Individual cerebellar metabolic connectome in patients with MTLE and NTLE associated with surgical prognosis.

PURPOSE: This study aimed to comprehensively explore the different metabolic connectivity topological changes in MTLE and NTLE, as well as their association with surgical outcomes. METHODS: This study enrolled a cohort of patients with intractable MTLE and NTLE. Each individual's metabolic connectome, as determined by Kullback-Leibler divergence similarity estimation for the [18F]FDG PET image, was employed to conduct a comprehensive analysis of the cerebral metabolic network. Alterations in network connectivity were assessed by extracting and evaluating the strength of edge and weighted connectivity. By utilizing these two connectivity strength metrics with the cerebellum, we explored the network properties of connectivity and its association with prognosis in surgical patients. RESULTS: Both MTLE and NTLE patients exhibited substantial alterations in the connectivity of the metabolic network at the edge and nodal levels (p < 0.01, FDR corrected). The key disparity between MTLE and NTLE was observed in the cerebellum. In MTLE, there was a predominance of increased connectivity strength in the cerebellum. Whereas, a decrease in cerebellar connectivity was identified in NTLE. It was found that in MTLE, higher edge connectivity and weighted connectivity strength in the contralateral cerebellar hemisphere correlated with improved surgical outcomes. Conversely, in NTLE, a higher edge metabolic connectivity strength in the ipsilateral cerebellar hemisphere suggested a worse surgical prognosis. CONCLUSION: The cerebellum exhibits distinct topological characteristics in the metabolic networks between MTLE and NTLE. The hyper- or hypo-metabolic connectivity in the cerebellum may be a prognostic biomarker of surgical prognosis, which might aid in therapeutic decision-making for TLE individuals.

Exploring ASL perfusion MRI as a substitutive modality for 18F-FDG PET in determining the laterality of mesial temporal lobe epilepsy.

OBJECTIVE: The aim of this investigation was to determine whether a correlation could be discerned between perfusion acquired through ASL MRI and metabolic data acquired via 18F-fluorodeoxyglucose (18F-FDG) PET in mesial temporal lobe epilepsy (mTLE). METHODS: ASL MRI and 18F-FDG PET data were gathered from 22 mTLE patients. Relative cerebral blood flow (rCBF) asymmetry index (AIs) were measured using ASL MRI, and standardized uptake value ratio (SUVr) maps were obtained from 18F-FDG PET, focusing on bilateral vascular territories and key bitemporal lobe structures (amygdala, hippocampus, and parahippocampus). Intra-group comparisons were carried out to detect hypoperfusion and hypometabolism between the left and right brain hemispheres for both rCBF and SUVr in right and left mTLE. Correlations between the two AIs computed for each modality were examined. RESULTS: Significant correlations were observed between rCBF and SUVr AIs in the middle temporal gyrus, superior temporal gyrus, and hippocampus. Significant correlations were also found in vascular territories of the distal posterior, intermediate anterior, intermediate middle, proximal anterior, and proximal middle cerebral arteries. Intra-group comparisons unveiled significant differences in rCBF and SUVr between the left and right brain hemispheres for right mTLE, while hypoperfusion and hypometabolism were infrequently observed in any intracranial region for left mTLE. CONCLUSION: The study's findings suggest promising concordance between hypometabolism estimated by 18F-FDG PET and hypoperfusion determined by ASL perfusion MRI. This raises the possibility that, with prospective technical enhancements, ASL perfusion MRI could be considered an alternative modality to 18F-FDG PET in the future.

Ablation of apparent diffusion coefficient hyperintensity clusters in mesial temporal lobe epilepsy improves seizure outcomes after laser interstitial thermal therapy.

