Temporal Lobe Epilepsy Research Articles

Serum MicroRNAs as Predictors of Diagnosis and Drug-resistance in Temporal Lobe Epilepsy: A Preliminary Study.

Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy, and the current clinical diagnosis is based on EEG, clinical neurological history and neuroimaging findings. So far, there are no blood-based molecular biomarkers of TLE to support clinical diagnosis, despite the pathogenic mechanisms underlying TLE involving defects in the regulation of gene expression. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression. Recent studies show the feasibility of detecting miRNAs in body fluids; circulating miRNAs have emerged as potential clinical biomarkers in epilepsy, although the TLE miRNA profile needs to be addressed. Here, we analysed the diagnostic potential of 8 circulating miRNAs in sera of 52 TLE patients and 40 age- and sex-matched donor controls by RT-qPCR analyses. We found that miR-34a-5p, -106b-5p, -130a-3p, -146a-5p, and -19a-3p are differently expressed in TLE compared to control subjects, suggesting a diagnostic role. Furthermore, we found that miR-34a-5p, -106b-5p, -146a-5p and miR-451a could become prognostic biomarkers, being differentially expressed between drug-resistant and drug-responsive TLE subjects. Therefore, serum miRNAs are diagnostic and drug-resistance predictive molecules of TLE.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer’s disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Automated and Interpretable Detection of Hippocampal Sclerosis in Temporal Lobe Epilepsy: AID-HS.

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.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses.

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Peri-ictal yawning: A potential lateralizing sign in temporal lobe epilepsy.

The primary objective of this retrospective analysis was to evaluate the incidence and lateralization value of peri-ictal yawning (PY) in people with temporal lobe epilepsy (TLE). PY has only occasionally been reported as a manifestation of focal epilepsy. We aimed to determine whether PY could serve as an indicator to help lateralize seizure onset during epileptic seizures. Among 236 consecutive TLE patients admitted for video-EEG monitoring, we analyzed the clinical characteristics, along with scalp video-EEG, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), Wada test, and stereo EEG (SEEG) in patients with PY. Among the 236 patients, 26 (11.0%) exhibited PY, and 36 of 1018 recorded seizures (3.5%) were associated with PY. Of the 26 patients with PY, 19 (73.1%) had non-dominant TLE, while 7 (26.9%) had dominant TLE. The majority of these patients presented with staring, arrest, and automatisms during their seizures with accompanying vegetative signs. PY occurred either during the ictal or postictal phase in all patients. Exception for 10 seizures (10/36, 27.8%) at the early stage (less than 25% total duration), PY was primarily linked to the late ictal and postictal phases. Surgical intervention was performed in 12 patients, 9 of whom (75%) achieved seizure freedom (Engel class I), with 7 of these 9 (77.8%) having non-dominant TLE. Yawning is a physiological phenomenon typically not associated with epilepsy. The present series suggests that PY is relatively uncommon in TLE, but may represent a rare vegetative sign, particularly in cases with non-dominant TLE. Further investigation with a larger cohort of surgically confirmed cases and using intracranial EEG is essential to deepen our understanding of this phenomenon. Yawning is a typical physiological response that is generally not linked to epilepsy. However, it can occasionally indicate seizure activity, particularly in TLE. PY happens more often observed in non-dominant TLE and usually occurs in the later stages of a seizure or just after it. It may hold potential as a lateralizing marker in TLE.

