Cell-specific extracellular vesicle-encapsulated exogenous GABA controls seizures in epilepsy.

BACKGROUND: Epilepsy affects ∼60 million people worldwide. Most antiseizure medications in the market act on voltage-gated sodium or calcium channels, indirectly modulating neurotransmitter GABA or glutamate levels or multiple targets. Earlier studies made significant efforts to directly deliver GABA into the brain with varied success. Herein, we have hypothesized to directly deliver exogenous GABA to the brain with epilepsy through extracellular vesicles (EVs) from human GABA-producing cells and their progenitors as EVs largely mimic their parent cell composition. METHODS: Human neural stem cells (NSCs), medial ganglionic eminence (MGE) cells, and GABAergic interneurons (INs) were generated from induced pluripotent stem cells (iPSCs) and characterized. EVs were isolated from NSCs, MGE cells, and INs and characterized for size and distribution, morphological features, and molecular markers. Exogenous GABA was passively loaded to the isolated EVs as a zwitterion at physiological pH, and the encapsulated dose of GABA was quantified. Epilepsy was developed through status epilepticus induction in Fisher rats by administration of repeated low doses of kainic acid. The extent of the seizures was measured for 10 h/ day for 3-6 months by video recording and its evaluation for stage III, IV and V seizures as per Racine scale. EVs from INs, MGE cells, and NSCs encapsulated with exogenous GABA were sequentially tested in the 4th, 5th, and 6th months by intranasal administration in the rats with epilepsy for detailed seizure, behavioral and synapse analysis. In separate experiments, several controls including exogenic GABA alone and EVs from INs and MGE cells were evaluated for seizure-controlling ability. RESULTS: Exogenic GABA could enter the brain through EVs. Treatment with EVs from INs and MGE cells encapsulated with GABA significantly reduced total seizures, stage V seizures, and total time spent in seizure activity. EVs from NSCs encapsulated with GABA demonstrated limited seizure control. Exogenic GABA alone and EVs from INs and MGE cells individually failed to control seizures. Further, exogenic GABA with EVs from MGE cells improved depressive behavior while partially improving memory functions. Co-localization studies confirmed exogenous GABA with presynaptic vesicles in the hippocampus, indicating the interaction of exogenous GABA in the brain with epilepsy. CONCLUSION: For the first time, the study demonstrated that exogenous GABA could be delivered to the brain through brain cell-derived EVs, which could regulate seizures in temporal lobe epilepsy. It is identified that the cellular origin of EVs plays a vital role in seizure control with exogenous GABA.

TNF-α: A serological marker for evaluating the severity of hippocampal sclerosis in medial temporal lobe epilepsy?

OBJECTIVE: By analysing the difference in TNF-α levels in the peripheral blood of patients with medial temporal lobe epilepsy (mTLE) with or without hippocampal sclerosis and the correlation between TNF-α and N-acetylaspartate levels in the hippocampus, we explored the relationship between TNF-α and the degree of damage to hippocampal sclerosis neurons in medial temporal lobe epilepsy. METHODS: This is a prospective, population-based study. A total of 71 Patients with medial temporal lobe epilepsy diagnosed by clinical seizures, video-EEG, epileptic sequence MRI, and other imaging examinations were recruited from October 2020 to July 2022 in the Department of Neurology, Affiliated Hospital of Xuzhou Medical University. Twenty age-matched healthy subjects were selected as the control group. The patients were divided into two groups: the medial temporal epilepsy with hippocampal sclerosis group (positive group, mTLE-HS-P group) and the medial temporal epilepsy without hippocampal sclerosis group (negative group, mTLE-HS-N group). The levels of IL-1ß, IL-5, IL-6, IL-8, IL-17, IFN-γ and TNF-α in the peripheral blood of the patients in the three groups were detected by multimicrosphere flow immunofluorescence assay. The level of N-acetylaspartate (NAA) in the hippocampus was measured by 1H-MRS. The differences in cytokine levels among the three groups were analysed, and the correlation between cytokine and NAA levels was analysed. RESULTS: The level of TNF-α in the peripheral blood of the patients in the mTLE-HS-P group was significantly higher than that of the patients in the mTLE-HS-N and healthy control groups, and the level of TNF-α in the patients in the mTLE-HS-N group was significantly higher than that of the patients in the healthy control group. The NAA level in mTLE-HS-P group patients was significantly lower than that of mTLE-HS-N patients and healthy controls, but there was no significant difference between mTLE-HS-N patients and healthy controls (P > 0.05). Spearman correlation analysis showed that TNF-α level (rs = -0.437, P < 0.05) and the longest duration of a single seizure (rs = -0.398, P < 0.05) were negatively correlated with NAA level. Logistic regression analysis showed that there was no significant correlation between the longest duration of a single seizure and hippocampal sclerosis, but TNF-α level was closely related to hippocampal sclerosis in patients with mTLE (OR = 1.315, 95 % CI 1.084-1.595, P = 0.005). CONCLUSION: The level of TNF-α in the peripheral blood of patients with medial temporal lobe epilepsy with hippocampal sclerosis was higher, and it was correlated with NAA and hippocampal sclerosis. The high expression of TNF-α may be of important value in the evaluation of hippocampal sclerosis patients.

