To identify potential biomarkers in cryptogenic new-onset refractory status epilepticus (C-NORSE) by discovering autoantibodies that mediate disease pathogenesis.

While C-NORSE is mediated by inflammatory responses, reliable serologic biomarkers for predicting functional outcomes remain lacking. Phage immunoprecipitation sequencing (PhIP-seq) enables the discovery of novel antibodies that may aid disease stratification and prognostication.

Cerebrospinal fluid (CSF) from patients enrolled in a multicenter C-NORSE cohort were analyzed using PhIP-seq. Enzyme-linked immunosorbent assay (ELISA) was used to validate and screen for LMOD1-IgG in serum and CSF of C-NORSE and other neurologic diseases. Clinical outcomes, including modified Rankin Scale (mRS) and Clinical Assessment Scale in Autoimmune encephalitis (CASE), were evaluated over two years.

PhIP-seq was performed in 26 C-NORSE CSF. Among the top hits, leiomodin-1 (LMOD1) was selected as the leading autoantigen based on its prognostic potential in the development set, CNS expression, and prior reports of antibody relevance.  The optical density cutoff for LMOD1-IgG ELISA was determined as 0.30 based on receiver operating characteristic  analysis. The diagnostic performance of CSF testing exceeded that of serum. Using this cutoff, a total of 266 CSF were screened for LMOD1-IgG (C-NORSE=57, other autoimmune neurologic diseases=104, other non-autoimmune neurological diseases=105). LMOD1-IgG was detected in 16.5% (44/266) of samples, indicating that the antibody is not specific to C-NORSE. However, LMOD1-IgG-positivity was strongly associated with poor prognosis in C-NORSE. One-year and 2-year mRS and CASE scores were significantly worse in the LMOD1-positive compared to the LMOD1-negative patients (all P<0.05). While LMOD1-negative showed gradual improvement, none of the LMOD1-positive patients achieved mRS≤2 during the two-year follow-up. In addition, the median duration of continuous intravenous anesthesia and unconsciousness were significantly longer in the LMOD1-positive group.

LMOD-IgG was associated with significantly worse outcomes in C-NORSE. The presence of the antibody may identify a vulnerable subgroup predisposed to severe disease and NORSE-related brain injury.