OBJECTIVE: Laser interstitial thermal therapy (LiTT) is a minimally invasive surgical procedure for intractable mesial temporal epilepsy (mTLE). LiTT is safe and effective, but seizure outcomes are highly variable due to patient variability, suboptimal targeting, and incomplete ablation of the epileptogenic zone. Apparent diffusion coefficient (ADC) is a magnetic resonance imaging (MRI) sequence that can identify potential epileptogenic foci in the mesial temporal lobe to improve ablation and seizure outcomes. The objective of this study was to investigate whether ablation of tissue clusters with high ADC values in the mesial temporal structures is associated with seizure outcome in mTLE after LiTT. METHODS: Twenty-seven patients with mTLE who underwent LiTT at our institution were analyzed. One-year seizure outcome was categorized as complete seizure freedom (International League Against Epilepsy [ILAE] Class I) and residual seizures (ILAE Class II-VI). Volumes of hippocampus and amygdala were segmented from the preoperative T1 MRI sequence. Spatially distinct hyperintensity clusters were identified in the preoperative ADC map. Proportion of cluster volume and number ablated were associated with seizure outcomes. RESULTS: The mean age at surgery was 37.5 years and the mean follow-up duration was 1.9 years. Proportions of hippocampal cluster volume (p = .013) and number (p = .03) ablated were significantly higher in patients with seizure freedom. For amygdala clusters, the proportion of cluster number ablated was significantly associated with seizure outcome (p = .026). In the combined amygdalohippocampal complex, ablation of amygdalohippocampal clusters reliably predicted seizure outcome by their volume ablated (area under the curve [AUC] = 0.7670, p = .02). SIGNIFICANCE: Seizure outcome after LiTT in patients with mTLE was associated significantly with the extent of cluster ablation in the amygdalohippocampal complex. The results suggest that preoperative ADC analysis may help identify high-yield pathological tissue clusters that represent epileptogenic foci. ADC-based cluster analysis can potentially assist ablation targeting and improve seizure outcome after LiTT in mTLE.

Animal models and human tissue compared to better understand and treat the epilepsies.

Animal models of human brain disorders permit researchers to explore disease mechanisms and to test potential therapies. However, therapeutic molecules derived from animal models often translate poorly to the clinic. Although human data may be more relevant, experiments on patients are constrained, and living tissue is unavailable for many disorders. Here, we compare work on animal models and on human tissue for three epileptic syndromes where human tissue is excised therapeutically: (1) acquired temporal lobe epilepsies, (2) inherited epilepsies associated with cortical malformations, and (3) peritumoral epilepsies. Animal models rest on assumed equivalencies between human brains and brains of mice, the most frequently used model animal. We ask how differences between mouse and human brains could influence models. General principles and compromises in model construction and validation are examined for a range of neurological diseases. Models may be judged on how well they predict novel therapeutic molecules or new mechanisms. The efficacy and safety of new molecules are evaluated in clinical trials. We judge new mechanisms by comparing data from work on animal models with data from work on patient tissue. In conclusion, we stress the need to cross-verify findings from animal models and from living human tissue to avoid the assumption that mechanisms are identical.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Altered expression of activating transcription factor 3 in the hippocampus of patients with mesial temporal lobe epilepsy-hippocampal sclerosis (MTLE-HS).

Aim of the study: Activating Transforming factor 3 (ATF3) is a stress induced gene and closely associated with neuro-inflammation while Transforming growth Factor Beta (TGFß) signalling is also reported to be involved in neuro-inflammation and hyper-excitability associated with drug resistant epilepsy. Animal model studies indicate the involvement of ATF3 and TGFß receptors to promote epileptogenesis. Human studies also show that TGFß signalling is activated in MTLE-HS. However, lack of studies on ATF3 and TGFßRI expression in MTLE-HS patients exists. We hypothesize that ATF3 and TGFßRI might be expressed in hippocampi of patients with MTLE-HS and playing role in epileptogenesis.Materials & methods: Protein expression of ATF3 and TGFßRI was performed by western blotting. Localisation of ATF3 was performed by immunohistochemistry and immunoflorescence.Results: Protein expression of ATF3 and TGFßRI was significantly up-regulated in hippocampi of patients as compared to controls. Also ATF3 IR was significantly expressed in hippocampi of patients and ATF3 was expressed predominantly in cytoplasm as compared to nucleus. No correlation was found between ATF3 expression and epilepsy duration and seizure frequency.Conclusions: ATF3 and TGFßRI are both important players in neuro-inflammation and might potentiate epileptogenesis in these patients.

