Autoimmunity Reviews 11 (2012) 863872

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Anti-NMDA receptor encephalitis. The disorder, the diagnosis and

the immunobiology
Harry E. Peery a, 1, Gregory S. Day b, Shannon Dunn c, Marvin J. Fritzler d,, Harald Prss e, f, Claire De Souza g,
Asif Doja h, Karen Mossman i, Lothar Resch j, Chenjie Xia k, Boris Sakic l, Larry Belbeck m, Warren G. Foster n
a
Department of Obstetrics and Gynecology, Division of Reproductive Biology, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
b
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
c
University Health Network and Women's College Research Institute, Department of Immunology, University of Toronto, 67 College St. Rm 4-409, Toronto, Ontario, Canada M5G 2 M1
d
Department of Medicine, Faculty of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4 N1
e
Charit Universittsmedizin Berlin, Experimentelle Neurologie und, Klinik und Poliklinik fr Neurologie, Charitplatz 1, 10117 Berlin, Germany
f
Harvard Medical School, Division of Immunology, 77 Avenue Louis Pasteur, NRB, Room 836, Boston, MA 02115, United States
g
Hospital for Sick Children, Department of Psychiatry, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
h
Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8 L1
i
Department of Pathology and Molecular Medicine, Michael DeGroote Institute of Infectious Disease Research, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
j
Division of Neuropathology, Department of Pathology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 2 T9
k
Department of Neurology, Montreal Neurological Institute and Hospital, 3801 University Street, Montreal, Quebec, Canada H3A 2B4
l
Department of Psychiatry and Behavioural Neurosciences, McMaster University, The Brain-Body Institute, St. Joseph's Healthcare, Juravinski Innovation Center T-3307, 50 Charlton Avenue East,
Hamilton, Ontario, Canada L8N 4A6
m
Department of Pathology and Molecular Medicine, Michael DeGroote School of Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
n
Department of Obstetrics and Gynecology, Division of Reproductive Biology, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5

a r t i c l e i n f o a b s t r a c t

Article history: Anti-NMDAR encephalitis is a newly characterized syndrome with a progressive, predictable clinical course
Received 1 March 2012 and the possibility of effective treatment. Accurate and timely diagnosis is critical to selection and implemen-
Accepted 7 March 2012 tation of treatments, and optimal patient outcomes. Outcomes are improved with early diagnosis via indirect
Available online 11 March 2012
immunouorescence or cell-based assays, and the rapid and appropriate administration of immunosuppres-
sant and anti-psychotic therapies. Three possible scenarios accounting for the immunopathogenesis of anti-
Keywords:
Neuroautoimmune disease
NMDAR encephalitis are presented, with the most probable one being that of paraneoplastic autoimmunity.
Anti-NMDA receptor Future efforts in this disorder should focus on elucidating the mechanisms that contribute to initiation of this
Encephalitis antibody response, as well as exploring the role of tumors, infectious triggers and immune-reactivation. Fi-
Seizures nally, accessible tools need to be developed that allow for reliable identication of specic antibody markers
Psychosis against synaptic proteins.
Cell based assay 2012 Elsevier B.V. All rights reserved.

Contents

1. Clinical description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864

1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
1.2. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
1.3. Autoimmune synaptic protein encephalopathy syndrome (ASPES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
1.4. Anti-NMDAR encephalitis: clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
1.4.1. Clinical phases: the prodromal phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
1.4.2. The psychotic and/or seizure phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
1.4.3. The unresponsive phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
1.4.4. The hyperkinetic phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

Corresponding author. Tel.: + 1 403 220 3533.

E-mail addresses: peeryh@mcmaster.ca (H.E. Peery), g.day@rogers.com (G.S. Day), dunn.shannon14@gmail.com (S. Dunn), fritzler@ucalgary.ca (M.J. Fritzler),
harald.pruess@charite.de (H. Prss), claire.desouza@sickkids.ca (C. De Souza), ADoja@cheo.on.ca (A. Doja), mossk@mcmaster.ca (K. Mossman), Lothar.Resch@cls.ab.ca (L. Resch),
chenjie.xia@mail.mcgill.ca (C. Xia), sakic@bell.net (B. Sakic), belbeckl@mcmaster.ca (L. Belbeck), fosterw@mcmaster.ca (W.G. Foster).
1
Tel.: + 1 905 525 9140x22648, + 1 613 504 1557.