SURG-09. IMPACT OF RESPONSIVE NEUROSTIMULATION IN PATIENTS WITH MESIAL TEMPORAL EPILEPSY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND Brain-responsive neurostimulation, known as the RNS therapy, proves to be a safe and effective adjuvant therapy in decreasing seizure frequency among medically refractory adults with partial-onset seizures who are either seizure-prone post-surgery or are not eligible candidates for surgery. Nevertheless, previous publications have not presented outcomes specifically on subjects with Mesial temporal lobe epilepsy (MTLE). This meta-analysis aims to evaluate the effectiveness of RNS therapy in patients with medically refractory MTLE. METHODS A comprehensive search was conducted across the PubMed, Cochrane, and Scopus databases for studies evaluating the impact of RNS on seizure frequency in patients with mesial temporal epilepsy. Relevant studies published up to March 2024 were included. The statistical analysis assessed the mean seizure reduction, responder rate, and seizure freedom. RESULTS We applied a random-effects model to data from 7 cohort studies with 207 patients, which revealed a significant mean reduction in seizures among individuals who received RNS therapy (68.76%, 95%CI=57.16-80.37%, p-value<0.01). A sub-analysis of 5 studies involving 164 patients demonstrated a substantial response rate (67%, 95%CI= 47-88%, p-value<0.01). Furthermore, an analysis of 4 studies comprising 154 patients indicated a considerable proportion of patients achieved seizure freedom after treatment (Proportion=0.29, 95%CI=0.03-0.55, p-value=0.03). Notably, there was moderate to high heterogeneity across the studies. CONCLUSION This single-arm meta-analysis demonstrates that responsive neurostimulation could be an effective therapeutic option for patients with MTLE, significantly reducing seizure frequency and a high proportion of patients achieving seizure freedom. Further research, including randomized controlled trials with control groups, larger sample sizes, and longer follow-up periods, is warranted to validate these results and optimize patient outcomes. Keywords: neurostimulation; mesial temporal epilepsy; systematic review; meta-analysis.

3D bioprinted in vitro epilepsy models for pharmacological evaluation in temporal lobe epilepsy

This study introduces a novelin vitromodel for intractable temporal lobe epilepsy (TLE) utilizing 3D bioprinting technology, aiming to replicate the complex neurobiological characteristics of TLE more accurately. Primary neural cell constructs were fabricated and subjected to epileptiform-inducing conditions, fostering synaptic proliferation and neuronal loss. Systematically electrophysiological and immunofluorescent analyses indicated that significant synaptic connectivity and sustained epileptiform activities within the constructs akin to those observed in human epilepsy models. Notably, the model responded to treatments with phenytoin and tetrodotoxin, illustrating its potential utility in drug response kinetics studies. Furthermore, we performed drug permeability simulations using COMSOL Multiphysics to analyze the diffusion characteristics of these drugs within the constructs. These results confirm that our 3D bioprinted neural model provides a physiologically relevant and ethically sustainable platform, which is beneficial for studying TLE mechanisms and developing therapeutic strategies with high accuracy and clinical relevance.

CNSC-39. INTEGRATED CLINICAL GENETIC ANALYSIS REVEALS NEUROTRANSMITTER RECEPTOR DYSREGULATION IN MENINGIOMAS CAUSING SEIZURE

Abstract Molecular correlates of seizures in meningioma remain unexplored. Previously, we identified MenG molecular grouping, wherein MenG C meningiomas recur more than MenG A or B. We therefore sought to identify molecular and clinical drivers of seizures in meningioma. We identified 144 primary supratentorial meningiomas, excluding those with pre-existing epilepsy. Whole exome sequencing assessed somatic mutation burden. Bulk RNA-sequencing identified differentially expressed genes and gene ontologies (GO). Immunohistochemistry confirmed protein levels. No differences in canonical gene mutation burden (NF2, TRAF7, AKT1, KLF4, SMO, SMARC) was found between seizure and non-seizure groups. MenG C tumors had higher seizure incidence compared to MenG A or B (p=0.03). Seizure causing meningiomas, though extra-axial, exhibited dysregulated neuronal signaling genes. GABAA receptor subunit genes GABRA3 and GABRG1 were downregulated in tumors causing seizure (Log2FC=-1.67, padj=0.014; Log2FC=-2.24, padj=0.009). Immunohistochemistry confirmed expression of GABRB2 subunit, the first documentation of GABA receptor expression in meningiomas. Neuropeptide Y Receptor Y1 (NPY1R) is downregulated in seizure causing meningiomas (Log2FC=-1.64, padj=0.002). NPY1R loss correlates is observed in mesial temporal lobe epilepsy and post-electroconvulsive shock mouse brains. In GO analysis, the terms “GABA signaling pathway,” “neuropeptide signaling,” “excitatory postsynaptic membrane potential,” and “ionotropic glutamate pathway,” were downregulated in meningiomas with seizure (padj<0.05). We assessed which alterations within MenG C tumors caused seizures by identifying genes associated with both seizure presentation and MenG C classification. Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) is downregulated in MenG C tumors (Log2FC=-2.29, padj=6.02E-07) and seizure causing tumors (Log2FC=-1.75, padj=0.03). Clinically, patients experiencing pre-operative seizures more frequently had cerebral edema, non-homogenous enhancement, intratumoral calcification, higher MIB-1, atypical grade 1, reduced GCS, and ER presentation; they were less likely to have incidental or headache presentation (p<0.05 for all). MenG classification predicts seizure presentation whereas somatic mutation status does not. Meningiomas causing seizures show pathologic neurotransmitter receptor dysregulation.

