Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report

Abstract

Myelin oligodendrocyte glycoprotein antibody-associated disease has been proposed as a separate inflammatory demyelinating disease of the central nervous system (CNS) since the discovery of pathogenic antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG). Antibodies targeting contactin-associated protein-like 2 (Caspr2), a component of voltage-gated potassium channel (VGKC) complex, have been documented to be associated with a novel autoimmune synaptic encephalitis with a low incidence. Herein, we reported an adult female with initial presentation of decreased vision in the right eye and subsequent episodes of neuropsychiatric disturbance including hypersomnia, agitation, apatheia, and memory impairment. Magnetic resonance imaging (MRI) revealed multiple lesions scattered in brain, brainstem, and cervical and thoracic spinal cord, showing hypointensity on T1-weighted images, hyperintensity on T2-weighted and fluid attenuated inversion recovery (FLAIR) images. Heterogenous patchy or ring-like enhancement was observed in the majority of lesions. The detection of low-titer MOG-IgG exclusively in cerebrospinal fluid (CSF; titer, 1:1) and Caspr2-IgG in both serum and CSF (titers, 1:100 and 1:1) led to a possible diagnosis of coexisting MOG-IgG-associated disease (MOGAD) and anti-Caspr2 antibody-associated autoimmune encephalitis. The patient was treated with immunosuppressive agents including corticosteroids and immunoglobulin, and achieved a sustained remission. To the best of our knowledge, this is the first report on the possible coexistence of MOGAD and anti-Caspr2 antibody-associated autoimmune encephalitis, which advocates for the recommendation of a broad spectrum screening for antibodies against well-defined CNS antigens in suspected patients with autoimmune-mediated diseases of the CNS.

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https://doi.org/10.1177/1756286420969462
https://doi.org/10.1177/1756286420969462
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Autoimmune Neurology
Introduction
In the last decade, the development of antibody
detection technique has remarkably expanded the
knowledge on autoimmune-mediated diseases of
the central nervous system (CNS). For instance,
the discovery of pathogenic myelin oligodendrocyte
glycoprotein immunoglobulin G (MOG-IgG) has
facilitated the identification of a novel disease
entity, namely MOG-IgG-associated disease
(MOGAD) with the characteristic manifestations
of optic neuritis (ON), longitudinally extensive
transverse myelitis (LETM), acute disseminated
encephalomyelitis (ADEM), brainstem encephali-
tis, or diencephalic syndrome suggestive of demy-
elination.1 Similarly, antibody against contactin
associated protein-like 2 (Caspr2) – a component
of the voltage-gated potassium channel (VGKC)
complex at the juxtaparanodal region of myelinated
axons – refers to a recently recognized autoimmune
encephalitis (AE) with a low incidence, and is also
detected in several peripheral neurological syn-
dromes including neuromyotonia and Morvan
Possible coexistence of MOG-IgG-associated
disease and anti-Caspr2 antibody-associated
autoimmune encephalitis: a first case report
Pei Liu*, Miao Bai*, Xu Yan*, Kaixi Ren, Jiaqi Ding, Daidi Zhao, Hongzeng Li,
Yaping Yan and Jun Guo
Abstract: Myelin oligodendrocyte glycoprotein antibody-associated disease has been proposed
as a separate inflammatory demyelinating disease of the central nervous system (CNS)
since the discovery of pathogenic antibodies against myelin oligodendrocyte glycoprotein
(MOG-IgG). Antibodies targeting contactin-associated protein-like 2 (Caspr2), a component of
voltage-gated potassium channel (VGKC) complex, have been documented to be associated
with a novel autoimmune synaptic encephalitis with a low incidence. Herein, we reported
an adult female with initial presentation of decreased vision in the right eye and subsequent
episodes of neuropsychiatric disturbance including hypersomnia, agitation, apatheia, and
memory impairment. Magnetic resonance imaging (MRI) revealed multiple lesions scattered
in brain, brainstem, and cervical and thoracic spinal cord, showing hypointensity on T1-
weighted images, hyperintensity on T2-weighted and fluid attenuated inversion recovery
(FLAIR) images. Heterogenous patchy or ring-like enhancement was observed in the majority
of lesions. The detection of low-titer MOG-IgG exclusively in cerebrospinal fluid (CSF; titer,
1:1) and Caspr2-IgG in both serum and CSF (titers, 1:100 and 1:1) led to a possible diagnosis
of coexisting MOG-IgG-associated disease (MOGAD) and anti-Caspr2 antibody-associated
autoimmune encephalitis. The patient was treated with immunosuppressive agents including
corticosteroids and immunoglobulin, and achieved a sustained remission. To the best of our
knowledge, this is the first report on the possible coexistence of MOGAD and anti-Caspr2
antibody-associated autoimmune encephalitis, which advocates for the recommendation of
a broad spectrum screening for antibodies against well-defined CNS antigens in suspected
patients with autoimmune-mediated diseases of the CNS.
