Drug-resistant Focal Epilepsy Research Articles

How does levetiracetam add-on compare with placebo for adults and children with drug-resistant focal epilepsy?

How does levetiracetam add-on compare with placebo for adults and children with drug-resistant focal epilepsy?

Prediction of baseline expressive and receptive language function in children with focal epilepsy using diffusion tractography-based deep learning network

PurposeFocal epilepsy is a risk factor for language impairment in children. We investigated whether the current state-of-the-art deep learning network on diffusion tractography connectome can accurately predict expressive and receptive language scores of children with epilepsy. MethodsWe studied 37 children with a diagnosis of drug-resistant focal epilepsy (age: 11.8 ± 3.1 years) using 3 T MRI and diffusion tractography connectome: G = (S, Ω), where S is an adjacency matrix of edges representing the connectivity strength (number of white-matter tract streamlines) between each pair of brain regions, and Ω reflects a set of brain regions. A convolutional neural network (CNN) was trained to learn the nonlinear relationship between ‘S (input)’ and ‘language score (output)’. Repeated hold-out validation was then employed to measure the Pearson correlation and mean absolute error (MAE) between CNN-predicted and actual language scores. ResultsWe found that CNN-predicted and actual scores were significantly correlated (i.e., Pearson’s R/p-value: 0.82/<0.001 and 0.75/<0.001), yielding MAE: 7.77 and 7.40 for expressive and receptive scores, respectively. Specifically, sparse connectivity not only within the left cortico-cortical network but also involving the right subcortical structures was predictive of language impairment of expressive or receptive domain. Subsequent subgroup analyses inferred that the effectiveness of diffusion tractography-based prediction of language outcome was independent of clinical variables. Intrinsic diffusion tractography connectome properties may be useful for predicting the severity of baseline language dysfunction and possibly provide a better understanding of the biological mechanisms of epilepsy-related language impairment in children.

Travelling waves reveal a dynamic seizure source in human focal epilepsy.

Treatment of patients with drug-resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured by intracranial EEG has traditionally been interpreted to suggest that the underlying cortex is actively involved in seizures. Here, we hypothesize that such activity instead reflects propagated activity from a relatively focal seizure source, even during later time points when ictal activity is more widespread. We used the time differences observed between ictal discharges in adjacent electrodes to estimate the location of the hypothesized focal source and demonstrated that the seizure source, localized in this manner, closely matches the clinically and neurophysiologically determined brain region giving rise to seizures. Moreover, we determined this focal source to be a dynamic entity that moves and evolves over the time course of a seizure. Our results offer an interpretation of ictal activity observed by intracranial EEG that challenges the traditional conceptualization of the seizure source.

Case Report: Aperiodic Fluctuations of Neural Activity in the Ictal MEG of a Child With Drug-Resistant Fronto-Temporal Epilepsy.

Successful surgical treatment of patients with focal drug-resistant epilepsy remains challenging, especially in cases for which it is difficult to define the area of cortex from which seizures originate, the seizure onset zone (SOZ). Various diagnostic methods are needed to select surgical candidates and determine the extent of resection. Interictal magnetoencephalography (MEG) with source imaging has proven to be useful for presurgical evaluation, but the use of ictal MEG data remains limited. The purpose of the present study was to determine whether pre-ictal variations of spectral properties of neural activity from ictal MEG recordings are predictive of SOZ location.We performed a 4 h overnight MEG recording in an 8-year-old child with drug-resistant focal epilepsy of suspected right fronto-temporal origin and captured one ~45-s seizure. The patient underwent a right temporal resection from the anterior temporal neocortex and amygdala to the mid-posterior temporal neocortex, sparing the hippocampus proper. She remains seizure-free 21 months postoperatively. The histopathological assessment confirmed frank focal cortical dysplasia (FCD) type IIa in the MEG-defined SOZ, which was based on source imaging of averaged ictal spikes at seizure onset. We investigated temporal changes (inter-ictal, pre-ictal, and ictal periods) together with spatial differences (SOZ vs. control regions) in spectral parameters of background brain activity, namely the aperiodic broadband offset and slope, and assessed how they confounded the interpretation of apparent variations of signal power in typical electrophysiological bands. Our data show that the SOZ was associated with a higher aperiodic offset and exponent during the seizure compared to control regions. Both parameters increased in all regions from 2 min before the seizure onwards. Regions anatomically closer to the SOZ also expressed higher values compared to contralateral regions, potentially indicating ictal spread. We also show that narrow-band power changes were caused by these fluctuations in the aperiodic component of ongoing brain activity. Our results indicate that the broadband aperiodic component of ongoing brain activity cannot be reduced to background noise of no physiological interest, and rather may be indicative of the neuropathophysiology of the SOZ. We believe these findings will inspire future studies of ictal MEG cases and confirm their significance.