Transcranial direct current stimulation in the management of epilepsy: a meta-analysis and systematic review

BackgroundTranscranial direct current stimulation (tDCS) has recently become a novel and non-invasive treatment option for refractory epilepsy. Previous systematic reviews have suggested that tDCS may be effective in treating epilepsy, this study presents the first meta-analysis on its effectiveness.MethodsWe searched PubMed, Embase, Cochrane Library, and Web of Science for relevant randomized controlled trials (RCTs) from database inception to May 2024. The Cochrane risk of bias tool RoB2.0 was used to assess the risk of bias. Primary outcomes included changes in seizure frequency from baseline and the proportion of patients with a ≥50% reduction in seizure frequency.ResultsOf the 608 studies initially identified, 14 were finally included. The pooled results from the random-effects model indicated that tDCS significantly reduced seizure frequency (WMD 0.41, 95% CI 0.24, 0.59). Further subgroup analysis revealed that tDCS significantly reduced seizure frequency in temporal lobe epilepsy, and seizure frequency was more alleviated in studies that had treatment sessions of fewer than 5 times, and followed up within 2 months' post-treatment. Only four studies provided data on patients with a ≥50% reduction in seizure frequency, showing no significant difference (RR 2.96, 95% CI 0.85, 10.32). In the systematic review, three studies analyzed cognitive function changes after tDCS treatment, but none reported significant improvements. The most common side effect during tDCS treatment was transient tingling, and no patients required additional life-support measures due to side effects.ConclusionThe current meta-analysis on available trials indicates that tDCS can effectively reduce seizure frequency in the short term and is well-tolerated. However, its impact on cognitive improvement in epilepsy patients requires further investigation.Systematic review registrationhttps://inplasy.com/inplasy-2024-6-0033/, identifier INPLASY202460033.

Temporal Lobe Epilepsy Focus Detection Based on the Correlation Between Brain MR Images and EEG Recordings with a Decision Tree

Background/Objectives: In this study, a medical decision support system is presented to assist physicians in epileptic focus detection by correlating MRI and EEG data of temporal lobe epilepsy patients. Methods: By exploiting the asymmetry in the hippocampus in MRI images and using voxel-based morphometry analysis, gray matter reduction in the temporal and limbic lobes is detected, and epileptic focus prediction is realized. In addition, an epileptic focus is also determined by calculating the asymmetry score from EEG channels. Finally, epileptic focus detection was performed by associating MRI and EEG data with a decision tree. Results: The results obtained from the proposed algorithm provide 100% overlap with the physician’s finding on the EEG data. Conclusions: MRI and EEG correlation in epileptic focus detection was improved compared with physicians. The proposed algorithm can be used as a medical decision support system for epilepsy diagnosis, treatment, and surgery planning.

Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept.

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.

Compartment-specific small non-coding RNA changes and nucleolar defects in human mesial temporal lobe epilepsy

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.

Lateralization of memory function in temporal lobe epilepsy using scene memory fMRI.

Functional magnetic resonance imaging (fMRI) offers an alternative to the traditional Wada test for presurgical language and memory lateralization that carries almost no risk. However, fMRI lateralization of episodic memory remains challenging because the hippocampus, which is fundamental to episodic memory, is smaller, more prone to susceptibility artifact, and harder to functionally modulate than language regions. We previously showed that a complex scene memory task can lateralize memory function in the mesial temporal lobe. Using data acquired from N = 45 patients with temporal lobe epilepsy acquired with an improved stimulus paradigm and high-resolution fMRI, we now demonstrate that memory activation can be successfully lateralized within hippocampus proper. PLAIN LANGUAGE SUMMARY: Epilepsy surgery can improve seizure control in patients with temporal lobe epilepsy (TLE) that cannot be controlled with medications also, but ablation or removal of temporal lobe brain tissue can also cause cognitive deficits. Functional MRI (fMRI) can noninvasively map brain activation and perform well in lateralizing and localizing language function, but localizing and lateralizing memory function is more challenging. Building upon prior work using complex scene encoding to map memory function, we demonstrate that the use of high-resolution fMRI along with an optimized task paradigm allows memory activation to be detected within the hippocampus. Because the hippocampus is both a common site of TLE and a key region underlying memory, this approach is expected to contribute to presurgical evaluation of TLE.

