Advertisement

Intrathecal oligoclonal IgG synthesis in multiple sclerosis

  • Axel Petzold
    Correspondence
    VU Medical Center, Department of Neurology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: +31 204445292.
    Affiliations
    Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
    UCL Institute of Neurology, Neuroimmunology & CSF Laboratory, Queen Square, London, United Kingdom
    Search for articles by this author

      Highlights

      • A review of the biology of intrathecal IgG production (CSF OCB)
      • A multi-centre laboratory analysis on the analytical accuracy of CSF OCB
      • A meta-analysis summarising the diagnostic accuracy of CSF OCB for MS
      • A review of the prognostic value of CSF OCB

      Abstract

      The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence for dissemination in space could be substituted by a paraclinical test, cerebrospinal fluid (CSF) oligoclonal bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be tested prospectively.

      Keywords

      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'

      Subscribe:

      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abraira V.
        • Alvarez-Cermeño J.C.
        • Arroyo R.
        • Cámara C.
        • Casanova B.
        • Cubillo S.
        • de Andrés C.
        • Espejo C.
        • Fernández
        • et al.
        Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice.
        J. Immunol. Methods. 2011; 371: 170-173
        • Andersson M.
        • Alvarez-Cermeño J.
        • Bernardi G.
        • Cogato I.
        • Fredman P.
        • Frederiksen J.
        • Fredrikson S.
        • Gallo P.
        • Grimaldi L.M.
        • Grønning M.
        Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.
        J. Neurol. Neurosurg. Psychiatry. 1994; 57: 897-902
        • Arneth B.
        • Birklein F.
        High sensitivity of free lambda and free kappa light chains for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid.
        Acta Neurol. Scand. 2009; 119: 39-44
      1. Axelsson M. Mattsson N. Malmestrom C. Nilsson S. Haghighi S. Rosengren L. Zetterberg H. Lycke J. Change in number and pattern of CSF oligoclonal bands in MS patients over time. Multiple Sclerosis Journal. vol. 17. 2011: P646 (S281. ECTRIMS ACTRIMS)
        • Bednárová J.
        • Stourac P.
        • Adam P.
        Relevance of immunological variables in neuroborreliosis and multiple sclerosis.
        Acta Neurol. Scand. 2005; 112: 97-102
        • Ben-Hur T.
        • Abramsky O.
        • River Y.
        The clinical significance of a single abnormal immunoglobulin band in cerebrospinal fluid electrophoresis.
        J. Neurol. Sci. 1996; 136: 159-161
        • Bossuyt Patrick M.
        • Reitsma Johannes B.
        • Bruns David E.
        • Gatsonis Constantine A.
        • Glasziou Paul P.
        • Irwig Les M.
        • Lijmer Jeroen G.
        • Moher David
        • Rennie Drummond
        • CWde Vet Henrica
        • Standards for Reporting of Diagnostic Accuracy
        Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative.
        BMJ. 2003; 326: 41-44
        • Bourahoui A.
        • De Seze J.
        • Guttierez R.
        • Onraed B.
        • Hennache B.
        • Ferriby D.
        • Stojkovic T.
        • Vermersch P.
        CSF isoelectrofocusing in a large cohort of MS and other neurological diseases.
        Eur. J. Neurol. 2004; 11: 525-529
        • Brennan Kathryn M.
        • Galban-Horcajo Francesc
        • Rinaldi Simon
        • O'Leary Colin P.
        • Goodyear Carl S.
        • Kalna Gabriela
        • Arthur Ariel
        • Elliot Christina
        • Barnett Sue
        • Linington Christopher
        • Bennett Jeffrey L.
        • Owens Gregory P.
        • Willison Hugh J.
        Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis.
        J. Neuroimmunol. 2011; 238: 87-95
        • Brettschneider Johannes
        • Czerwoniak Anne
        • Senel Makbule
        • Fang Lubin
        • Kassubek Jan
        • Pinkhardt Elmar
        • Lauda Florian
        • Kapfer Tamara
        • Jesse Sarah
        • Lehmensiek Vera
        • Ludolph Albert C.
        • Otto Markus
        • Tumani Hayrettin
        The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS).
