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Abstract Background Status epilepticus (SE) is one of the most common neurological emergencies and an acutely life-threatening condition characterized by high mortality and morbidity. Despite the well-established staged therapy of status epilepticus, especially stages 1 and 2, more than one third of patients develop (super-) refractory SE. Despite a large variety of potential treatment options for super-refractory SE, there is an unmet clinical need of potential new treatment ideas in this often desperate clinical situation. A number of studies have demonstrated the safety and efficacy of stiripentol (STP) in patients with Dravet syndrome (DS) and in children with focal epilepsy and generalized epilepsies. Some smaller series and case reports have documented the use of STP in the treatment of status epilepticus in adult patients. Methods We retrospectively analyzed all patients who were admitted to the Department of Neurology at Marburg University Hospital between 2013 and 2023 with a diagnosis of (super)-refractory status epilepticus and who received additional treatment of SE with STP. All patients who received STP during the SE were included, regardless of previous medication. Results SE ceased in 64% of 25 patients (13 female and 12 male). The mean age was 58.6 ± 21.9 years (mean ± SD). 72% had a structural epilepsy. In 20% of patients, SE was terminated by the administration of STP alone in 32% of cases, while in a further 32% of patients, the simultaneous administration of multiple anti-seizure medications (ASMs) including STP was potentially responsible for the cessation of the SE, with valproic acid (VPA), benzodiazepines and STP, being the most frequently implicated ASMs. In 12% of patients, there was at least a temporary improvement in the electroencephalogram (EEG). Stiripentol had to be discontinued in three cases due to a reduction in vigilance or hypercalcemia. Conclusions Stiripentol may represent a promising additional treatment option for refractory and super-refractory status epilepticus. The tolerability of this treatment has already been demonstrated in previous studies, and was also reflected in these data. Further prospective investigation in larger patient populations are necessary to ascertain the efficacy of stiripentol in SE. Trial registration NCT06540378, retrospectively registered.

Abstract Objective This study investigates the association of Body Mass Index (BMI) and age of epilepsy onset, in patients with epilepsy associated with temporal encephaloceles (TEs). Methods A comprehensive PubMed literature review was conducted using the keywords “temporal encephaloceles” and “epilepsy” for identifying articles for the analysis. Inclusion criteria encompassed all evidence levels reporting patients with TE-related epilepsy and documented BMI. Logistic regression analyses were performed to examine the effect of BMI on predicting epilepsy onset after the 25th year of age. Spearman’s correlation assessed the relationship between BMI with epilepsy onset. Finally, the association between BMI and postsurgical outcomes, distinguishing between more favourable outcomes (Engel Class I and II) and less favourable outcomes (Engell Class III and IV) was explored. Results Of the initially identified 88 articles, nine were included in the analysis, involving 127 patients with TE-related epilepsy and reported BMI. The mean age of epilepsy onset was 24.9 years (SD = 14.8 years), with a mean BMI of 28.0 kg/m2 (SD = 7.4 kg/m2). A significant positive correlation was observed between BMI and age of epilepsy onset (rho = 0.448, p

