Original article| Volume 45, 102382, October 2020

Impact of intrathecal IgG synthesis on neurological disability in patients with multiple sclerosis


      • Prognostic impact of serum and CSF biomarkers at diagnosis was evaluated in MS.
      • CSF IgG level and OCB count at diagnosis well predicted the subsequent EDSS score.
      • Derivatives of CSF IgG level showed stronger correlation with neurological outcomes.
      • Patients with primary progressive MS showed abnormally high CSF IgG levels.
      • CSF IgG and OCB are important predictors of long-term neurological disability in MS.



      The association between routine laboratory findings, including cerebrospinal fluid biomarkers, and neurological outcomes in patients with multiple sclerosis (MS) has not been fully elucidated. In this study, we evaluated blood and cerebrospinal fluid (CSF) analysis results at diagnosis and before treatment in patients with MS and assessed their correlations with neurological outcomes.

      Materials and methods

      In this study, 38 consecutive patients with MS (36 with relapsing-remitting MS and 2 with primary progressive MS) were recruited. Before treatment, all patients underwent routine CSF analysis at the time of diagnosis, including evaluation of albumin and immunoglobulin G (IgG) levels. The association between laboratory data and neurological outcomes was comprehensively evaluated. Subsequent neurological outcome was assessed by using the Expanded Disability Status Scale (EDSS) score at 1 year and 5 years after diagnosis and relapse frequency in the first year and in the first 5 years.


      The IgG level in the CSF (rho = 0.46, p = 0.004), oligoclonal band count (rho = 0.61, p = 0.006), ratio of IgG and total protein in CSF (rho = 0.59, p < 0.0001), and ratio of IgG and albumin in CSF (rho = 0.67, p < 0.0001) showed moderate to strong correlations with the subsequent EDSS score 1 year after diagnosis. These variables still showed significant correlations with EDSS 5 years later. Albumin and lactate dehydrogenase levels in CSF did not correlate with the subsequent EDSS score. Relapse frequency did not correlate with any of the studied serum and CSF biomarkers.


      IgG levels in CSF at MS diagnosis are significantly correlated with the level of neurological disability independent of the relapse frequency. Markers of intrathecal IgG synthesis, such as the IgG index, are useful in estimating the present and subsequent clinical severity in patients with MS.


