CASE REPORT
published: 22 April 2022
doi: 10.3389/fimmu.2022.799454

Case Report: Overlapping Syndrome
of Anti-NMDAR Encephalitis and
MOG Inﬂammatory Demyelinating
Disease in a Patient With Human
Herpesviruses 7 Infection
Sisi Li 1†, Minjin Wang 2†, Hancong Li 3, Jierui Wang 1, Qi Zhang 1, Dong Zhou 1
and Jinmei Li 1*
1 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China, 2 Department of Laboratory Medicine,
West China Hospital of Sichuan University, Chengdu, China, 3 West China School of Medicine, West China Hospital of
Sichuan University, Chengdu, China

Edited by:
Ryu Watanabe,
Osaka City University, Japan
Reviewed by:
Yoshiki Takai,
Tohoku University Hospital, Japan
Harry Alexopoulos,
National and Kapodistrian University of
Athens, Greece
*Correspondence:
Jinmei Li
lijinmei@wchscu.cn
†

These authors have contributed
equally to this work

Specialty section:
This article was submitted to
Autoimmune and Autoinﬂammatory
Disorders,
a section of the journal
Frontiers in Immunology
Received: 21 October 2021
Accepted: 28 March 2022
Published: 22 April 2022
Citation:
Li S, Wang M, Li H, Wang J, Zhang Q,
Zhou D and Li J (2022) Case Report:
Overlapping Syndrome of AntiNMDAR Encephalitis and MOG
Inﬂammatory Demyelinating
Disease in a Patient With Human
Herpesviruses 7 Infection.
Front. Immunol. 13:799454.
doi: 10.3389/fimmu.2022.799454

Objectives: This study reported a case of overlapping anti-N-methyl-D-aspartate
receptor (NMDAR) encephalitis and myelin oligodendrocyte glycoprotein (MOG)
inﬂammatory demyelinating disease with human herpesviruses 7 (HHV-7) infection.
Methods: The detailed clinical characteristics, neuroimaging features, and outcomes of
the patient were collected. Polymerase chain reaction (PCR), cell-based assay (CBA) and
the tissue-based indirect immunoﬂuorescence assay (TBA) were used for diagnosis.
Results: The clinical manifestations included headache, dizziness, fever, optic neuritis, and
epileptic-seizures. Brain magnetic resonance imaging (MRI) showed hyperintensities involving
the left frontal, orbital gyrus and bilateral optic nerve with substantial contrast enhancement.
Moreover, test for HHV-7 DNA by using the next generation sequencing metagenomics and
polymerase chain reaction showed positive result in CSF but not in the serum samples. AntiHHV-7 IgM and IgG antibodies were detected in both the serum and cerebrospinal ﬂuid.
NMDAR antibodies (1:10) were found positive in the patient’s CSF by a cell-based assay, and
MOG antibodies were positive in the serum (1:10) and CSF (1:32). The patient appeared to
respond well to immune therapy and it was found that the clinical symptoms including
epileptic-seizure as well as headache were relieved and cerebral lesions almost disappeared
after the treatment. However, his vision was not completely restored even at the 8-month
follow-up, especially the vision in his right eye which was more seriously damaged.
Discussion: We report a rare case of MOG antibodies and anti-NMDAR encephalitis
overlapping syndrome (MNOS) with HHV-7 infection for the ﬁrst time. The possibility of
MNOS needs be considered when optic neuritis occurs in the patients diagnosed with
anti-NMDAR encephalitis. Besides, immunotherapy should be initiated as early as
possible to improve the treatment outcomes and facilitate complete cure.
Keywords: anti-NMDAR encephalitis, optic neuritis, HHV-7 infections, case report, MOG antibodies and NMDAR
encephalitis overlapping syndrome (MNOS)

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virus can exhibit multiple immunomodulatory functions by
encoding some speciﬁc viral proteins, which could effectively
facilitate evasion of virus speciﬁc immune response and can
modify the host microenvironment to promote the viral
persistence (15). When investigating HHV-7 CNS disease, the
primary infection can be diagnosed through combining the CSF
polymerase chain reaction (PCR) with serology (16). To our best
knowledge, such case of HHV-7 infection and MNOS has not
been reported previously in the literature. Here, we describe the
case of a patient with overlapping MOG antibody disease and
anti-NMDAR encephalitis who was also found to have HHV7 infection.

