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Patients with multiple sclerosis, primary CNS lymphoma, aquaporin\u20104 immunoglobulin\u2009G positivity, non\u2010inflammatory disorders, and healthy individuals were used as controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 32 NS patients (59% women; median age, 59\u2009years [19\u201381]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin\u20104 immunoglobulin\u2009G positive, and 34 patients with non\u2010inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL\u20102, IL\u20106, IL\u201010, IL\u201013, BAFF, IL\u20108\/CXCL8, CXCL9, CXCL10, CXCL13, GM\u2010CSF, interferon\u2010gamma, and TNF\u2010alpha levels were significantly higher in NS patients compared with non\u2010inflammatory controls (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.02); elevations were more common in CSF than serum. Concurrent elevation of IL\u20106, CXCL9, CXCL10, GM\u2010CSF, interferon\u2010gamma, and TNF\u2010alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL\u20106, IL\u201010, IL\u201013, CXCL9, CXL10, GM\u2010CSF, and TNF\u2010alpha associated with measures of disease activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>NS CSF cytokine\/chemokine profiles suggest T cell (mainly T helper cell type\u20091), macrophage, and B\u2010cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. 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