Effective connectivity among the hippocampus, amygdala, and temporal neocortex in epilepsy patients: A cortico-cortical evoked potential study.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is one of the most common types of intractable epilepsy. The hippocampus and amygdala are two crucial structures of the mesial temporal lobe and play important roles in the epileptogenic network of MTLE. This study aimed to explore the effective connectivity among the hippocampus, amygdala, and temporal neocortex and to determine whether differences in effective connectivity exist between MTLE patients and non-MTLE patients. METHODS: This study recruited 20 patients from a large cohort of drug-resistant epilepsy patients, of whom 14 were MTLE patients. Single-pulse electrical stimulation (SPES) was performed to acquire cortico-cortical evoked potentials (CCEPs). The root mean square (RMS) was used as the metric of the magnitude of CCEP to represent the effective connectivity. We then conducted paired and independent sample t-tests to assess the directionality of the effective connectivity. RESULTS: In both MTLE patients and non-MTLE patients, the directional connectivity from the amygdala to the hippocampus was stronger than that from the hippocampus to the amygdala (P < 0.01); the outward connectivity from the amygdala to the cortex was stronger than the inward connectivity from the cortex to the amygdala (P < 0.01); the amygdala had stronger connectivity to the neocortex than the hippocampus (P < 0.01). In MTLE patients, the neocortex had stronger connectivity to the hippocampus than to the amygdala (P < 0.01). No significant differences in directional connectivity were noted between the two groups. CONCLUSIONS: A unique effective connectivity pattern among the hippocampus, amygdala, and temporal neocortex was identified through CCEPs analysis. This study may aid in our understanding of physiological and pathological networks in the brain and inspire neurostimulation protocols for neurological and psychiatric disorders.

Perampanel as first add-on choice on the treatment of mesial temporal lobe epilepsy: an observational real-life study.

PURPOSE: To evaluate the efficacy of perampanel (PER) in patients with a diagnosis of mesial temporal lobe epilepsy (MTLE) taking PER as first add-on option due to inefficacy of first antiepileptic drug (AED), rather than late add-on choice. METHODS: Thirty-seven MTLE patients aged ≥ 12 years were recruited consecutively with a minimum duration of follow-up of 1 year and intermediate follow-up of 3 months. Patients were divided into two groups: 20/37 taking PER as first add-on due to inefficacy of first AED (first group) and 17/37 taking PER as late add-on due to inefficacy of ≥ 2 AEDs (second group). Efficacy, retention rate, and safety were evaluated. RESULTS: At 3 months, the 70% of the first group had a reduction > 50% of seizure frequency, with six patients becoming also seizure free, while in the second group, only the 23.5% had a reduction > 50% of seizure frequency and none became seizure free (p = 0.005). Six patients of first group were also switched to a monotherapy of PER and five out of six remained seizure free at 12 months. At 1 year of follow-up, efficacy of PER was 70% for the first group, while only of 29.4% for the second group (p = 0.014). Retention rate of the first group at 3 months and 1 year was 85%, while for the second group was, respectively, 82.3% and 64.7%. CONCLUSION: PER was significantly successful and tolerated in MTLE patients when used as first add-on option rather than as late add-on.

Targeting Seizure-Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction.

Mesial temporal lobe epilepsy (mTLE), the most common form of medically refractory epilepsy in adults, is usually associated with hippocampal pathophysiology. Using rodent models of mTLE, many studies including work from our laboratory have shown that new neurons born around the onset of severe acute seizures known as status epilepticus (SE) are crucial for the process of epileptogenesis and targeting seizure-induced neurogenesis either genetically or pharmacologically can impact the frequency of chronic seizures. However, these studies are limited in their clinical relevance as none of them determines the potential of blocking new neurons generated after the epileptogenic insult to alleviate the development of chronic seizures. Therefore, using a pilocarpine-induced SE model of mTLE in mice of either sex, we show that >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis after SE can reduce the formation of spontaneous recurrent seizures by 65%. We also found that blocking post-SE neurogenesis does not lead to long-term seizure reduction as the effect was observed only transiently for 10 d with >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis. Thus, these findings provide evidence that seizure-induced neurogenesis when adequately reduced in a clinically relevant time period has the potential to transiently suppress recurrent seizures, but additional mechanisms need to be targeted to permanently prevent epilepsy development.SIGNIFICANCE STATEMENT Consistent with morphological and electrophysiological studies suggesting aberrant adult-generated neurons contribute to epilepsy development, ablation of seizure-induced new neurons at the time of the initial insult reduces the frequency of recurrent seizures. In this study, we show that continuous targeting of post-insult new neurons in a therapeutically relevant time period reduces chronic seizures; however, this effect does not persist suggesting possible additional mechanisms.

Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS).

Changes in the expression of HCN ion channels leading to changes in Ih function and neuronal excitability are considered to be possible mechanisms involved in epileptogenesis in kinds of human epilepsy. In previous animal studies of febrile seizures and temporal lobe epilepsy, changes in the expression of HCN1 and HCN2 channels at different time points and in different parts of the brain were not consistent, suggesting that transcriptional disorders involving HCNs play a crucial role in the epileptogenic process. Therefore, we aimed to assess the transcriptional regulation of HCN channels in Medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. This study included eight nonhippocampal sclerosis patients and 40 MTLE-HS patients. The mRNA expression of HCN channels was evaluated by qRT-PCR, while the protein expression was quantitatively analyzed by Western blotting. The subcellular localization of HCN channels in the hippocampus was explored by immunofluorescence. We demonstrated that the mRNA and protein expression of HCN1 and HCN2 are downregulated in controls compared to that in MTLE-HS patients. In the hippocampal CA1/CA4 subregion and GCL, in addition to a large decrease in neurons, the expression of HCN1 and HCN2 on neuronal cell membranes was also downregulated in MTLE-HS patients. These findings suggest that the expression of HCN channels are downregulated in MTLE-HS, which indicates that the decline in HCN channels in the hippocampus during chronic epilepsy in MTLE-HS patients leads to the downregulation of Ih current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.

Looking for indicative magnetic resonance imaging signs of hippocampal developmental abnormalities in patients with mesial temporal lobe epilepsy and healthy controls.

OBJECTIVE: To evaluate the frequency of qualitative features for hippocampal developmental abnormalities (HiDeA) definition on magnetic resonance imaging (MRI) in mesial temporal lobe epilepsy (MTLE) patients and healthy controls, highlighting which were more sensitive and specific to the epileptic syndrome. METHODS: We enrolled 93 healthy controls and 187 MTLE patients. Among patients, 133 were MRI-negative and 54 had hippocampal sclerosis (HS). Two blinded, trained investigators defined HiDeA if three signs were present, including at least one of the following: (1) globular hippocampal shape (HCS), (2) verticalized collateral sulcus, and (3) medial positioning of hippocampus (HCP). After evaluating the prevalence of HiDeA in MTLE and controls, we assessed the frequency of each sign. Then, we classified differences in type or number of HiDeA diagnostic features, calculating their sensitivity and specificity. Fisher exact test was used to assess statistical significance. RESULTS: HiDeA was detected in 36 of 187 MTLE cases (19.25%) and in eight of 93 (8.6%) controls. In particular, HiDeA was present in 25 of 133 (18.8%) patients with MRI-negative MTLE. Among all visual criteria here considered, HCS showed higher sensitivity both in the MRI-negative MTLE group (88%) and in the HS-MTLE group (91%). HCP, thickened subiculum, and reduction of the upper horizontal portion of the parahippocampal gyrus (HCTH) signs demonstrated a 100% specificity in both groups. In healthy controls, HCS was confirmed to have the highest sensitivity (100%), whereas HCP showed the highest specificity (98.8%). All these criteria were statistically associated with HiDeA. Electroencephalographic focus was concordant with the HiDeA side in 52.2% of MTLE patients. An association was not found among signs of HiDeA and treatment responsiveness. SIGNIFICANCE: We identified characteristic signs of HiDeA, such as HCTH or HCP, differentiating HiDeA features between MTLE and healthy controls. The identification of sensitive and, more importantly, specific criteria of HiDeA could be helpful to make a more confident visual diagnosis.

Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy.

Excitatory-inhibitory imbalance is central to epilepsy pathophysiology. Current surgical therapies for epilepsy, such as brain resection, laser ablation, and neurostimulation, target epileptic networks on macroscopic scales, without directly correcting the circuit-level aberrations responsible for seizures. The transplantation of inhibitory cortical interneurons represents a novel neurobiological method for modifying recipient neural circuits in a physiologically corrective manner. Transplanted immature interneurons have been found to disperse in the recipient brain parenchyma, where they develop elaborate structural morphologies, express histochemical markers of mature interneurons, and form functional inhibitory synapses onto recipient neurons. Transplanted interneurons also augment synaptic inhibition and alter recipient neural network synchrony, two physiological processes disrupted in various epilepsies. In rodent models of epilepsy, interneuron transplantation corrects recipient seizure phenotypes and associated behavioral abnormalities. As such, interneuron transplantation may represent a novel neurobiological approach to the surgical treatment of human epilepsy. Here, the authors describe the preclinical basis for applying interneuron transplantation to human epilepsy, discuss its potential clinical applications, and consider the translational hurdles to its development as a surgical therapy.

Temporal lobe structural evaluation after transsylvian selective amygdalohippocampectomy.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adolescents and adults, and in 65% of cases, it is related to hippocampal sclerosis (HS). Selective surgical approaches to the treatment of MTLE have as their main goal resection of the amygdala and hippocampus with minimal damage to the neocortex, temporal stem, and optic radiations (ORs). The object of this study was to evaluate late postoperative imaging findings on the temporal lobe from a structural point of view. METHODS: The authors conducted a retrospective evaluation of all patients with refractory MTLE who had undergone transsylvian selective amygdalohippocampectomy (SAH) in the period from 2002 to 2015. A surgical group was compared to a control group (i.e., adults with refractory MTLE with an indication for surgical treatment of epilepsy but who did not undergo the surgical procedure). The inferior frontooccipital fasciculus (IFOF), uncinate fasciculus (UF), and ORs were evaluated on diffusion tensor imaging analysis. The temporal pole neocortex was evaluated using T2 relaxometry. RESULTS: For the IFOF and UF, there was a decrease in anisotropy, voxels, and fibers in the surgical group compared with those in the control group (p < 0.001). An increase in relaxometry time in the surgical group compared to that in the control group (p < 0.001) was documented, suggesting gliosis and neuronal loss in the temporal pole. CONCLUSIONS: SAH techniques do not seem to totally preserve the temporal stem or even spare the neocortex of the temporal pole. Therefore, although the transsylvian approaches have been considered to be anatomically selective, there is evidence that the temporal pole neocortex suffers structural damage and potentially functional damage with these approaches.

Inverse national trends of laser interstitial thermal therapy and open surgical procedures for refractory epilepsy: a Nationwide Inpatient Sample-based propensity score matching analysis.

OBJECTIVE: Surgery for medically refractory epilepsy (RE) is an underutilized treatment modality, despite its efficacy. Laser interstitial thermal therapy (LITT), which is minimally invasive, is increasingly being utilized for a variety of brain lesions and offers comparable seizure outcomes. The aim of this study was to report the national trends of open surgical procedures for RE with the advent of LITT. METHODS: Data were extracted using the ICD-9/10 codes from the Nationwide Inpatient Sample (NIS, 2012-2016) in this retrospective study. Patients with a primary diagnosis of RE who underwent either open surgeries (lobectomy, partial lobectomy, and amygdalohippocampectomy) or LITT were included. Patient demographics, complications, hospital length of stay (LOS), discharge disposition, and index hospitalization costs were analyzed. Propensity score matching (PSM) was used to analyze outcomes. RESULTS: A cohort of 128,525 in-hospital patients with RE was included and 5.5% (n = 7045) of these patients underwent either open surgical procedures (94.3%) or LITT (5.7%). LITT is increasingly being performed at a rate of 1.09 per 1000 epilepsy admissions/year, while open surgical procedures are decreasing at a rate of 10.4/1000 cases/year. The majority of procedures were elective (92%) and were performed at large-bed-size hospitals (86%). All LITT procedures were performed at teaching facilities and the majority were performed in the South (37%) and West (30%) regions. The median LOS was 1 day for the LITT cohort and 4 days for the open cohort. Index hospitalization charges were significantly lower following LITT compared to open procedures ($108,332 for LITT vs $124,012 for open surgery, p < 0.0001). LITT was associated with shorter median LOS, high likelihood of discharge home, and lower median index hospitalization charges compared to open procedures for RE on PSM analysis. CONCLUSIONS: LITT is increasingly being performed in favor of open surgical procedures. LITT is associated with a shorter LOS, a higher likelihood of being discharged home, and lower index hospitalization charges compared to open procedures. LITT is a safe treatment modality in carefully selected patients with RE and offers an opportunity to increase the utilization of surgical treatment in patients who may be opposed to open surgery or have contraindications that preclude open surgery.

Laser ablation is effective for temporal lobe epilepsy with and without mesial temporal sclerosis if hippocampal seizure onsets are localized by stereoelectroencephalography.

