Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy.

OBJECTIVE: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments. METHODS: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. RESULTS: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p = .243; PER, p = .113) or responder status (BRV, p = .118; LCM, p = .478; PER, p = .069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). SIGNIFICANCE: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring.

A novel geometry-based analysis of hippocampal morphometry in mesial temporal lobe epilepsy.

Hippocampal volumetry is an essential tool in researching and diagnosing mesial temporal lobe epilepsy (mTLE). However, it has a limited ability to detect subtle alterations in hippocampal morphometry. Here, we establish and apply a novel geometry-based tool that enables point-wise morphometric analysis based on an intrinsic coordinate system of the hippocampus. We hypothesized that this point-wise analysis uncovers structural alterations not measurable by volumetry, but associated with histological underpinnings and the neuropsychological profile of mTLE. We conducted a retrospective study in 204 individuals with mTLE and 57 age- and gender-matched healthy subjects. FreeSurfer-based segmentations of hippocampal subfields in 3T-MRI were subjected to a geometry-based analysis that resulted in a coordinate system of the hippocampal mid-surface and allowed for point-wise measurements of hippocampal thickness and other features. Using point-wise analysis, we found significantly lower thickness and higher FLAIR signal intensity in the entire affected hippocampus of individuals with hippocampal sclerosis (HS-mTLE). In the contralateral hippocampus of HS-mTLE and the affected hippocampus of MRI-negative mTLE, we observed significantly lower thickness in the presubiculum. Impaired verbal memory was associated with lower thickness in the left presubiculum. In HS-mTLE histological subtype 3, we observed higher curvature than in subtypes 1 and 2 (all p < .05). These findings could not be observed using conventional volumetry (Bonferroni-corrected p < .05). We show that point-wise measures of hippocampal morphometry can uncover structural alterations not measurable by volumetry while also reflecting histological underpinnings and verbal memory. This substantiates the prospect of their clinical application.

Seizure underreporting in LGI1 and CASPR2 antibody encephalitis.

Patients with anti-leucine-rich glioma-inactivated 1 protein (LGI1) or anti-contactin-associated protein 2 (CASPR2) antibody encephalitis typically present with frequent epileptic seizures. The seizures generally respond well to immunosuppressive therapy, and the long-term seizure outcome seems to be favorable. Consequentially, diagnosing acute symptomatic seizures secondary to autoimmune encephalitis instead of autoimmune epilepsy was proposed. However, published data on long-term seizure outcomes in CASPR2 and LGI1 antibody encephalitis are mostly based on patient reports, and seizure underreporting is a recognized issue. Clinical records from our tertiary epilepsy center were screened retrospectively for patients with LGI1 and CASPR2 antibody encephalitis who reported seizure freedom for at least 3 months and received video-electroencephalography (EEG) for >24 h at follow-up visits. Twenty (LGI1, n = 15; CASPR2, n = 5) of 32 patients with LGI1 (n = 24) and CASPR2 (n = 8) antibody encephalitis fulfilled these criteria. We recorded focal aware and impaired awareness seizures in four of these patients (20%) with reported seizure-free intervals ranging from 3 to 27 months. Our results question the favorable seizure outcome in patients with CASPR2 and LGI1 antibody encephalitis and suggest that the proportion of patients who have persistent seizures may be greater. Our findings underline the importance of prolonged video-EEG telemetry in this population.

Cognitive reawakening and improved quality of life achieved after discontinuing 16 years of anti-seizure treatment with topiramate.

A 42-year-old female patient with epilepsy and a co-morbid migraine suffered from the severe cognitive side effects of topiramate (TPM) for more than 16 years with detrimental consequences for her daily functioning, career, and social interaction. Even a prodromal stage of dementia was suggested, giving rise to fears of developing a neurodegenerative disease. Recently, cognitive monitoring of attention and executive function before and after withdrawal of TPM revealed a significant recovery from the severe negative cognitive side effects of the long-standing and inefficacious antiseizure medication (ASM). Whereas the side effects were reversible after cessation, their consequences for the patient`s biography were permanent. A considerable increase in quality of life, however, was observed without TPM and family members were impressed by the improvements. This case illustrates the potentially severe consequences of negative cognitive side effects which affect daily functioning, career and social life, thus underscoring the importance of being knowledgeable of the potential cognitive risks when prescribing an ASM. Because cognitive side effects may not depend solely on ASM choice and drug load, but also on individual idiosyncratic intolerances, and patients might stay on their treatment for many years, cognitive monitoring is highly recommended.

