Summary
In patients with pharmacoresistant focal epilepsy, we demonstrate that magnetoencephalography (MEG) detects spike‐locked and spike‐independent epileptic high gamma oscillations (HGOs) using ...combined MEG and invasive electroencephalography (iEEG) from subdural macroelectrodes. Six patients, who underwent presurgical workup for epilepsy surgery with preoperative simultaneous MEG and subdural iEEG recordings, were investigated. HGOs in iEEG were detected automatically and served as triggers for averaging and localization of simultaneous MEG data. iEEG‐HGOs were detected in all patients and MEG‐HGOs in five patients. HGOs were highly associated with epileptic networks and correctly identified seizure‐onset zones in five (MEG) and six patients (iEEG). Minimum‐norm source analysis of MEG data yielded concordant localizations. Noninvasive analysis of HGOs may allow investigation of epileptic networks independent of spikes and seizures. Determination of sensitivity and specificity, as well as development of MEG‐HGO analysis without the need of iEEG should be addressed in a larger study.
•New protocol to co-register surgical brain samples with invasive EEG in patients with Focal Cortical Dysplasia (FCD) type II.•Seizure onset, spikes, fast gamma oscillations and theta-gamma ...phase-amplitude-coupling were related to areas with dysmorphic neurons.•Despite disorganized distribution of FCD, dysmorphic neurons showed significant phase-amplitude coupling, suggesting persisting anatomical connectivity.
Reliable localization of the epileptogenic zone is necessary for successful epilepsy surgery. Neurophysiological biomarkers include ictal onsets and interictal spikes. Furthermore, the epileptic network shows oscillations with potential localization value and pathomechanistic implications. The cellular origin of such markers in invasive EEG in vivo remains to be clarified.
In the presented pilot study, surgical brain samples and invasive EEG recordings of seven patients with surgically treated Focal Cortical Dysplasia (FCD) type II were coregistered using a novel protocol. Dysmorphic neurons and balloon cells were immunohistochemically quantified. Evaluated markers included seizure onset, spikes, and oscillatory activity in delta, theta, gamma and ripple frequency bands, as well as sample entropy and phase-amplitude coupling between delta, theta, alpha and beta phase and gamma amplitude.
Correlations between histopathology and neurophysiology provided evidence for a contribution of dysmorphic neurons to interictal spikes, fast gamma activity and ripples. Furthermore, seizure onset and phase-amplitude coupling in areas with dysmorphic neurons suggests preserved connectivity is related to seizure initiation. Balloon cells showed no association.
Phase-amplitude coupling, spikes, fast gamma and ripples are related to the density of dysmorphic neurons and localize the seizure onset zone.
The results of our pilot study provide a new powerful tool to address the cellular source of abnormal neurophysiology signals to leverage current and novel biomarkers for the localization of epileptic activity in the human brain.
Summary
Objective
Surgical volumes at large epilepsy centers are decreasing. Pediatric cohorts, however, show a trend toward more resections and superior outcome. Differences in pediatric and adult ...epilepsy surgery were investigated in our cohort.
Methods
The Bethel database between 1990 and 2014 was retrospectively analyzed.
Results
A total of 1916 adults and 1300 children underwent presurgical workup. The most common etiologies were medial temporal sclerosis (35.4%) in adults, and focal cortical dysplasias (21.1%) and diffuse hemispheric pathologies (14.7%) in children. Only 1.4% of the total cohort had normal histopathology. A total of 1357 adults (70.8%) and 751 children (57.8%) underwent resections. Surgery types for children were more diverse and showed a higher proportion of extratemporal resections (32.8%) and functional hemispherectomies (20.8%). Presurgical evaluations increased in both groups; surgical numbers remained stable for children, but decreased in the adult group from 2007 on. The patients’ decision against surgery in the adult nonoperated cohort increased over time (total = 44.9%, 27.4% in 1995‐1998 up to 53.2% in 2011‐2014; for comparison, in children, total = 22.1%, stable over time). Postsurgical follow‐up data were available for 1305 adults (96.2%) and 690 children (91.9%) 24 months after surgery. The seizure freedom rate was significantly higher in children than in adults (57.8% vs 47.5%, P < 0.001) and significantly improved over time (P = 0.016).
Significance
Pediatric epilepsy surgery has stable surgical volumes and renders more patients seizure‐free than epilepsy surgery in adults. A relative decrease in hippocampal sclerosis, the traditional substrate of epilepsy surgery, changes the focus of epilepsy surgery toward other pathologies.
