Hindawi

Mediators of Inflammation
Volume 2017, Article ID 6361479, 14 pages
https://doi.org/10.1155/2017/6361479

Review Article
Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe,
Potentially Reversible Autoimmune Encephalitis

Cai-yun Liu,1 Jie Zhu,1,2 Xiang-Yu Zheng,1 Chi Ma,3 and Xu Wang1
1
Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, China
2
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, 141 86 Stockholm, Sweden
3
Department of Neurosurgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China

Correspondence should be addressed to Xu Wang; [email protected]

Received 19 February 2017; Accepted 4 April 2017; Published 18 June 2017

Academic Editor: Yona Keisari

Copyright © 2017 Cai-yun Liu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder
characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm,
especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the
disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented
that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical
course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with
demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.

1. Introduction titer-dependent and reversible [4, 7, 8]. Clinically, after an

influenza-like antecedent infection, the patients manifest
The encephalitis associated with anti-N-methyl-D-aspartate with obvious behavioral and psychiatric symptoms, which
receptor (NMDAR) antibodies is a recently identified auto- are commonly accompanied by seizures, memory loss,
immune disorder with a progressive clinical course and the language dysfunctions, dyskinesias, and impaired conscious-
possibility of effective management and favorable outcome. ness. Additionally, the autonomic instability and hypoventi-
Since its first description by Dalmau et al. [1], it has gained lation are seen in many cases [1, 9]. These symptoms are
increasing attention. The California Encephalitis Project characteristic; however, misdiagnosis and delayed diagnosis
enrolling individuals younger than 30 years showed that the occur commonly. A poor outcome, such as persistent and
frequency of anti-NMDAR encephalitis surpassed that of severe neuropsychiatric deficit, may occur in up to 25% of
individual viral etiologies such as herpes simplex type 1 patients [4, 5]. Relapses are also observed [10, 11]. Despite
(HSV-1), West Nile virus (WNV), enteroviruses, and the complexity and severity of anti-NMDAR encephalitis, full
varicella-zoster virus (VZV) [2]. or substantial recovery has been achieved in most patients,
The triggers of the disorder comprise viral infections, who received early diagnosis and prompt multidisciplinary
tumors, and other unknown factors. It is reported that herpes therapy [4]. Here, we aim to review the recent studies on
simplex encephalitis (HSE) plays a vital role in triggering the the clinical and laboratory features, diagnosis, and treat-
synthesis of anti-NMDAR antibodies [3]. In young adult ments, as well as the mechanisms underlying this disorder.
females, the encephalitis is often accompanied with ovarian
teratomas [2, 4], while males and children are also affected, 2. Epidemiology
but the presence of a tumor is uncommon [5, 6]. The specific
IgG antibodies recognizing the GluN1 subunit of NMDARs It has been reported that anti-NMDAR encephalitis is the
result in the receptors’ removal from the synapse through a most common antibody-associated encephalitis [12]. Since
mechanism of crosslinking and internalization, which is the original description of anti-NMDAR encephalitis [1],
2 Mediators of Inflammation