        PLoS One. 2010; 5: e11986
        • Caudie Christiane
        • Medhi Birouk Al
        • Bancel Julien
        • ele Claudy Dani
        • Gignoux Laurence
        • Vukusic Sandra
        • Confavreux Christian
        Cytoimmunological profile of cerebrospinal fluid in diagnosis of multiple sclerosis.
        Pathol. Biol. (Paris). 2005; 53: 68-74
        • Chalbot Sonia
        • Zetterberg Henrik
        • Blennow Kaj
        • Fladby Tormod
        • Iqbal Inge Grundke-
        • Iqbal Khalid
        Cerebrospinal fluid secretory Ca2+-dependent phospholipase A2 activity: a biomarker of blood-cerebrospinal fluid barrier permeability.
        Neurosci. Lett. 2010; 478: 179-183
        • Chang K.H.
        • Lyu R.K.
        • Chen C.M.
        • Hsu W.C.
        • Wu Y.R.
        • Chen S.T.
        • Ro L.S.
        Clinical characteristics of multiple sclerosis in Taiwan: a cross-sectional study.
        Mult. Scler. 2006; 12: 501-506
        • Confavreux C.
        • Chapuis-Cellier C.
        • Arnaud P.
        • Robert O.
        • Aimard G.
        • Devic M.
        Oligoclonal “fingerprint” of CSF IgG in multiple sclerosis patients is not modified following intrathecal administration of natural betainterferon.
        J. Neurol. Neurosurg. Psychiatry. 1986; 49: 1308-1312
        • Correale Jorge
        • de los Milagros María
        • Molinas Bassani
        Oligoclonal bands and antibody responses in multiple sclerosis.
        J. Neurol. 2002; 249: 375-389
        • Davies G.
        • Keir G.
        • Thompson E.J.
        • Giovannoni G.
        The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study.
        Neurology. 2003; 60: 1106-1163
        • Di Filippo M.
        • Pini L.A.
        • Pelliccioli G.P.
        • Calabresi P.
        • Sarchielli P.
        Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2008; 79: 1224-1229
        • Dobson Ruth
        • Leddy Sara Geraldine
        • Gangadharan Sunay
        • Giovannoni Gavin
        Assessing fracture risk in people with MS: a service development study comparing three fracture risk scoring systems.
        BMJ Open. 2013; 3
        • Falip M.
        • Tintoré M.
        • Jardí R.
        • Duran I.
        • Link H.
        • Montalbán X.
        Clinical usefulness of oligoclonal bands.
        Rev. Neurol. 2001; 32: 1120-1124
        • Fortini Alexandre S.
        • Sanders Elizabeth L.
        • Weinshenker Brian G.
        • Katzmann Jerry A.
        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
        • Franciotta D.
        • Zardini E.
        • Bergamaschi R.
        • Grimaldi L.M.
        • Andreoni L.
        • Cosi V.
        Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis and other neurologic diseases.
        Acta Neurol. Scand. 2005; 112: 238-241
        • Franciotta Diego
        • Stefano Anna Luisa Di
        • Jarius Sven
        • Zardini Elisabetta
        • Tavazzi Eleonora
        • Ballerini Clara
        • Marchioni Enrico
        • Bergamaschi Roberto
        • Ceroni Mauro
        Cerebrospinal BAFF and Epstein–Barr virus-specific oligoclonal bands in multiple sclerosis and other inflammatory demyelinating neurological diseases.
        J. Neuroimmunol. 2011; 230: 160-163
        • Freedman M.S.
        • Thompson E.J.
        • Deisenhammer F.
        • Giovannoni G.
        • Grimsley G.
        • Keir G.
        • Ohman S.
        • Racke M.K.
        • Sharief M.
        • Sindic C.J.
        • Sellebjerg F.
        • Tourtellotte W.W.
        Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.
        Arch. Neurol. 2005; 62: 865-870
        • Fukazawa T.
        • Kikuchi S.
        • Sasaki H.
        • Hamada K.
        • Hamada T.
        • Miyasaka K.
        • Tashiro K.
        The significance of oligoclonal bands in multiple sclerosis in Japan: relevance of immunogenetic backgrounds.
        J. Neurol. Sci. 1998; 158: 209-214
        • Galea Ian
        • Freedman Mark S.
