Journal Pre-Proofs: Brain Research

Journal Pre-proofs
Review
Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mech-

anisms, treatment, prognosis
Qianyi Huang, Yue Xie, Zhiping Hu, Xiangqi Tang
PII: S0006-8993(19)30603-1
DOI: https://doi.org/10.1016/j.brainres.2019.146549
Reference: BRES 146549
To appear in: Brain Research
Received Date: 28 June 2019

Revised Date: 8 November 2019
Accepted Date: 9 November 2019
Please cite this article as: Q. Huang, Y. Xie, Z. Hu, X. Tang, Anti-N-methyl-D-aspartate receptor encephalitis: a
review of pathogenic mechanisms, treatment, prognosis, Brain Research (2019), doi: https://doi.org/10.1016/
j.brainres.2019.146549
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Anti-N-methyl-D-aspartate receptor encephalitis: a review of
pathogenic mechanisms, treatment and prognosis
Qianyi Huanga, Yue Xieb, Zhiping Hua, Xiangqi Tanga*
aDepartment of Neurology, The Second Xiangya Hospital, Central South University, Changsha,
Hunan 410011, China
bDepartment of Neurology, The Xiangya Hospital, Central South University, Changsha, Hunan
410011, China
*Corresponding Author: Xiangqi Tang
Department of Neurology, The Second Xiangya Hospital, Central South University
Renmin Road 139#, Changsha, Hunan 410011, China
Tel: +86 13875807186 Fax: 0731-84896038 Email: txq6633@csu.edu.cn
Abstract
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune
disorder characterized by prominent neuropsychiatric symptoms that predominantly affects
children and young adults. In this review, we discuss the pathogenic mechanisms and
immunologic triggers of anti-NMDAR encephalitis, and provide an overview of treatment and

prognosis of this disorder, with specific focus on the management of common symptoms,
complications, and patients during pregnancy. Most patients respond well to first-line treatment
and surgical resection of tumors. When first-line immunotherapy fails, second-line
immunotherapy can often improve outcomes. In addition, treatment with immunomodulators and
tumor resection are effective treatment strategies for pregnant patients. Benzodiazepines are the
preferred treatment for patients with catatonia, and electroconvulsive therapy (ECT) may be
considered when pharmacological treatment is ineffective. Age, antibody titer, cerebellar atrophy,
levels of biomarkers such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial
(mt)DNA in cerebral serum fluid (CSF), and timing from symptom onset to treatment are the main
prognostic factors. Patients without tumors or those who receive insufficient immunotherapy
during the first episode are more likely to relapse.
Keywords: anti-N-methyl-D-aspartate receptor encephalitis; pathogenic mechanism; treatment;
prognosis; immunotherapy
Contents
1. Introduction
2. Pathogenic mechanisms and clinical features of anti-NMDAR encephalitis
2.1 NMDARs
2.2 Pathogenic mechanisms
2.3 Clinical features
3.Treatment
3.1 Tumors
3.2 Immunotherapy
3.3 Symptomatic treatment
3.3.1 Management of psychiatric symptoms
3.3.2 Other symptoms
3.4 Complications
3.5 Pregnant patients
4.Prognosis
4.1 Factors associated with prognosis
4.2 Sequela and relapse
5.Conclusion
1. Introduction
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common
autoimmune encephalitis (Dalmau and Graus, 2018). Data from California Encephalitis Project
about the cause of encephalitis revealed that the frequency of anti-NMDAR encephalitis exceeded
that of any individual viral encephalitis among young individuals(Gable et al., 2012).
Anti-NMDAR encephalitis was first described in 2005 (Vitaliani et al., 2005), and its
autoantigens were discovered by Dalmau et al. in 2007 in a cohort of 12 female patients (14-44
years), most of whom had ovarian teratomas (Dalmau et al., 2007a). Since the first reported
cases of anti-NMDAR encephalitis, it has been widely studied. Epidemiologic studies suggest that
it primarily affects young patients with median age of 21 years (Tanguturi et al., 2019a);
however, it can also occur in patients as young as 2 months and as old as 85 years(Titulaer et
al., 2013). Anti-NMDAR encephalitis has a higher incidence among females (75%) at younger
ages, but after the age of 45 the male-to-female ratio is more balanced (Tanguturi et al.,
2019a).
The pathophysiology of anti-NMDAR encephalitis is thought to involve antibodies aganist the
NR1 subunit of N-methyl-D-aspartate receptor (NMDAR), which causes reversible internalization
of the receptor in neurons (Hughes et al., 2010). NMDAR is an ionotropic receptor that plays a
crucial role in neuroplasticity, synaptic transmission, memory, learning, and human behavior
(Dalmau et al., 2008a; Kuppuswamy et al., 2014). Excitotoxicity due to overactivity of
NMDAR is potentially associated with epilepsy, dementia, stroke, and chronic disorders such as
Huntington's disease and Parkinson's disease(Hallett and Standaert, 2004; Liu et al., 2017;
Olivares et al., 2012; Wu and Tymianski, 2018; Zeron et al., 2002). Decreased NMDAR
activity can cause symptoms similar to those observed in schizophrenia, autism, and other
disorders that mimic anti-NMDAR encephalitis (Schade and Paulus, 2016; Waxman and Lynch,
2005).
Nearly 7.8% to 59% of patients with anti-NMDAR encephalitis might have underlying tumors,
which are typically teratomas(Dalmau et al., 2011; Huang et al., 2015; Irani et al., 2010a;
Lim et al., 2014; Viaccoz et al., 2014; Wang et al., 2016a). The presence of a tumor
is dependent on age, sex, and ethnicity. Tumors preferentially occur in women aged 12-45 years
and black people(Titulaer et al., 2013; Venkatesan and Adatia, 2017; Viaccoz et al.,
2014). So management of anti-NMDAR encephalitis has not only focused on immunotherapy, but
also on detection and removal of tumors. First-line immunotherapy include high-dose steroids,
intravenous gamma globulin (IVIG), and plasma exchange (PE). Rituximab and
cyclophosphamide are often used as second-line immunotherapies (Dalmau et al., 2011).
Anti-NMDAR encephalitis seems to have better long-term outcome than that of other
autoimmune encephalitis such as anti-Hu-associated paraneoplastic encephalomyelitis, and
Voltage-Gated Potassium Channel autoimmune encephalitis (Yeshokumar et al., 2017).
Approximately 66-80% of patients with anti-NMDAR encephalitis recover nearly all baseline
neurological function. However, some patients suffer from severe deficits such as
neuropsychiatric or cognitive deficits, or death (Dalmau et al., 2008b; Dalmau et al., 2011;
Irani et al., 2010b; Lim et al., 2014; Titulaer et al., 2013). Approximately 12-25%
of patients experience relapse (Dalmau et al., 2008b; Dalmau et al., 2011; Irani et al.,
2010b; Titulaer et al., 2013; Wang et al., 2016a).
Although many observational studies have been reported, no randomized controlled trials have
been performed to date. Furthermore, most studies have focused on immunotherapy and treatment
of patients refractory to therapy. However, studies have not focused on treatment of complications
or common symptoms, which will be discussed in detail.
2.1 NMDARs
NMDARs are slow, ionic glutamate receptors (iGluRs). Glutamate receptors (GluRs) include
ionotropic glutamate receptors (iGluRs) and metabotropic G protein-coupled receptors (mGluRs),
and are the main excitatory receptors in the central nervous system (Traynelis et al., 2010).
Functional adult neuronal NMDARs are heteromeric complexes composed of two GluN1 subunits
and two GluN2 subunits (Waxman and Lynch, 2005). NR1 subunits bind to glycine, and NR2
subunits bind glutamate. GluN1 is expressed as eight different isoforms (GluN1–1a to 4a and
GluN1–1b to 4b), while GluN2 is expressed as four isoforms (GluN2A–GluN2D) (Regan et
al., 2015). NR1 and NR2 subunits share a common structure, with a middle region containing
four transmembrane domains (M1–M4), a reentrant membrane loop between the M3 and M4
domains, a long extracellular N-terminal ligand-binding region, and an intracellular C-terminal
region.
2.2 Pathogenic mechanisms (Fig1)
Antibody-associated encephalitides can be broadly classified into 2 categories according to the
location of their neuronal antigens: paraneoplastic encephalitis associated with antibodies
targeting intracellular antigens, and encephalitis associated with antibodies against neuronal
cell-surface or synaptic receptors(Kelley et al., 2017). Paraneoplastic encephalitis are more
closely associated with an underlying malignancy, for instance, anti-Hu encephalitis, the most
common paraneoplastic encephalitis, is associated with small-cell lung cancer in most
cases(Graus et al., 2001; Gultekin et al., 2000). It is widely accepted that the main
pathogenic mechanisms underlying anti-NMDAR encephalitis involves the binding of
auto-antibodies to the GluN1 subunit of NMDAR. In anti-NMDAR encephalitis, antibodies
against extracellular epitopes of cell-surface proteins can alter the structure and function of
receptors, resulting in the clinical syndrome. However, in paraneoplastic encephalitis, the
antibodies cannot reach intracellular epitopes; cytotoxic T-cells are believed to play a role in the
pathogenesis of paraneoplastic encephalitis (Dalmau and Graus, 2018).
Tumors and viral infection are two known potential immunologic triggers of anti-NMDAR
encephalitis. However, in about half of patients with anti-NMDAR encephalitis, the immunologic
triggers are still unknown. It is postulated that the antigen (NMDAR), which may be expressed in
nervous tissue-containing tumors (typically ovarian teratoma), or released by viral-induced
neuronal disruption, is directly transported to the local lymph nodes in soluble form or taken up by
antigen-presenting cells (APCs), resulting in the generation of memory B cells (Dalmau, 2016).
With the cooperation of CD4+ T cells, naive B cells exposed to NMDAR become activated and
are able to cross the blood-brain barrier via the choroid plexus. After reaching the central nervous
system, these activated B cells (memory B cells) undergo further stimulation, antigen-driven
maturation, and clonal expansion, finally differentiating to anti-NMDAR antibody-producing
plasma cells (Dalmau, 2016). The multistep process has only partially been
proved(Martinez-Hernandez et al., 2011) and efforts are still needed to explore its underlying
mechanisms.
Antibodies against the NMDARs typically cause selective crosslinking and internalization of
NMDARs (Hughes et al., 2010; Moscato et al., 2014), which may be related to disruption
of the interaction between NMDAR and ephrin type B2 (EphB2) receptor, a receptor that
stabilizes NMDAR at the synapse (Mikasova et al., 2012; Planaguma et al., 2016). A study
showed that EphB2 could protect mice from damage caused by NMDAR antibodies isolated from
patients(Planaguma et al., 2016), as demonstrated by antibodies from the CSF of patients with
anti-NMDAR encephalitis or recombinant human monoclonal antibodies which were cloned and
expressed from matching immunoglobulin heavy- and light-chain amplicons of clonally expanded
intrathecal plasma cells.(Malviya et al., 2017; Planaguma et al., 2015). After
internalization, the antibody-bound NMDARs were trafficked through recycling endosomes and
lysosomes (Moscato et al., 2014).