Epilepsy is a frequent neurological disorder, although onset and progression of seizures remain difficult to predict in affected patients, irrespective of their epileptogenic condition. Previous ...studies in animal models as well as human epileptic brain tissue revealed a remarkably diverse pattern of gene expression implicating epigenetic changes to contribute to disease progression. Here we mapped for the first time global DNA methylation patterns in chronic epileptic rats and controls. Using methyl-CpG capture associated with massive parallel sequencing (Methyl-Seq) we report the genomic methylation signature of the chronic epileptic state. We observed a predominant increase, rather than loss of DNA methylation in chronic rat epilepsy. Aberrant methylation patterns were inversely correlated with gene expression changes using mRNA sequencing from same animals and tissue specimens. Administration of a ketogenic, high-fat, low-carbohydrate diet attenuated seizure progression and ameliorated DNA methylation mediated changes in gene expression. This is the first report of unsupervised clustering of an epigenetic mark being used in epilepsy research to separate epileptic from non-epileptic animals as well as from animals receiving anti-convulsive dietary treatment. We further discuss the potential impact of epigenetic changes as a pathogenic mechanism of epileptogenesis.
Education tools and programs using interactive digital content, distributed on the internet, are increasingly becoming an integral part of postgraduate medical education. The coronavirus pandemic and ...global lockdown hoisted a major challenge for traditional teaching courses. A timely solution is to focus attention and reinforce web‐based teaching programs. For more than 15 years, the ILAE has been developing and managing a wide range of e‐learning programs. This paper provides an overview on the e‐learning portfolio of the ILAE, including tutored e‐courses, self‐paced interactive e‐courses and online multimedia resources, all linked to the ILAE curriculum and learning objectives addressing specific levels of professional experience. All e‐learning programs will become available through the new ILAE Academy platform (www.ilae-academy.org), in July 2020. E‐learning is an important tool for reaching the global educational mission of the ILAE.
Abstract
Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative ...MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection.
Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are ...often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD.
Teaching competency in the diagnosis and clinical management of epilepsy is of utmost importance for the ILAE. To achieve this mission, the Task Force for Epilepsy Education (EpiEd) developed a ...competency-based curriculum for epileptology, covering the spectrum of skills and knowledge for best medical practice. The curriculum encompasses seven domains, 42 competencies, and 124 learning objectives, divided into three levels: entry (Level 1), proficiency (Level 2), and advanced proficiency (Level 3). A survey of the currently existing ILAE-endorsed teaching activities identified a significant gap in education of basic knowledge of epileptology (Level 1). To bridge this gap, a web-based educational tool is being developed. A virtual campus will be constructed around the curriculum, integrating the various educational activities of the ILAE. This paper describes the development of the curriculum and future tasks necessary to achieve the educational goal of the ILAE.
Summary
Objective
Hippocampal sclerosis (HS) is the major structural brain lesion in patients with temporal lobe epilepsy (TLE). However, its internal anatomic structure remains difficult to ...recognize at 1.5 or 3 Tesla (T) magnetic resonance imaging (MRI), which allows neither identification of specific pathology patterns nor their proposed value to predict postsurgical outcome, cognitive impairment, or underlying etiologies. We aimed to identify specific HS subtypes in resected surgical TLE samples on 7T MRI by juxtaposition with corresponding histologic sections.
Methods
Fifteen nonsclerotic and 18 sclerotic hippocampi were studied ex vivo using an experimental 7T MRI scanner. T2‐weighted images (T2wi) and diffusion tensor imaging (DTI) data were acquired and validated using a systematic histologic analysis of same specimens along the anterior‐posterior axis of the hippocampus.
Results
In nonsclerotic hippocampi, differences in MR intensity could be assigned to seven clearly recognizable layers and anatomic boundaries as confirmed by histology. All hippocampal subfields could be visualized also in the hippocampal head with three‐dimensional imaging and angulated coronal planes. Only four discernible layers were identified in specimens with histopathologically confirmed HS. All sclerotic hippocampi showed a significant atrophy and increased signal intensity along the pyramidal cell layer. Changes in DTI parameters such as an increased mean diffusivity, allowed to distinguish International League Against Epilepsy (ILAE) HS type 1 from type 2. Whereas the increase in T2wi signal intensities could not be attributed to a distinct specific histopathologic substrate, that is, decreased neuronal or increased glial cell densities, intrahippocampal projections and fiber tracts were distorted in HS specimens suggesting a complex disorganization of the cellular composition, fiber networks, as well as its extracellular matrix.
Significance
Our data further advocate high‐resolution MRI as a helpful and promising diagnostic tool for the investigation of hippocampal pathology along the anterior‐posterior extent in TLE, as well as in other neurologic and neurodegenerative disorders.
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