MRZ Reaction Research Articles

The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis

BackgroundSome rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS.MethodsThe MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied.ResultsThere was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each).ConclusionsConsidering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND.

Do patients with schizophreniform and bipolar disorders show an intrathecal, polyspecific, antiviral immune response? A pilot study

BackgroundWe previously described inflammatory cerebrospinal fluid (CSF) alterations in a subgroup of patients with schizophreniform disorders and the synthesis of polyspecific intrathecal antibodies against different neurotropic infectious pathogens in some patients with bipolar disorders. Consequently, we have measured the prevalence of a positive MRZ reaction (MRZR)—a marker for a polyspecific, antiviral, intrathecal, humoral immune response composed of three antibody indices for the neurotropic viruses of measles (M), rubella (R), and varicella zoster (Z)—in these patients.MethodsWe analyzed paired CSF and serum samples of 39 schizophreniform and 39 bipolar patients. For comparison, we used a group of 48 patients with other inflammatory neurological disorders (OIND) and a cohort of 203 multiple sclerosis (MS) patients.ResultsWe found a positive MRZR in two patients with schizophreniform disorders (5.1%); both suffered from schizodepressive disorders without any other signs suggestive of MS. None of the bipolar patients (0%) and four members of the OIND group (8.3%) showed a positive MRZR. In the MS cohort, a positive MRZR was found significantly more frequently [in 99 patients (48.8%)] than in the other patient groups (p > 0.001). In summary, we did not find a positive MRZR in a relevant subgroup of patients with schizophreniform or bipolar disorders.ConclusionsOur results indicate that the MRZR is highly specific to MS. Nevertheless, two schizodepressive patients also had a positive MRZR. This finding corresponds to the few MRZR-positive patients with OIND or other autoimmune disorders with central nervous involvement, implicating that the MRZR specificity for MS is high, but not 100%.

Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis

BackgroundThe diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity.ObjectiveThe aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis.MethodsFindings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively.ResultsOligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60–80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood–CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively).ConclusionsPatients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood–CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.

Current Concepts of the Intrathecal Humoral Immune Response and the Diagnostic Significance of the Detection of Oligoclonal Immunoglobulins in Multiple Sclerosis

Multiple sclerosis (MS) is a presumptively autoimmune demyelinating diseases of the central nervous system. We present here a literature review including a list of potential antigens inducing the autoimmune response, these including myelin and nonmyelin structures. None of the antibodies to any of these antigens has sufficient specifi city and sensitivity for use in routine laboratory practice. Oligoclonal immunoglobulins identified by isoelectric focusing (IEF) are currently the main immunological markers for MS. The sensitivity and specifi city of the IEF method are 90% and 85%, respectively. The present article also discusses additional markers such as oligoclonal IgM and the MRZ reaction.

The MRZ reaction in primary progressive multiple sclerosis

BackgroundThe MRZ reaction (MRZR), composed of the three antibody indices (AI) against measles, rubella and varicella zoster virus and found positive in the majority of relapsing-remitting multiple sclerosis (RRMS) patients, is absent in other inflammatory neurological diseases (OIND). So far, it has been uncertain whether its differential diagnostic promise extends to patients with primary-progressive multiple sclerosis (PPMS).ObjectiveTo investigate the prevalence of MRZR in PPMS compared to RRMS and OIND patients.MethodsMRZR was assessed in patients with PPMS (n = 103), RRMS (n = 100) and OIND (n = 48). Both stringency levels for MRZR testing, MRZR-1 (≥1 AI positive) and MRZR-2 (≥2 AI positive), were applied.ResultsPrevalence of positive MRZR-1 was 83.5% in PPMS and 67.8% in RRMS (p < 0.05). A positive MRZR-2 was found in 54.4% of PPMS and in 43.0% of RRMS patients (not significant). Compared to both MS subgroups, OIND patients exhibit lower frequencies of positive MRZR (MRZR-1: 22.9%, MRZR-2: 8.3%; p < 0.0001 each).ConclusionPositive MRZR was at least as frequent in PPMS as in RRMS and much less frequent in OIND, confirming its promise as a potentially useful diagnostic tool for distinguishing both MS course types from OIND.

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

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

Validation of a multiplexing technique to determine the intrathecal, polyspecific antiviral immune response in multiple sclerosis

ABSTRACTBackground: Beside the determination of oligoclonal bands (OCBs) as a diagnostic biomarker in multiple sclerosis (MS), the presence of an intrathecal production of antibodies against the neurotropic viruses measles (M), rubella (R) and Varicella-Zoster (Z), the so called MRZ reaction (MRZR) is an even more specific diagnostic biomarker in MS.Methods: We compared and validated the determination of the MRZR in 97 cerebrospinal fluid (CSF) and serum sample pairs of a bead-based multiplexing technique and a classical enzyme-linked immunosorbent assay (ELISA).Results: Conformity of 94% (M), 94% (R), 94% (Z), 96% (H) and 97% for the interpretation of the MRZR was obtained.Conclusion: Based on our findings of high conformity between the multiplex technique and classical ELISA, as well as the time and cost savings multiplexing allows, we conclude that the multiplexing technique is applicable as a diagnostic tool for the determination of the MRZR.

Does MRZ Reaction Have a Real Significance in the Diagnosis of Multiple Sclerosis? (P2.155)

Does MRZ Reaction Have a Real Significance in the Diagnosis of Multiple Sclerosis? (P2.155)

The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort.

BackgroundA polyspecific, intrathecal humoral immune response against the neurotropic viruses, measles, rubella and varicella zoster virus, called “MRZ reaction” (MRZR), is present in the majority of patients with multiple sclerosis (MS). Neurosarcoidosis (NS) and acute disseminated encephalomyelitis (ADEM) are important clinical differential diagnoses of MS. Autoimmune encephalitis (AIE) represents a well characterized autoimmune CNS disorder with intrathecal antibody synthesis. The aim of this study was to investigate the specificity of MRZR for MS in patients with NS, ADEM and AIE for the first time, and to compare it with the diagnostic value of oligoclonal bands (OCB).Patients and methodsTwenty-two patients with NS, 17 with AIE, 8 with ADEM and 33 with MS serving as controls were analyzed for OCB and MRZR by calculation of the antibody index (AI) for each virus. MRZR was considered as positive if at least two AIs were ≥1.5.ResultsA positive MRZR was statistically significantly less frequent in NS (9 %), AIE (11 %) and ADEM (0 %) compared to MS patients (70 %; p < 0.001 each). The specificity of MRZR for MS was 92 % in the study cohort. In comparison to MRZR, the OCB showed a higher sensitivity (100 %), but a lower specificity (69 %) for MS.ConclusionThese results indicate that MRZR seems to be the most specific available CSF marker of MS.

Measles IgG Antibody Index Correlates with T2 Lesion Load on MRI in Patients with Early Multiple Sclerosis

BackgroundB cells and humoral immune responses play an important role in the pathogenesis and diagnosis of multiple sclerosis (MS). A characteristic finding in patients with MS is a polyspecific intrathecal B cell response against neurotropic viruses, specifically against measles virus, rubella virus, and varicella zoster virus, also known as an MRZ reaction (MRZR). Here, we correlated from the routine clinical diagnostics individual IgG antibody indices (AIs) of MRZR with magnetic resonance imaging (MRI) findings in patients with first MS diagnosis.Methods/ResultsMRZR was determined in 68 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting MS (RRMS). Absolute AI values for measles virus, rubella virus, and varicella zoster virus were correlated with T2 lesion load and gadolinium enhancing lesions on cerebral MRI (cMRI) and cMRI combined with spinal MRI (sMRI). Measles virus AI correlated significantly with T2 lesion load on cMRI (p = 0.0312, Mann-Whitney U test) and the sum of lesions on cMRI and sMRI (p = 0.0413). Varicella zoster virus AI also showed a correlation with T2 lesion load on cMRI but did not reach statistical significance (p = 0.2893).ConclusionThe results confirm MRZR as part of the polyspecific immune reaction in MS with possible prognostic impact on MRI and clinical parameters.Furthermore, the data indicate that intrathecal measles virus IgG production correlates with disease activity on cMRI and sMRI in patients with early MS.

IgG Antibodies against Measles, Rubella, and Varicella Zoster Virus Predict Conversion to Multiple Sclerosis in Clinically Isolated Syndrome

BackgroundMultiple sclerosis (MS) is characterized by a polyspecific B-cell response to neurotropic viruses such as measles, rubella and varicella zoster, with the corresponding antibodies measurable in CSF as the so-called “MRZ reaction” (MRZR). We aimed to evaluate the relevance of MRZR to predict conversion of patients with clinically isolated syndrome (CIS) to MS, and to compare it to oligoclonal bands (OCB) and MRI.Methodology/Principal FindingsMRZR was determined in a prospective study over 2 years including 40 patients that remained CIS over follow-up (CIS-CIS) and 49 patients that developed MS (CIS-RRMS) using ELISA. Using logistic regression, a score (MRZS) balancing the predictive value of the antibody indices included in MRZR was defined (9 points measles, 8 points rubella, 1 point varicella zoster, cutpoint: sum of scores greater 10).MRZR and MRZS were significantly more frequent in CIS-RRMS as compared to CIS-CIS (p = 0.04 and p = 0.02). MRZS showed the best positive predictive value (PPV) of all parameters investigated (79%, 95%-CI: 54–94%), which could be further increased by combination with MRI (91%, 95%-CI: 59–99%).Conclusions/SignificanceOur data indicate the relevance of MRZR to predict conversion to MS. It furthermore shows the importance of weighting the different antibody indices included in MRZR and suggest that patients with positive MRZR are candidates for an early begin of immunomodulatory therapy.

The intrathecal, polyspecific antiviral immune response: Specific for MS or a general marker of CNS autoimmunity?

Background 80–100% of patients with multiple sclerosis (MS) display a polyspecific, intrathecal humoral immune response against a broad panel of viral agents including antibodies to measles, rubella and varicella zoster virus as its three most abundant components (called MRZ reaction [MRZR]). However, a positive MRZR reaction can also be found in some patients with CNS vasculitis, another rare autoimmune condition, raising the question whether this marker is really of high specificity for MS as previously claimed or whether it just represents a non-specific marker of CNS autoimmunity. Besides MS and CNS vasculitis, paraneoplastic neurological disorders (PND) represent the best recognized models of CNS autoimmunity. Objective To investigate MRZR for the first time in patients with PND. Patients and methods Forty-two patients with MS and 34 with PND were compared in this study. The intrathecal synthesis of antibodies against measles, rubella, and varicella zoster virus was detected by calculation of the respective antibody indices (AI). Results A positive MRZ reaction as defined by a combination of at least two positive AIs was present in 37/42 patients with MS, but in none of the patients with PND ( p < 0.0001). Median AI values differed significantly between groups ( p < 0.0005). Conclusions Our results confirm that MRZR is not a general marker of CNS autoimmunity. Taking into account the very rarity of CNS vasculitis as well the lack of MRZR positivity in infectious inflammatory CNS conditions as previously demonstrated, MRZR might indeed be a promising marker of MS. Further investigations on MRZR in more rare autoimmune conditions, which were not available for analysis in this study, are now warranted to refine further the specificity of this parameter.

MRZ reaction could distinguish patients with NMO from those with MS

MRZ reaction could distinguish patients with NMO from those with MS

Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica

Background:A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80–100% of patients with multiple sclerosis (MS),...

Relevance of immunological variables in neuroborreliosis and multiple sclerosis

The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities. Three cohorts of patients were investigated: MS (n = 42), NB (n = 27) and other neurological diseases (OND) (n = 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Q(alb) (CSF/serum albumin ratio) as a marker of blood-CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining. Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually anti-measles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Q(alb) in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Q(alb) in 81.5% and normal cell count in 7.4%. MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.