        • Thompson Edward J.
        Cerebrospinal fluid analysis in the 2010 revised McDonald's multiple sclerosis diagnostic criteria.
        Ann. Neurol. 2011; 70 (author reply 184): 183-184
        • Gama Paulo Diniz da
        • Dos Ramos Machado Luís
        • Antonio Livramento José
        • Rodrigues Gomes Hélio
        • Adoni Tarso
        • Maria Martins Lino Angelina
        • Eurípedes Marchiori Paulo
        • de Rizo Morales Rogério
        • Aurélio Lana-Peixoto Marco
        • Callegaro Dagoberto
        Study of oligoclonal bands restricted to the cerebrospinal fluid in multiple sclerosis patients in the city of São Paulo.
        Arq. Neuropsiquiatr. 2009; 67: 1017-1022
        • Glehn Felipe von
        • Farias Alessandro S.
        • Penalva de Oliveira Augusto C.
        • Damasceno Alfredo
        • Longhini Ana Leda F.
        • Oliveira Elaine C.
        • Damasceno Benito P.
        • Mb Santos Leonilda
        • Otavio Brandao Carlos
        Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients.
        Mult. Scler. 2012; 18: 1038-1041
        • Gout Olivier
        • Bouchareine Annie
        • Moulignier Antoine
        • Deschamps Romain
        • Papeix Caroline
        • Gorochov Guy
        • Héran Françoise
        • Bastuji-Garin Sylvie
        Prognostic value of cerebrospinal fluid analysis at the time of a first demyelinating event.
        Mult. Scler. 2011; 17: 164-172
        • Haghighi S.
        • Andersen O.
        • Rosengren L.
        • Bergström T.
        • Wahlström J.
        • Nilsson S.
        Incidence of CSF abnormalities in siblings of multiple sclerosis patients and unrelated controls.
        J. Neurol. 2000; 247: 616-622
        • Haghighi S.
        • Lekman A.
        • Nilsson S.
        • Blomqvist M.
        • Andersen O.
        Myelin glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis.
        Acta Neurol. Scand. 2012; 125: 64-70
        • Hampel H.
        • Kötter H.U.
        • Padberg F.
        • Körschenhausen D.A.
        • Möller H.J.
        Oligoclonal bands and blood–cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: comparison with vascular dementia, major depression, and multiple sclerosis.
        Alzheimer Dis. Assoc. Disord. 1999; 13: 9-19
        • Harp Christopher
        • Lee Jane
        • Lambracht-Washington Doris
        • Cameron Elizabeth
        • Olsen Gregory
        • Frohman Elliot
        • Racke Michael
        • Monson Nancy
        Cerebrospinal fluid B cells from multiple sclerosis patients are subject to normal germinal center selection.
        J. Neuroimmunol. 2007; 183: 189-199
        • Harrer A.
        • Tumani H.
        • Niendorf S.
        • Lauda F.
        • Geis C.
        • Weishaupt A.
        • Kleinschnitz C.
        • Rauer S.
        • Kuhle J.
        • Stangel M.
        • Weber F.
        • Uhr M.
        • Linnebank M.
        • Wildemann B.
        • Jarius S.
        • Guger M.
        • Ayzenberg I.
        • Chan A.
        • Zettl U.
        • Wiendl H.
        • Pilz G.
        • Hitzl W.
        • Weber Jr
        • Kraus J.
        Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy.
        Mult. Scler. 2012; (Epub ahead of print)
        • Heard R.N.
        • Teutsch S.M.
        • Bennetts B.H.
        • Lee S.D.
        • Deane E.M.
        • Stewart G.J.
        Lack of restriction of T cell receptor beta variable gene usage in cerebrospinal fluid lymphocytes in acute optic neuritis.
        J. Neurol. Neurosurg. Psychiatry. 1999; 67: 585-590
        • Imrell Kerstin
        • Landtblom Anne-Marie
        • Hillert Jan
        • Masterman Thomas
        Multiple sclerosis with and without CSF bands: clinically indistinguishable but immunogenetically distinct.
        Neurology. 2006; 67: 1062-1064
        • Jacobs L.D.
        • Kaba S.E.
        • Miller C.M.
        • Priore R.L.