Abstract Objective Self‐management interventions may enhance health‐related quality of life (HRQoL) in epilepsy. However, several barriers often impair their implementation in the real world. Digital interventions may help to overcome some of these barriers. Considering this, the Helpilepsy Plus Prototype was developed as a prototype smartphone‐delivered self‐care treatment program for adults with epilepsy. Methods The 12‐week Helpilepsy Plus Prototype was evaluated through a randomized controlled feasibility trial with a waiting‐list control (WLC) group. Outcome measurement at baseline and at 12 weeks assessed adherence to the prototype intervention and changes in epilepsy‐related outcomes. The primary endpoint was patient autonomy measured with EASE, and secondary endpoints included HRQoL measured with QOLIE‐31, health literacy measured with HLQ, anxiety, and depression symptoms measured with HADS. Semi‐structured interviews were conducted with a heterogeneous sample of participants to assess user‐friendliness and usefulness. The prototype program was delivered through the Neuroventis Platform (Neuroventis, BV, Overijse, Belgium), a certified medical device (under EU/MDD Class I, and EU/MDR grace period). Results Ninety‐two patients were included (46 in the intervention group, 46 in WLC). Most participants (63%, 58/92 women, median age 30 years) had pharmacoresistant epilepsy (61%, 56/92). Only 22% of participants (10/46) in the intervention group completed at least half of all intervention sessions. No significant differences between the intervention group and WLC were observed. Although there was a larger proportion of patients in the intervention group with meaningful improvements in HRQoL compared to WLC (19/46 versus 11/46), the difference was not significant (p = 0.119). Qualitative feedback showed that participants would appreciate more personalization, such as adaptation of the content to their current epilepsy knowledge level, a more interactive interface, shorter text sections, and interaction through reminders and notifications. Significance Digital interventions should allow sufficient scope for personalization and interaction to increase patient engagement and enable benefits from self‐care apps. Feedback loops allow the participatory development of tailored interventions. Plain Language Summary In this study, we investigated the effectiveness of an app‐based self‐help intervention. Study participants were either randomly assigned to a group that had access to the app or a group that received access to the app after the end of the study. Although a larger proportion of participants in the intervention group showed a relevant improvement in quality of life, the difference between the two groups was not statistically significant. Less than one‐fifth of participants in the intervention group attended at least half of all intervention sessions; patient feedback showed that patients required more personalization and interactive options.

Abstract Background Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. Methods Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. Results Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P

Abstract Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson’s disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.

Abstract Objective Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. Methods This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. Results The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p

Abstract Background The risk of seizure recurrence after a first unprovoked epileptic seizure is reported to be approximately 40%. Little is known about the recurrence risk after a first seizure in elderly patients, who may be at higher risk due to an increased rate of structural lesions, encephalopathy, subcortical arteriosclerotic encephalopathy or brain atrophy. Methods In a retrospective approach, the recurrence rate in 304 patients aged 60 years and above who presented with a first seizure between 2004 and 2017 was analyzed. Hierarchical Cox regression was used to investigate the impact of EEG and neuroimaging results, age or the prescription of anti-seizure medication (ASM) on seizure recurrence. Results Seizure recurrence rates were 24.5% and 34.4% after one and two years, respectively. Anti-seizure medication was started in 87.8% of patients, in 28.8% despite the absence of clear epileptogenic lesions on neuroimaging or epileptiform potentials in the EEG. Medical treatment significantly reduced the risk of recurrence (hazard ratio = 0.47). Epileptiform potentials in the EEG, epileptogenic lesions in neuroimaging and age had no significant effect on seizure recurrence. Age and the presence of neurodegenerative and psychiatric comorbidities showed a significant association with ASM prescription. Conclusions The present data show a strong protective effect of ASM on seizure recurrence in patients above the age of 60, even in the absence of pathologic neuroimaging or EEG results needed for the diagnosis of epilepsy. Treatment with ASM therefore seems beneficial for reducing the recurrence risk in elderly patients. The lack of a significant association between seizure recurrence and epileptogenic lesions might be related to other confounding factors like encephalopathy, subcortical arteriosclerotic encephalopathy, neurodegenerative diseases or brain atrophy.

Abstract Background An increasing use of newer antiseizure medication (ASM) such as SV2A ligand brivaracetam is observed. However, data on newer antiseizure medication and therapeutic drug monitoring during pregnancy is scarce. Methods Therapeutic drug monitoring of brivaracetam (BRV) and topiramate (TPM) serum levels were performed during pregnancy, delivery and in the umbilical cord blood at delivery in a 34-year-old female patient with severe drug-resistant epilepsy. Results During pregnancy, the serum levels of brivaracetam and topiramate remained stable. At 39th week of pregnancy, the patient gave birth to a healthy daughter. 1.5 h after the last ASM intake, the penetration rate measured in umbilical cord blood was 45% lower for BRV and 35% lower for TPM. Conclusions While the pharmacokinetics of topiramate are well known and its use during pregnancy should only be undertaken under special circumstances, there have been few studies on newer ASM in pregnancy such as brivaracetam. Based on our results and other case reports of BRV use during pregnancy, further studies are necessary to confirm its pharmacokinetics and safety during pregnancy.

