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JAMA Neurol. 2020 Mar 9. doi: 10.1001/jamaneurol.2020.0187. [Epub ahead of print]

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

Keret O1, Hoang TD2,3, Xia F2,3, Rosen HJ1,4, Yaffe K1,2,3,4,5,6.

Author information

Global Brain Health Institute, University of California, San Francisco.
San Francisco Veterans Affairs Health Care System, San Francisco, California.
Northern California Institute for Research and Education, The Veterans Health Research Institute, San Francisco, California.
Department of Neurology, University of California, San Francisco.
Department of Psychiatry, University of California, San Francisco.
Department of Epidemiology and Biostatistics, University of California, San Francisco.



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.


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.


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.


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.

[Available on 2021-03-09]

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