Review Article| Volume 40, ISSUE 3, P369-377, September 2020

Cerebrospinal Fluid Testing for Multiple Sclerosis


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wallin M.T.
        • Culpepper W.J.
        • Nichols E.
        • et al.
        Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
        Lancet Neurol. 2019; 18: 269-285
        • Thompson A.J.
        • Baranzini S.E.
        • Geurts J.
        • et al.
        Multiple sclerosis.
        Lancet. 2018; 391: 1622-1636
        • Olek M.J.
        • Howard J.
        Clinical presentation, course, and prognosis of multiple sclerosis in adults.
        (Available at:) (Accessed March 11, 2020)
        • Thompson A.J.
        • Banwell B.L.
        • Barkhof F.
        • et al.
        Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
        Lancet Neurol. 2018; 17: 162-173
        • Okuda D.
        • Mowry E.
        • Beheshtian A.
        • et al.
        Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome.
        Neurology. 2009; 73: 1714
        • Lebrun C.
        • Kantarci O.H.
        • Siva A.
        • et al.
        Anomalies characteristic of central nervous system demyelination: radiologically isolated syndrome.
        Neurol Clin. 2018; 36: 59-68
        • Arrambide G.
        • Tintore M.
        CSF examination still has value in the diagnosis of MS - Commentary.
        Mult Scler. 2016;
        • Andersson M.
        • Alvarez-Cermeñio J.
        • Bernardi G.
        • et al.
        Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.
        J Neurol Neurosurg Psychiatry. 1994;
        • Stangel M.
        • Fredrikson S.
        • Meinl E.
        • et al.
        The utility of cerebrospinal fluid analysis in patients with multiple sclerosis.
        Nat Rev Neurol. 2013;
        • Freedman M.S.
        • Thompson E.J.
        • Deisenhammer F.
        • et al.
        Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.
        Arch Neurol. 2005; 62: 865-870
        • Deisenhammer F.
        • Zetterberg H.
        • Fitzner B.
        • et al.
        The cerebrospinal fluid in multiple sclerosis.
        Front Immunol. 2019; 10: 1-10
      1. Giovanni G. Cerebrospinal Fluid Analysis in Multiple Sclerosis and Related Disorders. Handbook of Clinical Neurology. (D.S. Goodin, Editor) Elsevier B.V.: Amsterdam, The Netherlands, 2014;122: 681-702.

        • Lo Sasso B.
        • Agnello L.
        • Bivona G.
        • et al.
        Cerebrospinal fluid analysis in multiple sclerosis diagnosis: an update.
        Med. 2019; 55: 3-7
        • Tintoré M.
        • Rovira A.
        • Río J.
        • et al.
        Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?.
        Neurology. 2008;
        • Dobson R.
        • Ramagopalan S.
        • Davis A.
        • et al.
        Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.
        J Neurol Neurosurg Psychiatry. 2013;
        • Kuhle J.
        • Disanto G.
        • Dobson R.
        • et al.
        Conversion from clinically isolated syndrome to multiple sclerosis: a large multicantre study.
        Mult Scler. 2015;
        • Tintore M.
        • Rovira À.
        • Río J.
        • et al.
        Defining high, medium and low impact prognostic factors for developing multiple sclerosis.
        Brain. 2015;
        • Huss A.M.
        • Halbgebauer S.
        • Öckl P.
        • et al.
        Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria.
        J Neurol. 2016;
        • Freedman M.S.
        • Thompson E.J.
        • Deisenhammer F.
        • et al.
        Cerebrospinal fluid analysis in the diagnosis of multiple sclerosis.
        Adv Neurol. 2006; 98: 147-160
        • Keren D.F.
        Protein electrophoresis in clinical diagnosis.
        American Society for Clinical Pathology Press, Chicago, Illinois2012
        • Fortini A.S.
        • Sanders E.L.
        • Weinshenker B.G.
        • et al.
        Cerebrospinal fluid oligoclonal bands in the diagnosis of multiple sclerosis: isoelectric focusing with IgG immunoblotting compared with high-resolution agarose gel electrophoresis and cerebrospinal fluid IgG index.
        Am J Clin Pathol. 2003; 120: 672-675
        • Lunding J.
        • Midgard R.
        • Vedeler C.A.
        Oligoclonal bands in cerebrospinal fluid: a comparative study of isoelectric focusing, agarose gel electrophoresis and IgG index.
        Acta Neurol Scand. 2000; 102: 322-325
        • Peter J.B.
        • McKeown K.L.
        • Agopian M.S.
        Assessment of different methods to detect increased autochthonous production of immunoglobulin G and oligoclonal immunoglobulins in multiple sclerosis.
        Am J Clin Pathol. 1992; 97: 858-860
      2. College of American Pathologists. Cerebrospinal fluid chemistry and oligoclonal bands (M-B 2019). 2019.

        • Franciotta D.M.
        • Grimaldi L.M.E.
        • Martino G.V.
        • et al.
        Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis.
        Ann Neurol. 1989; 26: 787-789
        • Ohman S.
        • Ernerudh J.
        • Forsberg P.
        • et al.
        Comparison of seven formulae and isoelectrofocusing for determination of intrathecally produced IgG in neurological diseases.
        Ann Clin Biochem. 1992; 29: 405-410
        • Magliozzi R.
        • Cross A.H.
        Can CSF biomarkers predict future MS disease activity and severity?.
        Mult Scler J. 2020; 26: 582-590
        • Link H.
        • Tibbling G.
        Principles of albumin and IgG analyses in neurological disorders. III. evaluation of igg synthesis within the central nervous system in multiple sclerosis.
        Scand J Clin Lab Invest. 1977; 37: 397-401
        • Petzold A.
        Intrathecal oligoclonal IgG synthesis in multiple sclerosis.
        J Neuroimmunol. 2013; 262: 1-10
        • Papadopoulos M.C.
        • Bennett J.L.
        • Verkman A.S.
        Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
        Nat Rev Neurol. 2014;
        • Papadopoulos M.C.
        • Verkman A.S.
        Aquaporin 4 and neuromyelitis optica.
        Lancet Neurol. 2012;
        • Di Pauli F.
        • Berger T.
        Myelin oligodendrocyte glycoprotein antibody-associated disorders: toward a new spectrum of inflammatory demyelinating CNS disorders?.
        Front Immunol. 2018; 9: 1-12
        • Menéndez-Valladares P.
        • García-Sánchez M.
        • Cuadri Benítez P.
        • et al.
        Free kappa light chains in cerebrospinal fluid as a biomarker to assess risk conversion to multiple sclerosis.
        Mult Scler J Exp Transl Clin. 2015; 1 (205521731562093)
        • Bourahoui A.
        • De Seze J.
        • Guttierez R.
        • et al.
        CSF isoelectrofocusing in a large cohort of MS and other neurological diseases.
        Eur J Neurol. 2004; 11: 525-529
        • Agnello L.
        • Lo Sasso B.
        • Salemi G.
        • et al.
        Clinical use of κ free light chains index as a screening test for multiple sclerosis.
        Lab Med. 2020;
        • Zozulya A.L.
        • Wiendl H.
        The role of regulatory T cells in multiple sclerosis.
        Nat Clin Pract Neurol. 2008; 4: 384-398
        • Lehmann-Horn K.
        • Kinzel S.
        • Weber M.S.
        Deciphering the role of B cells in multiple sclerosis—towards specific targeting of pathogenic function.
        Int J Mol Sci. 2017; 18
        • Schwenkenbecher P.
        • Konen F.F.
        • Wurster U.
        • et al.
        The persisting significance of oligoclonal bands in the dawning era of kappa free light chains for the diagnosis of multiple sclerosis.
        Int J Mol Sci. 2018; 19
        • Bracco F.
        • Gallo P.
        • Menna R.
        • et al.
        Free light chains in the CSF in multiple sclerosis.
        J Neurol. 1987;
        • Presslauer S.
        • Milosavljevic D.
        • Huebl W.
        • et al.
        Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: a multicenter study.
        Mult Scler. 2016; 22: 502-510
        • Presslauer S.
        • Milosavljevic D.
        • Brücke T.
        • et al.
        Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis.
        J Neurol. 2008; 255: 1508-1514
        • Forsberg P.
        • Henriksson A.
        • Link H.
        • et al.
