No abstract

SUMMARYTo elucidate, in a pilot-study, whether noninvasive transcutaneous vagus nerve stimulation (t-VNS) is a safe and tolerable alternative treatment option in pharmacoresistant epilepsy. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, we carried out prolonged outpatient videoelectroencephalography (EEG) monitoring. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The noninvasive t-VNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with 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.

Histopathologic evaluation of brain tissue derived from surgically treated patients with medically refractory temporal lobe epilepsy (TLE) frequently reveals structural brain lesions in the surgical specimen. While several of the most commonly encountered lesions such as low-grade neoplasms or vascular malformations are well established as structural substrates of epilepsy, the significance of subtle microscopic characteristics has remained controversial. Within the spectrum a broad range of microscopic features has previously been reported as "mild cortical dysplasia," "focal cortical dysplasia," or "microdysgenesis," including cortical laminar disorganization, columnar arrangement of cortical neurons, marked clustering of neurons throughout cortical layers II-VI, increased numbers of molecular layer neurons, marked perivascular clustering of oligodendroglia in the white matter, single heterotopic neurons in the deep white matter, glioneuronal hamartia, giant neurons, and balloon cell change. In this paper we report the frequency of these features in temporal lobe tissue of 47 surgically treated TLE-patients vs 29 normal autopsy controls. While most of them were found in both cases and controls, clustering of neurons throughout cortical layers II-VI, perivascular clustering of oligodendroglia in the white matter, increased single heterotopic white matter neurons, and glioneuronal hamartias predominated in tissue from patients with epilepsy (p < 0.05). A count of more than 10 white matter neurons/HPF was associated with a worse postoperative outcome (p < 0.05). These data suggest that certain microscopic characteristics are associated with the epileptic process, while others appear as normal variants.

The aim of epilepsy surgery in patients with focal, pharmacoresistant epilepsies is to remove the complete epileptogenic zone to achieve long-term seizure freedom. In addition to a spectrum of diagnostic methods, magnetoencephalography focus localization is used for planning of epilepsy surgery. We present results from a retrospective observational cohort study of 1000 patients, evaluated using magnetoencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecutive cases were included in the study, evaluated at the University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to 20 years. Sensitivity for interictal epileptic activity was evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar level. We evaluate magnetoencephalography characteristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In operated patients, resection of magnetoencephalography localizations were related to postsurgical seizure outcomes, including long-term results after several years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic accuracy were calculated for magnetoencephalography resection and lesionectomy. Sensitivity for interictal epileptic activity was 72% with significant differences between temporal and extra-temporal lobe epilepsy. Magnetoencephalography was concordant with the presurgical consensus in 51% and showed additional or more focal involvement in an additional 32%. Patients who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography results. Complete magnetoencephalography resection was associated with significantly higher chances to achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and extra-temporal lobe cases, but was significantly higher in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-lesional versus lesional cases (42.0 versus 6.2). The results show that magnetoencephalography provides non-redundant information, which significantly contributes to patient selection, focus localization and ultimately long-term seizure freedom after epilepsy surgery. Specifically in extra-temporal lobe epilepsy and non-lesional cases, magnetoencephalography provides excellent accuracy.