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Transcutaneous vagus nerve stimulation (tVNS) is a newly developed method which intends to overcome the disadvantage of surgical implantation of the stimulation device. The tVNS device is designed to stimulate the auricular branch of the vagus nerve via a bipolar electrode attached to the skin of the left ear conch. A randomized, double-blind controlled trial assessed efficacy and safety over 20 weeks of tVNS (n=39) vs. active control tVNS (n=37) in patients with drug-resistant epilepsy. While the mean seizure reduction per 28 days at end of treatment (2.9% reduction from baseline in the control group vs 23.4% in the active group) did not reach statistical significance, there was a significant reduction in seizure frequency (34 %) in patients in the tVNS group at the end of the treatment period (20 weeks). TVNS was well-tolerated. The results justify further trials with longer observation periods and possibly at earlier stages of epilepsy., (Copyright © 2019. Published by Elsevier B.V.)

Background: Especially in hidden lesions causing drug-resistant frontal lobe epilepsy (FLE), the localization of the epileptic zone EZ can be a challenge. Magnetoencephalography (MEG) can raise the chances for localization of the (EZ) in combination with electroencephalography (EEG). We investigated the impact of MEG-guided epilepsy surgery with the aid of neuronavigation and intraoperative MR imaging (iopMRI) on seizure outcome of FLE patients., Methods: Twenty-eight patients (15 females, 13 males; mean age 31.0±11.1 years) underwent surgery in our department. All patients underwent presurgical MEG monitoring (two-sensor Magnes II or whole head WH3600 MEG system; 4-D Neuroimaging, San Diego, CA, USA). Of those, six patients (group 1) with MRI-negative FLE were operated on before 2002 with intraoperative electrocorticography (ECoG) and invasive EEG mapping only. Eleven patients with MRI-negative FLE (group 2) and eleven with lesional FLE (group 3) underwent surgery using 1.5T-iopMRI and neuronavigation, including intraoperative visualization of the MEG localizations in 22 and functional MR imaging (for motor and speech areas) as well as DTI fiber tracking (for language and pyramidal tracts) in 13 patients., Results: In the first group, complete resection of the defined EZ including the MEG localization according to the latest postoperative MRI was achieved in four out of six patients. Groups two and three had complete removal of the MEG localizations in 20/22 (91%, 10 of 11 each). Intraoperative MRI revealed incomplete resection of the MEG localizations of four patients (12%; two in both groups), leading to successful re-resection. Transient and permanent neurological deficits alike occurred in 7.1%, surgery-associated complications in 11% of all patients. In the first group, excellent seizure outcome (Engel Class IA) was achieved in three (50%), in the second in 7 patients (61%) and third group in 8 patients (64%, two iopMRI-based re-resections). Mean follow-up was 70.3 months (from 12 to 284 months)., Conclusion: In our series, MEG-guided resection using neuronavigation and iopMR imaging led to promising seizure control rates. Even in non-lesional FLE, seizure control rates and the probability of complete resection of the MEG localizations was similar to lesional FLE using multimodal navigation., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: For safe 3T-MRI of patients with VNS (vagus nerve stimulator), specific conditions are mandatory. However, application of these conditions can lead to a loss of image quality. In this work, we evaluated the diagnostic value of 3T-MRI in VNS patients with pharmacoresistant epilepsy., Methods: Using a transmit-and-receive head coil and adapting our sequences to allow for low SAR (specific absorption rate), we examined 15 patients with pharmacoresistant epilepsy. Diagnostic quality was assessed by comparison of the SNR (signal to noise ratio) and CNR (contrast to noise ratio) of the hippocampus, the grey-white matter contrast and epileptogenic lesions to images of patients without VNS acquired with our routine 3T-MRI protocol and the 32-channel head coil., Results: 3T-MRI is feasible in VNS-patients. Image quality is adequate for detection and follow-up of epileptogenic lesions such as ganglioglioma or PNH (periventricular nodular heterotopia). Due to a significant reduction of SNR and CNR, the diagnostic value for subtle lesions may be decreased. Overall, the feasibility of 3T-MRI is beneficial in the diagnostic workup and follow-up of epilepsy-patients with VNS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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, ammon's 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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: The presence of hippocampal sclerosis (HS) on MRI has a great impact on the clinical evaluation and counselling of patients with temporal lobe epilepsy (TLE) and is considered as a key criterion for the decision to recommend epilepsy surgery. However, neuropathological studies describe evidence of HS in up to 10% of non-epileptic individuals, questioning the impact of this MRI finding in patients with TLE. We evaluated the prevalence of HS on MRI in the general population., Methods: 100 healthy subjects and 10 patients with TLE due to HS were investigated in a prospective study using a specific protocol for the detection of hippocampal pathology (coronal FLAIR, coronal T2 TSE and a T1 weighted 3D SPGR sequence)., Results: HS was detected in none of the healthy subjects (95% confidence interval=0-3.6%), but in all patients. Inter-rater agreement was perfect for presence of HS. Thirty-three subjects had an unilaterally enlarged temporal horn as an isolated secondary criterion for HS and inter-rater agreement was slight for this point. Incidental pathological findings were detected in two patients (2%): one had a low grade astrocytoma (1%), one an aneurysm of the posterior communicating artery (1%)., Conclusions: HS was not diagnosed in healthy subjects, supporting its impact on the evaluation of patients with temporal lobe epilepsy. An unilateral enlarged temporal horn that occurred in one third of the healthy subjects should not be considered as a pathologic finding or even as a marker for HS., (Copyright 2010 Elsevier B.V. All rights reserved.)

