Ophir Keret, MD, on Late-Onset Unprovoked Seizures of Unknown Etiology and Dementia Risk

Late-onset unprovoked seizures of unknown etiology (LOSU) may be associated with a doubled risk of developing dementia and may be the first sign of neurodegenerative disease among older veterans, according to new findings published in JAMA Neurology.

Senior study author Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco (UCSF), and colleagues arrived at their conclusion after performing a retrospective multicenter cohort study. Data for the study were obtained from US Veterans Health Administration medical centers from October 2001 to September 2015.

A total of 292,262 veterans (mean age 73.0 years; 96.7% men) were included in the final analysis. Exclusion criteria included lack of follow-up data and/or previous diagnoses of dementia, epilepsy, unprovoked seizures and conditions that could lead to seizures such as trauma, infections, brain tumors, stroke, and neurotoxin exposure.

The researchers defined LOSU as a new diagnosis of epilepsy or unprovoked seizures in the absence of a diagnosis of a secondary cause for seizures, and they assessed incident LOSU over a baseline period of 5 years. Mean follow-up after a LOSU diagnosis was 6.1 years.

Main outcomes included incident dementia during the follow-up period and the association between LOSU and increased risk of incident dementia, which was calculated used Fine-Gray proportional hazards models adjusted for cardiovascular risk factors, traumatic brain injury, depression, and demographic variables.

Ultimately, 2166 veterans developed LOSU over the course of the baseline period. Following multivariable adjustment, the results of the study indicated that veterans with LOSU had an increased risk of dementia compared with veterans without seizures (hazard ratio 1.89). Similar findings were observed after performing a sensitivity analysis that imposed a 2-year lag between incident LOSU and a diagnosis of dementia.

Neurology Consultant discussed the implications of these findings further with corresponding study author Ophir Keret, MD, with the Global Brain Health Institute at UCSF.

NEURO CON: In your study, you and your colleagues found that LOSU in older veterans may be associated with a 2-fold risk of developing dementia. Did your data suggest a potential mechanism behind this association, or have you hypothesized what the mechanism might be?

Dr Keret: We did not explore an association, as our study was not suited to elucidate the mechanism for this. However, we hypothesized 2 possible scenarios, each with support of previous literature: seizures are an early manifestation of Alzheimer disease or another neurodegenerative disease, or seizures are a risk factor for this disease or somehow accelerate its natural course.

NEURO CON: At this time, do you believe these results could be applicable to other patient populations, or is it specific to veterans?

Dr Keret: I believe they are applicable to other populations, and future studies in this area will likely evaluate other populations. Because our study consisted of mostly men (97%), the risk of dementia in women with late-life seizures should also be addressed in future studies. This is important, as emerging evidence suggests major differences in Alzheimer disease between men and women.

NEURO CON: You and your colleagues wrote, “While seizures are commonly thought to occur in late stages of dementia, these findings suggest unexplained seizures in older adults may be a first sign of neurodegenerative disease.” How might this finding impact screening and risk stratification protocol for dementia going forward?

Dr Keret: Dr Yaffe, the senior author of this paper, and I concluded that there is a need for more research before we can definitively say what is causing the seizures, but these findings ought to encourage clinicians to follow these patients more closely in terms of cognitive screening and possible interventions.

NEURO CON: What key takeaways do you hope to leave with neurologists on this topic?

Dr Keret: Our study has indicated that older adults with late-life seizures are at high risk of developing dementia within several years.

NEURO CON: What is the next step in terms of future research in this area?

Dr Keret: Future research initiatives should include the prospective evaluation of older adults with new, unexplained seizures for signs of dementia and Alzheimer disease biomarkers.

—Christina Vogt

Keret O, Hoang TD, Xia F, Rosen HJ, Yaffe K. Association of late-onset unprovoked seizures of unknown etiology with the risk of developing dementia in older veterans [Published online March 9, 2020]. JAMA Neurol. doi:10.1001/jamaneurol.2020.0187