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        • Akaishi T.
        • Takahashi T.
        • Nakashima I.
        Oligoclonal bands and periventricular lesions in multiple sclerosis will not increase blood-brain barrier permeability.
        J. Neurol. Sci. 2018; 387: 129-133
        • Arneth B.M.
        Impact of B cells to the pathophysiology of multiple sclerosis.
        J. Neuroinflammation. 2019; 16: 128
        • Bankoti J.
        • Apeltsin L.
        • Hauser S.L.
        • Allen S.
        • Albertolle M.E.
        • Witkowska H.E.
        • et al.
        In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses.
        Ann. Neurol. 2014; 75: 266-276
        • Barkhof F.
        • Filippi M.
        • Miller D.H.
        • Scheltens P.
        • Campi A.
        • Polman C.H.
        • et al.
        Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis.
        Brain. 1997; 120: 2059-2069
        • Becker M.
        • Latarche C.
        • Roman E.
        • Debouverie M.
        • Malaplate-Armand C.
        • Guillemin F.
        No prognostic value of routine cerebrospinal fluid biomarkers in a population-based cohort of 407 multiple sclerosis patients.
        BMC Neurol. 2015; 15: 79
        • Dalakas M.C.
        B cells as therapeutic targets in autoimmune neurological disorders.
        Nat. Clin. Pract. Neurol. 2008; 4: 557-567
        • Gasperi C.
        • Salmen A.
        • Antony G.
        • Bayas A.
        • Heesen C.
        • Kümpfel T.
        • et al.
        Association of intrathecal immunoglobulin G synthesis with disability worsening in multiple sclerosis.
        JAMA Neurol. 2019; 76: 841-849
        • Harbo H.F.
        • Gold R.
        • Tintoré M.
        Sex and gender issues in multiple sclerosis.
        Ther. Adv. Neurol. Disord. 2013; 6: 237-248
        • Harbo H.F.
        • Isobe N.
        • Berg-Hansen P.
        • Bos S.D.
        • Caillier S.J.
        • Gustavsen M.W.
        • et al.
        Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis.
        Mult. Scler. 2014; 20: 660-668
        • Idiman E.
        • Ozakbas S.
        • Dogan Y.
        • Kosehasanogullari G.
        The significance of oligoclonal bands in multiple sclerosis: relevance of demographic and clinical features, and immunogenetic backgrounds.
        J. Neuroimmunol. 2009; 212: 121-124
        • Joseph F.G.
        • Hirst C.L.
        • Pickersgill T.P.
        • Ben-Shlomo Y.
        • Robertson N.P.
        • Scolding N.J.
        CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients.
        J. Neurol. Neurosurg. Psychiatry. 2009; 80: 292-296
        • Kurtzke J.F.
        Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
        Neurology. 1983; 33: 1444-1452
        • Lublin F.D.
        • Reingold S.C.
        • Cohen J.A.
        • Cutter G.R.
        • Sørensen P.S.
        • Thompson A.J.
        • et al.
        Defining the clinical course of multiple sclerosis: the 2013 revisions.
        Neurology. 2014; 83: 278-286
        • Mameli G.
        • Cocco E.
        • Frau J.
        • Marrosu M.G.
        • Sechi L.A.
        Epstein Barr Virus and Mycobacterium avium subsp. paratuberculosis peptides are recognized in sera and cerebrospinal fluid of MS patients.
        Sci. Rep. 2016; 6: 22401
        • Martinelli V.
        • Rodegher M.
        • Moiola L.
        • Comi G.
        Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis.
        Neurol. Sci. 2004; 25 (S350-355)
        • Michel L.
        • Touil H.
        • Pikor N.B.
        • Gommerman J.L.
        • Prat A.
        • Bar-Or A.
        B Cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation.
        Front. Immunol. 2015; 6: 636
        • Milo R.
        • Miller A.
        Revised diagnostic criteria of multiple sclerosis.
        Autoimmun. Rev. 2014; 13: 518-524
        • Nakashima I.
        • Fujihara K.
        • Miyazawa H.
        • Misu T.
        • Fujimori J.
        • Sato S.
        • et al.
        Relevance of callosal and periventricular MRI lesions to oligoclonal bands in multiple sclerosis.
        Acta Neurol. Scand. 2006; 113: 125-131
        • Polman C.H.
        • Reingold S.C.
        • Banwell B.
        • Clanet M.
        • Cohen J.A.
        • Filippi M.
        • et al.
        Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
        Ann. Neurol. 2011; 69: 292-302
        • Reiber H.
        • Peter J.B.
        Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs.
        J. Neurol. Sci. 2001; 184: 101-122
        • Sato D.K.
        • Nakashima I.
        • Takahashi T.
        • Misu T.
        • Waters P.
        • Kuroda H.
        • et al.
        Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders.
        Neurology. 2013; 80: 2210-2216
        • Serafini B.
        • Rosicarelli B.
        • Magliozzi R.
        • Stigliano E.
        • Aloisi F.
        Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis.
        Brain Pathol. 2004; 14: 164-174
        • Siritho S.
        • Freedman M.S.
        The prognostic significance of cerebrospinal fluid in multiple sclerosis.
        J. Neurol. Sci. 2009; 279: 21-25
        • Takahashi T.
        • Fujihara K.
        • Nakashima I.
        • Misu T.
        • Miyazawa I.
        • Nakamura M.
        • et al.
        Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica.
        Tohoku J. Exp. Med. 2006; 210: 307-313
        • Thompson A.J.
        • Banwell B.L.
        • Barkhof F.
        • Carroll W.M.
        • Coetzee T.
        • Comi G.
        • et al.
        Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
        Lancet Neurol. 2018; 17: 162-173
        • Tintore M.
        • Rovira A.
        • Rio J.
        • Tur C.
        • Pelayo R.
        • Nos C.
        • et al.
        Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?.
        Neurology. 2008; 70: 1079-1083
        • Tur C.
        • Montalban X.
        CSF oligoclonal bands are important in the diagnosis of multiple sclerosis, unreasonably downplayed by the McDonald criteria 2010: no.
        Mult. Scler. 2013; 19: 717-718
        • Yamout B.
        • Al Khawajah M.
        Radiologically isolated syndrome and multiple sclerosis.
        Mult. Scler. Relat. Disord. 2017; 17: 234-237