there have been many studies on this disorder. A report from leads to crosslinking and internalization of those receptors
Germany indicated that anti-NMDAR encephalitis repre- instead of apoptosis. Then, the number of NMDA recep-
sented 1% of young individuals (18–35 years) hospitalized tors on the postsynaptic membrane decreases. The effect
in the intensive care unit (ICU) [13]. In a multicenter study is titer-dependent and reversible after antibody titers
in Korea, of the 721 patients (aged older than 18 years) with decrease [4, 8]. In contrast, other glutamate receptors and
encephalitis of unascertained cause, 40 (6%) were diagnosed synaptic proteins, number of synapses, presynaptic termi-
with anti-NMDAR encephalitis [14]. A prospective study in nals, dendritic complexity, dendritic spines, and cell viability
England recruited 203 patients with symptoms of encephali- are unaffected. An experiment in female Lewis rats showed
tis and showed that of 128 cases whose causes were definite, that the density of NMDA receptors in the hippocampus
HSV caused the most cases (36, 28%), while only 9 (7%) were was dramatically reduced after they were infused with anti-
attributable to anti-NMDAR encephalitis [12]. Another NMDAR antibodies from patients. It was similar to the find-
study reported that anti-NMDAR encephalitis was the lead- ings observed in the hippocampus of autopsied patients [8].
ing entity, more than 4 times as frequent as HSV-1, WNV, Thus, anti-NMDAR antibodies lead to a specific, titer-
or VZV [2]. The discrepancy may be due to the different dependent, and reversible reduction of NMDA receptors on
population composition, regions, and heterogenic factors. postsynaptic dendrites (Figure 1). Synaptic dysfunction
Nevertheless, there has been no study to report the prevalence caused by the loss of NMDA receptors results in the symptoms
rate of the anti-NMDAR encephalitis in a certain region to in patients with anti-NMDAR encephalitis, such as seizures,
date. The exact incidence of the disorder is also unknown. memory and learning deficits, and behavioral abnormities.
In 2005, anti-NMDAR encephalitis was first identified in It has been reported that interleukin-6 (IL-6), interleukin-
four young women who suffered from ovarian teratoma and 17A (IL-17A), and C-X-C motif chemokine 13 (CXCL13)
manifested with acute psychiatric symptoms, decreased level were elevated in the CSF, while only interleukin-2 (IL-2)
of consciousness, seizures, amnesia, and hypoventilation was increased in the serum of anti-NMDAR encephalitis
[15]. In the subsequent years, several reports showed that patients [25]. Both IL-17A and IL-6 are proinflammatory
females were significantly more likely to be involved than cytokines. IL-17A could induce the expression of inflamma-
males. Between September 2007 and February 2011, of the tory gene in target cells [26], negatively regulate the tight
32 cases who were identified anti-NMDAR encephalitis in junction molecules, and prompt leukocyte migrating across
the California Encephalitis Project, 75% (24) were females the blood-brain barrier (BBB) [27]. IL-6 could stimulate B-
[2]. In another report including 577 patients, the rate was cell differentiation [28], enhance the survival of plasmablasts,
81% [11]. In a case-series study containing 51 patients with and promote antibody production [29]. And IL-17A may
anti-NMDAR encephalitis from Southwest China, 32 (63%) trigger a positive-feedback loop for IL-6 signaling through
patients were females [16]. The disorder is more likely to signal transducer and activator of transcription 3 (STAT3)
affect younger individuals although patients of all ages can and nuclear factor (NF)-κB [30]. In this way, the coactivation
be affected. The median age of 577 patients diagnosed with of IL-6 and IL-17A might play an important role in the intra-
anti-NMDA receptor encephalitis was 21 years (range 1–85) thecal antibody synthesis of anti-NMDAR encephalitis. Fur-
[11]. Approximately 40% were children [4, 6, 11]. The ther researches are needed to prove this finding. CXCL13
minimum age reported was 2 months [17]. may be a potential biomarker of therapy response [31].
The increase of T cell-related cytokines (interferon-γ
3. Pathogenesis (INF-γ), tumor necrosis factor-α (TNF-α), and IL17A) in
CSF has suggested that T-cell mechanisms may be also
The NMDA receptors require binding of glycine and gluta- involved in the anti-NMDAR encephalitis [32], while
mate simultaneously, as well as membrane depolarization humoral immune response has been proposed to be more
for activation. The receptors are composed of NR1 and relevant with this disease [33].
NR2 (A-D) subunits, which bind glycine and glutamate, The triggers of the synthesis of anti-NMDAR antibod-
respectively [18]. Excitotoxicity caused by the overactivity ies include tumors, viral infections, and other unknown
of NMDA receptors may lead to such disorders as stroke, epi- factors. Ovarian teratomas have been demonstrated to
lepsy, Parkinson’s disease, Alzheimer’s disease, and Hunting- contain mature or immature neurons expressing NMDA
ton’s disease [19], while low activity of NMDA receptors may receptors in both the autopsy and pathological studies,
result in schizophrenia [20]. which reacted with patients’ antibodies [33]. Furthermore,
Anti-NMDAR antibodies bind selectively to synaptic and in the samples of teratomas from patients with anti-
extrasynaptic NMDA receptors. Originally, the target of the NMDAR encephalitis, inflammatory cell infiltrates were
antibodies was reported to be NR1/NR2B heteromer [1]. identified, including macrophages, T cells, B cells, and
Subsequently, Dalmau et al. [4] demonstrated that the main plasma cells, while were minimally present or absent in
epitope was in the N-terminal domain of the NR1 subunit. teratomas from patients without anti-NMDAR encephalitis
Then, a further study reported that amino acid 369 of the [33, 34]. Thus, teratomas may play a role in triggering the
NR1 subunit was the main target region, and it did not synthesis of anti-NMDAR antibodies. However, it is unclear
change when the disorder relapsed [21]. whether other tumors are triggers of anti-NMDAR encepha-
The pathogenic role of anti-NMDAR antibodies has been litis or unrelated coincidence. Anti-NMDAR encephalitis is
established in both in vitro and in vivo models [4, 8, 22–24]. often preceded by viral-like prodromal symptoms, and
The specific binding between the antibodies and receptors relapse occurs in 12% of patients with HSE although the
Mediators of Inflammation 3

(+) (+)

Blood-brain barrier (BBB)