Recently, it was shown that antibodies isolated from patients appear to activate NMDAR,
resulting in a longer NMDAR channel open time before the internalization of NMDARs. This
finding and the core symptoms of anti-NMDAR encephalitis led Lynch et al. to advance a new
hypothesis (Lynch et al., 2018). Antibodies preferentially bind to open synaptic NMDARs
(often GluN2A-containing) at active excitatory synapses. In contrast, on active inhibitory neurons,
antibodies preferentially bind to open extrasynaptic NMDARs (commonly GluN2B-containing).
Excessive extrasynaptic NMDAR signaling can trigger seizures, dyskinesias, and catatonia;
seizures are as well associated with excessive synaptic NMDAR signaling. This hypothesis may
partly explain why patients experience seizures which can be triggered by NMDAR agonists in an
NMDAR hypofunction state. Concerning the paradox of reduced NMDAR function and increased
seizures, studies by Symmonds et al. and Rosch et al. also provided some useful information.
Symmonds et al. estimated NMDAR function from EEG in patients with anti-NMDAR
encephalitis and encephalopathic patient controls. Their model-based estimates of NMDAR
function showed that patients with NMDAR-encephalitis have a selective deficit in NMDAR
signalling, which may reflect an increased propensity for seizures in these patients(Symmonds et
al., 2018). Rosch et al. showed that NMDAR antibodies could alter intrinsic cortical
connections and neuronal population dynamics to change the spectral composition of spontaneous
EEG activity and predispose brain dynamics to paroxysmal abnormalities(Rosch et al., 2018).
The mechanisms of anti-NMDAR encephalitis have been mostly studied in cultured neurons
or in mice exposed to antibodies isolated from patients. These studies showed reductions in
surface and synaptic NMDAR density and NMDAR-mediated currents (Hughes et al., 2010;
Moscato et al., 2014). Recently, to characterize the specific molecular mechanisms of

autoantibody-induced NMDAR internalization, Amedonu et al. showed that the scaffold protein
postsynaptic density protein 95 (PSD-95) could stabilize NMDARs in the cell membrane
(Amedonu et al., 2019). However, further studies of the mechanisms of internalization are
required.
Patients often present with six main symptoms: including psychiatric symptoms or cognitive
dysfunction, seizure, speech dysfunction, movement disorder, decreased level of consciousness,
and autonomic dysfunction or central hypoventilation. Prodromal symptoms such as headache,
fever, nausea, and upper respiratory-tract symptoms are observed in many patients (Graus et al.,
2016). Irani et al. divided the disease process into two stages. In the early stage, patients often
present with psychiatric symptoms or cognitive dysfunction and seizures. In the late stage,
decreased level of consciousness, movement disorder, and autonomic dysfunction are most
common (Irani et al., 2010b). There are some differences in symptoms in children and adults
with anti-NMDAR encephalitis. Typically, the early symptoms recognized in children are often
non-psychiatric, such as behavioral problems, seizure, speech dysfunction, and movement
disorders (Florance et al., 2009). In addition, psychiatric manifestations in children include
temper tantrums and hyperactivity or irritability, while adults often present with anxiety, paranoid
behaviors, and delusions. Dysautonomia is less likely to occur in children, but is more severe
when it occurs in children (Florance et al., 2009). Compared with adult women, adult male
patients are more likely to present with seizure as the initial symptom (Viaccoz et al., 2014).
Herpes simplex virus (HSV) infection may trigger an autoimmune response in the central nervous
system, inducing an autoimmune encephalitis mediated by antibodies against the NMDAR. The
overall clinical picture of HSV-induced anti-NMDAR encephalitis seems similar to that of
anti-NMDAR encephalitis not preceded by Herpes simplex encephalitis (HSE)(Nosadini et al.,
2017). Nosadini et al. conducted a systematic literature review about characteristics of
HSV-induced anti-NMDAR encephalitis, which showed that the anti-NMDAR encephalitis phase
was characterized by a significantly higher rate of movement disorder, compared with the
preceding episode of HSE(Nosadini et al., 2017). For more details, a review by Liu et al. (Liu
et al., 2017)provides a comprehensive overview of the clinical features and frequency of
anti-NMDAR encephalitis.
CSF examination often shows pleocytosis, with oligoclonal bands detected in some patients.
Electroencephalogram (EEG) shows focal or diffuse slowing, epileptic activity, or extreme delta
brush, which is considered characteristic of anti-NMDAR encephalitis. Recently, Foff et al.
demonstrated that a novel EEG phenomenon, beta:delta ratio (BDR), may be specific to
anti-NMDA encephalitis (Foff et al., 2017). MRI scans are normal in 50% of patients with
anti-NMDAR encephalitis, sometimes T2 or FLAIR signal hyperintensity might be seen in the
hippocampi, cerebellar or cerebral cortex, frontobasal and insular regions, basal ganglia and
brainstem(Dalmau et al., 2007b). According to an expert consensus advanced by Graus et al. in
2016, diagnosis may be based on the presence of one or more of the six main symptoms and
anti-GluN1 IgG antibodies after reasonable exclusion of other disorders (Graus et al., 2016).
3. Treatment (Table1)
Although there are no international guidelines for treatment, a 2016 expert consensus on
diagnosis was reported in The Lancet Neurology(Graus et al., 2016). In the present work,
treatment of anti-NMDAR encephalitis was reviewed on the basis of a large number of
observational studies and case series reports, including multi-center studies.
3.1 Tumors
In young women, anti-NMDAR encephalitis is often associated with ovarian teratomas(Gable
et al., 2012). Patients with IgA NMDAR antibodies in the CSF may be more likely to have
teratomas (Desestret et al., 2015). In children and males, the frequency of tumors is lower
and the histology is different from that in females. For example, other tumors such as lung
carcinoma, testicular carcinoma, breast carcinoma, colon carcinoma, and ectopic teratomas have
also been reported, but are mostly seen in males or older patients (Florance et al., 2009;
Titulaer et al., 2013). For patients with tumors who are candidates for surgery, resection of
tumors can accelerate improvement and decrease the chance of relapses (Iizuka et al., 2008;
Sabin et al., 2008). As such, it is important to investigate for an underlying tumor once
diagnosis is confirmed.
3.2 Immunotherapy
Anti-NMDAR encephalitis is considered an auto-immune response within the central nervous
system; therefore, emphasis is often placed on various forms of immunotherapy that target the
production of antibodies, reducing their effects on receptors (Tanguturi et al., 2019a). Good
outcomes have been achieved in 53-80% of patients using first-line immunotherapy alone, which
includes high-dose steroids (such as methylprednisolone), IVIG, and PE (Titulaer et al.,
2013). For patients who do not respond to first-line immunotherapy, it is generally accepted that
second-line immunotherapy (rituximab or cyclophosphamide) can improve outcomes (Ishiura
et al., 2008; Kadoya et al., 2015).

Although no systematic comparisons of the three first-line immunotherapy options have been
performed, early initiation of PE prior to IVIG may provide better outcomes. A long-term
follow-up conducted by Pham et al. showed that patients treated with IVIG after PE had better
outcomes than those who received IVIG prior to PE (Pham et al., 2011). In addition, PE can
remove the autoantibodies quickly, resulting in rapid symptomatic improvement in severe cases of
anti-NMDAR encephalitis. Because patients with severe anti-NMDAR encephalitis may suffer
from autonomic instability, it is important to evaluate whether they can tolerate PE procedures,
and their vital signs must be closely monitored during therapy. Recently, a study divided patients
with severe refractory anti-NMDAR encephalitis into a PE group and a non-PE group. The PE
group showed greater improvement in clinical symptoms than the non-PE group after 1 month and
2 months following treatment (Zhang et al., 2019), suggesting that early use of PE may be a
better treatment option. In pediatric anti-NMDAR encephalitis, early administration of PE and a
combination of PE and steroids both resulted in good outcomes (Suppiej et al., 2016). To
compare steroids and PE, DeSena et al. retrospectively evaluated 10 patients who were treated
with steroids and PE in succession. Only three of the patients showed improvements immediately
after steroid therapy, but seven of these patients improved immediately following PE use (DeSena
et al., 2015), which suggested that treatment with corticosteroids may not be as effective as
treatment with steroids followed by PE. However, the possibility that the benefit of steroids is
delayed and didn't start until PE was initiated may cloud the judgment of whether steroids are
helpful for these patients, further head-to-head studies are warranted.
Combination immunotherapy may result in better outcomes than mono-immunotherapy.
Wang et al. classified treatments into four categories: IVIG; PE; rituximab or cyclophosphamide;
and tumor resection, and found that the combination of at least two therapies resulted in better
outcomes than monotherapy (Wang, 2016). A large retrospective study in Europe also found that
there was a trend toward better outcomes when glucocorticosteroids were used in combination
with at least one other immunotherapy (Irani et al., 2010b).
For patients who fail to respond to surgery or first-line and second-line immunotherapy,
treatment with tocilizumab combined with methotrexate may be effective. Bortezomib and
antimetabolites such as azathioprine and mycophenolate mofetil may also be effective
(Bartolini and Muscal, 2017). Tocilizumab, an anti-interleukin 6 antibody, induced better
therapeutic effects in patients refractory to first- and second-line treatments than additional
rituximab treatment or no follow-up therapy in a small cohort (Lee et al., 2016). Several case
series have suggested that bortezomib, a proteasome inhibitor that depletes plasma cells, may be
effective for treatment of patients with severe anti-NMDAR encephalitis (Keddie et al., 2018;
Scheibe et al., 2017; Schroeder et al., 2018; Shin et al., 2018). Sveinsson et al. also
described an extremely severe case in which the patient received repeated cyclophosphamide,
tocilizumab, and bortezomib, which led to remission, after rituximab, bilateral oophorectomy, and
repeated cycles of high-dose steroids and PE (Sveinsson et al., 2017). It should be noted that
some cases have reported successful management following bilateral oophorectomy, when
teratomas are not visualized on ultrasound or CT scans(Johnson et al., 2010). In addition, Liba
and colleagues treated an eight-year old patient who did not respond to various immunotherapies
with alemtuzumab (an anti-CD52 antibody that reduces numbers of memory B cells and T cells)
and intrathecal methotrexate. The patient improved rapidly(Liba et al., 2013), but the efficacy
of alemtuzumab still remains to be studied due to lack of additional supporting evidence.

