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Background: Epilepsy and other seizure disorders account for a high disease burden in Germany. As a timely diagnosis and accurate treatment are crucial, improving the management of these disorders is important. Outside of Germany, outpatient long-term video EEGs (ALVEEGs) have demonstrated the potential to support the diagnosis and management of epilepsy and other seizure disorders. This study aims to evaluate the implementation of ALVEEGs as a new diagnostic pathway in eastern parts of Germany to diagnose epilepsy and other seizure disorders and to assess if ALVEEGs are equally effective as the current inpatient-monitoring gold standard, which is currently only available at a limited number of specialized centers in Germany., Methods: ALVEEG is a prospective, multicenter, randomized controlled equivalence trial, involving five epilepsy centers in the eastern states of Germany. Patients will be randomized into either intervention (IG) or control group (CG), using a permuted block randomization. The sample size targeted is 688 patients, continuously recruited over the trial. The IG will complete an ALVEEG in a home setting, including getting access to a smartphone app to document seizure activity. The CG will receive care as usual, i.e., inpatient long-term video-EEG monitoring. The primary outcome is the proportion of clinical questions being solved in the IG compared to the CG. Secondary outcomes include hospital stays, time until video EEG, time until diagnosis and result discussion, patients' health status, quality of life and health competence, and number and form of epilepsy-related events and epileptiform activity. Alongside the trial, a process implementation and health economic evaluation will be conducted., Discussion: The extensive evaluation of this study, including an implementation and health economic evaluation, will provide valuable information for health policy decision-makers to optimize future delivery of neurological care to patients affected by epilepsy and other seizure disorders and on the uptake of ALVEEG into standard care in Germany., Trial Registration: German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023., (© 2024. The Author(s).)

Magnetoencephalography (MEG) allows the non-invasive measurement of brain activity at millisecond precision combined with localization of the underlying generators. So far, MEG-systems consisted of superconducting quantum interference devices (SQUIDS), which suffer from several limitations. Recent technological advances, however, have enabled the development of novel MEG-systems based on optically pumped magnetometers (OPMs), offering several advantages over conventional SQUID-MEG systems. Considering potential improvements in the measurement of neuronal signals as well as reduced operating costs, the application of OPM-MEG systems for clinical neuroscience and diagnostic settings is highly promising. Here we provide an overview of the current state-of-the art of OPM-MEG and its unique potential for translational neuroscience. First, we discuss the technological features of OPMs and benchmark OPM-MEG against SQUID-MEG and electroencephalography (EEG), followed by a summary of pioneering studies of OPMs in healthy populations. Key applications of OPM-MEG for the investigation of psychiatric and neurological conditions are then reviewed. Specifically, we suggest novel applications of OPM-MEG for the identification of biomarkers and circuit deficits in schizophrenia, dementias, movement disorders, epilepsy, and neurodevelopmental syndromes (autism spectrum disorder and attention deficit hyperactivity disorder). Finally, we give an outlook of OPM-MEG for translational neuroscience with a focus on remaining methodological and technical challenges., (© 2024. The Author(s).)

Objective: Despite the availability of pharmacological treatment for seizures, people with epilepsy (PwE) commonly experience impairments in quality of life (QoL). Given the limited access to psychosocial treatments for PwE, digital interventions could bridge treatment gaps and help improve QoL. The objective of this study was to examine the effectiveness of emyna, a fully automated digital intervention based on cognitive behavioral therapy (CBT) techniques, in improving health-related QoL among PwE who reported impairments in QoL. A previous trial showed that emyna was effective in improving depressive symptoms among PwE with a comorbid depressive disorder, but its effects on QoL among PwE without comorbid depression remain unknown., Methods: A pragmatic randomized controlled trial was conducted with N = 438 PwE (mean age = 37.5, 70.3% women, physician-verified diagnoses) who were assigned to the intervention group (n = 216), which used emyna alongside treatment as usual (TAU), or the control group (n = 222), which received TAU only. QoL and secondary outcomes such as general self-efficacy, medication adherence, general distress, and epilepsy-related work and social adjustment were assessed at baseline, 3 months, and 6 months. The primary outcome was QoL assessed with the Quality of Life in Epilepsy [QOLIE-31] total score at 3 months post-randomization., Results: Findings from the intent-to-treat analyses showed that after 3 months, participants in the intervention group experienced significant and clinically relevant improvements in health-related QoL compared to the control group (baseline-adjusted group difference = 4.5; 95% CI = [2.0, 6.9], p < 0.001; Cohen's d = 0.32). Effects on secondary outcomes did not reach statistical significance., Significance: This study extends previous research by demonstrating that emyna facilitates improvements in QoL in a diverse group of PwE treated in routine care settings. This CBT-based digital intervention therefore presents a convenient and cost-effective addition to healthcare providers' treatment repertoire., Plain Language Summary: In our study, we tested a digital program called emyna, which conveys cognitive behavioral therapy (CBT) techniques to help improve the quality of life for people living with epilepsy. We found that those who used emyna alongside their usual treatments felt better about their quality of life compared to those who did not use the program. Emyna offers a new, convenient way for people with epilepsy to manage their condition, which can be used alongside currently available treatments., (© 2024 GAIA AG and The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Approximately two thirds of patients with epilepsy become seizure-free with antiseizure medication (ASM). A central question is whether and when ASM can be discontinued., Objective: To present an overview of the current knowledge about risks and benefits of discontinuation of ASM., Material and Methods: Review of the current literature, discussion of data on and recommendations for discontinuation of ASM., Results: The risk of seizure recurrence after discontinuation of ASM is approximately 40-50% and thus twice as high as continuing with ASM. Guidelines recommend considering discontinuation of ASM at earliest after a seizure-free period of 2 years. Predictive variables for seizure recurrence after stopping ASM include longer duration of epilepsy and higher number of seizures until remission, a shorter seizure-free interval until stopping ASM, older age at epilepsy onset, developmental delay or IQ < 70, febrile seizures in childhood, absence of a self-limiting epilepsy syndrome, and evidence of epileptiform activity in the electroencephalograph (EEG). The individual risk of seizure recurrence after stopping ASM can be estimated using an online prediction tool., Conclusion: Discontinuation of ASM should be discussed with patients at the earliest after 2 years of seizure freedom in a shared decision-making process weighing up the risks and benefits. The risk of a seizure recurrence depends on a number of clinical variables. Psychosocial aspects, such as impact on driving and occupational issues must be taken into consideration as well as individual fears and concerns of patients about seizure recurrence or the long-term use of ASM., (© 2024. The Author(s).)

