Association Between Midlife Risk Factors and Late-Onset Epilepsy

Abstract

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.

Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy

“…We previously found the incidence of LOE in ARIC participants to be 3.3 per 1,000 person-years, 13 somewhat higher than other recently reported incidences of 2.4-2.5 per 1,000 person-years 2,3 ; this may be due in part to the relatively high proportion of black participants (25% of ARIC participants) as the rate of LOE is known to be higher in black than in white individuals. 2,3,13 The strengths of this study are the longitudinal nature of comparison of white matter scores and later epilepsy, large size, and prospective nature. These strengths allow us to include and adjust for vascular and lifestyle risk factors in our models, which is of vital importance given the high association of hypertension and smoking with the imaging measures under study.…”

“…We adjusted for hypertension, diabetes, smoking, and APOE e4 genotype in our models, and excluded participants with known dementia, to attempt to address these considerations. The degree of these structural findings adds additional risk of LOE beyond the known risk factors of hypertension, diabetes, smoking, and APOE e4, 13 which were included in our models. This may imply that there is heterogeneity in susceptibility to the effects of these vascular and lifestyle risk factors; further studies to develop prediction models to identify patients at risk for LOE should incorporate imaging findings as well as medical and social risk factors.…”

“…Furthermore, evaluation of white matter and cortical volumes in LOE has been taken from casecontrol studies matched on age, without adjustment for hypertension, smoking, or other vascular risk factors that are known to be highly associated with white matter hyperintensities (WMHs) and markers of cerebrovascular disease 12 and that we previously demonstrated are associated with LOE. 13 The goals of this study were to determine the longitudinal association of white matter disease with the development of epilepsy in older adults, and to determine the cross-sectional association of brain cortical volumes with LOE, adjusting for demographic factors, APOE e4 genotype, hypertension, diabetes, and smoking.…”

Associations between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases

“…Atherosclerosis is a chronic inflammatory disease of the arteries, it is principally a lipid-driven process initiated by the accumulation of lipoprotein particles and an inflammatory process in focal areas of arteries as well. [38] Recently, miR-146a was recognized as a potent regulator in many physiological and pathological processes, including immune function, inflammatory reaction, metabolism, oxidative stress, neurodegenerative, and cardiovascular diseases. [39] Recent studies have shown that miR-146a can regulate the synthetic phenotype and proliferation of vascular smooth muscle cells by targeting Krüppel-like factor 4.…”

Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

“…The loss of GABA and GABAergic interneurons in AD patients may lead to network hyperactivity, most commonly observed through seizures. ApoE4 carriers have a higher risk [132–136] and earlier onset [137–139] of developing idiopathic or secondary temporal lobe epilepsy. It is still unclear whether these patients demonstrate a higher risk for developing AD later in life, or if indeed the proportion of AD patients with concomitant epilepsy is enriched for apoE4 carriers.…”