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The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis

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Abstract

Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI ≥ 1.5 and 2.0) were applied, and MRZR was considered positive in cases with ≥ 2 positive AIs (MRZR-2). Using the common AI threshold of ≥ 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p < 0.0001 for each comparison with the MS group) corresponding to a positive predictive value (PPV) of 89.6% and a negative predictive value (NPV) of 78.0%. On applying the stricter AI threshold of ≥ 2.0, 37.8% of MS patients were MRZR-2 positive; however, all patients with PCNSL and PD were MRZR-2 negative (p < 0.0001 for each comparison with the MS cohort) resulting in a PPV of 100% and an NPV of 71.4%. Consequently, a positive MRZR-2 result may contribute toward the distinction between MS and PCNSL owing to its high specificity and PPV for MS in the context of the present study. Among the other CSF parameters only a quantitative intrathecal IgG synthesis (present in 49.3% of MS patients but in none of the PCNSL or PD patients; p < 0.0001 for each comparison with the MS group) reliably indicated MS rather than PCNSL.

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Abbreviations

AI:

Antibody index

AIs:

Antibody indices

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ECOG PS:

Eastern Cooperative Oncology Group Performance Status

Ig:

Immunoglobulin

IgG/M/A:

Immunoglobulin G/M/A

LDH:

Lactate dehydrogenase

LP:

Lumbar puncture

MRI:

Magnetic resonance imaging

MRZR:

Measles virus, rubella virus, and varicella zoster virus reaction

MS:

Multiple sclerosis

NPV:

Negative predictive value

OCB:

Oligoclonal bands

PCNSL:

Primary central nervous system lymphoma

PD:

Psychiatric disorders

PPMS:

Primary progressive MS

PPV:

Positive predictive value

QAlb:

Albumin quotient

RRMS:

Relapsing–remitting MS

SD:

Standard deviation

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Acknowledgements

Special thanks are due to the staff of the Institute of Virology who performed the immunoassays for the MRZ-AI and to the staff of the CSF laboratory at the Department of Neurology who analysed the CSF/serum samples for the routine parameters.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The cost of the article-processing charge was covered by the Albert Ludwig University of Freiburg.

Author information

Author notes

  1. Tilman Hottenrott and Elisabeth Schorb are first authors and have contributed equally to this study.

  2. Dominique Endres and Oliver Stich are senior authors and have contributed equally to this study.

Authors and Affiliations

  1. Department of Neurology and Neurophysiology, Faculty of Medicine, Medical Centre-University of Freiburg, Breisacher Straße 64, 79106, Freiburg, Germany

    Tilman Hottenrott, Rick Dersch, Benjamin Berger & Sebastian Rauer

  2. Department of Haematology, Oncology, and Stem-Cell Transplantation, Faculty of Medicine, Medical Centre-University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany

    Elisabeth Schorb & Kristina Fritsch

  3. Institute of Virology, University Medical Centre Freiburg, Hermann-Herder-Straße 11, 79104, Freiburg, Germany

    Daniela Huzly

  4. Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, Medical Centre-University of Freiburg, Hauptstraße 5, 79104, Freiburg, Germany

    Ludger Tebartz van Elst & Dominique Endres

  5. Medical Care Unit Konstanz, Luisenstraße 7g, 78464, Constance, Germany

    Oliver Stich

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  1. Tilman Hottenrott
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Contributions

TH and ES initiated this study. TH performed parts of the statistical analyses and wrote the manuscript. ES and KF identified the PCNSL patients; DE and LTvE provided the psychiatric patients group. RD performed parts of the statistical analyses. DH supervised performance of the immunoassays in the Institute of Virology. OS supervised the performance of the CSF analyses. OS and DE supervised the study. All authors helped to draft the manuscript, read and approved the final manuscript version.

Corresponding author

Correspondence to Tilman Hottenrott.

Ethics declarations

Ethics approval and consent to participate

The ethics committee of the University Freiburg approved the study (EK-Fr 489/14).

Consent for publication

Not applicable.

Availability of data and supporting materials section

The data that support the findings of this study are included in this study or available from the corresponding author upon reasonable request.

Conflicts of interest

TH received travel grants from Bayer Vital GmbH and Novartis. ES, KF, RD and DE report no conflicts of interest with this study. BB received travel grants and/or training expenses from Bayer Vital GmbH, Ipsen Pharma GmbH, Norvartis, and Genzyme, as well as lecture fees from Ipsen Pharma GmbH. DH received lecture fees from Serion. LTvE received consulting and lecture fees, grant and research support from Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen, and Cyberonics. OS and SR report receiving consulting and lecture fees, grant and research support from Baxter, Bayer Vital GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis, RG, Sanofi-Aventis and Teva. Furthermore, SR indicates that he is a founding executive board member of ravo Diagnostika GmbH (Oltmannsstraße 5, D-79100 Freiburg, Germany), which is selling in vitro diagnostic medical devices for the detection of infectious diseases and paraneoplastic autoantibodies.

Author information

All authors except OS are doctors working at the Medical Centre-University Freiburg, Germany; OS is working as a consultant physician at the medical care unit in Konstanz, Germany. TH, RD and DE are resident physicians; ES and KF are consultant physicians; BB and DH are senior physicians. SR and LTvE are chief physicians.

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Hottenrott, T., Schorb, E., Fritsch, K. et al. The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis. J Neurol 265, 1106–1114 (2018). https://doi.org/10.1007/s00415-018-8779-x

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