External validation of automated focal cortical dysplasia detection using morphometric analysis.

Focal cortical dysplasias (FCDs) are a common cause of drug-resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1-weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set. In this retrospective study, we created a feed-forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross-validated on 113 patients (62 female, meanage ± SD=29.5±13.6years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD=30.2±9.6years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD=30±15.26years) and 70 healthy controls (42 females, mean age ± SD = 40.0±12.54years). In the cross-validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%. Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR-sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug-resistant focal epilepsy.

Quality of life and its determinants in patients with drug resistant focal epilepsy

Objective: to determine the factors influencing quality of life (QoL) in patients with drug-resistant focal epilepsy (DRFE). Material and methods. 111 adult patients with DRFE were included in the study. Quality of life was measured using the Quality Of Life In Patients with Epilepsy – 31 questionnaire (QOLIE-31). The severity of the disease (frequency and subjective assessment of the severity of seizures), the effect of pharmacotherapy (drug load and composition of the treatment regimen), the social status of patients, comorbid conditions (anxiety and depressive disorders, pathological fatigue) were assessed. Results. In the studied sample, a pronounced decrease in QoL was shown, the median of the final QOLIE-31 score was 65.4 points (interquartile range 53.0–72.6 points). A statistically significant decrease in QoL was found in subgroups of patients with seizures during the previous three months; taking carbamazepine or benzobarbital; with anxiety and depressive disorders; with pathological fatigue; and in unemployed patients. A multiple linear regression model (R2=0.66) was developed, which included the following determinants: Fatigue Severity Scale, Liverpool Seizure Severity Scale, and the risk of depression according to the NDDI-E questionnaire. Conclusion. In patients with drug-resistant focal epilepsy, there is a pronounced decrease in the quality of life due to combination of factors associated with the characteristics of the disease, treatment, comorbidities, and social status. The key QoL determinants in patients with DRFE are pathological fatigue, anxiety and depression, and subjective severity of epileptic seizures; employment is a positive factor. The role of epileptic seizures frequency in QoL formation in these patients requires further research.

Relation between coffee consumption and risk of seizure‐related respiratory dysfunction in patients with drug‐resistant focal epilepsy

Caffeine is an antagonist of the adenosine pathway, which is involved in regulation of breathing. Extracellular concentrations of adenosine are increased in the immediate aftermath of a seizure. Seizure-related overstimulation of adenosine receptors might promote peri-ictal apnea. However, the relation between caffeine consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy remains unknown. We performed a cross-sectional analysis of data collected in patients included in the SAVE study in Lyon's epilepsy monitoring unit at the Adult Epilepsy Department of the Lyon University Hospital between February 2016 and October 2018. The video-electroencephalographic recordings of 156 patients with drug-resistant focal epilepsy included in the study were reviewed to identify those with ≥1 focal seizure (FS), valid pulse oximetry (SpO2 ) measurement, and information about usual coffee consumption. This latter was collected at inclusion using a standardized self-questionnaire and further classified into four groups: none, rare (≤3 cups/week), moderate (4 cups/week to 3 cups/day), and high (≥4 cups/day). Peri-ictal hypoxemia (PIH) was defined as SpO2 < 90% for at least 5s occurring during the ictal period, the post-ictal period, or both. Ninety patients fulfilled inclusion criteria, and 323 seizures were analyzed. Both the level of usual coffee consumption (p=.033) and the level of antiepileptic drug withdrawal (p=.004) were independent risk factors for occurrence of PIH. In comparison with FS in patients with no coffee consumption, risk of PIH was four times lower in FS in patients with moderate consumption (odds ratio [OR]=.25, 95% confidence interval [CI]=.07-.91, p=.036) and six times lower in FS in patients with high coffee consumption (OR=.16, 95% CI=.04-.66, p=.011). However, when PIH occurred, its duration was longer in patients with moderate or high consumption than in those with no coffee consumption (p=.042). Coffee consumption may be a protective factor for seizure-related respiratory dysfunction, with a dose-dependent effect.