        • Brownscheidle C.M.
        Correlation of clinical, magnetic resonance imaging, and cerebrospinal fluid findings in optic neuritis.
        Ann. Neurol. 1997; 41: 392-398
        • Kabat E.A.
        • Moore D.H.
        • Landow H.
        An electrophoretic study of the protein components in cerebrospinal fluid and their relationship to the serum proteins.
        J. Clin. Invest. 1942; 21: 571-577
        • Kaiser R.
        • Obert M.
        • Kaufmann R.
        • Czygan M.
        IgG-antibodies to CNS proteins in patients with multiple sclerosis.
        Eur. J. Med. Res. 1997; 2: 169-172
        • Keir G.
        • Luxton R.W.
        • Thompson E.J.
        Isoelectric focusing of cerebrospinal fluid immunoglobulin G: an annotated update.
        Ann. Clin. Biochem. 1990; 27: 436-443
        • Keren D.F.
        Optimizing detection of oligoclonal bands in cerebrospinal fluid by use of isoelectric focusing with IgG immunoblotting.
        Am. J. Clin. Pathol. 2003; 120: 649-651
        • Khademi Mohsen
        • Kockum Ingrid
        • Andersson Magnus L.
        • Iacobaeus Ellen
        • Brundin Lou
        • Sellebjerg Finn
        • Hillert Jan
        • Piehl Fredrik
        • Olsson Tomas
        Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course.
        Mult. Scler. 2011; 17: 335-343
        • Klawiter Eric C.
        • Piccio Laura
        • Lyons Jeri-Anne
        • Mikesell Robert
        • O'Connor Kevin C.
        • Cross Anne H.
        Elevated intrathecal myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis.
        Arch. Neurol. 2010; 67: 1102-1108
        • Koch M.
        • Heersema D.
        • Mostert J.
        • Teelken A.
        • De Keyser J.
        Cerebrospinal fluid oligoclonal bands and progression of disability in multiple sclerosis.
        Eur. J. Neurol. 2007; 14: 797-800
        • Komori M.
        • Matsuyama Y.
        • Nirasawa T.
        • Thiele H.
        • Becker M.
        • Alexandrov T.
        • Saida T.
        • Tanaka M.
        • Matsuo H.
        • Tomimoto H.
        • Takahashi R.
        • Tashiro K.
        • Ikegawa M.
        • Kondo T.
        Proteomic pattern analysis discriminates among multiple sclerosis-related disorders.
        Ann Neurol. 2012; 71: 614-623
        • Krakauer M.
        • Schaldemose Nielsen H.
        • Jensen J.
        • Sellebjerg F.
        Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis.
        Acta Neurol. Scand. 1998; 98: 161-165
        • Kuhle J.
        • Leppert D.
        • Petzold A.
        • Regeniter A.
        • Schindler C.
        • Mehling M.
        • Anthony D.C.
        • Kappos L.
        • Lindberg R.L.P.
        Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis.
        Neurology. 2011; 76: 1206-1213
        • Lambracht-Washington Doris
        • O'Connor Kevin C.
        • Cameron Elizabeth M.
        • Andrea Jowdry E.
        • Ward Sally
        • Frohman Elliot
        • Racke Michael K.
        • Monson Nancy L.
        Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS.
        J. Neuroimmunol. 2007; 186: 164-176
        • Lechner-Scott J.
        • Spencer B.
        • de Malmanche T.
        • Attia J.
        • Fitzgerald M.
        • Trojano M.
        • Grand'maison F.
        • Antonio J.
        • Gomez C.
        • Izquierdo G.
        • Duquette P.
        • Girard M.
        • Grammond P.
        • Oreja-Guevara C.
        • Hupperts R.
        • Bergamaschi R.
        • Boz C.
        • Giuliani G.
        • van Pesch V.
        • Iuliano G.
        • Fiol M.
        • Cristiano E.
        • Verheul F.
        • Laura Saladino M.
        • Slee M.
        • Barnett M.
        • Deri N.
        • Fletcher S.
        • Vella N.
        • Shaw C.
        • Herbert J.
        • Moore F.
        • Petkovska-Boskova T.
        • Jokubatis V.
        • Butzkueven H.
        The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude.
