Mortality and Sudden death risk in middle-aged persons with epilepsy — a UK Biobank study
Authors: Shah Ravi A. , Chahal C. Anwar A. , Ranjha Shaheryar , Dabbagh Ghaith Sharaf , Asatryan Babken , Limongelli Ivan , Khanji Mohammed , Ricci Fabrizio , Paoli Federica De , Zucca Susanna , Tristani-Firouzi Martin , St. Louis Erik K. , So Elson L. , Somers Virend K. 
Published: July 2023

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

Clinical Perspective

What is new?

This is the large prospective cohort study of middle-aged (40-69 years) PWE, reporting a high prevalence of CVD, including hypertension, coronary artery disease, heart failure, valvular heart disease, congenital, atrial fibrillation and ventricular tachycardia.

PWE had a consistent 3-fold higher all-cause mortality and 6-fold higher sudden death-specific mortality than matched controls, even after multivariable adjustment.

Of known SUDEP risk factors, only male sex and higher resting heart rates were associated with increased mortality in persons with epilepsy, but intellectual disability and polypharmacy were not (which have been reported in younger patients as risk factors).

What are the clinical implications?

Evaluation of PWE who are middle-aged should include screening for CV disease.

This work highlights an excess burden of CVD and mortality amongst middle-aged persons with epilepsy, requiring research to identify mortality mechanisms so that this can translate to improve outcomes.