Unexplained Death In Epilepsy Research Articles

Knockout of DEPDC5, the gene associated with drug-resistant focal temporal epilepsy, causes abnormal Ca2+-waves in human iPS cell-induced neurons

Genetic variants in the DEP domain containing 5 (DEPDC5) are one of the most common causes of inheritable drug-resistant temporal focal epilepsy. Epilepsies caused by DEPDC5 variants are often associated with brain malformations and sudden unexplained death in epilepsy (SUDEP). It has been reported that the DEPDC5 genes regulates cell growth via rapamycin complex 1 (mTORC1) pathways. Though several animal models showed knockout of the DEPDC5 causes epilepsy, the underlying mechanism(s) by which DEPDC5 variants cause neuronal excitations remains unelucidated in human cells. To examine whether knockout of DEPDC5 causes abnormal excitations in human iPS cell (iPSC)-induced neurons, DEPDC5 was knocked out using CRISPR-Cas9 gene editing methods. Expression of DEPDC5 peptides was confirmed by a mass spectroscopy. Then, the cells were differentiated into neurons by Dual Smad Inhibition. Spontaneous cellular excitation was evaluated by Ca2+-imaging (AquaCosmos/Ratio imaging system, Hamamatsu Photonics). DNA sequencing of the DEPDC5-knockout cells showed a truncated change, c.251_258delCTTTGGGG:(p.Gly15Glyfs*5), in one allele. The DEPDC5 peptides encoded by exon 7 were decreased to less than half in the DEPDC5-knockout cells compared to the wild type (WT) cells. Ca2+-imaging showed abnormal Ca2+ bursts in neurons derived from the DEPDC5-knockout cells, while the WT cells did not show any abnormal Ca2+ waves. These results indicate that haploinsuffciency of DEPDC5 can cause abnormal excitation in human iPSC-induced neurons. Currently, we are planning to further investigate cellular excitations in iPSC-induced cardiomyocytes to dissect underlying mechanisms of SUDEP. This work was supported in part by a Grant-in-Aid for Scientific Research (C) [grant number 18K08900 and 21K08135 (to T.A.)] and a Grant-in-Aid for Young Scientists [grant number 22K15694 (to Y.H.)] from the Japan Society for the Promotion of Science. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Delays in the diagnosis and surgical treatment of drug-resistant epilepsy: A cohort study.

Delay in referral for epilepsy surgery of patients with drug-resistant epilepsy (DRE) is associated with decreased quality of life, worse surgical outcomes, and increased risk of sudden unexplained death in epilepsy (SUDEP). Understanding the potential causes of delays in referral and treatment is crucial for optimizing the referral and treatment process. We evaluated the treatment intervals, demographics, and clinical characteristics of patients referred for surgical evaluation at our level 4 epilepsy center in the U.S. Intermountain West. We retrospectively reviewed the records of patients who underwent surgery for DRE between 2012 and 2022. Data collected included patient demographics, DRE diagnosis date, clinical characteristics, insurance status, distance from epilepsy center, date of surgical evaluation, surgical procedure, and intervals between different stages of evaluation. Within our cohort of 185 patients with epilepsy (99 female, 53.5%), the mean ± standard deviation (SD) age at surgery was 38.4 ± 11.9 years. In this cohort, 95.7% of patients had received definitive epilepsy surgery (most frequently neuromodulation procedures) and 4.3% had participated in phase 2 intracranial monitoring but had not yet received definitive surgery. The median (1st-3rd quartile) intervals observed were 10.1 (3.8-21.5) years from epilepsy diagnosis to DRE diagnosis, 16.7 (6.5-28.4) years from epilepsy diagnosis to surgery, and 1.4 (0.6-4.0) years from DRE diagnosis to surgery. We observed significantly shorter median times from epilepsy diagnosis to DRE diagnosis (p < .01) and epilepsy diagnosis to surgery (p < .05) in patients who traveled further for treatment. Patients with public health insurance had a significantly longer time from DRE diagnosis to surgery (p < .001). Both shorter distance traveled to our epilepsy center and public health insurance were predictive of delays in diagnosis and treatment intervals. Timely referral of patients with DRE to specialized epilepsy centers for surgery evaluation is crucial, and identifying key factors that may delay referral is paramount to optimizing surgical outcomes.