[Transient epileptic amnesia-A rare phenomenon in temporal lobe epilepsies]. / Transiente epileptische Amnesie ­ ein seltenes Phänomen bei Temporallappenepilepsien.

BACKGROUND: Transient epileptic amnesia (TEA) is a rare phenomenon in temporal lobe epilepsy that is often unrecognized or misdiagnosed as transient global amnesia (TGA). It is postulated that TEA is due to both ictal and postictal disturbances. Response to antiseizure medication underlines its epileptic nature. In view of the increasing incidence of new-onset epilepsies in old age, an increase in TEA can be expected in the future. OBJECTIVE: Analysis of TEA features in a monocentric case series. MATERIAL AND METHODS: A search in our electronic patient data base yielded 10 patients with TEA out of 7899 patients over a period of 8 years. Clinical and paraclinical features as well as findings of additional examinations were retrospectively collected. Data are given as mean ± SD. RESULTS: All 10 patients were diagnosed with temporal lobe epilepsy. The mean age at manifestation of TEA was 59.1 ± 6.7 years, the diagnosis was made with a delay of 21.9 ± 26.3 months. The TEA lasted on average 56 ± 37 min, and 16 ± 9.9 TEA episodes per year were reported by the patients; out of the 10 patients 6 reported that TEA usually occurred upon awakening. In 9 of 10 patients, there was evidence of typical seizure symptoms or other semiological elements during TEA. Interictal neuropsychological disturbances of temporal functions were seen in 8 of 10 patients and evidence of depressive disorder in 6 of 10 patients. Video EEG recordings revealed epileptiform activity during sleep in 4 patients over the left and in 2 patients over both temporal regions. In 3 patients, magnetic resonance imaging displayed typical alterations of the temporomesial structures (in 2 patients on the left and in 1 the right side). Antiseizure medication improved seizure control in 7 of 10 patients (seizure freedom in 6 patients), 3 patients were lost to follow-up. DISCUSSION: TEA is rare, occurs in older adults and is correctly diagnosed after about 2 years. Thorough assessment of additional symptoms and circumstances, the recurrent occurrence as well as typical EEG and imaging findings of temporal lobe epilepsy enables the distinction between TEA and TGA.

Drebrin Autoantibodies in Patients with Seizures and Suspected Encephalitis.

OBJECTIVE: Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms. METHODS: Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure. RESULTS: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability. INTERPRETATION: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884.

COVID-19 vaccination in patients with epilepsy: First experiences in a German tertiary epilepsy center.

INTRODUCTION: Due to the high demand for information regarding COVID-19 vaccination in people with epilepsy (PWE), we assessed the symptoms and seizure control of PWE following their COVID-19 vaccination. METHODS: All adult patients who were treated at our center were asked to report on their vaccination status and, if vaccinated, about their experiences following their first COVID-19 vaccination with regard to adverse effects and seizure control. RESULTS: Fifty-four PWE have already received their first vaccination against COVID-19 (27 female, 20% seizure free, 96<% on antiseizure medication) and were included in the study. Two-thirds tolerated the vaccines generally either very well or well. Thirty-three percent reported general vaccination adverse effects. The most frequently reported general adverse effects were, in descending order, headache, fatigue and fever, and shivering. With regard to epilepsy-related adverse effects, one patient reported increased seizure frequency one day after the first COVID-19 vaccination was administered, and one reported the occurrence of a new seizure type. None of the patients reported a status epilepticus or aggravation of preexisting adverse effects. CONCLUSIONS: Our data suggest that vaccination against COVID-19 appears to be well tolerated in PWE, supporting the recommendation of vaccination to PWE.