The study of peptide repertoires presented by major histocompatibility complex (MHC) molecules and the identification of potential T-cell epitopes contribute to a multitude of immunopeptidome-based treatment approaches. Epitope mapping is essential for the development of promising epitope-based approaches in vaccination as well as for innovative therapeutics for autoimmune diseases, infectious diseases, and cancer. It also plays a critical role in the immunogenicity assessment of protein therapeutics with regard to safety and efficacy concerns. The main challenge emerges from the highly polymorphic nature of the human leukocyte antigen (HLA) molecules leading to the requirement of a peptide mapping strategy for a single HLA allele. As many autoimmune diseases are linked to at least one specific antigen, we established FASTMAP, an innovative strategy to transiently co-transfect a single HLA allele combined with a disease-specific antigen into a human cell line. This approach allows the specific identification of HLA-bound peptides using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Using FASTMAP, we found a comparable spectrum of endogenous peptides presented by the most frequently expressed HLA alleles in the world’s population compared to what has been described in literature. To ensure a reliable peptide mapping workflow, we combined the HLA alleles with well-known human model antigens like coagulation factor VIII, acetylcholine receptor subunit alpha, protein structures of the SARS-CoV-2 virus, and myelin basic protein. Using these model antigens, we have been able to identify a broad range of peptides that are in line with already published and in silico predicted T-cell epitopes of the specific HLA/model antigen combination. The transient co-expression of a single affinity-tagged MHC molecule combined with a disease-specific antigen in a human cell line in our FASTMAP pipeline provides the opportunity to identify potential T-cell epitopes/endogenously processed MHC-bound peptides in a very cost-effective, fast, and customizable system with high-throughput potential.

Abstract There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double‐blind, placebo‐controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization (“failure rate”). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10‐item version; National Institutes of Health Stroke Scale); post‐stroke depression (Patient Health Questionnaire‐9; PHQ‐9); and overall survival. Safety assessments include the evaluation of treatment‐emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ‐9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID‐19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol.

Abstract Objective Dysregulation of stress‐reactive neuroendocrine measures, as well as subjective stress, have been found to worsen epilepsy. Transcutaneous vagus nerve stimulation (tVNS) is a relatively new treatment option for epilepsy. We were interested in its effect on the activity of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS) as well as subjective stress and tiredness in patients with temporal lobe epilepsy (TLE). Methods Twenty patients (age 44 ± 11 years, 13 women) were enrolled in the study. They were free of seizures for more than 1 year. All took part in two sessions with 4 h of stimulation (tVNS vs. sham) in a randomized order. Saliva samples and subjective stress and tiredness levels were measured at five time points each session (before and after stimulation and three time points every hour in between). Data were analyzed using repeated measures analysis of variance as well as paired t‐tests. Results There was a dampened salivary cortisol (sCort) decrease during tVNS (time × condition effect: F[2.38, 38.15] = 6.50, P = 0.002, partial η2 = 0.29). Furthermore, we detected a dampened increase in salivary flow rate during tVNS (time × condition effect: F[3.28, 55.67] = 2.82, P = 0.043, partial η2 = 0.14). There was neither a difference in overall sCort or salivary alpha‐amylase (sAA) levels nor in subjective stress or tiredness levels between conditions. sAA levels at the last measurement point were slightly higher during tVNS (t(19) = 2.26, P = 0.035, d = 0.51), but this effect failed to reach significance when controlled for multiple comparisons. Significance Our results partially support that tVNS influences the regulation of stress‐reactive neuroendocrine systems (namely the HPA axis and ANS) in epilepsy. More research with larger samples is needed on the difference between short‐term and repeated long‐term stimulation.