Keywords: autoimmune, contactin-associated protein-like 2, encephalitis, MOG-IgG-associated
disease, myelin oligodendrocyte glycoprotein
Received: 4 August 2020; revised manuscript accepted: 1 October 2020.
Correspondence to:
Jun Guo
Department of Neurology,
Tangdu Hospital, Air Force
Military Medical University,
No. 569 Xinsi Road, Xi’an,
Shaanxi Province 710038,
China
guojun_81@163.com
Pei Liu
Department of Neurology,
Tangdu Hospital, Air Force
Military Medical University,
Xi’an, Shaanxi Province,
China
Department of Neurology,
The First Hospital of Xi’an,
Xi’an, Shaanxi Province,
China
Miao Bai
Kaixi Ren
Jiaqi Ding
Daidi Zhao
Hongzeng Li
Department of Neurology,
Tangdu Hospital, Air Force
Military Medical University,
Xi’an, Shaanxi Province,
China
Xu Yan
Department of Neurology,
Tangdu Hospital, Air Force
Military Medical University,
Xi’an, Shaanxi Province,
China
Department of Neurology,
Suide County Hospital,
Yulin, Shaanxi Province,
China
Yaping Yan
College of Life Sciences,
Shaanxi Normal
University, Xi’an, Shaanxi
Province, China
*These authors
contributed equally.
969462TAN0010.1177/1756286420969462Therapeutic Advances in
Neurological DisordersP Liu, M Bai
research-article20202020
Case Report

Therapeutic Advances in Neurological Disorders 13
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syndrome.2,3 Meanwhile, overlapping or coexisting
syndromes have been noticeable with double or
multi-antibodies targeting distinct CNS antigens
such as MOG, aquaporin-4 (AQP4), glial fibrillary
acidic protein (GFAP), N-methyl-d-aspartate recep-
tor (NMDAR), leucine-rich glioma-inactivated
protein 1 (LGI1), and Caspr2.4–6 However, double
positivity for MOG-IgG and Caspr2-IgG in the
same patient has not yet been reported. Herein, we
present the first case of the possible coexistence of
MOGAD and anti-Caspr2 antibody-associated
autoimmune encephalitis in whom low-titer MOG-
IgG was detected exclusively in cerebrospinal fluid
(CSF) and Caspr2-IgG in both serum and CSF.
This paper aims to strengthen the recommendation
of screening for broad-spectrum antibodies for
well-defined autoimmune diseases of the CNS
when atypical clinical manifestations and/or radio-
logical features are observed in patients with pre-
existing autoimmune diseases.