        Mult. Scler. 2012; 18: 974-982
        • Li B.
        • Dong H.
        • Zhang J.
        • Song X.
        • Guo L.
        Cerebrospinal fluid IgG profiles and oligoclonal bands in Chinese patients with multiple sclerosis.
        Acta Neurol. Scand. 2007; 115: 319-324
        • Link H.
        • Huang Y.M.
        Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness.
        J. Neuroimmunol. 2006; 180: 17-28
        • Link J.
        • Söderström M.
        • Olsson T.
        • Höjeberg B.
        • Ljungdahl A.
        • Link H.
        Increased transforming growth factor-beta, interleukin-4, and interferongamma in multiple sclerosis.
        Ann. Neurol. 1994; 36: 379-386
        • Losy J.
        • Niezgoda A.
        IL-18 in patients with multiple sclerosis.
        Acta Neurol. Scand. 2001; 104: 171-173
        • Lovato Laura
        • Willis Simon N.
        • Rodig Scott J.
        • Caron Tyler
        • Almendinger Stefany E.
        • Howell Owain W.
        • Reynolds Richard
        • O'Connor Kevin C.
        • Hafler David A.
        Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis.
        Brain. 2011; 134: 534-541
        • Lowenthal A.
        • Karcher D.
        • Van Sande M.
        The differential diagnosis of neurological diseases by fractionating electrophoretically the CSF gamma-globulins.
        J. Neurochem. 1960; 6: 51-56
        • 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
        • Malmeström C.
        • Haghighi S.
        • Rosengren L.
        • Andersen O.
        • Lycke J.
        Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS.
        Neurology. 2003; 61: 1720-1725
        • Mattson D.H.
        • Roos R.P.
        • Arnason B.G.
        Isoelectric focusing of IgG eluted from multiple sclerosis and subacute sclerosing panencephalitis brains.
        Nature. 1980; 287: 335-337
        • McAlpine D.
        Multiple Sckrosis. A Reappraisal.
        2nd ed. Churchill Livingstone, 1972: 225-226
        • McCombe P.A.
        • Brown N.N.
        • Barr A.E.
        • Parkin L.
        Monoclonal immunoglobulin bands in the cerebrospinal fluid.
        Aust. N. Z. J. Med. 1991; 21: 227-229
        • McDonald W.I.
        • Compston A.
        • Edan G.
        • et al.
        Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.
        Ann. Neurol. 2001; 50: 121-127
        • McMillan S.A.
        • McDonnell G.V.
        • Douglas J.P.
        • Hawkins S.A.
        Evaluation of the clinical utility of cerebrospinal fluid (CSF) indices of inflammatory markers in multiple sclerosis.
        Acta Neurol. Scand. 2000; 101: 239-243
        • Monson Nancy L.
        • Brezinschek Hans-Peter
        • Brezinschek Ruth I.
        • Mobley Angela
        • Vaughan Gwen K.
        • Frohman Elliot M.
        • Racke Michael K.
        • Lipsky Peter E.
        Receptor revision and atypical mutational characteristics in clonally expanded B cells from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients.
        J. Neuroimmunol. 2005; 158: 170-181
        • Morrissey S.P.
        • Borruat F.X.
        • Miller D.H.
        • Moseley I.F.
        • Sweeney M.G.
        • Govan G.G.
        • Kelly M.A.
        • Francis D.A.
        • Harding A.E.
        • McDonald W.I.
        Bilateral simultaneous optic neuropathy in adults: clinical, imaging, serological, and genetic studies.
        J. Neurol. Neurosurg. Psychiatry. 1995; 58: 70-74
        • Mygland A.
        • Trydal T.
        • Vinje B.U.
        • Vedeler C.
        Isoelectric focusing is superior to immunofixation electrophoresis in diagnosing CNS inflammation.
        Acta Neurol. Scand. 2007; 115: 122-125
        • Obermeier Birgit
        • Mentele Reinhard
        • Malotka Joachim
        • Kellermann Josef
        • Kümpfel Tania
        • Wekerle Hartmut
        • Lottspeich Friedrich
        • Hohlfeld Reinhard
        • Dornmair Klaus
        Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis.
        Nat. Med. 2008; 14: 688-693
        • Petersen A.A.
