Refractory Temporal Lobe Epilepsy Patients Research Articles

Progressive postoperative atrophy of ipsilateral thalamus, putamen, and globus pallidus in patients with temporal lobe epilepsy: A volumetric analysis.

Cortical atrophy close to medial temporal structures has been described consistently in patients with temporal lobe epilepsy (TLE). Successful TLE surgery may have a neuroprotective effect preventing further atrophy of temporal and extratemporal cortex. However, the effects of epilepsy surgery on subcortical structures demand additional enlightenment. This work aimed to determine how epilepsy surgery affects volumes of subcortical structures in medically refractory temporal lobe epilepsy patients. We compared MRI volumes of subcortical structures in 62 patients with TLE (36 left, 26 right) before and after anterior temporal lobectomy with 38 TLE patients (20 left, 18 right) who were considered to be good surgical candidates and had at least two brain MRIs. There were no volume differences in subcortical structures on preoperative and initial MRIs of non-operated TLE patients. At baseline, the ipsilateral thalamus and putamen in TLE patients were marginally smaller than contralateral structures. Operated patients showed a significant postoperative volume reduction in ipsilateral thalamus, putamen, and globus pallidus. In contrast, there were no significant volumetric reductions in non-operated patients longitudinally. There were no volumetric changes associated with different surgical outcomes or different postoperative cognitive outcomes. Our study demonstrated postoperative volume loss of thalamus, putamen and globus pallidus ipsilaterally to the side of resection. Our findings suggest surgery-related changes, likely Wallerian degeneration within subcortical networks not related to seizure or cognitive outcome. We studied 100 patients with epilepsy, comparing those who had surgery to those who did not. After surgery, the thalamus, putamen and globus pallidus on the same side as the surgery shrank significantly, but not in non-surgery patients. This suggests surgery-related changes in deeper brain structures, unrelated to seizure freedom or cognitive outcomes. This research sheds additional light on the response of the subcortical structure to epilepsy surgery, highlighting potential areas for further study.

28 Challenges to Lateralizing Visual Memory Dysfunction in TLE Patients

Objective:Neuropsychological assessment is an essential part of presurgical evaluation for epilepsy patients with refractory temporal lobe epilepsy. Evaluations assist in localizing and lateralizing epileptogenic focal points and identifying possible risks for cognitive decline following surgery. Researchers and clinicians consistently find that verbal memory dysfunction is an accurate indicator of left temporal lobe epilepsy (TLE) through verbal measures such as the CVLT-II. Although visual memory structures are assumed to be in the right (nondominant) hemisphere, visual memory assessments have not been reliable in identifying right TLE. It is hypothesized that assessments to test visual memory are confounded by verbal cueing to assist in visual learning. To account for this, researchers have identified that comparing verbal and visual score asymmetries does accurately differentiate left and right TLE patients. This study aimed to determine if verbalvisual asymmetry using the CVLT-II and BVMT-R accurately identifies left and right TLE relative weaknesses potentially associated with epileptogenic regions.Participants and Methods:As part of a pre-surgical neuropsychological evaluation, 37 well-characterized medically refractory TLE patients (18 right TLE; 19 left TLE) were administered the Brief Visuospatial Memory Test-Revised to evaluate visuospatial memory and the CVLT-II to evaluate verbal memory. A multivariate analysis of variance was used to compare RTLE and LTLE group performances on BVMT-R delay recall subscales, using T-scores. Then memory asymmetry scores were calculated by converting CVLT-II verbal delay memory scores to T-scores and subtracting BVMT-R delayed recall T-score from the verbal memory T-score. An independent samples t-test was used to compare asymmetry scores between the groups.Results:There were no significant differences between patients with RTLE and LTLE for BVMT-R Delay [F(2,34) = 0.11, p = .895]. There was not a significant difference when accounting for verbal-visual asymmetry (t (35) = 0.422, p = 0.675, d = 12.566) between left (M = -2.42, SD = 13.82) and right side (M = -4.17, SD = 11.09).Conclusions:The BVMT-R did not identify nondominant hemisphere dysfunction in this sample of 18 right TLE patients. Because visual memory performance did not inform lateralization, we investigated the usefulness of memory asymmetry. Inconsistent with our hypothesis, verbal-visual memory asymmetry scores did not differentiate RTLE from LTLE in this sample. These findings add to existing findings that the BVMT-R may not be able to identify visuospatial memory dysfunction in epilepsy. Additionally, these data indicate the inability to assess for visuospatial memory even when accounting for verbal abilities in epilepsy patients. Future research should consider alternate visuospatial measures for the evaluation of epilepsy patients.

