https://doi.org/10.

1093/brain/awad122 BRAIN 2023: 146; 3938–3948 | 3938

Diagnostic implications of MOG-IgG detection

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in sera and cerebrospinal fluids
Yuki Matsumoto,1,† Kimihiko Kaneko,1,2,† Toshiyuki Takahashi,3 Yoshiki Takai,1,2
Chihiro Namatame,1 Hiroshi Kuroda,1 Tatsuro Misu,1,2 Kazuo Fujihara4
and Masashi Aoki1,2

†
These authors contributed equally to this work.

The spectrum of MOG-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute dissemi­
nated encephalomyelitis (ADEM), brainstem encephalitis, cerebral cortical encephalitis (CE) and AQP4-IgG-negative
neuromyelitis optica spectrum disorder (NMOSD). In MOGAD, MOG-IgG are usually detected in sera (MOG-IgGSERUM),
but there have been some seronegative MOGAD cases with MOG-IgG in CSF (MOG-IgGCSF), and its diagnostic implica­
tions remains unclear.
In this cross-sectional study, we identified patients with paired serum and CSF sent from all over Japan for testing
MOG-IgG. Two investigators blinded to MOG-IgG status classified them into suspected MOGAD (ADEM, CE, NMOSD,
ON, MY and Others) or not based on the current recommendations. The MOG-IgGSERUM and MOG-IgGCSF titres were
assessed with serial 2-fold dilutions to determine end point titres [≥1:128 in serum and ≥1:1 (no dilution) in CSF
were considered positive]. We analysed the relationship between MOG-IgGSERUM, MOG-IgGCSF and the phenotypes
with multivariable regression.
A total of 671 patients were tested [405 with suspected MOGAD, 99 with multiple sclerosis, 48 with AQP4-IgG-positive
NMOSD and 119 with other neurological diseases (OND)] before treatment. In suspected MOGAD, 133 patients (33%)
tested MOG-IgG-positive in serum and/or CSF; 94 (23%) double-positive (ADEM 36, CE 15, MY 8, NMOSD 9, ON 15 and
Others 11); 17 (4.2%) serum-restricted-positive (ADEM 2, CE 0, MY 3, NMOSD 3, ON 5 and Others 4); and 22 (5.4%) CSF-
restricted-positive (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0 and Others 7). None of AQP4-IgG-positive NMOSD, multiple
sclerosis or OND cases tested positive for MOG-IgGSERUM, but two with multiple sclerosis cases were MOG-IgGCSF-posi­
tive; the specificities of MOG-IgGSERUM and MOG-IgGCSF in suspected MOGAD were 100% [95% confidence interval (CI)
99–100%] and 99% (95% CI 97–100%), respectively. Unlike AQP4-IgG-positive NMOSD, the correlation between MOG-
IgGSERUM and MOG-IgGCSF titres in MOGAD was weak. Multivariable regression analyses revealed MOG-IgGSERUM
was associated with ON and ADEM, whereas MOG-IgGCSF was associated with ADEM and CE. The number needed
to test for MOG-IgGCSF to diagnose one additional MOGAD case was 13.3 (14.3 for ADEM, 2 for CE, 19.5 for NMOSD, in­
finite for ON, 18.5 for MY and 6.1 for Others).
In terms of MOG-IgGSERUM/CSF status, most cases were double-positive while including either serum-restricted (13%)
or CSF-restricted (17%) cases. These statuses were independently associated with clinical phenotypes, especially in
those with ON in serum and CE in CSF, suggesting pathophysiologic implications and the utility of preferential diag­
nostic testing. Further studies are warranted to deduce the clinical and pathological significance of compartmenta­
lized MOG-IgG.

1 Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
2 Department of Neurology, Tohoku University Hospital, Sendai 980-8574, Japan
3 Department of Neurology, National Hospital Organization Yonezawa National Hospital, Yonezawa 992-1202, Japan
4 Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima 960-1295, Japan

