Modifiable Midlife Risk Factors Linked to Late-Onset Epilepsy

July 24, 2018

Potentially modifiable midlife vascular and lifestyle risk factors are associated with an increased risk of developing late-onset epilepsy, new research shows.

Results of a large cohort study of more than 10,000 individuals suggest hypertension, diabetes, smoking, physical activity level, and alcohol use were associated with the disorder in later life.

"This study gives us much more evidence that vascular risk factors such as hypertension, diabetes, smoking, lack of physical activity, are linked to the development of epilepsy in later life," lead author Emily L. Johnson, MD, from Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.

"This is yet another reason for people to follow a heathy lifestyle. And if epilepsy is suspected then lifestyle advice should be emphasized just as it is in heart disease," she said.

In a novel finding, the apolipoprotein E (APOE ε4) genotype was also associated with late-onset disease in a dose-dependent manner.

"We show here a dose-dependent relationship, with risk increasing with one allele and increasing still further with 2 alleles. This gene is associated with amyloid deposition. We have seen before that Alzheimer's patients have a higher risk of epilepsy, and our data raises the possibly that amyloid deposition may be involved in epilepsy as well as Alzheimer's," she added

The study was published online July 23 in JAMA Neurology.

Highest Incidence in Later Life

The investigators report that the annual incidence of epilepsy is 90 to 150 per 100,000, which is higher than at any other time of life. The prevalence is 1.1% by age 60 years, and there is a cumulative incidence of 4.4% by age 85 years.

Previous research, mainly consisting of cross-sectional studies, shows some vascular risk factors such as hypertension and elevated cholesterol are more common in adults with late-onset epilepsy. However, the researchers note that it is unknown whether lifestyle factors such as cigarette smoking, diet, or exercise are associated with the disease.

To determine whether midlife risk factors, including potentially modifiable risk factors, for stroke and cerebrovascular disease are associated with late-onset epilepsy the researchers analyzed data from the Atherosclerosis Risk in Communities study, a prospective cohort study of individuals from 4 US communities followed up since 1987.

The current analysis included 10,420 black or white participants from the Atherosclerosis Risk in Communities study with at least 2 years of Medicare coverage and evaluated the link among demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) and the development of late-onset epilepsy (detected by 2 or more diagnostic codes for epilepsy or seizures starting at 60 years or older).

Results showed that "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], 4.12-5.40 vs 2.88; 95% [confidence interval], 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), [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), 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," the authors write. The link between vascular and lifestyle risk factors was still significant in the absence of stroke or dementia.

Higher levels of physical activity (HR, 0.90) and moderate alcohol intake (HR, 0.72) at midlife were associated with a lower risk for late-onset epilepsy.

Microvascular Changes

Although the potential mechanism is not clear, Johnson said the hypothesis is that lifestyle factors that are known to cause vascular changes that lead to heart disease also cause microvascular changes in the brain that can lead to epilepsy.

The researchers further note that microvascular changes contribute to gliosis and blood–brain barrier breakdown, which have been implicated in epileptogenesis in animal studies.

"The finding that moderate alcohol consumption — 1 drink a day or less — was associated with a lower risk of late-onset epilepsy than complete abstinence is again similar to what has been seen in cardiovascular disease and is also probably related to the microvascular hypothesis," Johnson said.

The researchers note that APOE ε4 increases microvascular injury and exacerbates diabetes-related microvascular disease in animal studies, and that the dose-dependent association of APO E4 allele genotype and late-onset epilepsy identified in this study may suggest that amyloid deposition is a possible mechanism for late-onset epilepsy even in individuals without dementia.

They add that the results have a number of important implications, including the possibility of modifying lifestyle to lower the risk for late-onset epilepsy, identification of patients at risk for late-onset epilepsy who may benefit from clinical trials of targeted interventions for prevention, and the possibility of a role of amyloid deposition in late-onset epilepsy.

"The highest incidence of new-onset epilepsy occurs in the over-60s. The rate rises with every decade. But it is not always easy to diagnose. Patents may have had a partial seizure presenting as confusion or transient focal motor symptoms. These midlife risk factors may help with the diagnosis. Clinicians should have a higher index of suspicion if patients have several of these risk factors," said Johnson.

Additional Insight

Commenting on the findings for Medscape Medical News, Orrin Devinsky, MD, from New York University Langone Medical Center, New York City, said the findings provide additional insight into late-onset epilepsy risk factors.

"The role of APOE4 alleles has now emerged as a risk factor for epilepsy after trauma as well. The effect is small, but its emergence in separate domains suggests the relationship may well be causal, although more work is needed to understand mechanisms and inform potential preventive or therapeutic strategies," he said.

Also commenting on the study, Alison M. Pack, MD, professor of neurology of Columbia University Medical Center in New York City, and executive member of the Professional Advisory Board Epilepsy Foundation, note the research highlights importance of modifying risk factors such as hypertension and diabetes that are also associated with other poor health outcomes.

"Measurement and clarification of multiple risk factors including blood pressure, diabetes, smoking history, and alcohol use is unique (in this study) and provide insight as to why older persons may be at increased risk for developing epilepsy. Further study is needed to clarify whether modification of identified risk factors reduces incidence of late-onset epilepsy," she told Medscape Medical News.

JAMA Neurol. Published online July 23, 2018. Full text

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