Wang et al. BMC Neurology (2015) 15:107
DOI 10.1186/s12883-015-0366-5

CASE REPORT

Open Access

Anti-N-methyl-D-aspartate receptor
encephalitis concomitant with multifocal
subcortical white matter lesions on
magnetic resonance imaging: a case report
and review of the literature
Rui-Jin Wang1*, Bu-Dong Chen2 and Dong Qi1

Abstract
Background: Anti-N-methyl-D-aspartate receptor encephalitis is a severe autoimmune disorder characterized by severe
psychiatric symptoms, seizures, decreased consciousness, autonomic dysregulation, and dyskinesias. Multifocal subcortical
white matter lesions on fluid-attenuated inversion recovery and diffuse weighted images have rarely been reported in
previous literature, and serial magnetic resonance imaging changes after plasma exchange have not been presented before.
Case presentation: A previously healthy 24-year-old Chinese woman presented with acute psychiatric symptoms
characterized by fear and agitation followed by decreased consciousness, dyskinesias, and seizures. Magnetic resonance
imaging revealed hyperintense lesions on fluid-attenuated inversion recovery and diffuse weighted images in bilateral
subcortical white matter. Cerebrospinal fluid analysis revealed a mild pleocytosis with lymphocytic predominance.
Protein and glucose levels were normal. Aquaporin-4 antibodies in serum and cerebrospinal fluid were negative. Identification
of anti-N-methyl-D-aspartate receptor antibodies in serum and cerebrospinal fluid confirmed the diagnosis of
anti-N-methyl-D-aspartate receptor encephalitis. She was initially treated with combined intravenous immunoglobulin
and methylprednisolone without improvement. Plasma exchange was then initiated with good response; the patient
made a full recovery after several cycles of plasma exchange. Repeat magnetic resonance imaging performed 1 month
after plasma exchange showed partial resolution of the hyperintense lesions in bilateral subcortical white matter, and
follow-up magnetic resonance imaging 2 months after plasma exchange showed complete resolution.
Conclusion: Anti-N-methyl-D-aspartate receptor encephalitis may be concomitant with multifocal subcortical white
matter lesions. Such lesions may resolve after appropriate immunotherapy.
Keywords: Anti-N-methyl-D-aspartate receptor encephalitis, Subcortical white matter lesions, Plasma exchange,
Magnetic resonance imaging

Background
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a severe autoimmune disorder first described by
Dalmau and his colleagues in 2007 [1]. Patients with antiNMDA receptor encephalitis usually have an acute onset.
The typical clinical features include severe psychiatric
* Correspondence: wangrj73@sina.com
1
Department of Neurology, Beijing Friendship Hospital, Capital Medical
University, No. 95 Yong-An Road, Xicheng District, Beijing 100050, People’s
Republic of China
Full list of author information is available at the end of the article

symptoms, memory loss, seizures, decreased consciousness, autonomic dysregulation, and dyskinesias [2].
Here, we describe a case of anti-NMDA receptor encephalitis with multifocal subcortical white matter lesions on fluid-attenuated inversion recovery (FLAIR)
and diffuse weighted images (DWI). This patient
responded well to plasma exchange treatment. Serial
magnetic resonance imaging (MRI) changes after this
treatment are presented. To our knowledge, multifocal
subcortical white matter lesions on FLAIR and DWI

© 2015 Wang et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Wang et al. BMC Neurology (2015) 15:107

Page 2 of 4

have rarely been described in previous literature, and
serial MRI changes after plasma exchange have not been
presented before.