Received October 26, 2022. Revised March 01, 2023. Accepted March 26, 2023. Advance access publication April 15, 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
Diagnostics in sera and CSF MOG-IgG
Correspondence to: Tatsuro Misu
Department of Neurology, Tohoku University Hospital
1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Japan
E-mail: misu@med.tohoku.ac.jp
Keywords: myelin oligodendrocyte glycoprotein IgG; MOG-antibody-associated disease; neuromyelitis optica
spectrum disorder; aquaporin 4 IgG; cerebrospinal fluid
Introduction
MOG antibody-associated disorder (MOGAD) has recently been re­
cognized as a new inflammatory CNS demyelinating disease.1–4
The clinical spectrum of MOGAD includes acute disseminated en­
cephalomyelitis (ADEM), neuromyelitis optica spectrum disorder
(NMOSD), optic neuritis (ON), myelitis (MY), cerebral/brainstem de­
myelination5–7 and cerebral cortical encephalitis (CE).5,8–12 In
MOGAD, MOG-IgG has usually been measured in sera
(MOG-IgGSERUM), being rarely detected in typical multiple sclerosis
and AQP4-IgG-positive NMOSD cases.2,7,13,14 Furthermore, the
pathological features of MOGAD differ from those in multiple scler­
osis and AQP4-IgG-positive NMOSD, suggesting that MOGAD is an
independent clinical and pathological entity.12,15
Although several studies have confirmed that MOG-IgGSERUM is
a diagnostic prerequisite for MOGAD,16–18 its positive predictive va­
lue (PPV) was imperfect (72–85%), particularly when using a lower
cut-off value.13,19 In fact, the cases with low MOG-IgGSERUM titres in­
cluded both true-positive and false-positive cases (such as multiple
sclerosis).13,19,20 Moreover, not all cases with typical MOGAD
features are positive for MOG-IgG13,19SERUM. Recently, some cases with
typical clinical and radiological MOGAD features were found to be
positive for MOG-IgG in CSF (MOG-IgGCSF) but negative for
MOG-IgGSERUM.21–25 However, there are discrepancies in the clinical
significance and frequencies of MOG-IgGCSF positivity among
studies.21,23,26
In the present study, to clarify the diagnostic value of detecting
MOG-IgG in sera and CSF in MOGAD, we investigated the frequen­
cies of MOG-IgGSERUM and MOG-IgGCSF in patients with suspected
MOGAD in a large Japanese cohort and their relationships with
the clinical phenotypes.
Materials and methods
Patients recruited for MOG-IgG testing
In this retrospective cross-sectional study, we initially reviewed
4785 consecutive patients from all over Japan whose sera and/or
CSF were sent to our laboratory for MOG-IgG testing from 1
August 2015 to 31 January 2018 (Fig. 1). All patients had undergone
brain and/or spinal cord MRIs during the acute phase. We enrolled
patients using the following inclusion criteria: (i) both serum and
CSF samples were collected before any treatment in the acute
phase (<1 month after onset); and (ii) sufficient clinical data were
available for our analysis. The medical records were independently
reviewed by two neurologists (Y.M. and Y.T.) blinded to MOG-IgG
status to determine the pre-test probability of suspected MOGAD
according to the patients’ clinical assessment, AQP4-IgG serostatus
and MRI data. In case of disagreement, a decision was made by dis­
cussion between the two raters. ‘Suspected MOGAD’ was defined as
patients with acute attacks or any combination of (i) ON; (ii) MY; (iii)
brain or brainstem demyelination; (iv) CE; or (v) multifocal CNS de­
myelination.2,5,8–11,13,27,28 Patients with alternative diagnoses such
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as typical multiple sclerosis, AQP4-IgG-positive NMOSD or other
neurological diseases (OND; i.e. spinal cord infarction) were used
as control groups. MOG-IgG positivity in serum and/or CSF of sus­
pected MOGAD cases was considered a true-positive, while
MOG-IgG positivity in alternative diagnoses was considered a
false-positive.
The ‘suspected MOGAD’ cases were divided into six clinical phe­
notypes (ADEM, CE, AQP4-IgG-negative NMOSD, ON, MY and
‘Others’) by two independent evaluators (Y.M and T.Y) based on
current diagnostic recommendations.2,8,9,29,30 ADEM was diag­
nosed based on the current diagnostic criteria,30 but ADEM-like pre­
sentations (e.g. multifocal demyelinating brain lesions without
encephalopathy) were merged with ADEM and analysed as a single
group.6 We diagnosed AQP4-IgG-negative NMOSD if the patient ful­
filled the 2015 International Panel on NMO diagnosis (IPND) criteria
for the category at the time of sample collection.29 In cases with
overlapping features of two diseases (for example, ADEM and
AQP4-IgG-negative NMOSD, or ADEM and CE), ADEM was the pri­
mary diagnosis. Cases not falling into the above categories, i.e.
single brain or brainstem demyelination, were classified as
Others. The diagnostic agreement rate of the two evaluators was
calculated.
Assay of MOG-IgG presence and titres
MOG-IgG was evaluated with an in-house live cell-based assay
(CBA) using HEK293 cells expressing full-length human MOG with
a secondary antibody to human IgG1.7,16 The MOG-IgGSERUM and
MOG-IgGCSF titres were assessed by serial 2-fold dilutions from
1:16 to establish end-titre values (the last dilution with a positive re­
sult). Two independent investigators who were blinded to the clin­
ical, imaging and laboratory data (K.K. and T.T.) performed the
MOG-IgG detection assay and determined the titre. In case of dis­
agreement, they reached a decision by consensus. The agreement
rates for the MOG-IgGSERUM and MOG-IgGCSF titres were respectively
calculated. MOG-IgGSERUM was considered positive in 1:128 diluted
serum to exclude the patients with typical multiple sclerosis, as
we previously reported.7 For MOG-IgGCSF, we used non-diluted
samples in this study.21 Additionally, we compared the correlations
between the ratio of CSF to serum titres in MOG-IgG-positive cases
and AQP4-IgG-positive NMOSD cases.
Statistical analysis
Categorical variables were tested with a Fisher’s exact test or chi-
square test, depending on the expected frequencies. Continuous
variables were assessed by the Wilcoxon rank-sum test or Kruskal–
Wallis test. Correlation analyses and r-values were generated using
a linear regression model. Comparison of the correlations of CSF to
serum titres between MOG-IgG and AQP4-IgG were tested by a
Fisher’s Z model. A multivariable regression model was used to clar­
ify the relationship between six clinical phenotypes, MOG-IgGSERUM
and MOG-IgGCSF titres among MOGAD cases. The ratios of antibody
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Figure 1 Flow chart for the identification of suspected MOGAD cases with serum and CSF samples. We retrospectively reviewed 4785 consecutive pa­
tients whose sera and CSF were sent to our laboratory for testing MOG-IgG from all over Japan from 1 August 2015 to 31 January 2018. We excluded 3904
cases without CSF samples and 21 cases without sera. We also excluded 173 patients, because their serum or CSF samples had been collected after
treatment or its information was unavailable; serum or CSF samples were collected after intravenous steroid therapy (125 patients); oral steroid or im­
munosuppressants had been given (eight patients); or treatment information was unavailable (40 patients). Of 686 cases, two evaluators (Y.M. and Y.T.)
determined the pre-test probability of MOGAD and divided them into suspected MOGAD (n = 405), multiple sclerosis (n = 99), AQP4-IgG positive NMOSD
(n = 48) and ONDs (n = 119) based on clinical, MRI and laboratory data.

