Mortality and Sudden death risk in middle-aged persons with epilepsy — a UK Biobank study

Background Sudden death is the leading cause of mortality in medically refractory cases of epilepsy. Younger persons with epilepsy (PWE), particularly those <40 years, have higher all-cause mortality than those without. However, data are conflicting about mortality and burden of cardiovascular disease (CVD) in middle-aged PWE. Objective Determine all-cause and sudden death-specific mortality and burden of CVD in PWE in a middle-aged population. Methods Using UK Biobank, we identified 7,786 (1.6%) participants with a diagnosis of epilepsy; 566 individuals with prior history of stroke were excluded. The 7,220 PWE comprised the study cohort with the remaining 494,676 without epilepsy as the comparator group. PWE were identified based on clinical diagnostic code (validated) or self-reported diagnosis at assessment centre interview. Prevalence of CVD was determined using validated diagnostic codes. Cox proportional hazards regression were used to assess all-cause mortality and sudden death risk, in PWE vs those without epilepsy. Results Hypertension, coronary artery disease, heart failure, valvular heart disease, and congenital heart disease were all more prevalent in PWE. Arrhythmias including atrial fibrillation/flutter (12.2% vs 6.9%; p<0.01), bradyarrhythmias (7.7% vs 3.5%; p<0.01), conduction defects (6.1% vs 2.6%; p<0.01), and ventricular arrhythmias (2.3% vs 1.0%; p<0.01), as well as cardiac implantable electric devices (4.6% vs 2.0%; p<0.01) were all more common in PWE compared to comparator group. PWE had higher all-cause mortality (HR 3.9 [95% CI, 3.01-3.39]), higher sudden death-specific mortality (HR 6.65 [95% CI, 4.53-9.77]) both adjusted for age, sex and comorbidities; and were almost 2 years younger at death [68.1 vs 69.8; p<0.001]. Conclusions PWE have markedly higher burden of CVD including arrhythmias and heart failure. Middle-aged PWE have increased all-cause and sudden death specific mortality and higher burden of CVD. While efforts have focused on SUDEP in the young, further work is required to elucidate mechanisms underlying all-cause mortality and sudden death risk in PWE of middle age, to identify prognostic biomarkers and develop preventative therapies in PWE. Keywords : Sudden Death, Epilepsy, Cardiovascular disease, UK Biobank, Epidemiology What is new? What are the clinical implications? ### Competing Interest Statement VK Somers has served as a consultant for Respicardia, Bayer, Baker Tilly, Sleep Number and Jazz Pharmaceuticals, and is a member of the Sleep Number Scientific Advisory Board. He works with Mayo Health Solutions and their industry partners on intellectual property related to sleep and to obesity. S Zucca and I Limongelli have shares of enGenome srl, an Italian bioinformatics company. EnGenome had no role in the design of the study, in the collection, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. The rest of the authors had no conflicts to disclose. ### Clinical Trial N/A ### Funding Statement Supported by the American Heart Association [grant number 17POST33400211 to C.A.A.C.; V.K.S. is supported by the Alice Sheets Marriott Endowed Professorship. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the funding sources. C.A.A.C. and V.K.S. supported by Mayo Clinic Team Science Award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Mayo Clinic Institutional Review Board. Access to UKBB was provided under application 48286. This study complies with the Declaration of Helsinki and the work is covered by the ethical approval for UKBB studies from the NHS National Research Ethics Service on 17th June 2011 (Ref 11/NW/0382) and extended on 18 June 2021 (Ref 21/NW/0157). Written informed consent was obtained from all participants; participants who withdrew consent were excluded. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data is available per UK Biobank policy. * AED : Anti-epileptic drug CVD : Cardiovascular disease PWE : Persons with epilepsy UKBB : UK Biobank