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Association of Late-Onset Unprovoked Seizures of Unknown Etiology With the Risk of Developing Dementia in Older Veterans

Educational Objective
To see whether there is an association of late-onset unprovoked seizures of unknown etiology with dementia.
1 Credit CME
Key Points

Question  What is the association of late-onset unprovoked seizures of unknown etiology with the risk of dementia?

Findings  In this cohort study that included 292 262 US veterans 55 years and older, those with incident unprovoked seizures of unknown etiology were twice as likely to be diagnosed as having dementia during follow-up.

Meaning  Elderly individuals with new-onset unprovoked seizures of unknown etiology should be followed up for signs of dementia.


Importance  The incidence of unprovoked seizures and epilepsy increases considerably in late life, with approximately one-third of seizures being of unknown etiology. While individuals with dementia have a high risk of developing unprovoked seizures, it is unknown whether older adults with late-onset unprovoked seizures of unknown etiology (LOSU) are at risk of developing dementia.

Objective  To determine whether incident LOSU is associated with a higher risk of dementia among older US veterans.

Design, Setting, and Participants  This retrospective multicenter cohort study was conducted using data from US Veterans Health Administration medical centers from October 2001 to September 2015. Data were generated from all veteran inpatient and outpatient encounters that occurred within Veterans Health Administration facilities. A random sample of 941 524 veterans 55 years and older was generated. A total of 649 262 veterans previously diagnosed (using International Classification of Diseases, Ninth Revision, Clinical Modification codes) with dementia, unprovoked seizures, epilepsy, and conditions that could lead to seizures (brain tumors, trauma, infections, stroke, and neurotoxin exposure) as well as veterans without follow-up data were excluded. Data were analyzed from October 2018 to July 2019.

Exposures  Late-onset unprovoked seizures of unknown etiology were defined as a new diagnosis of epilepsy or unprovoked seizures without a diagnosis of a secondary cause for seizures. Incident LOSU was assessed during a 5-year baseline period.

Main Outcomes and Measures  Veterans were assessed for incident dementia diagnosis during an outcome period. Fine-Gray proportional hazards models were used to determine whether LOSU was associated with greater risk of incident dementia. Models were adjusted for demographic variables, cardiovascular risk factors, depression, and traumatic brain injury.

Results  Of the 292 262 included veterans, 282 628 (96.7%) were male, and the mean (SD) age was 73.0 [8.8] years. During the baseline period, 2166 veterans developed LOSU. The mean (SD) follow-up after LOSU was 6.1 (2.9) years. After multivariable adjustment, veterans with LOSU had greater risk of dementia compared with veterans without seizures (hazard ratio, 1.89; 95% CI, 1.62-2.20). A sensitivity analysis imposing a 2-year lag between incident LOSU and dementia diagnosis led to similar results.

Conclusions and Relevance  These findings suggest LOSU in older veterans is associated with a 2-fold risk of developing dementia. 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.

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Article Information

Accepted for Publication: January 16, 2020.

Corresponding Author: Ophir Keret, MD, Global Brain Health Institute, University of California, San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Ln, Ste 190, San Francisco, CA 94158 (ophir.keret@gbhi.org).

Published Online: March 9, 2020. doi:10.1001/jamaneurol.2020.0187

Author Contributions: Dr Keret had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Keret, Yaffe.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Keret, Yaffe.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Xia.

Obtained funding: Rosen, Yaffe.

Administrative, technical, or material support: Keret, Hoang.

Study supervision: Yaffe.

Conflict of Interest Disclosures: Dr Rosen has received grants from the National Institute on Aging and Biogen as well as personal fees from Ionis Pharmaceuticals and Novartis. No other disclosures were reported.

Funding/Support: This research was supported by grant W81XWH-12-PHTBI-CENC from the US Department of Defense (Dr Yaffe), grant K24 AG031155 from the National Institute on Aging (Dr Yaffe), and the Sierra Pacific VISN Mental Illness Research, Education, and Clinical Centers (Dr Yaffe).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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