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The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature

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Abstract

Background

It has long been known that the majority of patients with multiple sclerosis (MS) display an intrathecal, polyspecific humoral immune response to a broad panel of neurotropic viruses. This response has measles virus, rubella virus and varicella zoster virus as its most frequent constituents and is thus referred to as the MRZ reaction (MRZR).

Objective

Re-evaluation of the specificity of MRZR as a marker of MS.

Methods

Structured review of the existing English-, German- and Spanish-language literature on MRZR testing, with evaluation of MRZR in a cohort of 43 unselected patients with MS and other neurological diseases as a proof of principle.

Results

A positive MRZ reaction, defined as a positive intrathecal response to at least two of the three viral agents, was found in 78% of MS patients but only in 3% of the controls (p < 0.00001), corresponding to specificity of 97%. Median antibody index values were significantly lower in non-MS patients (measles, p < 0.0001; rubella, p < 0.006; varicella zoster, p < 0.02). The 30 identified original studies on MRZR reported results from 1478 individual MRZR tests. A positive MRZR was reported for 458/724 (63.3%) tests in patients with MS but only for 19/754 (2.5%) tests in control patients (p < 0.000001), corresponding to cumulative specificity of 97.5% (CI 95% 96–98.4), cumulative sensitivity of 63.3% (CI 95% 59.6–66.8) (or 67.4% [CI 95% 63.5–71.1] in the adult MS subgroup), a positive likelihood ratio of 25.1 (CI 95% 16–39.3) and a negative likelihood ratio of 0.38 (CI 95% 0.34–0.41). Of particular note, MRZR was absent in 52/53 (98.1%) patients with neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS.

Conclusion

MRZR is the most specific laboratory marker of MS reported to date. If present, MRZR substantially increases the likelihood of the diagnosis of MS. Prospective and systematic studies on the diagnostic and prognostic impact of MRZR testing are highly warranted.

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Abbreviations

ADEM:

Acute disseminated encephalomyelitis

AI:

Antibody index

APL:

Antiphospholipid syndrome

CI:

Confidence interval

CNS:

Central nervous system

EBV:

Epstein–Barr virus

HIV:

Human immunodeficiency virus

HSV:

Herpes simplex virus

HTLV-1:

Human T-lymphotropic virus 1

IgG:

Immunoglobulin G

M:

Measles virus

MRZR:

Measles virus, rubella virus, and varicella zoster virus reaction

MS:

Multiple sclerosis

NB:

Neuroborreliosis

NDT:

Not detectable

NIND:

Non-inflammatory neurological disorders

nLR:

Negative likelihood ratio

NMO:

Neuromyelitis optica

OIND/CNS:

Other inflammatory neurological disorders of the CNS

OND:

Other neurological disorders

RD/CNS:

Rheumatic disorders with CNS involvement

pLR:

Positive likelihood ratio

PND:

Paraneoplastic neurological disorders

Q:

Quotient

R:

Rubella virus

SLE:

Systemic lupus erythematosus

Z or VZV:

Varicella zoster virus

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Acknowledgements

This work was supported by a research fellowship from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) to SJ, by a research fellowship from the European Neurological Society (ENS) to SJ, and by research grants from Bayer Healthcare, from the Dietmar Hopp Foundation, and from MerckSerono to BW. We are grateful to Mrs D. Menzel, Mrs R. Herbst, Mrs M. Hoehne and Mrs H. Pahl, Department of Clinical Chemistry, Ludwig Maximilian University, Munich, Germany, and to Mrs Annemarie Eschlbeck, Department of Neurology, University of Heidelberg, Germany, for excellent technical assistance.

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Authors and Affiliations

  1. Molecular Neuroimmunology Group, Department of Neurology, Otto Meyerhof Center, University of Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

    S. Jarius & B. Wildemann

  2. Institute of Laboratory Medicine, Klinikum Großhadern, Ludwig Maximilian University, Munich, Germany

    P. Eichhorn & M. Wick

  3. IRCCS, National Neurological Institute C. Mondino, Pavia, Italy

    D. Franciotta

  4. Praxis rechts vom Rhein, Cologne, Germany

    H. F. Petereit

  5. Department of Neurology, Istanbul Bilim University, Istanbul, Turkey

    G. Akman-Demir

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Correspondence to S. Jarius.

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The study was approved by the institutional review board of the University of Heidelberg.

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Jarius, S., Eichhorn, P., Franciotta, D. et al. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 264, 453–466 (2017). https://doi.org/10.1007/s00415-016-8360-4

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  • DOI: https://doi.org/10.1007/s00415-016-8360-4

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