Levetiracetam, perampanel, and the issue of aggression: A self-report study.

This study investigated to which degree levetiracetam (LEV) and perampanel (PER), antiseizure medications (ASM) that are both known to cause aggression and irritability, share the same or different, behavioral side-effect profiles. In this self-report study, 68 participants with epilepsy treated with LEV (n = 35) or PER (n = 33) as part of their medication were asked to rate their behavioral experience with the respective drug as positive, neutral, or negative. Results of a German adaptation of the Adverse Events Profile (AEP) and of the "FPZ", a German personality questionnaire, were analyzed as a function of drug and rating. Thirty-eight percent of the LEV group and 36% of the PER group experienced negative change after the evaluated drug was introduced. By subdividing participants in the LEV sample into those who attributed the negative effects to LEV and those with neutral or positive experience with LEV, a negative evaluation of LEV was associated with significantly worse scores in cognition, mood, and physical domains (80% versus 20-40%). Subdividing participants in the PER sample into those who attributed negative the side effects to PER, and those with a neutral or positive experience with PER, significance could be shown for mood domains only (100% versus 50%), and within this domain only for increased aggression and irritability. Comparing features of the behavioral negative side effects of LEV and PER revealed that LEV appears to have a negative impact on a much broader range of behaviors than PER, which specifically seems to induce aggression and irritability and no other psychiatric side effects. Further research should aim at different expression and different mechanisms of aggression and irritability underlying the superficially similar effects of the two drugs.

Reduced past-oriented mind wandering in left compared to right medial temporal lobe epilepsy.

Mind wandering refers to a shift of attention away from a task at hand to task-unrelated thoughts. Several groups have shown increased activation of the left medial temporal lobe (MTL) before and during spontaneous thoughts suggesting that the left MTL may play a crucial role in mind wandering. Due to its relevance for long-term memory, we further hypothesized that the left MTL is particularly involved in mind wandering towards the past. Accordingly, we predicted a reduced propensity to mind wander and less past-oriented mind wandering in patients with left MTL epilepsies. To this end, we experimentally investigated mind wandering in 89 in-patients undergoing diagnostic evaluation of their putative epileptic disorder. Patients performed a sustained attention to response task with embedded experience sampling probes aiming to assess occurrence, meta-awareness and temporal orientation (past/present/future) of mind-wandering episodes. We did not find significant differences in the propensity to mind wander between patient subgroups. However, the left MTL epilepsy subgroup showed significantly reduced past-oriented mind wandering compared to right MTL epilepsies, as well as a trend towards diminished past-oriented mind wandering compared to idiopathic epilepsies. Possibly due to compensatory mechanisms, the right MTL epilepsy subgroup showed significantly increased past-oriented mind wandering compared to extratemporal epilepsies and patients with syncopes. These behavioural findings point to a rejection of the hypothesis that the amount of time engaged in mind wandering crucially depends on the left MTL. However, our data do support the idea that the left MTL is particularly involved in mind wandering towards the past.

Does the accumulated antiepileptic drug load in chronic epilepsy reflect disease severity?

OBJECTIVE: To ascertain factors that are related to the antiepileptic drug load in epilepsy. METHODS: In this cross-sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n = 1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n = 91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic-clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). RESULTS: Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%-10% of variance in drug load. Nearly the same variance (5%-8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. SIGNIFICANCE: Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long-lasting epilepsies.

Changes in cognition after introduction or withdrawal of zonisamide versus topiramate in epilepsy patients: A retrospective study using Bayes statistics.