Different faces of frontal lobe epilepsy: The clinical, electrophysiologic, and imaging experience of a tertiary center

ObjectiveFrontal lobe epilepsy (FLE) is the second most common epilepsy among drug-resistant focal epilepsies. Semiologic and electrophysiologic features of FLE present some difficulties because frontal lobe seizures are brief, accompanied by complex motor activities and emotional signs. The rich connectivity of the frontal lobe with other areas leads to the rapid and widespread propagation of seizure activity, which contribute to the difficulty of evaluating the semiologic and EEG patterns of the seizure. In this study, we investigated semiologic, interictal, ictal, and postictal EEG characteristics; the imaging data of patients with FLE and the possible contribution of these data to localization and lateralization of seizures. Materials and methodsThe medical records of patients who were diagnosed as having FLE between 2010 and 2019 in our clinic were evaluated retrospectively. The diagnosis of FLE was considered either when patients had a structural lesion in the frontal region or seizure semiology and EEG characteristics were compatible with FLE. Clinical, electrophysiologic, and imaging features were investigated in these patients. ResultsWe have evaluated 146 seizures in 36 patients (17 lesional and 19 non-lesional according to MRI). There were 110 focal motor or nonmotor seizures, 18 bilateral tonic-clonic seizures, and 18 subclinical seizures. There were 16 patients with aura. The most common semiologic feature was hyperkinetic movements. Among the interictal EEGs, 30.5 % included focal anomalies. Among the ictal EEGs, 69.1 % were non-localizing or lateralizing. The most common ictal pattern was rhythmic theta activity (21.2 %). In four patients, who had non-localizing or lateralizing EEG, the postictal EEG was informative. Our study showed a low percentage of localized FDG-PET, which, however, involved visual analysis. ConclusionOur results support the previously known difficulties in the determination of the epileptogenic zone of FLE. Semiologic and electrophysiologic correlation studies, longer postictal records, and quantitative analysis of FDG-PET may contribute to a better characterization of the disease.

The distinctive sleep pattern of the human calcarine cortex: a stereo-electroencephalographic study.

The aim of this study was to describe the spontaneous electroencephalographic (EEG) features of sleep in the human calcarine cortex, comparing them with the well-established pattern of the parietal cortex. We analyzed presurgical intracerebral EEG activity in calcarine and parietal cortices during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in seven patients with drug-resistant focal epilepsy. The time course of the EEG spectral power and NREM vs REM differences was assessed. Sleep spindles were automatically detected. To assess homeostatic dynamics, we considered the first vs second half of the night ratio in the delta frequency range (0.5-4 Hz) and the rise rate of delta activity during the first sleep cycle. While the parietal area showed the classically described NREM and REM sleep hallmarks, the calcarine cortex exhibited a distinctive pattern characterized by: (1) the absence of sleep spindles; (2) a large similarity between EEG power spectra of NREM and REM; and (3) reduced signs of homeostatic dynamics, with a decreased delta ratio between the first and the second half of the night, a reduced rise rate of delta activity during the first NREM sleep cycle, and lack of correlation between these measures. Besides describing for the first time the peculiar sleep EEG pattern in the human calcarine cortex, our findings provide evidence that different cortical areas may exhibit specific sleep EEG pattern, supporting the view of sleep as a local process and promoting the idea that the functional role of sleep EEG features should be considered at a regional level.