Purpose: Subjective and objective cognition often show weak overlap in persons with epilepsy (PWE). Over- as well as underestimation may occur. In particular after epilepsy surgery, objective memory decline is often not subjectively reported. Additionally, studies on how concordance of subjective and objective cognition changes over time are missing. Therefore, we study the extent of concordance in operated and non-operated PWE over time., Methods: Candidates for resective epilepsy surgery were assessed between 03/18 and 12/20 (T1) with self-report questionnaires and underwent a neuropsychological examination. For 21 operated as well as 27 non-operated PWE follow-up data was obtained one to three years later (T2). Concordance of attention and memory were compared between groups and time points. Moreover, reliable change was calculated and compared between groups., Results: Of the total sample, 42 % rated their attention performance realistically and 25 % showed memory concordance. Differences in patterns of over- and underestimation between groups and over time occurred for attention, but not for memory. Overestimation of memory was more frequent in operated than non-operated PWE, especially at T2 (67% vs. 11 %). In the operated group, we mainly observed reliable improvement in subjective cognition and decline in objective memory, whereas non-operated PWE showed more frequently decline of simple attention. Reliable subjective and objective change did not co-occur., Conclusion: Concordance of subjective and objective cognition is low. Over- as well as underestimation may persist over time. Domain-specific perspectives are necessary. Tendencies of operated PWE to develop overestimation of memory after surgery should be considered in neuropsychological interventions., Competing Interests: Declaration of interest MH has received speaker honoraria and/or consultancy fees from Angelini, Bial, Desitin, Eisai, Jazz Pharma and UCB within the last 3 years, all unrelated to the contents of this manuscript. None of the other authors has any conflict of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Objectives: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABA B R). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries., Methods: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABA B R-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models., Results: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABA B R-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABA B R., Discussion: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Objective: This study was undertaken to analyze whether the rate of breakthrough seizures in patients taking antiseizure medication (ASM) who have been seizure-free for at least 12 months varies among different types and etiologies of epilepsy. Given the relative ease of achieving seizure freedom with ASM in patients with post-ischemic stroke epilepsy, we hypothesized that this etiology is associated with a reduced risk of breakthrough seizures., Methods: We defined a breakthrough seizure as an unprovoked seizure occurring while the patient was taking ASM after a period of at least 12 months without seizures. Data were analyzed retrospectively from a tertiary epilepsy outpatient clinic. Patients were eligible for inclusion if they either had a breakthrough seizure at any time or a seizure-free interval of at least 2 years. Our primary endpoint was rate of breakthrough seizures. We conducted univariable and multivariable analyses to identify variables associated with breakthrough seizures., Results: Of 521 patients (53% females, median age = 49 years) included, 29% had a breakthrough seizure, which occurred after a median seizure-free interval of 34 months (quartiles = 22, 62). When controlling for clinically relevant covariates, breakthrough seizures were associated with post-ischemic stroke epilepsy (odds ratio [OR] = .267, 95% confidence interval [CI] = .075-.946), genetic generalized epilepsy (OR = .559; 95% CI = .319-.978), intellectual disability (OR = 2.768, 95% CI = 1.271-6.031), and the number of ASMs previously and currently tried (OR = 1.203, 95% CI = 1.056-1.371). Of the 151 patients with breakthrough seizures, 34.3% did not reachieve terminal 12-month seizure freedom at the last visit., Significance: This is the first study to show an association between type and etiology of epilepsy and risk of breakthrough seizures. Our data suggest that epilepsies in which seizure freedom can be obtained more easily also exhibit a lower risk of breakthrough seizures. These findings may help to better counsel seizure-free patients on their further seizure prognosis., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE)., Methods: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff., Results: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months)., Significance: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug-resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes., Methods: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F-statistics from comparisons of GM regions within each TLE cognitive phenotype and age- and sex-matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome., Results: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network-identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15., Interpretation: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug-resistant TLE. ANN NEUROL 2024;95:984-997., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The computational capabilities of neuronal networks are fundamentally constrained by their specific connectivity. Previous studies of cortical connectivity have mostly been carried out in rodents; whether the principles established therein also apply to the evolutionarily expanded human cortex is unclear. We studied network properties within the human temporal cortex using samples obtained from brain surgery. We analyzed multineuron patch-clamp recordings in layer 2-3 pyramidal neurons and identified substantial differences compared with rodents. Reciprocity showed random distribution, synaptic strength was independent from connection probability, and connectivity of the supragranular temporal cortex followed a directed and mostly acyclic graph topology. Application of these principles in neuronal models increased dimensionality of network dynamics, suggesting a critical role for cortical computation.

Background and Purpose: In patients with epilepsy and sustained seizure freedom, guidelines recommend considering discontinuation of antiseizure medication (ASM) based on shared decision-making. This study aims to identify factors associated with non-discontinuation of ASM in seizure-free patients., Methods: Retrospective data from three sites of an academic outpatient clinic were analyzed. Adult patients with epilepsy who have been seizure-free for ≥24 months on ASM monotherapy were included. The primary end-point was non-discontinuation of ASM, defined as no discontinuation or no dose reduction of ≥25% at the last outpatient clinic visit in the ultimate seizure-free interval. Secondary end-points included frequency of discussion on discontinuation attempts between patients and physicians, adherence to ASM discontinuation decisions, and post-discontinuation seizure outcomes., Results: Out of 338 included patients, 81.7% did not discontinue ASM and did not reduce its dose, 11.5% discontinued ASM and 6.8% had a significant dose reduction. Factors independently associated with non-discontinuation of ASM were history of focal to bilateral or generalized tonic-clonic seizures (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.08-5.06), history of breakthrough seizures (OR 3.32, 95% CI 1.10-10.04), history of failed attempts to discontinue or reduce the ASM dose (OR 4.67, 95% CI 1.03-21.11) and higher ASM load at the index visit (OR 6.10, 95% CI 2.09-17.78). Discontinuation attempts were made during the entire period of seizure freedom and were most commonly undertaken ≥10 years after the last seizure., Conclusions: This study provides insights into factors associated with the shared decision-making process regarding ASM discontinuation in seizure-free patients and highlights the importance of considering individual patient characteristics and seizure history., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K + efflux as a key signaling event, suggesting that K + -permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K + channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K + conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K + efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K + conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K + -independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation., (© 2024. The Author(s).)

Purpose: At onset of generalized seizures, focal electroclinical features are commonly seen, while generalized onset seizures with focal evolution (GOFE) are largely unknown bearing the risk of misclassification., Methods: In two German epilepsy-centers, patients with GOFE documented by video-EEG monitoring (VEM) between 2017 and 2022 were identified retrospectively. In addition to analysis of ictal electroclinical features, detailed epilepsy and family history, response to antiseizure medication (ASM), and findings from neuroimaging were considered., Results: We identified five patients with GOFE, three females, age 14 to 22 years. All patients developed genetic generalized epilepsy in childhood or adolescence, each presenting with two or three generalized seizure types. In each of the five patients, one GOFE was recorded by VEM. At onset, EEG seizure patterns were characterized by generalized spike-wave discharges at 2.5 to 3.5/sec for 9 to 16 s followed by focal evolution of the discharges. Interictally, all patients presented with generalized spike-wave discharges without focal abnormalities. Semiology at onset was behavioral arrest in two patients and generalized increase in tone in one, while two onsets were clinically inapparent. Semiological signs during focal evolution were variable, comprising head and body version, figure 4 sign, unilateral arm clonic activity, and staring with oral automatisms. In one case, focality involved both hemispheres successively., Conclusion: Prominent focal semiological features in GOFE carry a high risk of misclassification as focal seizures and epilepsy and thus wrong choice of ASM. This calls for low-threshold VEM if any doubts of focal genesis of seizures exist., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients., Methods: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors., Results: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression., Significance: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations., (© 2023 International League Against Epilepsy.)

Objectives: People with epilepsy (PWE) not only suffer from seizures but also from various psycho-social issues containing facets such as social functioning, anxiety, depression or stigmatization, and consequently quality of life. (1) Assessing reliable change of these issues is crucial to evaluate their course and potential treatment effects. As most psycho-social self-report questionnaires have been validated in separate samples, their clinical-socio-demographic differences may limit the comparability and generalizability of the scales' internal consistency, which is important for the reliable change index (RCI). Using a co-normalized approach, we provide the internal consistency and RCIs for a large set of questionnaires targeting quality of life (QOLIE-31-P), depressive symptoms (NDDI-E), anxiety (GAD-7), seizure severity (LSSS), subjective antiseizure medication adverse events (LAEP), stigma, epilepsy-related fear, and restrictions in daily life (PESOS), and subjective cognition (FLei). As for some German versions of these measures, psychometric data is still missing, we also add important information for the German language area. (2) In addition, knowledge about intercorrelations of these constructs is needed to shape questionnaire usage and treatment approaches. We thus investigate associations of these scales and compare weighted and unweighted subscales of the QOLIE-31-P., Methods: In our prospective study, 202 adult in-patients of the Epilepsy-Center Berlin-Brandenburg with a reliable diagnosis of epilepsy filled out a set of self-report questionnaires between 03/2018 and 03/2021. We calculated Cronbach's α, RCIs, and bivariate intercorrelations and compared the respective correlations of weighted and unweighted scales of the QOLIE-31-P., Results: For most of the scales, good to excellent internal consistency was identified. Furthermore, we found intercorrelations in the expected directions with strong links between scales assessing similar constructs (e.g., QOLIE-31-P Cognition and FLei), but weak relationships between measures for different constructs (e.g., QOLIE-31-P Seizure worry and FLei). The QOLIE-31-P Total score was highly correlated with most of the other scales. Some differences regarding their correlational patterns for weighted and unweighted QOLIE-31-P scales were identified., Conclusions: Psycho-social constructs share a large amount of common variance, but still can be separated from each other. The QOLIE-31-P Total score represents an adequate measure of general psycho-social burden., Competing Interests: Declaration of competing interest M.H. has received speaker honoraria and/or consultancy fees from Angelini, Bial, Desitin, Eisai, Jazz Pharma and UCB within the last 3 years, all unrelated to the contents of this manuscript. None of the other authors has any conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The epileptogenic properties of white matter lesions (WML) in cerebral small vessel disease (CSVD) are not yet understood. The aim of our systematic review and meta-analysis was to estimate the association between the extent of WML in CSVD and epilepsy, analyze whether these WML are associated with an increased risk of seizure recurrence, and evaluate if treatment with anti-seizure medication (ASM) is justified in first-seizure patients with WML and no cortical lesions., Methods: Following a pre-registered study protocol (PROSPERO-ID CRD42023390665), we systematically searched Pubmed and Embase for relevant literature comparing WML load between patients with epilepsy and controls as well as studies on seizure recurrence risk and ASM therapy in the presence vs. absence of WML. We calculated pooled estimates using a random effects model., Results: Eleven studies comprising 2983 patients were included in our study. Presence of WML (OR 2.14, 95% CI 1.38-3.33) and presence of relevant WML as assessed by visual rating scales (OR 3.96, 95% CI 2.55-6.16) but not WML volume (OR 1.30, 95% CI 0.91-1.85) were significantly associated with seizures. These results stayed robust in sensitivity analyses restricted to studies on patients with late-onset seizures/epilepsy. Only two studies assessed the association between WML and risk of seizure recurrence with conflicting results. Currently, there are no studies on the efficacy of ASM therapy in the presence of WML in CSVD., Conclusions: This meta-analysis suggests an association between presence of WML in CSVD and seizures. More research is needed addressing the association between WML and risk of seizure recurrence and ASM therapy focusing on a population of patients with a first unprovoked seizure., (© 2023. The Author(s).)