Inflammatory mechanisms are involved in the pathogenesis of epilepsy. Vice versa, immune functions are regulated by the brain. We measured postictal changes in serum levels of the immuno-modulating cytokines IL-1beta, IL-6 and TNFalpha in patients with well-defined temporal lobe epilepsy (TLE) and determined modifying factors. Serum levels of IL-1beta, IL-6 and TNFalpha were quantified by ELISA at baseline as well as immediately, 1h and 24h after a complex partial (CPS) or secondary generalized tonic-clonic seizure (GTCS) during video-EEG monitoring in 25 patients suffering from temporal epilepsy. IL-6 increased by 51% immediately after the seizure (p<0.01) and remained elevated for 24h. This increase lacked in patients with hippocampal sclerosis (HS; n=16, mean increase 28%, p>0.5, vs. 112%, p<0.01 in patients without HS). IL-6 levels were higher after right-sided seizures as compared to left-sided seizures 24h after the seizure (8.7pg/mL vs. 3.4pg/mL, p<0.05). In patients taking valproate (VPA, n=9), the levels of IL-1beta were higher as compared to patients not treated with VPA. The results suggest a relationship between the cytokine system and characteristics of TLE such as side and pathology.

We used transcranial magnetic stimulation (TMS) in patients with juvenile myoclonic epilepsy (JME) and healthy controls to characterise motorcortical excitability in the morning as compared to the evening. Intra- and interindividual comparisons in JME-patients and controls showed no significant differences of any TMS parameter. The expected rise of the resting motor thresholds (RMT) in JME-patients taking anticonvulsants could not be detected which may indicate a decreased RMT in JME-patients.

Objective: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery., Methods: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers., Results: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients)., Conclusion: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Ictal functional transcranial Doppler sonography (I-fTCD) was used to lateralize the ictal onset zone in the presurgical evaluation of two patients with temporal lobe epilepsy. In one patient, I-fTCD and ictal SPECT were performed simultaneously during EEG-monitoring. In both patients, results were concordant with the ictal SPECT findings, PET and semiology. I-fTCD seems to be an interesting new method to non-invasively lateralize the seizure onset zone with high temporal resolution. I-fTCD and SPECT may give complementary information to lateralize the seizure onset zone.

