IEC 2025 | Recent advances in understanding the pathophysiology of NORSE

I’m Aurelie Hanin, I’m an associate professor in biochemistry at the Pitié-Salpêtrière Hospital in Paris and I presented at the past International Epilepsy Congress meeting a talk about the recent advances in the pathophysiology of NORSE and consequences. So this is a presentation and work that is mostly based on a recent publication our team did about the inflammation in patients with new-onset refractory status epilepticus or NORSE. So over the past few years, we realized that in patients with NORSE, that’s patients who present with a refractory status epilepticus without prior epilepsy and without any clear cause identified in the first few days. So we identified that these patients presented with some modification of the immunity, especially with elevated levels of some pro-inflammatory cytokines associated with the innate immunity. So it was a work we published two years ago. And during the publication of this work, we received many samples from all over the world from patients with NORSE and FIRES. And we realized by analyzing them that not all patients presented with the exact same cytokine profile. And that this cytokine modification correlated with the prognosis of the patients. But we were more interested about the underlying mechanisms for these different cytokine profiles. So we identified some modification in the cytokine profile and by looking at an extended cytokine panel with 96 inflammatory biomarkers we realized that we had like three different clusters of patients with NORSE. So it was a work we conducted at the Paris Brain Institute in Paris with the help of Martin Guillermo, who is a PhD student in our team. And by looking at the inflammatory profile, we realized that all patients compared to control had some modification of the inflammation with more innate immunity dysregulation, but they don’t have all the same levels of dysregulation. And so we had clusters of patients who were older than the other patients. And those patients presented no specific sign of inflammation. So based on this result, we suggested that they may not benefit from targeted immunotherapies. We had a second group of patients who are around 20, 30 years old, and those patients presented with a very strong innate immunity dysregulation. And when we look at the protein pathway analysis, we realized that those patients had more dysregulation of lymphocyte, chemotaxis, recruitment, degranulation. So it’s more dysregulated innate immunity processes. And based on the cytokine involved in these pathways, those patients may benefit from treatment with anakinra, tocilizumab, anti-TNF alpha therapies, or intrathecal dexamethasone therapies. And we had a third group of patients around the same age as the patients in cluster B. And those patients presented with dysregulation of the autoimmunity processes. So they had dysregulation of more the adaptive immune cells with T-cells function and development and the JAK-STAT pathways. So based on this profile, those patients may benefit more from treatment targeting the adaptive immunity. So either for B-cells or for T-cells, like rituximab or cyclophosphamide or anti-JAK-STAT therapies. So I think the recent advances we had is the possibility to profile the immune dysregulation for each patient separately and have more like a biomarker-based therapeutic approaches. Even if we still need to disclaim that so far it’s just observation retrospective, but we haven’t conducted any prospective studies or clinical trial aiming to select the best treatment based on the results we observe and the cytokine profile, but it’s the next step we can reach.

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