Background: Acute symptomatic epileptic seizures are frequently seen in neurocritical care. To prevent subsequent unprovoked seizures, long-term treatments with antiseizure medications are often initiated although supporting evidence is lacking. This study aimed at prospectively assessing the risk of unprovoked seizure relapse with respect to the use of antiseizure medications. It was hypothesized that after a first acute symptomatic seizure of structural etiology, the cumulative 12-month risk of unprovoked seizure relapse is ≤ 25%., Methods: Inclusion criteria were age ≥ 18 and acute symptomatic first-ever epileptic seizure; patients with status epilepticus were excluded. Using telephone and mail interviews, participants were followed for 12 months after the acute symptomatic first seizure. Primary endpoint was the occurrence and timing of a first unprovoked seizure relapse. In addition, neuro-intensivists in Germany were interviewed about their antiseizure treatment strategies through an anonymous online survey., Results: Eleven of 122 participants with structural etiology had an unprovoked seizure relapse, resulting in a cumulative 12-month risk of 10.7% (95%CI, 4.7%-16.7%). None of 19 participants with a non-structural etiology had a subsequent unprovoked seizure. Compared to structural etiology alone, combined infectious and structural etiology was independently associated with unprovoked seizure relapse (OR 11.1; 95%CI, 1.8-69.7). Median duration of antiseizure treatment was 3.4 months (IQR 0-9.3). Seven out of 11 participants had their unprovoked seizure relapse while taking antiseizure medication; longer treatment durations were not associated with decreased risk of unprovoked seizure relapse. Following the non-representative online survey, most neuro-intensivists consider 3 months or less of antiseizure medication to be adequate., Conclusions: Even in case of structural etiology, acute symptomatic seizures bear a low risk of subsequent unprovoked seizures. There is still no evidence favoring long-term treatments with antiseizure medications. Hence, individual constellations with an increased risk of unprovoked seizure relapse should be identified, such as central nervous system infections causing structural brain damage. However, in the absence of high-risk features, antiseizure medications should be discontinued early to avoid overtreatment., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

Background: Antiseizure medications can have negative effects on plasma lipid levels., Objectives: To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE)., Design: Post hoc analysis of a phase III trial and OLE study., Methods: Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE., Results: A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% ( p  < 0.001); LDL cholesterol, +11.5% ( p  = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, -15.3% ( p  = 0.008); LDL cholesterol, -11.1% ( p  = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL-CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were -13.6% ( p  = 0.037) and -12.3% ( p  = 0.061), respectively; at the end of the OLE, these between-group differences were -6.0% ( p  = 0.360) and -0.6% ( p  = 1.000), respectively., Conclusion: A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly., Registration: ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36., Competing Interests: ET reports personal fees from EVER Pharma, Marinus, Arvelle, Angelini, Argenx, Medtronic, Bial-Portela & Cª, NewBridge, GL Pharma, GlaxoSmithKline, Boehringer Ingelheim, LivaNova, Eisai, UCB, Biogen, Sanofi, Jazz Pharmaceuticals, and Actavis. His institution received grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Osterreichischer Fond zur Wissenschaftsforderung, Bundesministerium für Wissenschaft und Forschung, and Jubiläumsfond der Österreichischen Nationalbank. RR is a consultant for Eisai, Bial, UCB, GlaxoSmithKline and Shire, and receives grant and research support from Bial, Eisai, and UCB. JC has received speaker’s honoraria and/or consultancy fees from Bial and Eisai and was granted with a Tecnifar Bursary. MJK reports personal fees as speaker or consultant from Arvelle, BIAL, Eisai, GW Pharmaceuticals, Novartis and UCB Pharma. He holds stocks for Prevep. MJK or his institution received grants from UCB Pharma, Eisai, Arvelle/Angelini, the European Union, Wellcome Trust and Medical Research Council. SR received unconditional research grants from UCB-pharma, honoraria from serving on the scientific advisory boards of Arvelle/Angelini, Bial, Eisai, GW/Jazz Pharmaceuticals, and UCB Pharma, and from serving as a consultant for Arvelle/Angelini, Eisai, Jazz Pharmaceuticals, Pfizer, Novartis, Sandoz, and UCB Pharma. He does not hold any stocks of any pharmaceutical industries or manufacturers of medical devices. He received funding from UCB Pharma, and the Swiss National Science Foundation. MH received speaker’s honoraria and/or consultancy fees from Angelini/Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals/Jazz, Neuraxpharm, UCB, and Zogenix with the last 3 years. JM, MMF and GCF are current employees of Bial – Portela & Cª, S.A. FI was an employee of Bial – Portela & Cª, S.A. at the time this study was conducted but is currently employed at Neuroscience Clinical Development, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK., (© The Author(s), 2023.)

Objective: To investigate cost in working hours for initial integration of interictal EEG source localization (ESL) into clinical practice of a tertiary epilepsy center, and to examine concordance of results obtained with three different ESL pipelines., Methods: This prospective study covered the first year of using ESL in the Epilepsy-Center Berlin-Brandenburg. Patients aged ≥14 years with drug-resistant focal epilepsy referred for noninvasive presurgical evaluation were included. Interictal ESL was based on low-density EEG and individual head models. Source maxima were obtained from two freely available software packages and one commercial provider. One physician and computer scientist documented their working hours for setting up and processing ESL. Additionally, a survey was conducted among epilepsy centers in Germany to assess the current role of ESL in presurgical evaluation., Results: Of 40 patients included, 22 (55%) had enough interictal spikes for ESL. The physician's working times decreased from median 4.7 hours [interquartile range 3.9-6.4] in the first third of cases to 2.0 hours [1.9-2.4] in the remaining two thirds; P < 0.01. In addition, computer scientist and physician spent a total of 35.5 and 33.0 working hours on setting up the digital infrastructure, and on training and testing. Sublobar agreement between all three pipelines was 20%, mean measurement of agreement (kappa) 0.13. Finally, the survey revealed that 53% of epilepsy centers in Germany currently use ESL for presurgical evaluation., Significance: This study provides information regarding expected effort and costs for integration of ESL into an epilepsy surgery program. Low result agreement across different ESL pipelines calls for further standardization., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: The increasing identification of specific autoantibodies against brain structures allows further refinement of the group of autoimmune-associated epilepsies and affects diagnostic and therapeutic algorithms. The early etiological allocation of a first seizure is particularly challenging, and the contribution of cerebrospinal fluid (CSF) analysis is not fully understood., Methods: In this retrospective study with a mean of 7.8 years follow-up involving 39 well-characterized patients with the initial diagnosis of new-onset seizure or epilepsy of unknown etiology and 24 controls, we determined the frequency of autoantibodies to brain proteins in CSF/serum pairs using cell-based assays and unbiased immunofluorescence staining of unfixed murine brain sections., Results: Autoantibodies were detected in the CSF of 30.8% of patients. Underlying antigens involved glial fibrillary acidic protein (GFAP) and N-methyl-D-aspartate (NMDA) receptors, but also a range of yet undetermined epitopes on neurons, glial and vascular cells. While antibody-positive patients had higher frequencies of cancer, they did not differ from antibody-negative patients with respect to seizure type, electroencephalography (EEG) and cranial magnetic resonance imaging (cMRI) findings, neuropsychiatric comorbidities or pre-existing autoimmune diseases. In 5.1% of patients with seizures or epilepsy of initially presumed unknown etiology, mostly CSF findings resulted in etiological reallocation as autoimmune-associated epilepy., Discussion: These findings strengthen the potential role for routine CSF analysis. Further studies are needed to understand the autoantibody contribution to etiologically unclear epilepsies, including determining the antigenic targets of underlying autoantibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schulz, Lütt, Stöcker, Teegen, Holtkamp and Prüss.)