Case presentation
In late January 2020, a previously healthy 48-year-
old female experienced acute decreased vision in
her right eye. Ophthalmic examination revealed
the right visual acuity was 0.3 (20/60) based on
the Snellen chart. She did not receive any treat-
ment, but the vision recovered spontaneously and
increased to 0.6 (20/35) 2 weeks later. In late
March, the patient was referred to local hospital
with main complaints of dizziness, slurred speech,
gait instability, and urinary incontinence. Shortly
after admission, she experienced multiple epi-
sodes of neuropsychiatric disturbance including
hypersomnia, agitation, apatheia, and memory
impairment. On neurologic examination, an
Expanded Disability Status Scale (EDSS) score
of 5.0 was obtained based on the abnormal find-
ings including decreased visual acuity in the right
eye with visual field defects, dysarthria, impaired
muscle strength in the left limbs (BMRC grade 3),
positive Romberg’s test, numbness of distal fin-
gers of the left hand, episodic urinary inconti-
nence, and cognitive impairment. Meanwhile, a
modified Rankin scale (mRS) score of 4.0 was
obtained based on disability of attending to own
partial needs, especially walk unassisted. Magnetic
resonance imaging (MRI) revealed multifocal
round or oval lesions scattered in bilateral frontal
and parietal lobes, the left occipital lobe, the right
insular subcortical and the left insular juxtacorti-
cal regions, as well as periventricular white mat-
ter, the body and splenium of the corpus callosum,
thalamus, periaqueductal gray matter, brainstem,
the left cerebellar peduncles, and cervical and
thoracic spinal cord, as manifested with hypoin-
tensity on T1-weighted images, and hyperinten-
sity on both T2-weighted and fluid attenuated
inversion recovery (FLAIR) images (Figures 1
and 2). Gadolinium (Gd)-enhanced MRI showed
heterogenous patchy or ring-like enhancement in
the majority of lesions (Supplemental Figure S1).
Video-electroencephalography showed no
remarkable findings except a slow wave back-
ground rhythm. No abnormalities were observed
on electromyography. Serological tests for infec-
tions, autoimmune, and neoplastic parameters
were all normal. Chest-abdominal-pelvic CT and
gynecologic ultrasound scanning eliminated the
possibility of associated malignancies. CSF analy-
sis revealed a normal white blood cell count but
with an increased lymphocyte ratio (90%) and a
slightly elevated protein level of 456 mg/l (normal
range: 80–430 mg/l). No oligoclonal IgG bands
(OCBs) were detected in serum and CSF. Cell-
based assays (CBA) revealed that serum MOG-
IgG was negative while CSF MOG-IgG was
positive with a low titer of 1:1 (Figure 3a). This
finding was verified by indirect immunofluores-
cence assay using monkey cerebellum tissue. The
patient was treated with intravenous methylpred-
nisolone pulse therapy (500 mg/day for 5 days,
250 mg/day for 3 days, 120 mg/day for 3 days)
plus intravenous immunoglobulin (IVIg; 0.4 g/kg
for five consecutive days). The patient was subse-
quently maintained on oral prednisone at 60 mg
daily for 20 days. Symptomatic treatments includ-
ing donepezil for cognitive impairment, and olan-
zapine and alprazolam for psychiatric disturbance
were given, but 2 days later were self-stopped by
the patient due to the unsatisfactory therapeutic
effects obtained in her view. Thereafter, the
patient was transferred by her relatives to our
department for further comprehensive assess-
ment of her condition.
On admission, neurologic examination revealed
numbness of distal fingers of the left hand, slightly
unsteady gait, and positive Romberg’s test. No motor
deficits and pathologic reflexes were found. The
Mini-Mental State Examination (MMSE) score was
27 and Montreal Cognitive Assessment (MoCA)
score was 26, which revealed mild cognitive impair-
ment especially in short-term memory and executive
function. Neuro-ophthalmologic examination
showed her visual acuity remained at 0.6 (20/35) in
the right eye and 0.8 (20/25) in the left eye. Visual

P Liu, M Bai et al.
journals.sagepub.com/home/tan 3
field defects were observed in the infero-nasal
quadrant and periphery of the right eye, and in the
periphery temporal of the left eye. A visual evoked
potential study disclosed no remarkable abnormali-
ties in the left optic nerve but significantly decreased
amplitude of P100 in the right. Optical coherence
tomography (OCT) revealed the thinning of retinal
nerve fiber layer (RNFL) in the temporal and
superior preponderance of the right eye, with values
of 35 µm and 65 µm, respectively. Collectively,
immunosuppressive therapy led to an obvious
improvement with the EDSS and mRS scores
reducing to 3.5 and 2.0, respectively. In parallel,
CSF MOG-IgG turned negative. Tests for other
auto antibodies in serum and CSF, including
NMDAR-IgG, AMPAR1-IgG, AMPAR2-IgG,
LGI1-IgG, GABABR-IgG, and AQP4-IgG were all
negative. Unexpectedly, but interestingly, Caspr2-
IgG was positive both in serum and CSF with titers
of 1:100 and 1:1, respectively (Figure 3b and c).
Figure 1. Brain MRI performed during acute attack. Axial FLAIR (a–j) and T2-weighted (k–t) images show multifocal round or oval
hyperintense lesions in the left cerebellar peduncles (a, k), the temporal horn of the left lateral ventricle (b, c, l, m), brainstem (b–e,
l–o), the left occipital lobe (d, n), the right thalamus (e, f, o, p), the right insular subcortical and the left insular juxtacortical regions
(f, p), bilateral frontal and parietal lobes (i, j, s, t), periventricular white matter (f-h, p-r), and the body and splenium of the corpus
callosum (g, h, q, r).
MRI, magnetic resonance imaging.

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Prior low-titer CSF MOG-IgG together with
serum and CSF Caspr2-IgG positivity resulted in a
possible diagnosis of coexisting MOGAD and anti-
Caspr2 antibody-associated autoimmune encepha-
litis. Considering the partial remission obtained with
immunotherapy in the patient, as a continuation of
the prior maintenance treatment with oral pred-
nisone, intravenous methylprednisolone at 60 mg
daily was subsequently given for six consecutive days
followed by oral prednisone starting at 40 mg daily
with a slow tapering schedule of 5 mg every month.
The patient was discharged in a stable condition, and
remained so during the follow-up period. At 1 month
after discharge, repeat brain and spinal cord MRI
revealed no obvious changes in lesion burden, and
the EDSS and mRS scores remained unchanged.
Meanwhile, no malignancies were found on repeat
chest-abdominal-pelvic CT at this time (approxi-
mately 6 months from disease onset). Face-to-face
follow-up visits have been attended on schedule.
Figure 2. Spinal cord MRI performed during acute attack. T2-weighted sagittal cervical (a) and thoracic
(b) spinal cord images show short-segment hyperintense lesions with well-defined borders (arrows). Axial
cervical spinal cord image shows one lesion involving the anterior white matter and the lateral column (a’,
arrow), and thoracic spinal cord image shows one lesion involving the central gray matter (b’, arrow). No
lesions are seen in lumbar spinal cord images (c, c’).
MRI, magnetic resonance imaging.
Figure 3. Detection of MOG-IgG and Caspr2-IgG by transfected CBA. Representative photographs (×400) show
positive MOG-IgG in CSF (a; titer, 1:1) as well as positive Caspr2-IgG in both serum (b; titer, 1:100) and CSF
(c; titer, 1:1).
Caspr2-IgG, antibodies against contactin-associated protein-like 2; CBA, cell-based assay; MOG-IgG, antibodies against
myelin oligodendrocyte glycoprotein.

P Liu, M Bai et al.
