Multiple Sclerosis and Related Disorders 8 (2016) 74–77

Contents lists available at ScienceDirect

Multiple Sclerosis and Related Disorders
journal homepage: www.elsevier.com/locate/msard

Case report

Anti-N-methyl-D-aspartate receptor encephalitis in a patient with
neuromyelitis optica spectrum disorders
Jing-Jing Luo a, He Lv a, Wei Sun a, Juan Zhao b, Hong-Jun Hao a, Feng Gao a,n, Yi-Ning Huang a
a
b

Department of Neurology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing 100034, China
Department of Neurology, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang Street, Dongcheng District, Beijing 100730, China

art ic l e i nf o

a b s t r a c t

Article history:
Received 29 December 2015
Received in revised form
10 April 2016
Accepted 1 May 2016

We described a female patient with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis occurring
sequentially with neuromyelitis optica spectrum disorders (NMOSD). The 19-year-old patient initially
presented a diencephalic syndrome with aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) and
brain lesions which involving bilateral medial temporal lobes and periependymal surfaces of the third
ventricle on magnetic resonance imaging (MRI). Ten months later, the patient developed cognitive impairment, psychiatric symptoms and dyskinesia with left basal ganglia lesions on brain MRI. Meanwhile,
the anti-NMDAR antibodies were positive in the patient's serum and cerebrospinal fluid, while the
screening tests for an ovarian teratoma and other tumors were all negative. Hence, the patient was
diagnosed NMOSD and anti-NMDAR encephalitis followed by low-dose rituximab treatment with a good
response. This case was another evidence for demyelinating syndromes overlapping anti-NMDAR encephalitis in Chinese patients.
& 2016 Elsevier B.V. All rights reserved.

Keywords:
Neuromyelitis optica spectrum disorders
Anti-N-methyl-d-aspartate receptor encephalitis
Demyelination
Aquaporin-4
N-methyl-d-aspartate receptor

1. Introduction
Neuromyelitis optica (NMO) is an inflammatory demyelinating
disorder of the central nervous system associated with antibodies
against aquaporin 4 (AQP4-immunoglobulin G [IgG]), and the International Panel for NMO Diagnosis (IPND) has just unified the
terms of NMO and Neuromyelitis optica spectrum disorders
(NMOSD) into NMOSD, and recommended revised diagnostic criteria for NMOSD (Wingerchuk et al., 2015). Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune
disorder associated with antibodies against the GluN1 subunit of
the NMDAR (Dalmau et al., 2011). In this study, we describe the
case of a Chinese female NMOSD patient who developed with antiNMDAR encephalitis.

2. Case presentation
A previous healthy 19-year-old female experienced intermittent dizziness, memory deficit and behavioral changes. Eighteen months before admission, she had presented with dizziness,
n

Corresponding author.
E-mail addresses: luojj1986@126.com (J.-J. Luo), cranehebmu@sina.com (H. Lv),
sunweibjmu@163.com (W. Sun), zhj7509@163.com (J. Zhao),
haohj1963@126.com (H.-J. Hao), gaofh2011@126.com (F. Gao),
ynhuang@sina.com (Y.-N. Huang).
http://dx.doi.org/10.1016/j.msard.2016.05.002
2211-0348/& 2016 Elsevier B.V. All rights reserved.

nausea, hypersomnia and temporarily pain in the right eye. Examination of cerebrospinal fluid (CSF) showed normal cell count,
mild elevation of protein (66.1 mg/dL). Laboratory investigations
demonstrated significant hyponatremia to a nadir of 114.6 mmol/L,
and mildly elevated prolactin but otherwise normal cortisol,
adrenocorticotropic hormone, luteinizing hormone, follicular stimulating hormone and thyroid studies. Electroencephalogram
(EEG) showed increased slow wave activity. A T2-weighted and
T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI revealed hyperintensity in bilateral medial temporal lobes, the third
ventricle and brain parenchyma surrounding the cerebral aqueduct (Fig. 1(A)). Treatment of hyponatremia, intravenous methylprednisolone pulse (IVMP) therapy (500 mg per day for 5 days),
intravenous immunoglobulins (IVIG) therapy (0.4 g/kg per day for
5 days), and antiviral therapy were administered as viral encephalitis was highly suspected. Then she received gradually tapered oral steroids for three months, during the course of steroid
therapy she was partially relieved and the MRI lesions disappeared. Both ten and six months before admission, she reported
two episodes of dizziness and axial T2-weighted MRI indicated
lesions in the left insular region and bilateral temporal lobes, but
the lesions were not enhanced on T1-weighted MRI with gadolinium (Fig. 1(B)). The serum AQP4-IgG and anti-SS-A antibody were
positive, while the serum anti-NMDAR antibodies (NMDAR-Ab)
were negative. Hence, the diagnosis of NMOSD was made, treatment with oral azathioprine (50 mg per day for 1 month, then
100 mg per day for 2 months) was given and she was stable for the

J.-J. Luo et al. / Multiple Sclerosis and Related Disorders 8 (2016) 74–77

75

Fig. 1. Brain magnetic resonance imaging of the patient. (A) 18 months before admission, T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows abnormal
hyperintense signals in bilateral medial temporal lobes and the brain parenchyma surrounding the third ventricle. (B) 10 months before admission, T2-weighted FLAIR MRI
demonstrates lesions involving bilateral medial temporal lobes and left insular region without gadolinium enhancement. (C) During hospitalization, left basal ganglia lesions
are depicted on T2-weighted FLAIR MRI, and the bilateral temporal lobes lesions are obviously relieved.

following three months.
Three months before admission, she complained of memory
dysfunction, irritable, attention deficit, apathy, insomnia and intermittent grope action of right upper limb. She could not remember where she had put her bicycle, could not write an essay,
and sometimes kept asking particular question. She also felt suffocated which could be released by inhaling oxygen. On admission,
her consciousness was clear. Neurology examination noted abnormal time and place orientation, deficit in recent and short-term
memory, other systems were normal.
Analysis of CSF showed lymphocytic pleocytosis (8 cells
per milliliter), mild increased protein concentration (61.0 mg/dL)
and IgG intrathecal synthesis rate (21.84 mg/24 h). The immunoglobulin G (IgG) index read 1.50, oligoclonal band was negative,
and no evidence of any active viral infections. Her serum and CSF
were tested for AQP4-IgG by indirect immunofluorescence and
cell-based assay (CBA) on a commercial assay (Euroimmun, Lubeck, Germany) proving positive in both samples. Tests for classical onconeural antibodies (Hu, Ri, Ma2, CV2/CMRP5, amphiphysin, Yo) and antibodies to myelin oligodendrocyte glycoprotein
(MOG) proved negative. The etiology of the patient's psychobehavioral symptoms was further examined, and the NMDAR-Ab was
found positive in her serum and CSF, while the AMPAR-, GABABR-,

LGI1- and CASPR2-antibodies were all negative. The anti-SS-A
antibody was positive, and the antinuclear, anti-thyroid peroxidase antibodies were negative. EEG showed α wave frequency
decreased. Brain MRI disclosed hyperintensity of the left basal
ganglia on T2-weighted/T2-weighted FLAIR images (Fig. 1(C)).
Ophthalmological examination showed delayed P100 latencies on
both sides on visual evoked potentials. To investigate her feeling of
suffocation, we performed a head-up tilt table test which identified she had postural orthostatic tachycardia syndrome (POST),
suggested sympathetic hyperactivity. No cancer was found (gynecological ultrasonography, pelvic ultrasonography, positron
emission tomography scan were all normal), especially ovarian
original tumors were not detected. Although she had anti-SSA
antibody, but she didn’t complain generalized dryness, including
xerostomia and keratoconjunctivitis sicca, and the salivary gland
biopsy result did not support Sjögren's syndrome either.
We treated the patient with IVMP (1 g per day for 3 days,
gradually tapered in 9 days), IVIG (0.4 g/kg per day for 5 days) and
oral azathioprine (100 mg per day). The symptoms were partially
relieved, her emotion stabilized and the involuntary movements
decreased. After the IVMP therapy, we replaced oral azathioprine
with intravenous rituximab (100 mg once a week for 4 weeks),
then her percentage of CD19 þ B cells dropped to 0 in peripheral