Scientists Identify Potential Mechanism for Sudden Unexplained Death in Epilepsy

Scientists Identify Potential Mechanism for Sudden Unexplained Death in Epilepsy

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis.

Patients with epilepsy frequently experience autonomic dysfunction, closely related to sudden unexplained death in epilepsy (SUDEP). SUDEP occurs most often at night or during sleep, and frequent nocturnal seizures are an established risk factor. This study investigated the influence of nocturnal seizures on autonomic dysfunction in epilepsy. This retrospective study enrolled frontal lobe epilepsy (FLE) patients who performed 24-hour EEG monitoring. All participants were divided into nocturnal FLE (NFLE, > 90% of seizures occurring during sleep) or diurnal FLE (DFLE) groups. EEG and ECG signals were simultaneously obtained during waking and sleep stages. EEG current density source and connectivity analysis of the autonomic network were performed. ECG was analyzed across time and frequency domains heart rate variability (HRV) analysis method was used. The obtained parameters were compared between the NFLE and DFLE groups. Fifteen NFLE and 16 DFLE patients were enrolled with no significant difference in age, sex, disease duration, seizure frequency, or the number of anti-seizure medications between the two groups. During sleep, a decrease in HRV parameters and an increase of the beta-1 (13-22 Hz) current source density power in the bilateral paracentral lobule (BA4,5,6), precuneus (BA7), and cingulate (BA31) were observed in the NFLE group compared to DFLE group. The NFLE group also showed hyperconnectivity in the central autonomic (12 edges distributed over 10 nodes), sympathetic (2 edges distributed over 3 nodes), and parasympathetic (4 edges distributed over 6 nodes) beta-1 frequency band networks during sleep. During wakefulness, central and cardiac autonomic variables were not significantly different between the NFLE and DFLE groups. Interictal cardiac and central autonomic dysfunction occurred simultaneously and can be attributed to the brain-heart autonomic axis. Our findings suggest that nocturnal seizures may contribute to interictal autonomic dysfunction during sleep in people with epilepsy.

A novel marker to predict cardiac arrhythmia in epilepsy patients: frontal QRS-T angle.

The most important complication of epilepsy, which is a chronic disorder of the central nervous system, is sudden unexplained death in epilepsy (SUDEP). The causes of SUDEP are complex and multifactorial. Epilepsy patients are at increased risk of cardiovascular events, SUDEP, and ventricular arrhythmias, due to both the disease itself and the effect of antiseizure medications. Previous studies have commonly focused on cardiac repolarization markers in epilepsy patients. This study aimed to investigate frontal QRS-T angle (FTQ angle), a relatively new repolarization parameter, in epilepsy patients. One hundred two epilepsy patients and 86 healthy volunteers as a control group were included in the study. The clinical data of all patients were prospectively recorded during patient visits. All participants underwent 12-lead surface electrocardiography (ECG). SPSS 22 was used to evaluate all data. p<0.05 was considered statistically significant. When the epilepsy patient group and the control group were compared in terms of QRS (89.59±43.63 vs. 80.00±9.82, p=0.050), QT (364.30±36.16 vs. 335.95±35.64, p<0.001), QTc (418.85±27.06 vs. 409.37±26.66, p=0.018) durations, and FTQ angle (46.55±22.06 vs. 20.84±12.70, p<0.001), statistically significant differences were found between the groups. We observed that FTQ angle was significantly higher in individuals exposed to the disease for more than 10 years (39.2±19.0 vs. 54.7±22.5, p<0.001). In addition, according to the multivariate logistic regression analysis, disease duration was an independent predictor of FTQ angle (β=0.263, p=0.009). FTQ angle, a relatively new repolarization parameter, can be used as an inexpensive, easy, reproducible, and reliable ECG marker to predict the risk of adverse cardiac events in epilepsy patients.

Novel GATOR1 variants in focal epilepsy

IntroductionVariants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers. Patients and MethodsNinety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology. ResultsFour previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance. ConclusionGATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.

Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.