1568-9972/$ see front matter 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2012.03.001
864 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872

1.5. Psychiatric manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

1.6. Anti-NMDAR encephalitis: clinical diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.7. Anti-NMDAR encephalitis: diagnostic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.7.1. Indirect immunouorescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.7.2. Cell-based assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.8. Anti-NMDAR encephalitis: treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.8.1. Medical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
1.8.2. Psychiatric management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
1.9. Anti-NMDAR encephalitis: outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
1.9.1. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
1.9.2. Long-term outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
1.9.3. Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2. Immunobiology of anti-NMDA receptor encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.1. Sex bias in anti-NMDA receptor encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.2. Anti-NMDA receptor encephalitis as an autoimmune disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.2.1. Resemblance to other auto-antibody-mediated disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.2.2. Autoimmune characteristics of anti-NMDA encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.3. How might anti-NMDAR encephalitis be initiated? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
2.3.1. Scenario: paraneoplastic autoimmunity and the role of non-specic infections in triggering anti-NMDAR encephalitis . . . . . 868
2.3.2. Scenario: infection-induced molecular mimicry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869
2.3.3. Scenario: extra-CNS NMDA receptor-induced autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
Take-home message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870

1. Clinical description diagnosis, and evidence supporting possible autoimmune mechanisms

1.1. Introduction
Anti-NMDA receptor (anti-NMDAR) encephalitis and variant dis-
orders are serious yet treatable neuroautoimmune diseases arising
from the generation of antibodies targeting synaptic proteins. Anti-
NMDAR encephalitis was initially classied as a paraneoplastic syn-
drome [1] due to the strong association (upwards of 60%) with a ter-
atoma or other tumor type. However, growing clinical experience
suggests that this disorder and related variants may be better classi-
ed as neuroautoimmune syndromes, in which antibodies formed in
response to a number of possible stimuli (i.e., tumor, infection),
cross-react with synaptic proteins, most commonly the N-methyl-D-
aspartate receptor (NMDAR) [24]. Despite a building body of
literature, these disorders remain under-recognized, attributable to
variations in clinical presentation, a paucity of specic ndings on
standard laboratory and radiologic investigations, and limitations in
clinician knowledge.
Retrospective analysis of serum from patients at one tertiary center
conrmed a diagnosis of anti-NMDAR encephalitis in 20% of encephalit-
ic patients [5]. In the California Encephalitis Project (CEP), half of the
children with idiopathic encephalitis and psychiatric symptoms had an-
tibodies against the NMDAR [6], and the frequency was four times that
of encephalitis caused by herpes simplex, varicella-zoster and West Nile
viruses [7]. In another study, 1% of young patients admitted to the inten-
sive care unit (ICU) had the disorder [8]. The nding of over 400 pa-
tients in a three-year period by one group further indicates that these
disorders are not rare; however, they are commonly misdiagnosed as
a seizure disorder or psychiatric illness [9]. In its most fulminant form,
anti-NMDAR encephalitis presents with an acute infection-like pro-
drome in 70% of patients [10] followed by rapid deteriorationoften re-
quiring prolonged hospitalization with cardio-respiratory support.
These symptoms and signs are not directly attributable to mass lesion,
metastases, secondary infection, nutritional deciencies, radiation or
chemotherapy [11]. The recent discovery of autoantibody markers has
remarkably aided clinicians in making a diagnosis and understanding
disease prevalence [9]. Herein, we review the clinical presentation,
that underlie this syndrome.
1.2. History
Demonic possession throughout history is the earliest appella-
tion given to what may have been anti-NMDAR encephalitis [12,13].
An 1895 report rst described in detail cerebral dysfunction in chil-
dren with inuenza [14]. Brief references to similar cases of encepha-
litis with an accompanying respiratory infection have dotted the
clinical literature over the past few centuries [13,15]. The disorder
was only formally recognized in 2005 in an observational study by
Dalmau and his colleagues documenting the coexistence of limbic
encephalitis in four women with ovarian teratomas [15]; a paraneo-
plastic connection was suggested. Two years later, a seminal paper
by this group described the underlying pathology: mediated by auto-
antibodies directed against the NR1 subunit of the NMDAR [1]. Addi-
tional work has since demonstrated that these autoantibodies cause a
decrease in the number of NMDARs in target cells by inducing cross-
linking and internalization of NMDARs by autophagy [16], akin to the
process through which acetylcholine receptors (AChRs) are degraded
by antibodies in myasthenia gravis (MG) [17].
1.3. Autoimmune synaptic protein encephalopathy syndrome (ASPES)
Though autoimmune encephalopathy associated with antibodies
against the NMDAR remains the most common and best understood
variant of these disorders, antibodies directed against other proteins
have also been described [10,18]. Antibodies directed against alpha-
amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) [19],
gamma-aminobutyric acid-B (GABAB) [20,18] and glycine receptors,
[21] the potassium channel-associated complex [22], including
leucine-rich glioma-inactivated 1 (LGI1) [10] and contactin-associated
protein-like 2 (Caspr2) [10,23], and the intracellular enzyme glutamate
decarboxylase (GAD) [20] have been detected in serum and cerebrospi-
nal uid (CSF) of patients. The previously reported autoimmune disrup-
tion of voltage-gated potassium channels [24] may also be due to
antibodies specic for LGI1 or Caspr2 [23]. We propose the term
 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872 865