Although the majority of patients experience good outcomes in response to immunotherapy, the
response to first-line immunotherapy is often slow (Florance-Ryan and Dalmau, 2010), and
blood-brain barrier may affect the efficacy of PE or IVIG (Tanguturi et al., 2019b). Further
studies are needed to identify more effective treatments.
Although immunotherapy is the primary treatment for anti-NMDAR encephalitis, psychiatric
symptoms often require additional treatment. Patients with anti-NMDAR encephalitis typically
present with neuropsychiatric symptoms such as agitation, hallucination, delusion, mood lability,
manic depression and catatonic syndromes.
Benzodiazepines (BZDs), typically lorazepam are the first choice for treatment of catatonia
(Fink, 2013). In addition, BZDs have been shown to strengthen the function of
gamma-aminobutyric acid (GABA) inter-neurons, which are thought to be hypofunctional in
anti-NMDAR encephalitis (Manto et al., 2010). ECT has been performed in psychiatric
practice for more than 50 years. However, routine use of ECT in adolescent populations is limited.
Fear of adverse side effects resulting from ECT and laws regulating use of ECT in adolescents
vary from state to state, which limits uniform implementation (Wilson et al., 2013). However,
ECT is generally regarded as a safe and effective treatment, and may save the lives of patients
suffering from malignant catatonia (Moussa et al., 2019; Zaw, 2006). A recent systematic
review found improvement in 65.2% of 30 cases with refractory psychiatric symptoms (primarily
catatonia) who received ECT (Warren et al., 2019). In addition, ECT is equally effective in
children and adults, with the same indications and contraindications (Zaw, 2006). The therapeutic
mechanisms of ECT are unclear. In rat models, ECT has been demonstrated to increase NMDAR
levels in the brain, which may explain why ECT is an effective treatment for anti-NMDAR
encephalitis (Watkins et al., 1998). Furthermore, ECT can increase GABA concentrations
(Sanacora et al., 2003), which are decreased in anti-NMDAR encephalitis (Manto et al.,
2010). However, considering that 4 of 30 patients worsened after ECT(Warren et al., 2019),
the use of ECT still need careful consideration, and it would be useful to define the ECT
parameters and confirm their safety in a prospectively recruited cohort.
For patients with agitation, atypical sedating antipsychotics (such as olanzapine) are preferable
because they induce fewer side effects, such as NMS and extrapyramidal symptoms (EPS), which
can worsen agitation (Kayser and Dalmau, 2011). Moreover, olanzapine has been shown to
prevent toxicity associated with NMDAR antagonists in animal experiments. Clonidine may help
reduce agitation through regulation of the autonomic nervous system (Scharko et al., 2015).
Typical and atypical antipsychotics have been administered alone or in combination to treat
hallucination and delusion (Kuppuswamy et al., 2014). Lithium and valproic acid are primarily
used to control manic symptoms. Owing to its anti-epileptic and mood stabilizing properties,
valproic acid can be used to effectively treat mood symptoms. Furthermore, valproic acid can be
used to treat choreiform movements and dyskinesia, which are commonly observed in
anti-NMDAR encephalitis (Scharko et al., 2015).
It should be noted that treatment of psychiatric symptoms often requires multiple psychotropic
drugs, which may be associated with increased risk of side effects such as NMS, which is
characterized by rigidity, fever, and mutism or coma (Lejuste et al., 2016). However, these
symptoms have also been observed in many patients who were not treated with psychotropic
drugs, and may represent the natural progression of this disorder (Berg et al., 2015; Warren et
al., 2018). So it’s important to identify the constellation of symptoms so that the appropriate
treatments can be administered.
Mohammad and colleagues performed a retrospective study of symptomatic management in
children. They proposed five medications for the treatment of movement disorders, seven
anticonvulsants for for the treatment of seizures, and eight sedatives and sleep medications for the
treatment of sleep disruption. Their study showed that long-acting BZDs, anticonvulsants and
sedatives such as clonidine can treat multiple symptoms including agitation, seizures, movement
disorders, sleep disruption, and psychiatric symptoms (Mohammad et al., 2016). These findings
may guide the choice of medications to treat these symptoms.
Antiepileptic drugs such as levetiracetam, phenobarbital, topiramate, lamotrigine, valproic acid,
phenytoin, and carbamazepine are commonly used to treat definite or suspected seizures.
Anesthetic agents, such as propofol and midazolam, may be required in patients with status
epilepticus. EEG monitoring is of great significance for diagnosis of patients with nonconvulsive
status epilepticus (NCSE), as well as for differential diagnosis of dyskinesia and seizure (Dalmau
et al., 2011; Kadoya et al., 2015). It’s worthy to note that the overall effect of antiepileptic
drugs in the symptomatic treatment of seizures is limited and immunotherapy is most important in
the treatment of seizures in patients with anti-NMDAR encephalitis(de Bruijn et al., 2019).
However, seizure freedom is not always achieved while using immunotherapy alone and
antiepileptic drugs are sometimes needed as well(de Bruijn et al., 2019). But, chronic use of
antiepileptic drugs may not be necessary in most patients long term, since it seems that most of
them could achieve seizure freedom within 2 years according to Liu et al.(Liu et al., 2017).
Medications used specifically for the treatment of movement disorders include
levodopa-carbidopa, central anticholinergics (benztropine; benzhexol), oral baclofen, amantadine,
and bromocriptine (Mohammad et al., 2016); however, these are less effective than BZDs.
Patients with anti-NMDAR encephalitis may experience central hypoventilation that requires
mechanical ventilation, which is a frequent cause of admission into intensive care unit (Dalmau et
al., 2008a; Titulaer et al., 2013). The percentage of patients who experience central
hypoventilation ranges from 9.4% to 66% , and is linked to age, ethnicity and the presence of
tumor. Children, Asian patients and patients without tumors are less likely to develop central
hypoventilation (Florance et al., 2009; Irani et al., 2010b; Lim et al., 2014; Titulaer
et al., 2013; Wang et al., 2016a).
Autonomic dysfunction is common in the the acute phase of anti-NMDAR encephalitis, and
manifests as tachycardia, bradycardia, hyperhidrosis, hypersalivation, and blood pressure
instability (Dalmau et al., 2011; Florance et al., 2009; Titulaer et al., 2013). Children
are less likely to present with severe dysautonomia. In one retrospective case-control study, Byun
et al. found that cardiac autonomic dysfunction primarily resulted from disruption of the
sympathetic nervous system, and was associated with poor prognosis (Byun et al., 2015). Some
patients may require cardiopulmonary resuscitation (CPR) and pacemaker placement due to
bradycardia or asystole (Dalmau et al., 2011; Florance et al., 2009; Mehr et al., 2016).
In general, it is important to recognize and treat dysautonomia owing to the increased risk of
arrhythmia, cardiac arrest, and abnormal blood pressure which may be life-threatening.
3.4 Complications
Extensive research has focused on the diagnosis and treatment of anti-NMDAR encephalitis.
However, studies that investigate the treatment of complications are rare. Common complications
of this disorder include infection (pneumonia, urinary tract infection, and acute severe
pancreatitis), gastrointestinal disorders, gastrointestinal hemorrhage, multiple organ dysfunction
syndrome (MODS), respiratory failure, shock (septic shock, hypovolemic shock), electrolyte
disorders, hypo-albuminemia, thrombocytopenia, and rash (Chi et al., 2017; Huang et al.,
2016; Jiang et al., 2018). A cohort study demonstrated that severe pneumonia, the most
common complication, was one of the main causes of death resulting from this disease (Chi et
al., 2017). Being bedridden for long durations, intubation, and immunosuppressive treatment
may contribute to increased rates of infection and sepsis. An 11-month-old male patient with
anti-NMDAR encephalitis developed Pneumocystis carinii infection as a direct complication of
use of rituximab (Garcia-Moreno et al., 2016). Thus, clinicians should carefully balance the
benefits of immunotherapy and the risk of infection when determining treatment strategies.
MODS, sepsis, and organ failure are frequent causes of death in patients with anti-NMDAR
encephalitis (Chi et al., 2017); therefore, it is important to manage these complications to
improve the survival rates of patients with anti-NMDAR encephalitis.
3.5 Pregnant Patients
Information regarding pregnant women with anti-NMDAR encephalitis is limited, and there is
no consensus on appropriate treatment strategies. To date, no more than 20 cases have been
reported in the literature (Chan et al., 2015; Grewal et al., 2018; Ito et al., 2010; Jagota
et al., 2014; Kalam et al., 2019; Keskin et al., 2019; Kim et al., 2015; Kumar et
al., 2010; Lamale-Smith et al., 2015; Lu et al., 2015; Magley et al., 2012; Mathis
et al., 2015; McCarthy et al., 2012; Shahani, 2015; Xiao et al., 2017). The first
description of a pregnant patient with this disorder was a 19-year-old female in her 2nd trimester
(Ito et al., 2010). This patient had a normal delivery and was discharged without sequelae
after treatment with high-dose methylprednisolone. The embryo or placenta may have triggered an
antigenic signal, resulting in an inappropriate immunological response (Ito et al., 2010);
furthermore, the effects of estrogen on antibody production and inhibition of T cell expression
may have exacerbated the disease during pregnancy (Peery et al., 2012). Two case series of
pregnant patients with anti-NMDAR encephalitis (Kalam et al., 2019; Shi et al., 2017)
showed that first-line immunotherapy and teratoma resection may be effective, and that recovery
was accelerated after delivery or termination of the pregnancy. Although some patients responded
to second-line treatments when the first-line immunotherapy failed (Shi et al., 2017),
cyclophosphamide (Acien et al., 2014) and rituximab should be avoided when the fetus is
viable owing to the risk of teratogenicity and premature delivery (Chakravarty et al., 2011)
unless potential benefit to the mothers’ health justifies the potential risk to the fetus (Chourasia
et al., 2018).
Among previously described cases, most infants were healthy, except for two fetuses with
neurological sequelae, and three cases of miscarriage and abortion. However, long-term follow-up
of these neonates is needed, as NMDAR plays an important role in brain development.
Furthermore, transplacental transfer of maternal antibodies in newborns has been reported
(Chourasia et al., 2018; Hilderink et al., 2015; Jagota et al., 2014). Jagota et al.
reported a pregnant patient whose baby tested positive for serum NMDAR antibody and suffered
from delayed cognitive development and seizures (Jagota et al., 2014). Recently, Chourasia et
al. also described an infant with elevated NMDAR antibodies (1:320) who exhibited poor
respiratory effort, poor feeding, and abnormal movements after birth. The mother had experienced
anti-NMDAR encephalitis 18 months earlier. This case highlights the importance of routine
testing of antibodies in pregnant female with a previous history of this disorder (Chourasia et
al., 2018).
4. Prognosis
Younger age is associated with better outcomes (Zhang and Fang, 2018). Although symptoms
are less severe in older patients, the prognosis for patients older than 45 is worse than that for
younger patients, which may result from delays in diagnosis and treatment, and greater likelihood
of having malignant tumors (Titulaer et al., 2013; Wang et al., 2016b). For children and
adolescents, being older than 12 years of age was a predictor of better outcomes, and an initial
modified Rankin scale (mRS) score of less than 3 was a predictor of complete recovery
(Zekeridou et al., 2015). Outcomes were similar for females and males (Viaccoz et al.,
2014).
Another study showed that prognosis was associated with the severity of the disease. Milder
symptoms, defined as requiring no intensive care, were an independent predictor of good
prognosis (Titulaer et al., 2013; Titulaer et al., 2013; Wang et al., 2019). Chi et
al. showed that a Glasgow Coma Scale score ≤ 8 at admission, number of complications, and
admission to an intensive care unit (ICU) were significantly associated with increased risk of
death (Chi et al., 2017).