Inhibitory dysfunction may cause prospective memory impairment in temporal lobe epilepsy (TLE) patients: an event-related potential study.

Prospective memory (PM) is the ability to remember future intentions, and PM function is closely related to independence in daily life, particularly in patients with temporal lobe epilepsy (TLE). As PM involves various cognitive components of attention, working memory, inhibition and other executive functions, this study investigated how TLE may affect PM components and the underlying neural mechanisms. Sixty-four subjects were recruited, including 20 refractory TLE patients, 18 well-controlled TLE patients and 26 age-matched healthy controls. A set of neuropsychological tests was administered to assess specific brain functions. An event-related potential (ERP) task was used to further explore how PM and its components would be differentially affected in the two TLE types. Our findings revealed that: (1) refractory TLE patients scored lower than the healthy controls in the digit span, Verbal Fluency Test and Symbol Digit Modalities Test; (2) refractory TLE patients exhibited impaired PM performance and reduced prospective positivity amplitudes over the frontal, central and parietal regions in ERP experiments when compared to the healthy controls; and (3) decreased P3 amplitudes in the nogo trials were observed over the frontal-central sites in refractory but not in well-controlled TLE patients. To our knowledge, this is the first ERP study on PM that has specifically identified PM impairment in refractory but not in well-controlled TLE patients. Our finding of double dissociation in PM components suggests that inhibition dysfunction may be the main reason for PM deficit in refractory TLE patients. The present results have clinical implications for neuropsychological rehabilitation in TLE patients.

Evaluation of Cognitive Impairment in Refractory Temporal Lobe Epilepsy Patients Concerning Structural Brain Lesions

Introduction: Temporal lobe epilepsy (TLE) is the most prevalent form of drug-resistant epilepsy with concurrent cognitive impairment. Prevention, earlier diagnosis, and personalized management of cognitive deficits in TLE require more understanding of underlying structural and functional brain Ialterations. No study has evaluated the performance of TLE patients in different cognitive domains based on their structural brain lesions. Methods: In this study, 69 refractory TLE patients underwent magnetic resonance imaging (MRI) epilepsy protocol and several neuropsychological tests, consisting of the Wechsler adult intelligence scale-revised, Rey-Osterrieth complex figure test, verbal fluency test, digit span test, spatial span test, Wechsler memory scale-III, design fluency test, Rey visual design learning test, auditory-verbal learning test, and trail making test. MRI findings were classified into the following groups: Focal cortical dysplasia, gliosis, atrophy, mesial temporal sclerosis (MTS), tumor, vascular malformation, and other lesions or normal. Results of neuropsychological tests were compared between MRI groups using a generalized linear model with gamma distribution and log link. Results: Patients with MTS showed better performance in general intellectual functioning, working memory, attentional span, and auditory-verbal learning compared to patients with non-MTS MRI lesions. Atrophy and focal cortical dysplasia had the largest differences from MTS. Conclusion: Cognitive performance of refractory TLE patients varies concerning structural brain alterations. Further neuroimaging studies of TLE lead to prevention and more accurate management of cognitive decline in clinical settings.