Objective: Many people with epilepsy report subjective cognitive impairment (SCI), i.e., problems with memory, attention, or executive functions, reducing quality of life. Nevertheless, overlap with objective cognitive impairment (OCI) is often weak. One reason may be a domain-specific mismatch between subjective reports and objective tests. We aimed to evaluate relations between SCI and OCI of corresponding domains and to assess whether these differ between persons who over- or underestimate their performance., Methods: In this prospective, cross-sectional sample of 104 adult inpatients with epilepsy, we performed multiple regression analyses predicting SCI in the domains attention, memory, and executive functions. We tested relationships with measures of psychomotor speed, short-term memory, verbal learning, verbal delayed recall, and word fluency while controlling for age, sex, seizure frequency, structural lesions, mono- versus polytherapy and adverse events of antiseizure medication (ASM), depressive and anxiety symptoms, level of education, and employment status. Furthermore, we tested whether these relationships differed between realistic raters and over- and underestimators., Results: We found domain-specific relations for attention and executive functions for the full sample, explaining a small proportion of variance of SCI (general dominance index = .03 and .004), whereas ASM adverse events and psychological variables were more important predictors. When dividing the sample according to the concordance of SCI and OCI, we found high frequencies of both over- (23%-46%) and underestimation (31%-35%) depending on the domain. The explanatory power of OCI for SCI was stronger within the subgroups compared to the full sample, suggesting nonlinear relationships and different underlying mechanisms for realistic raters, underestimators, and overestimators., Significance: Domain-specific SCI and OCI are related, and both should be assessed with standardized instruments. These relationships differ between over- and underestimators as well as realistic raters. Based on the concordance of self-ratings and objective measures, tailored counseling and treatment should be offered., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm 3 on the right and 461 mm 3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm 3 in healthy controls, ~0.40/ ~28 mm 3 in patients with TLE, and ~ 0.34/~29 mm 3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Many people with epilepsy (PWE) suffer from reduced everyday functioning such as unemployment, relationship difficulties, or lifestyle limitations. To identify whether subjective cognitive impairment (SCI) is a potential source of these impairments, associations with restrictions of daily life (RDL) and reduced daily activities (DA) were examined., Methods: In a prospective cross-sectional sample of 316 adult in-patients with epilepsy, multiple regression analyses were calculated predicting RDL and DA. The relationships between these two measures and SCI were controlled for age, sex, seizure frequency, presence of structural lesions, epilepsy duration, mono- vs polytherapy and adverse events of antiseizure medication (ASM), level of depressive and anxiety symptoms, education, and employment. We also checked for an interaction between depressive symptoms and SCI, to evaluate whether patients with more depressive symptoms are more vulnerable for unfavorable associations between SCI and RDL or DA, respectively. General dominance indices (GDIs) were calculated to compare predictors., Results: Substantial SCI was present in 46% of our sample. SCI was independently associated with RDL and DA. Comparison of relative predictor importance revealed that SCI accounted for 23% of the total variance of RDL (GDI SCI  = 0.12, R RDL 2  = 50%) and 24% of the total variance of DA (GDI SCI  = 0.08, R DA 2  = 32%). SCI was among the two most important predictors in both models. PWE with more depressive symptoms had stronger associations between SCI and RDL or DA, respectively., Significance: Subjective cognitive impairment represents a frequent concern in PWE and may have detrimental consequences for their everyday life. PWE with depressive symptoms may be at greater risk of unfavorable relationships between SCI and everyday functioning. Exchange and collaboration between professionals offering psychotherapeutic, neuropsychological, and psychosocial interventions are crucial to address the patients' individual needs., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In Germany, long-term video EEG as the gold standard for the diagnostics of epilepsy and other seizure disorders, is currently only available for inpatient monitoring in a limited number of specialized centers. These limited monitoring capacities and the large amount of associated time and work resources lead to a significant waiting time for this important diagnostic procedure nationwide. New portable sensor technology and automated data analysis methods are creating opportunities for gold standard long-term video EEG assessments in outpatient settings, which may help to resolve this barrier. Here, we report the results of a single-center feasibility study by implementing outpatient long-term video EEG (ALVEEG) as a diagnostic pathway in Germany. In the new diagnostic pathway, the use of innovative, portable video EEG monitoring systems along with artificial intelligence-assisted data analysis are intended to provide those patients affected by seizure disorders with a more rapid, efficient, and cross-sectoral access to gold standard diagnostics in the home environment. The diagnostics were well accepted by patients and clinicians and may represent a complementary option to inpatient monitoring to eliminate current bottlenecks in diagnostics and care., (© 2022. The Author(s).)

Objective: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes., Methods: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers., Results: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%)., Significance: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: In patients with drug-resistant focal epilepsy, resective surgery is the most successful treatment option to achieve seizure freedom. However, a surprisingly high rate of patients declines their physicians' recommendation to undergo removal of the seizure focus or-if necessary-further video-EEG monitoring (VEM)., Methods: In this prospective study, consecutive patients in presurgical assessment with at least one scalp VEM between 2016 and 2018 were included. We assessed both epilepsy-related and psychosocial variables as well as decision-making of physicians and patients, including reasons for decline in the latter., Results: Out of 116 patients with a total of 165 VEM, 20 patients were eventually found to be ineligible for resection, 51 declined, and 45 agreed on recommendations for resection or further VEM diagnostics. Patients most frequently declined due to general fear of brain surgery (n = 30, 59%) and currently lower seizure frequency (n = 11, 22%). An independent predictor of patients' decline was less epilepsy-related fear (OR 0.43; p = 0.02) assessed in a standardised questionnaire., Conclusion: Half of the patients potentially eligible for resective surgery decline the operation or further VEM procedures. Patients who decline are more fearful of brain surgery than of ongoing disabling seizures. More insight is needed to improve counselling of patients., (© 2022. The Author(s).)