The multifaceted role of Wnt canonical signalling in neurogenesis, neuroinflammation, and hyperexcitability in mesial temporal lobe epilepsy.

Epilepsy is a neurological disorder characterised by unprovoked, repetitive seizures caused by abnormal neuronal firing. The Wnt/ß-Catenin signalling pathway is involved in seizure-induced neurogenesis, aberrant neurogenesis, neuroinflammation, and hyperexcitability associated with epileptic disorder. Wnt/ß-Catenin signalling is crucial for early brain development processes including neuronal patterning, synapse formation, and N-methyl-d-aspartate receptor (NMDAR) regulation. Disruption of molecular networks such as Wnt/ß-catenin signalling in epilepsy could offer encouraging anti-epileptogenic targets. So, with a better understanding of the canonical Wnt/-Catenin pathway, we highlight in this review the important elements of Wnt/-Catenin signalling specifically in Mesial Temporal Lobe Epilepsy (MTLE) for potential therapeutic targets.

Exploring the effect of 6-BIO and sulindac in modulation of Wnt/ß-catenin signaling pathway in chronic phase of temporal lobe epilepsy.

The prospective involvement of the Wnt/ß-catenin signaling pathway in epilepsy, with the proposed therapeutic uses of its modulators, has been suggested; however, comprehensive knowledge in this regard is currently limited. Despite postulations about the pathway's significance and treatment potential, a systematic investigation is required to better understand its implications in chronic epilepsy. We investigated the role of key proteins like ß-catenin, GSK-3ß, and their modulators sulindac and 6-BIO, in Wnt/ß-catenin pathway during chronic phase of temporal lobe epilepsy. We also evaluated the role of modulators in seizure score, seizure frequency and neurobehavioral parameters in temporal lobe epilepsy. We developed status epilepticus model using lithium-pilocarpine. The assessment of neurobehavioral parameters was done followed by histopathological examination and immunohistochemistry staining of hippocampus as well as RT-qPCR and western blotting to analyse gene and protein expression. In SE rats, seizure score and frequency were significantly high compared to control rats, with notable changes in neurobehavioral parameters and neuronal damage observed in hippocampus. Our study also revealed a substantial upregulation of the Wnt/ß-catenin pathway in chronic epilepsy, as evidenced by gene and protein expression studies. Sulindac emerged as a potent modulator, reducing seizure score, frequency, neuronal damage, apoptosis, and downregulating the Wnt/ß-catenin pathway when compared to 6-BIO. Our findings emphasize the potential of GSK-3ß and ß-catenin as promising drug targets for chronic temporal lobe epilepsy, offering valuable treatment options for chronic epilepsy. The promising outcomes with sulindac encourages further exploration in clinical trials to assess its therapeutic potential.

Dynamical modulation of hypersynchronous seizure onset with transcranial magneto-acoustic stimulation in a hippocampal computational model.