Presynaptic

Hippocampus

Brain stem
Postsynaptic

Tumor cell NMDAR Glutamate

NR1 Glycine
Plasma cell

Virus NR2

Anti-
Vesicle NMDAR
antibody

Figure 1: Possible pathogenesis of anti-NMDAR encephalitis. Anti-NMDAR antibodies synthesized by peripheral plasma cells pass through
the broken blood-brain barrier (BBB). Tumors, which express NMDA receptors, as well as viral infections, may play a role in triggering the
synthesis of anti-NMDAR antibodies. IL-6 and IL-17A might play an important role in the intrathecal antibody synthesis. NMDA receptors
are expressed in many regions of the brain, including the hippocampus, brain stem, and neocortex. Anti-NMDAR antibodies bind selectively
to synaptic and extrasynaptic NMDA receptors. The specific bind leads to crosslinking and internalization of those receptors. The number of
NMDA receptors on the postsynaptic membrane decreases. The effect is titer-dependent and reversible after antibody titers decrease. Thus,
anti-NMDAR antibodies lead to a specific, titer-dependent, and reversible reduction of NMDA receptors on postsynaptic dendrites which
results in neuronal hypoactivity.
4 Mediators of Inflammation

clinical course of HSE is usually monophasic [35]. Anti- (2) Seizures—about 70% of anti-NMDAR cases present
NMDAR encephalitis occurs also as post-HSE choreoatheto- with seizures [2, 6]. In males, seizures are usually par-
sis [36]. There is a novel opinion that HSE plays a vital role in tial, while in females, generalized seizures are more
triggering the synthesis of anti-NMDAR antibodies, which common. Seizures are more frequent to act as initial
has been confirmed by many investigators [3, 17, 37–40]. symptom in adult male patients than in adult females
Those patients usually benefit from immunotherapy [38]. [47, 49]. In children and adolescents, seizures are
Thus, the intractable HSE or relapse post-HSE should catch usually partial motor or complex seizures [6]. Even,
the attention of clinicians, and detection of anti-NMDAR anti-NMDAR encephalitis causes prolonged status
antibody should be performed no matter whether it was pos- epilepticus [50, 51], which carries a poor prognosis,
itive or not on the first episode. with a mortality rate of 56% [52].
(3) Motor dysfunctions—a wide range of abnormal
4. Clinical Manifestations movements are frequently observed, for example
orofacial dyskinesias, chorea, ballismus, athetosis,
The clinical manifestations are variable and sometimes rigidity, stereotyped movements, myorhythmia, or
easily misdiagnosed with viral encephalitis [39], psychosis opisthotonus [2, 6, 53, 54]. Movement disorders are
[41–43], epilepsy, or other diseases, such as Hashimoto’s more common in children and atypical symptoms
encephalopathy [44] and Rasmussen syndrome [45]. Thus, such as hemiparesis or cerebellar ataxia predominate
it is a challenge to the psychiatrists, neurologists, and in this age group [11]. Orofacial dyskinesias are the
emergency physicians, as well as gynecologists and oncol- most frequent, including masticatory-like move-
ogists because of the association with teratoma or other ments, grimacing, and forceful jaw opening and
tumors. Recognizing the characteristic features of anti- closing. Those symptoms result in lip and tongue
NMDAR encephalitis is vital to diagnose exactly and to injuries or broken teeth [4].
permit a more timely treatment. The symptoms of the
disorder are categorized in 8 groups: (1) psychiatric and (4) Memory dysfunction—short-term memory loss is
behavioral symptoms, (2) seizures, (3) motor dysfunctions, common. However, it is usually underestimated,
(4) memory dysfunction, (5) speech disorders, (6) decrease because language dysfunctions and psychiatric prob-
in level of consciousness, (7) autonomic dysfunctions, and lems interfere with the evaluation of memory [4].
(8) central hypoventilation [11]. (5) Speech disorders—language dysfunctions, including
More than 80% of the patients with anti-NMDAR enceph- reduction of verbal output or mutism, echolalia (usu-
alitis have nonspecific symptoms with antecedent infection, ally with echopraxia), mumbling, or perseveration,
such as fever, headache, or a viral-like manifestation (diges- happen in more than 70% of patients with anti-
tive-tract or upper respiratory-tract symptoms) [4, 16]. The NMDAR encephalitis [2, 5].
percentage of patients who have antecedent infection in
children is much lower [6, 46]. Most systemic symptoms (6) Decrease in level of consciousness: 88 of 100 patients
cannot help us to distinguish anti-NMDAR encephalitis from presented with decreased consciousness during the
other causes of encephalitis. Within a few days, usually less first 3 weeks [4].
than two weeks, patients present with these 8 categories of
(7) Autonomic dysfunctions—the most common mani-
symptoms, frequently psychiatric problems leading to the
festations of autonomic instability are hyperthermia,
initial visit to psychiatrists [4].
cardiac dysrhythmias (tachycardia or bradycardia)
[55], hypersalivation, hypotension, hypertension, uri-
(1) Psychiatric and behavioral symptoms—approxi- nary incontinence, and sexual dysfunction [4]. Those
mately 80% develop obvious psychiatric and behav- dysfunctions occur frequently in the patients with
ioral symptoms [4], including anxiety, irritability, anti-NMDAR encephalitis (69%) [4], especially in
insomnia, paranoia, aggression, auditory or visual children (86%) [6], while they were not observed in
hallucinations, sexual disinhibition, mania, cognitive viral encephalitis [2]. In children, tachycardia, hyper-
disorder, and psychosis. In patients younger than 18 thermia, and hypertension occur predominantly [6].
years old, those symptoms are less frequent. The dif- (8) Central hypoventilation—approximately 70% of
ference may be attributable to the situation that the patients develop hypoventilation [4]. About 20% of
behavioral symptoms become difficult to detect in the patients require intubation because of central
young children, because they often manifest with hypoventilation [6]. The symptom often happens
hyperactivity, irritability, or temper tantrums [6, when the patient becomes comatose but it also
11]. In both sexes, psychiatric symptoms act as the appears earlier when the level of consciousness is
most frequent initial symptom (54% in men, 67% in relatively preserved.
women) [16, 47]. Isolated psychiatric symptoms are
rare (4%) but occur at the disease onset or during Psychiatric and behavioral problems are the most fre-
relapse. The isolated symptoms mainly include delu- quent initial symptoms [16, 47], especially in adults, while
sional thinking, mood disturbances (usually manic), neurologic symptoms (especially seizures) occur initially as
and aggression [48]. frequently as psychiatric symptoms in children [11, 36, 46].
Mediators of Inflammation 5