Objective: Identifying factors associated with surgical decision-making is important to understand reasons for underutilization of epilepsy surgery. Neurologists' recommendations for surgery and patients' acceptance of these recommendations depend on clinical epilepsy variables, for example, lateralization and localization of seizure onset zones. Moreover, previous research shows associations with demographic factors, for example, age and sex. Here, we investigate the relevance of patients' psycho-social profile for surgical decision-making., Methods: We prospectively studied 296 patients from two large German epilepsy centers. Multiple logistic regression analyses were used to investigate variables linked to neurologists' recommendations for and patients' acceptance of surgery or intracranial video-electroencephalographic monitoring. Patients' psycho-social profiles were assessed via self-reports and controlled for various clinical-demographic variables. Model selection was performed using the Akaike information criterion., Results: As expected, models for neurologists' surgery recommendations primarily revealed clinical factors such as lateralization and localization of the seizure onset zone, load with antiseizure medication (ASM), and site of the epilepsy-center. For this outcome, employment was the only relevant psycho-social aspect (odds ratio [OR] = .38, 95% confidence interval [CI] = .13-1.11). In contrast, three of the five relevant predictors for patients' acceptance were psycho-social. Higher odds were found for those with more subjective ASM adverse events (OR = 1.04, 95% CI = .99-1.00), more subjective seizure severity (OR = 1.12, 95% CI = 1.01-1.24), and lower subjective cognitive impairment (OR = .98, 95% CI = .96-1.00)., Significance: We demonstrated the relevance of the patients' psycho-social profile for decision-making in epilepsy surgery, particularly for patients' decisions. Thus, in addition to clinical-demographic variables, patients' individual psycho-social characteristics add to the understanding of surgical decision-making. From a clinical perspective, this calls for individually tailored counseling to assist patients in finding the optimal treatment option., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Patients with drug-resistant focal epilepsy may benefit from ablative or resective surgery. In presurgical work-up, intracranial EEG markers have been shown to be useful in identification of the seizure onset zone and prediction of post-surgical seizure freedom. However, in most cases, implantation of depth or subdural electrodes is performed, exposing patients to increased risks of complications., Methods: We analysed EEG data recorded from a minimally invasive approach utilizing foramen ovale (FO) and epidural peg electrodes using a supervised machine learning approach to predict post-surgical seizure freedom. Power-spectral EEG features were incorporated in a logistic regression model predicting one-year post-surgical seizure freedom. The prediction model was validated using repeated 5-fold cross-validation and compared to outcome prediction based on clinical and scalp EEG variables., Results: Forty-seven patients (26 patients with post-surgical 1-year seizure freedom) were included in the study, with 31 having FO and 27 patients having peg onset seizures. The area under the receiver-operating curve for post-surgical seizure freedom (Engel 1A) prediction in patients with FO onset seizures was 0.74 ± 0.23 using electrophysiology features, compared to 0.66 ± 0.22 for predictions based on clinical and scalp EEG variables (p < 0.001). The most important features for prediction were spectral power in the gamma and high gamma ranges. EEG data from peg electrodes was not informative in predicting post-surgical outcomes., Conclusion: In this hypothesis-generating study, a data-driven approach based on EEG features derived from FO electrodes recordings outperformed the predictive ability based solely on clinical and scalp EEG variables. Pending validation in future studies, this method may provide valuable post-surgical prognostic information while minimizing risks of more invasive diagnostic approaches., Competing Interests: Conflict of interest disclosure M.H. reports personal fees as speaker and consultant within the last 3 years from Angelini/Arvelle, Bial, Desitin, Eisai, GW Pharma, Neuraxpharm, UCB and Zogenix outside the submitted work. C.M is part of patent applications to detect and predict clinical outcomes and to manage, diagnose, and treat neurological conditions. The other authors have no conflicts of interest to disclose, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: In Germany, six previous representative surveys on attitudes toward epilepsy (AE) have been conducted between 1967 and 2008 using the four original Caveness questions (CQs) from 1949 to 1980. The aims of this study were (1) to investigate changes in AE over the time span of 50 years, including the current survey in 2018 (2) to investigate the first-time emotional reactions measured with the Scales of Attitudes toward People with Epilepsy (SAPE) (3) to identify predictors of AE., Methods: A representative face-to-face survey with CQ, in addition with the SAPE scales of Social Distance, Stereotypes, Personal Concerns, and Emotional Reactions was carried out in Germany in 2018. One thousand and twenty-six persons who ever had heard of epilepsy participated. Respondents who answered "don't know" in the CQs were subsequently asked to answer only yes/no. The analysis of trends from 1967 to 2018 was based on the pooled data of the surveys. The four CQs in the 2018 survey were included in the SAPE item pool and an exploratory principal axis factor analysis was performed. General linear models were performed to identify predictors., Results: For all four CQs, the trend of improved AE was significant over the past 50 years. In the 2018 survey, excluding the "don't know" answer option increased the proportion of negative responses for contact of one's own children with a person with epilepsy (PWE) from 6.9% to 11.4% and for the marriage of one's own children with a PWE from 13.9% to 23.8%. When encountering a PWE, 30.1% would feel insecure or uncomfortable and nearly 60% were concerned that the PWE might be injured in case of a seizure. Knowing what to do in case of a seizure, knowing that seizures can be treated successfully, personal contact with a PWE along with younger age, and higher education were found to be the strongest predictors for positive AE identified by multivariate analyses. Exploratory principal axis factor analysis revealed that three of the four CQs items loaded > 0.30 at the factors of Social Distance and Stereotypes of SAPE but none on the factors measuring emotional reactions., Significance: AE measured by CQs have markedly improved in Germany over the last 50 years. Germany is to our knowledge the only country with such a long-term trend investigation in AE. Negative AE may be underestimated by survey questions with "don't know" answer option. Emotional aspects of attitudes are underexposed resp. neglected in the CQs, which are used worldwide for measuring AE. Additional tools like SAPE can close this gap. The identified predictors may help to derive interventions against negative AE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H.M.H. has served on the scientific advisory board of Angelini, Corlieve, Eisai, GW, Sandoz, UCB Pharma and Zogenix. He served on the speakers’ bureau of or received unrestricted grants from Ad-Tech, Bracco, Desitin, Eisai, GW, Micromed, Nihon Kohden, Novartis, Pfizer, and UCB Pharma. M.H. received speaker’s honoraria and/or consultancy fees from Angelini/Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals, Neuraxpharm, UCB, and Zogenix within the last 3 years. A.S. reports personal fees and grants from Angelini Pharma/Arvelle Therapeutics, Desitin Arzneimittel, Eisai, GW Pharmaceuticals companies, Marinus Pharma, Precisis, UCB, UNEEG medical, and Zogenix. ASB reports research support or personal honoraria for lectures or advice from Angelini Pharma/Arvelle Therapeutics, BIAL Eisai, GW, UCB, UNEEG and Precisis. The other authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME., Methods: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed - last updated on March 11, 2021 - including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/)., Findings: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68-0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68-0·73)., Interpretation: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools., Funding: MING fonds., Competing Interests: AAA received a grant from the 10.13039/501100012155National Institute for Medical Research Development, royalties for a book publication from 10.13039/501100007723Oxford University Press, and speaker fees from Cobel Daruo, Tekaje, and Raymand Rad. CPB received research grants and honoraria from 10.13039/100011110UCB and 10.13039/501100003769Eisai, support for attending meetings by UCB, and served in the advisory board of Arvelle. CDB received consulting fees and honoraria from 10.13039/100014114GW Pharmaceuticals, 10.13039/100015661UCB Pharma, 10.13039/501100003769Eisai, 10.13039/501100006546Angelini Pharma and Bial. JPS received grants from the 10.13039/100000002National Institutes of Health, 10.13039/100000005Department of Defense, and the 10.13039/100000001National Science Foundation; and consulting fees from 10.13039/100015661UCB Pharma, AdCel Biopharma, LLC, iFovea, SK Life Sciences, and 10.13039/100013410LivaNova; and has stock options for iFovea and AdCel Biopharma. LEH-V participates in the Young Epilepsy Society, received speaker honorario from Armstrong, and was supported by Abbott pharmaceuticals to attend the Mexican Congress of Neurology. NP received honoraria from Zogenix and Ethos for Angelini Pharma. NS received honoraria from Biomarin, Livanova, GW Pharma, Zogenix and Marinus; and support to attend meetings from Livanova, GW Pharma and Zogenix; and participated on a data safety monitoring board for Marinus. SB received speaker fees from Eisai. PK received lecture honorarium from UCB Pharma and Eisai, consulting fees from 10.13039/501100003769Eisai and 10.13039/100013410LivaNova and his institution received research grants from 10.13039/100015661UCB Pharma and 10.13039/501100003769Eisai. MS received speaker honoraria from UCB Pharma and Eisai. KKS received research grants from the 10.13039/501100005416Norwegian Research Council, the DAMFoundation and the Norwegian National Advisory Unit on Rare diseases; and a networking grant from the 10.13039/501100004785NordForsk Foundation; and she acted as a paid PhD defense opponent at the University of Bergen, and attended a meeting for Nordic clinicians organised by Eisai. BJV received grants from the 10.13039/501100007870German Society for Epileptology and the 10.13039/501100001659Deutsche Forschungsgemeinschaft; and honoraria from University Medical Center Schleswig–Holstein and Cornelsen Verlag. MH received consulting fees and honoraria from Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals, UCB Pharma, and Zogenix. FvP has received speaker honoraria from Bial, Eisai, GW Pharmaceutical companies, Angelinipharma, Zogenix and UCB Pharma; and scientific advisory board honoraria from GW Pharmaceutical companies, UCB Pharma, and Angelinipharma. WD's salary is part-funded by The University of Melbourne; he has received travel, investigator-initiated, scientific advisory board and speaker honoraria from UCB Pharma Australia and Global; investigator-initiated, scientific advisory board, travel and speaker honoraria from Eisai Australia and Global; advisory board honoraria from Liva Nova and Tilray; educational grants from Novartis Pharmaceuticals, 10.13039/100014476Pfizer Pharmaceuticals and Sanofi-Synthelabo; educational; travel and fellowship grants from GSK Neurology Australia, and honoraria from SciGen Pharmaceuticals; and he has an equity interest in the device company EpiMinder. CPB received honaries and research support from EISAI, UCB and Arvelle. ET received speaker's honoraria from Arvelle, Abbott, Angelini Pharma, UCB, Biogen, Gerot-Lannacher, Bial, Eisai, Epilog, Takeda, Newbridge, Hikma, GW Pharmaceuticals, Sunovion Pharmaceuticals Inc., LivaNova and Novartis; consultancy funds from 10.13039/501100006546Angelini Pharma, Argenix, Arvelle, Epilog, 10.13039/100011110UCB, 10.13039/100005614Biogen, Gerot-Lannach, Bial, 10.13039/501100003769Eisai, 10.13039/100007723Takeda, Newbridge, 10.13039/100014114GW Pharmaceuticals, 10.13039/100009655Sunovion Pharmaceuticals Inc., Marinus, and 10.13039/100004336Novartis; directorship funds from Neuroconsult GmbH. ET's Institution received grants from 10.13039/100005614Biogen, Red Bull, 10.13039/100004334Merck, 10.13039/100011110UCB, 10.13039/501100000780European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and 10.13039/501100007148Bundesministerium für Wissenschaft und Forschung. JWS reports personal fees from Arvelle, personal fees from 10.13039/100011110UCB, grants from UCB, grants from 10.13039/100003997NEF, grants from UCB, personal fees from 10.13039/100012739Zogenix, grants from GW Phama, outside the submitted work; and his current position is endowed by the Epilepsy Society, he is a member of the Editorial Board of the Lancet Neurology, and receives research support from the Marvin Weil Epilepsy Research Fund. All other authors declare no potential competing interests. None of the above mentioned declarations represent a conflict of interest directly related to the present publication., (© 2022 The Author(s).)

