PMC:6610369 JSONTXT

Seize the Day for a Day With No Seizures: Modifiable Midlife Risk Factors Identified Abstract Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, Huang J, Alonso A, Gottesman RF. JAMA Neurol. 2018 Jul 23 [Epub ahead of print]. doi:10.1001/jamaneurol.2018.1935 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 between 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 [56.4%] women and 2794 [26.8%] black participants; 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% confidence interval [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 (APOE ε4) genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), 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. Commentary The definition of epilepsy is dependent on the chances of seizure recurrence. The old definition—two or more nonfebrile, unprovoked seizures that are more than 24 hours apart—has been broadened to also include a single seizure with a chance of recurrence that is equivalent to the chance of a third seizure after 2 unprovoked ones.1 It is generally agreed that a seizure that occurs in the setting of acute stroke does not necessitate treatment as it is considered provoked, whereas a seizure that occurs in a person with an old stroke fulfills the new definition of epilepsy due to the increased risk of recurrence, and thus necessitates long-term treatment. However, the chances of seizure recurrence after a first seizure in an individual after age 60 with history of smoking and hypertension, but no clear history of stroke, are still unknown. The incidence of epilepsy has a bimodal distribution, with peaks in early childhood and old age. Indeed, with the aging population, seizure onset is highest in the elderly,2 with cerebrovascular disease and neurodegenerative disorders being major causes. However, there is still a sizable subset of individuals with late-onset seizures who have no known risk factors, including no history of stroke or dementia. The association between late-onset seizures and stroke has been studied extensively. Cerebral infarction alone raises the risk of late onset of seizures in the first year following infarction up to 23 times that of the general population.3 Conversely, late-onset seizures strikingly predict a future stroke with a relative hazard of stroke in individuals with seizures being 2.89 (95% confidence interval, 2.45-3.41) compared to controls with no seizures.4 However, the association between midlife vascular risk factors and later epilepsy, aside from stroke or dementia, is still unknown, although one case–control study of 227 patients admitted for a first unprovoked seizure and 294 acute surgical controls found that history of hypertension was associated with a 4-fold risk of unprovoked seizures.5 Johnson et al used the Atherosclerosis Risk in Communities data, a large prospective cohort study of 15 792 participants from 4 US communities to assess the risk of late-onset epilepsy (after age 60) in people with vascular and lifestyle risk factors. In this study, the baseline was defined as factors present between the ages of 45 and 64 years. The authors found that 596 of 10 420 total participants developed late-onset epilepsy (3.33 per 1000 person-years), and the risk was higher in black than in white participants (4.71 vs 2.88 per 1000 person-years), specifically in Mississippi and North Carolina black participants compared to North Carolina white participants. Multivariable analysis found significant risks of late-onset epilepsy if, at baseline, the participants had hypertension, diabetes, smoking, apolipoprotein E ε4 (APOE ε4) genotype (dose-dependent effect with 1or 2 alleles), and incident stroke and dementia (see Figure 1). On the other hand, physical activity and moderate alcohol intake significantly lowered the risk of epilepsy. In univariate Cox analyses, no increased risks were predicted by glycemic load or hyperlipidemia, and in the final multivariable model, obesity was not associated with later epilepsy. Stratified analyses found that smoking increased the risk of epilepsy in women but not men. Figure 1. Midlife hazard ratios for developing epilepsy plotted as a distance from 1. None of the plotted risk factors had a 95% confidence interval that traversed 1 (i.e., all are significant). The strengths of the study include the large sample size of its prospective cohort and the length of follow-up. Although previous studies have reported increased risk of epilepsy in individuals with stroke and dementia, this study demonstrates the independent risk of hypertension, smoking, and APOE ε4 carrier status with later epilepsy. This suggests that epilepsy may be due to amyloid deposition even in the absence of dementia, and microvascular disease (possibly disrupting the blood–brain barrier) even in the absence of stroke history. The findings suggest that mitigation of vascular and lifestyle risk factors may help reduce the risk of later epilepsy, which may be studied in future prospective trials. Additionally, a future trial may disclose the risk of seizure recurrence after the occurrence of one unprovoked seizure in an older person if such vascular and lifestyle risk factors are present at baseline. Such risk assessment is important for the determination of whether antiseizure medications should be started and maintained. By Mohamad Koubeissi