titres in sera to those in CSF were compared in MOGAD and
AQP4-IgG-positive NMOSD cases. A two-sided P < 0.05 with
Bonferroni’s correction was considered statistically significant.
RStudio (v1.3.1073, Boston, USA) was used for all statistical analyses.
Standard protocol approvals, registration and
patient consent
The institutional review board of Tohoku University Graduate
School of Medicine approved this study. All study participants pro­
vided written informed consent.
Data availability
The datasets that support the findings of the current study are
available from the corresponding author on reasonable request.
The data are not publicly available because they contain informa­
tion that could compromise the privacy of the study participants.
Results
MOG-IgG-tested patients
In 859 patients with paired samples of sera and CSF (Fig. 1), 188
were excluded, because their samples were collected after im­
munosuppressive therapies or on an unknown date. The remaining
treatment-naïve patients were thoroughly reviewed, and we finally
identified 405 suspected MOGAD (high pre-test probability) cases,
and those with typical multiple sclerosis (n = 99), AQP4-IgG-positive
NMOSD (n = 48) or OND (n = 119) (summarized in Supplementary
Table 1) as the patients with alternative diagnoses (low pre-test prob­
ability). The two independent evaluators (Y.M. and Y.T.) agreed on
682 of 686 (99%) cases of suspected MOGAD or not (pre-test probabil­
ity assessment).
Table 1 shows the characteristics of the MOG-IgG tested patients.
The suspected MOGAD cases included 81 (20%) ADEM, 23 (5.7%) CE,
51 (13%) NMOSD, 70 (17%) ON, 122 (30%) MY and 58 (14%) Others
(24 with brainstem demyelination, 17 with brain demyelination, six
with ON + brain demyelination, five with brain demyelination + short
MY, three with brainstem demyelination + short MY, two with com­
bined central and peripheral demyelination and one with brain +
brainstem demyelination). All patients classified as Others did not
fulfill the diagnostic criteria for NMOSD or ADEM.29,30 The two inde­
pendent evaluators (Y.M. and Y.T.) agreed on 652 of 686 (95%) cases
for the classification of the six clinical phenotypes.
Quantification of MOG-IgG titre in sera and CSF
Two independent evaluators (K.K. and T.T.) agreed on the MOG-IgG
assay results in 663/671 (99%) of serum and 667/671 (99%) of CSF
samples (Fig. 2; representative CBA images of true-positive and false-
positive in MOG-IgG). Figure 3 shows MOG-IgGSERUM and MOG-IgGCSF
titres in suspected MOGAD (Fig. 3B), AQP4-IgG-positive NMOSD
(Fig. 3C), multiple sclerosis (Fig. 3D) or OND (Fig. 3E) and each of the
six clinical phenotypes of suspected MOGAD cases (Fig. 3F–K). Of
405 suspected MOGAD cases, 133 (33%) patients tested positive either
in the sera or CSF for MOG-IgG. Of these, 94 (70%) were positive in
Diagnostics in sera and CSF MOG-IgG BRAIN 2023: 146; 3938–3948 | 3941

Table 1 The characteristics of MOG-IgG-tested patients

MOG-IgG-tested patients

Suspected MOGAD AQP4-IgG-positive NMOSD MS OND

n 405 48 99 119
Age at specimen collection 39 (20–57) 43 (35–55) 38 (29–44) 57 (42–69)
Female: Male 195: 210 43: 5 70: 29 40: 79
Onset: relapse 109:296 21:27 31:68 –

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EDSS 3.0 (2.0–6.0) 5.0 (3.0–6.0) 2.5 (2.0–4.5) –
Clinical phenotypes
ADEM 81 (20%) – – –
CE 23(5.7%) – – –
NMOSD 51 (13%) – – –
ON
Total 70 (17%) – – –
Unilateral 55 (14%) – – –
Bilateral 15 (3.7%) – –
MY
Total 122 (30%) – – –
LETM 30 (7.4%) – – –
Short MY 92 (23%) – – –
Others 58 (14%) – – –
Interval between symptoms and sampling (days)
Serum 13 (5, 29) 12 (8, 18) 19 (8, 38) –
CSF 12 (4, 29) 12 (8, 18) 18 (7, 38) –
CSF cell count (/mm3) 6 (2–28) 5 (2–14) 2 (1–7) –
High IgG indexa 48/267 (18%) 5/34 (15%) 35/86 (41%) –
OCB positivity 33/231 (14%) 3/11 (27%) 46/82 (56%) –
CSF MBP (pg/ml) 40 (16–346) 42 (31–1616) 16 (16–55) –

Data are median (interquartile range), n (%), or n/N (%) when the denominator differs from the N value in the column heading. ADEM = acute disseminated encephalomyelitis; CE
= cerebral cortical encephalitis; EDSS = expanded disability status scale; LETM = longitudinal extensive transverse myelitis; MOGAD = MOG-IgG-associated disease; MS =
multiple sclerosis; MY = myelitis; NMOSD = neuromyelitis optica spectrum disorder; OCB = oligoclonal band; ON = optic neuritis.
a
IgG index was defined high if ≥0.75.