Case presentation
A 24-year-old Chinese woman presented with acute psychiatric symptoms characterized by fear and agitation.
Two days after symptom onset, she was admitted to a
psychiatric hospital, and her symptoms were temporarily
controlled. Seven days after symptom onset, she developed a low-grade fever and decreased consciousness, at
which point she was transferred to our hospital. Her
past medical history was unremarkable. On examination,
she was non-responsive to verbal or painful stimulation.
Her vital signs indicated slightly elevated heart rate and
body temperature and normal blood pressure and respiratory rate. The pupils were normal in size and reactive to light. Spontaneous eye movements were absent.
The oculocephalic responses were present. Babinski’s
sign was negative bilaterally, and both Kernig’s and
Brudzinski’s signs were negative.
Routine blood test and chemistry analysis including
liver, renal, and thyroid function were unremarkable.
The erythrocyte sedimentation rate was normal. Autoimmune markers including antinuclear antibodies,
anti-double-stranded DNA (anti-dsDNA) antibodies,
rheumatoid factor, and antineutrophilcytoplasmic antibodies (ANCA) were negative. Serum anti-thyroglobulin
(anti-TG) antibodies (38.4U/ml, normal range 0–60 U/ml,
radioimmunoassay) and anti-thyroid peroxidase (antiTPO) antibodies (28 U/ml, normal range 0–60 U/ml,
radioimmunoassay) were unremarkable. Brain computed
tomography (CT) was normal. MRI revealed FLAIR and
DWI hyperintense lesions in bilateral subcortical white
matter (Fig. 1a,b). Electroencephalography (EEG) showed
diffuse slow-waves. Cerebrospinal fluid (CSF) analysis revealed a mild pleocytosis (24 × 106/L) with lymphocytic
predominance. Protein and glucose levels were normal.
Aquaporin-4 antibodies in serum and CSF were negative.
Serological and polymerase chain reaction (PCR) investigation in serum and CSF were negative for infectious etiologies including varicella zoster virus, enterovirus, herpes
simplex virus, cytomegalovirus, and Epstein-Barr virus.
Bacterial cultures of the CSF were negative. Anti-NMDA
receptor antibodies were identified both in serum (titers
1:100) and CSF (titers 1:16).
The diagnosis of anti-NMDA receptor encephalitis
was established. Thorough evaluation, including ovarian
ultrasound and high resolution computed tomography
of the chest, abdomen, and pelvis, did not reveal an
ovarian teratoma or other tumors. Intravenous immunoglobulin (IVIg, 0.4 g/kg/day for 5 days) combined with
high dose methylprednisolone (1g/day for 5 days) was
initiated on day 18 after symptom onset. Despite IVIg

Fig. 1 Serial MRI findings: hyperintense lesions on FLAIR and DWI in
bilateral subcortical white matter before plasma exchange (a, b);
partial resolution of the lesions on FLAIR and DWI 1 month after
plasma exchange (c, d); full resolution of the lesions on FLAIR and
DWI 2 months after plasma exchange (e, f)

and steroid therapy, the patient’s level of consciousness
did not improve. She developed dyskinesias with mouth
chewing, tongue thrusting, and twisting of the upper
limbs. Episodes of generalized tonic-clonic convulsions
were also seen. Repeat EEG again revealed diffuse slowwaves. At this point, the patient was intubated and
mechanically ventilated. Valproic acid and intermittent
intravenous diazepam was administered to control the
seizures. On day 35, plasma exchange therapy was initiated; the patient regained consciousness after two cycles
of plasma exchange, and seizures and dyskinesias were
controlled after three cycles of this treatment. An
additional four cycles of plasma exchange were given to
reinforce the efficacy. Repeat MRI performed 1 month
after plasma exchange showed partial resolution of the
hyperintense lesions in bilateral subcortical white matter
on FLAIR and DWI (Fig. 1c,d). MRI performed 2
months after plasma exchange showed complete resolution (Fig. 1e,f ). Repeat CSF analysis revealed normal
leucocytes (2 × 106/L), as well as normal protein and
glucose levels. Anti-NMDA receptor antibodies were
undetectable in serum and CSF. At 12-months followup, the patient remained well and has had no relapse of
seizures and dyskinesias.

