. However, there are risks and challenges associated with these interventions, and careful patient selection and support are crucial. The future of epilepsy management may involve advances in neurotechnology, a focus on comorbidities, and continued research and clinical trials. The goal is to empower individuals with epilepsy to lead meaningful lives through personalized medicine, innovative treatments, and compassionate care. [Extracted from the article]

Gamma oscillation regularity (GOR) indicates the synchronization of inhibitory interneurons, while the reactivity of cortico-cortical evoked potentials (CCEPs) is supposed to reflect local cortical excitability. Under the assumption that the early response of CCEP near the stimulation site also indicates excitatory activity primarily mediated by pyramidal cells, we aimed to visualize the cortical inhibitory and excitatory activities using GOR and CCEP in combination and to use them to predict the epileptogenic zone (EZ) in mesial temporal lobe epilepsy (MTLE). In five patients who underwent intracranial electrode implantation, GOR and CCEP reactivity in the vicinity of the stimulation site was quantified. The interictal GOR was calculated using multiscale entropy (MSE), the decrease of which was related to the enhanced GOR. These parameters were compared on an electrode-and-electrode basis, and spatially visualized on the brain surface. As a result, elevated GOR and CCEP reactivities, indicative of enhanced inhibitory and excitatory activities, were observed in the epileptogenic regions. Elevated CCEP reactivity was found to be localized to a restricted area centered on the seizure onset region, whereas GOR elevation was observed in a broader region surrounding it. Although these parameters independently predicted the EZ with high specificity, we combined the two to introduce a novel parameter, the excitatory and inhibitory (EI) index. The EI index predicted EZ with increased specificity compared with GOR or CCEP reactivity alone. Our results demonstrate that GOR and CCEP reactivity provided a quantitative visualization of the distribution of cortical inhibitory and excitatory activities and highlighted the relationship between the two parameters. The combination of GOR and CCEP reactivities are expected to serve as biomarkers for localizing the epileptogenic zone in MTLE from interictal intracranial electroencephalograms. [ABSTRACT FROM AUTHOR]

Background: Visual perception of face images or face pareidolia can be evaluated with event-related potentials (ERP) for healthy subjects and patients with neurological conditions. In this study, we aimed to analyse event-related potential components such as P100, N100, N170, and vertex-positive potential (VPP) in response to face pareidolia perception in temporal lobe epilepsy (TLE) patients. Methods: ERPs were recorded during the pareidolia test. Waveforms were analzyed and current source density (CSD) maps were generated. Results: CSD profiles were shown to be interpretable when face and face pareidolia conditions. N100, P100, and N170 components showed larger amplitudes and longer latency in epilepsy patients in response to face pareidolia stimuli compared to real face images. However, the N170 component latency did not differ significantly between epilepsy patients and healthy participants, while the larger amplitude and longer latency of N100 and P100 responses were evoked in healthy patients. Conclusions: Our results indicate a difference in the neural mechanisms of processing real face information and pareidolia face-like information in TLE patients. [ABSTRACT FROM AUTHOR]

Background: Mesial temporal lobe epilepsy (MTLE) epileptiform discharges have been reported to arise from the hippocampus or the extrahippocampal medial temporal cortex, such as the amygdala, and then propagate to the temporal lobe cortex. The surgical ablation of which of these structures would result in a better postoperative outcome is debatable. Objective: To assess the possible factors that might have influenced the postoperative outcome of a group of drug-resistant mesial MTLE patients who underwent stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC). Design: Single-center, retrospective. Methods: The present study utilized a pre- and postoperative gray matter voxel-by-voxel ablation mapping comparison approach, along with a white matter mapping of longitudinal changes in the native space technique, to evaluate the association between the post-SEEG implantation signal recordings (obtained from clinically relevant electrode contacts used during RFTC) and the post-RFTC ablation volume of the different selected regions of interest (ROIs). Results: The study included 22 patients (12 men and 10 women, mean age 28.86 ± 14.04 years). Sixteen patients (72.72%) were seizure-free (SF), and six patients (27.27%) were non-SF. Five patients (22.72%) experienced mild side effects following RFTC. The post-RFTC follow-up period varied from 12 to 48 months, with an average of 24.17 ± 9.86 months. The SF group was associated with a higher number of implanted electrode contacts in the amygdala that were used during RFTC, a larger preoperative volume of the amygdala; a larger ablation volume of both the amygdala and rhinal cortex. The ablation volume of the white matter was statistically similar between both groups. Conclusion: This study provides valuable insights into the significance of the amygdala and rhinal cortex as ROIs in the preoperative evaluation of patients with MTLE. Future implantation scheme plans should consider evaluating the preoperative volume of these ROIs. Additionally, increasing the number of electrode contacts implanted within these regions might be beneficial to capture more clinically relevant signals and enhance their ablation volume. [ABSTRACT FROM AUTHOR]

