Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

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.

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.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.

Critical Care 2017, 21(Suppl 1):P349 Introduction Imbalance in cellular energetics has been suggested to be an important mechanism for organ failure in sepsis and septic shock. We hypothesized that such energy imbalance would either be caused by metabolic changes leading to decreased energy production or by increased energy consumption. Thus, we set out to investigate if mitochondrial dysfunction or decreased energy consumption alters cellular metabolism in muscle tissue in experimental sepsis. Methods We submitted anesthetized piglets to sepsis (n = 12) or placebo (n = 4) and monitored them for 3 hours. Plasma lactate and markers of organ failure were measured hourly, as was muscle metabolism by microdialysis. Energy consumption was intervened locally by infusing ouabain through one microdialysis catheter to block major energy expenditure of the cells, by inhibiting the major energy consuming enzyme, N+/K + -ATPase. Similarly, energy production was blocked infusing sodium cyanide (NaCN), in a different region, to block the cytochrome oxidase in muscle tissue mitochondria. Results All animals submitted to sepsis fulfilled sepsis criteria as defined in Sepsis-3, whereas no animals in the placebo group did. Muscle glucose decreased during sepsis independently of N+/K + -ATPase or cytochrome oxidase blockade. Muscle lactate did not increase during sepsis in naïve metabolism. However, during cytochrome oxidase blockade, there was an increase in muscle lactate that was further accentuated during sepsis. Muscle pyruvate did not decrease during sepsis in naïve metabolism. During cytochrome oxidase blockade, there was a decrease in muscle pyruvate, independently of sepsis. Lactate to pyruvate ratio increased during sepsis and was further accentuated during cytochrome oxidase blockade. Muscle glycerol increased during sepsis and decreased slightly without sepsis regardless of N+/K + -ATPase or cytochrome oxidase blocking. There were no significant changes in muscle glutamate or urea during sepsis in absence/presence of N+/K + -ATPase or cytochrome oxidase blockade. ConclusionsThese results indicate increased metabolism of energy substrates in muscle tissue in experimental sepsis. Our results do not indicate presence of energy depletion or mitochondrial dysfunction in muscle and should similar physiologic situation be present in other tissues, other mechanisms of organ failure must be considered. , and long-term follow up has shown increased fracture risk [2]. It is unclear if these changes are a consequence of acute critical illness, or reduced activity afterwards. Bone health assessment during critical illness is challenging, and direct bone strength measurement is not possible. We used a rodent sepsis model to test the hypothesis that critical illness causes early reduction in bone strength and changes in bone architecture. Methods 20 Sprague-Dawley rats (350 ± 15.8g) were anesthetised and randomised to receive cecal ligation and puncture (CLP) (50% cecum length, 18G needle single pass through anterior and posterior wa...

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Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Background and ObjectivesTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10−8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes.DiscussionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.