Abstract Background Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses. Methods In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection. Results We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients. Conclusions This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.

Abstract Objective The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. Methods Fifty‐two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. Results Median age was 27 years (range 20‐57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). Significance Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown‐up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.

Abstract Objective This study was performed to identify coexisting structural lesions in patients with epilepsy and known temporal encephaloceles (TEs). Methods Forty‐seven structural magnetic resonance imaging (MRI) scans of patients with epilepsy and radiologically diagnosed TEs were retrospectively reviewed visually and using an automated postprocessing software, the Morphometric Analysis Program v2018 (MAP18), to depict additional subtle, potentially epileptogenic lesions in the 3D T1‐weighted MRI data. All imaging findings were evaluated in the context of clinical and electroencephalographical findings. Results The study population consisted of 47 epilepsy patients (38.3% female, n = 18). The median age at the time of the scan was 40 years (range 12–81 years). Twenty‐one out of 47 MRI scans (44.7%) showed coexisting lesions in the initial MRI evaluation; in 38.3% (n = 18) of patients, those lesions were considered probably epileptogenic. After postprocessing, probable epileptogenic lesions were identified in 53.2% (n = 25) of patients. Malformations of cortical development had initially been reported in 17.0% (n = 8) of patients with TEs, which increased to 38.3% (n = 18) after postprocessing. TEs and other epileptogenic lesions were considered equally epileptogenic in 21.3% (n = 10) of the cases in the initial MR reports and 25.5% (n = 12) of the cases after postprocessing. Significance Temporal encephaloceles are a potential cause of MRI‐negative temporal lobe epilepsy. According to our data, TEs can occur with other lesions, suggesting that increased awareness is also required in patients with lesional epilepsy. TEs may not always be epileptogenic; hence, their occurrence with other structural pathologies may influence the presurgical evaluation and surgical approach. Finally, TEs can be associated with malformations of cortical development, which may indicate a common developmental etiology of those lesions.

ObjectiveTo investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP).Methods50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance.ResultsThe volume of the left subicular complex was highly correlated to learning performance (β = 0.284; p = 0.042) and free recall performance in the VLMT (β = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (β = 0.378; p = 0.006) and recognition performance in the VLMT (β = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance.ConclusionThe results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

Abstract We report detailed functional MRI (fMRI) analyses in a patient with reflex seizures elicited by driving along a specific rural crossroad or by watching a video thereof. Semiology consisted of epigastric aura, followed by a sensory seizure of the left hand and sporadic automotor seizures. The right amygdala‐region (rh‐amygdala) was surgically and electroclinically confirmed as the epileptogenic zone. Presurgical task‐fMRI was performed, during which videos of the driving along that specific crossroad (IC), of another crossroad (NC) or noise were presented. Independent component analysis was conducted, and one component was used to aid in selection of a seed region within the rh‐amygdala for subsequent psychophysiological interaction analysis (PPI). Here, the following regions showed stronger connectivity with the rh‐amygdala seed during the IC condition compared to NC: right > left visual cortex, bilateral insulae, and right secondary somatosensory cortex (S2), potentially explaining epigastric aura and left somatosensory seizure semiology. Contralateral analyses did not reproduce these results. Overall, the ictogenic stimulus elicited enhanced connectivity of the epileptogenic rh‐amygdala with visual cortex and further regions of potential seizure spread (S2, insula) as a putative mechanism of ictogenesis. Our results highlight the potential of PPI in the analysis of stimulus‐dependent networks in patients with reflex epilepsies to gain insight into seizure generation.

Background and purposeIn patients with epilepsies of structural origin, brain atrophy and pathological alterations of the tissue microstructure extending beyond the putative epileptogenic lesion have been reported. However, in patients without any evidence of epileptogenic lesions on diagnostic magnetic resonance imaging (MRI), impairment of the brain microstructure has been scarcely elucidated. Using multiparametric quantitative (q) magnetic resonance imaging MRI, we aimed to investigate diffuse impairment of the microstructural tissue integrity in MRI-negative focal epilepsy patients.Methods27 MRI-negative patients with focal epilepsy (mean age 33.1 ± 14.2 years) and 27 matched healthy control subjects underwent multiparametric qMRI including T1, T2, and PD mapping at 3 T. After tissue segmentation based on synthetic anatomies, mean qMRI parameter values were extracted from the cerebral cortex, the white matter (WM) and the deep gray matter (GM) and compared between patients and control subjects. Apart from calculating mean values for the qMRI parameters across the respective compartments, voxel-wise analyses were performed for each tissue class.ResultsThere were no significant differences for mean values of quantitative T1, T2, and PD obtained from the cortex, the WM and the deep GM between the groups. Furthermore, the voxel-wise analyses did not reveal any clusters indicating significant differences between patients and control subjects for the qMRI parameters in the respective compartments.ConclusionsBased on the employed methodology, no indication for an impairment of the cerebral microstructural tissue integrity in MRI-negative patients with focal epilepsy was found in this study. Further research will be necessary to identify relevant factors and mechanisms contributing to microstructural brain tissue damage in various subgroups of patients with epilepsy.

Abstract The vagus nerve constitutes a key link between the autonomic and the central nervous system. Previous studies provide evidence for the impact of vagal activity on distinct cognitive processes including functions related to social cognition. Recent studies in animals and humans show that vagus nerve stimulation is associated with enhanced reward-seeking and dopamine-release in the brain. Social interaction recruits similar brain circuits to reward processing. We hypothesize that vagus nerve stimulation (VNS) boosts rewarding aspects of social behavior and compare the impact of transcutaneous VNS (tVNS) and sham stimulation on social interaction in 19 epilepsy patients in a double-blind pseudo-randomized study with cross-over design. Using a well-established paradigm, i.e., the prisoner’s dilemma, we investigate effects of stimulation on cooperative behavior, as well as interactions of stimulation effects with patient characteristics. A repeated-measures ANOVA and a linear mixed-effects model provide converging evidence that tVNS boosts cooperation. Post-hoc correlations reveal that this effect varies as a function of neuroticism, a personality trait linked to the dopaminergic system. Behavioral modeling indicates that tVNS induces a behavioral starting bias towards cooperation, which is independent of the decision process. This study provides evidence for the causal influence of vagus nerve activity on social interaction.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively. Objective: To investigate the influence of taVNS on gastric motility of healthy participants using rtMRI. Methods: We conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI. Results: After HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003). Conclusion: We provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. Methods A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). Results We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. Methods We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. Results We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p

Abstract In recent years, the clinical usefulness of the Wada test (WT) has been debated among researchers in the field. Therefore, we aimed to assess its contribution to the prediction of change in verbal learning and verbal memory function after epilepsy surgery. Data from 56 patients with temporal lobe epilepsy who underwent WT and subsequent surgery were analyzed retrospectively. Additionally, a standard neuropsychological assessment evaluating attentional, learning and memory, visuospatial, language, and executive function was performed both before and 12 months after surgery. Hierarchical linear regression analyses were used to determine the incremental value of WT results over socio-demographic, clinical, and neuropsychological characteristics in predicting postsurgical change in patients’ verbal learning and verbal memory function. The incorporation of WT results significantly improved the prediction models of postsurgical change in verbal learning (∆R 2 = 0.233, p = .032) and verbal memory function (∆R 2 = 0.386, p = .005). Presurgical performance and WT scores accounted for 41.8% of the variance in postsurgical change in verbal learning function, and 51.1% of the variance in postsurgical change in verbal memory function. Our findings confirm that WT results are of significant incremental value for the prediction of postsurgical change in verbal learning and verbal memory function. Thus, the WT contributes to determining the risks of epilepsy surgery and, therefore, remains an important part of the presurgical work-up of selected patients with clear clinical indications.

