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

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.

Keywords: Antibody index; Behçet’s disease; Cerebrospinal fluid; Connective tissue disorders; Herpes simplex virus; MRZ reaction; Measles virus; Multiple sclerosis; Neuroborreliosis Aquaporin-4-IgG-positive neuromyelitis optica MOG-IgG-positive encephalomyelitis; Rubella virus; Varicella zoster virus.