Research recap: Empiric immunotherapy for highly refractory epilepsy: Dr. Elisabeth Doran

In a retrospective study of 31 patients with highly refractory epilepsy, 29% had more than a 50% reduction in seizures for at least 12 months after being treated with immunotherapy. Three of these patients became seizure free. Other than a trend toward a diagnosis of focal epilepsy, researchers did not identify any specific features predictive of treatment response. Sharp Waves spoke with the first author about the study and its implications.

The study was published in Epilepsia in April 2025.

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

Nancy Volkers: The paper discussed in this episode is titled “Sustained Rescue of Seizure Control in Patients with Highly Refractory Chronic Epilepsy using Empiric Immunotherapy.” The paper was published in Epilepsia in April 2025.

Dr. Elisabeth Doran: My name is Elizabeth Doran. I'm the head of the epilepsy service in St. James Hospital in Dublin, in Ireland. And I have been working in the service since 2017. I have an interest in improving access to care for vulnerable populations, such as patients who are homeless and patients with intellectual disability. And I also have an interest in immunotherapy in epilepsy.

Nancy Volkers: So we're here to talk about a recent study on empiric immunotherapy in drug resistant or pharmacoresistant epilepsy. I'm interested in how that study came about.

Dr. Elisabeth Doran: Yeah, so we started in 2018 and it was actually the senior author on this paper, Colin Doherty, who was the head of our service at the time. And at the time there was a lot of discussion about autoimmune encephalitis and treatment of autoimmune encephalitis.

And there was more and more discussion about patients potentially having autoimmune epilepsy and, in our service with quite a few patients, very complex epilepsies. We had one patient where we had a suspicion that maybe she had an autoimmune mediated epilepsy, and because we had failed treating her with conventional antiseizure medications, we had decided to maybe give her a trial of immunotherapy. I think it was very surprising to us, but she responded extremely well and she is one of our three patients that is still seizure free to date after one course of oral steroids. And I think that case really encouraged us to look more into this direction.

Nancy Volkers: Thank you. So the study follows 31 people in which you initiated immunotherapy and they all had pharmacoresistant epilepsy.

Dr. Elisabeth Doran: So it's a retrospective study. After our initial success with that one patient, we decided in a few other patients that had very resistant, highly refractory epilepsy with daily seizures, who had failed a lot of medications, to consider palliative trial of immunotherapy where all of their therapies had failed. And because some of the patients responded well, we were encouraged to try the treatment course of steroids maybe more widely. So then we decided that we probably need to structure this more to understand it better. So I developed a screening tool to help us pick patients that might benefit from this therapy.

Nancy Volkers: Excellent, thank you. So it was retrospective, so you went back in your records and pulled out these 31 people. So from the study, if I recall correctly, they received different types of immunotherapy. So how did you choose that, or did they all follow that protocol that you had developed after one point and the initial ones did not? Because I noticed a couple of them received oral steroids and then there were some IV and IVIG. And so can you talk a little bit about how the different treatments were chosen? 

Dr. Elisabeth Doran: So we looked at the available protocols at the time, and they were made mainly for treatment of autoimmune encephalitis. There was one German protocol by Christian Bien which included oral steroids. And because at the time it was more practical for us to treat patients on an outpatient basis because we didn't really have regular access to an inpatient infusion suite, we decided to trial this initially. 

As we treated more patients, we had a few patients who had quite a lot of side effects on the oral steroids because they're given over roughly six weeks. And that's when we decided that maybe going for intravenous steroids might cause less side effects. And then we had some patients who did not tolerate steroids well. So then we tried intravenous immunoglobulins as an alternative. And then depending on the patient response, if they had a good response but it wasn't sustained, we chose to give them more immunotherapy. And it was really quite an individualized process, because all these patients have very highly refractory epilepsy. 

We did try not to change the anti-seizure medications too much at the same time to because that would be very difficult to interpret then how their response was to immunotherapy, but it wasn't always possible. But generally we tried to avoid doing two things at the same time. 

And in terms of choosing steroids and IVIG, we try to choose steroids first, but if a patient had side effects or it didn't tolerate it well, or if we felt we had given so many courses that might affect their bone health in the long term, we then chose to give IVIG instead in some cases.

Nancy Volkers: Got it. Okay. So the patient population was these 31 people, I believe they were all having more than one seizure per week. Is that correct?

Dr. Elisabeth Doran: Yes. With both IVIG and steroids, you kind of have to expect that patients will respond within two weeks, but that their response will last for about six weeks. So if you choose someone who has too infrequent seizures it's really hard to know whether they've responded or not. If someone is having daily seizures or 10 seizures a day, it's quite clear to see whether there is a response or not. 