Long-term neuroplasticity in language networks after anterior temporal lobe resection.

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.

Histopathological substrate of increased T2 signal in the anterior temporal lobe white matter in temporal lobe epilepsy associated with hippocampal sclerosis.

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.

Acute depletion of complement C3 with cobra venom factor attenuates memory deficits induced by status epilepticus.

Status epilepticus (SE) significantly increases the risk for the development of unprovoked seizures, memory loss, and temporal lobe epilepsy. Our prior studies showed that SE increases complement C3 signaling in the hippocampus, which parallels memory deficits. Additionally, C3 knockout (KO) mice were protected against SE-induced memory impairments, suggesting a mechanistic role for C3 in this pathophysiology. In this study, we utilized cobra venom factor (CVF), a structural analog of C3 that results in its depletion, to investigate the protective effects of post-SE C3 ablation on memory deficits that develop during epileptogenesis. SE was induced in male rats using the chemoconvulsant pilocarpine. Two weeks later, control (C) and SE rats were treated with either vehicle (V) or CVF. Recognition memory was assessed using the novel object recognition (NOR) test in four groups (C + V, C + CVF, SE + V, and SE + CVF). Immunoblotting was used to measure hippocampal protein levels of C3 along with synaptic, astrocyte, and blood-brain barrier (BBB) stability markers, Psd95, GFAP, and albumin, respectively. In the NOR test, rats in the C + V and C + CVF groups spent more time exploring the novel object. SE + V rats explored both objects equally, while SE + CVF rats spent significantly more on the novel object, suggesting a rescue of cognitive performance by CVF. While CVF-mediated C3 depletion did not restore normal protein levels of Psd95 or GFAP in hippocampi of SE + CVF rats, CVF treatment attenuated SE-induced extravasation of albumin, suggesting potential rescue of BBB stability. Our findings indicate that acute C3 depletion with CVF can attenuate memory deficits that develop during SE-induced epileptogenesis. This finding further suggests that targeting C3 could hold promise in addressing cognitive comorbidities associated with SE and acquired epilepsy. A long-lasting seizure, known as status epilepticus (SE), can raise the chance of having more seizures in the future and can lead to memory problems. While the exact reasons for these issues are not completely known, it is believed that brain inflammation might be involved. In this study, we show that the activation of the body's immune response, especially a part called the C3 component, plays a role in the memory problems that occur after an episode of SE.

Ictal asystole is a rare complication of epilepsy

Ictal bradyarrhythmia (IB) and ictal asystole (IA) are rare complications of epilepsy. Onset latency of IB/IA implicates central nervous parasympathetic pathways, causing asystole, subsequent cerebral hypoxaemia, and potentially inducing a paradoxal, therapeutic effect by terminating both the seizure and the IA. This is a case report of a 68-year-old woman with mesial temporal lobe epilepsy and hippocampal sclerosis and IA. Association of IB/IA and sudden unexpected death in epilepsy lacks evidence and pacemaker therapy is rarely indicated. Treatment aims to minimize seizures and reduce the risk of falls.

Semiautomatic volumetry of the temporal lobes of the brain and correlation with electroencephalography results in dogs with assumed idiopathic epilepsy.

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.

Olfactory Dysfunction and Limbic Hypoactivation in Temporal Lobe Epilepsy.

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right-handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right-handed). In the TLE group, the presumed seizure onset zone was left-sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre-assessment. During a pre-testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five-point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two-sided Mann-Whitney U tests, FDR-p < 0.05) and less familiar (two-sided Mann-Whitney U tests, FDR-p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two-sided Mann-Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io).

Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) the amplitude of IPSCs in DGCs evoked by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous electrographic seizures in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished electrographic seizures. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy.