Intrathecal immunoglobulin production is a hallmark of central nervous system (CNS) inflammation and can be observed in autoimmune disorders of the CNS, primarily multiple sclerosis (MS), but also in other inflammatory conditions such as MOG antibody disease (MOGAD) and neuromyelitis optica spectrum disorder with aquaporin-4 antibodies (NMOSD-AQP4), as well as autoimmune encephalitis (AE). The assessment of intrathecal synthesis of immunoglobulins involves the detection of IgG oligoclonal bands (OCBs) via isoelectric focusing, the gold standard method, and the more recently developed automated kappa index. In MS, both markers possess equivalent diagnostic and prognostic value, and their potential utility in monitoring anti-humoral MS therapies is currently under investigation. Conversely, the absence of OCBs and a negative kappa index support the diagnosis of MOGAD and NMOSD-AQP4, given the low OCBs prevalence in these disorders. In MOGAD and NMOSD-AQP4, the prognostic and therapeutic predictive value of OCBs and the kappa index at baseline and during follow-up remains preliminary, with ongoing studies yielding variable results. As for AE, OCBs detection has been incorporated into diagnostic criteria exclusively in cases of NMDAR encephalitis and seronegative AE and have demonstrated usefulness as prognosis factor, the usefulness as monitoring tool being investigated. The detection of specific autoantibodies in serum and/or CSF is also integrated in diagnostic criteria of these diseases. Future approaches in monitoring CNS autoimmune disorders are likely to combine intrathecal immunoglobulin detection with other biomarkers such as serum neurofilament light chain (sNfL), indicative of neuronal injury, and glial fibrillary acidic protein (GFAP), reflective of astrocytic damage.