Cardiovascular Factors Significantly Increases Dementia Risk in Epilepsy


In addition to increased risk of dementia, focal epilepsy was associated with widespread structural brain change reflected by lower total hippocampal and total gray matter volume.

Xin You Tai, MD, clinical fellow, University of Oxford

Xin You Tai, MD

In a cross-sectional study of nearly 500,000 individuals with either epilepsy, stroke, or migraine, findings showed that focal epilepsy was associated with the greatest risk of developing dementia, which was magnified substantially in individuals with high cardiovascular risk.

Using data collected from the UK Biobank (n = 495,149), 3864 individuals had a diagnosis of focal epilepsy only, 6397 had a history of stroke only, and 14,158 had migraine only. After following patients for slightly over 10 years, patients who presented with focal epilepsy had a higher risk of developing dementia (HR, 4.02; 95% CI, 3.45-4.68; P <.001) compared with stroke (HR, 2.56; 95% CI, 2.28-2.87; P <.001) or migraine (HR, 1.02; 95% CI, 0.85-1.21; P = .94).

Prior to the analysis, patients were divided into low, moderate, or high cardiovascular risk groups based on factors that included waist to hip ratio, history of hypertension, hypercholesterolemia, diabetes, and smoking pack-years. Led by Xin You Tai, MD, clinical fellow, University of Oxford, findings showed that patients with focal epilepsy and high cardiovascular risk were more than 13 times more likely to develop dementia (HR, 13.66; 95% CI, 10.61-17.60; P <.001) compared with controls with low cardiovascular risk.

"Stroke is very useful [to study] because it’s closely related to vascular dementia. It’s a proximal risk factor to developing a vascular-type dementia. We thought that would be good to look at," Tai said on JAMA Neurology’s podcast. "Migraine was thrown in there as sort of a positive control, which is useful. From a hypothesis point of view, what we thought we’d find was that, ‘Yes, epilepsy has an effect, it increases dementia more than controls and migraine, but probably not as much as stroke, which is so closely related to vascular dementia."

After controlling for age using a model-free residual method, findings showed that focal epilepsy was associated with lower executive function than controls and migraine (mean difference, –0.09 [95% CI, –0.07 to –0.10]; t = 14.70; P <.001; mean difference, –0.08 [95% CI, –0.10 to –0.10]; t = –12.82; P <.001). There was no significant difference between executive function in focal epilepsy or stroke (mean difference, 0.01; 95% CI, –0.01 to 0.02; t = 14.70; P = .91).

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Among those with high cardiovascular risk and focal epilepsy (n = 762), 9.1% (n = 69) developed dementia compared with only 0.4% (523 of 132,716) of controls with low cardiovascular risk (HR, 13.66; 95% CI, 10.61-17.60). When comparing only individuals with high cardiovascular risk, those with focal epilepsy had an HR of 3.73 (95% CI, 2.94-4.76) for developing dementia compared controls while participants with stroke had an HR of 1.90 (95% CI, 1.65-2.20) when compared with controls.

"The neuroimaging data in this cohort was incredibly rich," Tai noted. In the study, MRI data was acquired on a Skyra 3-T scanner, including high-resolution, T1-weighted, 3-dimensional magnetization-prepared gradient echo structural images, and T2-weighted fluid-attenuated inversion recovery images. Investigators used imaging summary statistics of total hippocampal, gray matter, and white matter hyperintensity volumes, specifically because previous epilepsy studies have identified hippocampal atrophy and tau deposition.

Using these imaging techniques, focal epilepsy was shown to be associated with lower hippocampal volume (mean difference, –0.17; 95% CI, –0.02 to –0.32; t = –2.18; P = .03) and lower total gray matter volume (mean difference, –0.33; 95% CI, –0.18 to –0.48; t = –4.29; P <.001) compared with controls. In terms of white matter hyperintensity volume, there were no significant differences observed (mean difference, 0.10; 95% CI, –0.07 to 0.26; t = 1.14; P = .26). Across age, the difference in hippocampal volume was more apparent in older individuals with focal epilepsy.

Previous research has identified negative cognitive effects from antiseizure medications, which was thus examined in a subanalysis in the trial. To control for the possibility that the medications themselves might be affecting cognition, investigators examined individuals taking antiseizure medication who did not have a diagnosis of epilepsy. Despite the use of more antiseizure medications being associated with a lower executive function, using more antiseizure medications was not associated with a higher risk of developing dementia.

"The lack of association with number of prescribed antiseizure medications excludes an important potential confounder because some older antiseizure medications are also associated with increased vascular risk markers,” Tai et al wrote. “Dementia risk associated with early-onset and late-onset epilepsy was comparable in our study, which is consistent with other investigations showing that measures of epilepsy disease duration did not correspond with worse cognitive impairment or tau pathology burden."

1. Tai XY, Torzillo E, Lyall DM, et al. Association of dementia risk with focal epilepsy and modifiable cardiovascular risk factors. JAMA Neurol. Published online March 27, 2023. doi:10.1001/jamaneurol.2023.0339
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