Hypersynchronous (HYP) seizure onset is one of the frequently observed seizure-onset patterns in temporal lobe epileptic animals and patients, often accompanied by hippocampal sclerosis. However, the exact mechanisms and ion dynamics of the transition to HYP seizures remain unclear. Transcranial magneto-acoustic stimulation (TMAS) has recently been proposed as a novel non-invasive brain therapy method to modulate neurological disorders. Therefore, we propose a biophysical computational hippocampal network model to explore the evolution of HYP seizure caused by changes in crucial physiological parameters and design an effective TMAS strategy to modulate HYP seizure onset. We find that the cooperative effects of abnormal glial uptake strength of potassium and excessive bath potassium concentration could produce multiple discharge patterns and result in transitions from the normal state to the HYP seizure state and ultimately to the depolarization block state. Moreover, we find that the pyramidal neuron and the PV+ interneuron in HYP seizure-onset state exhibit saddle-node-on-invariant-circle/saddle homoclinic (SH) and saddle-node/SH at onset/offset bifurcation pairs, respectively. Furthermore, the response of neuronal activities to TMAS of different ultrasonic waveforms revealed that lower sine wave stimulation can increase the latency of HYP seizures and even completely suppress seizures. More importantly, we propose an ultrasonic parameter area that not only effectively regulates epileptic rhythms but also is within the safety limits of ultrasound neuromodulation therapy. Our results may offer a more comprehensive understanding of the mechanisms of HYP seizure and provide a theoretical basis for the application of TMAS in treating specific types of seizures.

Prognostic Value of Complete Resection of the High-Frequency Oscillation Area in Intracranial EEG: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: High-frequency oscillations (HFOs; ripples 80-250 Hz; fast ripples [FRs] 250-500 Hz) recorded with intracranial electrodes generated excitement and debate about their potential to localize epileptogenic foci. We performed a systematic review and meta-analysis on the prognostic value of complete resection of the HFOs-area (crHFOs-area) for epilepsy surgical outcome in intracranial EEG (iEEG) accessing multiple subgroups. METHODS: We searched PubMed, Embase, and Web of Science for original research from inception to October 27, 2022. We defined favorable surgical outcome (FSO) as Engel class I, International League Against Epilepsy class 1, or seizure-free status. The prognostic value of crHFOs-area for FSO was assessed by (1) the pooled FSO proportion after crHFOs-area; (2) FSO for crHFOs-area vs without crHFOs-area; and (3) the predictive performance. We defined high combined prognostic value as FSO proportion >80% + FSO crHFOs-area >without crHFOs-area + area under the curve (AUC) >0.75 and examined this for the clinical subgroups (study design, age, diagnostic type, HFOs-identification method, HFOs-rate thresholding, and iEEG state). Temporal lobe epilepsy (TLE) was compared with extra-TLE through dichotomous variable analysis. Individual patient analysis was performed for sex, affected hemisphere, MRI findings, surgery location, and pathology. RESULTS: Of 1,387 studies screened, 31 studies (703 patients) met our eligibility criteria. Twenty-seven studies (602 patients) analyzed FRs and 20 studies (424 patients) ripples. Pooled FSO proportion after crHFOs-area was 81% (95% CI 76%-86%) for FRs and 82% (73%-89%) for ripples. Patients with crHFOs-area achieved more often FSO than those without crHFOs-area (FRs odds ratio [OR] 6.38, 4.03-10.09, p < 0.001; ripples 4.04, 2.32-7.04, p < 0.001). The pooled AUCs were 0.81 (0.77-0.84) for FRs and 0.76 (0.72-0.79) for ripples. Combined prognostic value was high in 10 subgroups: retrospective, children, long-term iEEG, threshold (FRs and ripples) and automated detection and interictal (FRs). FSO after complete resection of FRs-area (crFRs-area) was achieved less often in people with TLE than extra-TLE (OR 0.37, 0.15-0.89, p = 0.006). Individual patient analyses showed that crFRs-area was seen more in patients with FSO with than without MRI lesions (p = 0.02 after multiple correction). DISCUSSION: Complete resection of the brain area with HFOs is associated with good postsurgical outcome. Its prognostic value holds, especially for FRs, for various subgroups. The use of HFOs for extra-TLE patients requires further evidence.

Molecular mechanism analyses of post-traumatic epilepsy and hereditary epilepsy based on 10× single-cell transcriptome sequencing technology.

