Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype
Prbstel et al. Journal of Neuroinflammation
Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype
Anne-Katrin Prbstel 1 3
Gabrielle Rudolf 0 2
Klaus Dornmair 4
Nicolas Collongues 0 2
Jean-Baptiste Chanson 0 2
Nicholas SR Sanderson 1 3
Raija LP Lindberg 1 3
Ludwig Kappos 1 3
Jrme de Seze 0 2
Tobias Derfuss 1 3
0 Department of Neurology, Hopital de Hautepierre, University Hospital Strasbourg , 1 Avenue Moliere, 67100 Strasbourg , France
1 Department of Neurology, University Hospital Basel , Petersgraben 4, 4031 Basel , Switzerland
2 Department of Neurology, Hopital de Hautepierre, University Hospital Strasbourg , 1 Avenue Moliere, 67100 Strasbourg , France
3 Department of Biomedicine, University of Basel , Hebelstrasse 20, 4031 Basel , Switzerland
4 Institute of Clinical Neuroimmunology, University Hospital Grosshadern , Max-Lebsche-Platz 31, 81377 Munich , Germany
Background: Antibodies against myelin oligodendrocyte glycoprotein (MOG) have been identified in a subgroup of pediatric patients with inflammatory demyelinating disease of the central nervous system (CNS) and in some patients with neuromyelitis optica spectrum disorder (NMOSD). The aim of this study was to examine the frequency, clinical features, and long-term disease course of patients with anti-MOG antibodies in a European cohort of NMO/NMOSD. Findings: Sera from 48 patients with NMO/NMOSD and 48 patients with relapsing-remitting multiple sclerosis (RR-MS) were tested for anti-aquaporin-4 (AQP4) and anti-MOG antibodies with a cell-based assay. Anti-MOG antibodies were found in 4/17 patients with AQP4-seronegative NMO/NMOSD, but in none of the AQP4-seropositive NMO/NMOSD (n = 31) or RR-MS patients (n = 48). MOG-seropositive patients tended towards younger disease onset with a higher percentage of patients with pediatric (<18 years) disease onset (MOG+, AQP4+, MOG/AQP4: 2/4, 3/31, 0/13). MOG-seropositive patients presented more often with positive oligoclonal bands (OCBs) (3/3, 5/29, 1/13) and brain magnetic resonance imaging (MRI) lesions during disease course (2/4, 5/31, 1/13). Notably, the mean time to the second attack affecting a different CNS region was longer in the anti-MOG antibody-positive group (11.3, 3.2, 3.4 years). Conclusions: MOG-seropositive patients show a diverse clinical phenotype with clinical features resembling both NMO (attacks mainly confined to the spinal cord and optic nerves) and MS with an opticospinal presentation (positive OCBs, brain lesions). Anti-MOG antibodies can serve as a diagnostic and maybe prognostic tool in patients with an AQP4-seronegative NMO phenotype and should be tested in those patients.
Neuromyelitis optica; Neuromyelitis optica spectrum disorder; Anti-aquaporin-4 antibodies; Anti-MOG antibodies; Inflammatory demyelinating CNS disease
Neuromyelitis optica (NMO) is a clinically defined entity
within the spectrum of inflammatory demyelinating diseases
of the central nervous system (CNS) which is characterized
by inflammatory attacks that are confined to the spinal cord
and the optic nerves [1,2]. Limited forms of the disease are
considered as NMO spectrum disorder (NMOSD) . The
finding of anti-aquaporin-4 (AQP4) antibodies in the
majority of patients with NMO  and some patients with
NMOSD has advanced our pathogenic understanding of the
disease  and has directed the therapeutic approach
towards a B cell-directed therapy . However, 10% to 50%
of NMO patients, depending on cohorts and assays used,
are AQP4-negative . Recent evidence suggests that some
of the NMO cases are related to antibodies against myelin
oligodendrocyte glycoprotein (MOG) [8-17].