Objective: To describe and assess the significance of EEG characteristics recorded during presurgical video-EEG monitoring (VEM) utilizing foramen ovale (FO) and epidural peg electrodes., Methods: Seizure onset (SOP) and termination pattern morphology and regions, ipsilateral and contralateral latencies, seizure duration, and interictal spike counts were examined in 106 patients (412 seizures). An EEG feature-based logistic regression model predicting one-year post-surgical seizure freedom was assessed using a 5-fold nested cross-validation approach., Results: Four SOPs and five termination patterns were identified. Seventy-one percent of patients had a single unique SOP, the most common being sharp activity ≤ 13 Hz (28.9% of seizures). Seizures recorded by FO electrodes were associated with SOPs ≤ 13 Hz (OR 1.9, p = .008). Focal-to-bilateral tonic-clonic seizures were associated with SOPs > 13 Hz (p = .04) and bilateral spike and wave termination (p < .001). In patients with temporal lobe epilepsy, logistic regression based prediction of post-surgical outcome had a mean area under the curve of 0.69, with the most important features being SOP, right sided interictal epileptic activity, and contralateral latency., Conclusions: FO and peg recordings yield characteristic EEG patterns., Significance: EEG features of FO and peg recordings may have diagnostic and prognostic utility in presurgical VEM., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This prospective study aimed at comparing quality of life (QoL) and psycho-socio-clinical profiles between patients with epilepsy, psychogenic nonepileptic seizures (PNES), and syncope. We also intended to identify predictors of QoL in these three seizure disorders., Methods: A total of 245 inpatients (epilepsy n = 182, PNES n = 50, syncope n = 13) from a tertiary epilepsy clinic were included. Information on QoL as well as on psychological, sociodemographic, and clinical profiles was retrieved using questionnaires and medical records. Group comparisons on QoL and psycho-socio-clinical profiles were performed via analyses of variance, chi-square tests, and related post hoc tests. Predictors of QoL in epilepsy and PNES were determined using general linear modeling, which was not possible for syncope due to a small sample size., Results: Patients with epilepsy, PNES, and syncope reported levels of QoL impairment that did not differ significantly between groups (p = 0.266). However, there were significant group differences regarding sex distribution (p < 0.001), seizure disorder duration (p = 0.004), seizure frequency (p = 0.019), current treatment with antiseizure medications (ASM) (p < 0.001), number of current ASM (p < 0.001), and adverse ASM events (p = 0.019). More depressive symptoms (p = 0.001), more adverse ASM events (p = 0.036), and unemployment (p = 0.046) (in this order) independently predicted a diminished QoL in epilepsy. For PNES, more depressive symptoms were the only independent predictor of lower QoL (p = 0.029)., Conclusions: Patients with epilepsy, PNES, and syncope experience similarly diminished QoL and show a general psycho-socio-clinical burden with a specific pattern for each seizure disorder diagnosis. Although clinical aspects play an undisputed role for QoL in epilepsy, the psychosocial aspects and consequences are equally, or for PNES probably even more, meaningful. A comprehensive approach to research and treatment of seizure disorders seems mandatory to increase QoL for these patients. More research on QoL in syncope is needed., Competing Interests: Declaration of Competing Interest MH reports personal fees as speaker and consultant within the last 3 years from Angelini/Arvelle, Bial, Desitin, Eisai, GW Pharma, UCB, and Zogenix outside the submitted work. The remaining authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Epilepsy surgery cases are becoming more complex and increasingly require invasive video-EEG monitoring (VEM) with intracranial subdural or intracerebral electrodes, exposing patients to substantial risks. We assessed the utility and safety of using foramen ovale (FO) and epidural peg electrodes (FOP) as a next step diagnostic approach following scalp VEM., Methods: We analyzed clinical, electrophysiological, and imaging characteristics of 180 consecutive patients that underwent FOP VEM between 1996 and 2021. Multivariate logistic regression was used to assess predictors of clinical and electrophysiological outcomes., Results: FOP VEM allowed for immediate resection recommendation in 36 patients (20.0%) and excluded this option in 85 (47.2%). Fifty-nine (32.8%) patients required additional invasive EEG investigations; however, only eight with bilateral recordings. FOP VEM identified the ictal onset in 137 patients, compared to 96 during prior scalp VEM, p = .004. Predictors for determination of ictal onset were temporal lobe epilepsy (OR 2.9, p = .03) and lesional imaging (OR 3.1, p = .01). Predictors for surgery recommendation were temporal lobe epilepsy (OR 6.8, p < .001), FO seizure onset (OR 6.1, p = .002), and unilateral interictal epileptic activity (OR 3.8, p = .02). One-year postsurgical seizure freedom (53.3% of patients) was predicted by FO ictal onset (OR 5.8, p = .01). Two patients experienced intracerebral bleeding without persisting neurologic sequelae., Conclusion: FOP VEM adds clinically significant electrophysiological information leading to treatment decisions in two-thirds of cases with a good benefit-risk profile. Predictors identified for electrophysiological and clinical outcome can assist in optimally selecting patients for this safe diagnostic approach., (© 2022. The Author(s).)

Purpose: Epilepsy is one of the most common neurological disorders with high costs for the healthcare systems and great suffering for patients. Beyond seizures, psychosocial comorbidities can have detrimental effects on the well-being of people with epilepsy. One source of social stress and reduced quality of life is epilepsy-related stigma that often occurs, e.g., due to public misconceptions or myths. Stigma has individual biological, psychological and social correlates. Moreover, environmental factors like living in remote areas are associated with stigma. However, little is known about the link between the social structure of the residence and stigma in epilepsy. Thus, we investigated the association between the structural socioeconomic status (SES) and perceived stigma in an urban epilepsy population., Methods: This prospective, cross-sectional study examined 226 adult in-patients with epilepsy from Berlin. Multiple regression analyses were performed to check the relationship between structural SES and stigma controlling for individual-level demographic, clinical, psychological and social factors. Continuous social indices (SI) of the districts and neighborhoods ("SI district" and "SI neighborhood") of Berlin were used to measure different levels of structural SES. Non-linear relationships are tested by grouping the SI in quartiles., Results: Both indicators of structural SES were independently linked to stigma ( p = 0.002). For "SI district", we identified a non-linear relationship with patients from the most deprived quartile feeling less stigmatized compared to those in the second ( p < 0.001) or least deprived quartile ( p = 0.009). Furthermore, more restrictions of daily life ( p < 0.001), unfavorable income ( p = 0.009) and seizure freedom in the past 6 months ( p = 0.05) were related to increased stigma. A lower "SI neighborhood" was associated with higher stigma ( p = 0.002)., Conclusion: Strategies to reduce epilepsy-related stigma need to consider the sociostructural living environment on different regional levels. Unfavorable relations with the immediate living environment may be directly targeted in patient-centered interventions. Non-linear associations with the structural SES of broader regional levels should be considered in public education programs. Further research is needed to examine possible underlying mechanisms and gain insight into the generalizability of our findings to other populations., Competing Interests: Author MH received speaker's honoraria and/or consultancy fees from Angelini, Bial, Desitin, Eisai, GW Pharmaceuticals, Neuraxpharm, UCB, and Zogenix. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hohmann, Berger, Kastell and Holtkamp.)

The combination of signals from different sensory modalities can enhance perception and facilitate behavioral responses. While previous research described crossmodal influences in a wide range of tasks, it remains unclear how such influences drive performance enhancements. In particular, the neural mechanisms underlying performance-relevant crossmodal influences, as well as the latency and spatial profile of such influences are not well understood. Here, we examined data from high-density electroencephalography (N = 30) recordings to characterize the oscillatory signatures of crossmodal facilitation of response speed, as manifested in the speeding of visual responses by concurrent task-irrelevant auditory information. Using a data-driven analysis approach, we found that individual gains in response speed correlated with larger beta power difference (13-25 Hz) between the audiovisual and the visual condition, starting within 80 ms after stimulus onset in the secondary visual cortex and in multisensory association areas in the parietal cortex. In addition, we examined data from electrocorticography (ECoG) recordings in four epileptic patients in a comparable paradigm. These ECoG data revealed reduced beta power in audiovisual compared with visual trials in the superior temporal gyrus (STG). Collectively, our data suggest that the crossmodal facilitation of response speed is associated with reduced early beta power in multisensory association and secondary visual areas. The reduced early beta power may reflect an auditory-driven feedback signal to improve visual processing through attentional gating. These findings improve our understanding of the neural mechanisms underlying crossmodal response speed facilitation and highlight the critical role of beta oscillations in mediating behaviorally relevant multisensory processing., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in the completion of this work., (Copyright © 2022. Published by Elsevier Inc.)