both the serum and CSF, 17 (13%) were positive in serum only and 22
(17%) were positive in CSF only. The remaining 272 patients tested
negative in both the sera and CSF. No AQP4-IgG-positive NMOSD
and OND cases tested positive for MOG-IgG in paired samples; one
patient with spinal cord infarction in OND showed 1:32 of
MOG-IgGSERUM (considered negative in the present study). One pa­
tient with multiple sclerosis showed 1:16 of MOG-IgGSERUM (consid­
ered negative in the present study) and two patients with multiple
sclerosis showed 1:4 of MOG-IgGCSF (considered positive in the pre­
sent study).
Correlation of autoantibody titres in serum and CSF
between MOGAD and AQP4-IgG-positive NMOSD
cases
We compared the correlations between the MOG-IgGSERUM and
MOG-IgGCSF titres (Fig. 3L) with those of AQP4-IgG (Fig. 3M). The cor­
relation coefficients of serum and CSF titres were r = 0.193 (P = 0.026)
for MOG-IgG and r = 0.943 (P < 0.0001) for AQP4-IgG. AQP4-IgG showed
a stronger correlation between serum and CSF titres than MOG-IgG (P
< 0.0001) due to the ratio of AQP4-IgG titration in blood and CSF close
to the physiological ratio of IgG levels at 1:512, as we previously re­
ported31; otherwise, the median of MOG-IgGCSF/MOG-IgGSERUM ratio
was 1:128 in this study. Therefore, some MOGAD cases, especially
those with ADEM (Fig. 3E) and CE (Fig. 3F), were found above the re­
gression line (Fig. 3L).
After excluding patients with MOG-IgGSERUM end-titres < 1:16 to
calculate the MOG-IgGCSF/MOG-IgGSERUM ratio, we compared the
MOG-IgGCSF/MOG-IgGSERUM ratio between the clinical phenotypes
of MOGAD and AQP4-IgG-positive NMOSD cases (Fig. 3N). The
MOG-IgGCSF/MOG-IgGSERUM ratio in CE patients was significantly
higher than those of MOG-IgG-positive ADEM, NMOSD, ON and
AQP4-IgG-positive NMOSD cases. The MOG-IgGCSF/MOG-IgGSERUM
ratios in MOG-IgG-positive ADEM cases were significantly higher
than those in AQP4-IgG-positive NMOSD cases.
Diagnostic sensitivity and specificity of MOG-IgG
detection in serum and CSF
The sensitivity of MOG-IgGSERUM and MOG-IgGCSF for the diagnosis
of MOGAD was 83% [95% confidence interval (CI), 76–89%] and 87%
(95% CI, 80–92%), respectively. The sensitivity of MOG-IgGSERUM in­
creased with a lower cut-off value [≥:64; 86% (95% CI, 79–92%),
≥1:32; 88% (95% CI, 81–93%), ≥:16; 90% (95% CI, 84–95%)]. The speci­
ficities of MOG-IgGSERUM and MOG-IgGCSF for MOGAD diagnosis
were 100% (95% CI, 99–100%) and 99% (95 %CI, 97–100%), respective­
ly. The overall PPVs of MOG-IgGSERUM and MOG-IgGCSF were 100%
(95% CI, 97–100%) and 98% (95% CI, 94–100%), respectively.
Although we set 1:128 as the cut-off value for MOG-IgGSERUM and
1:1 for MOG-IgGCSF in the current study, the PPV depended on the
titre; when analysing the data with different cut-offs (1:16–1:64 in
sera and 1:1∼1:8 in CSF), the PPVs of MOG-IgGSERUM were 85% for
1:16–1:64 (95% CI, 62–97%) and 100% for ≥1:128 (95% CI, 97–100%).
The PPVs of MOG-IgGCSF were 93% in 1:1–1:4 (95% CI, 76–99%) and
100% in ≥1:8 (95% CI, 96–100%). Supplementary Table 2 shows the
MOG-IgG positivity rate, PPV and negative predictive value strati­
fied according to different MOG-IgGSERUM and MOG-IgGCSF titre
cut-offs.
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Figure 2 Representative CBA images of true-positive and false-positive in MOG-IgG. Indirect immunofluorescence assay using human
MOG-transfected HEK 293 cells. Results of paired tests for serum at 1:16 dilution and undiluted CSF. Scale bar = 50 μm. (A–C) True-positive CBA images
in (A) a CE patient with both sero- and CSF-positivity; (B) a seronegative but CSF-positive patient with ADEM; and (C) a seropositive but CSF-negative
patient with ADEM. (D and E) False-positive images of two patients with multiple sclerosis showing seronegativity but CSF-positivity. Top: Fluorescence
images of serum [A(i)–E(i)] and CSF [A(iii)–E(iii)]. Bottom: Cell structures [A(ii)–E(ii) and A(iv)–E(iv)].