76

J.-J. Luo et al. / Multiple Sclerosis and Related Disorders 8 (2016) 74–77

Fig. 2. Disease course and treatments of the patient. Time 0 on X axis marks the admission to our hospital and divides pre- and post-hospitalization periods. The clinical
severities based on modified Rankin scale scores (mRS, solid line). The dotted line representing the percentage of CD19 þ B cells in peripheral blood after rituximab
treatment. Arrow: intravenous methylprednisolone pulse (IVMP), intravenous immune-globulins (IVIG), azathioprine (AZA).

blood which measured with flow cytometry, the AQP4-IgG was
still positive in serum, but the NMDAR-Ab turned negative in
serum.
In the next two months, the patient's recent and short-term
memory improved gradually, and the other symptoms disappeared. The AQP4-IgG turned negative in serum, the repopulation of CD19 þ B cells reached 0.03%, and there was no new lesions
on the follow-up brain MRI. So she was given prednisolone (15 mg
per day). Eight months later, AQP4-IgG was found in her serum
again, meanwhile the percentage of CD19 þ B cells exceeded 1%
(1.23%). However, the patient did not complain any new discomfort and exacerbation of symptoms. The physical examination,
EEG, and the conventional MRI scanning brain and spinal cord
were all negative. The clinical severities based on modified Rankin
scale scores (mRS) was evaluated (Fig. 2).

3. Discussion
We describe this case of a Chinese female patient who developed anti-NMDAR encephalitis with good recovery during the
course of NMOSD. The earlier clinical course of this patient met
the international consensus diagnostic criteria for NMOSD and the
later course was compatible with anti-NMDAR encephalitis. She
presented diencephalon symptoms, and probable subclinical optic
nerve involvement, positive test for AQP4-IgG using the CBA
method. The brain MRI demonstrated lesions involving the hypothalamus, periependymal surfaces of the third and fourth ventricle and left internal capsule which are compatible with the
NMOSD-typical brain lesion patterns (Kim et al., 2010; Pittock
et al., 2006). So the patient was treated as NMOSD, and the clinical
symptoms relieved by immunotherapy. Then the patient developed fulminant neuropsychiatric manifestations and behavioral
dysfunction, and positivity for the NMDAR-Ab in serum and CSF,
are atypical of NMOSD, which encouraged the diagnosis of antiNMDAR encephalitis overlapping NMOSD.
A previous review reported that 3.3% anti-NMDAR encephalitis
patients had prominent MRI and/or clinical features of demyelination, including 5 patients in whom anti-NMDAR encephalitis
were preceded or followed by independent episodes of NMOSD
(Titulaer et al., 2014). To the best of our knowledge, no similar case
has been previously reported in China. Most noteworthy were the

fact that all reported cases including this case, did not present with
tumors, suggesting that patients were prone to autoimmunity. The
patient was treated with low-dose rituximab, showed well tolerance and maintained good remission throughout the whole period
of ten months, while the AQP4-IgG appeared again and the CD19 þ
B cells exceeded 1%. It was reported a lower dosage of rituximab
was efficacious in depleting B cells, maintaining low B-cell counts,
and preventing disease progression in 5 Chinese NMO patients
(Yang et al., 2013). Meanwhile, most studies recommend reinfusion of rituximab whenever the percentage of CD19 þ B cells
reached 1% or the percentage of CD19 þ CD27 þ B cells was higher
than 0.05% instead of clinical relapse (Kim et al., 2013, 2011).
However, one study revealed that AQP4-IgG titer and CD19 þ B-cell
counts rise before relapse and fall with remission (Jarius et al.,
2008), yet another study indicates that the suppression of disease
activity by rituximab correlates with the extent of B-cell depletion,
not with serum AQP4-IgG titer (Pellkofer et al., 2011). Above all,
maybe the patient should receive additional rituximab infusion as
soon as possible instead of waiting for another clinical attack.
Rituximab is also used as a second-line therapy for antiNMDAR encephalitis (Titulaer et al., 2013). During the follow up of
the patient, the symptoms of limbic encephalitis are improving,
which suggests that a low-dose rituximab maybe also effective in
anti-NMDAR encephalitis.

4. Conclusion
We report a Chinese patient developed non-tumor associated
anti-NMDAR encephalitis with NMOSD, with a good response to
reduced dosage of rituximab. It's a challenge for physicians to recognize anti-NMDAR encephalitis in NMOSD patients who mainly
presented with brain involvement. Anyway, further investigations
on the definite linkage between the two diseases are still in need.

Conflict of interest
The authors declare no potential conflicts of interest related to
the research, authorship, and/or publication of this article.

J.-J. Luo et al. / Multiple Sclerosis and Related Disorders 8 (2016) 74–77

Funding source
None.

References
Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M.R., Balice-Gordon, R.,
2011. Clinical experience and laboratory investigations in patients with antiNMDAR encephalitis. Lancet Neurol. 10, 63–74.
Jarius, S., Aboul-Enein, F., Waters, P., Kuenz, B., Hauser, A., Berger, T., et al., 2008.
Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain
131, 3072–3080.
Kim, S.-H., Huh, S.-Y., Lee, S.J., Joung, A., Kim, H.J., 2013. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder.
JAMA Neurol. 70, 1110–1117.
Kim, S.-H., Kim, W., Li, X.F., Jung, I.-J., Kim, H.J., 2011. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in
patients with relapsing neuromyelitis optica over 2 years. Arch. Neurol. 68,
1412–1420.

77

Kim, W., Park, M.S., Lee, S.H., Kim, S.-H., Jung, I.J., Takahashi, T., et al., 2010. Characteristic brain magnetic resonance imaging abnormalities in central nervous
system aquaporin-4 autoimmunity. Mult. Scler. 16, 1229–1236.
Pellkofer, H., Krumbholz, M., Berthele, A., Hemmer, B., Gerdes, L., Havla, J., et al.,
2011. Long-term follow-up of patients with neuromyelitis optica after repeated
therapy with rituximab. Neurology 76, 1310–1315.
Pittock, S.J., Lennon, V.A., Krecke, K., Wingerchuk, D.M., Lucchinetti, C.F., Weinshenker, B.G., 2006. Brain abnormalities in neuromyelitis optica. Arch. Neurol.
63, 390–396.
Titulaer, M.J., Höftberger, R., Iizuka, T., Leypoldt, F., McCracken, L., Cellucci, T., et al.,
2014. Overlapping demyelinating syndromes and anti–N-methyl‐D-aspartate
receptor encephalitis. Ann. Neurol. 75, 411–428.
Titulaer, M.J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., et al.,
2013. Treatment and prognostic factors for long-term outcome in patients with
anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol.
12, 157–165.
Wingerchuk, D.M., Banwell, B., Bennett, J.L., Cabre, P., Carroll, W., Chitnis, T., et al.,
2015. International consensus diagnostic criteria for neuromyelitis optica
spectrum disorders. Neurology 85, 177–189.
Yang, C.-S., Yang, L., Li, T., Zhang, D.-Q., Jin, W.-N., Li, M.-S., et al., 2013. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis
optica. Neurology 81, 710–713.