BACKGROUND
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is
an immune-mediated disorder that is associated with IgG
antibodies to the GluN1 subunit of the NMDA receptor (1, 2).
The clinical manifestations of patients with anti-NMDAR
encephalitis include psychosis, memory deﬁcits, seizures,
language disintegration, abnormal movements, and autonomic
as well as breathing instability (3). Recently, it has been observed
that an underlying tumor (usually teratomas) (4) and virus
infections (5) can serve as the two triggers in the development
of anti-NMDAR encephalitis. Herpes simplex virus (HSV) -1
acts as one of the most commonly reported viral triggers for antiNMDAR encephalitis (6, 7), which has been detected in 27% of
patients with HSV encephalitis (8). For the pathophysiological
mechanisms underlying viruses-induced encephalitis, it had been
proposed that virus-mediated brain tissue damage could
potentially lead to exposure of the normally sequestered
neuronal cell antigens or that the cause of autoantibody
production could be possible “molecular mimicry” of viral
proteins due to the striking similarity between NMDAR and
viral antigenic peptides or antibodies (8).
Several cases have recently reported the coexistence of antiNMDAR and myelin oligodendrocyte glycoprotein (MOG)
antibodies (9–12). For instance, a study has reported that
11.9% of the patients with MOG antibody-associated
inﬂammatory demyelinating disease had anti-NMDAR
encephalitis, which had been deﬁned as MOG antibody disease
and anti-NMDAR encephalitis overlapping syndrome (MNOS)
(10). Among 184 patients with anti-NMDAR encephalitis, 2.7%
patients were identiﬁed as having overlapping MOG antibody
disease (12). The clinical manifestations included headache,
fever, seizures, cognitive impairment, psychiatric disorders,
disturbance of consciousness, and the symptoms of
demyelination (12).
Human Herpesviruses 7 (HHV-7) is a b-herpesvirus, which
usually infects during the childhood and can thereafter exist in a
lifelong latent state with possible reactivation in case of
immunodeﬁciency (13, 14). The virus exhibit multiple
immunomodulatory functions by encoding some speciﬁc viral
proteins, which could effectively facilitate evasion of virus-The

CASE REPORT
A 28-year-old man was brought to a local hospital in April 2021
because of the secondarily generalized epileptic-seizure, which
presented itself with a sudden loss of consciousness, staring eyes,
and stiffness of the limbs and convulsions. The various
symptoms lasted for several minutes and terminated before
reaching the hospital, and the patient was unable to recall the
onset of this seizure. The patient had only one epileptic episode.
The type of seizure was considered as focal impaired awareness
with motor onset seizure (17). For the past one week, he suffered
from headache and dizziness, but his medical history was
unremarkable. Magnetic Resonance Imaging (MRI) of the
brain showed signiﬁcant hyperintensity of the cortical and
subcortical of the left frontal lobe (Figures 1A–C). Thereafter,
lumbar puncture was performed two days later, which revealed
an increased intracranial pressure (250mmH2O), high protein
levels (1.28 g/L) and increased accumulation of cells (610 white
blood cells/mm3), but normal glucose and chloride levels.
During hospitalization, the patient occasionally suffered with
fever with a temperature of around 38.5°C. He was initially
diagnosed with meningoencephalitis. Therefore, he was
administered empirical intravenous (IV) anti-viral (acyclovir,
500mg/d, Q8h) and antibiotic (ceftriaxone sodium, 2000mg/d)
therapy, and the above symptoms were gradually alleviated. After
one week, the patient developed blurred vision in the right eye,
which deteriorated markedly with binocular vision loss after 10
days and continued to worsen continuously over the following
month. Repeated brain MRI showed enlarged lesion involving
the left frontal, orbital gyrus and bilateral optic nerve with
substantial contrast enhancement (Figures 1D–F). Hence, he
was transferred to our tertiary care center for further diagnosis.
Neurological examination revealed binocular vision loss with
only light perception, and lateral visual ﬁeld was impaired
(Supplementary Figures 2A, B). Muscle weakness, sensory
nervous system, cerebellar functions, Babinski sign and
meningeal irritation signs were observed to be in the
normal range.
Electroencephalograph (EEG) revealed a small amount of
scattered slow waves. Repeated lumbar puncture depicted lower
white blood cell count (11 cells/mm3) and protein (0.51 g/L)
level. Anti-HHV-7 IgM and IgG antibodies were detected in both
the serum and cerebrospinal ﬂuid (CSF). CSF testing for HHV-7
RNA by next generation sequencing (NGS) metagenomics and