Abstract Objective To evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam. Methods In this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation. Results Five hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure‐free. In the SS, 34.6% of patients reported treatment‐emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug‐related. Incidences of behavioral AEs before (3‐month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs). Significance Brivaracetam was effective and well‐tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.

PurposeIn the clinical routine, detection of focal cortical dysplasia (FCD) by visual inspection is challenging. Still, information about the presence and location of FCD is highly relevant for prognostication and treatment decisions. Therefore, this study aimed to develop, describe and test a method for the calculation of synthetic anatomies using multiparametric quantitative MRI (qMRI) data and surface-based analysis, which allows for an improved visualization of FCD.Materials and MethodsQuantitative T1-, T2- and PD-maps and conventional clinical datasets of patients with FCD and epilepsy were acquired. Tissue segmentation and delineation of the border between white matter and cortex was performed. In order to detect blurring at this border, a surface-based calculation of the standard deviation of each quantitative parameter (T1, T2, and PD) was performed across the cortex and the neighboring white matter for each cortical vertex. The resulting standard deviations combined with measures of the cortical thickness were used to enhance the signal of conventional FLAIR-datasets. The resulting synthetically enhanced FLAIR-anatomies were compared with conventional MRI-data utilizing regions of interest based analysis techniques.ResultsThe synthetically enhanced FLAIR-anatomies showed higher signal levels than conventional FLAIR-data at the FCD sites (p = 0.005). In addition, the enhanced FLAIR-anatomies exhibited higher signal levels at the FCD sites than in the corresponding contralateral regions (p = 0.005). However, false positive findings occurred, so careful comparison with conventional datasets is mandatory.ConclusionSynthetically enhanced FLAIR-anatomies resulting from surface-based multiparametric qMRI-analyses have the potential to improve the visualization of FCD and, accordingly, the treatment of the respective patients.

The aim of these two case reports is to demonstrate that a predefined, structured, multimodal clinical bed-side testing during seizures in a long-term video-EEG monitoring setting facilitates diagnosis of complex neuropsychological syndromes. To the best of our knowledge, we present the first case of conduction aphasia as the sole ictal semiology, and a patient with focal seizures producing an angular gyrus syndrome in the speech dominant hemisphere. The relevance of diagnosing ictal aphasic and angular gyrus syndromes and localizing the symptomatogenic zone is discussed. Current pathophysiological concepts are presented regarding conduction aphasia and Gerstmann's syndrome.

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.

Introduction: This study was designed to evaluate risk factors and incidence of epilepsy-related injuries and accidents (ERIA) at an outpatient clinic of a German epilepsy center providing healthcare to a mixed urban and rural population of over one million inhabitants.Methods: Data acquisition was performed between 10/2013 and 09/2014 using a validated patient questionnaire on socioeconomic status, course of epilepsy, quality of life (QoL), depression, injuries and accidents associated with seizures or inadequate periictal patterns of behavior concerning a period of 3 months. Univariate analysis, multiple testing and regression analysis were performed to identify possible variables associated with ERIA.Results: A total of 292 patients (mean age 40.8 years, range 18–86; 55% female) were enrolled and analyzed. Focal epilepsy was diagnosed in 75% of the patients. The majority was on an antiepileptic drug (AEDs) polytherapy (mean number of AEDs: 1.65). Overall, 41 patients (14.0%) suffered from epilepsy-related injuries and accidents in a 3-month period. Besides lacerations (n = 18, 6.2%), abrasions and bruises (n = 9, 3.1%), fractures (n = 6, 2.2%) and burns (n = 3, 1.0%), 17 mild injuries (5.8%) were reported. In 20 (6.8% of the total cohort) cases, urgent medical treatment with hospitalization was necessary. Epilepsy-related injuries and accidents were related to active epilepsy, occurrence of generalized tonic-clonic seizures (GTCS) and drug-refractory course as well as reported ictal falls, ictal loss of consciousness and abnormal peri-ictal behavior in the medical history. In addition, patients with ERIA had significantly higher depression rates and lower QoL.Conclusion: ERIA and their consequences should be given more attention and standardized assessment for ERIA should be performed in every outpatient visit.