BACKGROUND: Single-cell RNA sequencing analysis has been usually conducted on post-traumatic epilepsy (PET) and hereditary epilepsy (HE) patients; however, the transcriptome of patients with traumatic temporal lobe epilepsy has rarely been studied. MATERIALS AND METHODS: Hippocampus tissues isolated from one patient with PTE and one patient with HE were used in the present study. Single cell isolates were prepared and captured using a 10× Genomics Chromium Single-Cell 3' kit (V3) according to the manufacturer's instructions. The libraries were sequenced on an Illumina NovaSeq 6000 sequencing system. Raw data were processed, and the cells were filtered and classified using the Seurat R package. Uniform Manifold Approximation and Projection was used for visualization. Differentially expressed genes (DEGs) were identified based on a p-value ≤0.01 and log fold change (FC) ≥0.25. Gene Ontology (GO, http://geneontology.org/) and KEGG (Kyoto Encyclopedia of Genes and Genomes, www.genome.jp/kegg) analyses were performed on the DEGs for enrichment analysis. RESULTS: The reads obtained from the 10× genomic platform for PTE and HE were 39.56 M and 30.08 M, respectively. The Q30 score of the RNA reads was >91.6%. After filtering, 7479 PTE cells and 9357 HE cells remained for further study. More than 96.4% of the reads were mapped to GRCh38/GRCm38. The cells were differentially distributed in two groups, with higher numbers of oligodendrocytes (6522 vs. 2532) and astrocytes (133 vs. 52), and lower numbers of microglial cells (2242 vs. 3811), and neurons (3 vs. 203) present in the HE group than in the PTE group. The DEGs in four cell clusters were identified, with 25 being in oligodendrocytes (13 upregulated and 12 downregulated), 87 in microglia cells (42 upregulated and 45 downregulated), 222 in astrocytes (115 upregulated and 107 downregulated), and 393 in neurons (305 upregulated and 88 downregulated). The genes MTND1P23 (downregulated), XIST (downregulated), and RPS4Y1 (upregulated) were commonly expressed in all four cell clusters. The DEGs in microglial cells and astrocytes were enriched in the IL-17 signaling pathway. CONCLUSION: Our study explored differences in cells found in a patient with PE compared to a patient with HE, and the transcriptome in the different cells was analyzed for the first time. Studying inflammatory and immune functions might be the best approach for investigating traumatic temporal lobe epilepsy in neurons.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Identification of gene regulatory networks affected across drug-resistant epilepsies.

Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies). This systematic comparison characterized the global molecular signature of epilepsies, elucidating the key underlying mechanisms of disease pathology including neurotransmission and synaptic plasticity, brain extracellular matrix and energy metabolism. In addition, specific dysregulations in neuroinflammation and oligodendrocyte function were observed in TLE-HS and mTORopathies, respectively. The aforementioned mechanisms are proposed as molecular hallmarks of DRE with the identified upstream regulators offering opportunities for drug-target discovery and development.

Ascorbic acid mitigates the impact of oxidative stress in a human model of febrile seizure and mesial temporal lobe epilepsy.

Prolonged febrile seizures (FS) in children are linked to the development of temporal lobe epilepsy (MTLE). The association between these two pathologies may be ascribed to the long-term effects that FS exert on neural stem cells, negatively affecting the generation of new neurons. Among the insults associated with FS, oxidative stress is noteworthy. Here, we investigated the consequences of exposure to hydrogen peroxide (H2O2) in an induced pluripotent stem cell-derived neural stem cells (iNSCs) model of a patient affected by FS and MTLE. In our study, we compare the findings from the MTLE patient with those derived from iNSCs of a sibling exhibiting a milder phenotype defined only by FS, as well as a healthy individual. In response to H2O2 treatment, iNSCs derived from MTLE patients demonstrated an elevated production of reactive oxygen species and increased apoptosis, despite the higher expression levels of antioxidant genes and proteins compared to other cell lines analysed. Among the potential causative mechanisms of enhanced vulnerability of MTLE patient iNSCs to oxidative stress, we found that these cells express low levels of the heat shock protein HSPB1 and of the autophagy adaptor SQSTM1/p62. Pre-treatment of diseased iNSCs with the antioxidant molecule ascorbic acid restored HSBP1 and p62 expression and simultaneously reduced the levels of ROS and apoptosis. Our findings suggest the potential for rescuing the impaired oxidative stress response in diseased iNSCs through antioxidant treatment, offering a promising mechanism to prevent FS degeneration in MTLE.

Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images.