OBJECTIVE: Selective laser amygdalohippocampotomy (SLAH) using magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is emerging as a treatment option for drug-resistant mesial temporal lobe epilepsy (MTLE). SLAH is less invasive than open resection, but there are limited series reporting its safety and efficacy, particularly in patients without clear evidence of mesial temporal sclerosis (MTS). METHODS: We report seizure outcomes and complications in our first 30 patients who underwent SLAH for drug-resistant MTLE between January 2013 and December 2016. We compare patients who required stereoelectroencephalography (SEEG) to confirm mesial temporal onset with those treated based on imaging evidence of MTS. RESULTS: Twelve patients with SEEG-confirmed, non-MTS MTLE and 18 patients with MRI-confirmed MTS underwent SLAH. MTS patients were older (median age 50 vs 30 years) and had longer standing epilepsy (median 40.5 vs 5.5 years) than non-MTS patients. Engel class I seizure freedom was achieved in 7 of 12 non-MTS patients (58%, 95% confidence interval [CI] 30%-86%) and 10 of 18 MTS patients (56%, 95% CI 33%-79%), with no significant difference between groups (odds ratio [OR] 1.12, 95% CI 0.26-4.91, P = .88). Length of stay was 1 day for most patients (range 0-3 days). Procedural complications were rare and without long-term sequelae. SIGNIFICANCE: We report similar rates of seizure freedom following SLAH in patients with MTS and SEEG-confirmed, non-MTS MTLE. Consistent with early literature, these rates are slightly lower than typically observed with surgical resection (60%-80%). However, SLAH is less invasive than open surgery, with shorter hospital stays and recovery, and severe procedural complications are rare. SLAH may be a reasonable first-line surgical option for patients with both MTS and SEEG confirmed, non-MTS MTLE.

Social Perception in Mesial Temporal Lobe Epilepsy: Interpreting Social Information From Moving Shapes and Biological Motion.

Dysfunction in the understanding of social signals has been reported in persons with epilepsy, which may partially explain lower levels of life satisfaction in this patient population. Extensive assessment is necessary, particularly when the mesial temporal lobe, responsible for emotion processing, is affected. The authors examined multiple levels of social perception in patients with mesial temporal lobe epilepsy (MTLE), including judgments of point-light motion displays of human communicative interactions (Communicative Interactions Database-5 Alternative Forced Choice format) and theory-of-mind processes evaluated using geometric shapes (Frith-Happé animations [FHA]). This case-control study included MTLE patients with anterior temporal lobectomies (ATL+) (N=19), MTLE patients without lobectomies (ATL-) (N=21), and healthy controls (HCs) (N=20). Both groups of MTLE patients were less efficient in recognizing goal-directed and mentalizing interactions of FHA compared with HC subjects. The ATL+ group attributed emotions to FHA less accurately than HC subjects. Both the ATL- and ATL+ groups classified individual point-light animations more often as communicative than the HC group. ATL+ patients were also less efficient in interpreting point-light animations in terms of individual actions than the HC group. The number of years of epilepsy duration was inversely correlated with recognition of FHA interactions. The mean number of seizures was inversely correlated with the interaction identification in point-light stimuli. Patients with MTLE, irrespective of surgical treatment, present impaired social perception in domains assessed with abstract moving shapes or nonabstract biological motion. This impairment may be the basis of problems faced by patients reporting difficulties in understanding the intentions and feelings of other individuals.

Immunogenetic predisposing factors for mesial temporal lobe epilepsy with hippocampal sclerosis.

PURPOSE: Neuroinflammation appears as an important epileptogenic mechanism. Experimental and clinical studies have demonstrated an upregulation of pro-inflammatory cytokines such as IL-1ß 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-1ß), 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-1ß levels produced by this genotype. High IL-1ß levels may have neurotoxic effects or imbalance neurotransmission leading to seizures.

RNA-seq analysis of hippocampal tissues reveals novel candidate genes for drug refractory epilepsy in patients with MTLE-HS.

