Optogenetic Determination of Dynamic and Cell-Type-Specific Inhibitory Reversal Potentials.

The reversal potential refers to the membrane potential at which the net current flow through a channel reverses direction. The reversal potential is determined by transmembrane ion gradients and, in turn, determines how the channel's activity will affect the membrane potential. Traditional investigation into the reversal potential of inhibitory ligand-gated ion channels (EInh) has relied upon the activation of endogenous receptors, such as the GABA-A receptor (GABAAR). There are, however, challenges associated with activating endogenous receptors, including agonist delivery, isolating channel responses, and the effects of receptor saturation and desensitization. Here, we demonstrate the utility of using a light-gated anion channel, stGtACR2, to probe EInh in the rodent brain. Using mice of both sexes, we demonstrate that the properties of this optically activated channel make it a suitable proxy for studying GABAAR receptor-mediated inhibition. We validate this agonist-independent optogenetic strategy in vitro and in vivo and further show how it can accurately capture differences in EInh dynamics following manipulations of endogenous ion fluxes. This allows us to explore distinct resting EInh differences across genetically defined neuronal subpopulations. Using this approach to challenge ion homeostasis mechanisms in neurons, we uncover cell-specific EInh dynamics that are supported by the differential expression of endogenous ion handling mechanisms. Our findings therefore establish an effective optical strategy for revealing novel aspects of inhibitory reversal potentials and thereby expand the repertoire of optogenetics.

Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE).

OBJECTIVE: New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. METHODS: Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. RESULTS: Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. SIGNIFICANCE: Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.

Efficacy and tolerability of Brivaracetam in people with intellectual disability compared to those without intellectual disability.

INTRODUCTION: In England, nearly a quarter of people with intellectual disability (PwID) have epilepsy. Though 70 % of PwID have pharmaco-resistant seizures only 10 % are prescribed anti-seizure medication (ASMs) licenced for pharmaco-resistance. Brivaracetam (BRV) licenced in 2016 has had nine post-marketing studies involving PwID. These studies are limited either by lack of controls or not looking at outcomes based on differing levels of ID severity. This study looks at evidence comparing effectiveness and side-effects in PwID to those without ID prescribed Brivaracetam (BRV). METHODS: Pooled case note data for patients prescribed BRV (2016-2022) at 12 UK NHS Trusts were analysed. Demographics, starting and maximum dose, side-effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed. RESULTS: 37 PwID (mild 17 M/P 20) were compared to 102 without ID. Mean start and maximum dose was lower for PwID than non-ID. Mean maximum dose reduced slightly with ID severity. No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in BRV's efficacy i.e. >50 % seizure reduction or tolerability. Mental and behavioural side-effects were more prevalent for PwID (27.0 % ID, 17.6 % no ID) but not significantly higher (P = 0.441) or associated with ID severity (p = 0.255). CONCLUSION: This is the first study on BRV, which compares ID cohorts with differing severity and non-ID. Efficacy, tolerability and side-effects reported are similar across differing ID severity to those with no ID.

Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Efficacy and tolerability of levetiracetam in people with and without intellectual disabilities: A naturalistic case control study.

INTRODUCTION: People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV. METHODS: Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed. RESULTS: 173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID. CONCLUSION: PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.

Prevalence of all epilepsies in urban informal settlements in Nairobi, Kenya: a two-stage population-based study.