Surgery is an essential treatment option for patients with drug-resistant epilepsy. While most epilepsy patients worldwide live in low- and middle-income countries (LMIC), most of these countries do not have epilepsy surgery, and those that do have surgical epilepsy services lack capacities. The rapidly growing population in LMIC further widens the gap between the number of patients who can potentially benefit from surgery and those who can actually receive it. This makes the initiation of new surgical epilepsy centers in those countries an urgent issue. Epilepsy surgery is feasible in LMIC, even in resource-poor settings, but lack of local expertise is a major obstacle to the introduction of new surgical services. Importantly, expertise deficits can be compensated by collaborating with a well-established epilepsy center for knowledge transfer, skill building and mentoring. Such projects need to be organized in a multidisciplinary team, should focus on the given circumstances, and should use technologies and personnel that are reasonably available and can function sustainably. Local cultural factors and improvement of patients' quality of life are further spotlights reflected by an increasing number of studies. As a general outline for a new surgical epilepsy program in LMIC, it is recommended to initially focus on patients with mesial temporal lobe epilepsy due to hippocampal sclerosis or other well defined pathologies. These constellations have an excellent surgical outcome in terms of seizure control, can be diagnosed by non-invasive methods, and can be reliably identified even under low-resource conditions. Moreover, surgery can be performed with a highly standardized approach and at reasonable costs, and the vast majority of patients will benefit from surgical intervention. The range of services can then be gradually expanded, depending on growing expertise, local needs, prospects and constraints. Although the introduction of surgical epilepsy services in LMIC can face several challenges, none of them should be a permanent barrier for further establishments., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Objective: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant., Methods: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible., Results: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28)., Significance: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: When treating patients with epileptic seizures in the emergency room (ER), it is of paramount importance to rapidly assess whether the seizure was acute symptomatic or unprovoked as the former points to a potentially life-threatening underlying condition. In this study, we seek to identify predictors and analyze characteristics of acute symptomatic seizures (ASS)., Methods: Data from patients presenting with seizures to highly frequented ERs of two sites of a university hospital were analyzed retrospectively. Seizures were classified as acute symptomatic or unprovoked according to definitions of the International League Against Epilepsy. Univariate and multivariate analysis were conducted to identify predictors; furthermore, characteristics of ASS were assessed., Results: Finally, 695 patients were included, 24.5% presented with ASS. Variables independently associated with ASS comprised male sex (OR 3.173, 95% CI 1.972-5.104), no prior diagnosis of epilepsy (OR 11.235, 95% CI 7.195-17.537), and bilateral/generalized tonic-clonic seizure semiology (OR 2.982, 95% CI 1.172-7.588). Alcohol withdrawal was the most common cause of ASS (74.1%), with hemorrhagic stroke being the second most prevalent etiology. Neuroimaging was performed more often in patients with the final diagnosis of ASS than in those with unprovoked seizures (82.9% vs. 67.2%, p < 0.001). Patients with ASS were more likely to receive acute antiseizure medication in the ER (55.9% vs. 30.3%, p < 0.001)., Conclusions: In one quarter of patients presenting to the ER after an epileptic fit, the seizure had an acute symptomatic genesis. The independently associated variables may help to early identify ASS and initiate management of the underlying condition., (© 2021. The Author(s).)

Objective: The aims of this study were (1) to investigate psychometric properties of a new questionnaire (SAPE, Scales of the Attitudes toward People with Epilepsy) that assesses attitudes toward people with epilepsy (PWE) (2) to compare the effects of mode of survey administration (web-based vs. face-to-face) on attitudes, and (3) to identify predictors of attitudes., Methods: A face-to-face and a web-based survey were performed in Germany. Weighting factors were used to achieve representative samples of the German population. Reliability and validity of the 6 scales of the SAPE (social distance, stereotypes, personal concerns, and emotional reactions differentiated by fear, anger, and pity) were evaluated and compared for both surveys. Epilepsy knowledge was also assessed. General linear models were performed to investigate predictors of attitudes toward PWE including the type of survey., Results: In total, 1001 participants of the web-based survey and 1026 participants of face-to-face survey were included. Psychometric analyses indicated satisfactory reliability and validity of the scales and differed only slightly between modes of survey. In both surveys, fears and concerns were more pronounced than stereotypes and social distance. However, mean values of two scales were slightly or moderately higher in the face-to-face survey indicating more negative attitudes toward PWE (p < 0.001). Fewer participants of the face-to-face survey reported personal experience with PWE, claiming to know what to do in case of a seizure and claiming to know that seizures can be treated successfully (p < 0.001). These variables proved to be important predictors of positive attitudes toward PWE, besides demographic factors (e.g. age < 65, female gender). When controlling for them, the differences remained significant only for the scales Social Distance (moderately) and Fear (slightly)., Significance: In total, psychometric analyses show that web-based surveys using the SAPE may be an alternative to face-to-face surveys to assess attitudes toward PWE. This applies also to the scales Social Distance and Emotional Reactions that allow comparisons with other diseases, e.g. psychiatric disorders. Most scales differ only slightly between survey modes, except social distance. This indicates that single components of attitudes toward PWE may be dependent on the mode of survey or different characteristics of respondents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3β S9 phosphorylation and reducing STAT1 S727 and STAT3 Y705 phosphorylation levels in IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1 S727 and P-STAT3 Y705 . Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain., (© 2021 The Authors. GLIA published by Wiley Periodicals LLC.)

Genetic generalized epilepsy (GGE) syndromes start during childhood or adolescence, and four commonly persist into adulthood, making up 15-20% of all cases of epilepsy in adults. These four GGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic-clonic seizures alone. However, in ~20% of patients with GGE, characteristics of more than one syndrome are present. Novel insights into the genetic aetiology, comorbidities and prognosis of the GGE syndromes have emerged and challenge traditional concepts about these conditions. Evidence has shown that the mode of inheritance in GGE is mostly polygenic. Neuropsychological and imaging studies indicate similar abnormalities in unaffected relatives of patients with GGE, supporting the concept that underlying alterations in bilateral frontothalamocortical networks are genetically determined. Contrary to popular belief, first-line anti-seizure medication often fails to provide seizure freedom in combination with good tolerability. Nevertheless, long-term follow-up studies have shown that with advancing age, many patients can discontinue their anti-seizure medication without seizure relapses. Several outcome predictors have been identified, but prognosis across the syndromes is more homogeneous than previously assumed. Overall, overlap in pathophysiology, seizure types, treatment responses and outcomes support the idea that GGEs are not separate nosological entities but represent a neurobiological continuum., (© 2021. Springer Nature Limited.)

Background and Purpose: The KCNQ2 gene encodes for the K v 7.2 subunit of non-inactivating potassium channels. KCNQ2-related diseases range from autosomal dominant neonatal self-limited epilepsy, often caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S-Lic) in a mouse model of self-limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated., Experimental Approach: Effects of S-Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2 +/- ) and Kcnq2 +/+ mice were investigated. ESL in vivo efficacy was investigated in the 6-Hz psychomotor seizure model in both Kcnq2 +/- and Kcnq2 +/+ mice., Key Results: S-Lic increased the amplitude and decreased the incidence of physiological sharp wave-ripples in a concentration-dependent manner and slightly decreased gamma oscillations frequency. 4-Aminopyridine-evoked seizure-like events were blocked at high S-Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2 +/+ and Kcnq2 +/- mice, although the EC 50 estimation implicated higher efficacy in Kcnq2 +/- animals. In vivo, Kcnq2 +/- mice had a lower seizure threshold than Kcnq2 +/+ mice. In both genotypes, ESL dose-dependently displayed protection against seizures., Conclusions and Implications: S-Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2 +/- mice is effectively targeted by S-Lic high concentrations, presumably by blocking diverse sodium channel subtypes., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Electroencephalography (EEG) significantly contributes to the neuroprognostication after resuscitation from cardiac arrest. Recent studies suggest that the prognostic value of EEG is highest for continuous recording within the first days after cardiac arrest. Early continuous EEG, however, is not available in all hospitals. In this observational study, we sought to evaluate the predictive value of a 'late' EEG recording 5-14 days after cardiac arrest without sedatives., Methods: We retrospectively analyzed EEG data in consecutive adult patients treated at the medical intensive care units (ICU) of the Charité-Universitätsmedizin Berlin. Outcome was assessed as cerebral performance category (CPC) at discharge from ICU, with an unfavorable outcome being defined as CPC 4 and 5., Results: In 187 patients, a 'late' EEG recording was performed. Of these patients, 127 were without continuous administration of sedative agents for at least 24 h before the EEG recording. In this patient group, a continuously suppressed background activity < 10 µV predicted an unfavorable outcome with a sensitivity of 31% (95% confidence interval (CI) 20-45) and a specificity of 99% (95% CI 91-100). In patients with suppressed background activity and generalized periodic discharges, sensitivity was 15% (95% CI 7-27) and specificity was 100% (95% CI 94-100). GPDs on unsuppressed background activity were associated with a sensitivity of 42% (95% CI 29-46) and a specificity of 92% (95% CI 82-97)., Conclusions: A 'late' EEG performed 5 to 14 days after resuscitation from cardiac arrest can aide in prognosticating functional outcome. A suppressed EEG background activity in this time period indicates poor outcome., (© 2021. The Author(s).)