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE. [ABSTRACT FROM AUTHOR]

Background/Objectives: Although the involvement of progressive brain alterations in epilepsy was recently suggested, individual patients' trajectories of white matter (WM) disruption are not known. Methods: We investigated the disease progression patterns of WM damage and its associations with clinical metrics. We examined the cross-sectional diffusion tensor imaging (DTI) data of 155 patients with unilateral temporal lobe epilepsy (TLE) and 270 age/gender-matched healthy controls, and we then calculated the average fractional anisotropy (FA) values within 20 WM tracts of the whole brain. We used the Subtype and Stage Inference (SuStaIn) program to detect the progression trajectory of FA changes and investigated its association with clinical parameters including onset age, disease duration, drug-responsiveness, and the number of anti-seizure medications (ASMs). Results: The SuStaIn algorithm identified a single subtype model in which the initial damage occurs in the ipsilateral uncinate fasciculus (UF), followed by damage in the forceps, superior longitudinal fasciculus (SLF), and anterior thalamic radiation (ATR). This pattern was replicated when analyzing TLE with hippocampal sclerosis (n = 50) and TLE with no lesions (n = 105) separately. Further-progressed stages were associated with longer disease duration (p < 0.001) and a greater number of ASMs (p = 0.001). Conclusions: the disease progression model based on WM tracts may be useful as a novel individual-level biomarker. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti‐epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined. Methods: In this study, tropisetron was intraperitoneally injected into pilocarpine‐induced epileptic rats for 3 weeks. Alpha‐bungarotoxin (α‐bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ‐aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse‐associated protein (F‐actin, cofilin‐1) were quantified. Results: The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m6A modification of cofilin‐1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α‐bgt. Conclusion: In summary, these findings indicate that tropisetron exhibits an anti‐epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti‐epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE. [ABSTRACT FROM AUTHOR]

Objective: The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood–brain barrier. We investigated blood–brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1‐relaxometry. Methods: Gadolinium‐based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1‐relaxometry. Postictal and interictal images were co‐registered, and subtraction maps were created as biomarkers for peri‐ictal (∆qT1interictal‐postictal) and interictal (∆qT1noncontrast‐interictal) blood–brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex. Results: In temporal lobe epilepsy (n = 14), ∆qT1noncontrast‐interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1noncontrast‐interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1noncontrast‐interictal (ß = 0.001, p < 0.001) in all regions, while the association was strongest in the piriform cortex. Impaired verbal memory was associated with ∆qT1noncontrast‐interictal only in the piriform cortex (p = 0.04). ∆qT1interictal‐postictal did not show differences in any region. Interpretation: Interictal blood–brain barrier dysfunction occurs in the piriform cortex in temporal lobe epilepsy. This dysfunction is linked to longer disease duration and worse cognitive deficits, emphasizing the central role of the piriform cortex in the epileptogenic network of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG) plays a critical role in hippocampal circuitry, providing a "gate‐like" function to the downstream cornu ammonis (CA) sectors. Despite this critical role, pathologies in DG are less commonly described than those in the CA sectors in the diagnosis of mesial temporal lobe epilepsy (mTLE). To elucidate the role of the DG in mTLE, we analysed hippocampal sclerosis (HS), no‐HS, non‐TLE epilepsy control, and non‐epilepsy control cohorts using morphometry and gene expression profiling techniques. Morphometry techniques analysed DG cell spacing, nucleus size, and nucleus circularity. Our data show distinct DG morphometry and RNA expression profiles between HS and No‐HS. Dentate granule cells are more dispersed in patients with HS, and the DG shows an elevated expression of the complement system, apoptosis, and extracellular matrix remodelling–related RNA. We also observe an overall decrease in neurogenesis‐related RNA in HS DG. Interestingly, regardless of the pathological diagnosis, the DG morphometry correlates with post‐operative outcomes. Increased cell spacing is observed in the DG of mTLE cases that achieve seizure freedom post‐operatively. This study reveals the possible prognostic value of DG morphometry, as well as supporting the notion that HS and no‐HS TLE may be distinct disease entities with differing contributing mechanisms. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy in children is often secondary to various low-grade glial and glioneural tumors and rarely secondary to mesial temporal sclerosis. Despite the benign nature, tumor-associated TLE in children often becomes refractory over time. Abundant literature has shown the significant advantage of tumor resection compared to conservative treatment, in achieving seizure control, as well as the rates of antiseizure medication reduction. Despite these advantages, several considerations are to be related to when considering surgery. These include the impact of surgery on linguistic and neurocognitive development, especially at the younger age; the extent of resection and the role of ECoG; and the need for mesial temporal resection. Over recent years, traditional resection has been complemented with newer treatment options such as laser ablation and biological treatment, and these should be taken into account depending on the exact location and the ability to perform extensive resection in eloquent regions. In this overview manuscript, we discuss the various considerations treating tumor-associated pediatric temporal epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Low-grade glioma is the most common brain tumor among children and adolescents. When these tumors arise in the temporal lobe, patients frequently present with seizures that are poorly controlled with antiepileptic drugs. Here we summarize the clinical features, pathophysiology, preoperative evaluation, surgical treatment, and outcomes of pediatric patients with low-grade gliomas in the temporal lobe. Methods: We reviewed the literature on pediatric low-grade gliomas in the temporal lobe, focusing on cohort studies and systematic reviews that described surgical treatment strategies and reported both oncologic and epilepsy outcomes. Results: The differential diagnoses of pediatric low-grade gliomas in the temporal lobe include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, angiocentric glioma, and polymorphous low-grade neuroepithelial tumor of the young. There is no consensus on the optimal surgical approach for these tumors: lesionectomy alone, or extended lesionectomy with anterior temporal lobectomy, with or without removal of mesial temporal structures. Gross total resection and shorter preoperative duration of epilepsy are strongly associated with favorable seizure outcomes, defined as Engel Class I or Class II, approaching 90% in most series. The risk of surgical complications ranges from 4 to 17%, outweighing the lifetime risks of medically refractory epilepsy. Conclusion: Pediatric patients with temporal low-grade glioma and tumor-related epilepsy are best managed by a multidisciplinary epilepsy surgery team. Early and appropriate surgery leads to prolonged survival and a greater likelihood of seizure freedom, improving their overall quality of life. [ABSTRACT FROM AUTHOR]

The hippocampus is considered essential for several forms of declarative memory, including spatial and social memory. Despite the extensive research of the classic subfields of the hippocampus, the fasciola cinerea (FC)—a medially located structure within the hippocampal formation—has remained largely unexplored. In the present study, we performed a morpho‐functional characterization of principal neurons in the mouse FC. Using in vivo juxtacellular recording of single neurons, we found that FC neurons are distinct from neighboring CA1 pyramidal cells, both morphologically and electrophysiologically. Specifically, FC neurons displayed non‐pyramidal morphology and granule cell‐like apical dendrites. Compared to neighboring CA1 pyramidal neurons, FC neurons exhibited more regular in vivo firing patterns and a lower tendency to fire spikes at short interspike intervals. Furthermore, tracing experiments revealed that the FC receives inputs from the lateral but not the medial entorhinal cortex and CA3, and it provides a major intra‐hippocampal projection to the septal CA2 and sparser inputs to the distal CA1. Overall, our results indicate that the FC is a morphologically and electrophysiologically distinct subfield of the hippocampal formation; given the established role of CA2 in social memory and seizure initiation, the unique efferent intra‐hippocampal connectivity of the FC points to possible roles in social cognition and temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) frequently involves an intricate, extensive epileptic frontal‐temporal network. This study aimed to investigate the interactions between temporal and frontal regions and the dynamic patterns of the frontal‐temporal network in TLE patients with different disease durations. The magnetoencephalography data of 36 postoperative seizure‐free patients with long‐term follow‐up of at least 1 year, and 21 age‐ and sex‐matched healthy subjects were included in this study. Patients were initially divided into LONG‐TERM (n = 18, DURATION >10 years) and SHORT‐TERM (n = 18, DURATION ≤10 years) groups based on 10‐year disease duration. For reliability, supplementary analyses were conducted with alternative cutoffs, creating three groups: 0 < DURATION ≤7 years (n = 11), 7 < DURATION ≤14 years (n = 11), and DURATION >14 years (n = 14). This study examined the intraregional phase‐amplitude coupling (PAC) between theta phase and alpha amplitude across the whole brain. The interregional directed phase transfer entropy (dPTE) between frontal and temporal regions in the alpha and theta bands, and the interregional cross‐frequency directionality (CFD) between temporal and frontal regions from the theta phase to the alpha amplitude were further computed and compared among groups. Partial correlation analysis was conducted to investigate correlations between intraregional PAC, interregional dPTE connectivity, interregional CFD, and disease duration. Whole‐brain intraregional PAC analyses revealed enhanced theta phase‐alpha amplitude coupling within the ipsilateral temporal and frontal regions in TLE patients, and the ipsilateral temporal PAC was positively correlated with disease duration (r = 0.38, p <.05). Interregional dPTE analyses demonstrated a gradual increase in frontal‐to‐temporal connectivity within the alpha band, while the direction of theta‐band connectivity reversed from frontal‐to‐temporal to temporal‐to‐frontal as the disease duration increased. Interregional CFD analyses revealed that the inhibitory effect of frontal regions on temporal regions gradually increased with prolonged disease duration (r = −0.36, p <.05). This study clarified the intrinsic reciprocal connectivity between temporal and frontal regions with TLE duration. We propose a dynamically reorganized triple‐stage network that transitions from balanced networks to constrained networks and further develops into imbalanced networks as the disease duration increases. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS) is a surgically treatable epileptic syndrome. While the core of pre-surgical evaluations rely on video-EEG, recent studies question the necessity of recorded seizures denying a possible role of ictal EEG in surgical decision. This study aims to retrospectively assess the prognostic value of EEG ictal patterns in TLE-HS, in order to identify which patients need further investigations before offering surgery. Methods: We included TLE-HS patients who underwent surgery with at least one captured seizure during non-invasive pre-surgical video-EEG recordings. They were classified in "mesial" and "lateral/mixed", according to the ictal EEG patterns, defined by the frequency of the discharge (mesial ≥ 5 Hz, lateral < 5 Hz). Seizure outcome was assessed by Engel's Class. Statistical analyses were performed to evaluate associations between EEG patterns and post-surgical outcomes. Results: Sixty-nine exhibited a mesial pattern, forty- two displayed lateral/mixed patterns. Mesial pattern group had a significantly higher rate of postsurgical seizure freedom (82.7% vs. 28.6%). Gender, age of onset, age at surgery, duration of epilepsy, seizure frequency, and lateralization did not influence the outcome. Mesial pattern significantly correlated with favorable outcomes (p < 0.001), suggesting its potential predictive value. Conclusion: This retrospective study proposes ictal EEG patterns as possible predictors of postoperative prognosis in TLE-HS. A mesial pattern correlates with better outcomes, indicating a potentially more circumscribed epileptogenic zone. Patients with lateral/mixed patterns may benefit from additional investigations to delineate the epileptogenic zone. Further studies are warranted to validate and extend these findings. [ABSTRACT FROM AUTHOR]

