Ongoing Challenges in the Diagnosis of Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease

With recognition of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) as a distinct entity and wider availability of MOG-IgG testing, clinicians are frequently confronted with the challenge of diagnosing MOGAD.¹ To facilitate diagnosis, consensus-elaborated diagnostic criteria relying on the presence of MOG-IgG, core clinical events, and exclusion of differential diagnoses were proposed.² The criteria require clinical interpretation to exclude other diseases, such as multiple sclerosis (MS) (challenge 1), and rely on heterogeneous assay results (challenge 2); thus, diagnoses may not be unequivocal. We investigated the reliability of the MOGAD diagnostic criteria to address these 2 challenges.

We analyzed data from a multicenter study of patients with suspected or confirmed demyelinating diseases.³ Institutional review boards of participating centers approved this cross-sectional study. All patients provided written informed consent. We followed the STROBE reporting guideline.

For challenge 1, patients fulfilling diagnostic criteria for MS⁴ with positive MOG-IgG results in a live cell-based assay (CBA) were included and independently rated by 2 neurologists (A.B.A.G.R.G., A.P.) for final diagnosis (MOGAD² or MS⁴). For challenge 2, patients with at least 1 core clinical demyelinating event suggestive of MOGAD² and 2 independent MOG-IgG results in a live CBA and a fixed CBA were included (eMethods in Supplement 1).

Interrater reliability (Cohen κ coefficient), interassay, and intercenter diagnosic concordance rates were calculated (eMethods in Supplement 1). Data analysis was performed using Microsoft Excel 16.77 (Microsoft Corp) and RStudio 2022.07.2 with R 4.2.0 (RStudio) from January to August 2023.

We included 162 patients (121 females [74.7%], 41 males [25.3%]; mean [SD] age, 43.1 [15.3] years). Challenge 1 group included 28 patients with positive MOG-IgG results, of whom 21 (75%; 12 with clear-positive and 9 with low-positive results) received MS diagnosis, 2 (7%; 1 with clear-positive and 1 with low-positive results) MOGAD diagnosis, and 5 (18%; 2 with clear-positive and 3 with low-positive results) discordant diagnoses. Twenty-seven patients (96%) presented records of core demyelinating events that were compatible with MOGAD. All 28 patients fulfilled imaging criteria for the MS diagnosis, 21 of whom (75%) also presented at least 1 supporting magnetic resonance imaging (MRI) feature compatible with MOGAD diagnosis. All 5 patients with discordant diagnoses presented positive cerebrospinal fluid (CSF)–specific oligoclonal bands, which were usually associated with myelitis (4 [80%]), and supportive imaging features for MOGAD (Table). The interrater reliability was fair (Cohen κ = 0.35).

Challenge 2 group included 134 patients, of whom 108 (81%; 97 negative, 2 low-positive, 9 clear-positive) exhibited concordant MOG-IgG results. Among 26 patients with divergent results, 17 (65%) had low-positive results in either CBA. A 90% (121 of 134) diagnostic agreement rate was observed when applying the proposed criteria to each center’s MOG-IgG results (Figure).

Findings revealed that the proposed diagnostic criteria in some cases may not accurately distinguish MOGAD from MS, contributing to diagnostic inconsistencies across centers. MOG-IgG testing and consideration of MOGAD diagnosis are recommended only in the absence of better alternative causes, such as MS. While this recommendation prevents unwarranted MOG-IgG testing, with potential false-positive results, the precondition cannot always be met because patients often present with overlapping clinical and imaging features. Consideration of additional laboratory, advanced MRI, or optical coherence tomography features may be needed in establishing accurate diagnoses.

Inconsistent replicability of MOG-IgG detection across assays and decreased reproducibility of low-positive results pose additional challenges. Although the panel aimed to increase comparability by categorizing antibody results as clear-positive or low-positive,² additional strategies are necessary to mitigate the risk of false-positive or false-negative results. Standardized testing remains unavailable worldwide, but repeated testing of sera with alternative assays or CSF testing in cases of seronegative results may increase diagnostic certainty in patients with high disease suspicion. A study limitation was its retrospective and cross-sectional design.