Autoimmune Synaptic Protein Encephalopathy Syndrome (ASPES) to

plasmapheresis, B cell depletion (anti-CD20), IV (interferon-beta, glatiramer acetate), B cell

complement contribute to pathology [118]

Commonly between 20 and 40 years [116]

Evidence for involvement of a neurotropic
macrophages, and in 50% of cases, B cells,

Immunosuppression (prednisone, azathioprine), Immunosuppression, immunomodulation

Improves with pregnancy; Exacerbations
HLA gene cluster 6p21.3 major source of
encompass these variants.

genetic risk and other immune-related

Perivascular inltrates contain T cells,
T cells initiate disease. Antibody and
One distinguishing feature of ASPES is the strong association be-

Various myelin proteins, heat shock

tween autoantibody production and the presence of teratoma or

antibody and complement [118]

virus (EBV top candidate) [128]

other neoplasm. Co-morbidities of ASPES with small cell lung

depletion (anti-CD20) [139]

carcinoma, neuroblastoma, ovarian carcinoma, breast carcinoma, thy-

Some B cell involvement

proteins and lipids [114]

Yes (97% of cases) [116]
moma and testicular cancers have been reported [11], suggesting that
the autoantibody syndrome may be triggered by cross-reaction be-

post-partum [134]
Multiple sclerosis

T cell-mediated
tween antibodies produced in response to tumor presence and

genes [123]
antigenically-similar synaptic proteins within the central nervous

3:1 [131]
(CNS).
A tumor is not always found in ASPES. In the largest case series to

No
date, no teratoma or other type of tumor was detected in 41% (40/98)
of cases [9,25]. A tumor may go undetected, either because it is

HLA-risk alleles, population dependent [122]

destroyed or effectively repressed by the immune response [4], or be-

Women under 40, men over 60 years [122]

Case reports of EBV etiology [125], this is
cause the cellular burden remains below the threshold for detection

Autoantibody and complement degrade

with conventional imaging technologies (10 9 cells) [26]. In support

immunoglobulin, thymectomy [138]

Thyroid abnormalities (85%)[122]
of the former hypothesis is one case of paraneoplastic anti-Ma2

Worsens with pregnancy [133]

antibody-positive brainstem encephalitis in which a lung mass was
detected only by positron emission tomography (PET). Follow-up

controversial [126,127]
PET imaging demonstrated resolution of the mass (without therapeu-

AChR or MusK [113]

Antibody-mediated
tic or surgical intervention), and with it the encephalitis [27]. The lat-

T cell involvement
Myasthenia gravis

AChR, MusK [113]

Thymoma (15%)
ter hypothesis is also supported by post-mortem identication of
teratomas in patients [28].

