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October 08, 2019; 93 (15) Article

Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis

Catherina Pfuhl, Ulrike Grittner, René M. Gieß, View ORCID ProfileMichael Scheel, Janina R. Behrens, Ludwig Rasche, Florence C. Pache, Rüdiger Wenzel, View ORCID ProfileAlexander U. Brandt, Judith Bellmann-Strobl, Friedemann Paul, Klemens Ruprecht, Johanna Oechtering
First published September 9, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008237
Catherina Pfuhl
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Ulrike Grittner
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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René M. Gieß
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Michael Scheel
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Janina R. Behrens
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Ludwig Rasche
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Florence C. Pache
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Rüdiger Wenzel
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Alexander U. Brandt
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Judith Bellmann-Strobl
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Friedemann Paul
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Klemens Ruprecht
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Johanna Oechtering
From the Department of Neurology (C.P., J.R.B., F.C.P., R.W., F.P., K.R., J.O.), NeuroCure Clinical Research Center (C.P., R.M.G., M.S., J.R.B., L.R., F.C.P., A.U.B., J.B.-S., F.P.), Institute for Biometry and Clinical Epidemiology (U.G.), and Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (U.G.), Berlin; Department of Neurology (A.U.B.), University of California Irvine; Experimental and Clinical Research Center (J.B.-S., F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; and Neurological Clinic and Policlinic (J.O.), Basel University Hospital, Basel, Switzerland.
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Citation
Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis
Catherina Pfuhl, Ulrike Grittner, René M. Gieß, Michael Scheel, Janina R. Behrens, Ludwig Rasche, Florence C. Pache, Rüdiger Wenzel, Alexander U. Brandt, Judith Bellmann-Strobl, Friedemann Paul, Klemens Ruprecht, Johanna Oechtering
Neurology Oct 2019, 93 (15) e1439-e1451; DOI: 10.1212/WNL.0000000000008237

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Abstract

Objectives To evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS.

Methods Comprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments.

Results Intrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45–6.44], p = 0.003) after adjustment for age (0.96 [0.93–1.00], p = 0.059), OCB (0.92 [0.33–2.61], p = 0.879), intrathecal IgG production (0.98 [0.48–1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11–6.22], p = 0.028).

Conclusion Intrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.

Glossary

CEL=
contrast-enhancing lesions;
CI=
confidence interval;
CIS=
clinically isolated syndrome;
DIS=
dissemination in space;
DIT=
dissemination in time;
EDSS=
Expanded Disability Status Scale;
HR=
hazard ratio;
IEF=
isoelectric focusing;
IgA=
immunoglobulin A;
IgG=
immunoglobulin G;
IgM=
immunoglobulin M;
IQR=
interquartile range;
MPRAGE=
magnetization prepared rapid gradient echo;
MS=
multiple sclerosis;
OCB=
oligoclonal bands;
OR=
odds ratio;
RRMS=
relapsing-remitting multiple sclerosis;
T2W=
T2-weighted;
TE=
echo time;
TI=
inversion time;
TR=
repetition time

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • CME Course: NPub.org/cmelist

  • Received July 14, 2018.
  • Accepted in final form May 10, 2019.
  • © 2019 American Academy of Neurology
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Disputes & Debates: Rapid online correspondence

  • Author response: Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis
    • Klemens Ruprecht, Neurologist, Department of Neurology, Charité – Universitätsmedizin Berlin (Berlin, Germany)
    • Catherina Pfuhl, Doctoral student, Department of Neurology, Charité – Universitätsmedizin Berlin (Berlin, Germany)
    • Johanna Oechtering, Neurologist, Neurological Clinic and Policlinic, Basel University Hospital (Basel, Switzerland)
    Submitted May 14, 2020
  • Reader response: Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis
    • Carmen Alcalá, Neurologist, Neuroimmnunology Unit, Polythecnic and Universitary Hospital La Fe (Valencia, Spain)
    • Francisco C. Pérez-Miralles, Neurologist, Neuroimmnunology Unit, Polythecnic and Universitary Hospital La Fe (Valencia, Spain)
    • Sara Gil-Perotín, Neurologist, Neuroimmnunology Unit, Polythecnic and Universitary Hospital La Fe (Valencia, Spain)
    • Bonaventura Casanova, Neurologist, Neuroimmnunology Unit, Polythecnic and Universitary Hospital La Fe (Valencia, Spain)
    Submitted October 13, 2019
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