Computer Assisted Planning for Curved Laser Interstitial Thermal Therapy.

The clinical feasibility and potential of curved LiTT trajectories through steerable needles has yet to be investigated. This is the focus of our work. We propose a GPU-accelerated computer-assisted planning (CAP) algorithm for steerable needle insertions that generates optimized curved 3D trajectories with maximal ablation of the amygdalohippocampal complex and minimal collateral damage to nearby structures, while accounting for a variable ablation diameter ( 5-15 mm). Simulated trajectories and ablations were performed on 5 patients with mesial temporal sclerosis (MTS), which were identified from a prospectively managed database. The algorithm generated obstacle-free paths with significantly greater target area ablation coverage and lower PHG ablation variance compared to straight line trajectories. The presented CAP algorithm returns increased ablation of the amygdalohippocampal complex, with lower patient risk scores compared to straight-line trajectories. This is the first clinical application of preoperative planning for steerable needle based LiTT. This study suggests that steerableneedles have the potential to improve LiTT procedure efficacy whilst improving the safety and should thus be investigated further.

External validation of the Epilepsy Surgery Grading Scale in a Japanese cohort of patients with epilepsy.

The Epilepsy Surgery Grading Scale (ESGS) is a simple method to predict the likelihood of a patient with epilepsy proceeding to surgery and achieving seizure freedom. Usefulness of the ESGS has been confirmed in established epilepsy centres in the United States and Belgium for adult patients with drug-resistant focal epilepsy undergoing presurgical evaluation. However, the applicability of the ESGS has not yet been evaluated in a wider range of epilepsy patients that may reflect the general spectrum of epilepsy. The present study validated the ESGS in a Japanese epilepsy centre in which admission-based comprehensive epilepsy studies were indicated beyond presurgical evaluation. This single-centre retrospective study included adult patients with epilepsy admitted to the Epilepsy Monitoring Unit from 2010 to June 2019. Patients were classified as ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favourable). Patients were grouped into three cohorts: all patients, patients with drug-resistant focal epilepsy, and patients who underwent resective epilepsy surgery. We assessed progression to surgery and seizure freedom at one year after surgery. Of the 1,158 total admissions, 670 patients met the inclusion criteria and formed the total cohort. Of these, 435 (64.9%) had drug-resistant focal epilepsy and 78 (11.6%) proceeded to resective surgery. Overall, progression to surgery was observed in 41.3%, 16.6%, and 4.8% of patients with Grade 1, 2, and 3, respectively. In the surgical cohort, seizure freedom was observed in 85.2%, 65.2%, and 31.3% of patients with Grade 1, 2, and 3, respectively. Our results indicate that the ESGS is effective in predicting whether a patient proceeds to epilepsy surgery and achieves seizure freedom even in the general population of epilepsy patients, regardless of type or resistance to antiepileptic drugs.

Antibody Prevalence in Epilepsy before Surgery (APES) in drug-resistant focal epilepsy.

There is a growing recognition of immune-mediated causes in patients with focal drug-resistant epilepsy (DRE); however, they are not systematically assessed in the pre-surgical diagnostic workup. Early diagnosis and initiation of immunotherapy is associated with a favorable outcome in immune-mediated seizures. Patients with refractory focal epilepsy with neuronal antibodies (Abs) tend to have a worse surgical prognosis when compared to other etiologies. We studied the prevalence of serum Abs in patients ≥18years of age with DRE of unknown cause before surgery. We proposed and calculated a clinical APES (Antibody Prevalence in Epilepsy before Surgery) score for each subject, which was modified based on Dubey's previously published APE2 score. RESULTS`: A total of 335 patients were screened and 86 subjects were included in final analysis. The mean age at the time of recruitment was 44.84±14.86years, with age at seizure onset 30.89±19.88years. There were no significant differences among baseline clinical features between retrospective and prospective sub-cohorts. The prevalence of at least one positive Ab was 33.72%, and central nervous system (CNS)-specific Abs was 8.14%. APES score ≥4 showed slightly better overall prediction (area under the curve [AUC]: 0.84 vs 0.74) and higher sensitivity (100% vs 71.4%), with slightly lower but similar specificity (44.3% vs 49.4%), when compared to APE2 score ≥4. For subjects who had available positron emission tomography (PET) results and all components of APES score (n=60), the sensitivity of APES score ≥4 yielded a similar prediction potential with an AUC of 0.80. Our findings provide persuasive evidence that a subset of patients with focal DRE have potentially immune-mediated causes. We propose an APES score to help identify patients who may benefit from a workup for immune etiologies during the pre-surgical evaluation for focal refractory epilepsy with unknown cause.