High antibody titers are associated with negative outcomes (Dalmau et al., 2008a; Irani et
al., 2010b; Suhs et al., 2015; Titulaer et al., 2013). A multi-center study focusing on
antibodies in 250 serum and CSF samples showed that patients were likely to have better
outcomes if their antibody titers decreased within the first month, and titer changes in CSF were
more closely associated with relapses than titer changes in serum (Gresa-Arribas et al.,
2014). Most patients still have anti-NMDAR antibodies in the serum and CSF several months, or
years, after treatment. Several new potential prognostic biomarkers for anti-NMDAR encephalitis
have been reported, such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial (mt)
DNA, interleukin (IL)-17, YKL-40 (Chitinase 3-like 1), Neuron-specific enolase (NSE) and S100
calcium-binding protein B (S100B). Patients with high levels of these potential biomarkers in the
CSF are more likely to respond poorly to immunotherapy (Chen et al., 2018; Leypoldt et al.,
2015; Liu et al., 2018; Peng et al., 2019; Zeng et al., 2018). Most of these biomarkers
are associated with the underlying inflammatory process in patients, and with clinical mRS scores.
For instance, innate as well as adaptive immune system are involved in the pathomechanism of
anti-NMDAR encephalitis(Bauer et al., 2012), mtDNA is associated with the innate immune
system, since it is a damage-associated molecular pattern molecule that can initiate
inflammatory responses(Zhang et al., 2010). Potential inflammatory processes (viral, or yet
unknown) may trigger CXCL13-mediated B-cell attraction and lead to the development of
anti-NMDAR encephalitis(Leypoldt et al., 2015).
Iizuka et al. reported that cerebellar atrophy may be associated with prognosis. In a cohort of
fifteen patients, five presented with diffuse cerebral atrophy (DCA) on MRI. Although they had
more serious complications than those without DCA, DCA was reversible; further, DCA without
cerebellar atrophy did not correlate with adverse outcomes. In contrast, cerebellar atrophy was
irreversible and associated with a poor prognosis (Iizuka et al., 2016). In 2016, Titulaer
further suggested that cerebellar atrophy might be a complication of the disease. In two previous
cases with cerebellar atrophy reported by Iizuka et al, one patient experienced multiple cardiac
arrests and the other developed multiple organ failure, both of which can result in hypoxia
(Titulaer, 2016).
Early initiation of treatment is a predictor of good outcomes (DeSena et al., 2014). In one
multi-center observational cohort study of 577 patients, Titulaer et al. showed that early
immunotherapy may result in improved clinical outcomes (Titulaer et al., 2013). Another
study in Europe found that patients who were administered no immunotherapy, or treated more
than 40 days after the onset of illness, experienced significantly worse outcomes than those treated
within 40 days (Irani et al., 2010b). Moreover, Byrne et al. reported five children with
anti-NMDAR encephalitis who received immunotherapy within one week after onset (Byrne et
al., 2014). Four of these children had recovered completely at follow-up. A prospective
surveillance study by Wright et al. showed that patients with earlier diagnosis (within eight weeks)
had better outcomes than patients diagnosed later (more than six months) (Wright et al., 2015).
This result has been confirmed by many other studies (Lim et al., 2014; Moussa et al., 2019;
Titulaer et al., 2013). Early immunotherapy is also associated with better long-term
prognosis. Finke et al. studied the cognitive deficits in nine patients during the rehabilitation
process, and found that patients that received delayed treatment had more severe deficits (Finke
et al., 2012). However, owing to the wide range of clinical presentations, diagnosis of
anti-NMDAR encephalitis is challenging. Furthermore, the identification of NMDAR antibodies

in serum or CSF may take a long time which means the diagnosis may be delayed (Titulaer et
al., 2013). As such, more sensitive diagnostic tests are needed. Conventional tests such as MRI,
EEG, and FDG-PET may be potential techniques to decide early treatment strategies for probable
patients (Graus et al., 2016).
Taken together, antibody titers, CXCL13, and cerebellar atrophy may not be early or sensitive
markers; mtDNA, IL-17, YKL-40, NSE and S100B may present early biomarkers for the
identification of patients who need treatment. However, these biomarkers require further
validation. Recently, Balu et al. constructed a grading score, anti-NMDAR Encephalitis One-Year
Functional Status (NEOS) score, to predict patients’ neurologic function 1 year after diagnosis of
anti-NMDAR encephalitis, which may help to identify patients in poor functional status(Balu et
al., 2019). Delays in treatment may be reduced with more sensitive diagnostic tools for this
disorder. Further development of these tools is necessary to improve outcomes associated with
anti-NMDAR encephalitis.
During long-term follow-up, some patients with good outcomes can still manifest executive
dysfunction, cognitive defects, and visual dysfunction. The proportion of patients with these
deficits ranged from 27.3% to 85% (Brandt et al., 2016; Dalmau et al., 2008a; Dalmau et
al., 2011; Hinkle et al., 2017; Titulaer et al., 2013). Studies of deficits in patients with
anti-NMDAR encephalitis showed that severe deficits were more likely to occur in cases of
delayed immunotherapy, the presence of occult tumour, or in patients with higher likelihood of
tumour recurrence (Dalmau et al., 2008a; Ishiura et al., 2008; Titulaer et al., 2013).
(Brandt et al., 2016)

The recurrence rate ranged from 12% to 29%, with a median interval of 2 years (Dalmauetal.,
2008a; Dalmau et al., 2011; Irani et al., 2010b). Relapses were usually less severe than
the first episodes and did not result in additional deficits(Graus et al., 2016). Less relapses
were admitted in the intensive care unit, compared with patients at the first episode(Gabilondo et
al., 2011). Patients with delayed or insufficient immunotherapy (no or suboptimal
immunotherapy) during the first episode and patients without an underlying tumor were more
likely to relapse (Staley et al., 2019; Titulaer et al., 2013). For patients who had previous
relapses, second-line immunotherapy may have decreased the potential for further relapses (Graus
et al., 2016; Irani et al., 2010b; Titulaer et al., 2013). To prevent relapse, Dalmau
et al. recommend maintenance treatment with mycophenolate or azathioprine for at least one year
in patients without tumors (Dalmau et al., 2011). A study investigating maintenance treatment
in children found that no patients relapsed after various maintenance regimens including steroids,
IVIG, mycophenolate, rituximab, and cyclophosphamide. However, half of these patients had
severe complications, ranging from severe headache to sepsis (Brenton et al., 2016). Another
study of thirteen children who received pulse steroids every month as maintenance treatment
showed that three patients relapsed when treatments were discontinued, but all patients recovered
without severe complications after restarting therapy (Nagappa et al., 2016). More studies are
needed to elucidate the long-term effects of immunotherapy and predictive factors for relapse.
5. Conclusion
Although the majority of patients with anti-NMDAR encephalitis achieve favorable outcomes,
those who received delayed or insufficient immunotherapy consistently experienced worse
outcomes and were more prone to relapse. There is a need for sensitive diagnostic methods to
enable early identification of this disease. In addition, current treatment strategies focus primarily
on removal of antibodies in the periphery. However, antibodies present in the central nervous
system are responsible for disease pathogenesis, which may explain why patients with
anti-NMDAR encephalitis often require long hospital stays. Some drugs, such as bortezomib,
azathioprine, and mycophenolate mofetil have been reported to be beneficial for patients who do
not respond to tumor resection and immunosuppressive therapy; however, the effects of these
medications have not been systematically verified in large cohorts. Additional studies are required
to identify more effective treatment strategies. For patients with long-term sequelae, appropriate
rehabilitation methods and improved strategies for the prevention of and monitoring for relapse
are of critical importance.
Acknowledgments
Jian Wang helped illustrate the review.
Funding
This work was supported by the National Natural Science Foundation of China (Grant
No.81271298); and the Hunan Provincical Science and Technology Department in China (Grant
No.2007SK3038)
Declarations of interest
None
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Fig1. Possible pathogenic mechanisms of anti-NMDAR encephalitis (A )
N-methyl-D-aspartate receptors (NMDARs) released by tumors and viral infected neurons are
taken up by antigen presenting cells(APCs) after apoptosis occurs. APCs migrate to local lymph
nodes, and with the cooperation of CD4+ T cells, naive B cells in lymph nodes become memory B
cells and differentiate into plasma cells.These cells and anti-NMDAR antibodies produced by
peripheral plasma cells enter the brain, and immune cells such as B cells further undergo
stimulation and differentiation. (B) In patients, anti-NMDAR antibodies bind to the GluN1
subunits of synaptic and extrasynaptic NMDARs. This disrupts the interaction between NMDAR
and ephrin type B2 (EphB2) receptor, resulting in decreased NMDAR and neuronal hypoactivity.
But, antibodies can sometimes increase the opening of synaptic receptors before internalization
which may explain the seizures.
Table1. Treatment of anti-NMDAR encephalitis
Treatment indication
high-dose steroids (target B and T cells) first-line treatment
intravenous gamma globulin(target
antibodies)
plasma exchange (target antibodies)
tumors resection, if removable (target
immune triggers)
rituximab (target B cells) second-line immunotherapy
cyclophosphamide (target B and T cells)
tocilizumab (target IL-6) potentially useful
alemtuzumab (target B and T cells)
methotrexate
bortezomib (target B cells)
azathioprine
mycophenolate mofetil
benzodiazepines (BZDs) catatonia
electroconvulsive therapy (ECT)
typical antipsychotics agitation, hallucination and delusion
phenobarbital
clonidine, dexmedetomidine
lithium and valproic acid manic symptoms
BZDs movement disorders
levodopa-carbidopa, central anticholinergics
(benztropine ; benzhexol ), oral baclofen,
amantadine, and bromocriptine
valproic acid (choreiform movements and
dyskinesia), phenobarbital, and carbamazepine
clonidine (stereotypicalmovements) , dexme-
detomidine, and chloralhydrate
BZDs seizures
levetiracetam, phenobarbital, topiramate,
lamotrigine, valproic acid, phenytoin, and
carbamazepine
propofol and midazolam (status epilepticus)
BZDs sleep disruption
chloralhydrate, clonidine, melatonin,
ketamine, trimeprazine, dexmedetomidine,
zopiclone, and promethazine
mechanical ventilation central hypoventilation
atropine, isoprenaline, asystole
pacemaker replacement
glycopyrrolate, hyoscine patches hypersalivation
Red: benzodiazepines (BZDs); Yellow: anticonvulsants (in addition to BZDs) which can treat
multiple symptoms; Blue: sedatives and sleep medications (in addition to BZDs) which can treat
multiple symptoms
Anti-N-methyl-D-aspartate receptor encephalitis: a review of
pathogenic mechanisms, treatment and prognosis
Qianyi Huanga, Yue Xieb, Zhiping Hua, Xiangqi Tanga*