Artificial intelligence provides an opportunity to try to redefine disease subtypes based on similar pathobiology. Using a machine-learning algorithm (Subtype and Stage Inference) with cross-sectional MRI from 296 individuals with focal epilepsy originating from the temporal lobe (TLE) and 91 healthy controls, we show phenotypic heterogeneity in the pathophysiological progression of TLE. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2200062562). We identify two hippocampus-predominant phenotypes, characterized by atrophy beginning in the left or right hippocampus; a third cortex-predominant phenotype, characterized by hippocampus atrophy after the neocortex; and a fourth phenotype without atrophy but amygdala enlargement. These four subtypes are replicated in the independent validation cohort (109 individuals). These subtypes show differences in neuroanatomical signature, disease progression and epilepsy characteristics. Five-year follow-up observations of these individuals reveal differential seizure outcomes among subtypes, indicating that specific subtypes may benefit from temporal surgery or pharmacological treatment. These findings suggest a diverse pathobiological basis underlying focal epilepsy that potentially yields to stratification and prognostication - a necessary step for precise medicine.

Functional correlates of cognitive performance and working memory in temporal lobe epilepsy: Insights from task-based and resting-state fMRI.

Temporal lobe epilepsy (TLE) is a common form of medically intractable epilepsy. Although seizures originate in mesial temporal structures, there are widespread abnormalities of gray and white matter beyond the temporal lobes that negatively impact functional networks and cognition. Previous studies have focused either on the global impact on functional networks, or on the functional correlates of specific cognitive abilities. Here, we use a two-pronged approach to evaluate the link between whole-brain functional connectivity (FC) anomalies to overall cognitive performance, and how such abnormal connectivity alters the fronto-parietal brain regions involved in working memory (WMem), a cognitive disability often reported by TLE patients. We evaluated 31 TLE patients and 35 healthy subjects through extensive cognitive testing, resting-state functional magnetic resonance imaging (RS-fMRI), and task-based fMRI using Sternberg's task to evaluate WMem. As a group, TLE patients displayed cognitive abnormalities across different domains, although considerable within-group variability was identified. TLE patients showed disruptions of functional networks between and within the default mode network (DMN) and task-positive networks (TPN) resulting in associations with cognitive performance. Furthermore, during the WMem task, TLE patients showed abnormal activity of fronto-parietal regions that were associated with other forms of memory, and alterations of seed-based connectivity analyses. Our results show that different degrees of abnormal functional brain activity and connectivity are related to the severity of disabilities across cognitive spheres. Differential co-activation patterns between patients and healthy subjects suggest potential compensatory mechanisms to preserve adequate cognitive performance.

Parvalbumin neurons in the nucleus accumbens shell modulate seizure in temporal lobe epilepsy.

A growing number of clinical and animal studies suggest that the nucleus accumbens (NAc), especially the shell, is involved in the pathogenesis of temporal lobe epilepsy (TLE). However, the role of parvalbumin (PV) GABAergic neurons in the NAc shell involved in TLE is still unclear. In this study, we induced a spontaneous TLE model by intrahippocampal administration of kainic acid (KA), which generally induce acute seizures in first 2 h (acute phase) and then lead to spontaneous recurrent seizures after two months (chronic phase). We found that chemogenetic activation of NAc shell PV neurons could alleviate TLE seizures by reducing the number and period of focal seizures (FSs) and secondary generalized seizures (sGSs), while selective inhibition of PV exacerbated seizure activity. Ruby-virus mapping results identified that the hippocampus (ventral and dorsal) is one of the projection targets of NAc shell PV neurons. Chemogenetic activation of the NAc-Hip PV projection fibers can mitigate seizures while inhibition has no effect on seizure ictogenesis. In summary, our findings reveal that PV neurons in the NAc shell could modulate the seizures in TLE via a long-range NAc-Hip circuit. All of these results enriched the investigation between NAc and epilepsy, offering new targets for future epileptogenesis research and precision therapy.

[The relationship between immunological and psychopathological characteristics in patients with focal epilepsy depending on the profile of interhemispheric asymmetry]. / Vzaimosvyaz' immunologicheskikh i psikhopatologicheskikh kharakteristik u bol'nykh fokal'noi epilepsiei v zavisimosti ot profilya mezhpolusharnoi asimmetrii.

OBJECTIVE: To identify the possible influence of cellular immunity parameters and neurobiological variables (frequency of seizures of various semiotics and their severity) on comorbid psychopathological symptoms depending on the profile of interhemispheric asymmetry in patients with focal forms of epilepsy. MATERIAL AND METHODS: The study included 92 patients with epilepsy (38 men, 54 women, mean age 38.7+8.45 years). Focal temporal lobe epilepsy was diagnosed in 36 patients, focal frontal lobe epilepsy in 16 patients, and temporal-frontal lobe epilepsy in 40 patients. For each type of seizure, severity was assessed according to the National Seizure Severity Scale (NHS3). The mental status of patients was assessed using the SCL-90 self-report questionnaire. The Annette scale was used to assess the profile of interhemispheric asymmetry. The number of different clusters of lymphocytes was studied, including the number of T-lymphocytes (CD3+), T-helpers (CD3+CD4+), T-cytotoxic (CD3+CD8+), T-NK (natural killers CD3+CD16+CD56+), B-lymphocytes (CD3-CD19+), as well as immunoregulatory index (CD4/CD8 ratio). In order to identify any possible relationships between neurobiological and immune variables, on the one hand, and the SCL-90 constructs, on the other hand, a separate correlation analysis of Spearman ranks within the left-handed group and the right-handed group was carried out. RESULTS: We revealed the differences between groups of patients with epilepsy with right and left profiles of hemispheric asymmetry regarding the relationship between the frequency of seizures, their severity and accompanying psychopathological variables, on the one hand, and between immunity indices and psychopathological constructs, on the other hand. It has been established that neurobiological and immune variables in left-handers can determine the psychopathological structure of the comorbid mental disorder. CONCLUSION: Prediction of concomitant psychopathological syndromes in patients with epilepsy on the basis of clinical data and data on immunity is quite possible, but only in left-handed patients.

Improving Diagnostic Performance of MRI for Temporal Lobe Epilepsy With Deep Learning-Based Image Reconstruction in Patients With Suspected Focal Epilepsy.

OBJECTIVE: To evaluate the diagnostic performance and image quality of 1.5-mm slice thickness MRI with deep learning-based image reconstruction (1.5-mm MRI + DLR) compared to routine 3-mm slice thickness MRI (routine MRI) and 1.5-mm slice thickness MRI without DLR (1.5-mm MRI without DLR) for evaluating temporal lobe epilepsy (TLE). MATERIALS AND METHODS: This retrospective study included 117 MR image sets comprising 1.5-mm MRI + DLR, 1.5-mm MRI without DLR, and routine MRI from 117 consecutive patients (mean age, 41 years; 61 female; 34 patients with TLE and 83 without TLE). Two neuroradiologists evaluated the presence of hippocampal or temporal lobe lesions, volume loss, signal abnormalities, loss of internal structure of the hippocampus, and lesion conspicuity in the temporal lobe. Reference standards for TLE were independently constructed by neurologists using clinical and radiological findings. Subjective image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were analyzed. Performance in diagnosing TLE, lesion findings, and image quality were compared among the three protocols. RESULTS: The pooled sensitivity of 1.5-mm MRI + DLR (91.2%) for diagnosing TLE was higher than that of routine MRI (72.1%, P < 0.001). In the subgroup analysis, 1.5-mm MRI + DLR showed higher sensitivity for hippocampal lesions than routine MRI (92.7% vs. 75.0%, P = 0.001), with improved depiction of hippocampal T2 high signal intensity change (P = 0.016) and loss of internal structure (P < 0.001). However, the pooled specificity of 1.5-mm MRI + DLR (76.5%) was lower than that of routine MRI (89.2%, P = 0.004). Compared with 1.5-mm MRI without DLR, 1.5-mm MRI + DLR resulted in significantly improved pooled accuracy (91.2% vs. 73.1%, P = 0.010), image quality, SNR, and CNR (all, P < 0.001). CONCLUSION: The use of 1.5-mm MRI + DLR enhanced the performance of MRI in diagnosing TLE, particularly in hippocampal evaluation, because of improved depiction of hippocampal abnormalities and enhanced image quality.

Inhibition of Granule Cell Dispersion and Seizure Development by Astrocyte Elevated Gene-1 in a Mouse Model of Temporal Lobe Epilepsy.

Although granule cell dispersion (GCD) in the hippocampus is known to be an important feature associated with epileptic seizures in temporal lobe epilepsy (TLE), the endogenous molecules that regulate GCD are largely unknown. In the present study, we have examined whether there is any change in AEG-1 expression in the hippocampus of a kainic acid (KA)-induced mouse model of TLE. In addition, we have investigated whether the modulation of astrocyte elevated gene-1 (AEG-1) expression in the dentate gyrus (DG) by intracranial injection of adeno-associated virus 1 (AAV1) influences pathological phenotypes such as GCD formation and seizure susceptibility in a KA-treated mouse. We have identified that the protein expression of AEG-1 is upregulated in the DG of a KA-induced mouse model of TLE. We further demonstrated that AEG-1 upregulation by AAV1 delivery in the DG-induced anticonvulsant activities such as the delay of seizure onset and inhibition of spontaneous recurrent seizures (SRS) through GCD suppression in the mouse model of TLE, while the inhibition of AEG-1 expression increased susceptibility to seizures. The present observations suggest that AEG-1 is a potent regulator of GCD formation and seizure development associated with TLE, and the significant induction of AEG-1 in the DG may have therapeutic potential against epilepsy.

Postsurgical Outcomes of Mesial Temporal Lobe Epilepsy due to Hippocampal Sclerosis Associated with Calcified Neurocysticercosis.

The aim of this study was to analyze postsurgical outcomes for individuals with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who underwent anterior temporal lobectomy, based on the presence of calcified neurocysticercosis (cNCC). A retrospective cross-sectional study was conducted on 89 patients with MTLE-HS who underwent anterior temporal lobectomy between January 2012 and December 2020 at a basic epilepsy surgery center located in Lima, Peru. We collected sociodemographic, clinical, and diagnostic information. The postsurgical results were analyzed using bivariate analysis according to the Engel classification. We included 89 individuals with a median age of 28 years (interquartile range [IQR]: 24-37), and more than half (55.1%) were male. Seventeen (19.1%) were diagnosed with cNCC. A greater number of patients with cNCC had lived in rural areas of Peru during their early life compared with those without cNCC (12 [70.6%] versus 26 [36.1%]; P = 0.010). Patients with cNCC exhibited a greater median frequency of focal to bilateral tonic-clonic seizures per month (1 [IQR: 0-2] versus 0 [0-0.5]; P = 0.009). Conversely, a lower proportion of patients with cNCC reported a history of an initial precipitating injury in comparison to the group without cNCC (4 [23.5%] versus 42 [58.3%]; P = 0.014). At the 1-year follow-up, most patients (82.4%) with cNCC were categorized as Engel IA. Similarly, at the 2-year follow-up, nine (75.0%) were classified as Engel IA. Our findings suggest that most patients diagnosed with cNCC exhibit favorable postsurgical outcomes, comparable to those without cNCC. Additionally, it can be postulated that cNCC may play a role as an initial precipitating injury.

Current advances in rodent drug-resistant temporal lobe epilepsy models: Hints from laboratory studies.

Anti-seizure drugs (ASDs) are the first choice for the treatment of epilepsy, but there is still one-third of patients with epilepsy (PWEs) who are resistant to two or more appropriately chosen ASDs, named drug-resistant epilepsy (DRE). Temporal lobe epilepsy (TLE), a common type of epilepsy usually associated with hippocampal sclerosis (HS), shares the highest proportion of drug resistance (approximately 70%). In view of the key role of the temporal lobe in memory, emotion, and other physiological functions, patients with drug-resistant temporal lobe epilepsy (DR-TLE) are often accompanied by serious complications, and surgical procedures also yield extra considerations. The exact mechanisms for the genesis of DR-TLE remain unillustrated, which makes it hard to manage patients with DR-TLE in clinical practice. Animal models of DR-TLE play an irreplaceable role in both understanding the mechanism and searching for new therapeutic strategies or drugs. In this review article, we systematically summarized different types of current DR-TLE models, and then recent advances in mechanism investigations obtained in these models were presented, especially with the development of advanced experimental techniques and tools. We are deeply encouraged that novel strategies show great therapeutic potential in those DR-TLE models. Based on the big steps reached from the bench, a new light has been shed on the precise management of DR-TLE.

Cognitive decline in adult-onset temporal lobe epilepsy: Insights from aetiology.

