Background: New-onset refractory status epilepticus (NORSE) caused by anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis and cryptogenic etiologies are various in clinical features. The underlying mechanisms of the diseases have still remained elusive.Methods: 6 patients with anti-NMDAR encephalitis NORSE, 5 with cryptogenic NORSE (C-NORSE), and 5 controls were enrolled. Clinical data, including clinical features, cerebrospinal uid (CSF) samples, and cranial images were collected. CSF samples were tested for FAIMS based quantitative proteomic analysis, immunome protein microarray, and in ammatory cytokine array. Bioinformatics and immunostaining were used for interpretation and veri cation.Results: The clinical features of anti-NMDAR encephalitis NORSE and C-NORSE patients were similar to those reported previously. Proteomic analysis revealed that 101 proteins (63 up-regulated and 38 downregulated) and 56 proteins (42 up-regulated and 14 down-regulated) changed in CSF samples of anti-NMDAR encephalitis NORSE and C-NORSE patients, respectively. The mean fold-change of the upregulated proteins, namely up-proteomic score in this study, was positively associated with the severity of disease, including ICU stay, mRS score at discharge, and time taken for patients awaking from a coma. The distribution of changed proteins in CSF between the two diseases were quite different. Pathways of humoral immune response, wound healing, and epigenetic regulation of transcription were up-regulated in anti-NMDAR encephalitis NORSE. Pathways of innate and lymphocyte mediated immune response, synaptic functions, ubiquitination, and cell apoptosis were up-regulated in C-NORSE group, suggesting that C-NORSE could undergo neurodegeneration. This was consistent with a mouse model of SE, which showed high ubiquitination and cell apoptosis in CA1 to CA3 regions of hippocampus. Immunome microarray analysis demonstrated high autoantibody targeting 48 proteins in CSF samples of anti-NMDAR encephalitis NORSE. However, in C-NORSE, the reaction was kept at a very low level.In ammatory cytokine array, unexpectedly, showed no remarkable changes except for decreased level of interleukin-6 (IL-6) in both anti-NMDAR encephalitis NORSE and C-NORSE.Conclusions: The present study suggests that the up-proteomic score of CSF could be a promising indicator for assessment of the severity of anti-NMDAR encephalitis NORSE and C-NORSE. The distinct CSF proteomes imply different pathogenic mechanisms of the two diseases, and immunotherapy strategies as well.