3:1 [130]
Autoimmune encephalopathy associated with antibodies against
the NMDAR remains the most common and best understood form of

N/A

N/A
ASPES, supported by a rapidly expanding body of literature and im-
proved clinical experience [9,8]. This review will henceforth focus
on anti-NMDAR encephalitis.

plasmapheresis, B cell depletion (anti-CD20) [137]

1.4. Anti-NMDAR encephalitis: clinical presentation

Immunosuppression (prednisone, azathioprine),

HLA-risk alleles, population dependent [121]
Perivascular inltrates contain plasma cells,
Anti-NMDAR encephalitis most commonly presents in young fe-

Rare case reports of thymoma [135,136]

Autoantibody and complement deposits
males of reproductive age (Table 1) [29], but has been reported in
males and females of all ages (from 2 to 84 years) [30]. The younger

Exacerbations post-partum [132]

the patient, the less likely an underlying tumor will be detected at

Yes (3050%) of cases [124]

on astrocyte end-feet. [117]

the time of presentation [9]. Very rarely are teratomas found in the

Worsens with pregnancy;

eosinophils, neutrophils.
Yes (16% of cases) [115]

rst decade of life.

Neuromyelitis optica

Antibody-mediated
T cell involvement
Aquaporin-4 [63]

T cells rare [120]

1.4.1. Clinical phases: the prodromal phase

Late 30s[129]
In 70% of patients, anti-NMDAR encephalitis begins with a prodro-
mal phase lasting ve to fourteen days [9,31,30]. During this phase,
9:1 [129]

patients complain of fever, malaise, inability to concentrate, nausea,

Anti-NMDA receptor encephalitis compared to other neuroautoimmune disorders.

diarrhea, vomiting and headache. Patients who present to acute care

centers are often discharged with a clinical diagnosis of acute upper
Immunosuppression, plasmapheresis, intravenous
cells, but no complementT cells are rare [10,119]

respiratory tract infection or inuenza [9,5,32]. This is followed by

Yes in up to 59% cases: ovarian teratoma most

immunoglobulin, B cell depletion (anti-CD20),

Immune composition Perivascular inltrates contain B cells, plasma

Case report of 3 patients suggests condition

other clinical phases, which may vary in sequence, presentation,

and severity.
Immunopathogenesis Autoantibody-mediated capping of the

1.4.2. The psychotic and/or seizure phase

NMDAR and internalization [10]

The psychotic and/or seizure phase is characterized by emotional

improves post-partum [54]

and behavioral disturbances, including apathy, fear, depression, de-

CSF oligoclonal bands? Yes (60% of cases) [9,10]

Mean age: 19 years [10]

cyclophosphamide [9]
NMDA receptor [10,9]

creased cognitive skills, psychosis (delusions, and hallucinations)

Yes (70% of cases) [9]
NMDAR encephalitis

Antibody-mediated
T cell involvement

[4,33,8]. Ataxia and choreiform movements may be noted [31]. Pa-

tients presenting to acute care facilities during this phase are often re-
common [9]

ferred for psychiatric assessment, and may receive treatment with

Unknown

4:1 [10]

psychoactive agents, psychotherapy or admission to psychiatric facil-

ities. Patients may also have seizuresmost commonly generalized
tonicclonic [3]necessitating further work-up and specialist consul-
tation. Seizures may prove refractory to standard medical manage-
Infectious prodrome?

Tumor or teratoma?
Antibody specicity

Effective therapies

ment, requiring multiple anticonvulsant medications and admission

of CNS inltrate

Pregnancy effects
Sex ratio (F:M)
Genetic factors

to monitored settings for cardiac and respiratory support [30,34].