OBJECTIVE: We aim to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive. METHODS: In this retrospective observational study, we analyzed patients' records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions (EpiTrack), verbal memory (short version of verbaler lern- und merkfähigkeitstest, VLMT), and subjective health (extended Adverse Events Profile; quality of life in epilepsy inventory, QOLIE-10) was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn. The data were analyzed using Bayes statistics that quantify evidence for or against an effect through Bayes factors (BFs). RESULTS: There was decisive evidence for a negative effect of adjunctive ZNS and TPM on executive function (BF = 965.08) and a positive effect of their withdrawal (BF = 429.51). The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance. SIGNIFICANCE: This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function in a naturalistic treatment setting. Comparable to the well-known TPM effect, cognition worsens with adjunction and recovers with withdrawal of ZNS. However, the majority of patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Counseling of people with epilepsy via telemedicine: Experiences at a German tertiary epilepsy center during the COVID-19 pandemic.

INTRODUCTION: Driven by the challenges of alternative healthcare supply during the COVID-19 pandemic, acceptance and appreciation of telemedicine were assessed in a German tertiary epilepsy center. METHODS: Two hundred thirty-nine patients with epilepsy (53% female, 35% seizure-free, 97% on antiseizure medication) answered a structured audit on telemedical counseling as part of individual outpatients' care. RESULTS: Overall 82% of the participants were satisfied with the telemedical appointment. The telemedical appointment was rated equal to onsite appointments in means of time (91%), comprehensibility (94%), and opportunity to get answers to current questions (92%). It was evaluated as good as onsite appointments regarding comprehension of the disease (88%) and impact on following the physician's advice (82%). The participants considered immediate convenience and shortfall of travel expenses as advantages of telemedicine, whereas lack of personal contact and diagnostics (electroencephalogram [EEG] recordings, blood analysis) were seen as disadvantages. About 73% of the participants would appreciate the opportunity of future telemedical counseling, but the majority (75%) wished to have further appointments onsite. CONCLUSIONS: Overall, people with epilepsy appear to be satisfied with telemedical counseling. However, patients greatly appreciate the medical services onsite and consider telemedicine as an add-on service rather than a substitute to visits onsite.

Knowledge, expectations and fears of cannabis use of epilepsy patients at a tertiary epilepsy center.

INTRODUCTION: Medical cannabis is increasingly discussed as an alternative treatment option in neurological diseases, e.g. epilepsy. Supporters and opponents base their propositions mostly on subjective estimates, they confuse cannabis in whole versus extracts and botanical versus synthesized. METHODS: Two hundred seventy five patients with any kind of epilepsy (56% female, 44% seizure free, 91% on medication) answered a survey on the knowledge, expectations, fears, and willingness to be treated with medical cannabis. Data were analyzed with regard to patient characteristics and clinical data from patient files. RESULTS: Overall, 70.5% of the patients were familiar with the possibility of medical cannabis treatment, 36.7% with its use in epilepsy. A minority of 10.9% gained the information from their physicians. The majority knew about organic compared to synthetic cannabis. The interest in further information is high (71.3%). Regression analysis (explaining 53.8% of the variance) indicated that positive expectations (in the order of relevance) were seizure control, relaxation, mood, and tolerability whereas fears mostly concerned addiction and delirant intoxication. Men showed a greater interest than women. CONCLUSION: Many epilepsy patients knew about medical cannabis, were interested in this treatment, and wanted more information. Expectations, however, appear to be based on the connotations of the whole substance cannabis with tetrahydrocannabidiol and its commonly known effects. Unfortunately, patients did not get their information from physicians, but mostly by other sources. In order to avoid prejudices and potentially harmful self-medication, physicians and healthcare providers are called to become familiar with the substance and to inform patients adequately.

Knowledge of sudden unexpected death in epilepsy (SUDEP) among 372 patients attending a German tertiary epilepsy center.

BACKGROUND: There is evidence that the sudden unexpected death in epilepsy (SUDEP) risk can be reduced by good seizure control, nocturnal supervision, and by early cardiopulmonary resuscitation if cardiorespiratory arrest occurs in the aftermaths of generalized tonic-clonic seizures (GTCS). These measures, however, may critically depend on the knowledge of patients and relatives on SUDEP. Here, we assessed the basic knowledge on SUDEP of people with epilepsy at a tertiary epilepsy center in Germany. METHODS: Adult patients with epilepsy and relatives or caregivers of patients with epilepsy aged 16years or older attending our outpatient clinic from January to March 2014 were given the opportunity to participate in a (assisted or unassisted) written survey. In the anonymized questionnaire, people were asked if they had already heard about SUDEP, by what means and if they wish to learn (more) about SUDEP. Furthermore, age, sex, epilepsy duration, highest degree of education, number of GTCS during the last year, and estimation of subjective impairment by their disease were assessed. Statistics were done using mixed linear or logistic regression models. RESULTS: A total of 372 patients' questionnaires were included in this survey. More than 87% of the participants had never heard of SUDEP before. Whereas about 50% of the participants wanted to learn more about SUDEP, about 40% did not. Only the age at survey was significantly associated with both being informed and the desire of learning more about SUDEP: Younger patients had more often heard (p=0.022) and wanted to know more about SUDEP (p=0.020). Thirty-nine patients were considered at high risk for SUDEP. Of these, only 6 patients (15%) knew about SUDEP prior to this survey, but 18 patients (46%) wanted to learn more about this fatal complication. CONCLUSION: Our data suggest that the level of information on SUDEP among people with epilepsy is poor in Germany regardless of sex, school education, or epilepsy severity. Additionally, a considerable proportion of people with epilepsy seems to prefer not getting detailed information on SUDEP. More efforts are required to understand the potential barriers of the education of patients and relatives on sudden death with the ultimate goal of decreasing the risk of SUDEP.

Normalization and cross-sectional validation of an extended Adverse Event Profile (E AEP) in a large cohort of patients with epilepsy.

PURPOSE: The Liverpool Adverse Event Profile (L AEP) is commonly used in clinical practice and pharmacological trials for the monitoring of side effects of anti-seizure medication (ASM). However potentially unrelated, additional symptoms and normative data should be considered to put patients´ complaints into perspective. METHODS: An extended 32-item AEP (E AEP) was given to 537 healthy subjects and 1,605 patients with epilepsy as part of the Bonn ASM side effect registry. The tool was factor-analyzed, corrected for age, gender, and repeated application, and related to drug load and individual substances (with N> 100) on item and scale level (total E AEP and its subscales cognition, dizziness, energy, mood, bodily symptoms, aggression, and sexuality). RESULTS: Compared to non-normalized results, at item level, between one and two-thirds of responses suggesting impairment were found to be unlikely to be related to ASM treatment after normalization. Binary regression analyses revealed differential effects of medication choice, but also of antidepressants and neuroleptics on complaint domains. The explained variance was better for physical than psychological domains. The results reflect both known drug side effects and indications. Patients´ explicit attribution of problems to their medications barely improved the correlation of the E AEP and treatment parameters. CONCLUSION: Application of a norm-referenced AEP is highly recommended to avoid overestimation of treatment related problems in patients with epilepsy. It allows evaluation on item and scale level for individuals as well as groups in drug trials. Plausible relations to individual drugs and to drug load can be demonstrated. The explanatory power was better for physical than psychological domains. Drug-related complaint patterns reflect known drug side effects (e.g. perampanel and brivaracetam with aggression) as well as drug indications (e.g. lamotrigine for depression). This is likely to be particularly relevant when side effects may have affected treatment decisions. Longitudinal evaluation with repeated application of the E AEP with changes of drug treatment is in progress.

Short-term effects of transcutaneous auricular vagus nerve stimulation on T-wave alternans in people with focal epilepsy - An exploratory pilot study.

High levels of T-wave alternans (TWA) are linked to an increased risk of sudden cardiac death. People with epilepsy display elevated TWA levels that are decreased by chronic vagus nerve stimulation via implanted devices after 2-4 weeks or later. Our objective was to explore short-term effects of transcutaneous auricular vagus nerve stimulation (tVNS) on TWA. Five patients (3 female) with focal epilepsy undergoing video-EEG monitoring were included. TWA levels were determined using a one-channel modified lead I ECG via an open-source TWA-algorithm on two consecutive days, 1 h before, during and after tVNS via the left auricle. Data are given as mean ± SE. Mean TWA at baseline was 3.8 ± 0.4 µV and 3.0 ± 0.6 µV during stimulation on day 2. Stimulations on the second day were associated with TWA reductions by 22 ± 13 % that exceeded stimulation effects on the first day relative to baseline (p < 0.05). Linear mixed-models revealed effects of both stimulation (p < 0.05) and stimulation number (p < 0.005). Normalized TWA showed reproducible peak reductions at both days within 35 min after the initiation of tVNS (p < 0.05). Our observations suggest that tVNS has short-term effects on TWA, supporting the notion that vagus nerve stimulation has a beneficial impact on electrical cardiac properties.

Volumetric gray matter findings in autonomic network regions of people with focal epilepsy.

BACKGROUND AND PURPOSE: Voxel-based morphometry (VBM) studies of people with focal epilepsies revealed gray matter (GM) alterations in brain regions involved in cardiorespiratory regulation, which have been linked to the risk of sudden unexpected death in epilepsy (SUDEP). It remains unclear whether the type and localization of epileptogenic lesions influence the occurrence of such alterations. METHODS: To test the hypothesis that VBM alterations of autonomic network regions are independent of epileptogenic lesions and that they reveal structural underpinnings of SUDEP risk, VBM was performed in 100 people with focal epilepsies without an epileptogenic lesion identifiable on MRI (mean age ± standard deviation = 35 ± 11 years, 56 female). The group was further stratified in high (sample size n = 29) and low risk of SUDEP (n = 71). GM volumes were compared between these two subgroups and to 100 matched controls. RESULTS: People with epilepsy displayed higher GM volume in both amygdalae and parahippocampal gyri and lower GM volume in the cerebellum and occipital (p<.05, familywise error corrected). There were no significant volumetric differences between high and low SUDEP risk subgroups. CONCLUSION: Our findings confirm that autonomic networks are structurally altered in people with focal epilepsy and they question VBM as a suitable method to show structural correlates of the SUDEP risk score.

Impact of biological rhythms on the importance hierarchy of constituents in time-dependent functional brain networks.

Biological rhythms are natural, endogenous cycles with period lengths ranging from less than 24 h (ultradian rhythms) to more than 24 h (infradian rhythms). The impact of the circadian rhythm (approximately 24 h) and ultradian rhythms on spectral characteristics of electroencephalographic (EEG) signals has been investigated for more than half a century. Yet, only little is known on how biological rhythms influence the properties of EEG-derived evolving functional brain networks. Here, we derive such networks from multiday, multichannel EEG recordings and use different centrality concepts to assess the time-varying importance hierarchy of the networks' vertices and edges as well as the various aspects of their structural integration in the network. We observe strong circadian and ultradian influences that highlight distinct subnetworks in the evolving functional brain networks. Our findings indicate the existence of a vital and fundamental subnetwork that is rather generally involved in ongoing brain activities during wakefulness and sleep.

Modifying functional brain networks in focal epilepsy by manual visceral-osteopathic stimulation of the vagus nerve at the abdomen.

Non-invasive transcutaneous vagus nerve stimulation elicits similar therapeutic effects as invasive vagus nerve stimulation, offering a potential treatment alternative for a wide range of diseases, including epilepsy. Here, we present a novel, non-invasive stimulation of the vagus nerve, which is performed manually viscero-osteopathically on the abdomen (voVNS). We explore the impact of short-term voVNS on various local and global characteristics of EEG-derived, large-scale evolving functional brain networks from a group of 20 subjects with and without epilepsy. We observe differential voVNS-mediated alterations of these characteristics that can be interpreted as a reconfiguration and modification of networks and their stability and robustness properties. Clearly, future studies are necessary to assess the impact of such a non-pharmaceutical intervention on clinical decision-making in the treatment of epilepsy. However, our findings may add to the current discussion on the importance of the gut-brain axis in health and disease. Clinical Trial Registration: https://drks.de/search/en/trial/DRKS00029914, identifier DRKS00029914.