Characteristics in cases with or without
MOG-IgGSERUM/MOG-IgGCSF
Table 2 shows the demographic and clinical characteristics of
double-positive, CSF-restricted, serum-restricted and double-
negative cases. The double-positive group exhibited a relatively
shorter interval between symptoms onset/relapse and sample col­
lection than the other groups, but there were no statistically signifi­
cant differences in pairs after Bonferroni’s correction. Double-
negative cases were significantly older than double-positive and
CSF-restricted MOG-IgG cases (P = 0.046 and P < 0.001, respectively).
Sex, onset or relapse, expanded disability status scale, IgG index, oli­
goclonal band (OCB) positivity and myelin basic protein (MBP) level in
CSF were not different among the four groups. The white blood cell
count in CSF was higher in double-positive cases than in serum-
restricted MOG-IgG-positive and double-negative cases (P = 0.013
and P < 0.001, respectively), and the cell count in the CSF-restricted
MOG-IgG-positive cases was higher than in the double-negative
cases (P < 0.001).
The most frequent clinical phenotypes were ADEM in the
MOG-IgG double-positive cases (ADEM 36, CE 15, MY 8, NMOSD 9,
ON 15 and Others 11), Others in cases with CSF-restricted
MOG-IgG (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0 and Others 7), ON
in the cases with serum-restricted MOG-IgG (ADEM 2, CE 0, MY 3,
NMOSD 3, ON 5 and Others 4) and MY in the MOG-IgG
double-negative cases (ADEM 40, CE 4, MY 105, NMOSD 37, ON 50
and Others 36). Notably, CE was the most frequent in the cases
with CSF-restricted MOG-IgG but was not found among cases
with serum-restricted MOG-IgG, whereas ON was most frequent
in cases with serum-restricted MOG-IgG but not present in cases
with CSF-restricted MOG-IgG.
Among the patients with available information about treatment
in the acute stage, the kinds of treatment did not differ significantly
according to the detection pattern of MOG-IgG in serum and CSF.
We compared the proportion of patients with complete recovery
among the four groups and found a significant difference in the fre­
quency of patients showing complete recovery between the
double-positive (55%) and double-negative (29%) groups (P < 0.001).
MRI features in patients with CSF-restricted
MOG-IgG
We present the brain and spinal cord MRI images of true-positive
patients (MOGAD) in CSF-restricted MOG-IgG and false-positive pa­
tients (multiple sclerosis) (Fig. 4). These MRI findings of true-
positive patients with CSF-restricted MOG-IgG including multiple
white matter, brainstem (Fig. 4A) and cortical lesions (Fig. 4B), bilat­
eral optic neuritis, and MY with a H-shaped grey matter lesion (Fig.
4C) or longitudinally extensive transverse myelitis (Fig. 4D) were
compatible with typical MOGAD features. Two patients diagnosed
with multiple sclerosis and CSF-restricted MOG-IgG (false-positive)
had well-demarcated periventricular lesions typical for multiple
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Figure 3 MOG-IgGSERUM and MOG-IgGCSF titre in suspected MOGAD and alternative diagnoses, and the ratio of CSF to serum compared to AQP4-IgG. (A)
The x-axis represents the MOG-IgGSERUM titre, the y-axis shows the MOG-IgGCSF and dotted lines indicate the cut-off values. MOG-IgGSERUM and
MOG-IgGCSF titres in 405 suspected MOGAD cases (B), 48 AQP4-IgG-positive NMOSD cases (C), 99 multiple sclerosis cases (D), and 119 OND cases (E).
(F–K) Results of MOG-IgG analysis of six clinical phenotypes in suspected MOGAD cases. (L) Scatter plot of MOG-IgGSERUM and MOG-IgGCSF titres in
133 MOGAD cases [r = 0.193 (P = 0.026)] and (M) those in 48 AQP4-IgG-positive NMOSD cases [r = 0.943 (P < 0.0001)]. (N) Box and dot plots showing the
differences in MOG-IgGCSF/MOG-IgGSERUM ratio in clinical phenotypes of MOGAD and AQP4-IgG-positive NMOSD. For this analysis, we excluded
MOG-IgGSERUM with a titre less than 1:16. MOG-IgGCSF/MOG-IgGSERUM of patients with CE were significantly higher than those who
were MOG-IgG-positive with ADEM (P = 0.0083), NMOSD (P = 0.0090), ON (P < 0.001) and AQP4-IgG-positive NMOSD patients (P < 0.001). MOG-IgGCSF/
MOG-IgGSERUM ratios in MOG-IgG-positive ADEM were significantly higher than those in AQP4-IgG-positive NMOSD (P < 0.001). All P-values were ad­
justed by Bonferroni’s correction. ***P < 0.01, ****P < 0.001. ADEM = acute disseminated encephalomyelitis; CE = cerebral cortical
encephalitis; MOGAD = MOG-IgG-associated disease; MS = multiple sclerosis; MY = myelitis; NMOSD = neuromyelitis optica spectrum disorder; ON
= optic neuritis.
3944 | BRAIN 2023: 146; 3938–3948 Y. Matsumoto et al.

Table 2 The characteristics of patients with suspected MOGAD in serum and CSF MOG-IgG positivity

Patients with suspected MOGAD

Double-positive CSF-restricted Serum-restricted Double-negative P-valuea

n 94 22 17 272 –
Age at specimen collection 21 (8, 38) 34 (22, 43) 25 (13, 47) 44 (30, 64) <0.001
Female: Male 40: 54 11:11 8:9 136:136 0.7
Onset: relapse 25: 69 6: 16 6:11 72:200 0.9

