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Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA)subA/subreceptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.

Predicting survival in patients with post-hypoxic encephalopathy (HE) after cardiopulmonary resuscitation is a challenging aspect of modern neurocritical care. Here, continuous electroencephalography (cEEG) has been established as the gold standard for neurophysiological outcome prediction. Unfortunately, cEEG is not comprehensively available, especially in rural regions and developing countries. The objective of this monocentric study was to investigate the predictive properties of repetitive EEGs (rEEGs) with respect to 12-month survival based on data for 199 adult patients with HE, using log-rank and multivariate Cox regression analysis (MCRA). A total number of 59 patients (29.6%) received more than one EEG during the first 14 days of acute neurocritical care. These patients were analyzed for the presence of and changes in specific EEG patterns that have been shown to be associated with favorable or poor outcomes in HE. Based on MCRA, an initially normal amplitude with secondary low-voltage EEG remained as the only significant predictor for an unfavorable outcome, whereas all other relevant parameters identified by univariate analysis remained non-significant in the model. In conclusion, rEEG during early neurocritical care may help to assess the prognosis of HE patients if cEEG is not available.

Predicting survival in patients with post-hypoxic encephalopathy (HE) after cardiopulmonary resuscitation is a challenging aspect of modern neurocritical care. Here, continuous electroencephalography (cEEG) has been established as the gold standard for neurophysiological outcome prediction. Unfortunately, cEEG is not comprehensively available, especially in rural regions and developing countries. The objective of this monocentric study was to investigate the predictive properties of repetitive EEGs (rEEGs) with respect to 12-month survival based on data for 199 adult patients with HE, using log-rank and multivariate Cox regression analysis (MCRA). A total number of 59 patients (29.6%) received more than one EEG during the first 14 days of acute neurocritical care. These patients were analyzed for the presence of and changes in specific EEG patterns that have been shown to be associated with favorable or poor outcomes in HE. Based on MCRA, an initially normal amplitude with secondary low-voltage EEG remained as the only significant predictor for an unfavorable outcome, whereas all other relevant parameters identified by univariate analysis remained non-significant in the model. In conclusion, rEEG during early neurocritical care may help to assess the prognosis of HE patients if cEEG is not available.

Background: Inflammation, particularly cytokine release, contributes to epileptogenesis by influencing the cerebral tissue remodeling and neuronal excitability that occurs after a precipitating epileptogenic insult. While several cytokines have been explored in this process, release kinetics are less well investigated. Determining the time course of cytokine release in the epileptogenic zone is necessary for precisely timed preventive or therapeutic anti-inflammatory interventions. Methods: Hippocampal extracellular levels of six cytokines and chemokines (IL-1β, IL-6, IL-10, CCL2, CCL3, and CCL5) were quantified at various time points during epileptogenesis in a rat model of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) using microdialysis (MD). Results: The analysis of microdialysates demonstrated consistent elevation at all time points during epileptogenesis for IL-1β and IL-10. IL-10 release was maximal on day 1, IL-1β release peaked at day 8. No correlation between local hippocampal IL-1β concentrations and IL-1β blood levels was found. Conclusion: The release kinetics of IL-1β are consistent with its established pro-epileptogenic properties, while the kinetics of IL-10 suggest a counter-regulatory effect. This proof-of-concept study demonstrates the feasibility of intraindividual longitudinal monitoring of hippocampal molecular inflammatory processes via repetitive MD over several weeks and sheds light on the kinetics of hippocampal cytokine release during epileptogenesis.

In einer alternden Gesellschaft werden auch Epilepsien im Alter ein immer relevanteres Krankheitsbild. Die Diagnosestellung ist dabei oft erschwert, da sich im hohen Alter meist fokale Anfalle zeigen, die leicht verkannt werden konnen. Insbesondere bei alteren Patienten, die beispielsweise zusatzlich an einer Demenz leiden, erfolgt die Diagnosestellung haufig nur verzogert. Die Ursachen der Epilepsien im Alter konnen im alternden Gehirn vielfaltig sein. Eine weitere Herausforderung fur den Neurologen stellt die medikamentose Therapie der Altersepilepsie dar, da viele Antikonvulsiva mit deutlichen Neben- und Wechselwirkungen einhergehen. Die Evidenz zur Wirksamkeit und Vertraglichkeit der Antikonvulsiva im Alter ist hierbei nur unzureichend, sodass stets eine individuelle Abwagung der Therapie der Wahl erfolgen muss. Der Status epilepticus als neurologischer Notfall tritt bei alteren Menschen nicht nur haufiger auf als bei jungeren, sondern geht auch mit einer erhohten Mortalitat einher, sodass stets eine rasche Diagnosestellung und die adaquate Therapie erforderlich sind.