Abbreviations: HHV, Human Herpesviruses; NMDAR, anti-N-methyl-Daspartate receptor; VZV, Varicella-zoster virus; EBV, Epstein-Barr Virus; HSV,
Herpes simplex virus; FLAIR, ﬂuid-attenuated inversion recovery; PCR,
polymerase chain reaction; CBA, Cell-based assay; TBA, Tissue-based indirect
immunoﬂuorescence assay; NGS, Next generation sequencing; CNS, Central
nervous system; CSF, Cerebrospinal ﬂuid; MOG, Myelin oligodendrocyte
glycoprotein; MOGAD, MOG-IgG associated inﬂammatory demyelinating
disease; MNOS, MOG antibodies and NMDAR encephalitis overlapping
syndrome; AQP4, Anti-aquaporin 4; GFAP, Glial ﬁbrillary acidic protein; MRI,
Magnetic Resonance Imaging; EEG, Electroencephalograph; IV, Injection of vein;
IVMP, Intravenous methylprednisolone; IVIG, Intravenous immunoglobulin;
NMDA, N-methyl-D-aspartate; anti-GABAB, Anti-gamma-aminobutyric acid-B
receptor; LGI1, Leucine-rich glioma-inactivated protein 1; CASPR2, Contactinassociated protein-like 2; AMPAR a-amino-3-hydroxy-5-methyl4isoxazolepropionic acid receptor; DPPX, Dipeptidyl peptidase-like protein-6;
mGluR5 metabotropic glutamate receptor 5.

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FIGURE 1 | Brain MRI performance. (A–C) The MRI data of patient at two weeks after the symptom onset showed hyperintensity of the left frontal lobe on ﬂuidatten uated inversion recovery (FLAIR) imaging and T2-weighted imaging (arrows). (D–F) MRI of the brain was repeated at 6 weeks and showed enhancement of the
left frontal lobe lesion involved the bilateral optic nerve (arrows) on FLAIR imaging conducted with gadolinium contrast. (G–I) Brain MRI scan performed at three
months after initial symptom onset depicted a signiﬁcant improvement of the imaging abnormality.

(Supplementary Table 1). NGS metagenomics tests, TBA tests,
and CBA tests for anti-neural antibodies and CNS demyelinating
antibodies also were performed at the Center for Precision
Medicine, West China Hospital, Sichuan University. Study
methods are provided in the Supplementary Material.