        Reference values for CSF-igm, CSF-igm/s-igm ratio and igm index, and its application to patients with multiple sclerosis and aseptic meningoencephalitis.
        Scand J Clin Lab Invest. 1984; 44: 7-12
        • Pfuhl C.
        • Grittner U.
        • Gieß R.M.
        • et al.
        Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis.
        Neurology. 2019; 93: e1439-e1451
        • Villar L.M.
        • Masjuan J.
        • González-Porqué P.
        • et al.
        Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS.
        Neurology. 2002; 59: 555-559
        • Perini P.
        • Ranzato F.
        • Calabrese M.
        • et al.
        Intrathecal IgM production at clinical onset correlates with a more severe disease course in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 2006; 77: 953-955
        • Rotstein D.L.
        • Healy B.C.
        • Malik M.T.
        • et al.
        Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort.
        JAMA Neurol. 2015; 72: 152-158
        • Domingues R.B.
        • Fernandes G.B.P.
        • Leite FBV de M.
        • et al.
        The cerebrospinal fluid in multiple sclerosis: far beyond the bands.
        Einstein (Sao Paulo). 2017; 15: 100-104
        • Dendrou C.A.
        • Fugger L.
        • Friese M.A.
        Immunopathology of multiple sclerosis.
        Nat Rev Immunol. 2015; 15: 545-558
        • Vladić A.
        • Horvat G.
        • Vukadin S.
        • et al.
        Cerebrospinal fluid and serum protein levels of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R gp80) in multiple sclerosis patients.
        Cytokine. 2002; 20: 86-88
        • Malmeström C.
        • Andersson B.A.
        • Haghighi S.
        • et al.
        IL-6 and CCL2 levels in CSF are associated with the clinical course of MS: implications for their possible immunopathogenic roles.
        J Neuroimmunol. 2006; 175: 176-182
        • Matsushita T.
        • Tateishi T.
        • Isobe N.
        • et al.
        Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis.
        PLoS One. 2013; 8
        • Romme Christensen J.
        • Börnsen L.
        • Khademi M.
        • et al.
        CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis.
        Mult Scler J. 2013; 19: 877-884
        • Alvarez E.
        • Piccio L.
        • Mikesell R.J.
        • et al.
        CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions.
        Mult Scler J. 2013; 19: 1204-1208
        • Ferraro D.
        • Galli V.
        • Vitetta F.
        • et al.
        Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: association with oligoclonal IgM bands and prediction of multiple sclerosis diagnosis.
        J Neuroimmunol. 2015;
        • Gaiottino J.
        • Norgren N.
        • Dobson R.
        • et al.
        Increased neurofilament light chain blood levels in neurodegenerative neurological diseases.
        PLoS One. 2013; 8
        • Lycke J.N.
        • Karlsson J.E.
        • Andersen O.
        • et al.
        Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 1998; 64: 402-404
        • Burman J.
        • Zetterberg H.
        • Fransson M.
        • et al.
        Assessing tissue damage in multiple sclerosis: a biomarker approach.
        Acta Neurol Scand. 2014; 130: 81-89
        • Salzer J.
        • Svenningsson A.
        • Sundström P.
        Neurofilament light as a prognostic marker in multiple sclerosis.
        Mult Scler. 2010; 16: 287-292
        • Novakova L.
        • Axelsson M.
        • Khademi M.
        • et al.
        Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis.
        J Neurochem. 2017; 141: 296-304
        • Quintana E.
        • Coll C.
        • Salavedra-Pont J.
        • et al.
        Cognitive impairment in early stages of multiple sclerosis is associated with high cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain.
        Eur J Neurol. 2018; 25: 1189-1191
        • Rosengren L.E.
        • Lycke J.
        • Andersen O.
        Glial fibrillary acidic protein in CSF of multiple sclerosis patients: relation to neurological deficit.
        J Neurol Sci. 1995; 133: 61-65
        • Petzold A.
        • Eikelenboom M.J.
        • Gveric D.
        • et al.
        Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations.
        Brain. 2002; 125: 1462-1473
        • Malmeström C.
        • Haghighi S.
        • Rosengren L.
        • et al.
        Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS.
        Neurology. 2003;
        • Salzer J.
        The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level - YES.
        Mult Scler. 2015; 21: 1239-1240