This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors.COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors.In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18-83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18-24 years (b = -€2945) and 25-34 years (b = -€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI.This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.

G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. Various GPCRs are upregulated in activated CD4 T cells, including P2Y10, a putative lysophospholipid receptor that is officially still considered an orphan GPCR, i.e., a receptor with unknown endogenous ligand. Here we show that in mice lacking P2Y10 in the CD4 T cell compartment, the severity of experimental autoimmune encephalomyelitis and cutaneous contact hypersensitivity is reduced. P2Y10-deficient CD4 T cells show normal activation, proliferation and differentiation, but reduced chemokine-induced migration, polarization, and RhoA activation upon in vitro stimulation. Mechanistically, CD4 T cells release the putative P2Y10 ligands lysophosphatidylserine and ATP upon chemokine exposure, and these mediators induce P2Y10-dependent RhoA activation in an autocrine/paracrine fashion. ATP degradation impairs RhoA activation and migration in control CD4 T cells, but not in P2Y10-deficient CD4 T cells. Importantly, the P2Y10 pathway appears to be conserved in human T cells. Taken together, P2Y10 mediates RhoA activation in CD4 T cells in response to auto-/paracrine-acting mediators such as LysoPS and ATP, thereby facilitating chemokine-induced migration and, consecutively, T cell-mediated diseases., P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

ObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate 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 two independent risk loci harboring genome-wide significant variants (P < 5 × 10−8, OR ≤ 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one 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 (eQTL) 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.ConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the 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.

In an aging society, epilepsy in old age will become a more and more relevant disease. The diagnosis is often difficult because of the frequent occurrence of focal seizures in old age, which are easily overlooked. The diagnosis is often delayed, particularly in older patients who, for example also suffer from dementia. The causes of the epilepsy can be manifold in the aging brain. Another challenge for neurologists is the medicinal treatment of geriatric epilepsy, as many anticonvulsive drugs can be associated with serious side effects and interactions. The evidence for the effectiveness and tolerability of anticonvulsive drugs in old age is insufficient, so that the choice of drugs must be made on an individual basis. Status epilepticus is a neurological emergency, which occurs not only more frequently in older than in younger persons but is also associated with a higher mortality, so that immediate diagnosis and adequate treatment is necessary.

Introduction Patient education is a central component of quality care. Enhancing patient knowledge can improve patients’ quality of life and facilitate successful self-management. We sought to identify patients’ knowledge levels and knowledge gaps regarding epilepsy-related risks, morbidity, and mortality. Methods Adult patients with epilepsy presenting to the university hospitals in Frankfurt, Greifswald, and Marburg between February 2018 and May 2020 were asked to participate in this questionnaire-based study. Results A total of 238 patients (52% women), with a mean age of 39.2 years (range: 18–77 years), participated in this study. Spontaneously, the majority of patients (51.3%) named driving a car, and other traffic-related accidents as possible causes of morbidity and mortality, and 23.9% of patients reported various causes of premature death, such as suffocation, drowning, and respiratory or cardiac arrest due to seizures. Falls due to epilepsy (19.7%) and injuries in general (17.6%) were named as further causes of morbidity and mortality. The vast majority were aware that alcohol (87.4%), sleep deprivation (86.6%), and risky activities in daily life (80.3%) increased the risk of seizure occurrence or increased morbidity and mortality. Regarding overall mortality, 52.1% thought that people with epilepsy were at greater risk of premature death, whereas 46.2% denied this fact to be true. Only 29.4% were aware of status epilepticus, and 27.3% were aware of sudden unexpected death in epilepsy (SUDEP). Driving ability, working ability, and seizure risk were named as major or moderate concerns among patients, but the risk of premature mortality was not a major concern. One-quarter of all patients (26.9%) indicated that they were not counseled about any risk factors or causes of morbidity or mortality by their physicians. Conclusions A lack of knowledge concerning premature mortality, SUDEP, and status epilepticus exists among adult patients with epilepsy. A substantial number of patients indicated that these issues were not discussed adequately by their physicians.