Most cases (87%) develop four or more of those 8 ipilimumab) for metastatic melanoma [67]. Antibody-
classifications of symptoms four weeks after onset, while only negative limbic encephalitis occurred one year after starting
1% remain monosymptomatic [11], such as isolated psycho- pembrolizumab for malignant melanoma [68]. Immune
sis [48], abnormal movements [56, 57], or seizures [58]. At checkpoint inhibition may contribute to the development of
the peak of anti-NMDAR encephalitis, each of the following immune responses against neuronal antigens, causing auto-
symptoms occur in more than 50% of the cases: psychiatric immune encephalitis. Another possibility is that it belongs
and behavioral problems, seizures, movement disorders, to the classic paraneoplastic neurologic disorders (PNDs)
cognitive dysfunctions (anterograde amnesia, alteration of associated with metastatic melanoma [69]. Further researches
mental status, and speech disorder), and decreased level of are required to confirm if there is causality between melano-
consciousness [47]. Symptom presentation is different mas and autoimmune encephalitis or immune checkpoint
between adults and children (“more psychiatric in adults”, inhibition can trigger autoimmune encephalitis.
“more neurological in children”) [11]. Memory loss, as well On the other hand, some patients with teratoma
as central hypoventilation, is observed more frequently in developed several kinds of encephalitis without NMDAR
adults, while motor dysfunctions and ataxia predominate in antibodies. Among those forms of encephalitis, a syndrome
children. Within the first month, most cases progress to a sim- with brainstem-cerebellar symptoms stood out. In those
ilar spectrum of manifestations regardless of age [11, 36, 59]. patients without NMDAR antibodies, psychosis and behav-
In addition to those characteristic manifestations, central ioral change were less likely to act as the initial symptom,
neurogenic hyperventilation has beenreportedin such patients and other symptoms except psychosis and behavioral change
[60]. The cranial nerves are also involved in anti-NMDAR (such as dyskinesias) were uncommon [70].
encephalitis. Moreover, cervical rigidity is less frequent to
appear [2]. Some patients suffer from sleep dysfunction, such 6. Laboratory Findings and Imaging
as hypersomnia and inversion of sleep patterns [4]. Manifestations
The modified Rankin scale (mRS) has been used to assess
the neurological status of patients with anti-NMDAR In order to make a precise diagnosis, especially in the initial
encephalitis [61]. In a large sample cohort study, the disease phase of anti-NMDAR encephalitis, the rational assistant
severity showed that 87% of patients had a maximum mRS of examinations are necessary. The conventional CSF test, the
5, and 77% needed the support of ICU. On the other hand, examinations by magnetic resonance imaging (MRI), and
spontaneous improvement also occurred in several patients electroencephalogram (EEG) could provide the valuable
[11]. The clinical features of anti-NMDAR encephalitis in information on anti-NMDAR encephalitis.
adults and children are presented in Table 1.
(1) CSF test—abnormal alterations in CSF are seen in
5. Association with Tumors more than 90% of patients. These abnormities include
mild-to-moderate lymphocytic pleocytosis (90%),
Anti-NMDAR encephalitis has been found to associate with
mild increase of protein concentration (30%), and
ovarian teratoma in young women [15]. The frequency of
CSF-specific oligoclonal bands (60%) [4]. The median
an underlying tumor is dependent on sex, age, and ethnic
value of white blood cells (23/mm3) is significantly
background of the patients [4, 6, 11]. An underlying neo-
lower than that in cases of viral etiologies. The protein
plasm could be found in a large group of the patients
level with a median of 24 mg/dl is also significantly
(38%), especially in women (46%). It is rarely in girls younger
lower. The glucose value is usually within normal
than 12 years (6%) and male patients (6%). The presence of a
range [2]. The oligoclonal bands are detected even
tumor predominates in cases between 12 and 45 years [11].
when routine CSF examinations are normal. In the
Tumor is usually less discovered in the younger patients [5,
early stage, few oligoclonal bands are observed but
6]. Twenty-three percent of the patients older than 45 years
become more prominent later in the disease course
have underlying tumors, which are usually carcinomas rather
[71]. The changed profile of CSF in children resembles
than teratomas [62]. Black patients are more likely to have an
that in adults [6]. The incidences of CSF abnormities
underlying tumor than other ethnic groups [5]. Ovarian ter-
(pleocytosis or increase of protein concentration)
atoma, most of which is mature [4], is the most common
reported in China [16, 72, 73] were lower than that
underlying tumor (94%). Extraovarian teratoma (2%) and
reported by Dalmau et al. [4]. The distinction may be
other tumors (4%, such as tumors of the lung, breast, testis,
attributed to the difference in sample size, population
ovary, uterus, thymus, and pancreas) are also detected. Those
composition, or ethnic background which needs fur-
tumors other than teratomas are often detected in patients
ther studies to prove.
older than 45 years [11, 63–65].
Hepatic lesions, which were focal nodular hyperplasia (2) MRI manifestations—the results of routine MRI
by biopsy, were reported in a 12-year-old girl with anti- examinations in the brain are abnormal only in
NMDAR encephalitis. The association between anti- 30%–50% of patients with anti-NMDAR encephalitis
NMDAR encephalitis and liver tumors is unclear [66]. It [2, 4, 11]. Increased signals on fluid-attenuated inver-
is recently reported that anti-NMDAR encephalitis sion recovery (FLAIR) and/or on T2 sequence are
developed shortly after receiving combination treatment observed frequently in the cortical and subcortical
with immune checkpoint inhibitors (nivolumab and regions and hippocampus, sometimes in the basal
6 Mediators of Inflammation

Table 1: Clinical features of anti-NMDAR encephalitis in adults and children.

Adults Children
Antecedent infec- More than 80% of patients; fever, headache, digestive-tract or upper
Less common
tion (0–2 weeks) respiratory-tract symptoms
About 80% of the cases; anxiety, irritability, insomnia, paranoia,
Psychiatric and
aggression, auditory or visual hallucinations, sexual disinhibition,
behavioral Less common
mania, cognitive disorder and psychosis; isolated psychiatric symptoms
symptoms
are rare
About 70% of the cases; usually partial in males, and generalized in Usually partial motor or complex seizures;
Seizures
females; prolonged status epilepticus may occur initially as frequently as psychiatric symptoms
More common; atypical symptoms such as
Motor Orofacial dyskinesias, chorea, ballismus, athetosis, rigidity, stereotyped
hemiparesis or cerebellar ataxia predominate
dysfunctions movements, myorhythmia, or opisthotonus
in this age group
Memory
Short-term memory loss Less common
dysfunction
More than 70% of patients; reduction of verbal output or mutism,
Speech disorders
echolalia (usually with echopraxia), mumbling, or perseveration
Decrease in level
88% of patients during the first 3 weeks
of consciousness
About 70% of the cases; hyperthermia, cardiac dysrhythmias
Autonomic More common; predominantly tachycardia,
(tachycardia or bradycardia), hypersalivation, hypotension,
dysfunctions hyperthermia, and hypertension
hypertension, urinary incontinence, and sexual dysfunction
Central
Approximately 70% of patients Less common
hypoventilation

ganglia, posterior fossa, or medial temporal regions. course and should raise consideration of anti-
The cortical-meningeal enhancement with gadolin- NMDAR encephalitis [77]. The EEG abnormities are
ium is less frequent and transient. Most of the abnor- often subclinical, while some movement disorders
malities in MRI manifestations are often mild, suggestive of seizures have no EEG correlation [6].
transient, and nonspecific [2]. Multifocal or extensive EEG will be helpful to distinguish between seizures
demyelinating changes are also found, which suggests and movement disorders.
that anti-NMDAR encephalitis patients may develop
episodes of demyelinating disorders simultaneously
or separately [74]. Despite normal manifestations in 7. Anti-NMDAR Antibodies
routine MRI, extensive alterations of white matter
Antibodies of the IgG class against subunit NR1 of NMDAR
integrity and substantial changes of functional con-
were first demonstrated in connection with anti-NMDAR
nectivity are visible in patients with anti-NMDAR
encephalitis as the indicator of this disorder [4]. The patho-
encephalitis using diffusion tensor imaging and func-
genic role of these antibodies has been demonstrated in
tional MRI. The changes of white matter are most
cultured neurons and in vivo models [7, 23]. The technologic
frequently observed in the cingulum and these
methods of detection of anti-NMDAR antibodies comprise
changes are correlated with disease severity [75].
immunohistochemistry and cell-based assay (CBA) with
Normal MRI findings may change after a sudden
fixed or live cells, which are reliable antibody-testing
hypoxic period caused by seizures, respiratory failure
methods. NMDAR antibodies could be detected using the
or cardiac arrest, because some regions become hyper-
techniques in CSF (both sensitivity and specificity as 100%).
metabolic and susceptible to hypoxia [76].
However, it is less sensitive and specific using CBA to detect
(3) EEG—EEG is abnormal in 90% or even more patients the antibodies in serum, in which the misdiagnosis rate is
with anti-NMDAR encephalitis. Most patients 13%. Even if both of those techniques are used, the missed
develop extensive EEG abnormalities characterized diagnosis rate remains 7% [21]. To avoid misdiagnosis as
by focal or generalized slow activity with or without other diseases, such as Creutzfeldt-Jakob disease [78] and
epileptic discharges [2, 4, 6, 11]. Extreme delta brush schizophrenia [79], it is recommended that either using
is regarded as a unique electrographic pattern of CBA detects the NMDAR antibodies in both serum and
anti-NMDAR encephalitis. It is characterized by CSF or applying both CBA and immunohistochemistry tech-
generalized rhythmic delta activity at 1–3 Hz with niques detect the antibodies in serum.
superimposed rhythmic 20–30 Hz beta frequency Seropositive findings are more likely to be observed in
activity. The pattern was previously described in 30% patients with teratoma than those without a tumor. In addi-
of 23 adult patients undergoing continuous EEG mon- tion, there is an association between high levels of antibody
itoring. The delta brush is related to a more prolonged and the teratoma and/or poor outcome. Over time, the
Mediators of Inflammation 7

