Importance: Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes. Objective: To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy. Design, Setting, and Participants: This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded. Exposures: Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF). Main Outcomes and Measures: Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes. Results: A total of 78 patients with cNORSE (mean 95% CI age, 37 30-41 years; 44 female 56%) and 2 independent cohorts of 211 patients (mean 95% CI age, 69 66-71 years; 128 female 61%) and 73 patients (mean 95% CI age, 56 45-65 years; 39 male 53%) with eSE were included. NfL concentrations were markedly elevated in cNORSE-approximately 10-fold higher in CSF and 4-fold higher in serum-compared with the eSE cohorts (CSF: median IQR, 6408 1503-22 963 pg/mL compared with 694 219-2389 pg/mL; serum: median IQR, 231 99-855 pg/mL compared with 55 20-135 pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median IQR, 11 7-19 and 7 5-14 pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median IQR, 101 51-137 pg/mL), week 2 (median IQR, 197 117-324 pg/mL), and week 3 (median IQR, 598 163-1000 pg/mL) after onset (P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve AUROC, 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03). Conclusions and Relevance: Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.
Meletti et al. (2026) studied this question.