Wang et al. BMC Neurology (2015) 15:107

Discussion
Our patient presented with acute psychiatric symptoms,
followed by low-grade fever, decreased consciousness,
dyskinesias, and seizures. This case demonstrates the
classic clinical presentation of anti-NMDA receptor encephalitis. Identification of anti-NMDA receptor antibodies in serum and CSF confirmed the diagnosis.
In recent years, autoimmune etiologies of encephalitis
are increasingly being recognized. Anti-NMDA receptor
encephalitis has been regarded as the second most
common immune-mediated cause, after acute disseminated encephalomyelitis, and is more prevalent than all
antibody-associated encephalitis. This disease is a highly
characteristic and recognizable neuropsychiatric syndrome, although atypical cases may exist [3–5]. It is
most common in young women and children. Over half
of the patients have an associated tumor, most commonly an ovarian teratoma [2].
Brain MRI in patients with anti-NMDA receptor
encephalitis may be either normal or abnormal. The frequency of abnormal brain MRI is not as common as in
infectious encephalitis such as herpes simplex encephalitis (HSE). It has previously been described that more
than 90% of patients with HSE have MRI abnormalities,
usually in the temporal lobe, frontobasal, and insular regions [6]. In a clinical-radiological comparison between
herpetic encephalitis and limbic encephalitis of autoimmune etiologies (including anti-NMDA receptor encephalitis), MRI was abnormal in all cases of the former,
but only in 60% of the latter [7].
In a cohort of 100 patients with anti-NMDA receptor
encephalitis, brain MRI was unremarkable in 45 patients;
in the other patients, T2 or FLAIR signal hyperintensity
was seen in the hippocampi, cerebellar or cerebral cortex, frontobasal and insular regions, basal ganglia, and
brainstem [8]. In another cohort of 44 patients, only 4
patients had abnormalities in the hippocampi, and 6
patients had abnormalities within white matter regions
on T2/FLAIR [9].
The initial MRI of our case showed hyperintense lesions in bilateral subcortical white matter on FLAIR and
DWI. FLAIR combined with DWI is more sensitive in
detecting abnormalities than conventional MRI sequences.
DWI has long been established as a routine imaging procedure in acute ischemic stroke. It is exquisitely sensitive
in demonstrating even minute acute ischemic lesions [10].
It is now also used to diagnose other disorders including
limbic system encephalitis. To our knowledge, multifocal
subcortical white matter lesions on FLAIR and DWI have
rarely been reported in previous literature, and serial MRI
changes after plasma exchange have not been presented
before. The clinical presentation of our patient, however,
seemed unrelated to the lesions seen on FLAIR and
DWI. Such abnormalities on MRI resemble that of

Page 3 of 4

demyelinating diseases such as acute disseminated
encephalomyelitis, neuromyelitis optica, or multiple
sclerosis. This may reflect autoimmune-mediated
white matter disease. Literature suggests that antiNMDA receptor encephalitis may have overlapping
characteristics with other autoimmune diseases. For
example, Zoccarato et al. described a case of antiNMDA receptor encephalitis followed by neuromyelitis optica [11]. The coexistence of multiple autoimmune diseases is increasingly recognized among
autoantibody-associated neurological syndromes [12].
The treatment of anti-NMDA receptor encephalitis includes immunotherapy and tumor removal, if applicable.
As of yet, no randomized trials have been performed to
evaluate the efficacy of immunotherapy. In a cohort of
577 patients (501 assessable), 472 underwent first-line
immunotherapy (steroids, IVIg, or plasma exchange) or
tumor removal, resulting in improvement within 4
weeks in 251 patients. Of the 221 patients who did not
improve with first-line treatment, 125 received secondline immunotherapy (rituximab or cyclophosphamide),
which resulted in a better outcome. Predictors of good
outcome were early treatment and no admission to an
intensive care unit [13]. For immunotherapy of antiNMDA receptor encephalitis, Dalmau et al. prefer
concurrent IVIg and methylprednisolone to plasma exchange because plasma exchange is more difficult to do
in children, poorly cooperative patients, or patients with
autonomic instability. If no response is seen after 10
days, second-line therapy should be initiated [14]. Other
methods of immunotherapy have also been reported on
rare occasions. Liba et al. described an 8-year old girl
with anti-NMDA receptor encephalitis who had no response to sequential IVIg, plasma exchange and highdose corticosteroids, rituximab, and cyclophosphamide
treatment, but responded well to alemtuzumab, an antiCD52 monoclonal antibody that affects memory B cells
and T cells [15].
Our patient was initially treated with combined IVIg
and methylprednisolone without demonstrable improvement. However, she responded well after plasma exchange was initiated. After several cycles of plasma
exchange, she made a full recovery. Repeat detection of
anti-NMDA receptor antibodies in serum and CSF were
negative, and repeat MRI performed 1 month and 2
months after plasma exchange showed gradual resolution of the lesions.

Conclusions
We describe a case of anti-NMDA receptor encephalitis
concomitant with multifocal subcortical white matter
lesions on FLAIR and DWI. This patient responded well
to plasma exchange treatment, after which the lesions
resolved.

