The MRZ Reaction As a Highly Specific Marker of Multiple Sclerosis: Re-evaluation and Structured Review of the Literature

Overview

Journal J Neurol

Specialty Neurology

Date 2016 Dec 23

PMID 28005176

Citations 66

Authors

S Jarius

P Eichhorn

D Franciotta

H F Petereit

G Akman-Demir

M Wick

B Wildemann

Affiliations

Soon will be listed here.

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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References

Godec M, Asher D, MURRAY R, Shin M, GREENHAM L, Gibbs Jr C . Absence of measles, mumps, and rubella viral genomic sequences from multiple sclerosis brain tissue by polymerase chain reaction. Ann Neurol. 1992; 32(3):401-4. DOI: 10.1002/ana.410320317. View

Hochberg M . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40(9):1725. DOI: 10.1002/art.1780400928. View

Brecht I, Weissbrich B, Braun J, Toyka K, Weishaupt A, Buttmann M . Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis. PLoS One. 2012; 7(7):e40431. PMC: 3392215. DOI: 10.1371/journal.pone.0040431. View

Graef I, Henze T, Reiber H . [Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement]. Z Arztl Fortbild (Jena). 1994; 88(7-8):587-91. View

Andersson M, Bernardi G, Cogato I, Fredman P, Frederiksen J, Fredrikson S . Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994; 57(8):897-902. PMC: 1073070. DOI: 10.1136/jnnp.57.8.897. View

Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K . MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016; 13(1):280. PMC: 5086042. DOI: 10.1186/s12974-016-0718-0. View

Dennin R, Herb E . Immunological diagnosis in viral infections of the central nervous system: course of antibody titres against homo- and heterologous viruses. Med Microbiol Immunol. 1989; 178(5):255-68. DOI: 10.1007/BF00191060. View

Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek V . IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One. 2009; 4(11):e7638. PMC: 2766627. DOI: 10.1371/journal.pone.0007638. View

Wingerchuk D, Banwell B, Bennett J, Cabre P, Carroll W, Chitnis T . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015; 85(2):177-89. PMC: 4515040. DOI: 10.1212/WNL.0000000000001729. View

10.

Norrby E, Link H, Olsson J, Panelius M, Salmi A, Vandvik B . Comparison of antibodies against different viruses in cerebrospinal fluid and serum samples from patients with multiple sclerosis. Infect Immun. 1974; 10(4):688-94. PMC: 423007. DOI: 10.1128/iai.10.4.688-694.1974. View

11.

Meinl E, Krumbholz M, Hohlfeld R . B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol. 2006; 59(6):880-92. DOI: 10.1002/ana.20890. View

12.

Reiber H, Teut M, Pohl D, Rostasy K, Hanefeld F . Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler. 2009; 15(12):1466-80. DOI: 10.1177/1352458509348418. View

13.

Jarius S, Eichhorn P, Wildemann B, Wick M . Usefulness of antibody index assessment in cerebrospinal fluid from patients negative for total-IgG oligoclonal bands. Fluids Barriers CNS. 2012; 9(1):14. PMC: 3487855. DOI: 10.1186/2045-8118-9-14. View

14.

Petereit H, Reske D . Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients - follow-up and clinical implications. Cerebrospinal Fluid Res. 2005; 2:3. PMC: 1173126. DOI: 10.1186/1743-8454-2-3. View

15.

Schubert J, Weissbrich B . Detection of virus-specific intrathecally synthesised immunoglobulin G with a fully automated enzyme immunoassay system. BMC Neurol. 2007; 7:12. PMC: 1899514. DOI: 10.1186/1471-2377-7-12. View

16.

Mathiesen T, von Holst H, Fredrikson S, Wirsen G, HEDERSTEDT B, Norrby E . Total, anti-viral, and anti-myelin IgG subclass reactivity in inflammatory diseases of the central nervous system. J Neurol. 1989; 236(4):238-42. DOI: 10.1007/BF00314506. View

17.

Jacobi C, Arlt S, Reiber H, Westner I, Kretzschmar H, Poser S . Immunoglobulins and virus-specific antibodies in patients with Creutzfeldt-Jakob disease. Acta Neurol Scand. 2005; 111(3):185-90. DOI: 10.1111/j.1600-0404.2005.00330.x. View

18.

Jarius S, Eichhorn P, Jacobi C, Wildemann B, Wick M, Voltz R . The intrathecal, polyspecific antiviral immune response: Specific for MS or a general marker of CNS autoimmunity?. J Neurol Sci. 2008; 280(1-2):98-100. DOI: 10.1016/j.jns.2008.08.002. View

19.

Jacobi C, Lange P, Reiber H . Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol. 2007; 187(1-2):139-46. DOI: 10.1016/j.jneuroim.2007.04.002. View

20.

Jacobs L, Beck R, Simon J, Kinkel R, Brownscheidle C, Murray T . Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000; 343(13):898-904. DOI: 10.1056/NEJM200009283431301. View