This study aims to present the longitudinal clinical profiles, predictive factors for outcomes, optimal regimen and duration of immunotherapy, and pathogenic biomarkers in cNORSE patients.

Patients with cNORSE, as defined by consensus criteria, were screened from a prospective autoimmune encephalitis screening cohort at a national referral hospital in Korea. The primary outcomes assessed were longitudinal functional scales, seizure frequency, and the number of anti-seizure medications. Key parameters included NORSE-related clinical features such as the duration of unconsciousness, immunotherapy profiles, and serial MRI scans, alongside pathogenic biomarkers such as cytokine/proteomics analysis and whole genome sequencing (WGS).

A total of 74 cNORSE patients were analyzed, with a mean age of 38.0 ± 18.2 years, including 36 males (48.6%). Poor one-year outcomes (mRS≥3) were predicted by the presence of mesial temporal lobe (mTL) and extra-mTL lesions at the 3-month MRI, as well as prolonged unconsciousness (≥ 60 days). Patients with mTL atrophy experienced a higher seizure burden post-NORSE. The SIRT protocol, consisting of steroid/IVIg, rituximab, and tocilizumab, was identified as the most effective treatment, with the optimal duration of immunotherapy appearing to be more than 18 weeks. Elevated levels of innate autoinflammatory cytokines were observed in serum and CSF, correlating with MRI lesion burden. Although no specific mutations were found in WGS, cNORSE patients had higher polygenic risk scores for other autoimmune-autoinflammatory diseases, correlating with immunotherapy response and showing a higher variant burden in brain tissue-enriched genes. An increased CSF tau level in cNORSE patients was a predictor for one-year outcomes.

This study provides insights into the clinical dynamics, prognostic factors, immunotherapy guidance, and genomic-proteomic biomarkers for cNORSE. These findings could help standardize the understanding of cNORSE pathogenesis and improve clinical decision-making.