Exploring pathways leading to drug-resistant epilepsy for patients with cryptogenic new onset refractory status epilepticus

Objective: Cryptogenic new onset refractory status epilepticus (cNORSE) carries high risks of long-term disability and post-NORSE epilepsy, but mechanisms remain unclear. We aimed to assess the predictive value of inflammatory and brain injury biomarkers and determine whether immune disturbances persist in the chronic phase. Methods: We enrolled 93 cNORSE patients from the Pitié-Salpêtrière Hospital and the Yale NORSE/FIRES biorepository (2013–2025). Serum and cerebrospinal fluid (CSF) samples were collected during status epilepticus (SE), with outcomes assessed 6–12 months after resolution. To investigate post-cNORSE epilepsy, we compared 39 post-cNORSE patients (25 with paired acute samples) to 40 patients with temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS) and 20 with chronic immune-mediated encephalitis. Results: During cNORSE, elevated innate cytokines (serum CXCL8, CCL2; CSF IL-6, CXCL8, CCL2, MIP-1α, G-CSF) and brain injury biomarkers (serum and CSF neurofilament light chain [NfL], CSF neuron-specific enolase) correlated with worse functional outcomes. Multivariate models demonstrated that adding serum NfL to cytokines improved poor outcome prediction (area under the curve =.75). In contrast, no acute biomarker predicted post-cNORSE epilepsy, which was instead associated with prolonged SE, magnetic resonance imaging abnormalities, and the need for more intensive treatment. In paired analyses, most serum cytokines normalized during the chronic phase, particularly IL-6, IL-10, and IL-1β, although new adaptive immune disturbances (IL-17A, IL-12p70, TNFα) appeared in 20% of patients. No chronic elevations of innate cytokines were observed in post-cNORSE patients. Conversely, elevated age-adjusted NfL levels were more frequent in post-cNORSE epilepsy (64%) than encephalitis (45%) and TLE-HS (20%), (p <.001), with elevated NfL levels correlating with poor functional outcomes (p =.019). Significance: Innate immune activation is a hallmark of acute cNORSE but largely resolves in the chronic phase, arguing against persistent innate inflammation as the driver of post-cNORSE epilepsy. In contrast, persistently elevated NfL levels suggest ongoing axonal injury, potentially contributing to poor outcomes. Integrating inflammatory and neuroaxonal injury biomarkers may improve risk stratification and guide long-term management.