Previously, we showed that anti-MOG antibodies are
present in about 25% of pediatric patients with a first
episode of acute demyelination and that these antibodies
correlate with the disease course [18,19]. The aims of the present
study were a) to analyze the presence of anti-MOG
antibodies in an independent blinded cohort of patients with
NMO/NMOSD and multiple sclerosis (MS) using the
previously described cell-based assay (CBA) , b) to correlate
antibody findings to clinical and magnetic resonance
imaging (MRI) parameters of MOG-seropositive and
AQP4seropositive NMO patients and NMO patients with no
detectable antibodies, and c) to characterize the long-term
clinical outcome of the MOG-seropositive patients.
A total of 135 patients including patients with NMO/
NMOSD (n = 48), relapsing-remitting MS (n = 48), and
healthy donors (n = 39) were analyzed. NMO/NMOSD and
MS patient samples were collected at the University
Hospital, Strasbourg, France between 2006 and 2012. The
clinical data were obtained retrospectively from the European
Database for Multiple Sclerosis (EDMUS). Healthy donor
samples were obtained from the blood donation center,
Etablissement Franais du Sang (EFS), Strasbourg, France.
Diagnoses of NMO/NMOSD or MS were based on the
revised Wingerchuk criteria or the McDonald criteria,
respectively [2,20]. Baseline sera for the NMO and MS
patients were collected within an average of 8 years (0 to
Figure 1 Overview of patient cohort, antibody status, and anti-MOG antibody levels. (A) Patient cohort and antibody status: The study
comprised a total of 135 participants including patients with NMO/NMOSD (n = 48), relapsing-remitting multiple sclerosis (RR-MS) (n = 48), and
healthy donors (n = 39). Of the NMO/NMOSD patients, 31 were positive for anti-AQP4 antibodies (AQP4+) with the cell-based assay (CBA) while
only 22 patients tested positive with indirect immunofluorescence (iIF). All of the AQP4-seropositive patients were negative for anti-MOG
antibodies (MOG). Of the AQP4-seronegative patients (AQP4), four patients had anti-MOG antibodies (MOG+) (CBA), while 13 patients had no
detectable antibodies against either AQP4 or MOG. (B) Anti-MOG antibody levels: Anti-MOG reactivity was analyzed with the CBA and is
expressed as the geometric mean channel fluorescence (GMCF) ratio of the MOG-transfected cell line divided by the empty vector-transfected
cell line. Values shown represent the (mean) GMCF ratio of one to four experiments. The cutoff used (dotted line) is the mean GMCF ratio
of the healthy donor group measured in parallel (n = 39) plus two standard deviations (cutoff = 1.45). Using this cutoff, 4 of the 17 (23.5%)
NMO/NMOSD sera were positive for anti-MOG antibodies (empty red squares), all of which were AQP4-seronegative (filled red squares).
None of the AQP4-seropositive NMO/NMOSD patients (filled red circles) and none of the RR-MS patients (filled light red triangles) were positive
for anti-MOG antibodies.
42 years) (MOG vs. AQP4 vs. seronegative: 17 (3 to 32), 6
(0 to 42), 7 (0 to 15) years) and 14 years (3 to 37 years) of
the first inflammatory episode, respectively. The mean
period of observation for the NMO/NMOSD patients was
19 years (3 to 35) for the MOG-positive patients, 11 years
(3 to 44) for the AQP4-positive patients, and 9 years (2 to
17) for the seronegative patients. Anti-AQP4 antibodies
were measured by two different methods: indirect
immunofluorescence (iIF) and CBA. Anti-MOG antibodies in
the sera were measured by flow cytometry using a CBA
with full-length, human, native conformational MOG as
previously described . The analysis was carried out
blinded. Anti-MOG antibody positivity was determined by
the ratio of the geometric mean channel fluorescence
(GMCF) of the MOG-transfected and the empty
vectortransfected cell line. The cutoff was calculated to be 1.45
(mean GMCF ratio plus two standard deviations of the
healthy donor control group measured in parallel). The
study was approved by the local ethical committee of the
University Hospital of Strasbourg (DC-2009-1002; CPP 09/
40; DC-2014-2222), and all patients gave their informed
consent for the study.