        • Sellebjerg F.
        • Frederiksen J.
        • Olesen J.
        • Vejlsgaard G.L.
        Soluble ICAM-1, demyelination, and inflammation in multiple sclerosis and acute optic neuritis.
        J. Neuroimmunol. 1998; 88: 120-127
        • Petzold Axel
        Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss.
        J. Neurol. Sci. 2005; 233: 183-198
        • Petzold A.
        Biological markers.
        Mult. Scler. J. 2012; 18 (oral presentation): 121
        • Petzold A.
        Progressive multiple sclerosis.
        in: Wilkins A. Chap. Biomarkers of Disease Progression. Springer-Verlag, 2013: 115-146
        • Petzold A.
        • Eikelenboom M.J.
        • Gveric D.
        • Keir G.
        • Chapman M.
        • Lazeron R.H.
        • et al.
        Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations.
        Brain. 2002; 125: 1462-1473
        • Petzold A.
        • Keir G.
        • Sharpe L.T.
        Spectrophotometry for xanthochromia.
        N. Engl. J. Med. 2004; 351: 1695-1696
        • Piazza F.
        • DiFrancesco J.C.
        • Fusco M.L.
        • Corti D.
        • Pirovano L.
        • Frigeni B.
        • Mattavelli L.
        • Andreoni S.
        • Frigo M.
        • Ferrarese C.
        • Tredici G.
        • Cavaletti G.
        Cerebrospinal fluid levels of BAFF and APRIL in untreated multiple sclerosis.
        J. Neuroimmunol. 2010; 220: 104-107
        • Polman C.H.
        Reply.
        Ann. Neurol. 2011; 70: 521
        • Polman C.H.
        • Koetsier J.C.
        • Wolters E.C.
        Multiple sclerosis: incorporation of results of laboratory techniques in the diagnosis.
        Clin. Neurol. Neurosurg. 1985; 87: 187-192
        • Polman C.H.
        • Reingold S.C.
        • Edan G.
        • Filippi M.
        • Hartung H.P.
        • Kappos L.
        • Lublin F.D.
        • Metz L.M.
        • McFarland H.F.
        • O'Connor P.W.
        • Sandberg-Wollheim M.
        • Thompson A.J.
        • Weinshenker B.G.
        • Wolinsky J.S.
        Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.
        Ann. Neurol. 2005; 58: 840-846
        • Polman Chris H.
        • Reingold Stephen C.
        • Banwell Brenda
        • Clanet Michel
        • Cohen Jeffrey A.
        • Filippi Massimo
        • Fujihara Kazuo
        • Havrdova Eva
        • Hutchinson Michael
        • Kappos Ludwig
        • Lublin Fred D.
        • Montalban Xavier
        • O'Connor Paul
        • Sandberg-Wollheim Magnhild
        • Thompson Alan J.
        • Waubant Emmanuelle
        • Weinshenker Brian
        • Wolinsky Jerry S.
        Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
        Ann. Neurol. 2011; 69: 292-302
        • Poser C.M.
        • Paty D.W.
        • Scheinberg L.
        • McDonald W.I.
        • Davis F.A.
        • Ebers G.C.
        • Johnson K.P.
        • Sibley W.A.
        • Silberberg D.H.
        • Tourtellotte W.W.
        New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
        Ann. Neurol. 1983; 13: 227-231
        • Presslauer Stefan
        • Milosavljevic Dejan
        • Brücke Thomas
        • Bayer Peter
        • Hübl Wolfgang
        • Hübl Walter
        Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis.
        J. Neurol. 2008; 255: 1508-1514
        • Racke Michael K.
        The role of B cells in multiple sclerosis: rationale for B-cell-targeted therapies.
        Curr. Opin. Neurol. 2008; 21: S9-S18
        • Reiber H.
        External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients.
        Clin. Chem. 1995; 41: 256-263
        • Rolak L.A.
        • Beck R.W.
        • Paty D.W.
        • Tourtellotte W.W.
        • Whitaker J.N.
        • Rudick R.A.
        Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial.
        Neurology. 1996; 46: 368-372
        • Rutter C.M.
        • Gatsonis C.A.
        A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations.