polymerase chain reaction (PCR) yielded positive result. All other
CSF tests for the neurotropic viruses and other bacteria displayed
negative results. Upon search for anti-neural antibodies (to antiNMDAR, anti-LGI1, anti-CASPR2, anti-AMPAR, anti-GABABR,
anti-DPPX, and anti-mGLuR5), NMDAR antibodies (1:10) were
found positive in the patient’s CSF by cell-based assay (CBA)
(Euroimmun, Lübeck, Germany) (Figure 2A). We also used CBA
(Euroimmun, Lübeck, Germany) to detect CNS demyelinating
antibodies (AQP4, MOG, GFAP), MOG antibodies were found
positive in CSF (1:32) (Figure 2B) and the serum (1:10)
(Figure 2C), whereas both AQP4 antibody (not shown) and
GFAP antibody (Figure 2D) were negative. Besides, we found a
weak ﬂuorescence response in the TBA detection, which indicated
that the disease was immunological in nature (Supplementary
Figures 1A, B). The various tests conducted for the paraneoplastic
antibodies, rheumatological autoantibodies, blood routine
examination, biochemistry, tumor markers, thyroid proﬁle,
mycobacteria, treponema pallidum, human cytomegalovirus,
and viral serological were all found to be negative

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TREATMENT AND OUTCOMES
The patient was prescribed IV ganciclovir for 21 days and IV
methylprednisolone (IVMP) for 5 days (1000 mg/day). He was
continued with immunosuppressive treatment with prednisolone
(1mg/kg/d) after discharge.
Two months after the discharge, it was found that the patient
was free of headache and seizures. Repeated brain MRI scan results
showed that the lesions in the left frontal cortex as well as the subcortex had almost disappeared, and bilateral optic nerve
enhancement was also signiﬁcantly diminished (Figures 1G–I).
However, the patient’s vision was not completely resolved. His
visual acuity was 20/167 in the right eye, and 20/33 in the left eye,

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FIGURE 2 | (A) Cerebrospinal ﬂuid (CSF) showing the binding to the surface of the cells expressing anti-NMDAR receptors (NMDAR) (1:10) (scale bar 20mm).
(B) Myelin oligodendrocyte glycoprotein (MOG) antibodies (1:32) were detected in the CSF (scale bar 100mm). (C) MOG antibodies (1:1) were detected in serum
(scale bar 100mm). (D) GFAP antibodies were found negative in the CSF (scale bar 100mm).

and his ﬁeld of vision was still impaired (Supplementary
Figures 2C, D). As a result of the long-term hormone therapy,
the patient gained weight and developed acne on the skin of his face.
Blood routine examination and liver as well as kidney function
showed no obvious abnormality. The patient started the second-line
immunosuppressant therapy with mycophenolate in August 2021.
After being treated with the second-line immune therapy, the
patient no longer suffered from the recurrent headache and
seizure. His visual acuity was found to be 20/80 in the right
eye, and 20/25 in the left eye, and his ﬁeld of vision was
marginally better than before (Supplementary Figures 2E, F).
A follow-up performed 6 months after the discharge, the patient
was found negative for anti-HHV-7 IgM antibodies, anti-HHV-7
IgG antibodies, HHV-7 DNA, MOG antibodies (Supplementary
Figure 1C), and anti-NMDAR antibodies (Supplementary
Figure 1D) in the CSF analysis, and weakly positive for antiHHV-7 IgG antibodies in the serum. Despite remaining partially
visually impaired, his daily life was not signiﬁcantly affected and
he had returned to work. The whole disease course and the
therapeutic modalities used have been summarized as a graphical
abstract (Figure 3).

primary HHV-7 infection with invasion of the CNS and
consequential disease had occurred (17). Besides, anti-HHV-7
IgM and IgG antibodies were observed to be positive in both CSF
and serum, thus HHV-7 encephalitis was considered in this
patient. Additionally, according to the clinical manifestations of
bilateral optic neuritis, imaging features of MRI, positive
NMDAR antibodies as well as MOG antibodies in the CSF,
and a good response to IVMP therapy, the patient was diagnosed
as MNOS. Since the ﬁrst wave of the symptoms were headache,
dizziness, and seizure, which were relieved after antiviral and
antibacterial treatment, whereas the second wave of symptoms
(optic neuritis) appeared on the 26th day of onset, we believed
that HHV-7 encephalitis was secondary to MNOS. At last, a ﬁnal
diagnosis of overlapping syndrome of anti-NMDAR encephalitis
and MOG inﬂammatory demyelinating disease with human
herpesviruses 7 infection was made.

