Novel Associations Between Functional Seizures and Cerebrovascular Disease Identified

Lea Davis, PhD

Findings from a recent case-control study of more than 3000 patients with functional seizures suggest that there is an association with cerebrovascular disease, including stroke—a novel link between the conditions.¹

Functional seizures, also known as psychogenic nonepileptic seizures, were also associated with posttraumatic stress disorder (PTSD) and sexual assault trauma.

First author Slavina Goleva, graduate student, Molecular Physiology and Biophysics, Vanderbilt University Medical Center (VUMC), noted in a statement that roughly 80% of patients experiencing functional seizures are initially misdiagnosed with epilepsy and treated with anti-epileptic drugs. This diagnostic delay can last, on average, 7 years.² An estimated 17% to 22% of patients with functional seizures do have concurrent epilepsy.

"Our report is the first direct calculation of the prevalence of functional seizures," Goleva said, adding that the epilepsy monitoring unit at VUMC might have a higher prevalence of functional seizures compared to the general population.

In total, the study included 3341 patients with functional seizures (period prevalence, 0.14%; 140 per 100,000), chosen from more than 2.3 million patients aged 18 years or older in the electronic health record (EHR) system from 1989 to 2018. Of the full VUMC-EHR population, 1431 patients were diagnosed with functional seizures, 2251 with epilepsy and functional seizures, and 4715 with epilepsy without functional seizures. There were 502,200 control patients who received treatment at VUMC for a minimum of 3 years.

The effort was by Lea Davis, PhD, associate professor of medicine, and investigator, Vanderbilt Genetics Institute. "The story gave the patient perspective on these seizures—the stigma that patients felt and the difficulties they experienced in the medical system. I felt like studies within electronic health records could potentially be really impactful for this community," Davis said in a statement, referring to an NPR story on these seizures that inspired her to commit to this work.

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All told, 13 novel and significant associations with cerebrovascular disease (OR, 1.08; 95% CI, 1.06–1.09; P <3.02 x 10−5) and transient cerebral ischemia (OR, 1.09; 95% CI, 1.08–1.11, P <3.02 x 10−5) were identified. Additionally, previously reported associations with psychiatric disorders, including PTSD, were confirmed (odds ratio [OR], 1.22; 95% CI, 1.21–1.24; P <3.02 x 10−5), anxiety (OR, 1.14; 95% CI, 1.13–1.15; P <3.02 x 10−5), and depression (OR, 1.14; 95% CI, 1.13–1.15; P <3.02 x 10−5).

Notably, phenome-wide association analyses among functional seizures cases vs epilepsy cases, and epilepsy cases vs controls, suggested broad associations between cerebrovascular disease and epileptic and nonepileptic seizures. Cerebrovascular disease (Hierarchical code families [phecode] 433) was more strongly associated with epilepsy than functional seizures (functional seizures: OR, 1.08; 95% CI, 1.06–1.09; P = 2.6 x 10−40; epilepsy: OR, 1.20; 95% CI, 1.18–1.21; P <3.02 x 10−05).

"We initially recognized that finding these patients within the EHR would be a challenge because the ICD [International Classification of Diseases] codes are not as specific as they are for a lot of diseases," Goleva said. In addition to ICD codes, the researchers included Current Procedural Terminology (CPT) codes and used natural language processing to search within the records for a list of keywords.

Among those with both functional seizures and cerebrovascular disease, 29% were diagnosed with functional seizures prior to the onset of cerebrovascular disease, 23% were diagnosed with cerebrovascular disease and functional seizures within 90 days of one another, and 48% were diagnosed with functional seizures post-cerebrovascular disease diagnosis.

"If there is a suspicion that someone presenting with seizures could have functional seizures rather than epileptic seizures, it's critical to refer those patients to an epilepsy monitoring unit for accurate diagnosis and appropriate treatment," coauthor Kevin Haas, MD, PhD, associate professor of Neurology, VUMC, said in a statement. "Historically, even once diagnosed, care of these patients has often fallen through the cracks between neurology and psychiatry, but we are now actively developing a more integrated approach to care for this patient population."

REFERENCES
1. Goleva SB, Lake AM, Torstenson ES, et al. Epidemiology of Functional Seizures Among Adults Treated at a University Hospital. JAMA Netw Open. 2020;3(12):e2027920. doi:10.1001/jamanetworkopen.2020.27920
2. Functional seizures associated with stroke, psychiatric disorders in EHR study. News release. Vanderbilt University Medical Center. January 7, 2021. Accessed January 7, 2021. www.eurekalert.org/pub_releases/2021-01/vumc-fsa010721.php