Array-based profiling studies have shown implication of aberrant gene expression patterns in epileptogenesis. We have performed transcriptome analysis of hippocampal tissues resected from patients with MTLE-HS using RNAseq approach. Healthy tissues from tumour margins obtained during tumour surgeries were used as non-epileptic controls. RNA sequencing was performed using standard protocols on Illumina HiSeq 2500 platform. Differential gene expression analysis of the RNAseq data revealed 56 significantly regulated genes in MTLE patients. Gene cluster analysis identified 3 important hubs of genes mostly linked to, neuroinflammation and innate immunity, synaptic transmission and neuronal network modulation which are supportive of intrinsic severity hypothesis of pharmacoresistance. This study identified various genes like FN1 which is central in our analysis, NEUROD6, RELN, TGFßR2, NLRP1, SCRT1, CSNK2B, SCN1B, CABP1, KIF5A and antisense RNAs like AQP4-AS1 and KIRREL3-AS2 providing important insight into the understanding of the pathophysiology or genomic basis of drug refractory epilepsy due to MTS.

High-Throughput LC-MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development.

Uncovering the molecular mechanisms of mesiotemporal lobe epilepsy (MTLE) is critical to identify therapeutic targets. In this study, we performed global protein expression analysis of a kainic acid (KA) MTLE mouse model at various time-points (1, 3, and 30 days post-KA injection -dpi), representing specific stages of the syndrome. High-resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination with label-free protein quantification using three processing approaches for quantification, was applied. Following comparison of KA versus NaCl-injected mice, 22, 53, and 175 proteins were differentially (statistically significant) expressed at 1, 3 and 30dpi, respectively, according to all three quantification approaches. Selected findings were confirmed by multiple reaction monitoring LC-MS/MS. As a positive control, the astrocyte marker GFAP was found to be upregulated (3dpi: 1.9 fold; 30dpi: 12.5 fold), also verified by IHC. The results collectively suggest that impairment in synaptic transmission occurs even right after initial status epilepticus (1dpi), with neurodegeneration becoming more extensive during epileptogenesis (3dpi) and sustained at the chronic phase (30dpi), where also extensive glial- and astrocyte-mediated inflammation is evident. This molecular profile is in line with observed phenotypic changes in human MTLE, providing the basis for future studies on new molecular targets for the disease.

Up-regulation of P2X7 receptor-mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex.

OBJECTIVE: Thirty percent of patients with epilepsy are refractory to medication. The majority of these patients have mesial temporal lobe epilepsy (MTLE). This prompts for new pharmacologic targets, like ATP-mediated signaling pathways, since the extracellular levels of the nucleotide dramatically increase during in vitro epileptic seizures. In this study, we investigated whether sodium-dependent high-affinity γ-aminobutyric acid (GABA) and glutamate uptake by isolated nerve terminals of the human neocortex could be modulated by ATP acting via slow-desensitizing P2X7 receptor (P2X7R). METHODS: Modulation of [(3) H]GABA and [(14) C]glutamate uptake by ATP, through activation of P2X7R, was investigated in isolated nerve terminals of the neocortex of cadaveric controls and patients with drug-resistant epilepsy (non-MTLE or MTLE) submitted to surgery. Tissue density and distribution of P2X7R in the human neocortex was assessed by Western blot analysis and immunofluorescence confocal microscopy. RESULTS: The P2X7R agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP, 3-100 µm) decreased [(3) H]GABA and [(14) C]glutamate uptake by nerve terminals of the neocortex of controls and patients with epilepsy. The inhibitory effect of BzATP (100 µm) was prevented by the selective P2X7R antagonist, A-438079 (3 µm). Down-modulation of [(14) C]glutamate uptake by BzATP (100 µm) was roughly similar in controls and patients with epilepsy, but the P2X7R agonist inhibited more effectively [(3) H]GABA uptake in the epileptic tissue. Neocortical nerve terminals of patients with epilepsy express higher amounts of the P2X7R protein than control samples. SIGNIFICANCE: High-frequency cortical activity during epileptic seizures releases huge amounts of ATP, which by acting on low-affinity slowly desensitizing ionotropic P2X7R, leads to down-modulation of neuronal GABA and glutamate uptake. Increased P2X7R expression in neocortical nerve terminals of patients with epilepsy may, under high-frequency firing, endure GABA signaling and increase GABAergic rundown, thereby unbalancing glutamatergic neuroexcitation. This study highlights the relevance of the ATP-sensitive P2X7R as an important negative modulator of GABA and glutamate transport and prompts for novel antiepileptic therapeutic targets.