To investigate the longitudinal clinical profiles and prognostic factors for cryptogenic New-Onset Refractory Status Epilepticus (NORSE).

C-NORSE lacks comprehensive knowledge regarding its longitudinal clinical phenotypes and long-term treatment outcomes. We aimed to investigate the longitudinal clinical profiles for long-term outcomes and prognostic factors in C-NORSE patients.

In a prospective cohort study for encephalitis, C-NORSE patients diagnosed based on the ILAE consensus definition between January 1, 2014, to March 31, 2023 were analyzed. The primary study outcomes included longitudinal clinical data during a 2-year follow-up (mRS, CASE score, seizure frequency, and the number of anti-seizure medications) and a 3-month follow-up MRI, featuring serial brain volumetric analyses for two years.

Among 135 NORSE patients, 74 with C-NORSE (median age 32.7 [IQR 23.5-47.3], 36 [48.6%] male) were included. All patients received first-line immunotherapy (steroids or IVIG), with 83.8% (62/74) regaining mental functionality within a median duration of 30 days [IQR 14-56]. One year later, 37.1% (26/70) of individuals achieved favorable outcomes (mRS 0, 1, and 2), increasing to 50% (31/62) after two years. Unfavorable one-year prognosis correlated with hippocampal atrophy plus extra-limbic lesions observed at 3-month MRI (OR 1.295, 95% CI 1.086 to 1.544, P = .006) and prolonged unconsciousness exceeding 60 days (OR 1.426, 95% CI 1.101 to 1.847, P = .010). On longitudinal MRI brain volumetric analysis, significantly different rates of hippocampal atrophy were observed between the good and poor outcome groups (β = -44.2; 95% CI, -69.69 to -16.71; P = .002). Continuous immunotherapy appeared effective up to the 18^th week following NORSE onset, but its efficacy beyond that point remained uncertain.

This study elucidates the prognostic factors in C-NORSE. The presence of hippocampal atrophy and extra-limbic lesions on 3-month follow-up MRI were the poor prognostication factors. Continuous immunotherapy may benefit C-NORSE patients up to the 18^th week from onset.