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EDSS 3.5 (2.0, 5.5) 3.0 (2.0, 5.0) 3.5 (2.0, 5.0) 3.0 (2.0, 6.5) 0.8
Clinical phenotype
ADEM 36 (38%) 3 (14%) 2 (12%) 40 (15%) <0.001
CE 15 (16%) 4 (18%) 0 (0%) 4 (1.5%) <0.001
NMOSD 9 (9.6%) 2 (9.1%) 3 (18%) 37 (14%) 0.6
ON 15 (16%) 0 (0%) 5 (29%) 50 (18%) 0.046
MY 8 (8.5%) 6 (27%) 3 (18%) 105 (39%) <0.001
Others 11 (12%) 7 (32%) 4 (24%) 36 (13%) 0.062
Treatment in acute stage
IVMP 86/91 (95%) 22/22 (100%) 15/16 (94%) 231/258 (90%) 0.2
Plasma exchange 4/91 (4.4%) 3/22 (14%) 1/16 (6.2%) 13/258 (5.0%) 0.3
IVIg 6/91 (6.6%) 2/22 (9.1%) 0/16 (0%) 12/258 (4.7%) 0.5
Outcome of treatments – – – – 0.003
Complete recovery 45/82 (55%) 9/22 (41%) 5/12 (42%) 48/165 (29%) –
Partial recovery 37/82 (45%) 12/22 (54%) 7/12 (58%) 110/165 (67%) –
Non-response 0/82 (0%) 1/22 (4.5%) 0/12 (0%) 7/165 (4.2%) –
Interval between symptoms and sampling (days)
Serum 10 (3,32) 19 (9, 33) 19 (8, 33) 14 (5, 29) 0.028
CSF 8 (4, 20) 20 (8, 35) 19 (11, 33) 13 (5, 29) 0.009
CSF WBC (/mm3) 22 (7, 92) 18 (11, 32) 2 (1, 31) 4 (1, 14) <0.001
High IgG indexb 10/50 (20%) 3/17 (18%) 3/14 (21%) 32/186 (17%) >0.9
OCB positivity 3/45 (6.7%) 2/12 (17%) 1/7 (14%) 27/167 (16%) 0.4
CSF MBP (pg/ml) 270 (20, 477) 96 (16, 273) 20 (20, 30) 20 (16, 222) 0.2

Data are median (interquartile range), n (%) or n/N (%) when the denominator differs from the N-value in the column. ADEM = acute disseminated encephalomyelitis; CE
= cerebral cortical encephalitis; EDSS = expanded disability status scale; IVIg = intravenous immunoglobulin; IVMP = intravenous methylprednisolone; MY = myelitis; NMOSD =
neuromyelitis optica spectrum disorder; OCB = oligoclonal band; ON = optic neuritis; WBC = white blood cell.
a
Statistical tests performed: Kruskal–Wallis test; chi-square test of independence; Fisher’s exact test.
b
IgG index was defined as high if ≥0.75.

sclerosis (Fig. 4E and F). We present various clinical phenotypes
with various pattern of serum- or CSF-dominant MOG-IgG in paedi­
atric and adult MOGAD cases in Supplementary Figs 1 and 2.
Multivariable regression analysis
Since the MOG-IgGCSF/MOG-IgGSERUM ratios were high in CE and
ADEM, we applied multivariable regression models to explore the
contribution of MOG-IgGSERUM and MOG-IgGCSF (logarithmic trans­
formed) to each clinical phenotype considering age and sex. As a re­
sult, MOG-IgGSERUM was associated with ADEM [B = 2.5 (95% CI 0.51–
4.5), P = 0.014] and ON phenotypes [B = 3.3 (95% CI 1.2–5.5), P = 0.002]
independent of age, sex and MOG-IgGCSF titre (Supplementary
Table 3), whereas MOG-IgGCSF titres were significantly elevated in
ADEM [B = 1.5 (95% CI 0.25–2.7), P = 0.019] and CE phenotypes
[B = 2.0 (95% CI 0.66–3.3), P = 0.004] (Table 3).
diagnosed without CSF testing (Fig. 5A), but all ON cases were diag­
nosed with serum (Fig. 5B).
The number needed to test (NNT) for MOG-IgGCSF to diagnose
one additional MOGAD patient was 13.3 (Supplementary Table 4).
The NNTs in individual phenotypes were 14.3 (ADEM), 2 (CE), 19.5
(NMOSD), infinite (ON), 18.5 (MY) and 6.1 (Others). If
MOG-IgGSERUM tested negative, the probability of MOG-IgGCSF test­
ing positive in clinical phenotypes (95% CI) was 7% (1–19%) in
ADEM, 50% (16–84%) in CE, 5% (1–17%) in NMOSD, 0% (0–7%) in
ON, 5% (2–11%) in MY and 16% (7–31%) in Others. Therefore, we rec­
ommend starting with serum testing in suspected MOGAD pa­
tients, but for CE, both serum and CSF testing should be
considered from the beginning. On the other hand, our results
show that testing CSF is generally unnecessary for patients with
ON if MOG-IgG in serum is negative (Fig. 5C).

