Parvovirus B19 and mumps virus antibodies are major constituents of the intrathecal immune response in European patients with MS and increase the diagnostic sensitivity and discriminatory power of the MRZ reaction

Abstract

Abstract Background A positive MRZ reaction, as defined by intrathecal IgG production against at least two of its constituents, measles virus (M), rubella virus (R) and varicella zoster virus (Z), is detectable in ~ 63% of patients with multiple sclerosis (MS) and is currently considered the laboratory marker with the highest specificity and positive likelihood ratio for MS. However, M, R and Z are only the most well-established constituents of a broader intrathecal humoral immune response in MS. Objective To identify additional anti-microbial antibodies inclusion of which in the classical MRZ panel may result in increased sensitivity without compromising the marker’s high specificity for MS. Methods We determined the antibody indices (AIs) for 11 viral and bacterial agents (M, R, Z, herpes simplex virus, Epstein–Barr virus, mumps virus, cytomegalovirus, parvovirus B19, Bordetella pertussis, Corynebacterium diphtheriae, and Clostridium tetani) in paired cerebrospinal fluid and serum samples from patients with MS and disease controls. Results A positive ‘classical’ MRZ reaction was found in 17/26 (65.4%) MS patients. The five most frequently positive AIs among patients with MS were M (76.9%), Z (61.5%), R (57.7%), parvovirus B19 (42.3%), and mumps (28%). Addition of parvovirus B19 and mumps virus to the MRZ panel resulted in an increase in sensitivity in the MS group from 65.4% to 73.1%, with 22% of the initially MRZ-negative patients exhibiting a de novo-positive response. The extended MRZ panel (‘MRZplus’) distinguished sharply between MS (≥ 3 AIs in 90% of all positives) and controls (varying diagnoses, from migraine to vasculitis; 0-1 AIs; p < 0.000001). The highest median AI in the MS group was found for parvovirus B19 (3.97), followed by measles virus (2.79). Conclusion Inclusion of parvovirus B19 and mumps virus in the test panel resulted in an increase in the sensitivity and discriminatory power of MRZ. Our results provide a strong rational for prospective studies investigating the role of extended MRZ panels in the differential diagnosis of MS.