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Original Investigation
November 2018

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study

Author Affiliations
  • 1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland
  • 3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut
  • 4Department of Epidemiology, University of North Carolina at Chapel Hill
  • 5Department of Neurology, University of Mississippi Medical Center, Jackson
  • 6Department of Epidemiology, Emory University, Atlanta, Georgia
JAMA Neurol. 2018;75(11):1375-1382. doi:10.1001/jamaneurol.2018.1935
Key Points

Question  Are midlife risk factors for stroke and cerebrovascular disease also risk factors for late-onset epilepsy?

Findings  In this cohort study of 10 420 adults, hypertension, diabetes, smoking, APOE ε4 allele number, activity level, and alcohol use were associated with late-onset epilepsy.

Meaning  Potentially modifiable midlife vascular and lifestyle factors were associated with epilepsy in later life.


Importance  The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear.

Objective  To identify midlife vascular and lifestyle risk factors for late-onset epilepsy.

Design, Setting, and Participants  The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018.

Exposures  Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors.

Main Outcomes and Measures  Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures.

Results  Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia.

Conclusions and Relevance  Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.