O039 / #583 PATIENT-SPECIFIC STRUCTURAL CONNECTIVITY PREDICTS OUTCOMES OF RESPONSIVE NEUROSTIMULATION FOR TEMPORAL LOBE EPILEPSY: TRACK 2: NEUROMODULATION FOR EPILEPSY

Responsive neurostimulation (RNS) is an effective therapy option for refractory temporal lobe epilepsy patients. However, seizure reduction is variable across patients and the optimal stimulation location or parameters are currently undefined. We hypothesize that this variability may be related to the networks modulated with RNS. Our objective was to determine if stimulation location or stimulation-dependent networks are predictive of seizure reduction.

Chapter 29 - Surgery procedures in temporal lobe epilepsies

Temporal lobe epilepsy (TLE) is the most common cause of refractory epilepsy amenable for surgical treatment and seizure control. Surgery for TLE is a safe and effective strategy. The seizure-free rate after surgical resection in patients with mesial or neocortical TLE is about 70%. Resective surgery has an advantage over stereotactic radiosurgery in terms of seizure outcomes for mesial TLE patients. Both techniques have similar results for safety, cognitive outcomes, and associated costs. Stereotactic radiosurgery should therefore be seen as an alternative to open surgery for patients with contraindications for or with reluctance to undergo open surgery. Laser interstitial thermal therapy (LITT) has also shown promising results as a curative technique in mesial TLE but needs to be more deeply evaluated. Brain-responsive stimulation represents a palliative treatment option for patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior mesial temporal lobe resection. Overall, despite the expansion of innovative techniques in recent years, resective surgery remains the reference treatment for TLE and should be proposed as the first-line surgical modality. In the future, ultrasound therapies could become a credible therapeutic option for refractory TLE patients.

Quantitative analysis of cerebellar lobule morphology and clinical cognitive correlates in refractory temporal lobe epilepsy patients

PurposeThis study was conducted to explore the cerebellar substructure volumetric alterations in refractory unilateral temporal lobe epilepsy (TLE) patients and the relationship with clinical factors and cognitive scores. MethodsA total of 48 unilateral refractory TLE patients and 48 age- and gender-matched normal controls (NCs) were retrospectively studied. All subjects underwent high-resolution magnetic resonance imaging (MRI) and automatically segmented volumetric brain information was obtained using volBrain and Data Processing Assistant for Resting-State fMRI (DPARSF) separately. Clinical seizure features and cognitive scores were acquired by a structured review of medical records. ResultsThe total volumes (TVs) of bilateral crus I, crus II, and IX were significantly smaller in the refractory unilateral TLE epilepsy patients. The gray matter volumes (GMVs) of cerebellar lobules showed lateralized reduction in ipsilateral III, IX, and contralateral crus II. Contralateral crus II GMV showed significant negative correlation with the duration of epilepsy (r = −0.31, p = 0.035) and positive association with the cognitive scores including long-term memory (LTM) (r = 0.39, p = 0.017), short-term memory (STM) (r = 0.51, p = 0.001) verbal comprehension index (VCI) (r = 0.37, p = 0.024), and perceptual organization index (POI) (r = 0.36, p = 0.030). The voxel-based morphometry (VBM) analysis proved similar results. The contralateral crus I GMV was significantly smaller in the generalized onset group (t = 2.536, p = 0.015). ConclusionsThe lobules of the cerebellar in refractory TLE patients manifest different volumetric change characteristics. Crus II contralateral GMV is negatively correlated with the duration of epilepsy and positively associated with the cognitive scores.

Cognitive impairment in temporal lobe epilepsy: contributions of lesion, localization and lateralization.

Cognitive impairment is an importantcomorbidityof refractory temporal lobe epilepsy (TLE). We aimed to explore the impact of (i) specific lesions, such as dysembryoplastic neuroepithelial tumor (DNET), dysplasia, or hippocampal sclerosis, (ii) focus localization (medial versus lateral) and (iii) focus lateralization (right versus left) on the neuropsychological profile of refractory TLE adult patients. We examined the neuropsychological characteristics of 312 adults with refractory TLE: 100 patients without hippocampal sclerosis (HS) and 212 with HS. Scores on tests of intelligence (Global IQ, Verbal IQ and Performance IQ), working memory, episodic memory (verbal and visual learning and forgetting), executive functions and language abilities were analyzed. Three main factors influenced the neuropsychological profile of refractory TLE patients: (i) the lesion, patients with HS obtaining poorer cognitive performances than patients without HS and specifically DNET patients performing better than patients with HS, (ii) the focus side, that seems only relevant for verbal memory abilities which are affected in left but not right TLE patients and (iii) the localization of seizure focus, patients with medial TLE exhibiting lower memory performances than patients with lateral TLE. Lesion, localization and lateralization are major contributors of the cognitive impairment depicted in TLE. Hippocampal sclerosis appears as the main contributor.

Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy.

ObjectiveCognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE), but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface‐shape patterns to verbal and visual learning.MethodsWe analyzed hippocampal surface shapes on high‐resolution magnetic resonance images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients, and 39 age‐ and sex‐matched healthy volunteers.ResultsBoth left TLE (LTLE) and right TLE (RTLE) patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8, RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8, visual 39 ± 6; p < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline.InterpretationMemory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020 ANN NEUROL 2020;88:170–182

The contribution of sphenoidal electrodes placed under fluoroscopy in lateralization of bilateral refractory temporal lobe epilepsy: a clinical study

Aim: The aim of this study is to investigate the contribution of sphenoidal electrodes placed under fluoroscopic guidance to scalp electrodes, in the lateralization of temporal ictal onsets in bilateral refractory temporal lobe epilepsy. Also we determine the actual locations of sphenoidal electrodes by computerized tomography. Materials and Methods: We performed a prospective study on 10 patients with intractable epilepsy who has underwent sphenoidal electrode placement from 2010 to 2012. Refractory temporal lobe epilepsy patients whose localization and lateralization of epileptic focus couldn’t established with scalp EEG, or patients diagnosed bitemporal epilepsy with bitemporal seizure activity in video-EEG but no seizure onset identified, were evaluated. Sphenoidal electrodes placed double-sided to patients under sedation in the operating room. The control of the sphenoidal electrodes’ last position and several parameters displayed with 3D tomography. Patients monitorized at video-EEG unit. Simultaneously sphenoidal electrodes and scalp electrodes recordings obtained. Sphenoidal electrode lateralization results are compared with MRI, PET, SCALP EEG lateralization. Results: The utility rate of sphenoidal electrode recordings were found to be 28.1%. 2 of 10 cases lateralized were localized, 4 of 8 patients were lateralized by sphenoidal electrodes. Conclusion: Sphenoidal electrodes and scalp electrodes are similar in their ability to detect seizures. The optimal placement of sphenoidal electrodes with our technique provided additional localizing and lateralizing information in this series.

Visual seizure annotation and automated seizure detection using behind‐the‐ear electroencephalographic channels

ObjectiveSeizure diaries kept by patients are unreliable. Automated electroencephalography (EEG)‐based seizure detection systems are a useful support tool to objectively detect and register seizures during long‐term video‐EEG recording. However, this standard full scalp‐EEG recording setup is of limited use outside the hospital, and a discreet, wearable device is needed for capturing seizures in the home setting. We are developing a wearable device that records EEG with behind‐the‐ear electrodes. In this study, we determined whether the recognition of ictal patterns using only behind‐the‐ear EEG channels is possible. Second, an automated seizure detection algorithm was developed using only those behind‐the‐ear EEG channels.MethodsFifty‐four patients with a total of 182 seizures, mostly temporal lobe epilepsy (TLE), and 5284 hours of data, were recorded with a standard video‐EEG at University Hospital Leuven. In addition, extra behind‐the‐ear EEG channels were recorded. First, a neurologist was asked to annotate behind‐the‐ear EEG segments containing selected seizure and nonseizure fragments. Second, a data‐driven algorithm was developed using only behind‐the‐ear EEG. This algorithm was trained using data from other patients (patient‐independent model) or from the same patient (patient‐specific model).ResultsThe visual recognition study resulted in 65.7% sensitivity and 94.4% specificity. By using those seizure annotations, the automated algorithm obtained 64.1% sensitivity and 2.8 false‐positive detections (FPs)/24 hours with the patient‐independent model. The patient‐specific model achieved 69.1% sensitivity and 0.49 FPs/24 hours.SignificanceVisual recognition of ictal EEG patterns using only behind‐the‐ear EEG is possible in a significant number of patients with TLE. A patient‐specific seizure detection algorithm using only behind‐the‐ear EEG was able to detect more seizures automatically than what patients typically report, with 0.49 FPs/24 hours. We conclude that a large number of refractory TLE patients can benefit from using this device.

Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study.

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole-brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high-resolution 7T T2-weighted magnetic resonance imaging (MRI) and resting-state BOLD-fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE-MTS) and MRI-negative nonlesional patients (TLE-NL). Using an automated multi-atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE-MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE-NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole-hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE-NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE-MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging-based network properties within the MTL can distinguish between TLE subtypes. High-resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.

Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7years (range 0.9-18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9years (range 0-7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE.

Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical, pathological and neuroimaging evidence.

Cognitive decline is increasingly described as a co-morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)-related TLE. Accelerated cognitive decline is described in groups of adult HS-related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post-temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post-operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS-related TLE and correlated to post-operative cognitive decline in some patients. A traumatic head injury-related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross-sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine invivo pathways and further explore cognitive decline in TLE.

Altered spontaneous brain activity in MRI-negative refractory temporal lobe epilepsy patients with major depressive disorder: A resting-state fMRI study

ObjectiveTo investigate alterations in spontaneous brain activity in MRI-negative refractory temporal lobe epilepsy patients with major depressive disorder using resting-state functional magnetic resonance imaging (RS-fMRI). MethodsEighteen MRI-negative refractory temporal lobe epilepsy patients with major depressive disorder (PDD), 17 MRI-negative refractory temporal lobe epilepsy patients without major depressive disorder (nPDD), and 21 matched healthy controls (HC) were recruited from West China Hospital of SiChuan University from April 2016 to June 2017. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 17-item Hamilton Depression Rating Scale were employed to confirm the diagnosis of major depressive disorder and assess the severity of depression. All participants underwent RS-fMRI scans using a 3.0T MRI system. MRI data were compared and analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) to measure spontaneous brain activity. These two methods were both used to evaluate spontaneous cerebral activity. ResultsThe PDD group showed significantly altered spontaneous brain activity in the bilateral mesial prefrontal cortex, precuneus, angular gyrus, right parahippocampal gyrus, and right temporal pole. Meanwhile, compared with HC, the nPDD group demonstrated altered spontaneous brain activity in the temporal neocortex but no changes in mesial temporal structures. ConclusionThe PDD group showed regional brain activity alterations in the prefrontal-limbic system and dysfunction of the default mode network. The underlying pathophysiology of PDD may be provided for further studies.

MiR-153 regulates expression of hypoxia-inducible factor-1α in refractory epilepsy.

Mesial temporal lobe epilepsy (mTLE), the most common type of temporal lobe epilepsy (TLE), is particularly relevant due to its high frequency of therapeutic resistance of anti-epileptic therapies. MicroRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE. The present study aimed to explore the expression and functions of miRNA-153 in mTLE. The expression levels of miRNA-153 in refractory TLE patients were evaluated. The bioinformatics analysis showed that the potential target genes of miR-153 were involved in biological processes, molecular functions, and cellular components. miRNA-153 is significantly dysregulated in temporal cortex and plasma of mTLE patients. We identify HIF-1α as a direct target of miRNA-153, and luciferase reporter assays demonstrated that miR-153 could regulate the HIF-1αexpression via 3'-UTR pairing. These data suggest that miR-153 might represent a useful biomarker and treatment target for patients with mTLE.