Disorder type

Age of onset

1.4.3. The unresponsive phase

Table 1

During this phase, patients not already admitted to hospital pre-

sent to the emergency department because they no longer follow
866 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872
verbal commands, and may appear mute and akinetic. Patients may
maintain gaze as if in a catatonic state, smile inappropriately, or
demonstrate stereotyped athetotic movements [28,35].
1.4.4. The hyperkinetic phase
The hyperkinetic phase is characterized by autonomic instability
manifesting with cardiac arrhythmia, hypotension, hypertension,
hypoventilation, and hyper- or hypothermia. Dyskinesias, extra-
pyramidal signs and stereotyped motor automatisms (lip-smacking,
sustained jaw movements, clenching of teeth, grimacing and oculogy-
ric crises) may also be observed [33]. Autonomic dysregulation is less
common in children, while speech dysfunction is more prevalent
[4,36].
1.5. Psychiatric manifestations
Within the framework of the Diagnostic and Statistical Manual of
Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) [37], the psy-
chiatric manifestations of anti-NMDAR encephalitis [3739] meet cri-
teria for diagnosis of delirium due to a general medical condition
(GMC), psychotic disorder due to a GMC and catatonic disorder due
to a GMC, where the GMC is anti-NMDAR encephalitis. Fluctuations
in mental status predominate throughout the course of illness; thus,
the psychiatric presentation is best conceptualized as a delirium or
as an encephalopathic or acute confusional state that develops over
a short period of time, uctuates over the course of the day and man-
ifests with changes in cognition, affect, behavior and perception. Ini-
tially the features may be subtle, but over days to weeks, there may
be dramatic worsening, culminating in an unresponsive and catatonic
state. In many patients there is no previous psychiatric history. From
a cognitive standpoint, patients may be disoriented; attention is often
impaired, manifesting as difculty sustaining or shifting focus, and
impairment in memory formation and recall. The disturbance of con-
sciousness manifests as a reduced awareness of their environment.
There may be changes in the sleepwake cycle. Language- and
speech-based problems include word-nding difculties, aphasia
and dysarthria. Echolalia and echopraxia have also been described.
Patients may exhibit labile mood, experiencing a wide range of emo-
tions including anxiety, low mood, irritability and apathy. Changes in
behavior may include periods of agitation or restlessness, alternating
with episodes of somnolence. Perceptual disturbances are common,
including misinterpretations, illusions or hallucinations (visual and
auditory) and delusions (often pertaining to hallucinations). During
the unresponsive phase, patients have been referred to as catatonic
with features involving purposeless motor activity, extreme negativ-
ism (resistance to being moved), bizarre posturing, grimacing, mut-
ism, echolalia and echopraxia.
Given the disturbances in cognition, mood, behavior and percep-
tion, patients may be at risk of harming themselves or others, requir-
ing constant observation. Daynight reversal should be corrected
when present through the use of pharmacologic (sedative and anti-
psychotic medications) and supportive measures (orienting cues, fa-
miliar items, reassurance and support in a low stimulation environ-
ment). More research is needed for effective management of
psychiatric symptoms (acute and long-term).
1.6. Anti-NMDAR encephalitis: clinical diagnosis
Anti-NMDAR encephalitis and variants can be challenging to
diagnose. While the fulminant syndrome of psychiatric symptoms, auto-
nomic dysfunction and neurologic decompensation is present in the ma-
jority of patients, variations in clinical presentation and the protracted
course of symptom development can lead to delays in treatment and
misdiagnoses. Magnetic resonance imaging (MRI) is unremarkable in
