Burkhard S. Kasper

Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy.

Mesial temporal sclerosis (MTS) is the most common lesion in chronic, intractable temporal lobe epilepsies (TLE) and characterized by segmental neuronal cell loss in major hippocampal segments. Another histopathological hallmark includes granule cell dispersion (GCD), an architectural disturbance of the dentate gyrus encountered in approximately 50% of patients with mesial temporal sclerosis. Reelin, which plays a key role during hippocampal development and maintenance of laminar organization, is synthesized and released by Cajal-Retzius cells of the dentate molecular layer, and previous studies have shown that Reelin transcript levels are downregulated in human temporal lobe epilepsies specimens. To investigate whether epigenetic silencing by Reelin promoter methylation may be an underlying pathogenetic mechanism of GCD, DNA was harvested from 3 microdissected hippocampal subregions (i.e. molecular and granule cell layers of the dentate gyrus and presubiculum) from 8 MTS specimens with GCD, 5 TLE samples without GCD, and 3 autopsy controls. Promoter methylation was analyzed after bisulfite treatment, cloning, and direct sequencing; immunohistochemistry was performed to identify Cajal-Retzius cells. Reelin promoter methylation was found to be greater in TLE specimens than in controls; promoter methylation correlated with GCD among TLE specimens (p < 0.0002). No other clinical or histopathological parameter (i.e. sex, age, seizure duration, medication or extent, of MTS) correlated with promoter methylation. These data support a compromised Reelin-signaling pathway and identify promoter methylation as an epigenetic mechanism in the pathogenesis of TLE.

Microdysgenesis in mesial temporal lobe epilepsy: a clinicopathological study.

The interrelationship of mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis, and febrile convulsions still remains an enigma. Additional microscopical cortical dysplasia or microdysgenesis has been suggested as pre‐existent susceptibility factor rendering the affected brain vulnerable to the development of MTLE after initial precipitating injuries such as febrile convulsions. Twenty‐four MTLE cases with histopathologically definite hippocampal sclerosis were examined for clearly defined features of microdysgenesis and further signs of neocortical dysplasia. Although unequivocal signs of dysplasia were absent, 29.2% of cases showed cortical neuronal clustering, 25.0% showed perivascular clustering, and 20.8% showed increased white matter neurons. The features of microdysgenesis studied here were not linked with each other and were not related to initial precipitating injuries, positive family history, or any other clinical parameter. Their suggested fundamental role as dysplastic factor within development of hippocampal sclerosis and MTLE is not confirmed. Ann Neurol 2003;54:501–506

Autobiographical memory in temporal lobe epilepsy: Role of hippocampal and temporal lateral structures

The present study was aimed at investigating the impact of hippocampal and temporal cortical lesions on remote autobiographical memories in temporal lobe epilepsy (TLE). Episodic specificity, episodic richness, and personal semantic memory from different life periods were assessed using a modified version of the Autobiographical Memory Interview (AMI) (M.D. Kopelman, A.E. Wilson, A. Baddeley, The autobiographical memory interview. Bury St. Edmunds: Thames Valley Test Co.; 1990) in 47 patients with unilateral mesial or lateral TLE and 38 healthy controls. Patients with TLE performed significantly more poorly than controls. Patients with left and right mTLE were equally moderately impaired, but patients with left lateral TLE had the most severe episodic memory deficits, particularly for childhood memories. With respect to personal semantic memory, patients with left TLE were significantly more impaired than those with right TLE, most pronounced for childhood memories. Both autobiographical memory aspects, episodic and personal semantic memory, were significantly intercorrelated, but both did not correlate with anterograde memory, indicating a structural dissociation between both functions.

Epilepsy outcomes in elderly treated with topiramate

Objectives –  To explore effectiveness, tolerability and quality of life in elderly patients with epilepsy treated with topiramate.