Neuronal zinc-α2-glycoprotein is decreased in temporal lobe epilepsy in patients and rats

Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein encoded by the AZGP1 gene that is known as a lipid mobilizing factor and is highly homologous to major histocompatibility complex class I family molecules. Recently, transcriptomic research has shown that AZGP1 expression is reduced in the brain tissue of epilepsy patients. However, the cellular distribution and biological role of ZAG in the brain and epilepsy are unclear. Patients with refractory temporal lobe epilepsy (TLE) and brain trauma were included in this study, and pentylenetetrazole (PTZ)-kindled rats were also used. The existence and level of ZAG in the brain were identified using immunohistochemistry, double-labeled immunofluorescence and western blot, and the expression level of AZGP1 mRNA was determined with quantitative real-time polymerase chain reaction (qrt-PCR). To explore the potential biological role of ZAG in the brain, co-immunoprecipitation (Co-IP) of phosphorylated ERK (p-ERK), TGF-β1 and ZAG was also performed. ZAG was found in the cytoplasm of neurons in brain tissue from both patients and rats. The levels of AZGP1 mRNA and ZAG were lower in refractory TLE patients and PTZ-kindled rats than in controls. In addition, the ZAG level decreased as PTZ kindling continued. Co-IP identified direct binding between p-ERK, TGF-β1 and ZAG. ZAG was found to be synthesized in neurons, and both the AZGP1 mRNA and ZAG protein levels were decreased in epilepsy patients and rat models. The reduction in ZAG may participate in the pathogenesis and pathophysiology of epilepsy by interacting with p-ERK and TGF-β1, promoting inflammation, regulating the metabolism of ketone bodies, or affecting other epilepsy-related molecules.

Expression of microRNA-129-2-3p and microRNA-935 in plasma and brain tissue of human refractory epilepsy

ObjectiveNumerous microRNAs (miRNAs) are differentially expressed in specific diseases, suggesting possible use as diagnostic or prognostic biomarkers. The purpose of this study is to investigate the expression levels of miR-129-2-3p and miR-935 in cortical brain tissue and plasma samples from controls and refractory temporal lobe epilepsy (TLE) patients to evaluate the utility of these measures as diagnostic biomarkers. MethodsThe study was divided into three phases. First, cortical brain tissue samples from nine refractory TLE patients and eight controls were screened for differential miRNA expression using the Affymetrix miRNA 4.0 microarray. Second, real-time quantitative PCR (qRT-PCR) was used to verify the microarray results in brain tissue samples from 13 refractory TLE patients and 13 healthy controls (including those studied by microarray analysis). Third, we tested the expression levels of selected miRNAs in plasma samples from 25 refractory TLE patients and 25 healthy volunteers by qRT-PCR. The capacity of miR-129-2-3p and miR-935 expression to distinguish refractory TLE from health controls was tested by receiver operator characteristics (ROC) curve analysis. Results(1) High-resolution miRNA arrays indicated that miR-129-2-3p and miR-935 were significantly upregulated in the cortical brain tissues of TLE patients compared to controls. (2) qRT-PCR confirmed upregulated miR-129-2-3p expression in the brain tissue(P<0.0001) and plasma samples(P=0.0008) of refractory TLE patients. (3) The expression of miR-935 in epilepsy patients was higher than control group, however, there are no significant statistical differences between them whether in plasma samples(P=0.644) or in tissue samples(P=0.258). (4) ROC analysis of miRNA-129-2-3p showed that the area under the curve (AUC) was 0.929 (95% CI: 0.833–1.000; p=0.000) for brain tissue and 0.778 (95% CI: 0.640–0.915; p=0.001) for plasma. ConclusionExpression of miRNA-129-2-3p was upregulated in cortical brain tissue and plasma samples from patients with refractory TLE, but miR-935 not. Plasma miRNA-129-2-3p has great potential as a non-invasive biomarker for early detection and clinical evaluation of refractory TLE.

Interhemispheric microstructural connectivity in bitemporal lobe epilepsy with hippocampal sclerosis

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. The most frequent pathologic finding in this condition is hippocampal sclerosis (HS). In addition, in a small proportion (14–23%) of refractory TLE patients, the presence of HS is bilateral. TLE involves grey matter (GM) and white matter (WM) abnormalities in a wide cortico-subcortical network. However, the impact of neuronal loss on specific WM fiber pathways and associated functional systems as well as seizure propagation pathways remains unclear. There is still much controversy regarding the role of the commissures (corpus callosum, hippocampal commissure and anterior commissure) in interhemispheric seizure propagation. This study aimed to investigate the integrity of WM interhemispheric connectivity in a singular sample of patients with TLE and bilateral HS using structural magnetic resonance imaging (MRI). We performed multimodal structural MRI [high resolution T1-weighted and diffusion tensor imaging (DTI)] analyses of seven patients with medically refractory TLE with bilateral HS, fourteen unilateral left TLE patients and fifteen matched healthy individuals. Whole-brain voxel-wise analysis techniques were used. These patients evidenced WM derangement [reduced fractional anisotropy (FA), increased mean diffusivity (MD) or reduced WM volume] in temporal and extratemporal tracks, but also in commissural pathways, compared to the unilateral left TLE patients and the control group. Presence of reduced FA or increased MD in the fornix, cingulum and uncinate fasciculus in addition to reduced WM volume in the fornix was also encountered. Neuropsychological assessment was performed without significant correlations with structural data. The current results support the idea that commissural pathways play a contributory role in interhemispheric TLE seizure propagation in bilateral HS and offer new perspectives about the long-term effects on interhemispheric connectivity associated with seizure propagation patterns in TLE patients.

Association of insulin receptor H1085H C>T, insulin receptor substrate 1 G972R and insulin receptor substrate 2 1057G/A polymorphisms with refractory temporal lobe epilepsy in Han Chinese

PurposeInsulin/insulin receptor (INSR) signaling plays diverse roles in the central nervous system, including regulation of blood glucose, synaptic plasticity, dendritic growth, modulation of electrophysiological activity, proliferation of astrocytes and neuronal apoptosis. Interestingly, many of these and/or related processes represent biological mechanisms associated with temporal lobe epilepsy (TLE). Thus, insulin signaling may play a role in the development of TLE and its therapeutic responses. We hypothesized that functional polymorphisms in the insulin pathway genes INSR, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with the therapeutic responses of TLE. Therefore, in this study we analyzed the association of three single nucleotide polymorphisms (SNPs) showing a risk for TLE drug resistance using a hospital-based case–control design. MethodTwo hundred and one patients with refractory TLE and one hundred and seventy-five drug-responsive TLE patients were recruited for the study. Polymerase chain reaction–restriction fragment length polymorphism was used to detect the genotypes of INSR His1085His, IRS1 G972R and IRS2 1057G/A. ResultsNo significant differences between refractory and drug-responsive TLE patients were observed for the IRS1 G972R and IRS2 1057G/A polymorphisms (P>0.05), but a significant association was found for the INSR His1085His polymorphism for both genotypes (P=0.035) and alleles (P=0.011). IRS2 1057G/A combined with the INSR His1085His polymorphism increased the odds ratio of drug resistance in TLE (P=0.011, OR=2.263, 95% CI: 1.208–4.239). ConclusionThese results suggest that a genetic variation in the insulin signaling pathway genes may affect the therapeutic response of TLE.