Diagnostic features of initial demyelinating events associated with serum MOG-IgG

https://doi.org/10.1016/j.jneuroim.2020.577260Get rights and content

Highlights

  • There's still uncertainty about diagnostic sensitivity and specificity of serum MOG-IgG

  • This is an observational study including 91 patients with a demyelinaing event of unclear aetiology, 24 MOG-IgG positive

  • We evaluated sensitivity and specificity of simplified requirements for MOG-IgG testing

  • These requirements are easily applicable compared to previous indications for testing

Abstract

Background

Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated.

Materials and methods

Between October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics.

Results

Clinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl.

Conclusions

Simplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.

Introduction

Serum antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been identified in a broad spectrum of inflammatory diseases, such as optic neuritis (ON), acute myelitis (AM), brainstem encephalitis, and acute disseminated encephalomyelitis (ADEM) (Jarius et al., 2016a; Jarius et al., 2016b; Cobo-Calvo et al., 2017; Jurynczyk et al., 2017; Ramanathan et al., 2018; Mader et al., 2011; Sato et al., 2014; Spadaro et al., 2015). Recent studies have suggested that MOG-IgG-associated disorders could represent a distinct entity from “classical” demyelinating diseases, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) with serum aquaporin-4 (AQP4)-IgG (dos Passos et al., 2018; Reindl et al., 2017). However, the relevant overlap among these diseases may lead to diagnostic misclassification, with potential therapeutic implications. Moreover, the overall sensitivity of serum MOG-IgG across different demyelinating conditions is controversial. This is due to the lack of clear indications for MOG-IgG testing to narrow down the associated clinical spectrum. An expert international panel (EIP) recently proposed recommendations for MOG-IgG testing, and provided a list of “red flags” that should prompt physicians to challenge the validity of a positive MOG-IgG test result (supplementary material) (Jarius et al., 2018).

The aim of this study was to assess sensitivity and specificity of serum MOG-IgG for the above mentioned EIP indications and to propose possible simplified recommendations for MOG-IgG testing in the diagnosis of demyelinating events (DEs) of unclear aetiology.

Section snippets

Study design and data collection

Study patients were consecutively enrolled, after signing written informed consent, in an ongoing multicenter observational study that was approved by the ethics committee of the Azienda Ospedaliera Universitaria Integrata Verona, Italy. Between October 2015 and July 2017 eligible cases were recruited at eight participating Italian centers, according to the following inclusion criteria: patients ≥18-years-old of both sexes with a DE not fulfilling 2010 McDonald criteria for MS at serum sampling

Results

We included 91 eligible patients (49 females). Median follow-up after DE onset was 32 months (range: 12–48). Twenty-four (26.4%) patients were MOG-IgG positive (i.e. titre ≥1:160), while MOG-IgG was not detected in 57 patients (62.6%) and detected at titre <1:160 in 10 (11%). Of 10 cases with low titres (i.e. from 1:20 to 1:80), 3 had ION, 3 had AM, 3 had CIS, 1 had MEM. Seventeen out of 24 positive samples had been tested also for IgG1 subclass. All 17 analysed samples were reactive for IgG1

Discussion

The results of this study indicate that MOG-IgG spectrum disorders have heterogeneous features that match only in part those of widely recognized demyelinating diseases of the CNS, such as MS, NMOSD, and ADEM.

Compared to most of previously published series of MOG-IgG positive patients, we observed a higher proportion of males in our cohort. However, some studies have reported a preponderance of males among MOG-IgG positive patients (Sato et al., 2014; de Mol et al., 2019; Hamid et al., 2017).

Conclusions

Our proposed set of criteria meets several of the clinical, radiological and laboratory features that have been specifically related to MOG-IgG-associated disorders (Weber et al., 2018). Moreover, these potential recommendations could simplify the clinical and laboratory findings that should be considered to perform MOG-IgG testing without compromising sensitivity and specificity of the assay in adult patients with a DE not fulfilling McDonald criteria for MS and who are AQP4-IgG negative at

Disclosures

Sara Mariotto received support for attending scientific meetings from Merck and Euroimmun.

M. Reindl is an academic editor for PLoS One. The University Hospital, and Medical University of Innsbruck (Austria, Markus Reindl) receives payments for antibody assays (NMDAR, AQP4, and other autoantibodies) and for MOG and AQP4 antibody validation experiments organized by Euroimmun (Lübeck, Germany).

None of the other authors report disclosures relevant to this manuscript.

The study was supported by

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