PURPOSE: To identify patients with adult-onset temporal lobe epilepsy (TLE) at risk of developing cognitive decline. Detecting which patients, aetiologies, or factors are most closely related with memory decline would allow us to identify patients that would eventually benefit from more specific treatment. METHODS: Single centre, retrospective analysis of a prospectively followed-up cohort study, including all patients with the diagnosis of adult-onset TLE during 2013, with a minimum follow-up of five years. Memory and cognitive decline were analysed at 5 years and at last follow-up. RESULTS: Of 89 initially selected patients, 71 were included. After 5 years, 11/71 (15.5%) patients suffered cognitive decline, of which 1/71 (4%) developed dementia. At last follow-up (range 65-596 m) a total of 34/71 (47.8%) patients were diagnosed with cognitive decline, specifically either memory decline or dementia. Cognitive decline at 5 years was related to: 1. Age at onset: 62.65 years (SD 9.04) in the group with cognitive decline vs 50.33 y. (SD 13.02 in the group without cognitive decline; p=0.004); 2. Onset as status epilepticus (3/6 in patients with memory decline vs 8/65 in patients without cognitive decline; p=0.04); 3. Immune aetiology: 42% compared with unknown (10%) and structural (10%) aetiologies; p=0.036; 4. Hippocampal sclerosis on MRI: 5/11 patients with cognitive decline vs 9/51 patients without cognitive decline; p=0.035. Cognitive decline was not related to seizure frequency, sex, or age (p=0.78; p=0.40; p=0.95, respectively). CONCLUSIONS: Older age at epilepsy onset, onset as status epilepticus, immune aetiology, and hippocampal sclerosis are risk factors for developing cognitive decline in patients with adult-onset temporal lobe epilepsy.

Glucose Metabolism of Hippocampal Subfields in Medial Temporal Lobe Epilepsy.

PURPOSE: Reduced glucose metabolism in the hippocampus is commonly observed in cases of medial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS). Glucose metabolism among the various hippocampal subfields has not been thoroughly investigated. PATIENTS AND METHODS: This study examined 29 patients (18 females; 15-58 years) diagnosed with HS who underwent surgery for drug-resistant epilepsy. FreeSurfer 7.1.1 was used in the processing of MRI data and 18 F-FDG PET scans to derive volumetric data and the FDG SUVr in the whole hippocampus and hippocampal subfields, including the CA1, CA2-4, granule cell and molecular layer of the dentate gyrus (GC-ML-DG), and subiculum. Asymmetries in the volume and SUVr between the 2 sides from the subfields of the hippocampus were defined in terms of an asymmetry index. Comparisons of the asymmetry index among these regions were performed. The correlations between asymmetry index values and postoperative outcomes and presurgical neuropsychological test results were also evaluated. RESULT: The CA1, CA2-4, subiculum, GC-ML-DG, and whole hippocampus presented reductions in volume and hypometabolism ipsilateral to MTLE. Asymmetries in volume and SUVr were significantly less pronounced in the CA1 and subiculum than in the CA2-4 or GC-ML-DG. Postoperative seizure outcomes were not correlated with the asymmetry index for volume or SUVr in any hippocampal subfield. In cases of left MTLE, scores of immediate logical memory and delayed logical memory were positively correlated with the asymmetry index for SUVr in the following subfields: CA1 ( R = 0.829, P = 0.021; R = 0.770, P = 0.043), CA2-4 ( R = 0.825, P = 0.022; R = 0.894, P = 0.007), subiculum ( R = 0.882, P = 0.009; R = 0.853, P = 0.015), GC-ML-DG ( R = 0.850, P = 0.015; R = 0.796, P = 0.032), and whole hippocampus ( R = 0.841, P = 0.018; R = 0.822, P = 0.023). In cases of right MTLE, the scores for delayed face memory were positively correlated with the asymmetry index for SUVr in the subiculum ( R = 0.935, P = 0.006). CONCLUSIONS: In cases of HS, changes in glucose metabolism levels varied among the hippocampal subfields. Asymmetries in glucose metabolism among the CA-1, CA2-4, subiculum, and GC-ML-DG subregions were correlated with scores for verbal memory among patients with left MTLE. Asymmetric glucose metabolism in the subiculum was also correlated with visual memory scores among patients with right MTLE.