Automatic seizure detection in long-term scalp EEG using an adaptive thresholding technique: A validation study for clinical routine

OBJECTIVE In a previous study we proposed a robust method for automatic seizure detection in scalp EEG recordings. The goal of the current study was to validate an improved algorithm in a much larger group of patients in order to show its general applicability in clinical routine. METHODS For the detection of seizures we developed an algorithm based on Short Time Fourier Transform, calculating the integrated power in the frequency band 2.5-12 Hz for a multi-channel seizure detection montage referenced against the average of Fz-Cz-Pz. For identification of seizures an adaptive thresholding technique was applied. Complete data sets of each patient were used for analyses for a fixed set of parameters. RESULTS 159 patients (117 temporal-lobe epilepsies (TLE), 35 extra-temporal lobe epilepsies (ETLE), 7 other) were included with a total of 25,278 h of EEG data, 794 seizures were analyzed. The sensitivity was 87.3% and number of false detections per hour (FpH) was 0.22/h. The sensitivity for TLE patients was 89.9% and FpH=0.19/h; for ETLE patients sensitivity was 77.4% and FpH=0.25/h. CONCLUSIONS The seizure detection algorithm provided high values for sensitivity and selectivity for unselected large EEG data sets without a priori assumptions of seizure patterns. SIGNIFICANCE The algorithm is a valuable tool for fast and effective screening of long-term scalp EEG recordings.

Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology

In partial epilepsy, a localized hypersynchronous neuronal discharge evolving into a partial seizure affecting a particular cortical region or cerebral subsystem can give rise to subjective symptoms, which are perceived by the affected person only, that is, ictal hallucinations, illusions, or delusions. When forming the beginning of a symptom sequence leading to impairment of consciousness and/or a classic generalized seizure, these phenomena are referred to as an epileptic aura, but they also occur in isolation. They often manifest in the fully awake state, as part of simple partial seizures, but they also can be associated to different degrees of disturbed consciousness. Initial ictal symptoms often are closely related to the physiological functions of the cortical circuit involved and, therefore, can provide localizing information. When brain regions related to sensory integration are involved, the seizure discharge can cause specific kinds of hallucinations, for example, visual, auditory, gustatory, olfactory, and cutaneous sensory sensations. In addition to these elementary sensory perceptions, quite complex hallucinations related to a partial seizure can arise, for example, perception of visual scenes or hearing music. By involving psychic and emotional spheres of human perception, many seizures also give rise to hallucinatory emotional states (e.g., fear or happiness) or even more complex hallucinations (e.g., visuospatial phenomena), illusions (e.g., déjà vu, out-of-body experience), or delusional beliefs (e.g., identity change) that often are not easily recognized as epileptic. Here we suggest a classification into elementary sensory, complex sensory, and complex integratory seizure symptoms. Epileptic hallucinations, illusions, and delusions shine interesting light on the physiology and functional anatomy of brain regions involved and their functions in the human being. This article, in which 10 cases are described, introduces the fascinating phenomenology of subjective seizure symptoms.

Magnetic Resonance Spectroscopy and Histopathological Findings in Temporal Lobe Epilepsy

Summary:  Purpose: In some patients with temporal lobe epilepsy, histopathological evaluation of resected brain tissue after surgical treatment may reveal several features indicative of discrete cortical malformations. We sought to determine whether these histopathological features were accompanied by hippocampal changes detectable preoperatively by proton magnetic resonance (MR) spectroscopy and to evaluate their relationship with postoperative outcome.

Increased membrane shedding--indicated by an elevation of CD133-enriched membrane particles--into the CSF in partial epilepsy.