Wang et al. BMC Neurology (2015) 15:107

Consent
Written informed consent was obtained from the patient
for publication of this case report and the accompanying
images. A copy of the written consent is available for
review by the editor of this journal.
Abbreviations
Anti-NMDA receptor encephalitis: Anti-N-methyl-D-aspartate receptor
encephalitis; CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging;
FLAIR: Fluid-attenuated inversion recovery; DWI: Diffuse weighted images;
anti-dsDNA: Anti-double-stranded DNA; ANCA: Antineutrophilcytoplasmic
antibodies; anti-TG antibodies: Anti-thyroglobulin antibodies; anti-TPO
antibodies: Anti-thyroid peroxidase antibodies; CT: Computed tomography;
EEG: Electroencephalography; PCR: Polymerase chain reaction;
IVIg: Intravenous immunoglobulin; HSE: Herpes simplex encephalitis.

Page 4 of 4

11. Zoccarato M, Saddi MV, Serra G, Pelizza MF, Rosellini I, Peddone L, et al.
Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor
encephalitis. J Neurol. 2013;260:3185–7.
12. Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system
neuronal surface antibody associated syndromes: review and guidelines for
recognition. J Neurol Neurosurg Psych. 2012;83:638–45.
13. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Lizuka T, et al.
Treatment and prognostic factors for long-term outcome in patients with
anti-NMDA receptor encephalitis: an observational cohort study. Lancet
Neurol. 2013;12:157–65.
14. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon
R. Clinical experience and laboratory investigations in patients with
anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
15. Liba Z, Sebronova V, Komarek V, Sediva A, Sedlacek P. Prevalence and
treatment of anti-NMDA receptor encephalitis. Lancet Neurol. 2013;12:424.

Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
RJW contributed to data collection and draft of the manuscript. DQ contributed
to data collection and patient follow-up. BDC contributed to collection and
analysis of MRI data. All authors read and approved the final manuscript.
Acknowledgements
The authors thank Dr. Hong-Yan Bi, Department of Neurology, Beijing Friendship
Hospital, Capital Medical University, Beijing, People’s Republic of China, for her
helpful suggestions to the manuscript.
Author details
1
Department of Neurology, Beijing Friendship Hospital, Capital Medical
University, No. 95 Yong-An Road, Xicheng District, Beijing 100050, People’s
Republic of China. 2Department of Radiology, Beijing Friendship Hospital,
Capital Medical University, No. 95 Yong-An Road, Xicheng District, Beijing
100050, People’s Republic of China.
Received: 7 February 2015 Accepted: 28 June 2015

References
1. Dalmau J, Tuzun E, Wu H, Masjuan J, Rossi JE, Voloschin A, et al.
Paraneoplastic anti-Nmethyl-D-aspartate receptor encephalitis associated
with ovarian teratoma. Ann Neurol. 2007;61:25–36.
2. Dalmau J, Rosenfeld MR. Autoimmune encephalitis update. Neuro Oncol.
2014;16:771–8.
3. Kruer MC, Koch TK, Bourdette DN, Chabas D, Waubant E, Mueller S, et al.
NMDA receptor encephalitis mimicking seronegative neuromyelitis optica.
Neurology. 2010;74:1473–5.
4. Lekoubou A, Viaccoz A, Didelot A, Anastasi A, Marignier R, Ducray F, et al.
Anti-N-methyl-D-aspartate receptor encephalitis with acute disseminated
encephalomyelitis-like MRI features. Eur J Neurol. 2012;19:e16–7.
5. Outteryck O, Baille G, Hodel J, Giroux M, Lacour A, Honnorat J, et al.
Extensive myelitis associated with anti-NMDA receptor antibodies. BMC
Neurol. 2013;13:211–4.
6. Domingues RB, Fink MC, Tsanaclis AM, de Castro CC, Cerri GG, Mayo MS, et al.
Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and
polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci.
1998;157:148–53.
7. Oyanguren B, Sánchez V, González FJ, de Felipe A, Esteban L, López-Sendón
JL, et al. Limbic encephalitis: a clinical-radiological comparison between
herpetic and autoimmune etiologies. Eur J Neurol. 2013;20:1566–70.
8. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al.
Anti-NMDA receptor encephalitis: case series and analysis of the effects of
antibodies. Lancet Neurol. 2008;7:1091–8.
9. Irani SR, Bera K, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al.
N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical
and paraclinical observations in a predominantly non-paraneoplastic disorder of
both sexes. Brain. 2010;133:1655–67.
10. Gass A, Ay H, Szabo K, Koroshetz WJ. Diffusion-weighted MRI for the ‘small
stuff’: the details of acute cerebral ischaemia. Lancet Neurol. 2004;3:39–45.

Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit