NeuroVoices: Lea Davis, PhD, and Slavina Goleva, on Epidemiology of Functional Seizures

Lea Davis, PhD

A case-control study that included more than 3000 patients with functional seizures recently read out data that suggested that there is an association with cerebrovascular disease, including stroke, and a novel link between the conditions.

The data not only showed evidence to support previously reported associations but discovered new associations between functional seizures and post-traumatic stress disorder (PTSD), anxiety, depression, and sexual assault trauma. Notably, sexual assault trauma was found to mediate nearly a quarter of the associations between female sex and functional seizures in the Vanderbilt University Medical Center (VUMC) electronic health records.

Slavina Goleva

Slavina Goleva, graduate student, Molecular Physiology and Biophysics, VUMC, and colleague Lea Davis, PhD, associate professor of medicine, Vanderbilt Genetics Institute, were among the investigators of the study. As part of the latest edition of NeuroVoices, Goleva and Davis sat down to discuss their findings, what in particular stood out to them, and the crossover between psychiatry and epilepsy.

NeurologyLive: Can you provide background on your study? How did it come about and what were the major takeaways?

Lea Davis, PhD: I’m a faculty member in the division of Genetic Medicine at Vanderbilt. I study a wide range of complex traits, chronic conditions, and diseases. I do a lot of work in neuropsychiatric and neurodevelopmental disorders, and in particular, understanding how the genetic contributions to those also affects health and other domains throughout the lifespan. I actually heard about functional seizures for the first time on a story on NPR. They were reporting, from the patient perspective, the challenges that people experienced, including finding the right diagnosis, and finding treatment for that diagnosis. It occurred to me that this was conceptually very much in my wheelhouse of expertise and interest.

At Vanderbilt, we have access to a large, completely de-identified, mirror image of the electronic health record. That includes on average, about 3 million people. In doing a bit of background research, I found that a lot of the studies on functional seizures were pretty small. I realized that the health record resource could potentially help us expand our sample sizes and conduct a well-powered study. We also have excellent colleagues in the neurology department who were eager to engage with us in research.

Slavina Goleva: In terms of major findings, one of the most major things we saw was the prevalence. We’ve estimated it at around .14%. That’s the first direct prevalence that’s been calculated for this disorder. Even though it’s a pretty high prevalence, it actually had only been indirectly estimated previously. That was a really big contribution to the field. It was actually a little bit higher than what we expected. I think that really highlights that there are a lot of patients that are suffering from this disorder and that we need to put more resources and research into it.

The other key finding we found was the number of associations with psychiatric disorders. We looked at around 1600 different phenotypes, the associations between functional seizures, and each of those phenotypes. Most of the phenotypes we had in the mental disorders category were actually positively associated with functional seizures. That work has, to some extent, been done before. It’s been shown that there are associations between functional seizures and for example, major depressive disorder, as well as anxiety disorders and post-traumatic disorder. But it was really nice to be able to replicate that in such a large sample size, and to find some additional psychiatric associations such as schizophrenia and insomnia, which will need follow-up studies as well.

That’s also been really helpful, because that gives us evidence to say, if someone shows up to a clinic with seizures and they have a high burden of psychiatric illnesses as comorbidities, then they should immediately be referred for diagnostic video or EEG to figure out whether they do have epilepsy, which is another seizure disorder that 80% of functional seizure patients actually get misdiagnosed with, or if they do have functional seizures.

The other big finding was the association with cerebrovascular disease or stroke. That had not been previously reported. We’ve been really eager to follow that up and see what’s causing that association. We also found both an association between functional seizure and sexual assault trauma in our electronic health record system, as well as that about a quarter of the association between female sex and functional seizures is actually caused by the presence of sexual assault trauma.

Were you shocked to see the number of associations between the numerous phenotypes of cerebrovascular disease? Was there any association that stuck out to you more?

Lea Davis, PhD: I would say that we weren’t shocked, but definitely were interested in the scope of the association with cerebrovascular disease diagnoses in the electronic health record. It’s important to understand that a lot of those diagnoses may be overlapping. For example, it might be some of the same individuals that have 1 cerebrovascular disease code or diagnosis, and then later, they get another 1 that’s maybe similar, or along the path to their final diagnosis. Those signals may not all be independent.

I do think though that the finding in general of enrichment for cerebrovascular disease diagnoses in functional seizure patients had not been reported previously. That was something we were definitely very interested in. We’re continuing to follow that up by digging deeper into the identified charts to try to understand what’s happening first, whether people are developing the seizure disorder first and then developing the vascular disease. Is this vice versa as well? Are there other elements of the cerebrovascular disease that we can get more specific on to try to better understand? For example, what is the specific risk among people with functional seizures? That needs some replication and further investigation.

Slavina Goleva: I totally agree with what Lea said, and to add to it, it wasn’t necessarily surprising, but once we found that association and started to think about it, it did actually make a lot of sense that there might be some association between a seizure disorder, which theoretically would be neurological in nature and some capacity.

Stroke is either the occlusion of blood going to the brain or other cerebrovascular diseases like hemorrhaging. Instinctively it made sense that perhaps there is some aberrant blood flow going to the brain that might be either causing these seizures, or a result of seizures, or just in some way associated. The other thing was that although it’s not been associated with functional seizures, there’s a strong association between epilepsy and stroke. It has been pretty widely reported that after a stroke, a lot of people tend to develop epilepsy. That’s a nice parallel with another seizure disorder, which has given us a lot of room to jump off of and do parallel studies.

Should epilepsy care crossover with more psychological care, and vice versa, should therapists/psychologists seek epilepsy specialists to assist?

Slavina Goleva: I do think there should be a lot of crossover. Actually, the current gold standard in treatment once someone is fully diagnosed with functional seizures is more of a team approach between neurology and psychiatry, from what our neurologist colleagues have been telling us. I do think it is already headed in that direction, which is really good, because this is sort of a disorder that’s on the border of psychiatry and neurology, and you do need both for effective patient care.

But I would like at the onset of seizures for a referral to psychiatry and getting that process started earlier. One of the main things that had been previously reported and was replicated in this study, is that it takes about 8 years, from the time someone shows up to the hospital with seizures, for them to be diagnosed with functional seizure disorder, on average, which is a really long time to be suffering from these seizures without a diagnosis or treatment.

The other thing is that maybe going the opposite way, wouldn’t make as much sense. For psychiatric care, it’s great for them to be aware of this disorder in case they see a patient reporting seizure and then can know where to refer them. But until a patient starts having seizures, I don’t necessarily see it as that big of a concern.

Transcript edited for clarity.

REFERENCE

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