PURPOSE Recent analyses provided evidence that human adult cerebrospinal fluid (CSF) in addition to soluble proteins also contains membrane particles that moreover carry the somatic stem cell marker CD133. The significance of CD133 as a potential marker of cellular proliferation, including neurogenesis, remains unresolved. As adult neurogenesis has been implicated to be induced by epileptic seizures this study investigated whether patients with partial epilepsy show a varying amount of membrane-associated CD133 in CSF as compared to healthy adults. METHODS CSF samples of 34 partial epilepsy patients were analyzed and compared to 61 healthy controls. Following sequential centrifugation up to 200,000 g quantitative immunoblotting was performed using a mouse monoclonal antibody. Antigen-antibody complexes were detected using enhanced chemiluminescence, and visualized and quantified digitally. RESULTS The overall amount of membrane particle-associated CD133 was significantly increased in epilepsy patients compared to healthy controls (9.6±2.9 ng of bound CD133 antibody versus 7.4±3.8 ng; p<0.01). There were no differences according to etiology of epilepsy (cryptogenic, neoplasia, dysplasia, ammons horn sclerosis, and others). Dichotomization of the patients according to temporal versus extratemporal foci revealed a significant increase of membrane particle-associated CD133 in patients with temporal lobe epilepsy (10.88±3.3 ng of bound CD133 antibody versus 8.35±3.48 ng; p<0.05). CONCLUSION The increased amount of membrane particle-associated CD133 in the CSF of patients with partial epilepsy contributes to the ongoing debate of the source of these particles potentially emerging from subventricular zone astrocytes serving as neural stem cells. As neurogenesis in adults is related to the hippocampus, the significance of the increase of membrane particle-associated CD133 especially in temporal lobe epilepsy needs further clinical correlation.

Improved resection in lesional temporal lobe epilepsy surgery using neuronavigation and intraoperative MR imaging: Favourable long term surgical and seizure outcome in 88 consecutive cases

PURPOSE To investigate the value of intraoperative MR imaging (iopMRI) combined with neuronavigation to avoid intraoperative underestimation of the resection amount during surgery of lesional temporal lobe epilepsy (LTLE) patients. METHODS We retrospectively investigated 88 patients (40 female, 48 male, mean age 37.2 yrs, from 12 to 69 yrs, 41 left sided lesions) with LTLE operated at our department, including 40.9% gangliogliomas (GG), 26.1% cavernomas (CM), 10.2% dysembryoplastic neuroepithelial tumours (DNT) and 11.4% focal cortical dysplasias (FCD), excluding hippocampal sclerosis. RESULTS Complete resection was achieved in 85 of 88 patients (96.6%), as proven by postoperative MRI 6 months after surgery. In contrast, the routine first iopMR imaging before closure revealed radical resection in only 66 of these 88 patients (75%). After re-intervention, the second iopMR imaging demonstrated complete resection in 19 more patients. Thus, as a direct effect of iopMRI and neuronavigation, overall resection rate was increased by 21.6%. An excellent seizure outcome Engel Class I was found in 76.1% of patients during a mean follow-up of 26.4 months, irrespective of histological entity (74% in CM, 75% in GG, 78% in DNT and 60% in FCD). No severe postoperative complications occurred; permanent superior visual field defects were detected in 10.2% and permanent dysphasia/dyscalculia in 1.1%. CONCLUSION Refined surgery using neuronavigation combined with iopMR imaging in LTLE surgery led to radical resection in 96.6% of the patients, due to immediate correction of underestimated resection in 21.6% of patients. This protocol resulted in a favourable seizure outcome and a low complication rate.

Efficacy of perampanel: a review of clinical trial data

The efficacy of adjunctive perampanel has been investigated in an extensive clinical development program across a broad, multinational population of patients with refractory partial‐onset seizures. Further to the results of two Phase II dose‐finding studies, perampanel was evaluated in three large Phase III registration studies at the predicted no‐effect dose of 2 mg/day and the predicted effective doses of 4, 8, and 12 mg/day. In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial‐onset seizures compared with placebo. Improvements in responder rates and seizure freedom rates were also observed. In addition, data from recent interim analyses of extension studies have indicated that these efficacy outcomes may be maintained with long‐term treatment. Overall, these studies form a solid evidence base to support the efficacy of adjunctive perampanel in the treatment of refractory partial‐onset seizures.