50% of patients; the remainder show T2 or FLAIR hyperintensity in a
number of non-specic regions [1]. Video electroencephalograms are
abnormal, exhibiting non-specic slow disorganized activity, sometimes
interspersed with seizure patterns [28]. More research and dissemination
of knowledge is required to improve clinicians' ability to make the diag-
nosis and exclude important disease mimics based on clinical and radio-
logical evidence. We propose that anti-NMDAR encephalitis should be
included in the differential diagnosis of all patients presenting with nd-
ings of viral encephalitisregardless of age or sex. Further, all patients
with suspected anti-NMDAR encephalitis should be thoroughly investi-
gated for the presence of a teratoma or other tumor [9,30,1].
1.7. Anti-NMDAR encephalitis: diagnostic testing
Another barrier to diagnosis is access to sensitive and specic lab-
oratory tests for autoantibodies directed against target autoantigens
of clinical signicance. The recent development of techniques to de-
tect autoantibodies directed against synaptic proteins has dramatical-
ly improved the potential for accurate diagnosis.
1.7.1. Indirect immunouorescence
The conventional laboratory approach for the detection of anti-
NMDAR uses indirect immunouorescence (IIF) on cryopreserved
sections of rodent or primate hippocampus or cerebellum. The char-
acteristic staining pattern shows autoantibody binding to the molec-
ular (third) layer of the hippocampus and the granular (third) layer of
the cerebellum (Fig. 1). While the characteristic IIF patterns may be a
good screening test in distinguishing sera that are positive from those
that are not, the specicity of the IIF is less than ideal, creating a de-
mand for more specialized techniques.
1.7.2. Cell-based assay
More conventional immunoassay platforms widely used for a vari-
ety of other autoantibody systems (i.e., ELISA, line immunoassays) are
not easily adapted to detection of NMDAR antibodies because the key
epitope, the extracellular N-terminal domain of the NR1 subunit
[9,10], is conformational. For this reason, a cell-based assay (CBA)
was developed with the intent of providing a more specic and sen-
sitive immunoassay that preserves the conformational epitope(s)
[28]. In the CBA platform, tissue culture cells (i.e., HEK293) are trans-
fected with the complementary DNA (cDNA) representing the single
or assembled NR1NR2 subunits. The cognate proteins are over-
expressed and antibodies are then detected by conventional IIF and
expressed as either end-point titres or relative uorescence units. Ini-
tial testing is performed on patient serum and if antibodies are
detected by CBA (positive test), testing of the CSF is not required.
However, since CSF antibody titres have been shown to be higher
than serum levels in affected patients [28], further testing of CSF
should be performed to maximize sensitivity if antibodies are not
detected by CBA (negative test). CSF testing is especially important
in patients receiving active treatment that may modulate serum anti-
body expression (e.g., plasmapheresis, IVIg, rituximab).
1.8. Anti-NMDAR encephalitis: treatment
1.8.1. Medical management
The mainstay of medical therapy for suspected anti-NMDAR en-
cephalitis involves initial treatment with acyclovir until herpes sim-
plex virus (HSV) encephalitis has been excluded. Anti-convulsant
therapies are frequently required for control of seizures. Once the di-
agnosis of anti-NMDAR encephalitis is conrmed, potent immuno-
suppressants including high-dose intravenous corticosteroids,
intravenous immunoglobulin, anti-inammatory agents, plasma ex-
change and monoclonal antibodies (e.g., rituximab) directed against
CD-20 B-lymphocytes should be used in sequence or in combination
[2,40,28]. While some patients recover with supportive care alone,
the majority of patients require extended hospital admissions and ad-
vanced monitoring in an intensive care setting. Hospital stay ranges
 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872 867