antibody titer may decrease regardless of outcome [4, 21]. disorders with the anti-NMDAR encephalitis have been
The patients with an early decrease of antibody levels in reported [74, 90–95].
CSF within the first months tend to have a good outcome In a study of 691 patients suffering from anti-NMDAR
[21]. After clinical recovery, CSF and serum from some encephalitis with the median age as 27 years (range 4–62
patients may remain antibody positive [21, 80, 81]. The level years), 23 patients (3.3%) manifested with obvious clinical
change of the antibodies in CSF is more closely related with and/or MRI features suggesting demyelination [74]. In 12
clinical relapses than that in serum [21]. of those 23 patients, anti-NMDAR encephalitis was identi-
Regardless of immunoglobulin class (IgM, IgA, and IgG), fied before or after the independent episodes of demyelinat-
all circulating autoantibodies against the NR1 subunit of ing disorders evidenced by detections of antibodies against
NMDA receptors may have pathogenic potential on access aquaporin-4 (AQP4) and myelin oligodendrocyte glycopro-
to the brain in the condition of increased BBB permeability tein (MOG) using CBA and immunohistochemistry, includ-
[82]. In contrast to IgG antibody which has high disease ing neuromyelitis optica spectrum disorder (NMOSD) and
specificity of anti-NMDAR encephalitis [21], IgA and IgM brainstem or multifocal demyelinating syndromes. In 5 cases
antibodies may be elevated in healthy individuals and many with NMOSD, 4 were anti-AQP4 antibody positive. All 7
disease carriers, ranging from major depression and schizo- cases with brainstem or multifocal demyelinating syndromes
phrenia [42] to hypertension, diabetes and stroke [83] and were anti-MOG antibody positive. The other eleven patients
to multiple sclerosis (MS) [84], dementia [85, 86], Alzhei- developed anti-NMDAR encephalitis and demyelinating
mer’s and Parkinson’s disease [87, 88]. Those patients with features simultaneously (5 anti-AQP4 antibody positive, 2
high levels of IgA and IgM antibodies may potentially benefit anti-MOG antibody positive). Teratoma was less frequent
from immunotherapy. in those 23 patients with overlapping syndromes than anti-
NMDAR antibody only controls. Clinical symptoms in
majority of patients with anti-NMDAR encephalitis coexist-
8. Diagnosis ing with demyelinating diseases have improved after immu-
Recently, the diagnostic criteria for anti-NMDAR encephali- notherapy. More intensive care was needed in patients with
tis have been made by Graus et al. [89], which are based on demyelinating episodes and those patients remained more
the clinical manifestations, evidences of CSF, brain MRI residual deficits [74].
and EEG, and the antibodies against the NR1 subunit of A previous healthy 44-year-old Chinese woman who was
NMDARs in the CSF and/or serum. followed up for 8 years in the First Hospital of Jilin University
The diagnosis of probable anti-NMDAR encephalitis can developed anti-NMDAR encephalitis coexisting with
be made when all three of the following conditions have been NMOSD with negative anti-AQP4 antibody in serum and
reached: (1) at least four of the six major groups of symptoms CSF (submission).
occur within 3 months, including behavioral (psychiatric) Anti-NMDAR encephalitis in coexistence with demye-
abnormity or cognitive dysfunction, speech dysfunction linating diseases made the clinical manifestations too
(pressured speech, reduction of verbal output, and mutism), complex to recognize. Therefore, the rational assistant
seizures, motor dysfunction, decreased level of conscious- examinations, especially detection of anti-NMDAR anti-
ness, autonomic instability or central hypoventilation—cases bodies and other antibodies related to diagnosis of demye-
with three of the above groups of symptoms together with a linatory disorders in CSF and/or serum are conducive to
systemic teratoma can also be diagnosed; (2) at least one of early diagnosis.
the following laboratory findings: EEG abnormity (focal or In practice, clinicians should be aware that overlapping
diffuse slow or disorganized activity, extreme delta brush, syndromes may occur and specific antibody testing should
or epileptic activity) and CSF abnormity (pleocytosis or oli- be performed when patients with anti-NMDAR encephalitis
goclonal bands); (3) exclude other disorders. develop demyelinating features, and patients with NMOSD
The diagnosis can be definite when one or more of the six or other demyelinating disorders develop atypical symptoms
groups of symptoms are present and IgG antibodies against (e.g., seizures, psychosis).
the GluN1 subunit of the NMDA receptor are detected. Also, The exact contribution of these antibodies (NMDAR,
reasonable exclusion of other disorders is necessary. Anti- AQP4, MOG, or unknown antibodies) to myelin dysfunction
body testing should include CSF analysis. If only serum is is unclear, but it should be noted that there are NMDA recep-
available, in addition to CBA, live neurons or tissue immuno- tors on oligodendrocytes [96] that are the target cells in most
histochemistry should be used as confirmatory test. demyelinatory disorders in the CNS. Thus, future studies are
needed to determine whether NMDA receptors on oligoden-
drocytes could be affected by those antibodies.
9. Anti-NMDAR Encephalitis Coexistences with A recent study reported a 22-year-old male with human
Demyelinating Disorders immunodeficiency virus (HIV) infection manifested with
obvious psychiatric symptoms and had anti-NMDAR anti-
Anti-NMDAR encephalitis coexisting with demyelinating bodies in his serum using CBA and immunohistochemistry
diseases may occur in some individuals sequentially or simul- [97]. This patient might develop an overlapping syndrome.
taneously. Acute demyelinating encephalomyelitis (ADEM), Another possibility is that infection of HIV could trigger
neuromyelitis optica (NMO), optic neuritis, myelitis, MS, anti-NMDAR encephalitis. To date, the similar reports are
prominent brainstem dysfunction, or other demyelinating rare and underlying mechanism is still unknown.
8 Mediators of Inflammation