The proposed criteria mark a breakthrough toward improved MOGAD diagnosis. However, additional research and validation are needed to establish standardized assays and develop novel biomarkers to refine these criteria.

Accepted for Publication: August 31, 2023.

Published Online: October 10, 2023. doi:10.1001/jamaneurol.2023.3956

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Lipps P et al. JAMA Neurology.

Corresponding Author: Anne-Katrin Pröbstel, MD, Head Autoimmune Encephalitis Clinic & Research Group Experimental Neuroimmunology, Departments of Neurology, Biomedicine and Clinical Research, University and University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland (anne-katrin.proebstel@usb.ch).

Author Contributions: Dr Pröbstel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lipps and Ayroza Galvão Ribeiro Gomes and Ms Kulsvehagen contributed equally.

Concept and design: Lipps, Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Papadopoulou, Pröbstel.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lipps, Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Pröbstel.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Lipps, Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Pröbstel.

Obtained funding: Pröbstel.

Administrative, technical, or material support: Papadopoulou, Pröbstel.

Supervision: Kuhle, Papadopoulou, Pröbstel.

Conflict of Interest Disclosures: Dr Lipps reported receiving grants from Goldschmidt-Jacobson Stiftung during the conduct of the study and a European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) travel grant outside the submitted work. Dr Ayroza Galvão Ribeiro Gomes reported receiving grants (paid to the University of Sao Paulo for the collection and shipment of samples) from Roche, an ECTRIMS Clinical Fellowship, and a Swiss Government Excellence Scholarship during the conduct of the study. Ms Kulsvehagen reported receiving other from the Amsterdam University Fund. Dr Kuhle reported receiving grants from Swiss Multiple Sclerosis (MS) Society, Swiss National Research Foundation, Novartis, Biogen, Merck, Bristol Myers Squibb, Roche, and Sanofi outside the submitted work. Dr Papadopoulou reported receiving grants from University of Basel, University Hospital of Basel, Swiss MS Society, Swiss National Science Foundation (SNSF), and Freie Akademische Gesellschaft Basel during the conduct of the study and other from Sanofi-Genzyme, Eli Lilly, Abbvie, Lundbeck, Teva Pharmaceuticals, Hoffmann-La Roche, and Bayer AG outside the submitted work. Dr Pröbstel reported receiving grants from SNSF, National MS Society, Propatient Foundation, Fondation Pierre Mercier pour la Science, Goldschmidt Jacobson Foundation, and Gottfried and Julia Bangerter Rhyner Foundation during the conduct of the study and other from Biogen, Roche, and Novartis outside the submitted work. No other disclosures were reported.

Meeting Presentation: This paper was presented at the 9th Joint ECTRIMS-ACTRIMS Meeting, October 12, 2023, Milan, Italy.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank all patients for their participation. Jasmine Lerner; Anne-Catherine Lecourt, MSc; Alessandro Cagol, MD; and Johanna Lieb, MD (University Hospital of Basel and University of Basel, Switzerland) provided technical support in data acquisition. Carolin Schwake, MD, and llya Ayzenberg, MD (Ruhr University Bochum, Germany); Marius Ringelstein, MD, and Orhan Aktas, MD (Heinrich Heine University Düsseldorf, Germany); Patrick Schindler, MD, and Friedemann Paul, MD (Charité – Universitätsmedizin Berlin, Germany); and Dagoberto Callegaro, MD, PhD (University of Sao Paulo, Brazil) performed data acquisition and entrusted us with clinical data from their centers. Tobias Derfuss, MD, Ludwig Kappos, MD, and Cristina Granziera, MD, PhD (University Hospital of Basel and University of Basel, Switzerland) provided conceptual support. These individuals received no additional compensation, outside of their usual salary, for their contributions.