MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin

In total, 614 serum samples and 18 CSF samples from 522 subjects were tested for MOG-IgG. Group I comprised 386 serum samples from 300 patients referred for routine MOG-IgG testing by 11 European academic centers, including the departments of neurology at the University of Heidelberg, the Charité-University Medicine Berlin, the University of Düsseldorf, the University of Bochum, Hannover Medical School, the University of Würzburg, the University of Rostock, the University of Freiburg, all in Germany; the University of Southern Denmark, Denmark; the MS Center at the Azienda Ospedaliero Universitaria San Luigi Gonzaga, Orbassano, Italy; and the IRCCS, C. Mondino National Neurological Institute, Pavia, Italy; eight of which are members of the German Neuromyelitis optica Study Group (NEMOS). Samples were taken for routine clinical assessment. Diagnoses at the time of blood sampling as reported by the referring centers, all of which were tertiary care university hospitals with specialized neuroimmunological departments, included “ON and myelitis” in 54 patients (1 x AQP4-IgG-positive; 79 serum samples available for testing), “monophasic ON” in 66 (69 samples), “recurrent ON” in 37 (median number of ON attacks 4, range 2–15; 76 samples), “longitudinally extensive transverse myelitis” in 45 (57 samples), “relapsing remitting MS” (RRMS) in 50 (54 samples), “secondary progressive MS” (SPMS) in 2 (2 samples), “primary progressive MS” (PPMS) in 2 (2 samples), and “other neurological disorder” (OND) in 44 (47 samples).

Group II consisted of 89 anonymized serum samples from 83 control patients with AQP4-IgG-positive ON and/or myelitis. Of those, 56 had a history of ON and myelitis, 22 of myelitis but no ON, and 5 of ON but no myelitis. AQP4-IgG had been previously detected by use of a commercial CBA (Euroimmun, Lübeck, Germany) in these patients [8] and by means of an ELISA (RSR, Cardiff, UK) [10].

Group III was made up of 85 anonymized serum samples from 85 control patients with MS according to the McDonald criteria (RRMS in 73, SPMS in 9, PPMS in 3).

Group IV comprised 54 anonymized samples from 9 control patients with OND (including 8 with connective tissue disorders and brain involvement [39]) and from 45 healthy controls.

All sera were tested using a live-cell CBA employing HEK293A cells transfected with full-length human MOG as previously described [17]. Screening of serum samples was performed at dilutions of 1:20 and 1:40, and antibody titers of positive serum samples were determined by serial dilutions. MOG-antibody titers of ≥1:160 were classified as seropositive [17]. If samples were tested more than once, the highest titer obtained with each sample was used for analysis in all control groups to ensure that data on assay specificity were as conservative as possible. Low-titer results (1:160–1:320) were confirmed in a second, methodologically independent CBA employing formalin-fixed HEK293 cells transfected with full-length human MOG (Euroimmun). CSF samples were screened undiluted, and antibody titers of positive samples were determined by serial dilutions (1:2, 1:4, etc.). The control samples were tested with MOG-IgG-positive serum samples interspersed. MOG-IgG serostatus and titers were determined by two independent investigators blinded to all clinical data (M.R., K.S.). To assess the origin of CSF MOG-IgG, the MOG-specific antibody index (AI_MOG) was determined. Calculation of AIs allows quantification of antigen-specific intrathecal antibody synthesis [40–43]. Briefly, AI_MOG values were calculated as the ratio between the CSF/serum quotient for MOG-IgG, Q_MOG-IgG, and the CSF/serum quotient for total IgG, Q_IgG(total), or Q_lim, if Q_IgG(total) exceeded Q_lim; i.e., AI_MOG = Q_MOG-IgG/Q_IgG(total), if Q_IgG(total) < Q_lim, and AI_MOG = Q_MOG-IgG/Q_lim, if Q_IgG(total) > Q_lim. CSF and serum samples were obtained at the same time. Usually, values >1.5 are considered as evidence of intrathecal specific antibody synthesis [40, 41]. However, if titers instead of concentrations are used to calculate the AI, a cut-off value of 4 has been recommended [44]. Reiber’s empiric hyperbolic function Q_lim was applied to control for possible underestimation of intrathecal specific synthesis due to disturbances of the blood-CSF barrier function and was calculated as follows [45]: \( {\mathsf{Q}}_{\mathsf{lim}\left(\mathsf{I}\mathsf{g}\mathsf{G}\right)}=\mathsf{0}.\mathsf{93}\sqrt{{\left({\mathsf{Q}}_{\mathsf{Alb}}\right)}^{\mathsf{2}}+\mathsf{6}\times \mathsf{1}{\mathsf{0}}^{{\textstyle \hbox{-}}\mathsf{6}}}-\mathsf{1}.\mathsf{7}\times \mathsf{1}{\mathsf{0}}^{{\textstyle \hbox{-}}\mathsf{3}} \)

The study was approved by the institutional review boards of the participating centers and patients gave their informed consent for publication of clinical data. The control samples were tested in anonymized fashion as requested by the institutional review board of the University of Heidelberg. The Mann-Whitney U test was used to compare antibody titers between groups, and the Kruskal-Wallis test with Dunn’s post test to compare more than two groups. Differences with P values <0.05 were considered statistically significant.

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