Introduction: There remains a critical need for precise localization of the epileptogenic foci in individuals with drug-resistant epilepsy (DRE). 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging can reveal hypometabolic regions during the interval between seizures in patients with epilepsy. However, visual-based qualitative analysis is time-consuming and strongly influenced by physician experience. CortexID Suite is a quantitative analysis software that helps to evaluate PET imaging of the human brain. Therefore, we aimed to evaluate the efficacy of CortexID quantitative analysis in the localization of the epileptogenic zone in patients with temporal lobe epilepsy (TLE). Methods: A total of 102 patients with epilepsy who underwent 18F-FDG-PET examinations were included in this retrospective study. The PET visual analysis was interpreted by two nuclear medicine physicians, and the quantitative analysis was performed automatically using CortexID analysis software. The assumed epileptogenic zone was evaluated comprehensively by two skilled neurologists in the preoperative assessment of epilepsy. The accuracy of epileptogenic zone localization in PET visual analysis was compared with that in CortexID quantitative analysis. Results: The diagnostic threshold for the difference in the metabolic Z-score between the right and left sides of medial temporal lobe epilepsy (MTLE) was calculated as 0.87, and that for lateral temporal lobe epilepsy (LTLE) was 2.175. In patients with MTLE, the area under the curve (AUC) was 0.922 for PET visual analysis, 0.853 for CortexID quantitative analysis, and 0.971 for the combined diagnosis. In patients with LTLE, the AUC was 0.842 for PET visual analysis, 0.831 for CortexID quantitative analysis, and 0.897 for the combined diagnosis. These results indicate that the diagnostic efficacy of CortexID quantitative analysis is not inferior to PET visual analysis (p > 0.05), while combined analysis significantly increases diagnostic efficacy (p < 0.05). Among the 23 patients who underwent surgery, the sensitivity and specificity of PET visual analysis for localization were 95.4% and 66.7%, and the sensitivity and specificity of CortexID quantitative analysis were 100% and 50%. Conclusion: The diagnostic efficacy of CortexID quantitative analysis is comparable to PET visual analysis in the localization of the epileptogenic zone in patients with TLE. CortexID quantitative analysis combined with visual analysis can further improve the accuracy of epileptogenic zone localization. [ABSTRACT FROM AUTHOR]

