IEC 2023 | Inflammation in new-onset refractory status epilepticus

I will present this study we started both at the Yale University School of Medicine and in the Hôpital de La Pitié-Salpêtrièr in Paris. This project we conducted on biospecimens that have been collected for several years now, to better understand the pathophysiological mechanisms underlying the development of new onset refractory status epilepticus. New Onset Refractory Status Epilepticus is for is the full name of NORSE, which is one of the most severe neurological conditions in which patients will experience very refractory seizures, continuous seizures, and they do not respond to anticonvulsant medication. Most of the time these patients have to be managed in intensive care units and require prolonged anesthesia with coma inducing drugs to get the seizure under control. Since the past five years, there was several evidence suggesting that this pathology may be due to a disorder of immunity leading to exacerbated cerebral inflammation. But until we started the study, we just had a few case reports published with a maximum of ten cases suggesting that some inflammation biomarker may be used either to diagnose NORSE, or to better understand what happens in such patients. With only few patients, it was hard to really define what was going on. So that’s why we would like to conduct a study with a much larger cohort of patients.

In this study, we investigated the inflammation by measuring cytokines in both serum and CSF from patients with NORSE. We compare the cytokine profile to patients with other form of refractory status epilepticus. So, 37 of those patients compared to 61 NORSE patients, and patients without status epilepticus. We noticed that overall patients with status epilepticus had a significant increase of several pro-inflammatory cytokines when compared to patients without status epilepticus, and that contained mostly interleukin-6 interleukin-8, CCL2 or MIP-1α.

And in a second time we study more specifically the NORSE population, and we compared the cytokine profile to the other patients with refractory status epilepticus, but not NORSE. The differences between these two groups of patients are mostly the etiology, because to be defined as a NORSE patient, you should not have any history of epilepsy and any active or acute, toxic structural or metabolic cause found in the first 72 hours. So, if you have a cause like a brain trauma or tumor, you will not be defined as a NORSE patient. When we compare the profile of the NORSE patients to the other status epilepticus patients, we found that patients with NORSE had a significant increase of serum pro-inflammatory cytokines. This was the case for interleukin-8, MIP-1α, and CCL2, the CSF also has an increase of interleukin-1β. This study seems to let us know that NORSE patients share some pathophysiological mechanisms not found in other status epilepticus patients.

The last part of our project was to investigate the patient for whom no etiology has been found at the end of the hospitalization, despite a very extensive workup with biological tests, EEG, MRI, clinical evaluation, to patients for whom we found an etiology. We noticed that the cytokine interleukin-8, CCL2, and MIP-1α were still much higher in the serum of those patients compared to those with an etiology. So, we conclude on this result that the serum innate immunity cytokine may be important to explain why status epilepticus occurred in these patients. This was the most important part of our project.

Our second part, thanks to the large cohort of patients we analyzed, was to investigate if the patient who have the most important dysregulation of this immunity, may also have the worst outcomes. For the first time, we used a heatmap correlation and we look at the correlation between serum or CSF, cytokine levels and patient’s outcome. And we observed that patients who have the most important concentration of the proinflammatory cytokine had the worst outcomes both at ICU discharge but also several months after status epilepticus onset. Based on that, we made the hypothesis that if you target this immune dysregulation, you may prevent and improve patient outcomes at short and long term.

We have two main perspectives on this project. The first one is to continue measuring the cytokine profile in other patients with NORSE and FIRES. Now we are able to receive biospecimen from all over the world, from patients with NORSE, for that we just need to enroll the patient in an open biorepository named the NORSE and FIRES Biorepository at Yale. When physicians have some patient and would like to get some cytokine results, they can just contact us. We have a generic email address is [email protected] and based on this we can enroll the patient in the biorepository, receive biospecimens, we perform the cytokine measurement, and we send back the result to the centers. By increasing the number of patients, we are also able to investigate the impact of specific immune therapies and the cytokine levels to know if, for example, when a patient has been started with a cytokine targeting interleukin 6, if that will be followed by a decrease of the interleukin-6 level in the blood and the CSF. So, it’s the first perspective we have to continue measuring samples and try to figure out the impact of immunotherapies on the cytokine level.

And our second part is more for therapeutic purposes. We demonstrated that immune therapies could really be efficient for such patients according to their cytokine profile. We would like to be able to guide the treatment strategy for patients who are refractory to first line immunotherapies like steroids, plasma exchange or in intravenous immunoglobulins. So currently we know that for these patients it’s recommended within one week to start a second line immunotherapy that can target interleukin-1β with anakinra, interleukin-6 with tocilizumab or other stuff. But currently we don’t know for which patient we have to use anakinra and for which we have to use tocilizumab, for example. We aim to be able to define some guidelines according to cytokine profiles, to be able to know which patients have to be treated by which therapy. I think currently a randomized clinical trial will be the best idea just to evaluate the efficacy of these therapeutics in such patients.