Fig. 1. This gure illustrates the sequential use of IIF and CBA as a screening test and more specic conrmatory test, respectively. In this illustration, IIF was used to detect anti-
NMDA/NR1 autoantibodies on cryopreserved sections of primate hippocampus and cerebellum, and then reex tested by a CBA that utilized HEK cells that over-expressed the
NMDA/NR1 after they were transfected with the cognate NMDA/NR1 cDNA. The molecular layer of the hippocampal neurons (neuropil) and the granular layer of the cerebellum
are stained. More specic detection of anti-NR1 antibodies is achieved by IIF of the transfected HEK cells where the cellular uorescence is indicative of a highly positive response. Sera can
be serially diluted to achieve end point titres[112]. Reproduced with kind permission from Springer Science+Business Media: Der Nervenarzt, Anti-NMDA-Rezeptor-Enzephalitis
Ein interdisziplinres Krankheitsbild, Volume 81, Number 4, Pages 396-408, 2010, H. Pr, J. Dalmau, V. Arolt and K.-P. Wandinger. Fig. 2 and Pabst Science Publishers, from the original
published article wherein mmunouorescence gure provided by Klaus-Peter Wandinger, AG Medical Laboratory Diagnostics.

from 2 to 14 months [32]. Recovery may take three years or longer
[35,32], and the patient may not always return to their premorbid
level of motor function and cognition [33,28].
1.8.2. Psychiatric management
Although there is limited literature on use of psychiatric medica-
tions in this population, general principles may be applied. Treatment
of delirium can support medical management in the short-term and
improve cognitive outcomes in the long-term. Delirium can be man-
aged with the use of low-dose atypical antipsychotics to target the
various cognitive, affective, behavioral and perceptual abnormalities.
Monitoring for adverse effects associated with antipsychotics is
essential. Common side effects include dystonia, akathisia and drug-
induced parkinsonism. Less commonly, prolongation of the QT
interval and reduction of seizure threshold may be seen. It may be dif-
cult to distinguish neuroleptic malignant syndrome from fulminant
anti-NMDAR encephalitis, as either can cause rigidity, autonomic in-
stability and elevated creatinine kinase. Rigidity due to antipsychotics
may be treated with benzotropine. Patients experiencing catatonia
may be managed with low-dose lorazepam (given twice, or three-
times daily). Lorazepam may, however, worsen delirium [41]. Elec-
troconvulsive therapy may also be considered as a possible treatment
option for catatonia due to a medical condition [39]. Psychotropics in-
cluding typical antipsychotics, trazodone, gabapentin, stimulants,
mood stabilizers, melatonin and clonidine have been used to target
various psychiatric symptoms with variable success [41]. Psychiatric
medications should be continued until mental status improves,
which normally corresponds with adequate suppression of the im-
mune response [41].
1.9. Anti-NMDAR encephalitis: outcome
1.9.1. Prognosis
With prompt, aggressive treatment, the prognosis remains good.
In a cohort of 360 patients [9], 75% experienced complete or near-
complete recovery (Modied Rankin Scale [MRS, [42]] 12) [36].
The remainder had sequelae that severely affected quality of life
(MRS 3), or resulted in death (MRS = 6) in 4% (14/360). In cases
where treatment is delayed or ineffective, the mortality rate may be
as high as 100% (3/3) [30], with cause of death related to autonomic
instability or complications of prolonged hospital admission and
cardio-respiratory support.
1.9.2. Long-term outcome
Long-term outcomes are negatively impacted by executive dysfunc-
tion involving inattention, poor organization, poor planning, impulsivi-
ty, and disinhibition [41]. A frontal lobe syndrome has been described
with perseveration, apathy, reduced speech and at affect [43,39].
Long-term cognitive defects have been reported [44]. The behavioral,
language and social skill problems are amongst the last to improve
[45]. This observation emphasizes the importance of an interdisciplin-
ary approach to disease and symptom management. Once medically
stabilized, patients benet from physiotherapy, occupational therapy,
speech therapy and social work. The role of cognitive, speech and
868 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872
physical rehabilitation is particularly important following the acute
phase of illness [41].
1.9.3. Recurrence
Relapses have been reported to occur in 20 to 25% of patients
[5,3,28,46], occurring at intervals between three months to nine
years after the initial presentation. Multiple relapses may occur, pre-
senting most commonly with speech dysfunction, psychiatric symp-
toms, seizures, or with disturbances of consciousness or attention
[9,47,8]. Relapse rates may be higher in patients not treated with im-
munotherapeutics during the rst episode [46,5], and in cases not
