NORSE is a severe neurological disorder with high rates of morbidity and mortality. While certain commonly tested viruses (i.e. herpes simplex virus 1) and antibodies (i.e. NMDA, GAD65, VGKC) may trigger NORSE, >50% of cases remain cryptogenic. A better understanding of the host immune response in cryptogenic NORSE (cNORSE) may provide insight into dysregulated pathways that could inform more targeted treatment approaches.

To investigate cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) and host transcriptomics of cryptogenic New-onset refractory status epilepticus (NORSE).

cNORSE and pediatric cNORSE cohorts were a median age of 34.0 and 14.1 and 39% and 22% male, respectively. 25/38 (66%) met criteria for febrile infection-related epilepsy syndrome (FIRES). NMDA-receptor and viral encephalitis cohorts were a median age of 14.0 and 8.1 and 43% and 22% male, respectively. There were no viral infections identified on mNGS in the cNORSE cohort. There were no significant differences in gene expression signatures between pediatric cNORSE and NMDA-receptor encephalitis. 2,471 genes were differentially expressed between pediatric cNORSE and viral encephalitis (p<0.01, LogFC >|1|). Significant upregulated pathways correlated with epileptogenesis including glutaminergic receptor signaling, endocannabinoid neuronal synapse, and reelin signaling in neurons.