Lateralization value of peri-ictal headache in drug-resistant focal epilepsy

ObjectiveTo examine the lateralizing value of unilateral peri-ictal and interictal headaches in patients with drug-resistant focal epilepsy (DRFE). MethodsFour-hundred consecutive patients undergoing presurgical evaluation for DRFE were interviewed. Patients with headache were broadly divided into two groups: peri-ictal and interictal headache. The lateralizing value of unilateral headache was compared in each group between three diagnoses: temporal lobe epilepsy (TLE), extratemporal lobe epilepsy (ETLE), and temporal-plus epilepsy (TEMP+ epilepsy). ResultsOut of 400 patients, 169 (42.25%) had headaches. Peri-ictal headaches were experienced in 106 patients (26.5%) and interictal headaches were experienced in 63 (15.75%). In the peri-ictal group, unilateral headaches were present in 48 out of 60 patients (80%) with TLE; they were ipsilateral to the seizure focus in 45 out of 48 patients (93.75%). Unilateral headaches in patients with ETLE were present in 20 out of 31 patients (64.5%) and were ipsilateral to the seizure focus in 14 out of 20 patients (70%). In patients with TEMP + epilepsy, unilateral peri-ictal headaches were present in 9 out of 15 patients (60%); they were ipsilateral to the seizure focus in all 9 patients (100%). In the interictal headache group, unilateral headaches were ipsilateral the seizure focus in 9 out of 10 patients (90%) with TLE and 5 out of 6 patients (83.3%) with ETLE. None of the TEMP + epilepsy patients had a unilateral interictal headache. ConclusionHeadache is a frequently encountered symptom in patients with DRFE. When occurring in a unilateral fashion, it has a high lateralizing value in temporal and extratemporal lobe epilepsies. This has been demonstrated to be true for both peri-ictal and interictal headaches. In the vast majority of patients with DRFE, unilateral headache occurs ipsilateral to the seizure focus.

Gabapentin add-on treatment for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2018. Epilepsy is a common neurological disorder characterised by recurrent seizures. Most people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially people with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCTs) of gabapentin, when used as an add-on treatment for drug-resistant focal epilepsy. To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant focal epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 11 August 2020. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy. We imposed no language restrictions. Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant focal epilepsy. We also included trials using an active drug control group or comparing different doses of gabapentin. Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: seizure frequency, seizure freedom, treatment withdrawal (any reason) and adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best-case and worst-case analyses. We estimated summary risk ratios (RR) for each outcome and evaluated dose-response in regression models. We identified no new studies for this update, therefore, the results and conclusions are unchanged. In the previous update of this review, we combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for reduction in seizure frequency of 50% or more compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55; 6 studies, 1206 participants; moderate-certainty evidence). Dose regression analysis (for trials in adults) showed increasing efficacy with increasing dose, with 25.3% (95% CI 19.3 to 32.3) of people responding to gabapentin 1800 mg compared to 9.7% on placebo, a 15.5% increase in response rate (95% CI 8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49; 6 trials, 1206 participants; moderate-certainty evidence). Adverse effects were significantly associated with gabapentin compared to placebo. RRs were as follows: ataxia 2.01 (99% CI 0.98 to 4.11; 3 studies, 787 participants; low-certainty evidence), dizziness 2.43 (99% CI 1.44 to 4.12; 6 studies, 1206 participants; moderate-certainty evidence), fatigue 1.95 (99% CI 0.99 to 3.82; 5 studies, 1161 participants; low-certainty evidence) and somnolence 1.93 (99% CI 1.22 to 3.06; 6 studies, 1206 participants; moderate-certainty evidence). There was no evidence of a difference for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35; 6 studies, 1206 participants; moderate-certainty evidence) or nausea (RR 0.95, 99% CI 0.52 to 1.73; 4 trials, 1034 participants; moderate-certainty evidence). Overall, the studies were at low to unclear risk of bias due to information on each risk of bias domain not being available. We judged the overall certainty of the evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide CIs. Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy, and seems to be fairly well-tolerated. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types. Further trials are needed to assess the long-term effects of gabapentin, and to compare gabapentin with other add-on drugs.