ObjectivesThe German socio-demographic estimation scale was developed by Jahn et al. (1) to quickly predict premorbid global cognitive functioning in patients. So far, it has been validated in healthy adults and has shown a good correlation with the full and verbal IQ of the Wechsler Adult Intelligence Scale (WAIS) in this group. However, there are no data regarding its use as a bedside test in epilepsy patients.MethodsForty native German speaking adult patients with refractory epilepsy were included. They completed a neuropsychological assessment, including a nine scale short form of the German version of the WAIS-III and the German socio-demographic estimation scale by Jahn et al. (1) during their presurgical diagnostic stay in our center. We calculated means, correlations, and the rate of concordance (range ±5 and ±7.5 IQ score points) between these two measures for the whole group, and a subsample of 19 patients with a global cognitive functioning level within 1 SD of the mean (IQ score range 85–115) and who had completed their formal education before epilepsy onset.ResultsThe German demographic estimation scale by Jahn et al. (1) showed a significant mean overestimation of the global cognitive functioning level of eight points in the epilepsy patient sample compared with the short form WAIS-III score. The accuracy within a range of ±5 or ±7.5 IQ score points for each patient was similar to that of the healthy controls reported by Jahn et al. (1) in our subsample, but not in our whole sample.ConclusionOur results show that the socio-demographic scale by Jahn et al. (1) is not sufficiently reliable as an estimation tool of global cognitive functioning in epilepsy patients. It can be used to estimate global cognitive functioning in a subset of patients with a normal global cognitive functioning level who have completed their formal education before epilepsy onset, but it does not reliably predict global cognitive functioning in epilepsy patients in general, who often do not fulfill these criteria. It is therefore not a useful tool to be applied in the general neuropsychological presurgical evaluation of epilepsy patients.

ObjectivesTo assess first clinical experiences with brivaracetam (BRV) in the treatment of epilepsies.MethodsData on patients treated with BRV from February to December 2016 and with at least one clinical follow-up were collected from electronic patient records. Data on safety and efficacy were evaluated retrospectively.ResultsIn total, 93 patients were analyzed; 12 (12.9%) received BRV in monotherapy. The mean duration to follow-up was 4.85 months (MD = 4 months; SD = 3.63). Fifty-seven patients had more than one seizure per month at baseline and had a follow-up of more than 4 weeks; the rate of ≥50% responders was 35.1% (n = 20) in this group, of which five (8.8%) patients were newly seizure-free. In 50.5% (47/93), patients were switched from levetiracetam (LEV) to BRV, of which 43 (46.2%) were switched immediately. Adverse events (AE) occurred in 39.8%, with 22.6% experiencing behavioral and 25.8% experiencing non-behavioral AE. LEV-related AE (LEV-AE) were significantly reduced by switching to BRV. The discontinuation of BRV was reported in 26/93 patients (28%); 10 of those were switched back to LEV with an observed reduction of AE in 70%. For clinical reasons, 12 patients received BRV in monotherapy, 75% were seizure–free, and previous LEV-AE improved in 6/9 patients. BRV-related AE occurred in 5/12 cases, and five patients discontinued BRV.ConclusionBRV seems to be a safe, easy, and effective option in the treatment of patients with epilepsy, especially in the treatment of patients who have psychiatric comorbidities and might not be good candidates for LEV treatment. BRV broadens the therapeutic spectrum and facilitates personalized treatment.

