Late-Onset Unprovoked Seizures Lead to Higher Risk of Dementia in Veterans


Study results suggest that unexplained seizures in older adults may also be a first sign of a neurodegenerative disease.

Ophir Keret, MD

Ophir Keret, MD

Findings from a retrospective study suggest that late-onset unprovoked seizures of unknown etiology (LOSU) are associated with a 2-fold risk of developing dementia in older veterans. Notably, these findings may also suggest that unexplained seizures may be the first sign of a neurodegenerative disease.

Led by Ophir Keret, MD, fellow, GBHI University of California San Francisco (UCSF) Memory and Aging Center, the data showed that veterans with LOSU had a greater risk of dementia compared with veterans without seizures (hazard ratio [HR], 1.89; 95% CI, 1.62—2.20) when adjusting for depression and traumatic brain injury (TBI).

This retrospective cohort study sampled inpatient and outpatient encounters from 941,524 veterans aged 55 years and older using the US Veterans Health Administration (VHA) National Patient Care Database. Only veterans whose first encounter came between October 2001 and September 2015 were included in the study.

Using the International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification codes, researchers narrowed down the cohort by excluding patients who had possible secondary causes of seizures stemming from cardiovascular disease (CVD), intracranial tumors, previous brain infections, dementia, or neurotoxin exposure. A total of 649,262 veterans were excluded from the study, including those who did not have follow-up data.

Researchers used a Fine-Gray regression model to examine time to dementia in the study. Initially, analysis was conducted using models that adjusted for demographic characteristics such as age, sex, education, race/ethnicity, and income, and then used models adjusted for possible compounding variables associated with dementia, including medical comorbidities, depression, and TBI.

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In total, 292,262 veterans were included in the analysis, with 2166 veterans diagnosed as having seizures before or during baseline (LOSU). Among those 2166, 181 veterans were diagnosed with dementia during follow-up. Of the 290,096 veterans not diagnosed as having seizures before or during baseline, there were 13,895 diagnosed with dementia during follow-up.

Of the 292,262 included veterans, 282,628 (96.7%) were male, with a mean age of 73.0 (Standard Deviation [SD], 8.8) years. Additionally, the mean time from inclusion to LOSU diagnosis was 2.2 (SD, 1.6) years. Researchers also noted that veterans with LOSU tended to be younger, black, have lower income, and have a higher baseline prevalence of comorbidities.

As mentioned, veterans with LOSU were found to have higher rates of death than those without LOSU. In total, 58,608 veterans (20.1%) died during the outcome period, 2166 of them with LOSU and 58,007 without. Of those with LOSU, 601 died (27.7%), compared to 290,096 deaths (20.0%) in those without (P <.001).

In addition to the risk of death nearly doubling for veterans with LOSU than those without, the association of LOSU with dementia risk remained elevated after adjustment for demographic and medical comorbidities (adjusted HR, 1.95, 95% CI, 1.67—2.27). Researchers used a 2-year lag between LOSU diagnosis and dementia diagnosis to mitigate possible reverse causation. They found little difference, with estimated effect sizes and significance similar to primary model (HR, 1.71; 95% CI, 1.39–2.11).

“While seizures commonly occur in late stages of dementia, our results suggest it can also precede dementia by several years. These findings emphasize the need for comprehensive research on late-onset seizures and dementia,” Keret and coauthors concluded.


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. JAMA Neurol. Published online March 9, 2020. doi:10.1001/jamaneurol.2020.0187

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