Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing

Abstract

Importance: Myelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct central nervous system-demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur.

Objective: To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center.

Design, setting, and participants: This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded.

Main outcomes and measures: Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed.

Results: A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P < .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%.

Conclusions and relevance: This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.

Figure 1.. Distribution of Antibody Titers and IgG-Binding Index (IBI) Values Among True-Positive and False-Positive Myelin Oligodendrocyte Glycoprotein (MOG)–IgG1 Cases

A and B, Boxplots showing the distribution of MOG-IgG1 end titers and screening IBI values, respectively, among false-positive and true-positive MOG-IgG1–associated disorder (MOGAD). Titers of 1000 or more and IBI values of 76.4 or more yield 100% specificity and positive predictive values for true MOGAD. C, Boxplot showing the correlation between MOG-IgG1 titer and IBI value (Spearman ρ, 0.86). True-positive and false-positive MOG-IgG1–positive cases in the 3 plots are displayed in gray open circles and orange dots, respectively.

Figure 2.. Representative Examples of Magnetic Resonance Imaging (MRI) Findings in True-Positive vs False-Positive Myelin Oligodendrocyte Glycoprotein (MOG)–IgG1 Cases

True-positive cases (A-D): axial fluid-attenuated inversion recovery (FLAIR) image showing large, multifocal, poorly demarcated lesions on brain MRI in a patient with an acute disseminated encephalomyelitis attack in MOG-IgG1–associated disorder (MOGAD) (A); axial postgadolinium T1-weighted orbit MRI showing longitudinally extensive enhancement of the left optic nerve sheath in a patient with optic neuritis as a manifestation of MOGAD (B); sagittal T2-weighted images showing a longitudinally extensive myelitis lesion along the lower thoracic spinal cord, with predominant involvement of the central gray-matter on axial images in MOGAD (C and D). False-positive cases (E-K): sagittal FLAIR image showing Dawson-finger T2-hyperintense lesions perpendicular to the ventricle, typical of multiple sclerosis (E); axial postgadolinium T1-weighted images showing multiple areas of nodular enhancement in the pons that brainstem biopsy confirmed to be a histiocytic disorder (F); axial T2-weighted image showing a peripheral dorsolateral hyperintense lesion abutting the surface of the spinal cord, in another patient with multiple sclerosis (G); sagittal T2-weighted image showing a faint longitudinally extensive T2-hyperintense lesion accompanied by marked cervical spinal cord swelling with an intralesional cyst (H), also appreciable on axial images (I), which biopsy confirmed to be a glioma; sagittal (J) and axial (K) T2-weighted spinal cord MRI showing normal signal intensity and initial atrophy in a young adult man with X-linked adrenomyeloneuropathy.