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated. [ABSTRACT FROM AUTHOR]

Electroencephalography-based (EEG) microstate analysis is a promising and widely studied method in which spontaneous cerebral activity is segmented into sub second level quasi-stable states and analyzed. Currently it is being widely explored due to increasing evidence of the association of microstates with cognitive functioning and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). In our study using the four archetypal microstates (A, B, C and D), we investigated the changes in resting state EEG microstate dynamics in persons with temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) compared to healthy controls (HC). Machine learning was applied to study its feasibility in differentiating between different groups using microstate statistics. We found significant differences in all parameters related to Microstate D (fronto-parietal network) in TLE patients and Microstate B (visual processing) in IGE patients compared to HCs. Occurrence, duration and time coverage of Microstate B was highest in IGE when compared to the other groups. We also found significant deviations in transition probabilities for both epilepsy groups, particularly into Microstate C (salience network) in IGE. Classification accuracy into clinical groups was found to exceed 70% using microstate parameters which improved on incorporating neuropsychological test differences. To the best of our knowledge, the current study is the first to compare and validate the use of microstate features to discriminate between two disparate epilepsy syndromes (TLE, IGE) and HCs using machine learning suggesting that resting state EEG microstates can be used for endophenotyping and to study resting state dysfunction in epilepsy. [ABSTRACT FROM AUTHOR]

Transient global amnesia (TGA) is characterized by sudden and temporary memory impairment, while transient epileptic amnesia (TEA) represents amnestic attacks as the main manifestation of focal epilepsy with presumed temporal origin. We present a 48‐year‐old patient who experienced transient amnesia 10 weeks after right selective amygdalo‐hippocampectomy for right temporal lobe epilepsy. Despite TEA being a plausible explanation for amnesia in patients with temporal lobe epilepsy, no epileptiform discharges were found during the amnestic episode and key features indicative of TGA, including long duration, isolated occurrence, and dense anterograde amnesia of the episode, argued against a diagnosis of TEA in this case. Notably, the patient has remained seizure‐free (now 4,5 years) and stopped taking antiseizure medication 32 months after surgery. Although TGA clinical criteria formally exclude patients with recent active epilepsy, neurologists should be aware that TGA can occur after epilepsy surgery in the temporal lobe. Therefore, we consider it of high clinical relevance to establish a careful differential diagnosis between TGA and epileptic amnestic attacks after epilepsy surgery to avoid unnecessary reintroduction or continuation of antiseizure medication. Additionally, this case presents the first comparison of detailed neuropsychological test results before and after a presumed TGA episode, revealing a complete recovery of anterograde memory functions within 1 day. Plain Language Summary: A 48‐year‐old patient experienced an episode of transient amnesia 10 weeks after epilepsy surgery. Given the patient's history, an epileptic origin of the episode initially seemed likely. However, tests revealed no seizure activity during the episode and the characteristics matched a condition called transient global amnesia. This case highlights the importance of correctly diagnosing memory impairments after epilepsy surgery to prevent unnecessary treatment. [ABSTRACT FROM AUTHOR]