Malformations of cortical development (MCD) represent a group of rare diseases with severe clinical presentation as epileptic and pharmacoresistant encephalopathies. Morphological studies in tissue from MCD patients have revealed reduced GABAergic efficacy and increased intracellular chloride concentration in neuronal cells as important pathophysiological mechanisms in MCD. Also, in various animal models, alterations of GABAergic inhibition have been postulated as a predominant factor contributing to perilesional hyperexcitability. Along with this line, the NKCC1 inhibitor bumetanide has been postulated as a potential drug for treatment of epilepsy, mediating its antiepileptic effect by reduction of the intracellular chloride and increased inhibitory efficacy of GABAergic transmission. In the present study, we focused on the focal freeze-lesion model of MCD to compare antiepileptic drugs with distinct mechanisms of action, including NKCC1 inhibition by bumetanide. For this purpose, we combined electrophysiological and optical methods in slice preparations and assessed the properties of seizure like events (SLE) induced by 4-aminopyridine. In freeze-lesioned but not control slices, SLE onset was confined to the perilesional area, confirming that this region is hyperexcitable and likely triggers pathological activity. Bumetanide selectively reduced epileptic activity in lesion-containing slices but not in slices from sham-treated control rats. Moreover, bumetanide caused a shift in the SLE onset site away from the perilesional area. In contrast, effects of other antiepileptic drugs including carbamazepine, lacosamide, acezatolamide and zonisamide occurred mostly independently of the lesion and did not result in a shift of the onset region. Our work adds evidence for the functional relevance of chloride homeostasis in the pathophysiology of microgyrus formation as represented in the focal freeze-lesion model. Further studies in different MCD models and human tissue will be required to validate the effects across different MCD subtypes and species and to assess the translational value of our findings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: In focal epilepsy, data on the etiology-specific response to antiseizure medication (ASM) are surprisingly sparse. In this study, we sought to reappraise whether seizure outcome of pharmacological treatment is linked to the underlying etiology. Furthermore, we assessed ASM load with respect to the cause of epilepsy., Methods: Data were retrospectively obtained from the electronic database of the three sites of an academic adult epilepsy outpatient clinic. For each patient, presumed cause of epilepsy was categorized into one of nine etiological groups. Individual drug loads were calculated according to the 2020 World Health Organization Center for Drug Statistics Methodology ATC/DDD Index. Univariate and multivariate analyses were conducted to explore the association between different etiologies and outcome regarding 12-month seizure freedom as well as ASM load., Results: A total of 591 patients with focal epilepsy were included in the final analysis. Ischemic stroke was the etiology with the highest rate of 12-month terminal seizure freedom (71.2%, 95% confidence interval [CI] = 57.9-82.2) and, considering all etiological groups, was an independent predictor of seizure freedom (odds ratio = 2.093, 95% CI = 1.039-4.216). The lowest rates of seizure freedom were observed in patients with hippocampal sclerosis (28.2%, 95% CI = 15.0-44.9) and malformation of cortical development (16.7%, 95% CI = 2.1-48.4). In patients with ischemic stroke, median ASM load (1.0, interquartile range [IQR] = .5-1.8) was significantly lower compared to that in patients with hippocampal sclerosis (median = 1.8, IQR = 1.2-3.0, p = .008) and brain tumors (median = 1.7, IQR = .7-3.2, p = .049)., Significance: Response to treatment with ASM is highly etiology-specific and best in patients with epilepsy due to ischemic stroke. Interestingly, this most favorable treatment outcome can be achieved by the lowest ASM load considering all etiological groups. In focal epilepsy, etiology should be taken into account when counseling patients about their expected seizure outcome with pharmacological treatment and when tailoring initial ASM doses., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objectives: In genetic generalized epilepsies (GGE), valproic acid (VPA) is the most efficacious compound. However, due to teratogenicity and increased risk for impaired cognitive development after intrauterine exposure, its use in women of fertile age is strictly regulated but sometimes unavoidable., Methods: All patients with GGE treated at the outpatient clinic of a tertiary epilepsy center with at least one visit between January 2015 and April 2020 were included in this retrospective study. The rate of women aged 18 to 49 years taking VPA was compared to that of men of the same age group and to women > 49 years. Furthermore, in each group, clinical variables associated with VPA use were sought., Results: Twenty-eight out of 125 women of fertile age (22%) were treated with VPA, compared to 28 out of 56 men ≤ 49 years (50%; p = .002) and to 22 out of 40 female patients > 49 years (55%; p < .001). VPA dose was lower in fertile women compared to men, with no difference in seizure freedom rates. In women ≤ 49 years, multivariate analysis demonstrated age as the only variable independently associated with VPA use (OR 1.095; 95% CI 1.036-1.159). In the other two groups, no associated variables were identified., Conclusions: Despite warnings with respect to teratogenicity and impaired cognitive development with VPA, from 2015 to 2020, almost every fourth women of fertile age with GGE received this compound. Inevitably lower VPA doses in these women seem sufficient for favorable seizure freedom rates., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Eslicarbazepine acetate (ESL) is a once-daily antiseizure medication (ASM) that is approved in Europe and the USA for the treatment of focal-onset seizures. The Euro-Esli study, which included over 2000 patients, investigated the real-world effectiveness, safety and tolerability of ESL when used in everyday clinical practice in Europe. This post-hoc analysis of Euro-Esli employed univariate and multivariate binary logistic regression analyses to investigate the relationship between demographic and baseline characteristics (including epilepsy- and treatment-related factors) and the likelihood of seizure freedom, response and retention in adult patients with focal seizures after 12 months of ESL treatment in the real-world setting. Multivariate analysis revealed that the factors associated with seizure freedom and response at 12 months (N = 1054) were generally those characterising patients who were relatively early in their disease course and/or less refractory to treatment, such as older age at onset of epilepsy, absence of seizures at baseline and lower number of concomitant ASMs at baseline. Although it was not possible to construct a multivariate model to predict retention on ESL treatment at 12 months, when the univariate regression model was adjusted for age and epilepsy duration, the factors found to be significantly associated with retention at 12 months (N = 1559) comprised shorter duration of epilepsy, absence of any seizures at baseline, lower baseline seizure frequency (<5 vs. ≥ 5 seizures/month), lower number of previous ASMs, lower number of concomitant ASMs, and the absence of concomitant use of lamotrigine at baseline. These findings therefore identify baseline characteristics that are predictive of the effectiveness of ESL treatment in clinical practice, which may help clinicians choose appropriate ASM therapy for patients., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: To describe incidence, risk factors, and treatment of poststroke epilepsy (PSE) in Germany based on claims data., Methods: Retrospective analysis of claims data from a German public sickness fund (AOK PLUS). Patients with acute stroke hospitalizations from January 01, 2011 and December 31, 2015 (index hospitalization) were followed for 12-72 months. Outcomes included incidence of PSE (patients with ≥2 seizure claims [during/after index hospitalization], or ≥1 seizure claim after index hospitalization), multivariate Cox-regression analyses of time to seizure claim and death after index stroke hospitalization discharge, and antiepileptic drug (AED) treatment., Results: Among 53 883 patients with stroke (mean follow-up of 829.05 days [median 749]), 6054 (11.24%) had ≥1 seizure claim (mean age 73.95 years, 54.18% female). 2130 (35.18%) patients had a seizure claim during index hospitalization (indicative of acute symptomatic seizures). Estimated incidence of PSE (cases/1000 patient-years) was 94.49 within 1 year. Risk of seizure claim following hospital discharge was higher in patients with hemorrhagic stroke (hazard ratio [HR] =1.13; p <.001) vs those with cerebral infarction. Seizure claim during index hospitalization was a risk factor for seizure claims after hospital discharge (HR =6.97; p <.001) and early death (HR =1.78; p <.001). In the first year of follow-up, AEDs were prescribed in 73.75% of patients with seizure claims., Conclusions: Incidence of PSE was in line with previous studies. Hemorrhagic stroke and seizure claim during index hospitalization were risk factors for seizure claims after hospital discharge. Most patients with seizure claims received AED treatment., (© 2021 UCB Pharma. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd-Verify.)