In total, 48 patients with NMO/NMOSD were
included in the study: 4 of the 48 patients tested positive
for anti-MOG antibodies, all of which were negative
for anti-AQP4-antibodies (Figure 1). Tested with the
iIF assay, 22 patients were positive for
anti-AQP4antibodies, while testing with the CBA revealed that
31 patients were anti-AQP4 antibody-positive (Figure 1A).
Only one patient was tested positive with the iIF
assay, but negative with the CBA. The remaining 13
patients were seronegative for both antibodies tested
The median age at first attack was slightly younger in
the MOG-seropositive group (31 years; range 15 to
55 years) compared to the age of the AQP4-seropositive
group (38 years; range 15 to 60 years) or the
seronegative group (36 years; range 23 to 53 years). Of note, two
out of four of the MOG-seropositive patients had a
disease onset in childhood (<18 years), whereas this was
the case only in three out of thirty one of the
AQP4seropositive and none of the seronegative patients. In terms
of clinical presentation, half of the MOG-seropositive (2/4)
Table 1 Clinical, paraclinical, and MRI characteristics of MOG-seropositive NMO patients compared to AQP4-seropositive
and AQP4/MOG-seronegative NMO/NMOSD patients
Clinical follow-up (years), mean (range) 19 (3 to 35) 11 (3 to 44) 9 (2 to 17)
aNot available n = 1; bNot available n = 2; cExcluding patients with combined ON/TM at disease onset. Abbreviations: AQP4, aquaporin-4; CSF, cerebrospinal fluid;
EDSS, Expanded Disability Status Scale; LETM, longitudinally extensive transverse myelitis; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance
imaging; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; OCB, oligoclonal bands; ON, optic neuritis; TM, transverse myelitis.
Age (years), median (range)
Age at first attack <18 years
Clinical presentation at first attack
Second territorial involvement
Time to second territory involvement (years), mean (range)c
or AQP4-seropositive (16/31) patients and about two thirds
(8/13) of the seronegative patients had an initial
presentation with uni-/bilateral optic neuritis (ON) (Table 1). A
quarter of the MOG-seropositive (1/4) and about a third of
the AQP4-seropositive (10/31) and seronegative (4/13)
patients had a disease manifestation with transverse myelitis
(TM). Remarkably, the mean time to the second attack
affecting a different CNS region was longer in the
MOGseropositive patients (11.3 years; range 1 to 30 years) as
compared to the AQP4-seropositive (3.2 years; range 0 to
9 years) and seronegative (3.4 years; range 0 to 7 years)
patients (Table 1). Oligoclonal bands (OCBs) were more often
found in the MOG-seropositive patients (3/3, not available
in 1) compared to the AQP4-seropositive (5/29, not available
in 2) and seronegative (1/13) patients.
MOG-seropositive patients showed brain lesions during
the disease course more frequently (2/4) as compared to
AQP4-seropositive (5/31) and seronegative (1/13) patients.
Follow-up brain MRI in two MOG-seropositive patients
revealed juxtaventricular lesions in one patient, and lesions in
the thalamus and corpus callosum in another patient
fulfilling the Barkhof criteria (Figure 2). All of the patients had
longitudinally extensive transverse myelitis (LETM) in the
cervical and/or thoracic spinal cord.
Longitudinal follow-up samples, which were
available in two patients with anti-MOG antibodies,
showed fluctuating antibody levels over the follow-up
period of 22 and 74 months (Figure 3). An increase of
anti-MOG antibodies was associated in one patient
(STB01) with an increased relapse frequency, but was
independent of any disease activity in another patient
(STB02) (Figure 3).
We identified four patients with antibodies against
native conformational MOG in a blinded cohort of 48
NMO/NMOSD patients. All four patients fulfilled the
diagnostic criteria of NMO at disease onset (1/4) or at
the time of second territorial involvement (3/4).
AntiMOG antibodies were detected in 4 out of 48 NMO/
NMOSD patients and 4 out of 17 AQP4-seronegative
patients. These findings are in line with other recent
reports that identified antibodies against MOG in a
subgroup of AQP4-seronegative patients with NMO/
NMOSD [8-10,12-16] (Table 2).
MOG-seropositive patients tended to have an earlier
or even pediatric onset in our cohort. Two recent
studies already indicated that anti-MOG antibodies are
present in some pediatric NMO patients [15,17]. Since
our samples were taken in adulthood later during the
disease course, one can speculate that anti-MOG
antibodies might develop early on and persist over many
years in some of these patients. Since anti-MOG
antibodies are also found in pediatric MS and acute
Figure 2 Brain MRI abnormalities in an anti-MOG
antibodypositive patient. Axial T2-FLAIR (fluid-attenuated inversion recovery)
brain MRI of a MOG-seropositive NMO patient 31 years after disease
manifestation with combined optic neuritis and transverse myelitis
showed multiple abnormalities fulfilling Barkhof criteria and resembling
multiple sclerosis lesions.
Figure 3 Longitudinal follow-up of MOG-seropositive patients of
up to 6 years reveals fluctuating anti-MOG antibody levels.
Longitudinal serum samples were available for two of the four anti-MOG
antibody-positive patients. Serum samples were taken 30 or 29 years after
disease onset over a time course of about 2 or 6 years (22 or 74 months).
Anti-MOG reactivity is expressed as the geometric mean channel
fluorescence (GMCF) ratio. The cutoff used (dotted line) is the mean GMCF
ratio of the healthy donor group measured in parallel (n = 39) plus two
standard deviations (cutoff = 1.45). The arrow indicates a clinical relapse.
Antibodies against MOG fluctuated over the disease course: An increase of
anti-MOG antibodies was associated in one patient (STB01) with an
increased relapse frequency, but was independent of disease activity in
the other patient (STB02).
n = 10
n = 8
n = 4
n = 16
n = 9
n = 16
n = 9
Table 2 Review of literature on anti-MOG antibodies in adult NMO/NMOSD
MOG+ NMO (SD)
Characteristics of MOG+ NMOSD patients
Gender (%fem.) Clinical presentation/MRI
Monophasic simultaneous or
sequential TM and ON;
lower spinal cord
involvement on MRI
More restricted phenotype (ON > TM);
bilateral simultaneous ON; single
attack; lower spinal cord involvement
conus and deep gray nuclei
involvement on MRI
Higher frequency of involvement
of all spinal cord regions
Strong association with BON;
optic disk swelling
Excellent recovery (12)
Good recovery in 88% (24)
Better outcomes; less
risk for disability (18)
less risk for disability (67)
Propensity to relapse (28)
Summary of the published literature on anti-MOG antibodies in adult NMO/NMOSD listed in PubMed until October 2014: The first three publications of the table
summarize the literature not solely focused on NMO/NMOSD, while the other reports summarize the publications with a systematic analysis of anti-MOG
antibodies in NMO/NMOSD. Abbreviations: BON, bilateral optic neuritis; CBA, cell-based assay; ELISA, enzyme-linked immunosorbent assay; fem., female; f/u,
follow-up; MOG, myelin oligodendrocyte glycoprotein; n.a., not available; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disease; ON, optic
neuritis; TM, transverse myelitis.
disseminated encephalomyelitis (ADEM) [18,21-26] the
picture emerges that the age of disease onset influences
the nature of the autoantigen.
Furthermore, compared to AQP4-seropositive and to
seronegative patients, the anti-MOG-positive patients
in our group resembled a more MS-like phenotype
with more common brain involvement during the
disease course and positive OCBs in the CSF. The
presence of OCBs is different from other recent reports
which have found no or less frequent OCBs in the
MOG-seropositive NMOSD patients [12-16].
Regarding brain lesions on MRI in the MOG-seropositive
group, the lesions were more reminiscent of MS than
NMO lesions with supratentorial, periventricular
localization. Moreover, brainstem lesions, which are a
hallmark of AQP4-seropositive NMO, were absent in
our MOG-seropositive patients, which has also been
suggested by other recent reports [13,15].
Our long-term follow-up enabled us to also analyze
the disease course over up to 44 years. Looking at the
temporal dynamics of anti-MOG antibodies in two
patients over up to 6 years indicates a fluctuating pattern
of these antibodies as it has been seen in pediatric MS
and NMO cases [17,18,27]. It is therefore necessary to test
patients longitudinally to assess anti-MOG serostatus.
We identified anti-MOG antibodies in a subgroup of
antiAQP4 antibody-negative NMO patients (about 25%), but
not in anti-AQP4 antibody-positive patients. Interestingly,
some of the MOG-seropositive patients presented with a
pediatric disease onset. The MOG-seropositive patients
might show a more benign clinical course with a lower
relapse rate and a longer time to a second attack affecting a
different CNS region compared to the AQP4-seropositive
and seronegative patients.
Our data suggest that MOG-seropositive patients show a
diverse clinical phenotype with clinical features resembling
NMO (attacks confined to the spinal cord and the optic
nerves) and MS with an opticospinal presentation (positive
OCBs, brain lesions). Further studies with larger cohorts
need to be conducted to consolidate these findings and
potentially lead to therapeutic recommendations which also
address the seemingly more benign clinical course with
a lower relapse frequency in the majority of the
ADEM: acute disseminated encephalomyelitis; AQP4: aquaporin-4; CBA:
cell-based assay; CNS: central nervous system; FLAIR: fluid-attenuated
inversion recovery; GMCF: geometric mean channel fluorescence;
LETM: longitudinally extensive transverse myelitis; MOG: myelin
oligodendrocyte glycoprotein; MRI: magnetic resonance imaging;
NMO: neuromyelitis optica; NMOSD: neuromyelitis optica spectrum disorder;
OCBs: oligoclonal bands; ON: optic neuritis; RRMS: relapsing-remitting
multiple sclerosis; TM: transverse myelitis.
AKP has received travel support and holds a research fellowship from
Genzyme. GR has no competing interests. KD received research support from
the German National Science Foundation through the Collaborative Research
Centres CRC TR 128 (Initiating/effector versus regulatory mechanisms in
multiple sclerosis). NC, JBC, and NSRS have no competing interests. RLPL has
received research support from the Swiss MS Society, the Swiss National
Science Foundation, the European FP6 and IMI JU programs, Roche Postdoc
Fellowship Program (RPF-program), unrestricted research grants from
Novartis and Biogen. LK received institutional research support from Acorda,
Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill, Biogen
Idec, Boehringer Ingelheim, Elan, Genmab, Glenmark, GlaxoSmithKline, Merck
Serono, MediciNova, Novartis, sanofi-aventis, Santhera, Shire, Roche, Teva,
UCB, Wyeth, the Swiss MS Society, the Swiss National Science Foundation,
the European Union, the Gianni Rubatto Foundation, and the Novartis and
Roche Research Foundation. JdS has no competing interests. TD serves on
scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec,
Genzyme, Mitsubishi Pharma, TEVA Pharma, and Bayer Schering Pharma; has
received funding for travel and/or speaker honoraria from Biogen Idec,
Genzyme, Novartis, Merck Serono, and Bayer Schering Pharma; and receives
research support from Biogen Idec, Novartis Pharma, the European Union,
the Swiss National Science Foundation, and the Swiss MS Society.
AKP participated in the design of the study, performed the antibody testing,
carried out the analysis of the clinical data and the statistical analysis, and
prepared the manuscript. GR participated in the collection of the material,
the collection and analysis of the clinical data, and the preparation of the
manuscript. KD produced the transfectant cell lines and prepared the
manuscript. NC and JBC participated in the collection of the material and
the clinical data. NSRS and RLPL participated in the data analysis and
preparation of the manuscript. LK participated in the study design and in the
preparation of the manuscript. JdS participated in the study design, the
collection of the material, the analysis of the clinical data, and the
preparation of the manuscript. TD participated in the study design, the
analysis of the clinical data, and prepared the manuscript. All authors read
and approved the final manuscript.
We thank Maria Zimmermann at the Department of Biomedicine, University
of Basel, Basel, Switzerland, for technical support. The study was partly
funded by the Swiss Multiple Sclerosis Society and intramural funding by the
University of Basel.
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