Clinical probability and the utility of MOG-IgGCSF
assay
The alluvial plots (Fig. 5A and B) showed the proportion of MOG-IgG
positivity in serum and CSF in each clinical phenotype. About half
of ADEM and the majority of CE cases were positive for either
MOG-IgGSERUM or MOG-IgGCSF, while more than 60% of patients in
the NMOSD, ON, MY and Others groups were negative for
MOG-IgG. Half of seronegative CE patients could not have been
Discussion
MOG-IgG positivity is essential to the diagnosis of MOGAD, and in
the most previous studies, MOG-IgG was examined mainly in
sera. However, several studies reported on cases with
CSF-restricted MOG-IgG and clinical and MRI features consistent
with MOGAD. In addition, for low MOG-IgGSERUM titres, the results
could be false-positive.13 Therefore, the present study aimed to
clarify the diagnostic implications of MOG-IgGSERUM and
MOG-IgGCSF in MOGAD in a large cohort.
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Figure 4 Representative images of brain and spinal MRI images in patients with CSF-restricted MOG-IgG. (A–D) True-positive cases. (A) Multifocal cere­
bral white matter (left) and brainstem hyperintensity lesions (right) on fluid-attenuated inversion recovery (FLAIR) images in a 31-year-old female
(ADEM as her onset event, who was refractory to intravenous methylprednisolone (IVMP), plasma exchange and IVIg therapy). (B) T2-hyperintensity
in the bilateral cerebral cortex (left)with meningeal gadolinium enhancement (right) in a 26-year-old male (CE as the onset event). He completely recov­
ered with IVMP therapy. (C) Bilateral ON and MY in a 31-year-old male (NMO as the onset event, he completely recovered with IVMP). ON in the STIR
image (top left) and T2-hyperintensity lesion in spinal cord (bottom left, and right), which was confined to the spinal grey matter. (D) A 20-year-old male
with onset MY with T2-weighted lesion that extended from C1 to C6. He completely recovered with IVMP and plasma exchange therapy. (E and
F) False-positive cases. (E) Ill-defined right internal capsule lesion in a 49-year-old male with left hemiparesis and hemianopia (multiple sclerosis).
(F) Ill-defined dorsal pontine lesions in a 25-year-old female with typical multiple sclerosis lesions. MOG-IgGSERUM and MOG-IgGCSF titre were shown
in each patient’s image. ADEM = acute disseminated encephalomyelitis; CE = cerebral cortical encephalitis; MY = myelitis; NMOSD = neuromyelitis
optica spectrum disorder; STIR = short tau inversion recovery.
3946 | BRAIN 2023: 146; 3938–3948
Table 3 Regression model for MOG-IgGCSF
Variable B 95%CI
Age 0.01 −0.01, 0.03
Female 0.02 −0.70, 0.75
MOG-IgGSERUM 0.07 −0.04, 0.18
Clinical phenotypes
Other – –
ADEM 1.5 0.25, 2.7
CE 2.0 0.66, 3.3
NMOSD −0.56 −2.0, 0.91
ON −0.63 −2.0, 0.72
MY 0.24 −1.1, 1.6
ADEM = acute disseminated encephalomyelitis; B = beta; CE = cerebral cortical
encephalitis; MY = myelitis; NMOSD = neuromyelitis optica spectrum disorder; ON =
optic neuritis.
*Significance P < 0.05.
Most importantly, we identified 22 CSF-restricted MOG-IgG
cases (17%) in MOGAD cases. This group included cases with
ADEM, NMOSD and CE phenotypes, and their clinical and MRI fea­
tures were compatible with those in MOG-IgGSERUM-positive cases,
except for a lack of isolated ON cases. Based on these findings, we
conclude that, among suspected MOGAD cases, patients with
CSF-restricted MOG-IgG are consistent with a diagnosis of MOGAD.
In line with the results in previous studies by Mariotto et al.21 and
Kwon et al.,23 no MOGAD patient with CSF-restricted MOG-IgG had
isolated ON in our cohort (Fig. 5B). Actually, the MOG-IgGSERUM titres
but not MOG-IgGCSF titres were associated with ON in the multivari­
able analyses (Table 3 and Supplementary Table 3). In addition, the
higher the MOG-IgGSERUM and MOG-IgGCSF titres, the more frequent
were brain lesions such as those seen in ADEM and CE phenotypes.
As a result, isolated ON cases were unlikely to test positive for
MOG-IgGCSF. However, we should pay careful attention that a few pa­
tients with isolated ON have been reported to test positive for
MOG-IgG in CSF only (Supplementary Table 5). We might have to
test MOG-IgGCSF in seronegative cases with typical
MOG-IgG-positive ON features, such as bilateral optic neuritis, peri­
neural enhancement or disc oedema.7,32
In this study, we detected CSF-restricted MOG-IgG positivity in
7.5% (22/294) of seronegative cases with suspected MOGAD. To
our knowledge, there have been seven reports on MOGAD with
CSF-restricted MOG-IgG (Supplementary Table 5).33 In a previous
study by Mariotto and colleagues,21 3 of 44 (6.8%) MOG-IgG/
AQP4-IgG-seronegative patients showed CSF-restricted MOG-IgG
positivity. A Korean study reported a similar proportion of patients
with CSF-restricted MOG-IgG, where 9 of 217 (4.1%) had MOG-IgG
detectable only in their CSF.23 In contrast, the study reported by
Pace et al.26 showed that the frequency of CSF-restricted MOG-IgG
was only 0.8% (4/533; two with transverse MY, one with pneumo­
coccal meningitis and one without details) of patients with paired
CSF-serum samples. Although the reason for these different results
is unclear, differences in the tested MOG-IgG cohort could have
contributed to them, i.e. the UK study included cases with low pre­
test probabilities such as pneumococcal meningitis (our study and
the Korean one included patients with infectious meningitis in the
negative control group).23 As shown in our multivariable analysis,
MOG-IgGCSF was closely associated with ADEM and CE; thus, the
frequency of CSF-restricted MOG-IgG might depend on the