Objective Patients with temporal lobe epilepsy caused by autoimmune limbic encephalitis (AI-TLE) clinically resemble patients with temporal lobe epilepsy with non-autoimmune etiologies (NAI-TLE) but have a different prognosis and require specific adjusted therapies. The objective of this study was to investigate whether patients with these forms of TLE can be discerned by means of neuropsychological assessment. Methods Data from 103 patients with TLE (n = 39 with AI-TLE and n = 64 with NAI-TLE, including n = 39 with hippocampal sclerosis [HS] and n = 25 with low-grade epilepsy-associated tumors [LEAT]) and 25 healthy controls who underwent comprehensive neuropsychological assessments were analyzed retrospectively. The neuropsychological characteristics (mean z-scores) were compared between groups using one-way ANOVA, independent-samples t-tests, and discriminant function analysis (DFA). Results The groups of patients with TLE showed significantly lower performance in attentional, visuospatial, verbal memory, and nonverbal memory functions compared to the healthy controls. Solely in the domain of executive functions, patients with AI-TLE showed significantly lower performance compared to patients with NAI-TLE regarding cognitive flexibility (p = 0.002) and verbal fluency (p = 0.018). Moreover, the DFA identified cognitive flexibility to be most appropriate to differentiate between patients with AI-TLE and patients with HS. Group membership was correctly predicted through neuropsychological assessment alone in 66.7% of the patients using cross-validation. Significance We were able to identify specific neuropsychological features in our sample of patients with AI-TLE. While all groups of patients with TLE showed the expected TLE-typical memory impairments, significant differences between patients with AI-TLE and NAI-TLE were present only in the cognitive domain of executive functions. This finding facilitates the choice of suitable psychometric tests in clinical routine and, thus, the clinical differential diagnosis between these entities.

Introduction When the SARS-CoV-2 pandemic reached Europe in 2020, a German governmental order forced clinics to immediately suspend elective care, causing a problem for patients with chronic illnesses such as epilepsy. Here, we report the experience of one clinic that converted its outpatient care from personal appointments to telemedicine services. Methods Documentations of telephone contacts and telemedicine consultations at the Epilepsy Center Frankfurt Rhine-Main were recorded in detail between March and May 2020 and analyzed for acceptance, feasibility, and satisfaction of the conversion from personal to telemedicine appointments from both patients' and medical professionals' perspectives. Results Telephone contacts for 272 patients (mean age: 38.7 years, range: 17–79 years, 55.5% female) were analyzed. Patient-rated medical needs were either very urgent (6.6%, n = 18), urgent (23.5%, n = 64), less urgent (29.8%, n = 81), or nonurgent (39.3%, n = 107). Outpatient service cancelations resulted in a lack of understanding (9.6%, n = 26) or anger and aggression (2.9%, n = 8) in a minority of patients, while 88.6% (n = 241) reacted with understanding, or relief (3.3%, n = 9). Telemedicine consultations rather than a postponed face-to-face visit were requested by 109 patients (40.1%), and these requests were significantly associated with subjective threat by SARS-CoV-2 (p = 0.004), urgent or very urgent medical needs (p = 0.004), and female gender (p = 0.024). Telemedicine satisfaction by patients and physicians was high. Overall, 9.2% (n = 10) of patients reported general supply problems due to SARS-CoV-2, and 28.4% (n = 31) reported epilepsy-specific problems, most frequently related to prescriptions, or supply problems for antiseizure drugs (ASDs; 22.9%, n = 25). Conclusion Understanding and acceptance of elective ambulatory visit cancelations and the conversion to telemedicine consultations was high during the coronavirus disease 2019 (COVID-19) lockdown. Patients who engaged in telemedicine consultations were highly satisfied, supporting the feasibility and potential of telemedicine during the COVID-19 pandemic and beyond., Highlights • Health care systems worldwide had to face reorganization during SARS-CoV-2 pandemic • Acceptance of the SARS-CoV-2-related conversion to telemedicine services was high • Urgent concerns, perception of SARS-CoV-2-associated threats, and female gender were associated with use of telemedicine • Patient and physician satisfaction with telemedicine services was high • Supply problems severely affected epilepsy patients during the SARS-CoV-2 pandemic