10. Treatment, Relapses, and Outcome good outcome by multivariable analysis. Longer follow-up
was associated with better outcome.
Despite the severity of anti-NMDAR encephalitis, patients In another study including 105 patients with anti-
often get improvement with the support of multidisciplinary NMDAR encephalitis, patients with a tumor (mostly tera-
care, including immunotherapy, surgery, ICU support, and toma) were more likely to achieve substantial improvement
sometimes prolonged hospitalizations [4]. Immunotherapy after first-line immunotherapy and tumor resection than
and detection and removal of a teratoma should be initially those without a tumor (80% versus 48%). Second-line immu-
focused on (Figure 2 presents the procedure of diagnosis notherapy was needed more often in those patients without a
and treatment of anti-NMDAR encephalitis). First-line tumor. The final outcome was quite similar in patients with
immunotherapy consists of steroids, intravenous immuno- or without a tumor [5].
globulin (IVIG), and/or plasma exchange (PE), which could The findings have demonstrated that early and aggressive
be used alone or combined [11]. If tumors are found, the immunotherapy and tumor resection (if present) contribute
surgical resection should be taken into account [1, 98]. When to achieve favorable outcomes, which is in line with other
diagnosis is delayed, or patients do not have a tumor, or the reports [14, 71, 107].
first-line immunotherapy fails, additional treatment with Dalmau et al. has reported that recovery of anti-NMDAR
second-line immunotherapy is usually applied [5, 11], which encephalitis often develops as a multistage process that
includes cyclophosphamide, rituximab, azathioprine, myco- occurs in the reverse order of symptom appearance [5]. The
phenolate mofetil, methotrexate, and so on [99, 100]. median hospital admission is 2.5 months [4], but longer
Supporting therapies play an important role, for example anti- hospitalizations in rehabilitation centers may be needed for
epileptic and antipsychotic treatment, respiratory and cardiac many patients [46, 102, 108]. Approximately 50% of patients
support, management of blood pressure and temperature, and achieve full recovery, while 28% and 18% remain mild and
prevention of deep venous thrombosis (DVT) and bedsore severe deficits, respectively [4]. The mortality rate of this
[46, 101]. After the acute phase, many patients need rehabili- disorder is about 6% [4, 11]. There is an association between
tation therapies, such as occupational and physical therapy, high antibody-titers and poor outcome. Patients with an
as well as therapies for dysphagia and speech [46, 102]. early decrease of antibody titers in CSF within the first four
A drastically different outcome occurred in identical twin weeks of the disease tend to have a good outcome [21].
sisters with anti-NMDAR encephalitis. Neither of them Relapse is defined as worsening of symptoms or the new
responded to immunotherapy. Imaging examinations onset occurring after more than 2 months of stabilization or
showed normal-appearing ovaries, which were confirmed improvement. Some patients has one or multiple relapses,
by autopsy or pathology. The first twin received immuno- which represents a 12% risk of relapses within 2 years [11].
therapy only (prednisone, cyclophosphamide, rituximab, Relapses predominantly affect those patients without tumors
and plasmapheresis) and died from the disease, while the sec- or who are treated with delayed immunotherapy and tumor
ond twin accepted a bilateral salpingo-oophorectomy and resection (if present) [4, 10, 11]. The first relapse may occur
recovered gradually, except for slight memory deficits. That many years after the initial episode (range 0.5–13 years,
unique clinical scenario suggests that patients who fail to median 2 years). More than 50% of the relapses may present
respond to first- and second-line immunotherapy may bene- with partial aspects of the previous episodes, and they do not
fit from the removal of normal-appearing ovaries [103]. add residual deficit [10, 11].
Additionally, when patients with anti-NMDAR encephalitis Responses to immune treatment in children and teen-
do not improve after first- and second-line treatments, local agers (younger than 18 years) are slow and variable [6]. It is
intrathecal treatment with methotrexate and/or methylpred- reported that 75%–85% have full or substantial recovery after
nisolone may be a promising alternative therapy [104, 105]. immunotherapy or tumor resection [6, 36, 46], which is
Furthermore, coenzyme Q10 may have a beneficial role in similar to that of adults [11]. Relapses occur in 15%–25% of
treatment of anti-NMDAR encephalitis [106]. children with anti-NMDAR encephalitis [6, 46].
In a multi-institutional study including 577 patients In patients older than 45 years, the outcome is usually less
(1–85 years, median 21 years) [11], 501 patients were favorable than in younger patients even though the clinical
followed up to assess the therapeutic effects and outcome. manifestations are less severe. These may account for the
472 (94%) cases were treated with first-line immunotherapy discrepancy: (1) in this age group (older than 45 years),
or tumor removal, approximately 50% of whom improved underlying tumors are less common, but if present, they are
within four weeks. In the remaining 221 patients who failed usually carcinomas rather than teratomas; (2) delays in diag-
to respond to first-line treatment, 125 (57%) patients nosis and treatment are more frequent. Except for no need
received second-line immunotherapy (rituximab and cyclo- for ICU, early treatment, and longer follow-up, younger age
phosphamide) and got better outcome than those who is also a predictor of good outcome [62].
did not. Of those 501 patients, 79% got good outcome
(mRS 0–2) within the first 24 months (median 6 months). 11. Conclusion
81% had a good outcome at a 24-month follow-up, and
some patients continued to improve thereafter. In multi- Anti-NMDAR encephalitis mainly affects young women
variable analysis, predictors of good outcome included early with ovarian teratomas but also occurs in other subjects.
treatment and no need for ICU. The use of second-line It is a potentially lethal but treatable autoimmune disorder
immunotherapy was identified as an additional factor for characterized by obvious psychiatric and neurologic
Mediators of Inflammation 9