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Discussion
Discovery of new antibodies against CNS antigens
such as AQP4, MOG, GFAP, NMDAR, LGI1,
and Caspr2 has contributed to the identification
of novel disease entities and expanded disease
spectrum of autoimmune disorders of the CNS.1,7–10
More recently, detection of two or even more anti-
bodies in the same patient has helped to understand
the complexity involved in these diseases,4,6,11,12 and
provided new insight into the possible mecha-
nisms underlying the pathogenesis of overlapping
or coexisting syndromes. In this paper, we reported
the first case on the possible coexistence of
MOGAD and anti-Caspr2 antibody-associated
autoimmune encephalitis based on the evidence of
low-titer CSF MOG-IgG together with serum and
CSF Caspr2-IgG positivity. MOG has been dem-
onstrated to be expressed exclusively in the CNS
and be located on the outermost surface of myelin
sheath and cell membrane of oligodendrocytes,
acting as a cell adhesion molecule and a regulator
of microtubule stability.1 The predominant sub-
type IgG1 antibodies to MOG initiate CNS demy-
elinating process via T cell-mediated cytotoxicity
and B cell-mediated immune responses with com-
plement activation.1,13 As part of VGKC complex,
Caspr2 is located in the juxtaparanodal region of
myelinated fibers in both CNS and peripheral
nervous system (PNS), and participates in syn-
apse synthesis and construction of central neural
network.2,3,14,15 Non-complement-activating IgG4
antibodies dominate in anti-Caspr2 antibody-
associated autoimmune encephalitis.10,12 Although
mechanisms responsible for coexisting double or
more autoantibodies are still undetermined, the
phenomenon may be partially explained by the
concept of epitope spreading, that is, persistent
recognition and activation to self-antigens lead to
chronic immune responses accompanying with
the development of antibodies against diverse
dominant epitopes within the same antigen (intra-
molecular) or to different antigens (intermolecular).5,16
Previous studies have shown epitope spreading in
pediatric multiple sclerosis (MS) patients and in
animal models such as experimental autoimmune
encephalomyelitis (EAE) and myasthenia gravis
(EAMG).17–19 Unfortunately in our case, it
remains unclear whether MOG-IgG and Caspr2-
IgG has emerged simultaneously or successively
due to the missed testing of Caspr2-IgG at the
patient’s local hospital. Even so, the fact that the
patient initially presented acute optic neuritis asso-
ciated with MOG-IgG followed by neuro psychiatric
disturbance highly suggestive of autoimmune
encephalitis appears to support the involvement of
intermolecular epitope spreading from MOG to
Caspr2 in the pathogenesis of the possible coexist-
ing syndrome. Further investigation is needed to
verify this hypothesis.
Detection of disease-specific antibodies is of
crucial importance in the diagnosis of antibody-
associated autoimmune disorders of the CNS.
CBA has been preferentially recommended owing
to its high sensitivity and specificity. Likewise in
our case, positivity for Caspr2-IgG was deter-
mined by CBA with titers of 1:100 in serum and
1:1 in CSF, which was sufficient to make a diag-
nosis of anti-Caspr2 antibody-associated autoim-
mune encephalitis. By contrast, MOG-IgG was
detected only in the first assay with a low titer of
1:1 in CSF. Despite previous evidence of almost
exclusive extrathecal MOG-IgG synthesis, a small
minority of patients have been observed with
exclusive MOG-IgG (titer range, 1:2–1:128) in
CSF,20–22 where antibody-producing B cells could
reside in the CNS reflecting intrathecal IgG syn-
thesis rather than passive diffusion of serum anti-
bodies into the CNS.20 Apart from CBA, an
indirect immunofluorescence assay using monkey
cerebellum tissue also verified the presence of
MOG-IgG. Although a low-titer CSF MOG-IgG
has been speculated to be pathogenic and seems
to present the characteristics of those with high-
titer serum MOG-IgG,20 the fact that CSF MOG-
IgG titer of our case was lower than the presumed
cut-off titer of 1:2 in previous studies is still not
convincing enough to make a definite diagnosis,
and eventually resulted in a possible diagnosis of
MOGAD.
MRI examination may also provide valuable clues
for the diagnosis of autoimmune diseases of the
CNS, since the distribution of lesions depend to a
large extent on the region-specific expression of
self-antigens. In our case, diffuse lesions involving
brain and spinal cord particularly in subcortical
white matter, juxtacortical regions and deep grey
matter were noted mimicking ADEM-like pat-
tern. The specific lesions combined with optic
nerve involvement are highly suggestive of
MOGAD, though the titer of MOG-IgG was low
during the same period. Previous studies have
shown that MOG-IgG titers were associated with
severity of disease and prognosis,23–26 but whether
MRI lesion burden and activity in the CNS cor-
relates with MOG-IgG titers during the course of
the disease has not been addressed. Of note, the

Therapeutic Advances in Neurological Disorders 13
6 journals.sagepub.com/home/tan
first assay was performed 2 months after initial
symptom onset in our case, but, unfortunately, it
was not clarified whether the titer of MOG-IgG
had increased from a lower level in parallel with
the aggravation of symptoms or remained at a
higher level at the earlier stage. Thus, dynamic
monitoring of antibody titers and MRI lesion bur-
den should be performed to clarify this point.