BACKGROUND: WHO estimates that more than 50 million people worldwide have epilepsy and 80% of cases are in low-income and middle-income countries. Most studies in Africa have focused on active convulsive epilepsy in rural areas, but there are few data in urban settings. We aimed to estimate the prevalence and spatial distribution of all epilepsies in two urban informal settlements in Nairobi, Kenya. METHODS: We did a two-stage population-based cross-sectional study of residents in a demographic surveillance system covering two informal settlements in Nairobi, Kenya (Korogocho and Viwandani). Stage 1 screened all household members using a validated epilepsy screening questionnaire to detect possible cases. In stage 2, those identified with possible seizures and a proportion of those screening negative were invited to local clinics for clinical and neurological assessments by a neurologist. Seizures were classified following the International League Against Epilepsy recommendations. We adjusted for attrition between the two stages using multiple imputations and for sensitivity by dividing estimates by the sensitivity value of the screening tool. Complementary log-log regression was used to assess prevalence differences by participant socio-demographics. FINDINGS: A total of 56 425 individuals were screened during stage 1 (between Sept 17 and Dec 23, 2021) during which 1126 were classified as potential epilepsy cases. A total of 873 were assessed by a neurologist in stage 2 (between April 12 and Aug 6, 2022) during which 528 were confirmed as epilepsy cases. 253 potential cases were not assessed by a neurologist due to attrition. 30 179 (53·5%) of the 56 425 individuals were male and 26 246 (46·5%) were female. The median age was 24 years (IQR 11-35). Attrition-adjusted and sensitivity-adjusted prevalence for all types of epilepsy was 11·9 cases per 1000 people (95% CI 11·0-12·8), convulsive epilepsy was 8·7 cases per 1000 people (8·0-9·6), and non-convulsive epilepsy was 3·2 cases per 1000 people (2·7-3·7). Overall prevalence was highest among separated or divorced individuals at 20·3 cases per 1000 people (95% CI 15·9-24·7), unemployed people at 18·8 cases per 1000 people (16·2-21·4), those with no formal education at 18·5 cases per 1000 people (16·3-20·7), and adolescents aged 13-18 years at 15·2 cases per 1000 people (12·0-18·5). The epilepsy diagnostic gap was 80%. INTERPRETATION: Epilepsy is common in urban informal settlements of Nairobi, with large diagnostic gaps. Targeted interventions are needed to increase early epilepsy detection, particularly among vulnerable groups, to enable prompt treatment and prevention of adverse social consequences. FUNDING: National Institute for Health Research using Official Development Assistance.

Multimodal wearable EEG, EMG and accelerometry measurements improve the accuracy of tonic-clonic seizure detection.

Objective. This paper aims to investigate the possibility of detecting tonic-clonic seizures (TCSs) with behind-the-ear, two-channel wearable electroencephalography (EEG), and to evaluate its added value to non-EEG modalities in TCS detection.Methods. We included 27 participants with a total of 44 TCSs from the European multicenter study SeizeIT2. The wearable Sensor Dot (Byteflies) was used to measure behind-the-ear EEG, electromyography (EMG), electrocardiography, accelerometry (ACC) and gyroscope. We evaluated automatic unimodal detection of TCSs, using sensitivity, precision, false positive rate (FPR) and F1-score. Subsequently, we fused the different modalities and again assessed performance. Algorithm-labeled segments were then provided to two experts, who annotated true positive TCSs, and discarded false positives.Results. Wearable EEG outperformed the other single modalities with a sensitivity of 100% and a FPR of 10.3/24 h. The combination of wearable EEG and EMG proved most clinically useful, delivering a sensitivity of 97.7%, an FPR of 0.4/24 h, a precision of 43%, and an F1-score of 59.7%. The highest overall performance was achieved through the fusion of wearable EEG, EMG, and ACC, yielding a sensitivity of 90.9%, an FPR of 0.1/24 h, a precision of 75.5%, and an F1-score of 82.5%.Conclusions. In TCS detection with a wearable device, combining EEG with EMG, ACC or both resulted in a remarkable reduction of FPR, while retaining a high sensitivity.Significance. Adding wearable EEG could further improve TCS detection, relative to extracerebral-based systems.

Reflex cardioinhibitory syncope potentially related to SARS-CoV-2 infection: a case report / Síncope cardioinibitória reflexa potencialmente relacionada à infecção por SARS-CoV-2: um relato de caso

Autonomic dysfunction related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is increasingly described in the literature. We report the case of a 30-year-old male with a background of asthma and migraine who experienced a second episode of SARS-CoV-2 infection characterized by mild respiratory symptoms. Twenty-four days after the symptom onset, he developed acute syncope. A tilt test revealed a neuromediated cardioinhibitory response with asystole (Vasovagal Syncope International Study ­ VASIS type 2B). The temporal association between SARS-CoV-2 infection and syncope seems to indicate a probable causal relationship, which requires corroboration by future studies.

Disfunção autonômica relacionada à infecção por coronavírus-2 da síndrome respiratória aguda grave (SARS-CoV-2) vem sendo cada vez mais descrita na literatura. Relatamos o caso de um homem de 30 anos de idade, com histórico de asma e enxaqueca, que apresentou um segundo episódio de infecção por SARS-CoV-2 caracterizado por sintomas respiratórios leves. Vinte e quatro dias após o início dos sintomas, desenvolveu um quadro agudo de síncope. Um teste de inclinação revelou uma resposta cardioinibitória neuromediada com assistolia (Vasovagal Syncope International Study ­ VASIS tipo 2B). A associação temporal entre infecção por SARS-CoV-2 e síncope parece indicar uma provável relação causal, a qual requer corroboração por estudos futuros.