MOG encephalomyelitis: international recommendations on diagnosis and antibody testing

Jarius et al. Journal of Neuroinflammation (2018) 15:134 https://doi.org/10.1186/s12974-018-1144-2 REVIEW Open Access MOG encephalomyelitis: international recommendations on diagnosis and antibody testing S. Jarius1*, F. Paul2,3,4, O. Aktas5, N. Asgari6, R. C. Dale7, J. de Seze8, D. Franciotta9, K. Fujihara10, A. Jacob11, H. J. Kim12, I. Kleiter13, T. Kümpfel14, M. Levy15, J. Palace16, K. Ruprecht4, A. Saiz17, C. Trebst18, B. G. Weinshenker19 and B. Wildemann1* Abstract Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation. Keywords: Myelin oligodendrocyte glycoprotein (MOG) antibodies, Consensus recommendations, Diagnosis, Antibody testing, Multiple sclerosis (MS), Neuromyelitis optica spectrum disorders (NMOSD), Optic neuritis (ON), Myelitis Background Over the past few years, the role of immunoglobulin G serum antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in patients with inflammatory CNS demyelination has been revisited. While antibodies to MOG were originally thought to be involved in multiple sclerosis (MS), based on results from enzyme-linked immunosorbent assays employing linearized or denatured MOG peptides as antigen, more recent studies using new-generation cellbased assays have demonstrated a robust association of antibodies to full-length, conformationally intact human MOG protein with (mostly recurrent) optic neuritis (ON), * Correspondence: ; 1 Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany Full list of author information is available at the end of the article myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations, rather than with classic MS [1–11]. Based on evidence from (a) immunological studies suggesting a direct pathogenic impact of MOG-IgG, (b) neuropathological studies demonstrating discrete histopathological features, (c) serological studies reporting a lack of aquaporin-4 (AQP4)-IgG in almost all MOGIgG-positive patients, and (d) cohort studies suggesting differences in clinical and paraclinical presentation, treatment response and prognosis, MOG-IgG is now considered to denote a disease entity in its own right, distinct from classic MS and from AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD), which is now often referred to as MOG-IgG-associated encephalomyelitis (MOG-EM) [11–13]. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jarius et al. Journal of Neuroinflammation (2018) 15:134 Importantly, however, MOG-EM and MS show a relevant phenotypic, i.e., clinical as well as radiological, overlap [3, 14]: like MS, MOG-EM follows a relapsing course in most cases [3, 6], at least in adults, and 33 and 15% of adult patients with MOG-EM meet McDonald’s and Barkhof’s criteria for MS, respectively, at least once over the course of disease [3, 14]. Accordingly, many patients with MOG-EM were falsely classified as having MS in the past [3, 4]. However, such misclassification has potential therapeutic implications: (a) similar to what has been observed in AQP4-IgG-positive NMOSD, some drugs approved for MS might be ineffective or even harmful in MOG-EM owing to differences in immunopathogenesis [3, 4, 15–17]; (b) MOG-EM is associated with a high risk of flare-ups after cessation of steroid treatment for acute attacks and may thus require close monitoring and careful steroid tapering [3, 18–22]; and (c) patients positive for MOG-IgG might be particularly responsive to antibody-depleting treatments for acute attacks such as plasma exchange or immunoadsorption [3, 4, 9, 14, 23, 24], to B cell-targeted long-term therapies such as rituximab, to treatment with intravenous immunoglobulins (IVIG) (especially in children [25]), and to immunosuppressive treatments [3, 6, 14, 25, 26]. Therefore, increasing numbers of patients with suspected or established MS are currently being screened for MOG-IgG. However, screening of large unselected populations for rare biomarkers generally decreases the positive predictive value of diagnostic tests by increasing the rate of falsepositive results [27, 28]. Even if assays with high specificity (≥99%) are used, true-positive (TP) results can easily be outnumbered by false-positive (FP) results if the prevalence of a marker is low and the number of samples tested is high. This also applies to MOG-IgG testing. Based on a hypothetical prevalence of 1% genuinely MOG-IgGpositive cases among all patients currently diagnosed with MS, testing of 100,000 patients with an almost flawless, 99% specific and 100% sensitive assay would result in an unacceptable ratio of 990 FP results to 1000 TP results. Therefore, unselected screening of all patients with suspected or established MS for MOG-IgG should be discouraged and more specific criteria for MOG-IgG testing are urgently needed. In this paper, we propose for the first time indications for MOG-IgG testing based on expert consensus. In addition, (...truncated)