        Stat. Med. 2001; 20: 2865-2884
        • Sá Maria José
        • Sequeira Lucinda
        • Rio Maria Edite
        • Thompson Edward J.
        Oligoclonal IgG bands in the cerebrospinal fluid of Portuguese patients with multiple sclerosis: negative results indicate benign disease.
        Arq. Neuropsiquiatr. 2005; 63: 375-379
        • Sarchielli Paola
        • Di Filippo Massimiliano
        • Ercolani Maria Vittoria
        • Chiasserini Davide
        • Mattioni Alessia
        • Bonucci Michele
        • Tenaglia Serena
        • Eusebi Paolo
        • Calabresi Paolo
        Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients.
        Neurosci. Lett. 2008; 435: 223-228
        • Schumacher G.A.
        • Beebe G.
        • Kebler R.F.
        • et al.
        Problems of experimental trials of therapy in multiple sclerosis.
        Ann. N.Y. Acad. Sci. 1965; 122: 552-568
        • Sellebjerg F.
        • Christiansen M.
        Qualitative assessment of intrathecal IgG synthesis by isoelectric focusing and immunodetection: interlaboratory reproducibility and interobserver agreement.
        Scand. J. Clin. Lab. Invest. 1996; 56: 135-143
        • Sellebjerg F.
        • Madsen H.O.
        • Frederiksen J.L.
        • Ryder L.P.
        • Svejgaard A.
        Acute optic neuritis: myelin basic protein and proteolipid protein antibodies, affinity, and the HLA system.
        Ann. Neurol. 1995; 38: 943-950
        • Silber E.
        • Semra Y.K.
        • Gregson N.A.
        • Sharief M.K.
        Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit.
        Neurology. 2002; 58: 1372-1381
        • Skov A.G.
        • Skov T.
        • Frederiksen J.L.
        Oligoclonal bands predict multiple sclerosis after optic neuritis: a literature survey.
        Mult. Scler. 2011; 17: 404-410
        • Stangel Martin
        • Fredrikson Sten
        • Meinl Edgar
        • Petzold Axel
        • Stüve Olaf
        • Tumani Hayrettin
        The utility of cerebrospinal fluid analysis in patients with multiple sclerosis.
        Nat. Rev. Neurol. 2013; 9: 267-276
        • Stoevring Birgitte
        • Vang Ole
        • Christiansen Michael
        (alpha)Bcrystallin in cerebrospinal fluid of patients with multiple sclerosis.
        Clin. Chim. Acta. 2005; 356: 95-101
        • Thompson E.J.
        • Kaufmann P.
        • Rudge P.
        Sequential changes in oligoclonal patterns during the course of multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 1983; 46: 547-550
        • Tintoré M.
        • Rovira A.
        • Río J.
        • Tur C.
        • Pelayo R.
        • Nos C.
        • Téllez N.
        • Perkal H.
        • Comabella M.
        • Sastre-Garriga J.
        • Montalban X.
        Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?.
        Neurology. 2008; 70: 1079-1083
        • Tourtellotte W.W.
        Koetsier J.C. The Cerebrospinal Fluid in Multiple Sclerosis. vol. 3. North–Holland Publishing Company, Amsterdam1985: 79-130 (Wiley Interscience Division — John Wiley & Sons, Inc., New York)
        • Tumani H.
        • Tourtellotte W.W.
        • Peter J.B.
        • Felgenhauer K.
        Acute optic neuritis: combined immunological markers and magnetic resonance imaging predict subsequent development of multiple sclerosis. The Optic Neuritis Study Group.
        J. Neurol. Sci. 1998; 155: 44-49
        • Tumani Hayrettin
        • Deisenhammer Florian
        • Giovannoni Gavin
        • Gold Ralf
        • Hartung Hans-Peter
        • Hemmer Bernhard
        • Hohlfeld Reinhard
        • Otto Markus
        • Stangel Martin
        • Wildemann Brigitte
        • Zettl Uwe K.
        Revised McDonald criteria: the persisting importance of cerebrospinal fluid analysis.
        Ann. Neurol. 2011; 70: 520
        • Verbeek M.M.
        • Notting E.A.
        • Faas B.
        • Claessens-Linskens R.
        • Jongen P.J.H.
        Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
        Acta Neurol. Scand. 2010; 121: 309-314
        • Villar L.M.
        • Gonzalez-Porque P.
        • Masjuan J.
        • Alvarez-Cermeno J.C.
        • Bootello A.
        • Keir G.
        A sensitive and reproducible method for the detection of oligoclonal IgM bands.
        J. Immunol. Methods. 2001; 258: 151-155
        • Villar L.M.
        • Masjuan J.
        • Gonzalez-Porque P.
        • Plaza J.
        • Sadaba M.C.
        • Roldan E.
        • Bootello A.
        • Alvarez-Cermeno J.C.
        Intrathecal IgM synthesis in neurologic diseases: relationship with disability in MS.
        Neurology. 2002; 58: 824-826
        • Villar L.M.
        • Masjuan J.
        • Gonzalez-Porque P.
        • Plaza J.
        • Sadaba M.C.
        • Roldan E.
        • Bootello A.
        • Alvarez-Cermeno J.C.
        Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis.
        Ann. Neurol. 2003; 53: 222-226
        • Villar L.M.
        • Sádaba M.C.
        • Roldán E.
        • Masjuan J.
        • et al.
        Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS.
        J. Clin. Invest. 2005; 115: 187-194
        • Villar Luisa M.
        • Masjuan Jaime
        • Sádaba María C.
        • González-Porqué Pedro
        • Plaza José
        • Bootello Alfredo
        • Alvarez-Cermeño José C.
        Early differential diagnosis of multiple sclerosis using a new oligoclonal band test.
        Arch. Neurol. 2005; 62: 574-577
        • Vogt M.H.J.
        • Teunissen C.E.
        • Iacobaeus E.
        • Heijnen D.A.M.
        • Breij E.C.W.
        • Olsson T.
        • Brundin L.
        • Killestein J.
        • Dijkstra Christine D.
        Cerebrospinal fluid anti-myelin antibodies are related to magnetic resonance measures of disease activity in multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2009; 80: 1110-1115
        • Xiao B.G.
        • Zhang G.X.
        • Ma C.G.
        • Link H.
        The cerebrospinal fluid from patients with multiple sclerosis promotes neuronal and oligodendrocyte damage by delayed production of nitric oxide in vitro.
        J. Neurol. Sci. 1996; 142: 114-120
        • Yao S.Y.
        • Stratton C.W.
        • Mitchell W.M.
        • Sriram S.
        CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens.
        Neurology. 2001; 56: 1168-1176
        • Yu Xiaoli
        • Burgoon Mark
        • Green Miyoko
        • Barmina Olga
        • Dennison Kathryn
        • Pointon Tiffany
        • Davis Molly
        • Gilden Don
        Intrathecally synthesized IgG in multiple sclerosis cerebrospinal fluid recognizes identical epitopes over time.
        J. Neuroimmunol. 2011; 240–241: 129-136
        • Zadro Ivana
        • Brinar Vesna
        • Horvat Gordana
        • Brinar Marko
        Clinical relevance of antibodies against myelin oligodendrocyte glycoprotein in different clinical types of multiple sclerosis.
        Clin. Neurol. Neurosurg. 2007; 109: 23-26
        • Zeman A.Z.
        • Kidd D.
        • McLean B.N.
        • Kelly M.A.
        • Francis D.A.
        • Miller D.H.
        • Kendall B.E.
        • Rudge P.
        • Thompson E.J.
        • McDonald W.I.
        A study of oligoclonal band negative multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 1996; 60: 27-30
        • Zhou S.R.
        • Maier C.C.
        • Mitchell G.W.
        • LaGanke C.C.
        • Blalock J.E.
        • Whitaker J.N.
        A cross-reactive anti-myelin basic protein idiotope in cerebrospinal fluid cells in multiple sclerosis.
        Neurology. 1998; 50: 411-417
        • Zipoli V.
        • Hakiki B.
        • Portaccio E.
        • Lolli F.
        • Siracusa G.
        • Giannini M.
        • Pantoni L.
        • Pescini F.
        • Sorbi S.
        • Amato M.P.
        The contribution of cerebrospinal fluid oligoclonal bands to the early diagnosis of multiple sclerosis.
        Mult. Scler. 2009; 15: 472-478