Exploring Pathways Leading to Drug-Resistant Epilepsy for Patients with Cryptogenic New Onset Refractory Status Epilepticus (cNORSE)

A recent study coming out of our Rare Epilepsy Partnership Award with NORSE Institute examined whether biological markers in blood and cerebrospinal fluid could help predict outcomes in patients with Cryptogenic New-Onset Refractory Status Epilepticus (cNORSE), a rare condition in which people with no prior epilepsy suddenly develop prolonged seizures that do not respond to standard treatments and have no clear cause. 

The study included 93 patients from international centers. Samples were collected during the acute seizure phase, and patients’ recovery was evaluated 6–12 months later, with additional long-term samples from some patients who later developed epilepsy. 

During the acute phase, patients with higher levels of inflammatory molecules and Neurofilament Light Chain (NfL)—a protein released when nerve cells are damaged—tended to have worse long-term functional outcomes. Combining inflammatory markers with NfL improved the ability to predict long-term disability. 

However, these early biomarkers did not predict which patients would later develop epilepsy. Instead, the risk of post-cNORSE epilepsy was linked to clinical factors, such as longer-lasting seizures, abnormal MRI findings, and the need for more intensive treatments. 

Over time, most inflammatory markers returned to normal. In contrast, many patients who developed epilepsy after cNORSE continued to have elevated NfL levels even years later, suggesting ongoing nerve fiber injury. Overall, the findings indicate that early immune activation influences the severity of the initial illness, while long-term epilepsy after cNORSE appears more related to lasting neuronal damage than persistent inflammation. 

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