Studies have revealed that the specific MRI mani-
festation associated with Caspr2-IgG include T2
hyperintensity in the medial temporal lobes,
hippocampal atrophy, and mesial temporal or hip-
pocampal sclerosis.3 However, no similar abnor-
malities were found in our case. Moreover,
ADEM-like pattern of lesions involving brain,
brainstem, spinal cord, and optic nerves has not
been reported in autoimmune encephalitis associated
with Caspr2-IgG. Molecular imaging such as 18
F-fluorodeoxi glucose positron emission tomography
(FDG-PET) has been used recently to help iden-
tify anti-Caspr2 antibody-associated autoimmune
encephalitis, and the most common abnormality
was temporomesial hypometabolism.27,28
Unfortunately, our patient could not afford the
FDG-PET examination. In the future, more
imaging techniques would be incorporated to pre-
sent the detailed radiological features of autoim-
mune encephalitis associated with Caspr2-IgG.
Treatments of coexisting or overlapping syn-
dromes may encounter several challenges, such as
therapeutic options, duration of treatment, and
timing of immunosuppressive agent initiation,
given that diverse pathogeneses possibly underlie
different antibody-mediated autoimmune dis-
eases. In most cases, MOGAD has a favorable
response to steroid treatment but could recur eas-
ily after rapid tapering of steroids.26,29–31
Meanwhile, anti-Caspr2 antibody-associated
autoimmune encephalitis is a IgG4-dominant dis-
ease, and intravenous immunoglobulin is adopted
more commonly than steroids and other immuno-
therapies.10,14,32 In our case, a combination of
high-dose methylprednisolone and intravenous
immunoglobulin was given, followed by oral pred-
nisone with a slow tapering regime; the patient’s
clinical symptoms were significantly alleviated and
a long-term remission was obtained. More fortu-
nately, MOG-IgG declined to undetectable levels
after immunotherapy, possibly predicting a benign
disease course and a favorable clinical outcome.
Nevertheless, contemporary high-titer Caspr2-
IgG indicates a possible need for longer-term
immunotherapy or other immunosuppressive
agents with higher efficacy. Since it has been
proven that disease severity of MOGAD corre-
lates with the fluctuation of MOG-IgG titers,23,24
and symptom remission of autoimmune encepha-
litis is accompanied by a decline in Caspr2-IgG
titers,33 dynamic monitoring of clinical picture
combined with antibody titers is required and is of
great importance to guide treatment and prevent
recurrence.
Conclusion
To the best of our knowledge, this is the first report
of the possible coexistence of MOGAD and anti-
Caspr2 antibody-associated autoimmune encepha-
litis. Since the crucial role of disease-specific
antibodies in diagnosing autoimmune diseases, as
suggested by our case, screening for broad-
spectrum autoantibodies against well-defined CNS
antigens should be recommended in patients with
suspected autoimmune diseases, especially when
atypical clinical manifestations and/or radiological
features are observed in patients with pre-existing
autoimmune diseases. Given that coexisting anti-
bodies possibly mediate adverse pathogeneses,
therapeutic options should be assessed comprehen-
sively and a long-term follow up is needed.
Acknowledgements
The authors appreciate the assistance provided by
Shaanxi MYBiotech Co., Ltd. and Guangzhou
V-Medical Laboratory in the detection and verifi-
cation of MOG-IgG and Caspr2-IgG. We would
like to thank Hui Liu for his excellent work in
revising and polishing this paper.
Conflict of interest statement
The authors declare that there is no conflict of
interest.
Ethics statement and patient consent
Written informed consent was obtained from the
patient for publication of this paper. The present
study was approved by the Ethics Committees of
Tangdu Hospital, Air Force Military Medical
University.
Funding
The authors disclosed receipt of the following
financial support for the research, authorship, and/
or publication of this article: The present study
was supported by the Science and Technology
Innovation and Development Foundation of
Tangdu Hospital (grant number 2019LCYJ010).

P Liu, M Bai et al.
journals.sagepub.com/home/tan 7
ORCID iD
Jun Guo https://orcid.org/0000-0001-8053-
881X
Supplemental material
Supplemental material for this article is available
online.
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