Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis Patients Research Articles

Early identification of seizure freedom with medical treatment in patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is usually associated with a poor response to antiseizure medications. We focused on MTLE-HS patients who were seizure free on medication to: (1) determine the clinical factors associated with seizure freedom and (2) develop a machine-learning classifier to better earlier identify those patients. We performed a retrospective, multicentric study comparing 64 medically treated seizure-free MTLE-HS patients with 200 surgically treated drug-resistant MTLE-HS patients. First, we collected medical history and seizure semiology data. Then, we developed a machine-learning classifier based on clinical data. Medically treated seizure-free MTLE-HS patients were seizure-free for at least 2years, and for a median time of 7years at last follow-up. Compared to drug-resistant MTLE-HS patients, they exhibited: an older age at epilepsy onset (22.5 vs 8.0years, p < 0.001), a lesser rate of: febrile seizures (39.0% vs 57.5%, p = 0.035), focal aware seizures (previously referred to as aura)(56.7% vs 90.0%, p < 0.001), autonomic focal aware seizures in presence of focal aware seizure (17.6% vs 59.4%, p < 0.001), dystonic posturing of the limbs (9.8% vs 47.0%, p < 0.001), gestural (27.4% vs 94.0%, p < 0.001), oro-alimentary (32.3% vs 75.5%, p < 0.001) or verbal automatisms (12.9% vs 36.0%, p = 0.001). The classifier had a positive predictive value of 0.889, a sensitivity of 0.727, a specificity of 0.962, a negative predictive value of 0.893. Medically treated seizure-free MTLE-HS patients exhibit a distinct clinical profile. A classifier built with readily available clinical data can identify them accurately with excellent positive predictive value. This may help to individualize the management of MTLE-HS patients according to their expected pharmacosensitivity.

Mesial Temporal Lobe Epilepsy (MTLE) Drug-Refractoriness Is Associated With P2X7 Receptors Overexpression in the Human Hippocampus and Temporal Neocortex and May Be Predicted by Low Circulating Levels of miR-22.

Objective: ATP-gated ionotropic P2X7 receptors (P2X7R) actively participate in epilepsy and other neurological disorders. Neocortical nerve terminals of patients with Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) express higher P2X7R amounts. Overexpression of P2X7R bolsters ATP signals during seizures resulting in glial cell activation, cytokines production, and GABAergic rundown with unrestrained glutamatergic excitation. In a mouse model of status epilepticus, increased expression of P2X7R has been associated with the down-modulation of the non-coding micro RNA, miR-22. MiR levels are stable in biological fluids and normally reflect remote tissue production making them ideal disease biomarkers. Here, we compared P2X7R and miR-22 expression in epileptic brains and in the serum of patients with MTLE-HS, respectively.Methods: Quantitative RT-PCR was used to evaluate the expression of P2X7R in the hippocampus and anterior temporal lobe of 23 patients with MTLE-HS and 10 cadaveric controls. Confocal microscopy and Western blot analysis were performed to assess P2X7R protein amounts. MiR-22 expression was evaluated in cell-free sera of 40 MTLE-HS patients and 48 healthy controls.Results: Nerve terminals of the hippocampus and neocortical temporal lobe of MTLE-HS patients overexpress (p < 0.05) an 85 kDa P2X7R protein whereas the normally occurring 67 kDa receptor protein dominates in the brain of the cadaveric controls. Contrariwise, miR-22 serum levels are diminished (p < 0.001) in MTLE-HS patients compared to age-matched control blood donors, a situation that is more evident in patients requiring multiple (>3) anti-epileptic drug (AED) regimens.Conclusion: Data show that there is an inverse relationship between miR-22 serum levels and P2X7R expression in the hippocampus and neocortex of MTLE-HS patients, which implies that measuring serum miR-22 may be a clinical surrogate of P2X7R brain expression in the MTLE-HS. Moreover, the high area under the ROC curve (0.777; 95% CI 0.629–0.925; p = 0.001) suggests that low miR-22 serum levels may be a sensitive predictor of poor response to AEDs among MTLE-HS patients. Results also anticipate that targeting the miR-22/P2X7R axis may be a good strategy to develop newer AEDs.

Epilepsy progression is associated with cumulative DNA methylation changes in inflammatory genes.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common focal epilepsy in adults. It is characterized by alarming rates of pharmacoresistance. Epileptogenesis is associated with the occurrence of epigenetic alterations, and the few epigenetic studies carried out in MTLE-HS have mainly focused on the hippocampus. In this study, we obtained the DNA methylation profiles from both the hippocampus and anterior temporal neocortex of MTLE-HS patients subjected to resective epilepsy surgery and autopsied non-epileptic controls. We assessed the progressive nature of DNA methylation changes in relation to epilepsy duration. We identified significantly altered hippocampal DNA methylation patterns encompassing multiple pathways known to be involved in epileptogenesis. DNA methylation changes were even more striking in the neocortex, wherein pathogenic pathways and genes were common to both tissues. Most importantly, DNA methylation changes at many genomic sites varied significantly with epilepsy duration. Such progressive changes were associated with inflammation-related genes in the hippocampus. Our results suggest that the neocortex, relatively spared of extensive histopathological damage, may also be involved in epilepsy development. These results also open the possibility that the observed neocortical impairment could represent a preliminary stage of epileptogenesis before the establishment of chronic lesions or a consequence of prolonged seizure exposure. Our two-tissue multi-level characterization of the MTLE-HS DNA methylome suggests the occurrence of a self-propagating inflammatory wave of epigenetic dysregulation.

Altered hippocampal kynurenine pathway metabolism contributes to hyperexcitability in human mesial temporal lobe epilepsy-hippocampal sclerosis.

Glutamate receptor-mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid and quinolinic acid are two important tryptophan-kynurenine pathway metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of tryptophan-kynurenine pathway metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission. Levels of tryptophan-kynurenine pathway metabolites were determined using HPLC and LC-MS/MS in hippocampal samples from patients with MTLE-HS, compared with autopsy and non-seizure control samples. mRNA and protein expressions of tryptophan-kynurenine pathway enzymes were determined by qPCR and Western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in the presence of kynurenine and kynurenic acid, using whole-cell patch clamp. Levels of kynurenic acid were reduced and quinolinic acid levels were raised in hippocampal samples from MTLE-HS patients, whereas kynurenine levels remained unaltered, compared with levels in non-seizure controls. Spontaneous glutamatergic activity in MTLE-HS hippocampal samples was higher than that in non-seizure controls. Treatment with kynurenine inhibited glutamatergic activity in non-seizure control samples but not in MTLE-HS samples. However, exogenously applied kynurenic acid inhibited glutamatergic activity in both non-seizure control and MTLE-HS hippocampal samples. Also, levels of kynurenine aminotransferase II and its cofactor pyridoxal phosphate were reduced in MTLE-HS samples. Our findings indicate that altered metabolism of tryptophan-kynurenine pathway metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS.

Female preponderance in genetic generalized epilepsies

IntroductionEpilepsy is more prevalent in men but Genetic Generalized Epilepsies (GGE) seem to be more common in women. A predominant maternal inheritance has been previously described in GGE. Our objective was to determine sex and inheritance patterns in a GGE population compared to mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS). MethodsWe performed a prospective observational study including adult GGE and MTLEHS patients followed up at a tertiary epilepsy center from January 2016 to December 2019. Patients’ familial history was obtained by a detailed questionnaire. Clinical and demographic data was retrieved from clinical notes. ResultsA cohort of 641 patients, 403 with GGE and 238 with MTLEHS, was analyzed. GGE was more common in women than MTLEHS (58.8% vs 44.5%, OR=1.63, p = 0.004). Compared to MTLEHS patients, more GGE patients had familial history of epilepsy (45.4% vs 25.2%; p<0.001). The GGE group had a higher percentage of female relatives with epilepsy (55% vs 37%; p = 0.006). The prevalence of maternal inheritance was not different between GGE and MTLEHS groups (62.9% vs 57.7%; p = 0.596). Photosensitivity was more common in females than in males (44.7% vs 34.3%, p = 0.036). ConclusionThere is a female preponderance in GGE when compared to MTLEHS, as both GGE patients and their affected relatives are more frequently women. The prevalence of maternal inheritance was not higher in GGE than in MTLEHS.

Ictal fear is associated with anxiety symptoms and interictal dysphoric disorder in drug-resistant mesial temporal lobe epilepsy

Interictal dysphoric disorder (IDD) is a poorly understood psychiatric disorder of epilepsy patients. Interictal dysphoric disorder is characterized by depressive, somatoform, and affective symptoms observed in up to 5.9% of drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). This study aimed to evaluate the association between ictal fear (IF) and the psychiatric symptoms and diagnosis in MTLE-HS patients. We included 116 (54.3% male) consecutive adult patients (36 ± 11 years) with MTLE-HS. Anxiety and depression symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS) and the psychiatric diagnosis were according to Fourth Edition of the Diagnosis and Statistical Manual of Mental Disorders (DSM-IV). The independent association between the occurrence of IF aura and the psychiatric diagnosis was determined by binary regression. When compared to those with other auras or without aura, patients reporting IF have higher HADS anxiety, but not HADS depression, scores. Ictal fear was independently associated with the diagnosis of interictal dysphoric disorder (OR, IC 95% = 7.6, 1.3–43.2, p = 0.02), but not with the diagnosis of anxiety (OR, CI 95% = 0.72, 0.08–6.0, p = 0.73), depression (OR, CI 95% = 0.94, 0.19–4.8, p = 0.94) or psychotic disorders (p = 0.99). Only patients with drug-resistant MTLE-HS were included and the small number of cases with DD diagnosis in the sample. In MTLE-HS patients, the occurrence of IF is associated with higher levels of anxiety symptoms and IDD. The results provide insights about fear-related neural network connections with anxiety symptoms and the IDD in MTLE-HS.

Role of Altered Expression, Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy.

Expression of circulating microRNAs as predictors of diagnosis and surgical outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

MicroRNAs have been progressively investigated as post-transcriptional regulators playing important roles in epilepsy pathophysiology. Here we investigate three promising microRNAs (miR-27a-3p, miR-328-3p and miR-654-3p) previously described in the literature as possible peripheral biomarkers for epilepsy diagnose and surgical prognosis. Serum samples from 28 patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) were analyzed, 14 with good surgical prognosis (Engel I) and 14 with unfavorable surgical prognosis (Engel III-IV). Serum samples from 11 healthy volunteers were the control group. The microRNAs expression analysis was performed using real-time PCR. The present results did not endorse the role of miR-27a-3p as a peripheral biomarker for epilepsy diagnosis or surgical prognosis. MiR-328-3p, however, presented significant area under the curve (AUC) values when comparing controls to Engel I (90.3%), controls to Engel III-IV (96.8%) and controls to Engel I + Engel III-IV (i.e., epilepsy patients, AUC = 93.5%). Additionally, miR-654-3p displayed AUC = 74.7% when comparing controls to Engel I patients (p = 0.004), and AUC = 73.6% (p = 0.04) in the attempt to discriminate unfavorable from favorable surgical prognosis. In conclusion, the ANOVA and ROC analyzes with the respective AUC, specificity and sensitivity values allows us to conclude that miR-328-3p is the most important peripheral biomarker for the diagnosis of MTLE-HS. In terms of predicting the surgical prognosis of MTLE-HS patients, miR-654-3p proved to be the only microRNA evaluated to present statistical power to differentiate, as a peripheral biomarker, Engel I from Engel III-IV patients.

Abnormalities of Cortical Thickness in Pediatric Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common intractable seizure type of pediatric epilepsy, with alterations in the cortex across the whole brain. The aim of this study is to investigate the abnormalities of cortical thickness in pediatric MTLE-HS. Subjects were recruited from Shenzhen Children's Hospital between September 2015 and December 2016. MTLE was confirmed by the experienced neurological physician based on International League Against Epilepsy (ILAE) diagnosis criteria, and structural magnetic resonance imaging (MRI) was performed at 3T for quantitative assessment of cortical thickness. A general linear model with age and gender as covariates was used to examine the vertex-wise differences in cortical thickness between 1) left MTLE-HS (LMTLE-HS) and healthy controls (HC), and 2) right MTLE-HS (RMTLE-HS) and HC. The family-wise error corrected significance threshold was set at P < 0.05. Through a combination of probability and cluster-size thresholding, cluster-wise P values were obtained for the resulting clusters. 13 LMTLE-HS, 6 RMTLE-HS, and 20 age-matched HC were finally enrolled in the study. No significant difference in the mean age (LMTLE-HS vs. HC, p=0.57; RMTLE-HS vs. HC, p=0.39) and gender ratio (LMTLE-HS vs. HC, p=0.24; RMTLE-HS vs. HC, p=0.72) was found between MTLE-HS and HC. In LMTLE-HS, cortical thickness was found significantly decreased in the ipsilateral caudal middle frontal gyrus (p=0.012) and increased in the contralateral inferior temporal gyrus (p=0.020). In RMTLE-HS, cortical thickness significantly decreased in the ipsilateral posterior parietal lobe (superior, p<0.001 and inferior parietal gyrus, p=0.03), the anterior parietal lobe (postcentral gyrus, p=0.006), the posterior frontal lobe (precentral gyrus, p=0.04 and the lateral occipital gyrus, p<0.001), and the contralateral lateral occipital gyrus, middle frontal (p<0.0001) and superior frontal gyrus (p<0.001), and pericalcarine cortex (p=0.020). We detected significant cortical abnormalities in pediatric MTLE-HS patients compared with HC. These cortical abnormalities could be explained by specific pathogenesis in MTLE-HS, and may finally contribute to understanding the intrinsic mechanism of MTLE-HS.

Expression of MicroRNAs miR-145, miR-181c, miR-199a and miR-1183 in the Blood and Hippocampus of Patients with Mesial Temporal Lobe Epilepsy.

The aim of this study was to analyze the expression profiles of the microRNAs (miRNAs) miR-145, miR-181c, miR-199a and miR-1183 in the hippocampus and blood of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and to investigate whether these can be used as diagnosis and prognosis biomarkers for epilepsy. Hippocampus and blood samples were collected from 20 patients with MTLE-HS, ten of whom had a favorable surgical outcome (Engel I) and ten with an unfavorable surgical outcome (Engel III-IV). Hippocampus samples from autopsied individuals with no neurological or psychiatric medical history (necropsy samples) and blood samples from healthy individuals were used as controls. Real-time quantitative PCR (RQ-PCR) was used to analyze miRNA expression. The results showed that the expressions of these miRNAs differed quantitatively in the hippocampus and blood of patients with MTLE-HS in comparison to the respective control. This difference was most pronounced for miR-145, which was hypo-expressed in the hippocampus and hyper-expressed in the blood of MTLE-HS patients. MiRNAs miR-145, miR-181c, miR-199a and miR-1183 were hyper-expressed in the blood of patients with MTLE-HS. No statistical differences in the levels of these miRNAs in the blood or hippocampus were found between Engel I patients and Engel III-IV patients. These results suggest that the analyzed microRNAs are potential circulating biomarkers for epilepsy diagnosis.

Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy: Commentary on: "Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study".

Although studies have shown cortical and subcortical changes in first-degree relatives of patients with familial forms of temporal lobe epilepsy, few studies have addressed extrahippocampal morphology changes in unaffected siblings of patients with sporadic mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Alhusaini et al1 described subtle reduced cortical volumes in the anteromedial temporal cortex of asymptomatic siblings of sporadic MTLE-HS patients, suggesting that such localized traits are possibly heritable. In this issue of Epilepsia, Yaakub et al2 replicated these findings in first-degree asymptomatic relatives of patients with MTLE-HS.2 A positive history of simple febrile convulsions before the age of 4 years was present in two relatives in this study.2 Both these relatives had values above the median of the relative group for the reduced surface area in the anteromedial temporal cortex, further strengthening the possibility that these subtle morphological changes are inherited.2 Limitations of this study include the small number of subjects studied and that they side-flipped the images to increase power to detect differences, thus treating both hemispheres as if they were equal, which is not the case, as shown recently by Kong et al.3 The study by Alhusaini et al1 showed that the alterations of cortical morphology found in anteromedial regions of unaffected siblings of subjects with left MTLE-HS (more in the left entorhinal cortex and parahippocampal gyrus) differed from those found in unaffected siblings of subjects with right MTLE-HS (more in the right entorhinal cortex and temporal pole). It is of relevance that both studies1, 2 used FreeSurfer (http://surfer.nmr.mgh.harvard.edu), which measures cortical volume as a product of two distinct aspects of the cortical architecture: cortical thickness and surface area.4 Cortical thickness and surface area measurements appear to represent different early neurodevelopmental events with distinct genetic influences, as shown by Panizzon et al5 in a magnetic resonance imaging study of twins. They found that, although cortical thickness and surface area are both highly heritable (>0.80), they are mostly unrelated genetically (genetic correlation = 0.08).5 These results suggest some independence of these two surface-based measures, and potentially, their asymmetry patterns. A recent study that mapped cortical brain asymmetry in 17 141 healthy individuals showed regions with different asymmetrical patterns in cortical thickness and surface area and a significant heritability of these asymmetry characteristics.3 Effect sizes of cortical thickness and surface area were independent, and the asymmetry was generally more prominent for surface area compared with that of cortical thickness.3 Most regions showed significant asymmetry in surface area, although with no clear directional pattern affecting neighboring regions, or along the anterior-posterior axis, as they observed for cortical thickness.3 Widespread cerebral cortical thinning has been identified in patients with MTLE as compared to healthy controls within several cortical regions, including the mesiotemporal, limbic, and central sensorimotor cortices.6 This pattern of cortical thinning appeared progressive in patients with medically refractory epilepsy,6 but also to a lesser degree in MTLE patients under seizure control.7 Less attention has been paid to cortical surface area in studies of MTLE patients. Interestingly, both Alhusaini et al1 and Yaakub et al2 found reduced cortical surface areas in anteromedial temporal regions of asymptomatic siblings of sporadic MTLE-HS patients, but no significant changes in cortical thickness. This lack of cortical thickness changes has been confirmed in 127 asymptomatic first-degree relatives of MTLE-HS patients from three independent cohorts, each with a healthy control group.8 These findings altogether indicate that the previously characterized progressive cortical thinning in patients with MTLE-HS is not heritable and is likely driven by disease-related factors, whereas changes in the cortical surface area may represent an inherited trait that preceded seizure onset. This hypothesis needs to be confirmed in further studies with multiple large cohorts, also taking into account the asymmetric nature of cerebral hemispheres. The author has no conflict of interest to disclose. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A) and The State-Trait Anxiety Inventory (STAI) accuracy for anxiety disorders detection in drug-resistant mesial temporal lobe epilepsy patients.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most prevalent type ofsurgically remediable epilepsy and highly associated with psychiatric comorbidities. This study aimed to evaluate Hospital anxiety and depression scale-anxiety subscale (HADS-A) and The State-Trait Anxiety Inventory - Trait subscale (STAI-T) accuracy for detection of anxiety disorders in patients with drug-resistant MTLE-HS. One hundred three consecutive patients with drug-resistant MTLE-HS were enrolled. Diagnosis was based on the anamnesis, neurological examination, video-electroencephalogram (VEEG) analyses, and magnetic resonance imaging (MRI). Psychiatric interviews were based on DSM-IV-TR criteria and ILAE Commission of Psychobiology classification as a gold standard; HADS-A and STAI-T were used as psychometric diagnostic tests, and receiver operating characteristic (ROC) curves were used to determine the optimal threshold scores. The areas under the curve (AUCs) were higher than 0.7 (0.6-0.8) for both scales. The STAI-T cutoff point of ˃53 and the HADS-A cutoff point of ˃7 showed both around of 80% (44.4-97.7) sensitivity and 80% (66.9-86.9) and 60% (46.5-68.6) of specificity, respectively. In this sample the prevalence of anxiety disorders was 11.7% and both scales showed a high negative predictive value such as 96% (87.1-99.0) but low positive predictive value such as 30% (22.1-45.2) and 20% (15.0-27.2) respectively. The small number of cases in the diagnostic population; the results are only applied to drug resistant MTLE-HS; the psychiatric diagnosis were not based on a structured psychiatric interview; possible observer bias in 7 illiterate patients; the antidepressant treatment was not controlled. In MTLE-HS, STAI-T and HADS-A had a similar and low positive predictive value and high negative predictive value. The implications for the HADS-A and STAI-T usefulness for anxiety disorders screening in patients with other epilepsies types deserve further investigations. If replicated in other populations, these findings may have important relevance for the presurgical screening of anxiety disorders in MTLE-HS patients who are candidates to epilepsy surgery.

Is self-report sleepiness associated with cognitive performance in temporal lobe epilepsy?

Sleepiness and cognitive impairment are common symptoms observed in patients with epilepsy. We investigate whether self-reported sleepiness is associated with cognitive performance in patients with refractory mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Seventy-one consecutive patients with MTLE-HS were evaluated with the Stanford Sleepiness Scale (SSS) before neuropsychological evaluation. Their mean SSS scores were compared with controls. Each cognitive test was compared between patients with (SSS ≥ 3) or without sleepiness (SSS < 3). Imbalances were controlled by regression analysis. Patients reported a significantly higher degree of sleepiness than controls (p < 0.0001). After multiple linear regression analysis, only one test (RAVLT total) remained associated with self-reported sleepiness. Self-reported sleepiness was significantly higher in MTLE-HS patients than controls, but did not affect their cognitive performance. If confirmed in other populations, our results may have implications for decision making about sleepiness screening in neuropsychological settings.

New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE-HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE-HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo-electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE-HS heterogeneity.

Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosis

ABSTRACTPurpose: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro-inflammatory cytokines such as IL-1β and TNF-α, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Expression of these cytokines can be modulated by polymorphisms such as rs16944 and rs1800629, respectively, both of which have been associated with febrile seizures (FS) and MTLE-HS development. The human leukocyte antigen (HLA) system has also been implicated in diverse epileptic entities, suggesting a variable role of this system in epilepsy. Our aim was to analyse the association between immunogenetic factors and MTLE-HS development. For that rs16944 (-511 T>C, IL-1β), rs1800629 (-308 G>A, TNF-α) polymorphisms and HLA-DRB1 locus were genotyped in a Portuguese Population.Methods: We studied 196 MTLE-HS patients (108 females, 88 males, 44.7 ± 12.0 years, age of onset = 13.6 ± 10.3 years, 104 with FS antecedents) and 282 healthy controls in a case–control study.Results: The frequency of rs16944 TT genotype was higher in MTLE-HS patients compared to controls (14.9% in MTLE-HS vs. 7.7% in controls, p = 0.021, OR [95% CI] = 2.20 [1.13–4.30]). This association was independent of FS antecedents. No association was observed between rs1800629 genotypes or HLA-DRB1 alleles and MTLE-HS susceptibility. Also, no correlation was observed between the studied polymorphisms and disease age of onset.Conclusion: The rs16944 TT genotype is associated with MTLE-HS development what may be explained by the higher IL-1β levels produced by this genotype. High IL-1β levels may have neurotoxic effects or imbalance neurotransmission leading to seizures.

Meta-analysis of voxel-based morphometry studies of gray matter abnormalities in patients with mesial temporal lobe epilepsy and unilateral hippocampal sclerosis.

We aimed to perform a meta-analysis to systematically determine the most consistent regions of gray matter volume (GMV) abnormality in patients of unilateral mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), and to reveal the difference of GMV abnormality between the patients with left-sided and right-sided MTLE-HS. A comprehensive and systematic search was performed in PubMed for voxel-based morphometry (VBM) studies of MTLE-HS. A total of 12 MTLE-HS studies, including 9 left-sided MTLE-HS (LMTLE-HS) and 8 right-sided MTLE-HS (RMTLE-HS) studies were included. The activation likelihood estimation (ALE) method was applied in our meta-analysis. Compared to the healthy controls, MTLE-HS patients showed significant GMV decrease in the parahippocampal gyrus, left pulvinar and right pyramis. For LMTLE-HS, the most consistent GMV decrease was detected in the left parahippocampal gyrus. For RMTLE-HS, the most consistent GMV decrease was found in the right parahippocampal gyrus. No shared regions of significant GMV reduction were found between LMTLE-HS and RMTLE-HS either. This meta-analysis revealed that MTLE-HS patients had significant GMV reduction even beyond the hippocampus, and the subtypes showed distinct reduction patterns. Our findings, if were further verified with larger samples, would have implications for the clinical diagnosis of MTLE-HS.

Parahippocampal Involvement in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A Proof of Concept from Memory-Guided Saccades.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural damage and dysfunction. The accuracy of medium-term spatial memory can be tested by memory-guided saccades (MGS) to evaluate a functional impairment of the parahippocampal cortex (PHC), while voxel-based morphometry (VBM) analysis can be used to detect a structural damage of the latter region. MGS with 3- and 30-s memorization delays were compared between 7 patients affected by right MTLE-HS (r-MTLE-HS), 6 patients affected by left MTLE-HS, and 13 healthy controls. The same subjects underwent brain MRI for a VBM analysis. Correlation analysis was performed between the results of VBM and MGS and with patients' clinical data. Right MTLE-HS patients showed impaired accuracy of leftward MGS with a 30-s memorization delay; their gray-matter volume was reduced in the right hippocampus and inferior temporal gyrus, and bilaterally in the cerebellum. Left MTLE-HS patients had normal MGS accuracy; their gray-matter volume was reduced in the left hippocampus, in the right-inferior temporal gyrus and corpus callosus, and bilaterally in the insular cortex and in the cerebellum. The difference between right and left parahippocampal volumes correlated with MGS accuracy, while right and left hippocampal volumes did not. Hippocampal and parahippocampal volume did not correlate with clinical variables such as febrile seizures, age at disease onset, disease duration, and seizure frequency. MGS abnormalities suggested the functional involvement of the right PHC in patients with r-MTLE-HS, supporting a right lateralization of spatial memory control and showing a relation between functional impairment and degree of atrophy.

Brain expression of inflammatory mediators in Mesial Temporal Lobe Epilepsy patients

Neuroinflammation may be central in epileptogenesis. In this study we analysed inflammatory reaction markers in brain tissue of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) patients. TLR4, IL-1β and IL-10 gene expression as well as the presence of activated HLA-DR+ microglia was evaluated in 23 patients and 10 cadaveric controls. Inflammation characterized by the presence of HLA-DR+ microglia and TLR4, IL-1β overexpression was evident in hippocampus and anterior temporal cortex of MTLE-HS patients. Anti-inflammatory IL-10 was also overexpressed in MTLE-HS patients. Our results show that hippocampal neuroinflammation extends beyond lesional limits, as far as the anterior temporal cortex.

Pharmacoresistance with newer anti-epileptic drugs in mesial temporal lobe epilepsy with hippocampal sclerosis

This study aims to evaluate the overall prognosis, prognostic factors, and efficacy of treatment in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who have access to third generation anti-epileptic drugs but not to epilepsy surgery. Eighty-five MTLE-HS patients were retrospectively placed into a seizure-free (seizure-free for >1year) or drug-resistant group, and the two groups were compared on the basis of age, sex, age at onset of seizures, duration of epilepsy, side of lesion, handedness, EEG findings, history of CNS infection, history of febrile convulsions, history of head trauma, history of cognitive impairment, family history of seizures, number of current anti-epileptic drugs (AEDs), total number of AED trials, and presence of individual AEDs. Only 24.7% of MTLE-HS patients had achieved seizure freedom for >1 year. Poor prognosis and drug-resistance were associated with younger age at onset of seizures (p=0.002), longer duration of epilepsy (p=0.018), greater number of current AEDs (p<0.001), and greater total number of AED trials (p<0.001). In addition, regimens with newer AEDs had no greater efficacy than regimens with older AEDs. Most medically managed MTLE-HS patients do not achieve seizure freedom despite multiple AED trials, and treatment with third generation AEDs should not preclude evaluation for epilepsy surgery.

Brain Infiltration of Immune Cells in CASPR2-Antibody Associated Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

Antibodies directed against neuronal surface antigens have recently been identified in patients with focal temporal lobe epilepsy (TLE) of unknown cause and mesial TLE with hippocampal sclerosis (MTLE-HS), thereby emphasizing the role of autoimmunity in TLE. Antibodies to contactin-associated protein-like 2 (CASPR2) are prevalent in MTLE-HS patients. We aimed to find out whether anti-neuronal autoimmunity might be involved in CASPR2 antibody-related MTLE-HS. Surgically resected medial temporal lobe specimens of seropositive and seronegative MTLE-HS patients were examined with hematoxylin and eosin and immunohistochemical staining using specific immune cell markers. Two of 5 CASPR2 antibody-positive MTLE-HS patients showed polymorphonuclear and mononuclear cells infiltrating the subarachnoidal region. One of these patients also showed mononuclear cell infiltration in the parenchyma of the temporal lobe cortex. Subarachnoidal and parenchymal infiltrates contained CD3+, CD8+, and CD68+ cells. None of the 13 seronegative MTLE-HS patients displayed cellular infiltrates in their brain samples, and all MTLE-HS patients showed marked neuronal cell loss but no immune cell infiltration in their hippocampi. Our results show that CASPR2 antibody-associated MTLE-HS can present with central nervous system inflammation; thus, this subtype of MTLE-HS might have an autoimmune origin.