And I think also because you're asking someone to get an IV infusion for three to five days in a row, it's, it's a big commitment. So we felt that especially these patients who very frequent seizures will benefit from this and we will be justified to go to a treatment like that, that was probably controversial at the time and not really standard.

Nancy Volkers: Yeah, that makes sense. I believe they also all had focal seizures, correct. There was no one in the study that had only generalized? 

Dr. Elisabeth Doran: No, there were some patients included that had generalized epilepsy, but none of them responded. So we didn't really go down that avenue anymore, and the majority of patients in the study are focal onset.

Nancy Volkers: Okay. Got it. Could you talk about the results then? Responses and partial responses.

Dr. Elisabeth Doran: Yes, so we were surprised by the results ourselves. We had, over the course of treating these patients, we had three patients who responded with seizure freedom. Two patients actually after courses of oral steroids, and both of them were still seizure free to date. And we had a third patient who had a more protracted, kind of prolonged course of a mixture of IVIG and steroids, but in the end it was another course of steroids. And since then she's been seizure free. And she had really quite very frequent seizures. That's a few years ago now, and she continues to be seizure free. So that was very promising. 

And then we had a few patients who had a more than 50% improvement in their seizure frequency, And they, all of those patients required repeated courses of immunotherapy. Some of them have since managed to come off immunotherapy. They still have better seizure control than they did before. Some patients actually were worked up for surgery in parallel, so they went down other avenues. But it was about a third of patients who responded in a sustained way, with more than 50% improvement in seizure control. Obviously, they're self-reported improvements in seizure control, which is the limitation.

Nancy Volkers: Yeah. That, that was going to be a future question, but maybe we could touch on that now. So it was patient-reported seizures that you used as your measure. So did they keep seizure diaries, or…

Dr. Elisabeth Doran: Seizure diaries. Yeah. But in some of, a lot of the patients, because the seizures were so frequent, so someone went from multiple seizures daily to about one a week that, you know, it's probably easier to grasp the difference, because they were so frequent.

And for example, the patient that we treated first due to her frequency just had nocturnal seizures, but they were up to 15 seizures a night. And after the treatment, she's now back in university and living her life and is not even coming to our service, all the time anymore.

Nancy Volkers: Did you find any factors that correlated with partial response? Or, you said you had three people who were now seizure free. Did you find any patterns there, any potential correlations? 

Dr. Elisabeth Doran: No, we were hoping to find a pattern. So what we looked at is kind of the typical profile of an autoimmune encephalitis. We looked at whether patients had neuropsychiatric issues, whether there was something on their MRI, whether they had antibodies in the serum. We looked at gender, or the EEG changes, but we didn't really find anything that significantly predicted a response to immunotherapy. I mean, it's a small cohort, so, but certainly in that very diverse cohort, there was no clear pattern. 

Nancy Volkers: So, what are some potential mechanisms for response…you said you didn't find any correlation with autoantibodies. What other factors could be at work? 

Dr. Elisabeth Doran: Yeah, so how steroids or IVIG work on the brain is not that well understood, but they do reduce inflammation. I think there's increasing evidence that focal inflammation in the brain can lead to increased seizures through activation of microglia and just local inflammation. And obviously both IVIG and steroids are anti-inflammatory medications. So it may be, rather than actually targeting a specific antibody, it may just be a reduction in inflammation.

And with steroids also, there's some evidence that it can stabilize the blood-brain barrier and that may be a way how it reduces seizure frequency. Because once the blood-brain barrier is more stabilized, there may be less inflammation.

Nancy Volkers: And you said the three people who responded completely and were seizure free in the study are still seizure free today? 

Dr. Elisabeth Doran: Yes. 

Nancy Volkers: And the study data were collected through 2022, if I remember, correct? 

Dr. Elisabeth Doran: Yes. We started this in 2018 and then we included the patients that we had to a certain point, but then we said, you know, we really feel we should publish this data because it's so interesting. And so eventually we had to cut off somewhere. So we only included patients that were followed up for at least six months, but some of the patients have much longer follow up, 

Nancy Volkers: Got it. Was there anything else you wanted to mention as far as results or strengths or limitations? 

Dr. Elisabeth Doran: I think it's really important and interesting approach and it is something I think to consider, especially when patients are being worked up for surgery because surgery is an invasive, permanent option. So I think it is something to consider on the route, or it's for anyone who has really highly refractory focal seizures. 

Nancy Volkers: Do you have future research in this area that you're interested in pursuing?

Dr. Elisabeth Doran: We're currently undertaking a study where we look at the blood-brain barrier in patients who are getting steroids in our service. So we're doing this with contrast enhanced MRI imaging, but we're still in the process of doing that because we're very interested in what steroids do to the blood-brain barrier and trying to understand better what happens and why, you know, why did this work?

So, but that's a work in progress.