DISCUSSION
We report for the ﬁrst time a rare case about a patient who was
diagnosed with overlapping anti-NMDAR encephalitis and
MOG inﬂammatory demyelinating disease after HHV-7
infection. Neurotropic viruses linked to anti-NMDAR
encephalitis have been previously described in the literature.
Several studies have proposed that HSV infections might have
meaningful association with the development of anti-NMDAR
encephalitis (18, 19). Except for HSV, recent clinical observations
have postulated that other viruses may also potentially elicit anti-

DIAGNOSTIC ASSESSMENT
The patient’s clinical manifestations such as fever, headache, and
epileptic seizure were similar to the presentation of the HHV-7
encephalitis. The ﬁnding of the viral DNA in the CSF by PCR
and NGS but not in the serum samples suggested that the

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FIGURE 3 | Timeline with clinical manifestation, treatment progression and diagnosis time. EEG, Electroencephalograph; MRI, Magnetic Resonance Imaging; IVMP,
Intravenous methylprednisolone; HHV-7, Human Herpesviruses-7; NMDAR, Anti-N-methyl-D-aspartate receptor; MOG, Myelin oligodendrocyte glycoprotein.

accompanied with manifestations of serious symptoms are
exceptionally rare (33). Moreover, only one case has been
reported about a child who was diagnosed with MNOS
secondary to the viral encephalitis, but the common
neurotropic virus (including HSV, EBV, and enterovirus) was
not found in CSF samples by PCR analysis (34). To our best
knowledge, no case of CNS HHV-7 infection association with
MNOS has been documented in the literature.
Optic neuritis is rare in patients with anti-NMDAR encephalitis,
but has been often reported in the patients diagnosed with MNOS
(9). Chen et al. reported that 37.9% of patients with MNOS had
symptoms of optic neuritis, and 46.7% of them displayed abnormal
signals on MRI involving cerebral cortical (12). The typical
manifestation of bilateral optic neuritis and abnormal signals of
the cerebral cortical on MRI for the present case are the speciﬁc
characteristic of MNOS. Therefore, we detected MOG antibodies by
CBA and obtained a positive result. Since the seizure occurred in the
ﬁrst week after the onset of initial symptoms, it was classiﬁed as the
ﬁrst wave of the symptoms. In addition, epileptic seizures have also
been reported as one of the common manifestations of HHV-7
encephalitis, so it was thought that the epileptic seizure of this
patient may be related to HHV-7. Nevertheless, unilateral cortical
MRI encephalitis with epileptic seizure has been reported to be
closely associated with MOG-antibodies (35, 36), thus the possibility
of seizures caused by MOG antibodies should also be considered.
Although most patients with MNOS respond well to the ﬁrstline immunotherapy, recurrence still needs to be considered.
Steroids combined with second-line immunotherapy can
effectively help to reduce the rates of recurrence (12). In our
case, the patient was thereafter treated with IVMP combined
with ganciclovir antiviral therapy, and the second-line
immunosuppressant therapy treated with mycophenolate. In
general, the patient responded well to immunotherapy and
displayed improved clinical symptoms as well as radiographic
ﬁndings during the follow-up. Nevertheless, his sight was not
completely recovered, especially in his right eye, which was more
severely damaged. The results from the study suggested that a
longer immunotherapy treatment and follow-up may be

NMDAR encephalitis. Varicella zoster viruses (VZV) have been
detected in the patients with anti-NMDAR encephalitis (20–22),
thus acting as a trigger for the disease. In the post-solid organ
transplant patients, Epstein-Barr Virus (EBV) and NMDAR
antibodies have been reported as double positive in rare
infected cases (23). Human parvovirus B19 infection has been
reported to be associated with GABAA receptor encephalitis
(24). Recently, a case of encephalitis associated to
immunoreactivity related to SARS-CoV-2 infection has also
been reported (25). Except for case reports, a study based on
Mayo clinic neuroimmunology laboratory was conducted to
report the frequency of coexisting herpes viruses (HSV-1,
HSV-2, VZV, EBV, cytomegalovirus, or HHV-6) and
autoantibodies in patients with encephalitis (26). They
conﬁrmed that para-infectious autoimmunity may occur in the
context of EBV and VZV, and demonstrated that a spectrum of
co-existence of herpes viruses and antibodies extends beyond
HSV-1 and NMDAR antibodies (26).
HHV-7 is a T-lymphotropic virus, primarily infecting CD4+
and CD8+ primary lymphocytes (27), and usually occurs during
the childhood (28). The common presenting clinical
manifestations of HHV-7 encephalitis include fever, headache,
seizure, and altered level of consciousness (16). Neurological
complications of HHV-7 are very rare in immunocompetent
adults, and most of them have been predominantly reported in
HIV-positive patients (29) or transplant recipients (30). In
immune-competent patients, HHV-7 infections have been
associated with severe neurologic disease including encephalitis
and Guillain-Barre syndrome in adolescents (16), polymyeloradiculopathy (14) and limbic encephalitis (31) in adults.
The clinical manifestations of the present patient such as fever,
headache, and epileptic seizure were similar to those of the
HHV-7 encephalitis cases, which may possibly be associated
with activation of HHV-7 virus. Moreover, loss of the visual
acuity and papilledema were reported as the initial presentation
in an immune-competent adult male patient with HHV-7 DNA
detection from CSF (32). As almost all adults were infected with
HHV-7 in early childhood, delayed primary infection

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required when optic neuritis occurs in patients with MNOS.
Besides, immunotherapy should be initiated as early as possible
to improve the treatment outcomes and facilitate complete cure.

interpreted the data. DZ revised the manuscript for content. JL
designed the study and revised the manuscript. All authors
contributed to the article and approved the submitted version.

PATIENT PERSPECTIVE

FUNDING

When my eyesight suddenly failed in both eyes, my world
plunged into darkness and I felt very frightened and helpless.
But when I received treatment and my eyesight gradually
returned, I began to gain conﬁdence. At present, my daily life
is basically not signiﬁcantly affected, but the vision of my right
eye has still not been fully restored to normal, and I feel that it
might be difﬁcult to restore it completely.

This work was supported by grants from National Natural
Science Foundation of China (Grant No. 81571272) and from
science and technology project of Sichuan Province (Grant
No. 2019YFH0145).

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

The authors thank the patient for sample contribution.

The original contributions presented in the study are included in
the article/Supplementary Material. Further inquiries can be
directed to the corresponding author.

SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/ﬁmmu.2022.
799454/full#supplementary-material

ETHICS STATEMENT
The patient in this case report provided written informed
consent for publication.

AUTHOR CONTRIBUTIONS

Supplementary Figure 1 | Tissue-based indirect immunoﬂuorescence assay
(TBA) detected weak ﬂuorescence responses, with speciﬁc ﬂuorescence responses
in (A) interstitial connective tissue (arrows) from the monkey optic nerve section as
well as (B) Purkinje cells (arrows) from the monkey cerebellum brain section (scale
bar 100mm). Cerebrospinal ﬂuid MOG (C) and anti-NMDAR (D) antibodies were
negative by cell-based assay at 8 months of follow-up (scale bar 100mm).

SL and MW drafted and revised the manuscript. HL collected
data and revised the manuscript. JW and QZ collected and

Supplementary Figure 2 | Changes of visual ﬁled in different periods after onset:
(A, B) one month, (C, D) three months, and (E, F) eight months.

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April 2022 | Volume 13 | Article 799454