aDepartment of Neurology, The Second Xiangya Hospital, Central South University, Changsha,
Hunan 410011, China
bDepartment of Neurology, The Xiangya Hospital, Central South University, Changsha, Hunan
410011, China
*Corresponding Author: Xiangqi Tang
Department of Neurology, The Second Xiangya Hospital, Central South University
Renmin Road 139#, Changsha, Hunan 410011, China
Tel: +86 13875807186 Fax: 0731-84896038 Email: txq6633@csu.edu.cn
Abstract
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune
disorder characterized by prominent neuropsychiatric symptoms that predominantly affects
children and young adults. In this review, we discuss the pathogenic mechanisms and
immunologic triggers of anti-NMDAR encephalitis, and provide an overview of treatment and
prognosis of this disorder, with specific focus on the management of common symptoms,
complications, and patients during pregnancy. Most patients respond well to first-line treatment
and surgical resection of tumors. When first-line immunotherapy fails, second-line
immunotherapy can often improve outcomes. In addition, treatment with immunomodulators and
tumor resection are effective treatment strategies for pregnant patients. Benzodiazepines are the
preferred treatment for patients with catatonia, and electroconvulsive therapy (ECT) may be
considered when pharmacological treatment is ineffective. Age, antibody titer, cerebellar atrophy,
levels of biomarkers such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial
(mt)DNA in cerebral serum fluid (CSF), and treatment time are the main prognostic factors.
Patients without tumors or those who receive insufficient immunotherapy during the first episode
are more likely to relapse.
Keywords: anti-N-methyl-D-aspartate receptor encephalitis; pathogenic mechanism; treatment;
prognosis; immunotherapy
Contents
1. Introduction
2.1 NMDARs
2.2 Pathogenic mechanisms
3.Treatment
3.1 Tumors
3.2 Immunotherapy

3.4 Complications
3.5 Patients with pregnancy
4.Prognosis
5.Conclusion
6. Introduction
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common
autoimmune encephalitis (Dalmau and Graus, 2018). It was first described in 2005 (Vitaliani
et al., 2005), and its autoantigens were discovered by Dalmau et al. in 2007 in a cohort of 12
female patients (14-44 years), most of whom had ovarian teratomas (Dalmau et al., 2007).
Since the first reported cases of anti-NMDAR encephalitis, it has been widely studied.
Epidemiologic studies suggest that it primarily affects young patients with median age of 21 years
(Tanguturi et al., 2019a); however, it can also occur in older individuals. Anti-NMDAR
encephalitis has a higher incidence among females (75%) at younger ages, but after the age of 45
the male-to-female ratio is more balanced (Tanguturi et al., 2019a).
The pathophysiology of anti-NMDAR encephalitis is thought to involve antibodies aganist the
NR1 subunit of N-methyl-D-aspartate receptor (NMDAR), which causes reversible internalization
of the receptor in neurons (Hughes et al., 2010). NMDAR is an ionotropic receptor that plays a
crucial role in neuroplasticity, synaptic transmission, memory, learning, and human behavior
(Dalmau et al., 2008a; Kuppuswamy et al., 2014). Excitotoxicity due to overactivity of

NMDAR is associated with epilepsy, dementia, stroke, and chronic disorders such as Huntington's
disease and Parkinson's disease. Decreased NMDAR activity can cause symptoms similar to those
observed in schizophrenia, autism, and other disorders that mimic anti-NMDAR encephalitis
(Schade and Paulus, 2016; Waxman and Lynch, 2005).
Management of anti-NMDAR encephalitis has focused on detection and removal of tumors and
immunotherapy. First-line treatments include high-dose steroids, intravenous gamma globulin
(IVIG), and plasma exchange (PE). Rituximab and cyclophosphamide are often used as
second-line immunotherapies (Dalmau et al., 2011).
Anti-NMDAR encephalitis has better outcomes than other forms of encephalitis.
Approximately 66-80% of patients recover nearly all baseline neurological function. However,
some patients suffer from severe deficits such as neuropsychiatric or cognitive deficits, or death
(Dalmau et al., 2008b; Dalmau et al., 2011; Irani et al., 2010; Lim et al., 2014;
Titulaer et al., 2013). Approximately 12-25% of patients experience relapse (Dalmau et al.,
2008b; Dalmau et al., 2011; Irani et al., 2010; Titulaer et al., 2013; Wang et al.,
2016a).
Although many observational studies have been reported, no randomized controlled trials have
been performed to date. Furthermore, most studies have focused on immunotherapy and treatment
of patients refractory to therapy. However, studies have not focused on treatment of complications
or common symptoms, which will be discussed in detail.
2.1 NMDARs
NMDARs are slow, ionic glutamate receptors (iGluRs). Glutamate receptors (GluRs) include
ionotropic glutamate receptors (iGluRs) and metabotropic G protein-coupled receptors (mGluRs),
and are the main excitatory receptors in the central nervous system (Traynelis et al., 2010).
Functional adult neuronal NMDARs are heteromeric complexes composed of two GluN1 subunits
and two GluN2 subunits (Waxman and Lynch, 2005). NR1 subunits bind to glycine, and NR2
subunits bind glutamate. GluN1 is expressed as eight different isoforms (GluN1–1a to 4a and
GluN1–1b to 4b), while GluN2 is expressed as four isoforms (GluN2A–GluN2D) (Regan et
al., 2015). NR1 and NR2 subunits share a common structure, with a middle region containing
four transmembrane domains (M1–M4), a reentrant membrane loop between the M3 and M4
domains, a long extracellular N-terminal ligand-binding region, and an intracellular C-terminal
region.
2.2 Pathogenic mechanisms (Fig1)
It is widely accepted that the main pathogenic mechanisms underlying anti-NMDAR
encephalitis involves the binding of auto-antibodies to the GluN1 subunit of NMDAR. In
anti-NMDAR encephalitis, antibodies against extracellular epitopes of cell-surface proteins can
alter the structure and function of receptors, resulting in the clinical syndrome. However, in
paraneoplastic encephalitis, the antibodies cannot reach intracellular epitopes; cytotoxic T-cells,
instead of B cells, are believed to play a role in the pathogenesis of anti-NMDAR encephalitis
(Dalmau and Graus, 2018).
Anti-NMDAR encephalitis occurs in patients as a result of two potential immunologic triggers:
tumors and viral infection. It is believed that the antigen (NMDAR), which is expressed in
nervous tissue-containing tumors (typically ovarian teratoma), or released by viral-induced

neuronal disruption, is directly transported to the local lymph nodes in soluble form or taken up by
antigen-presenting cells (APCs), resulting the generation of memory B cells (Dalmau, 2016).
With the cooperation of CD4+ T cells, naive B cells exposed to NMDAR become activated and
are able to cross the blood-brain barrier via the choroid plexus. After reaching the central nervous
system, these activated B cells (memory B cells) undergo further stimulation, antigen-driven
maturation, and clonal expansion, finally differentiating to anti-NMDAR antibody-producing
plasma cells (Dalmau, 2016). However, in about half of these patients, the immunologic triggers
are still unknown.
Antibodies against the NMDARs typically cause selective crosslinking and internalization of
NMDARs (Hughes et al., 2010; Moscato et al., 2014), which may be related to disruption
of the interaction between NMDAR and ephrin type B2 (EphB2) receptor, a receptor stabilizes
NMDAR at the synapse (Mikasova et al., 2012; Planaguma et al., 2016). A study showed
that EphB2 could protect rats from damages caused by antibodies isolated from patients, as
demonstrated by antibodies from the CSF of patients with anti-NMDAR encephalitis or human
recombinant antibody rebuilt from expanded CSF plasma cells (Malviya et al., 2017;
Planaguma et al., 2015). After internalization, the antibody-bound NMDARs were trafficked
through recycling endosomes and lysosomes (Moscato et al., 2014).
Recently, it was shown that antibodies isolated from patients appear to activate NMDAR,
resulting in a longer NMDAR channel open time before the internalization of NMDARs. This
finding and the core symptoms of anti-NMDARE encephalitis led Snyder et al. to advance a new
hypothesis (Lynch et al., 2018). Antibodies preferentially bind to open synaptic NMDARs
(often GluN2A-containing) at active excitatory synapses. In contrast, on active inhibitory neurons,

antibodies preferentially bind to open extrasynaptic NMDARs (commonly GluN2B-containing).
Excessive extrasynaptic NMDAR signaling can trigger seizures, dyskinesias, and catatonia;
seizures are as well associated with excessive synaptic NMDAR signaling. This hypothesis may
partly explain why patients experience seizures which can be triggered by NMDAR agonists in an
NMDAR hypofunction state.
The mechanisms of anti-NMDAR encephalitis have been mostly studied in cultured neurons or
in mice exposed to antibodies isolated from patients. These studies showed reductions in surface
and synaptic NMDAR density and NMDAR-mediated currents (Hughes et al., 2010; Moscato
et al., 2014). Recently, to characterize the specific molecular mechanisms of
autoantibody-induced NMDAR internalization, Amedonu et al. showed that the scaffold protein
postsynaptic density protein 95 (PSD-95) could stabilize NMDARs in the cell membrane
(Amedonu et al., 2019). However, further studies of the mechanisms of internalization are
required.
Patients often present with six main symptoms: including psychiatric symptoms or cognitive
dysfunction, seizure, speech dysfunction, movement disorder, decreased level of consciousness,
and autonomic dysfunction or central hypoventilation. Prodromal symptoms such as headache,
fever, nausea, and upper respiratory-tract symptoms are observed in many patients (Graus et
al., 2016). Irani et al. divided the disease process into two stages. In the early stage, patients
often present with psychiatric symptoms or cognitive dysfunction and seizures. In the late stage,
decreased level of consciousness, movement disorder, and autonomic dysfunction are most
common (Irani et al., 2010). There are some differences in symptoms in children and
adults with anti-NMDAR encephalitis. Typically, the early symptoms recognized in children are
often non-psychiatric, such as behavioral problems, seizure, speech dysfunction, and movement
disorders (Florance et al., 2009). In addition, psychiatric manifestations in children
include temper tantrums and hyperactivity or irritability, while adults often present with anxiety,
paranoid behaviors, and delusions. Dysautonomia is less likely to occur in children, but is more
severe than in adults (Florance et al., 2009). Compared with adult women, adult male
patients are more likely to present with seizure as the initial symptom (Viaccoz et al.,
2014), Furthermore, their clinical pattern of seizures is different than that of women, which may
be attributable to hormonal influences.
CSF examination often shows pleocytosis, with oligoclonal bands detected in some patients.
Electroencephalogram (EEG) shows focal or diffuse slow activity, epileptic activity, or extreme
delta brush, which is considered characteristic of anti-NMDAR encephalitis. Recently, Foff et al.
demonstrated that a novel EEG phenomenon, beta:delta ratio (BDR), may be specific to
anti-NMDA encephalitis (Foff et al., 2017). No special features are identified by magnetic
resonance imaging (MRI), and MRI scans are normal in 66% of patients with anti-NMDAR
encephalitis. According to an expert consensus advanced by Graus et al. in 2016, diagnosis may
be based on the presence of one or more of the six main symptoms and anti-GluN1 IgG antibodies
after reasonable exclusion of other disorders (Graus et al., 2016).
8. Treatment (Table1)
Although there are no international guidelines for treatment, a 2016 expert consensus on
diagnosis was reported in The Lancet Neurology. In the present work, treatment of anti-NMDAR
encephalitis was reviewed on the basis of a large number of observational studies and case series
reports, including multi-center studies.
3.1 Tumors
About 7.8% to 59% of patients with anti-NMDAR encephalitis have underlying tumors, which
are typically teratomas. Furthermore, patients with IgA NMDAR antibodies in the CSF may be
more likely to have teratomas (Desestret et al., 2015). In children and males, the frequency
of tumors is lower and the histology is different from that in females. For example, other tumors
such as lung carcinoma, testicular carcinoma, breast carcinoma, colon carcinoma, and ectopic
teratomas have also been reported, but are mostly seen in males or older patients (Florance et
al., 2009; Titulaer et al., 2013). For patients with tumors who are candidates for surgery,
resection of tumors can accelerate improvement and decrease the chance of relapses (Iizuka et
al., 2008; Sabin et al., 2008). As such, it is important to investigate for an underlying
neoplasm once diagnosis is confirmed.
3.2 Immunotherapy
Anti-NMDAR encephalitis is considered an auto-immune response within the central nervous
system; therefore, emphasis is often placed on various forms of immunotherapy that target the
production of antibodies, reducing their effects on receptors (Tanguturi et al., 2019a). Good
outcomes have been achieved in 53-80% of patients using first-line immunotherapy alone, which
includes high-dose steroids (such as methylprednisolone), IVIG, and PE (Titulaer et al.,
2013). For patients who do not respond to first-line immunotherapy, it is widely accepted that
second-line immunotherapy (rituximab or cyclophosphamide) can improve outcomes (Ishiura

Although no systematic comparisons of the three first-line immunotherapy options have been
performed, early initiation of PE prior to IVIG may provide better outcomes. A long-term
follow-up conducted by Pham et al. showed that patients treated with IVIG after PE had better
outcomes than those who received IVIG prior to PE (Pham et al., 2011). In addition, PE can
remove the autoantibodies quickly, resulting in rapid symptomatic improvement in severe cases of
anti-NMDAR encephalitis. Because patients with severe anti-NMDAR encephalitis may suffer
from autonomic instability, it is important to evaluate whether they can tolerate PE procedures,
and their vital signs must be closely monitored during therapy. Recently, a study divided patients
with severe refractory anti-NMDAR encephalitis into a PE group and a non-PE group. The PE
group showed greater improvement in clinical symptoms than the non-PE group after 1 month and
2 months following treatment (Zhang et al., 2019), suggesting that early use of PE may be a
better treatment option. In pediatric anti-NMDAR encephalitis, early administration of PE and a
combination of PE and steroids both resulted in good outcomes (Suppiej et al., 2016). To
compare steroids and PE, DeSena et al. retrospectively evaluated 10 patients who were treated
with steroids and PE in succession. Only three of the patients showed improvements immediately
after steroid therapy, but seven of these patients improved immediately following PE use (DeSena
et al., 2015), which suggested that treatment with corticosteroids may not be as effective as
treatment with steroids followed by PE.
Combination immunotherapy may result in better outcomes than mono-immunotherapy. Wang
et al. classified treatments into four categories: IVIG; PE; rituximab or cyclophosphamide; and
tumor resection, and found that the combination of at least two therapies resulted in better
outcomes than monotherapy (Wang, 2016). A large retrospective study in Europe also found that
there was a trend toward better outcomes when glucocorticosteroids were used in combination
with at least one other immunotherapy (Irani et al., 2010).
For patients who fail to respond to surgery or first-line and second-line immunotherapy,
treatment with monoclonal antibodies such as tocilizumab or alemtuzumab combined with
methotrexate may be effective. Bortezomib and antimetabolites such as azathioprine and
mycophenolate mofetil may also be effective (Bartolini and Muscal, 2017). Tocilizumab, an
anti-interleukin 6 antibody, induced better therapeutic effects in patients refractory to first- and
second-line treatments than additional rituximab treatment or no follow-up therapy in a small
cohort (Lee et al., 2016). Liba and colleagues treated an eight-year old patient who did not
respond to various immunotherapies with alemtuzumab (an anti-CD52 antibody that reduces
numbers of memory B cells and T cells) and intrathecal methotrexate. The patient improved
rapidly, suggesting that this combination treatment was effective (Liba et al., 2013). Several
case series have suggested that bortezomib, a proteasome inhibitor that depletes plasma cells, may
be effective for treatment of patients with severe anti-NMDAR encephalitis (Keddie et al.,
2018; Scheibe et al., 2017; Schroeder et al., 2018; Shin et al., 2018). Sveinsson
et al. also described an extremely severe case in which the patient received repeated
cyclophosphamide, tocilizumab, and bortezomib, which led to remission, after rituximab, bilateral
oophorectomy, and repeated cycles of high-dose steroids and PE (Sveinsson et al., 2017).
Although the majority of patients experience good outcomes in response to immunotherapy, the
response to first-line immunotherapy is often slow (Florance-Ryan and Dalmau, 2010), and
blood-brain barrier may affect the efficacy of PE or IVIG (Tanguturi et al., 2019b), or other
promising therapeutic drugs such as alemtuzumab. Further studies are needed to identify more
effective treatments.
Although immunotherapy is the primary treatment for anti-NMDAR encephalitis, psychiatric
symptoms often require additional treatment. Patients with anti-NMDAR encephalitis typically
present with neuropsychiatric symptoms such as agitation, hallucination, delusion, mood lability,
manic depression and catatonic syndromes.
Benzodiazepines (BZDs), typically lorazepam are the first choice for treatment of catatonia
(Fink, 2013). In addition, BZDs have been shown to strengthen the function of
gamma-aminobutyric acid (GABA) inter-neurons, which are thought to be hypofunctional in
anti-NMDAR encephalitis (Manto et al., 2010). If BZD treatment is ineffective, it is important
to shift quickly to electroconvulsive therapy (ECT), and the combination of lorazepam with ECT
may be superior to BZD treatment alone (Petrides et al., 1997). ECT has been performed in
psychiatric practice for more than 50 years. However, routine use of ECT in adolescent
populations is limited. Fear of adverse side effects resulting from ECT and laws regulating use of
ECT in adolescents vary from state to state, which limits uniform implementation (Wilson et al.,
2013). However, ECT is generally regarded as a safe and effective treatment, and may save the
lives of patients suffering from malignant catatonia (Moussa et al., 2019; Zaw, 2006). A recent
systematic review found improvement in 65.2% of 30 cases with refractory psychiatric symptoms
(primarily catatonia) who received ECT (Warren et al., 2019). In addition, ECT is equally
effective in children and adults, with the same indications and contraindications (Zaw, 2006).
Furthermore, ECT is effective for treatment of neuroleptic malignant syndrome (NMS), status
epilepticus, and dyskinesias (Warren et al., 2019). The therapeutic mechanisms of ECT are
unclear. In rat models, ECT has been demonstrated to increase NMDAR levels in the brain, which
may explain why ECT is an effective treatment for anti-NMDAR encephalitis (Watkins et al.,
1998). Furthermore, ECT can increase GABA concentrations (Sanacora et al., 2003), which
are decreased in anti-NMDAR encephalitis (Manto et al., 2010).
For patients with agitation, atypical sedating antipsychotics (such as olanzapine) are preferable
because they induce fewer side effects, such as NMS and extrapyramidal symptoms (EPS), which
can worsen agitation (Kayser and Dalmau, 2011). Moreover, olanzapine has been shown to
prevent toxicity associated with NMDAR antagonists in animal experiments. Clonidine may help
reduce agitation through regulation of the autonomic nervous system (Scharko et al., 2015).
Typical and atypical antipsychotics have been administered alone or in combination to treat
hallucination and delusion (Kuppuswamy et al., 2014). Lithium and valproic acid are primarily
used to control manic symptoms. Owing to its anti-epileptic and mood stabilizing properties,
valproic acid can be used to effectively treat mood symptoms. Furthermore, valproic acid can be
used to treat choreiform movements and dyskinesia, which are commonly observed in
anti-NMDAR encephalitis (Scharko et al., 2015).
It should be noted that treatment of psychiatric symptoms often requires multiple psychotropic
drugs, which may be associated with increased risk of side effects such as NMS, which is
characterized by rigidity, fever, and mutism or coma (Lejuste et al., 2016). However, these
symptoms have also been observed in many patients who were not treated with psychotropic
drugs, and may represent the natural progression of this disorder (Berg et al., 2015; Warren et
al., 2018). So it’s important to identify the constellation of symptoms so that the appropriate
treatments can be administered.
Mohammad and colleagues performed a retrospective study of symptomatic management in
children. They proposed five medications for the treatment of movement disorders, seven
anticonvulsants for for the treatment of seizures, and eight sedatives and sleep medications for the
treatment of sleep disruption. Their study showed that long-acting BZDs, anticonvulsants and
sedatives such as clonidine can treat multiple symptoms including agitation, seizures, movement
disorders, sleep disruption, and psychiatric symptoms (Mohammad et al., 2016). These findings
may guide the choice of medications to treat these symptoms.
Antiepileptic drugs such as levetiracetam, phenobarbital, topiramate, lamotrigine, valproic acid,
phenytoin, and carbamazepine are commonly used to treat definite or suspected seizures.
Anesthetic agents, such as propofol and midazolam, may be required in patients with status
epilepticus. EEG monitoring is of great significance for diagnosis of patients with nonconvulsive
status epilepticus (NCSE), as well as for differential diagnosis of dyskinesia and seizure (Dalmau
Medications used specifically for the treatment of movement disorders include
levodopa-carbidopa, central anticholinergics (benztropine; benzhexol), oral baclofen, amantadine,
and bromocriptine (Mohammad et al., 2016); however, these are less effective than BZDs.
Patients with anti-NMDAR encephalitis may experience central hypoventilation that requires
tracheotomy or mechanical ventilation, which is a frequent cause of admission into intensive care
unit (Dalmau et al., 2008a; Titulaer et al., 2013). The percentage of patients who
experience central hypoventilation ranges from 9.4% to 66% , and is linked to age, ethnicity and
the presence of tumor. Children, Asian patients and patients without tumors are less likely to
develop central hypoventilation (Florance et al., 2009; Irani et al., 2010; Lim et al.,
2014; Titulaer et al., 2013; Wang et al., 2016a).
Autonomic dysfunction is common in the the acute phase of anti-NMDAR encephalitis, and
manifests as tachycardia, bradycardia, desudation, hypersalivation, and blood pressure liability
(Dalmau et al., 2011; Florance et al., 2009; Titulaer et al., 2013). Children are less
likely to present with severe dysautonomia. In one retrospective case-control study, Byun et al.
found that cardiac autonomic dysfunction primarily resulted from disruption of the sympathetic
nervous system, and was associated with poor prognosis (Byun et al., 2015). Some patients
may require cardiopulmonary resuscitation (CPR) and pacemaker installation due to asystole
(Dalmau et al., 2011; Florance et al., 2009; Mehr et al., 2016). In general, it is important
to recognize and treat dysautonomia owing to the increased risk of arrhythmia, cardiac arrest, and
abnormal blood pressure which may be life-threatening.
3.4 Complications
Extensive research has focused on the diagnosis and treatment of anti-NMDAR encephalitis.
However, studies that investigate the treatment of complications are rare. Common complications
of this disorder include infection (pneumonia, urinary tract infection, and acute severe
pancreatitis), gastrointestinal disorders, gastrointestinal hemorrhage, multiple organ dysfunction
syndrome (MODS), respiratory failure, shock (septic shock, hypovolemic shock), electrolyte
disorders, hypo-albuminemia, thrombocytopenia, and rash (Chi et al., 2017; Huang et al.,
2016; Jiang et al., 2018). A cohort study demonstrated that severe pneumonia, the most
common complication, was one of the main causes of death resulting from this disease (Chi et
al., 2017). Being bedridden for long durations, intubation, and immunosuppressor treatment
may contribute to increased rates of infection and sepsis. An 11-month-old male patient with
anti-NMDAR encephalitis developed Pneumocystis carinii infection as a direct complication of
use of rituximab (Garcia-Moreno et al., 2016). Thus, clinicians should carefully balance the
benefits of immunotherapy and the risk of infection when determining treatment strategies.
MODS, sepsis, and organ failure are frequent causes of death in patients with anti-NMDAR
encephalitis (Chi et al., 2017); therefore, it is important to manage these complications to
improve the survival rates of patients with anti-NMDAR encephalitis.
3.5 Patients with pregnancy
Information regarding pregnant women with anti-NMDAR encephalitis is limited, and there is
no consensus on appropriate treatment strategies. To date, no more than 20 cases have been
reported in the literature (Chan et al., 2015; Grewal et al., 2018; Ito et al., 2010; Jagota
et al., 2014; Kalam et al., 2019; Keskin et al., 2019; Kim et al., 2015; Kumar et
al., 2010; Lamale-Smith et al., 2015; Lu et al., 2015; Magley et al., 2012; Mathis
et al., 2015; McCarthy et al., 2012; Shahani, 2015; Xiao et al., 2017). The first
description of a pregnant patient with this disorder was a 19-year-old female in her 2nd trimester
(Ito et al., 2010). This patient had a normal delivery and was discharged without sequelae
after treatment with high-dose methylprednisolone. The embryo or placenta may have triggered an
antigenic signal, resulting in an inappropriate immunological response (Ito et al., 2010);
furthermore, the effects of estrogen on antibody production and inhibition of T cell expression
may have exacerbated the disease during pregnancy (Peery et al., 2012). Two case series of
pregnant patients with anti-NMDAR encephalitis (Kalam et al., 2019; Shi et al., 2017)
showed that first-line immunotherapy and teratoma resection may be effective, and that recovery
was accelerated after delivery or termination of the pregnancy. Although some patients responded
to second-line treatments when the first-line immunotherapy failed (Shi et al., 2017),
cyclophosphamide (Acien et al., 2014) and rituximab should be avoided when the fetus is
viable owing to the risk of teratogenicity and premature delivery (Chakravarty et al., 2011)
unless potential benefit to the mothers’ health justifies the potential risk to the fetus (Chourasia
et al., 2018).
Among previously described cases, most infants were healthy, except for two fetuses with
neurological sequelae, and three cases of miscarriage and abortion. However, long-term follow-up
of these neonates is needed, as NMDAR plays an important role in brain development.
Furthermore, transplacental transfer of maternal antibodies in newborns has been reported
(Chourasia et al., 2018; Hilderink et al., 2015; Jagota et al., 2014). Jagota et al.
reported a pregnant patient whose baby tested positive for serum NMDAR antibody and suffered
from delayed cognitive development and seizures (Jagota et al., 2014). Recently, Chourasia et
al. also described an infant with elevated NMDAR antibodies (1:320) who exhibited poor
respiratory effort, poor feeding, and abnormal movements after birth. The mother had experienced
anti-NMDAR encephalitis 18 months earlier. This case highlights the importance of routine
testing of antibodies in pregnant female with a previous history of this disorder (Chourasia et
al., 2018).
9. Prognosis