Background/Objectives: Glucagon-like peptide-1 receptor agonists such as liraglutide are known for their neuroprotective effects in neurodegenerative disorders, but their role in temporal lobe epilepsy (TLE) remains unclear. We aimed to investigate the effects of liraglutide on several biological processes, including inflammation, antioxidant defense mechanisms, mitochondrial dynamics, and function, as well as cognitive and behavioral changes in the TLE model. Methods: Low-dose, repeated intraperitoneal injections of lithium chloride–pilocarpine hydrochloride were used to induce status epilepticus (SE) in order to develop TLE in rats. Fifty-six male Sprague Dawley rats were subjected and allocated to the groups. The effects of liraglutide on inflammatory markers (NLRP3, Caspase-1, and IL-1β), antioxidant pathways (Nrf-2 and p-Nrf-2), and mitochondrial dynamics proteins (Pink1, Mfn2, and Drp1) were evaluated in hippocampal tissues via a Western blot. Mitochondrial function in peripheral blood mononuclear cells (PBMCs) was examined using flow cytometry. Cognitive-behavioral outcomes were assessed using the open-field, elevated plus maze, and Morris water maze tests. Results: Our results showed that liraglutide modulates NLRP3-mediated inflammation, reduces oxidative stress, and triggers antioxidative pathways through Nrf2 in SE-induced rats. Moreover, liraglutide treatment restored Pink1, Mfn2, and Drp1 levels in SE-induced rats. Liraglutide treatment also altered the mitochondrial function of PBMCs in both healthy and epileptic rats. This suggests that treatment can modulate mitochondrial dynamics and functions in the brain and periphery. Furthermore, in the behavioral aspect, liraglutide reversed the movement-enhancing effect of epilepsy. Conclusions: This research underscores the potential of GLP-1RAs as a possibly promising therapeutic strategy for TLE. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is typically resistant to pharmacological interventions; however, achieving seizure freedom is possible through surgery. Our objective was to focus on the pregnancy and seizure outcomes during pregnancy of women with TLE-HS, and aim to identify predictors of seizure control. Methods: The West China Registry of Pregnancy of Women with Epilepsy (WCPR_EPi) was a monocentric prospective cohort study of women with epilepsy (WWE). We screened women with TLE-HS in this database. Their clinical profile, anti-seizure medication (ASM) use, and pregnancy outcomes were extracted from the records of the registry (2010–2023). Results: Out of 2320 WWE followed up, 47 pregnancies in women with TLE-HS were identified and analyzed. Seizure exacerbation occurred in 40.4% of pregnancies, and seizure freedom was present in 34.0% of these during pregnancy. Factors associated with seizure exacerbation during pregnancy was ASM non-adherence (odds ratio [OR] =7.00, 95% confidence interval [CI] 1.43–34.07, P=0.016). The surgery group showed a significantly higher seizure freedom rate (OR = 6.87, 95% CI 1.02–46.23, P=0.016) and lower rate of induced labor (0.0% vs 26.5%, P=0.047) compared to the medically-treated group alone. Caesarean section was chosen in 77.1% of cases due to seizure concerns, with comparable in epilepsy-related (n=20) and obstetric causes (n=24). No major congenital malformations were reported. Conclusions: Surgical treatment before pregnancy appears to offer a higher chance of seizure freedom compared to medication alone. Most of women with TLE-HS can deliver healthy offspring regardless of suboptimal seizure control and unwarranted concerns. [ABSTRACT FROM AUTHOR]

Idiopathic epilepsy (IE), is a group of epileptic syndromes with no structural brain lesion, but with microstructural changes in neuronal networks leading to neuropsychological consequences. Therefore, the assessment of saccadic eye movements can provide insight into the integrity of cerebral networks as it involves large cortical and subcortical brain areas and circuitries. Describe saccadic eye movement abnormalities in patients with IE and correlate them with disease characteristics and antiseizure medication. Case–control study including IE patients followed in the Neurology Department of Razi University Hospital and healthy controls matched. Participants underwent a recording of saccadic eye movements. Pursuit, prosaccade, and anti-saccade tasks were performed. 115 patients and 98 matched healthy controls were included. The gender ratio (male to female) was 0.6. The mean age at onset was 16.3 ± 12 years. Diagnosed epileptic syndromes were juvenile myoclonic epilepsy (JME), epilepsy with generalized tonic-clonic seizures, childhood absence epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, and rolandic epilepsy. Saccadic eye movements were impaired in 52.2% of our patients and significantly more altered in those with JME (p = .021). Prolonged horizontal saccades latencies were the most frequent eye movement abnormalities (32.1%), followed by altered horizontal smooth pursuit (22.6%). A positive correlation was found between age at eye movements recording, age at onset, disease duration, global cognitive impairment, and saccadic eye movements. However, no definite relationship was identified. Saccadic eye movement illustrates extending anatomic alterations in IE including frontal and temporoparietal cortical areas and cortico-subcortical circuits. Eye movement recording is a useful and reproducible tool in the assessment of epileptic patients and provides a better understanding of neuronal mechanisms in epilepsy. [ABSTRACT FROM AUTHOR]

Background: During epilepsy surgery, it is equally important to record electrocorticography (ECoG) for detecting epileptogenic activity and guiding brain resection, and to evaluate neuromonitoring data, particularly motor evoked potentials (MEP), for avoidance of postoperative neurological complications. However, sevoflurane, which is commonly used during recording of ECoG, may attenuate the MEP response. It enforces anesthesiologists and neurosurgeons to select one anesthetic agent over another, facilitating either ECoG or MEP monitoring. Case presentation: In the presented case of a 20-year-old man, who underwent surgery for temporal lobe epilepsy, a novel technique of neuroanesthesia was introduced, integrating initial induction of the total intravenous anesthesia (TIVA) with propofol (effect-site concentration, 2.3–3.0 μg/ml), its subsequent switching to sevoflurane (end-tidal concentration, 2.5%) for ECoG recording, and further change back to TIVA for MEP monitoring during brain resection. Conclusions: Intraoperative switch of anesthetic agents according to specific intraoperative requirements may be useful for cases of brain surgery requiring both ECoG recordings and MEP monitoring. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease characterised by recurrent seizures with complex aetiology. Temporal lobe epilepsy, the most common form in adults, can be acquired following brain insults including trauma, stroke, infection or sustained status epilepticus. The mechanisms that give rise to the formation and maintenance of hyperexcitable networks following acquired insults remain unknown, yet an extensive body of literature points towards persistent gene and epigenomic dysregulation as a potential mediator of this dysfunction. While much is known about the function of specific classes of epigenetic regulators (writers and erasers) in epilepsy, much less is known about the enzymes, which read the epigenome and modulate gene expression accordingly. Here, we explore the potential role for the epigenetic reader bromodomain and extra‐terminal domain (BET) proteins in epilepsy. Using the intra‐amygdala kainic acid model of temporal lobe epilepsy, we initially identified widespread dysregulation of important epigenetic regulators including EZH2 and REST as well as altered BRD4 expression in chronically epileptic mice. BRD4 activity was also notably affected by epilepsy‐provoking insults as seen by elevated binding to and transcriptional regulation of the immediate early gene Fos. Despite influencing early aspects of epileptogenesis, blocking BET protein activity with JQ1 had no overt effects on epilepsy development in mice but did alter glial reactivity and influence gene expression patterns, promoting various neurotransmitter signalling mechanisms and inflammatory pathways in the hippocampus. Together, these results confirm that epigenetic reader activity is affected by epilepsy‐provoking brain insults and that BET activity may exert cell‐specific actions on inflammation in epilepsy. [ABSTRACT FROM AUTHOR]

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3β (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes. [ABSTRACT FROM AUTHOR]

The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR β/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium–pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis. [ABSTRACT FROM AUTHOR]

Mesial temporal sclerosis (MTS) stands out as a prevalent etiology of medically intractable temporal lobe epilepsy. Understanding the pathological alterations, clinical manifestations and risk factors of MTS is crucial for the recognition and suspicion of this condition. In this paper, we provide a comprehensive narrative review on the pathophysiology, clinical manifestations, and treatment options for MTS. By doing so, we aim to provide an up-to-date understanding of this condition. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder that affects millions of people worldwide, disrupting brain networks and causing recurrent seizures. In this regard, investigating the distinctive characteristics of brain connectivity is crucial to understanding the underlying neural processes of epilepsy. However, the various graph-theory frameworks and different estimation measures may yield significant variability among the results of different studies. On this premise, this study investigates the brain network topological variations between patients with temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) using both directed and undirected network connectivity methods as well as different graph-theory metrics. Our results reveal distinct topological differences in connectivity graphs between the two epilepsy groups, with TLE patients displaying more disassortative graphs at lower density levels compared to ETLE patients. Moreover, we highlight the variations in the hub regions across different network metrics, underscoring the importance of considering various centrality measures for a comprehensive understanding of brain network dynamics in epilepsy. Our findings suggest that the differences in brain network organization between TLE and ETLE patients could be attributed to the unique characteristics of each epilepsy type, offering insights into potential biomarkers for type-specific epilepsy diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Ictal brain perfusion SPECT provides higher sensitivity for the identification of the epileptic seizure onset zone (SOZ) than interictal SPECT. However, ictal SPECT is demanding due to the unpredictable waiting period for the next seizure to allow for ictal tracer injection. Thus, starting with an interictal scan and skipping the ictal scan if the interictal scan provides a SOZ candidate with high confidence could be an efficient approach. The current study estimated the rate of high-confidence SOZ candidates and the false lateralization rate among them for interictal and ictal SPECT. Methods: 177 patients (48% females, median age 38y, interquartile range 27–48y) with ictal and interictal SPECT acquired with 99mTc-HMPAO (n = 141) or -ECD (n = 36) were included retrospectively. The vast majority of the patients was suspected to have temporal lobe epilepsy. Visual interpretation of the SPECT data was performed independently by 3 readers in 3 settings: "interictal only" (interictal SPECT and statistical hypoperfusion map), "ictal only" (ictal SPECT and hyperperfusion map), and "full" setting (side-by-side interpretation of ictal and interictal SPECT including statistical maps and SISCOM analysis). The readers lateralized the SOZ (right, left, none) and characterized their confidence using a 5-score. A case was considered "lateralizing with high confidence" if all readers lateralized to the same hemisphere with at least 4 of 5 confidence points. Lateralization of the SOZ in the "full" setting was used as reference standard. Results: The proportion of "lateralizing with high confidence" cases was 4.5/31.6/38.4% in the "interictal only"/"ictal only"/"full" setting. One (12.5%) of the 8 cases that were "lateralizing with high confidence" in the "interictal only" setting lateralized to the wrong hemisphere. Among the 56 cases that were "lateralizing with high confidence" in the "ictal only" setting, 54 (96.4%) were also lateralizing in the "full" setting, all to the same hemisphere. Conclusions: Starting brain perfusion SPECT in the presurgical evaluation of epilepsy with an interictal scan to skip the ictal scan in case of a high-confidence interictal SOZ candidate is not a useful approach. In contrast, starting with an ictal scan to skip the interictal scan in case of a high-confidence ictal SOZ candidate can be recommended. [ABSTRACT FROM AUTHOR]