Behavioral (psychiatric)
abnormity or cognitive
dysfunction

CSF: mild‒to‒moderate
Speech dysfunction
lymphocytic pleocytosis,
mild increase of protein
concentration, and
CSF-specific oligoclonal Clinical manifestations Seizures
bands suggesting anti‒NMDAR
encephalitis
Motor dysfunction

Decreased level of consciousness

MRI: increased signals on

FLAIR/T2 sequence in Assistant
cortical and subcortical Autonomic instability or
examinations
regions and hippocampus, central hypoventilation
sometimes in the basal
ganglia, posterior fossa, or
medial temporal regions

Detection of anti‒NMDAR (‒) Consider alternative

⁎ diagnosis or
antibodies (CSF and serum)
retesting
(+)
EEG: focal or
generalized slow
Anti-NMDAR
activity with or without
encephalitis
epileptic discharges,
extreme delta brush

Detection (‒) Steroids + IVIG or Supporting

(+) of tumors plasma exchange &
Tumor therapies
removal
Little or no response

Second‒line Good
immunotherapy※ response

Little or no Good
response response

Consider alternative Rehabilitation, chronic

immunosuppressants and immunotherapy, and tumor
tumor surveillance surveillance

Figure 2: Procedure of diagnosis and treatment of anti-NMDAR encephalitis. ∗ indicates that detection of antibodies should include CSF
analysis. If only serum is available, in addition to cell-based assay (CBA), live neurons or tissue immunohistochemistry should be used as
confirmatory test. &Supporting therapies include antiepileptic and antipsychotic treatments, respiratory and cardiac support, management
of blood pressure and temperature, and prevention of deep venous thrombosis (DVT) and bedsore. ※Cyclophosphamide, rituximab, or both.

manifestations. Laboratory and imaging as well as EEG Prompt immunotherapy, complete tumor resection, and
examinations often show abnormalities. The diagnosis is ICU support contribute to a favorable outcome. Future
based on the detection of IgG antibodies against the studies should focus on exploring the associations with
GluN1 subunit of NMDA receptors in CSF and/or serum. tumors and infectious triggers, underlying mechanisms of
Anti-NMDAR encephalitis in coexistence with demyelinat- anti-NMDAR encephalitis and overlapping syndrome, and
ing disorders makes the disease more difficult to recognize. developing new therapies.
10 Mediators of Inflammation

Abbreviations and the Swedish Research Council (K2013-66X-22337-01-3

and Diarienummer: 2015-03005).
ADEM: Acute demyelinating encephalomyelitis
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