BackgroundThere is a lack of data concerning socioeconomic outcome and quality of life (QoL) in patients after status epilepticus (SE) in Germany.Patients and methodsAdult patients treated between 2011 and 2015 due to SE at the university hospitals in Frankfurt, Greifswald, and Marburg were asked to fill out a questionnaire regarding long-term outcome of at least 3 months after discharge. The SE cohort consisted of 25.9% patients with an acute symptomatic, 42% with a remote symptomatic and previous epilepsy, 22.2% with a new-onset remote symptomatic, and 9.9% with other or unknown etiology. A matched case–control analysis was applied for comparison with patients with drug refractory epilepsy and seizure remission, both not previously affected by SE.ResultsA total of 81 patients (mean age: 58.7 ± 18.0 years; 58% female) participated. A non-refractory course was present in 59.3%, while 27.2% had a refractory SE (RSE) and 13.6% had a superrefractory SE (SRSE). Before admission, a favorable modified Rankin Scale (mRS) of 0–3 was found in 82.7% (67/81), deteriorating to 38.3% (31/81) (p = 0.003) at discharge. The majority returned home [51.9% (42/81)], 32.1% entered a rehabilitation facility, while 12.3% were transferred to a nursing home and 3.7% to another hospital. The overall mRS at follow-up did not change; 61.8% (45/74) reached an mRS of 0–3. In RSE and SRSE, the proportion with a favorable mRS increased from 45.5% at discharge to 70% at follow-up, while QoL was comparable to a non-refractory SE course. Matched epilepsy controls in seizure remission were treated with a lower mean number of anticonvulsants (1.3 ± 0.7) compared to controls with drug refractory epilepsy (1.9 ± 0.8; p

Susanne Knake1, Johannes T Heverhagen2, Katja Menzler1, Boris Keil2, Wolfgang H Oertel1, Karin Stiasny-Kolster11Department of Neurology, Center of Nervous Diseases, 2Department of Radiology, Philipps University, Marburg, GermanyAbstract: Using a T2* gradient echo magnetic resonance imaging (MRI) sequence, regional T2 signal intensity (SI) values, a surrogate marker for T2 values, were determined in 12 regions of interest (substantia nigra, pallidum, caudate head, thalamus, occipital white matter, and frontal white matter bilaterally) and in two reference regions (cerebrospinal fluid and bone) in 12 patients suffering from moderate to severe idiopathic restless legs syndrome (RLS; mean age 58.5 ± 8.7 years) for 12.1 ± 9.1 years and in 12 healthy control subjects (mean age 56.8 ± 10.6 years). Iron deposits shorten T2 relaxation times on T2-weighted MRI. We used regional T2* SI to estimate regional T2-values. A T2-change ratio was calculated for each region of interest relative to the reference regions. We did not find significant differences in any of the investigated brain regions. In addition, serum measures involved in iron metabolism did not correlate with T2 SI values. We could not replicate earlier findings describing reduced regional brain iron concentrations in patients with RLS. Our results do not support the view of substantially impaired regional brain iron in RLS.Keywords: restless legs syndrome, pathophysiology, iron, MRI, substantia nigra

Status epilepticus (SE) is one of the most frequent neurological emergencies with an incidence of 20/100,000 per year and a mortality between 3% and 40% depending on etiology, age, SE type and duration. Generalized convulsive forms of SE (GTCSE), in particular, require aggressive treatment. Presently, only 55—80% of cases of GTCSE are controlled by initial therapy. Therefore, there is a need for new options for the treatment of SE. Here we review the current standard treatment including recent advances and provide a summary of preclinical and clinical data regarding treatment options which may become available in the near future. The initial treatment of SE usually consists of a benzodiazepine (preferably lorazepam 0.1 mg/kg) followed by phenytoin or fosphenytoin or valproic acid (where approved for SE therapy). With intravenous formulations of levetiracetam, available since 2006, and lacosamide, which is expected for autumn of 2008, new treatment options have become available, that should be evaluated in prospective controlled trials. If SE remains refractory, the induction of general anaesthesia using propofol, midazolam, thiopental, or pentobarbital is warranted in GTCSE.