Purpose: Levetiracetam (LEV) is a new compound with anticonvulsive efficacy in focal and generalized epilepsies. Recent in vitro studies suggest LEV to act as a selective N-type-calcium-channel blocker., Methods: We used transcranial magnetic stimulation (TMS) in order to investigate if ion-channel blockade is relevant to the inhibitory CNS effects of LEV in vivo and if motor thresholds (MTs) are a valid TMS parameter to detect this mode of action. In a double blind, placebo-controlled, crossover study, the effects of single oral doses of 500 and 2000 mg LEV on motor thresholds, recruitment curves (REC), cortical induced silent period (CSP) and on intracortical inhibition (ICI) and facilitation (ICF) were studied in 10 healthy subjects., Results: A significant increase of motor thresholds was noticed after 2000 mg LEV as compared to placebo. The recruitment curve showed a trend towards motor evoked potential (MEP) amplitude reduction after LEV. LEV had no significant effect on CSP or on intracortical excitability as measured by inhibition and facilitation., Conclusions: We conclude that the modulation of ion-channel function, reflected by motor threshold elevation and a trend towards recruitment curve suppression, is relevant to the inhibitory CNS effects of LEV in vivo, and therefore, may contribute to the anticonvulsive efficacy of LEV. GABAergic or glutamatergic mechanisms seem to be less important in vivo as measured by TMS.

Purpose: To evaluate the relative impact of 3 and 5 min of hyperventilation (HV) and different sleep stages on the sensitivity of the interictal EEG in focal epilepsy., Methods: We examined 20 patients with temporal lobe epilepsy (TLE, 85%) or extratemporal epilepsy during EEG-monitoring. We compared 6 min EEG (12 epochs of 30s) during/after each: (a) waking; (b) 5 or 3 min of HV; (c) sleep stages 1, 2, 3/4 and REM regarding the frequency of epileptiform discharges (ED). The Wilcoxon matched pairs signed rank test was used. The main endpoint was the comparison of 5 min of HV with sleep stage 2., Results: During sleep stage 2, ED were more frequent than during/after 5 min of HV (P=0.002). Compared to the waking EEG, all NREM-sleep stages activated ED. Sleep stage 2 was associated with the strongest activation. There was no difference between the waking state and REM-sleep. Compared to the waking EEG, neither 3 nor 5 min of HV showed an activation of ED., Conclusion: In patients with TLE, sleep stage 2 shows a significantly higher sensitivity for ED than 5 min of HV. Compared to the waking EEG, HV showed no activating effect on ED. These results suggest that in patients with the clinical diagnosis of TLE (and possibly other focal epilepsies) measures to record sleep stage 2 (such as sleep deprivation) should be increased whereas HV appears to be dispensable in this setting.

Focal clonic seizures are a frequent epileptic phenomenon. However, there are little data about their pathomechanism. In four patients with focal epilepsy and subdural electrodes, focal clonus was elicited by electrical stimulation of the motor cortex. Three additional patients underwent intraoperative stimulation of the spinal cord. Rhythmic clonic muscle responses were elicited by cortical stimulation with 20-50 Hz. The clonus consisted of simultaneous trains of compound muscle action potentials (CMAP) in agonistic and antagonistic muscles alternating with periods of muscular silence despite continuous stimulation. Clonus frequency decreased from 4.0-8.0 Hz at 50 Hz stimulation to 3.0-3.5 Hz at 20 Hz paralleled by a prolongation of the trains of CMAP. The stimulation frequency correlated with the number of stimuli blocked during relaxation. During the stable stimulation periods, the clonus frequency decreased over time. The number of stimuli which formed a train of CMAP and which were blocked during relaxation increased towards the end of the stimulation periods. Increasing intensity of stimulation at the same frequency converted a clonic to a tonic response. There was always an 1:1 relationship between stimulus and CMAP during spinal cord stimulation. We hypothesize that during cortical stimulation, clonus is elicited by synchronous activation of pyramidal tract (PT) neurons which results in excitation of intracortical GABA(B)ergic interneurons by recurrent axon-collaterals. This leads to stepwise hyperpolarization of PT neurons intermittently suppressing the output of PT neurons despite continuous stimulation. This mechanism can explain our finding that temporal and spatial summation of the stimuli were needed for clonus generation., (Copyright 2002 Elsevier Science B.V.)