To test a Chinese character version of the phonemic verbal fluency task in patients with temporal lobe epilepsy (TLE) and assess the verbal fluency deficiency pattern in TLE with and without hippocampal sclerosis, a cross-sectional study was conducted including 30 patients with TLE and hippocampal sclerosis (TLE-HS), 28 patients with TLE and without hippocampal sclerosis (TLE-NHS), and 29 demographically matched healthy controls (HC). Both sexes were enrolled. Participants finished a Chinese character verbal fluency (VFC) task during functional MRI. The activation/deactivation maps, functional connectivity, degree centrality, and community features of the left frontal and temporal regions were compared. A neural network classification model was applied to differentiate TLE-HS and TLE-NHS using functional statistics. The VFC scores were correlated with semantic fluency in HC while correlated with phonemic fluency in TLE-NHS. Activation and deactivation deficiency was observed in TLE-HS and TLE-NHS (p < 0.001, k≥10). Functional connectivity, degree centrality, and community features of anterior inferior temporal gyri were impaired in TLE-HS and retained or even enhanced in TLE-NHS (p < 0.05, FDR-corrected). The functional connectivity was correlated with phonemic fluency (p < 0.05, FDR-corrected). The neural network classification reached an area under the curve of 0.90 in diagnosing hippocampal sclerosis. The VFC task is a Chinese phonemic verbal fluency task suitable for clinical application in TLE. During the VFC task, functional connectivity of phonemic circuits was impaired in TLE-HS and was enhanced in TLE-NHS, representing a compensative phonemic searching strategy applied by patients with TLE-NHS. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy (TLE) is among the most common types of epilepsy and often leads to cognitive, emotional, and psychiatric issues due to the frequent seizures. A notable pathological change related to TLE is hippocampal sclerosis (HS), which is characterized by neuronal loss, gliosis, and an increased neuron fibre density. The mechanisms underlying TLE-HS development remain unclear, but the reactive transcriptomic changes in glial cells and neurons of the hippocampus post-epileptogenesis may provide insights. Methods: To induce TLE, 200 nl of kainic acid (KA) was stereotactically injected into the hippocampal CA1 region of mice, followed by a 7-day postinjection period. Single-cell RNA sequencing (ScRNA-seq), single-nucleus RNA sequencing (SnRNA-seq), and Xenium-based spatial transcriptomics analyses were employed to evaluate the changes in mRNA expression in glial cells and neurons. Results: From the ScRNA-seq and SnRNA-seq data, 31,390 glial cells and 48,221 neuronal nuclei were identified. Analysis of the differentially expressed genes (DEGs) revealed significant transcriptomic alterations in the hippocampal cells of mice with TLE, affecting hundreds to thousands of mRNAs and their signalling pathways. Enrichment analysis indicated notable activation of stress and inflammatory pathways in the TLE hippocampus, while pathways related to axonal development and neural support were suppressed. Xenium analysis demonstrated the expression of all 247 genes across mouse brain sections, revealing the spatial distributions of their expression in 27 cell types. Integrated analysis of the DEGs identified via the three sequencing techniques revealed that Spp1, Trem2, and Cd68 were upregulated in all glial cell types and in the Xenium data; Penk, Sorcs3, and Plekha2 were upregulated in all neuronal cell types and in the Xenium data; and Tle4 and Sipa1l3 were downregulated in all glial cell types and in the Xenium data. Conclusion: In this study, a high-resolution single-cell transcriptomic atlas of the hippocampus in mice with TLE was established, revealing potential intrinsic mechanisms driving TLE-associated inflammatory activation and altered cell interactions. These findings provide valuable insights for further exploration of HS development and epileptogenesis. [ABSTRACT FROM AUTHOR]