The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management. In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes SCN1A, SCN2A, SCN8A, SYNGAP1, NEXMIF, CHD2, PCDH19, STXBP1, GRIN2A, KCNT1, and KCNQ2 and with Angelman syndrome (AS). The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with SCN1A-associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet SCN1A-DEEs. CSE was also notable in patients with pathogenic variants in KCNT1 (6/10; 60%; 95% CI 26-88) and SCN2A (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet SCN1A-DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with CHD2-DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: SCN1A, SCN2A, SCN8A, and STXBP1. The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3). We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.

Adherence patterns in antiseizure medications influencing risk of sudden unexplained death in epilepsy: A data linkage study using dispensed prescriptions.

Medication adherence is considered an important risk factor for sudden unexpected death in epilepsy (SUDEP), although measurement accuracy is difficult. Using prescription dispensations, this study aims to estimate antiseizure medication (ASM) adherence and identify adherence patterns that influence epilepsy mortality. This is a retrospective cohort study of tertiary epilepsy outpatients seen at St Vincent's Hospital Melbourne, Victoria, Australia, from January 1, 2012 until December 31, 2017. Privacy-preserving data linkage with the Australian national prescription, death, and coroner's databases was performed. We fitted a four-cluster longitudinal group-based trajectory model for ASM adherence from recurring 90-day windows of prescription dispensations during a 3-year "landmark period" from January 1, 2012 to December 31, 2014, using the AdhereR package. We estimated the risk of SUDEP and all-cause death for each adherence pattern during an "observation period" from January 1, 2015 to December 31, 2017. The Cox proportional hazards and logistic regression models were adjusted for age, sex, socioeconomic status, epilepsy duration, comorbidity, drug resistance, and inadequate seizure control. One thousand one hundred eighty-seven participants were observed for a median of 3.2 years (interquartile range=2.4-4.0 years). We observed 66 deaths with 10 SUDEP cases during the observation period. We identified four patterns of ASM adherence: good, 51%; declining, 24%; poor, 16%; and very poor, 9%. Declining adherence was associated with an increased risk for SUDEP, with hazard ratio (HR) = 8.43 (95% confidence interval [CI] = 1.10-64.45) at 1year and HR=9.17 (95% CI=1.16-72.21) at 3 years. Compared to no ASM therapeutic change, the addition of a second to fourth ASM offered increased protection against SUDEP in patients with continuing drug-resistant epilepsy. ASM nonadherence was observed in half of outpatients with epilepsy. A declining pattern of adherence, observed in a quarter of patients, was associated with more than eight times increased risk of SUDEP. Any ongoing medication interventions must include strategies to maintain and improve ASM adherence if we are to reduce the risk of SUDEP.

Synapsin 2 regulates NCX1 trafficking and is down-regulated in the failing myocardium, which increases the risk of ventricular arrhythmia and heart failure mortality

Abstract Background Synapsin 2 (Syn2) modulates vesicle transport in the post-synaptic terminal in the brain, and has been linked to sudden unexplained death in epilepsy, but has never previously been studied in the myocardium. Purpose Given the association of vesicle transport in the brain and the heart, and the similarity of sudden death in epilepsy and cardiac arrhythmias, we have studied the role of Syn2 in the heart. Methods We explored left ventricular (LV) Syn2 levels in various experimental heart failure (HF) models and assessed mortality in Syn2 knock out (KO) mice vs. wild type (WT) littermates after pressure-overload induced by aortic banding. We used confocal imaging and virus transduction to characterize Syn2 localization and co-localization with NCX and Rab proteins. We verified Syn2-NCX interaction by immunoprecipitation, mass spectrometry, and surface resonance experiments. We investigated calcium handling in isolated cardiomyocytes. Susceptibility for ventricular arrhythmias was also tested in Langendorff-perfused hearts. Results We found Syn2, but not synapsin 1, to be expressed in the myocardium. LV Syn2 levels were markedly downregulated in the failing myocardium after experimental myocardial infarction or aortic banding. Syn2 KO mice had increased mortality compared to WT littermates following aortic banding, but demonstrated no clear clinical or echocardiographic phenotype, except reduced fractional shortening. Given no clear etiology for increased mortality, we next explored the association between Syn2 and ion-channel vesicle transport, calcium handling and ventricular arrhythmias. By confocal imaging and viral transduction, we found Syn2 to localize in vesicles in HL-1 cells, where Syn2 co-localized with Rab2, Rab3, Rab7 and NCX1. Syn2 was also found to interact with NCX1 as tested by immunoprecipitation, mass spectrometry, and surface resonance experiments. NCX1 levels were downregulated in the membrane fraction in the left ventricle of Syn2 KO mice compared to WT littermates following aortic banding. We observed increased frequency of calcium sparks and waves in isolated Syn2 KO cardiomyocytes compared to controls. We found enhanced susceptibility of Syn2 KO mice for ventricular arrhythmias compared to WT littermates mice during ISO stress testing in explanted hearts. Hearts from Syn2 KO mice also demonstrated more severe ventricular arrhythmias compared to hearts from WT littermates controls. Conclusions We report for the first time that Syn2 is expressed in the myocardium and that Syn2 seems to regulate NCX1 transport and localization. We also found markedly reduced LV Syn2 levels in HF individuals and mice that lacked Syn2 more frequent displayed severe ventricular arrhythmias and had increased mortality. Hence, our data suggest that reduced Syn2 in the failing myocardium may lead to increased mortality, possibly linked to altered NCX trafficking and subsequent ventricular arrhythmias. Funding Acknowledgement Type of funding sources: None.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Neurostimulation as a Method of Treatment and a Preventive Measure in Canine Drug-Resistant Epilepsy: Current State and Future Prospects.

Modulation of neuronal activity for seizure control using various methods of neurostimulation is a rapidly developing field in epileptology, especially in treatment of refractory epilepsy. Promising results in human clinical practice, such as diminished seizure burden, reduced incidence of sudden unexplained death in epilepsy, and improved quality of life has brought neurostimulation into the focus of veterinary medicine as a therapeutic option. This article provides a comprehensive review of available neurostimulation methods for seizure management in drug-resistant epilepsy in canine patients. Recent progress in non-invasive modalities, such as repetitive transcranial magnetic stimulation and transcutaneous vagus nerve stimulation is highlighted. We further discuss potential future advances and their plausible application as means for preventing epileptogenesis in dogs.

Sudden Unexpected Death in Epilepsy: A Report of Three Commonly Encountered Anatomic Findings in the Forensic Setting With Recommendations for Best Practices.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in children and young adults with epilepsy with epileptic patients harboring a 27 times increased risk of death from SUDEP. Structural brain lesions are encountered in up to 50% of autopsy cases. In this case series, we report 3 previously undiagnosed structural causes of SUDEP discovered at autopsy at our institution including schizencephaly, ganglioglioma, and focal cortical dysplasia. Our major recommendation is in cases with suspected SUDEP, formal neuropathological examination and tissue sampling should be employed to identify and characterize specific potential anatomic etiologies.

QT prolongation in patients with index evaluation for seizure or epilepsy is predictive of all-cause mortality.

Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy. The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures. We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period. Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59). Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

Nationwide study of sudden cardiac death among children and young adults in Iceland

Abstract Introduction Sudden cardiac death (SCD) in children and young adults is a devastating event. Ischemic heart disease is the predominant cause of sudden cardiac death in older persons. Whereas among persons 1–35 years of age, SCD is more often caused by structural heart disease or purely arrhythmogenic causes. In studies on SCD in the young up to 40% of all autopsies show no cardiac abnormalities. Which raises suspicion of underlying arrhythmogenic causes. Many of these arrhythmogenic causes of SCD have an underlying genetic basis and are inherited. Purpose In Iceland, the true impact of SCD in children and young adults is unknown. The aim of this investigation is to study the incidence and causes of SCD in persons aged 1–35 years in nationwide settings. Methods This is a nationwide retrospective population-based study in Iceland. All deaths in persons aged 12–35 years in 1974–2015 and all deaths in persons aged 1–12 years 2005–2015 were included. Death certificates, autopsy reports and medical records were reviewed to confirm SCD. Medical records were also reviewed for medical history and circumstances of death. Individuals that were resuscitated after cardiac arrest but died later in hospitals were included. Individuals that fulfilled the criteria of SUDEP (sudden unexpected death in epilepsy) were excluded from the study. Results We found 73 (68% male) cases of SCD, of which 64 (88%) were autopsied. The most common find in autopsy was structurally normal heart (16%), myocarditis (16%), hypertrophic cardiomyopathy (16%) and ischemic heart disease (16%). Death occurred during daily activities in 36% of cases, sleep in 27% cases and physical activities in 19% of cases. Incidence rate was 1.4 per 100.000 in 1–35 years old in the years 2005–2015 and 1.6 per 100.000 for 12–35 years old in the years 1974–2015. Conclusion Incidence of SCD in the young in Iceland is similar as for other nations. Post-mortem diagnoses are often difficult to establish. Because of the possibility of unrecognized underlying inherited cardiac disorder it is important to consider genetic analysis as a part of the post-mortem examination. Majority of SCD in the young occurred related to normal daily activities or during sleep or at rest. This raises many questions about the connections between any underlying cause of SCD and behaviour. It is important to discuss and study further the connection between sudden unexplained death in epilepsy (SUDEP) and SCD. SUDEP is most often unwitnessed events with cases found deceased in bed. SUDEP is characterized by an absence of any identifiable cause of death post-mortem, which can suggest underlying arrhythmogenic cause. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Generalized tonic-clonic seizures are accompanied by changes of interrelations within the autonomic nervous system

PurposeA seizure is a strong central stimulus that affects multiple subsystems of the autonomic nervous system (ANS), and results in different interactions across ANS modalities. Here, we aimed to evaluate whether multimodal peripheral ANS measures demonstrate interactions before and after seizures as compared to controls to provide the basis for seizure detection and forecasting based on peripheral ANS signals. MethodsContinuous electrodermal activity (EDA), heart rate (HR), peripheral body temperature (TEMP), and respiratory rate (RR) calculated based on blood volume pulse were acquired by a wireless multi-sensor device. We selected 45 min of preictal and 60 min of postictal data and time-matched segments for controls. Data were analyzed over 15-min windows. For unimodal analysis, mean values over each time window were calculated for all modalities and analyzed by Friedman’s two-way analysis of variance. ResultsTwenty-one children with recorded generalized tonic-clonic seizures (GTCS), and 21 age- and gender-matched controls were included. Unimodal results revealed no significant effect for RR and TEMP, but EDA (p = 0.002) and HR (p < 0.001) were elevated 0–15 min after seizures. The averaged bimodal correlation across all pairs of modalities changed for 15-min windows in patients with seizures. The highest correlations were observed immediately before (0.85) and the lowest correlation immediately after seizures. Overall, average correlations for controls were higher. SignificanceMultimodal ANS changes related to GTCS occur within and across autonomic nervous system modalities. While unimodal changes were most prominent during postictal segments, bimodal correlations increased before seizures and decreased postictally. This offers a promising avenue for further research on seizure detection, and potentially risk assessment for seizure recurrence and sudden unexplained death in epilepsy.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice.

ObjectiveDravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a +/−) recapitulates several core phenotypes, including temperature‐dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a +/− mice exhibit a similar clinical response to standard anticonvulsants. Cholesterol 24‐hydroxlase (CH24H) is a brain‐specific enzyme responsible for cholesterol catabolism. Recent research has indicated the therapeutic potential of CH24H inhibition for diseases associated with neural excitation, including seizures.MethodsIn this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a +/− mice to investigate its ability to improve Dravet‐like phenotypes in this preclinical model.ResultsSoticlestat treatment reduced seizure burden, protected against hyperthermia‐induced seizures, and completely prevented SUDEP in Scn1a +/− mice. Video–electroencephalography (EEG) analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures.SignificanceThis study demonstrates that soticlestat‐mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Editors' Note: Temporal Trends and Autopsy Findings of SUDEP Based on Medicolegal Investigations in the United States

In “Temporal Trends and Autopsy Findings of SUDEP Based on Medicolegal Investigations in the United States,” Cihan et al. reviewed medical examiner reports in 3 cities in the United States and found that although there was no correlation between sudden unexplained death in epilepsy (SUDEP) and diurnal patterns or time of year, there was a reduction in the incidence of SUDEP between 2009 and 2016. There was also no difference in autopsy findings between SUDEP- and non–SUDEP-related deaths associated with epilepsy. Bleasel was encouraged by these findings, which he attributed to increased awareness of SUDEP, access to affordable medical care, and prescribing antiseizure medications. However, he emphasized the importance of continued patient and family education about the risk of SUDEP, medication compliance, and treatment of comorbidities. He also noted that other studies have shown respiratory center neuronal cellular abnormalities in patients with SUDEP. Friedman et al. agreed that this positive trend is encouraging, but that it does not obviate the need to 1) counsel patients and families about SUDEP as part of general epilepsy care or 2) continue to pursue research to explain this reduction and minimize the risk of SUDEP as much as possible. In “Temporal Trends and Autopsy Findings of SUDEP Based on Medicolegal Investigations in the United States,” Cihan et al. reviewed medical examiner reports in 3 cities in the United States and found that although there was no correlation between sudden unexplained death in epilepsy (SUDEP) and diurnal patterns or time of year, there was a reduction in the incidence of SUDEP between 2009 and 2016. There was also no difference in autopsy findings between SUDEP- and non–SUDEP-related deaths associated with epilepsy. Bleasel was encouraged by these findings, which he attributed to increased awareness of SUDEP, access to affordable medical care, and prescribing antiseizure medications. However, he emphasized the importance of continued patient and family education about the risk of SUDEP, medication compliance, and treatment of comorbidities. He also noted that other studies have shown respiratory center neuronal cellular abnormalities in patients with SUDEP. Friedman et al. agreed that this positive trend is encouraging, but that it does not obviate the need to 1) counsel patients and families about SUDEP as part of general epilepsy care or 2) continue to pursue research to explain this reduction and minimize the risk of SUDEP as much as possible.

Definite SUDEP population in Bexar County, Texas: A 36-year data registry

ObjectiveSudden unexplained death in epilepsy (SUDEP) is one of the leading causes of mortality in epilepsy. In this study, cases of definite SUDEP are reported for Bexar County from a 36-year period. MethodsDeath reports by Bexar County Medical Examiner (BCME) from 1983 to 2018 were reviewed to identify cases with definite SUDEP. The findings were based upon investigators’ reports, which included medical history, medication list, sleep position, time of death, and pathology reports. In addition to these potential risk factors, body mass indices (BMI), as well as heart, lung, and brain weights were compared between SUDEP victims with therapeutic vs subtherapeutic anti-seizure medication (ASM) levels. ResultsDefinite SUDEP was identified in 286 cases. The incidence of definite SUDEP was 0.51 ± 0.26/1000 person-years among PWE and 0.56 ± 0.29 per 100,000 person-years among the general population in Bexar County. The median age was 37 years old (interquartile range 27–48), and the majority were male (65%). While 171 (60%) people were prescribed at least one ASM, ASM levels were subtherapeutic in 239 cases (83.6%). Risk factors for SUDEP did not differ between SUDEP victims with therapeutic vs subtherapeutic ASM levels. While BMIs were only slightly increased in adherent vs nonadherent SUDEP victims, they were significantly associated with subtherapeutic ASM levels. Abnormal lung, heart, and brain weights were reported in 48 (16.8%), 67 (23.4%), and 43 (15.0%) SUDEP cases, respectively. SignificanceThis study is one of the largest autopsy-based registries of definite SUDEP. Subtherapeutic ASM levels measured in post-mortem blood samples suggest that nonadherence to ASM therapy was a leading risk factor for SUDEP. As BMI was elevated in this cohort, and obesity was significantly associated with subtherapeutic ASM levels, it may also be a risk factor for SUDEP. Case-controlled studies are needed to validate the specific role of obesity and related comorbidities in this population.

797 Obstructive Sleep Apnea is a Risk Factor for Sudden Unexplained Death in Epilepsy (SUDEP)

Abstract Introduction Epilepsy is associated with a substantial risk of morbidity and mortality, including sudden unexplained death in epilepsy (SUDEP). Prior data demonstrated a possible association between obstructive sleep apnea (OSA) based on nocturnal oximetry oxyhemoglobin saturation index (ODI) and risk of SUDEP. We aimed to evaluate the relationship between PSG-defined OSA and SUDEP risk using the revised SUDEP Risk Inventory (rSUDEP-7). Methods We identified adults with epilepsy who underwent PSG between January 2004 and December 2016 at Cleveland Clinic. OSA was defined as an apnea-hypopnea index (AHI) ≥5 and moderate-to-severe OSA as an AHI ≥ 15. SUDEP risk was determined by the rSUDEP-7. The higher the rSUDEP-7 score, the greater the risk for SUDEP. Associations between rSUDEP-7 score and OSA groups (AHI&amp;gt;15 vs. &amp;lt;15) used Wilcoxon rank sum tests, and multivariable linear models adjusting for age, sex, BMI, and smoking status. Spearman correlations measured relationships between rSUDEP-7 score with AHI and ODI. Results 214 patients were identified; 134 (62.6%) had OSA, moderate-to-severe in 75 (35%). Those with AHI≥15 were older and more likely to have: pharmacoresistant epilepsy, nocturnal seizures, higher BMI, and longer epilepsy duration (all p&amp;lt;0.05). Median rSUDEP-7 score was 1(0,3), and &amp;gt; 35% had rSUDEP-7 score of &amp;gt; 3. Patients with moderate-to-severe OSA had higher rSUDEP-7 than those with AHI&amp;lt;15 (p=0.001). Higher AHI and ODI positively correlated with rSUDEP-7 (p=0.002 and p=0.016) while SpO2 nadir negatively correlated with rSUDEP-7 (p=0.007). After adjustment, those with AHI≥15 had mean rSUDEP-7 score 1.14 points (95%CI 0.55–1.72, p&amp;lt;0.001) higher than those with AHI&amp;lt;15. Conclusion Epilepsy patients with moderate-to-severe OSA, have higher risk of SUDEP based on the rSUDEP-7. Our findings provide further support for routine screening of OSA in epilepsy populations. Support (if any):

802 Seizure-Associated Central Respiratory Events: What’s Sleep Go To Do With It?

Abstract Introduction Seizure-related respiratory dysfunction has been reported in patients with epilepsy(PWE) on scalp EEG. We assessed this in Stereo-EEG(SEEG) recordings in patients with pharmacoresistant focal epilepsy. Methods PWE undergoing SEEG wore temperature/pressure-based airflow,RIP belts, SpO2, and EtCO2/TcpCO2. Interpretable recordings required SpO2 and at least one airflow and effort channel. Respiratory events including apneas, hypopneas(3%) and central pauses (5 to&amp;lt;10sec). Respiratory events, respiratory rate(RR), SpO2 nadir, total desaturation time, Peak EtCO2/TcpCO2, and hypercapnia duration were analyzed surrounding seizures. Frequency and duration of central events were compared in sleep-onset and awake seizures. Linear mixed-effects models evaluated relationships between respiratory variables and the frequency and duration of central events associated with seizures and compared respiratory variables between seizures with and without events. Results 44 seizures were recorded in 23 patients. Seizures were focal-onset in 79.5%(n=35), GTC in 20.5%(9). Respiratory events accompanied 61.4%(27) of the seizures with median duration/seizure duration of 0.40(IQR: 0.27, 0.61). Of the 47 respiratory events, 42 were central events, and 66.6%(28) were central apneas. Respiratory events occurred during the seizure in 73.8%, postictal in 26.2%; median SpO2 nadir was 90%(77.0, 93.0), total desaturation duration 104.3(50.3, 195.0)sec, peak TcpCO2 41.3(38.7, 44.8) mmHg, hypercapnia duration 157.6(51.0, 367.9) sec, and ictal-postictal RR change 3.3 ± 4.0bpm. For every 1 sec duration increase in central event duration, there was a significant increase in peak TcpCO2 0.35(95%CI [0.09,0.62],p=0.015) and TcpCO2 change 0.25(95%CI [0.02,0.49],p=0.037). Presence of central events were associated with increased peak TcpCO2(9.82[3.77,15.9], p=0.006). Seizures with central events trended greater changes in RR, SpO2, and EtCO2/TcpCO2, desaturation and hypercapnia time, with negative changes in SpO2 nadir. No significant difference on central event frequency was found between sleep-onset and awake seizures. Conclusion Central events including apneas and pauses are common in focal seizures arising from sleep and wake and are associated with hypercapnia. In addition to the significant association between TcpCO2 and the frequency and duration of central events, there is a positive trend of association of other respiratory dysfunction parameters. These findings suggest that central events may lead to a cascade of respiratory disturbance that may participate in the pathophysiology of sudden unexplained death in epilepsy. Support (if any):