Y. Matsumoto et al.
proportion of such cases. Additionally, the exclusion of the patients
under any immunosuppressive treatment in the present study
P-value might have increased the positivity rate of MOG-IgGCSF.
0.47 A possible explanation of the mechanism in CSF-restricted
0.95 MOG-IgG might be intrathecal production in MOGAD. We previous­
0.19 ly reported the CSF specific IgG synthesis in MOG-IgG compared
with AQP4-IgG, even though the albumin quotient in serum and
CSF did not differ in the two autoantibody-associated diseases.22
0.019* In AQP4-IgG-positive NMOSD, AQP4-IgG produced in the periphery
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0.004*
is thought to flow into the CNS following blood–brain barrier dis­
0.45
ruption.31,34–40 In addition, some of MOG-IgG-positive ADEM cases
0.36
had higher MOG-IgGCSF titres than MOG-IgGSERUM ones, while no
0.72
AQP4-IgG-positive patients did.31,34 In view of the present results
(Table 3 and Fig. 3), an influx of MOG-IgG from the peripheral blood
into the CNS cannot explain the high end-titre of MOG-IgGCSF in
such cases. Interestingly, our exploratory analysis to compare the
MOG-IgGCSF titre between OCB-positive (n = 6) and -negative cases
(n = 58) in MOGAD revealed that MOG-IgGCSF was higher in the cases
with OCB than in those without OCB, whereas MOG-IgGSERUM was
not (Supplementary Fig. 3). Thus, the intrathecal production of
MOG-IgG may be connected with OCB in some cases of MOGAD.
Although we present data indicating that testing MOG-IgG in
CSF would improve the diagnostic sensitivity of MOGAD in some
cases, two patients with multiple sclerosis (2.0%) were false-
positive for CSF-restricted MOG-IgG in the present study. In a
Korean study, 8.9% (4/45) of the patients with multiple sclerosis
showed CSF-restricted MOG-IgG.23 If we set a cut-off for the
MOG-IgGCSF value higher than 1:4 to exclude the two patients
with multiple sclerosis, it would concurrently exclude a patient
with short MY and three patients with the ‘Others’ phenotype [cere­
bral white matter demyelination + short MY (n = 2), brainstem de­
myelination + short MY (n = 1)] from the suspected MOGAD
patients in our cohort. Further studies should identify an appropri­
ate cut-off value for MOG-IgGCSF titres as shown in MOG-IgGSERUM.13
There are some limitations to the present study. First, there
might be a selection bias, because we analysed a patient cohort
in which both sera and CSF were collected during acute exacerba­
tions, possibly including more cases with severe and cerebral le­
sions other than ON. In fact, the most of studies showed 20–70%
of the cases of MOGAD were ON, while ON comprised 15% (20/
133) in our cohort.4 Second, the present study included a small
number of patients with neurosarcoidosis (n = 2; one was diag­
nosed by histopathological findings of lymph node and the other
was diagnosed due to bilateral hilar lymphadenopathy and ele­
vated CD4/CD8 in bronchoalveolar lavage) and primary CNS vas­
culitis (a pathologically-proven case) in the negative control.
Third, the clinical, MRI and laboratory features of MOGAD appear
to be relatively common among studies in various geographical
regions and different ethnicities, but our results in the Japanese
cohort may need to be confirmed in other ethnic groups. Fourth,
since this was a cross-sectional study, it is conceivable that the
formation of brain lesions in ADEM and CE cases may have caused
an increase in MOG-IgGCSF. However, this is unlikely, since neither
MOG-IgGSERUM nor MOG-IgGCSF titres increased in relapsed cases
(Supplementary Table 6). Last, the present study is retrospective,
like other previous studies33; thus, a long-term prospective study
is needed to explore unresolved issues such as whether the posi­
tivity of MOG-IgGCSF is transient or stable and whether
MOG-IgGCSF can predict future relapse, disability progression
and final prognosis.
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Figure 5 The MOG-IgGSERUM and MOG-IgGCSF positivity, the NNT of MOG-IgGCSF to diagnose one additional case and testing strategy in suspected
MOGAD cases. (A and B) Alluvial plots showing the MOG-IgGSERUM and MOG-IgGCSF positivity in (A) ADEM, CE and NMOSD, and in (B) ON, MY and
Others. (C) A schematic figure showing the testing strategy for MOG-IgGSERUM and MOG-IgGCSF in six clinical phenotypes. ADEM = acute disseminated
encephalomyelitis; CE = cerebral cortical encephalitis; MOGAD = MOG-IgG-associated disease; MS = multiple sclerosis; MY = myelitis; NMOSD = neu­
romyelitis optica spectrum disorder; ON = optic neuritis.

Conclusion Education, Culture, Sports, Science and Technology/JSPS WISE

Programme and Grants-in-Aid for Scientific Research from the
The present study confirmed that MOG-IgG is highly specific to Ministry of Health, Labour and Welfare of Japan.
MOGAD, but the rate of MOG-IgGSERUM and MOG-IgGCSF positivity
differs. The different MOG-IgG detection patterns such as double-
positive, CSF-restricted or serum-restricted positivity appear to be Competing interests
linked with MOGAD clinical phenotypes, suggesting the diagnostic
The authors report no competing interests.
priority to test serum and/or CSF. On the other hand, we need to pay
attention not to misinterpret the assay results of MOG-IgG since
false-positives and false-negatives can occur.
Supplementary material
Supplementary material is available at Brain online.
Acknowledgements
The authors thank Ms Mayu Atsumi and Ms Yukari Watanabe for References
their technical assistance.
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