Younger age is associated with better outcomes (Zhang and Fang, 2018). Although symptoms
are less severe in older patients, the prognosis for patients older than 45 is worse than that for
younger patients, which may result from delays in diagnosis and treatment, and greater likelihood
of having malignant tumors (Titulaer et al., 2013; Wang et al., 2016b). For children and
adolescents, being older than 12 years of age was a predictor of better outcomes, and an initial
modified Rankin scale (mRS) score of less than 3 was a predictor of complete recovery
(Zekeridou et al., 2015). Outcomes were similar for females and males (Viaccoz et al.,
2014).
Another study showed that prognosis was associated with the severity of the disease. Milder
symptoms, defined as requiring no intensive care, were an independent predictor of good
prognosis (Titulaer et al., 2013; Titulaer et al., 2013; Wang et al., 2019). Chi et
al. showed that a Glasgow Coma Scale score ≤ 8 at admission, number of complications, and
admission to an intensive care unit (ICU) were significantly associated with increased risk of
death (Chi et al., 2017).
High antibody titers are associated with negative outcomes (Dalmau et al., 2008a; Irani et
al., 2010; Suhs et al., 2015; Titulaer et al., 2013). A multi-center study focusing on
antibodies in 250 serum and CSF samples showed that patients were likely to have better
outcomes if their antibody titers decreased within the first month, and titer changes in CSF were
more closely associated with relapses than titer changes in serum (Gresa-Arribas et al.,
2014). Most patients still have anti-NMDAR antibodies in the serum and CSF several months, or
years, after treatment. Several new potential prognostic biomarkers for anti-NMDAR encephalitis
have been reported, such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial (mt)
DNA, interleukin (IL)-17, YKL-40 (Chitinase 3-like 1), Neuron-specific enolase (NSE) and S100
calcium-binding protein B (S100B). Patients with high levels of these potential biomarkers in the
CSF are more likely to respond poorly to immunotherapy (Chen et al., 2018; Leypoldt et al.,
2015; Liu et al., 2018; Peng et al., 2019; Zeng et al., 2018). Most of these biomarkers
are associated with the underlying inflammatory process in patients, and with clinical mRS scores.
Iizuka et al. reported that cerebellar atrophy may be associated with prognosis. In a cohort of
fifteen patients, five presented with diffuse cerebral atrophy (DCA) on MRI. Although they had
more serious complications than those without DCA, DCA was reversible; further, DCA without
cerebellar atrophy did not correlate with adverse outcomes. In contrast, cerebellar atrophy was
irreversible and associated with a poor prognosis (Iizuka et al., 2016). In 2016, Titulaer
further suggested that cerebellar atrophy might be a complication of the disease. In two previous
cases with cerebellar atrophy reported by Iizuka et al, one patient experienced multiple cardiac
arrests and the other developed multiple organ failure, both of which can result in hypoxia
(Titulaer, 2016).
Early initiation of treatment is a predictor of good outcomes (DeSena et al., 2014). In one
multi-center observational cohort study of 577 patients, Maarten et al. showed that early
immunotherapy may result in improved clinical outcomes (Titulaer et al., 2013). Another
study in Europe found that patients who were administered no immunotherapy, or treated more
than 40 days after the onset of illness, experienced significantly worse outcomes than those treated
within 40 days (Irani et al., 2010). Moreover, Byrne et al. reported five children with
anti-NMDAR encephalitis who received immunotherapy within one week after onset (Byrne et
al., 2014). Four of these children had recovered completely at follow-up. A prospective
surveillance study by Wright et al. showed that patients with earlier diagnosis (within eight weeks)
had better outcomes than patients diagnosed later (more than six months) (Wright et al., 2015).
This result has been confirmed by many other studies (Lim et al., 2014; Moussa et al., 2019;
Titulaer et al., 2013). Early immunotherapy is also associated with better long-term
prognosis. Finke et al. studied the cognitive deficits in nine patients during the rehabilitation
process, and found that patients that received delayed treatment had more severe damage (Finke
et al., 2012). However, owing to the wide range of clinical presentations, diagnosis of
anti-NMDAR encephalitis is challenging. Furthermore, the identification of NMDAR antibodies
in serum or CSF may take a long time which means the diagnosis may be delayed (Titulaer et
al., 2013). As such, more sensitive diagnostic tests are needed. Conventional tests such as MRI,
EEG, and FDG-PET may be potential techniques to decide early treatment strategies for probable
patients (Graus et al., 2016).
Taken together, age and severity of symptoms seem unlikely to change. Antibody titers,
CXCL13, and cerebellar atrophy may not be early or sensitive markers; however, mtDNA, IL-17,
YKL-40, NSE and S100B may present early biomarkers for the identification of patients who
need treatment. However, these biomarkers require further validation. Recently, Balu et al.
constructed a grading score, anti-NMDAR Encephalitis One-Year Functional Status (NEOS)
score, to predict patients’ neurologic function 1 year after diagnosis of anti-NMDAR encephalitis,
which may help to identify patients in poor functional status(Balu et al., 2019). Delays in
treatment may be reduced with more sensitive diagnostic tools for this disorder. Further
development of these tools is necessary to improve outcomes associated with anti-NMDAR
encephalitis.
During long-term follow-up, some patients with good outcomes can still manifest executive
dysfunction, cognitive defects, and visual dysfunction. The proportion of patients with these
deficits ranged from 27.3% to 85% (Brandt et al., 2016; Dalmau et al., 2008a; Dalmau et
al., 2011; Hinkle et al., 2017; Titulaer et al., 2013). Studies of deficits in patients with
anti-NMDAR encephalitis showed that severe deficits were more likely to occur in cases of
delayed immunotherapy, the presence of occult tumour, or in patients with higher likelihood of
tumour recurrence (Dalmau et al., 2008a; Ishiura et al., 2008; Titulaer et al., 2013).
(Brandt et al., 2016)
The recurrence rate ranged from 12% to 29%, with a median interval of 2 years (Dalmauetal.,
2008a; Dalmau et al., 2011; Irani et al., 2010). (Nagappa et al., 2016)Relapses were
usually less severe than the first episodes and did not result in additional deficits (Graus et al.,
2016). Patients with delayed or insufficient immunotherapy during the first episode and patients
without an underlying tumor were more likely to relapse (Staley et al., 2019; Titulaer et
al., 2013). For patients who had previous relapses, second-line immunotherapy may have
decreased the potential for further relapses (Graus et al., 2016; Irani et al., 2010;
Titulaer et al., 2013). To prevent relapse, Dalmau et al. recommend maintenance treatment
with mycophenolate or azathioprine for at least one year in patients without tumors (Dalmau et
al., 2011). A study investigating maintenance treatment in children found that no patients
relapsed after various maintenance regimens including steroids, IVIG, mycophenolate, rituximab,
and cyclophosphamide. However, half of these patients had severe complications, ranging from
severe headache to sepsis (Brenton et al., 2016). Another study of thirteen children who
received pulse steroids every month as maintenance treatment showed that three patients relapsed
when treatments were discontinued, but all patients recovered without severe complications after
restarting therapy (Nagappa et al., 2016). More studies are needed to elucidate the long-term
effects of immunotherapy and predictive factors for relapse.
10. Conclusion
Although the majority of patients with anti-NMDAR encephalitis achieve favorable outcomes,
those who received delayed or insufficient immunotherapy consistently experienced worse
outcomes and were more prone to relapse. There is a need for sensitive diagnostic methods to
enable early identification of this disease. In addition, current treatment strategies focus primarily
on removal of antibodies in the periphery. However, antibodies present in the central nervous
system are responsible for disease pathogenesis, which may explain why patients with
anti-NMDAR encephalitis often require long hospital stays. Some drugs, such as bortezomib,
azathioprine, and mycophenolate mofetil have been reported to be beneficial for patients who do
not respond to tumor resection and immunosuppressive therapy; however, the effects of these
medications have not been systematically verified in large cohorts. Additional studies are required
to identify more effective treatment strategies. For patients with long-term sequelae, appropriate
rehabilitation methods and improved strategies for the prevention of relapse are of critical
importance.
Acknowledgments
Jian Wang helped illustrate the review.

Funding
This work was supported by the National Natural Science Foundation of China (Grant
No.81271298); and the Hunan Provincical Science and Technology Department in China (Grant
No.2007SK3038)
Declarations of interest
None
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Fig1. Possible pathogenic mechanisms of anti-NMDAR encephalitis (A ) N-methyl-D-aspartate
receptors (NMDARs) released by tumors and viral infected neurons are taken up by antigen
presenting cells(APCs) after apoptosis occurs. APCs migrate to local lymph nodes, and with the
cooperation of CD4+ T cells, naive B cells in lymph nodes become memory B cells and
differentiate into plasma cells.These cells and anti-NMDAR antibodies produced by peripheral
plasma cells enter the brain, and immune cells such as B cells further undergo stimulation and
differentiation. (B) In patients, anti-NMDAR antibodies bind to the GluN1 subunits of synaptic
and extrasynaptic NMDARs. This disrupts the interaction between NMDAR and ephrin type B2
(EphB2) receptor, resulting in decreased NMDAR and neuronal hypoactivity. But, antibodies can
sometimes increase the opening of synaptic receptors before internalization which may explain the
seizures.
Table1. Treatment of anti-NMDAR encephalitis

Treatment indication
high-dose steroids (target B and T cells) first-line treatment
intravenous gamma globulin(target
antibodies)
plasma exchange (target antibodies)
tumors resection, if removable (target
immune triggers)
rituximab (target B cells) second-line immunotherapy
cyclophosphamide (target B and T cells)
tocilizumab (target IL-6) potentially useful
alemtuzumab (target B and T cells)
methotrexate
bortezomib (target B cells)
azathioprine
mycophenolate mofetil
benzodiazepines (BZDs) catatonia
electroconvulsive therapy (ECT)
typical antipsychotics agitation, hallucination and delusion
phenobarbital
clonidine, dexmedetomidine
lithium and valproic acid manic symptoms
BZDs movement disorders
levodopa-carbidopa, central anticholinergics
(benztropine ; benzhexol ), oral baclofen,
amantadine, and bromocriptine
valproic acid (choreiform movements and
dyskinesia), phenobarbital, and carbamazepine
clonidine (stereotypicalmovements) , dexme-
detomidine, and chloralhydrate
BZDs seizures
levetiracetam, phenobarbital, topiramate,
lamotrigine, valproic acid, phenytoin, and
carbamazepine
propofol and midazolam (status epilepticus)
BZDs sleep disruption
chloralhydrate, clonidine, melatonin,
ketamine, trimeprazine, dexmedetomidine,
zopiclone, and promethazine
tracheotomy or mechanical ventilation central hypoventilation
atropine, isoprenaline, pacemaker installation asystole
glycopyrrolate, hyoscine patches hypersalivation
Highlights:
Treatment with immunomodulators and tumor resection are effective treatment strategies for
pregnant patients.
Age; antibody titers; cerebellar atrophy; levels of biomarkers such as C-X-C motif chemokine
13, cell-free mitochondrial DNA, interleukin-17, YKL-40 (Chitinase 3-like 1), Neuron-specific
enolase, and S100 calcium-binding protein B in cerebral serum fluid and treatment time are the
main prognostic factors.
Patients with delayed or insufficient immunotherapy during the first episode and patients
without an underlying tumor were more likely to relapse.

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Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mech-

Qianyi Huang, Yue Xie, Zhiping Hu, Xiangqi Tang

To appear in: Brain Research

Received Date: 28 June 2019

© 2019 Published by Elsevier B.V.

pathogenic mechanisms, treatment and prognosis

Qianyi Huanga, Yue Xieb, Zhiping Hua, Xiangqi Tanga*

Hunan 410011, China

*Corresponding Author: Xiangqi Tang

Department of Neurology, The Second Xiangya Hospital, Central South University

Renmin Road 139#, Changsha, Hunan 410011, China

Tel: +86 13875807186 Fax: 0731-84896038 Email: txq6633@csu.edu.cn

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune

disorder characterized by prominent neuropsychiatric symptoms that predominantly affects

immunologic triggers of anti-NMDAR encephalitis, and provide an overview of treatment and

and surgical resection of tumors. When first-line immunotherapy fails, second-line

levels of biomarkers such as C-X-C motif chemokine 13 (CXCL13), cell-free mitochondrial

during the first episode are more likely to relapse.

Keywords: anti-N-methyl-D-aspartate receptor encephalitis; pathogenic mechanism; treatment;

2. Pathogenic mechanisms and clinical features of anti-NMDAR encephalitis

2.2 Pathogenic mechanisms

2.3 Clinical features

3.3 Symptomatic treatment

3.3.1 Management of psychiatric symptoms

3.3.2 Other symptoms

3.5 Pregnant patients

4.1 Factors associated with prognosis

4.2 Sequela and relapse

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common

The pathophysiology of anti-NMDAR encephalitis is thought to involve antibodies aganist the

NR1 subunit of N-methyl-D-aspartate receptor (NMDAR), which causes reversible internalization

(Dalmau et al., 2008a; Kuppuswamy et al., 2014). Excitotoxicity due to overactivity of

cyclophosphamide are often used as second-line immunotherapies (Dalmau et al., 2011).

autoimmune encephalitis such as anti-Hu-associated paraneoplastic encephalomyelitis, and

Voltage-Gated Potassium Channel autoimmune encephalitis (Yeshokumar et al., 2017).

2010b; Titulaer et al., 2013; Wang et al., 2016a).

or common symptoms, which will be discussed in detail.

2. Pathogenic mechanisms and clinical features of anti-NMDAR encephalitis

ionotropic glutamate receptors (iGluRs) and metabotropic G protein-coupled receptors (mGluRs),

GluN1–1b to 4b), while GluN2 is expressed as four isoforms (GluN2A–GluN2D) (Regan et

domains, a long extracellular N-terminal ligand-binding region, and an intracellular C-terminal

2.2 Pathogenic mechanisms (Fig1)

Antibody-associated encephalitides can be broadly classified into 2 categories according to the

location of their neuronal antigens: paraneoplastic encephalitis associated with antibodies

cell-surface or synaptic receptors(Kelley et al., 2017). Paraneoplastic encephalitis are more

common paraneoplastic encephalitis, is associated with small-cell lung cancer in most

pathogenic mechanisms underlying anti-NMDAR encephalitis involves the binding of

auto-antibodies to the GluN1 subunit of NMDAR. In anti-NMDAR encephalitis, antibodies

receptors, resulting in the clinical syndrome. However, in paraneoplastic encephalitis, the

pathogenesis of paraneoplastic encephalitis (Dalmau and Graus, 2018).

nervous tissue-containing tumors (typically ovarian teratoma), or released by viral-induced

maturation, and clonal expansion, finally differentiating to anti-NMDAR antibody-producing

intrathecal plasma cells.(Malviya et al., 2017; Planaguma et al., 2015). After

lysosomes (Moscato et al., 2014).

(often GluN2A-containing) at active excitatory synapses. In contrast, on active inhibitory neurons,

antibodies preferentially bind to open extrasynaptic NMDARs (commonly GluN2B-containing).

encephalitis and encephalopathic patient controls. Their model-based estimates of NMDAR

Moscato et al., 2014). Recently, to characterize the specific molecular mechanisms of

2.3 Clinical features

dysfunction, seizure, speech dysfunction, movement disorder, decreased level of consciousness,

and autonomic dysfunction or central hypoventilation. Prodromal symptoms such as headache,

non-psychiatric, such as behavioral problems, seizure, speech dysfunction, and movement