How does vigabatrin add-on therapy compare with placebo for adults and adolescents with drug-resistant focal epilepsy?

How does vigabatrin add-on therapy compare with placebo for adults and adolescents with drug-resistant focal epilepsy?

Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)

Focal malformations of cortical development (MCD) are linked to somatic brain mutations occurring during neurodevelopment. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly recognized clinico-pathological entity associated with pediatric drug-resistant focal epilepsy, and amenable to neurosurgical treatment. MOGHE is histopathologically characterized by clusters of increased oligodendroglial cell densities, patchy zones of hypomyelination, and heterotopic neurons in the white matter. The molecular etiology of MOGHE remained unknown so far. We hypothesized a contribution of mosaic brain variants and performed deep targeted gene sequencing on 20 surgical MOGHE brain samples from a single-center cohort of pediatric patients. We identified somatic pathogenic SLC35A2 variants in 9/20 (45%) patients with mosaic rates ranging from 7 to 52%. SLC35A2 encodes a UDP-galactose transporter, previously implicated in other malformations of cortical development (MCD) and a rare type of congenital disorder of glycosylation. To further clarify the histological features of SLC35A2-brain tissues, we then collected 17 samples with pathogenic SLC35A2 variants from a multicenter cohort of MCD cases. Histopathological reassessment including anti-Olig2 staining confirmed a MOGHE diagnosis in all cases. Analysis by droplet digital PCR of pools of microdissected cells from one MOGHE tissue revealed a variant enrichment in clustered oligodendroglial cells and heterotopic neurons. Through an international consortium, we assembled an unprecedented series of 26 SLC35A2-MOGHE cases providing evidence that mosaic SLC35A2 variants, likely occurred in a neuroglial progenitor cell during brain development, are a genetic marker for MOGHE.

Gastrodin alleviates seizure severity and neuronal excitotoxicities in the rat lithium-pilocarpine model of temporal lobe epilepsy via enhancing GABAergic transmission

Ethnopharmacological relevanceTemporal lobe epilepsy remains one of the most drug-resistant focal epilepsy, leading to enormous healthcare burden. Among traditional herb medicine, some ingredients have the potential to treat seizure and alleviate the neuronal excitoxicity. The dried rhizome of Gastrodia elata Blume has been used to treat convulsive disorder, dizziness, dementia and migraine in eastern Asia. Aim of the studyTo determine whether gastrodin, an active ingredient of Gastrodia elata Blume, can reduce lithium-pilocarpine induced seizure severity and neuronal excitotoxicity and explore the underlying mechanism. Materials and methodsWe divided the Sprague-Dawley rats into an experimental group (gastrodin group) and a control group (Dimethyl sulfoxide, vehicle group) and performed the behavioral analysis and electroencephalography to determine the effect of gastrodin on the seizure severity induced by lithium-pilocarpine injection. Nissl-stained histopathology elucidated the degree of rat hippocampal neuronal damage as markers of acute and subacute neuronal excitotoxicity. Besides, the Western blotting of dissected hippocampus was carried out to demonstrate the protein expression involving GABAergic transmission and metabolic pathway. ResultsGastrodin reduced the acute seizure severity in lithium-pilocarpine-induced seizure model. In electroencephalography recording, gastrodin exerted inhibitory action on epileptiform discharge. Compared with control group, gastrodin exhibited neuroprotective effect against seizure related hippocampal neuronal damage at acute and subacute stages. The Western blotting showed that gastrodin reversed the degradation of GABAA receptor after pilocarpine-induced seizures. ConclusionsIn the experimental seizure model, gastrodin showed anti-seizure and neuroprotective abilities. Enhancing the expression of GABAA receptor plays an important role in its antiepileptic mechanism. The results offer a new insight of developing new antiepileptic drugs from traditional Chinese medicine.

Role of Interictal Arterial Spin Labeling Magnetic Resonance Perfusion in Mesial Temporal Lobe Epilepsy.

Context:Electrophysiological and hemodynamic data can be integrated to accurately identify the generators of abnormal electrical activity in drug-resistant focal epilepsy. Arterial Spin Labeling (ASL), a magnetic resonance imaging (MRI) technique for quantitative noninvasive measurement of cerebral blood flow (CBF), can provide a direct measure of variations in cerebral perfusion associated with the epileptogenic zone.Aims:1. To evaluate usefulness of ASL for detecting interictal temporal hypoperfusion to localize the epileptogenic zone in patients of drug resistant mesial temporal lobe epilepsy (MTLE). 2. Correlation of localization of epileptogenic zone on ASL MR perfusion with structural MRI and EEG.Methods and Materials:30 patients with MTLE and10 age and gender matched normal controls were studied. All patients underwent ictal video EEG monitoring non-invasively, MR imaging with epilepsy protocol and pseudocontinuous ASL (PCASL) perfusion study. Relative CBF (rCBF) values in bilateral mesial temporal lobes were measured utilizing quantitative analysis of perfusion images. A perfusion asymmetry index (AI) was calculated for each region.Results:In patients, ipsilateral mesial temporal rCBF was significantly decreased compared with contralateral mesial temporal rCBF (p = 0.021). Mesial temporal blood flow was more asymmetric in patients than in normal control participants (p = 0.000). Clear perfusion asymmetry on PCASL-MRI was identified despite normal structural-MRI in 5 cases, agreeing with EEG laterality.Conclusions:Pseudo-continuous ASL offers a promising approach to detect interictal hypoperfusion in TLE and as a clinical alternative to SPECT and PET due to non-invasiveness and easy accessibility. Incorporation of ASL into routine pre-surgical evaluation protocols can help to localize epileptogenic zone in surgical candidates.

Effects of anterior thalamic nuclei stimulation on hippocampal activity: Chronic recording in a patient with drug-resistant focal epilepsy.

Implanted neurostimulation devices are gaining traction as palliative treatment options for certain forms of drug-resistant epilepsy, but clinical utility of these devices is hindered by incomplete mechanistic understanding of their therapeutic effects. Approved devices for anterior thalamic nuclei deep brain stimulation (ANT DBS) are thought to work at a network level, but limited sensing capability precludes characterization of neurophysiological effects outside the thalamus. Here, we describe a patient with drug-resistant temporal lobe epilepsy who was implanted with a responsive neurostimulation device (RNS System), involving hippocampal and ipsilateral temporal neocortical leads, and subsequently received ANT DBS. Over 1.5years, RNS System electrocorticography enabled multiscale characterization of neurophysiological effects of thalamic stimulation. In brain regions sampled by the RNS System, ANT DBS produced acute, phasic, frequency-dependent responses, including suppression of hippocampal low frequency local field potentials. ANT DBS modulated functional connectivity between hippocampus and neocortex. Finally, ANT DBS progressively suppressed hippocampal epileptiform activity in relation to the extent of hippocampal theta suppression, which informs stimulation parameter selection for ANT DBS. Taken together, this unique clinical scenario, involving hippocampal recordings of unprecedented chronicity alongside ANT DBS, sheds light on the therapeutic mechanism of thalamic stimulation and highlights capabilities needed in next-generation devices.

GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?

Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.