associated with removable tumor [9], suggesting a benet to early
immune suppression [48] and tumor resection [49] (akin to the po-
tential benet of immunosuppression and thymic resection in MG).
On the basis of this association, prolonged use (one year) of myco-
phenolate mofetil or azathioprine has been suggested to mitigate
risk of recurrence, particularly in patients with anti-NMDAR enceph-
alitis without tumor resection [9]. The benet of chronic immune
suppression has yet to be demonstrated in prospective trials.
2. Immunobiology of anti-NMDA receptor encephalitis
2.1. Sex bias in anti-NMDA receptor encephalitis
Like a number of other autoimmune diseases, anti-NMDAR en-
cephalitis and other variants in the ASPES spectrum exhibit a female
predominance (female to male ratio 4:1) [50], primarily targeting
women of child-bearing age [51,50]. One reason for the female bias
in anti-NMDAR encephalitis may relate to the frequent association
with ovarian teratomas. In addition, women exhibit more robust im-
mune responses, possibly increasing susceptibility to autoimmune
disease [52,53]. One case report has further suggested that the
disease may improve postpartum [54], which also occurs with other
antibody-mediated disorders: MG, neuromyelitis optica (NMO) and
systemic lupus erythematosus (SLE) [55,56]. A detrimental effect of
pregnancy in anti-NMDAR encephalitis thus distinguishes this disease
from T cell disorders MS or rheumatoid arthritis [57], which are
expected to improve with pregnancy (Table 1).
The reasons for the female predilection and pregnancy effects on
anti-NMDAR encephalitis have not yet been explored. If the same
mechanisms apply as in other autoimmune conditions, the effect of
sex hormones on autoreactive T and B cells may provide insight
[52]. Whereas male sex hormones inhibit the activity of T helper
cells [52] (affording relative protection from initiation of autoimmune
disease), the female sex hormone, estrogen, has divergent effects on B
and T cell activation. Estrogen has the general effect of stimulating
B cell survival and antibody production, whereas it can suppress
T cell expansion when present at high levels (as seen in pregnancy)
[52,53] Such observations explain why autoantibody disorders may
are with pregnancy while T cell disorders like MS improve [58,59].
In regard to effects on B cells, estrogens promote B cell survival via
upregulation of anti-apoptotic factor BCL-2 [60], and lower the
threshold of B cell activation by reducing the expression of CD22
and SHP-1 [60]. Estrogens also activate the expression of activation-
induced deaminase [61], a key enzyme that operates in class switch-
ing recombination (CSR) [62] and somatic hypermutation.
2.2. Anti-NMDA receptor encephalitis as an autoimmune disease
2.2.1. Resemblance to other auto-antibody-mediated disorders
The B cell targets of anti-NMDAR encephalitis have some things
in common with other antibody-mediated disorders, most notably:
1) MG, a disease in which autoantibodies target AChRs at the neu-
romuscular junction, leading to direct antibody receptor blocking,
immune-directed receptor cross-linking and degradation, and
complement-mediated destruction of the neuromuscular junction
[19]; 2) NMO, a demyelinating disease preferentially affecting spi-
nal cord (causing transverse myelitis) and optic nerves, where au-
toantibodies directed against the aquaporin 4 water channel bind
to and target this protein on CNS astrocytes [63]; and, 3) neuro-
psychiatric SLE (NP SLE) in which autoantibodies directed against
NR2A and NR2B subunits of the NMDAR have been implicated in
the production of the neuropsychiatric features that characterize
this disease [64,65]. In contrast to the neuron-sparing antibody-
mediated receptor autophagy seen with anti-NMDAR encephalitis,
antibodies in NP SLE cross-react with NR2 subunits on neurons,
causing neuronal apoptotic death by excitotoxicity [66], Table 1
contrasts anti-NMDAR encephalitis with MG, NMO, and the pre-
dominantly T cell-mediated autoimmune disease, MS.
2.2.2. Autoimmune characteristics of anti-NMDA encephalitis
Autoimmune diseases are considered to be antibody-mediated if
the following criteria are met: 1) the disease-specic autoantibody
is detected in the majority of patients; 2) the autoantibody binds to
and alters the functioning of the target extracellular antigen; 3) abla-
tion of the antibody leads to reversal of the disease; and, 4) transfer of
patient antibodies into mice or immunization of mice with the target
autoantigen (and adjuvant) recapitulates the disease [67]. To date,
studies have demonstrated that anti-NMDAR encephalitis fullls
three of these four criteria: NMDAR antibodies are detected within
the serum or CSF of most patients; in vitro, antibodies lead to destruc-
tion of CNS NMDARs [16] and, agents used in treatment of this disease
lead to depletion of circulating antibodies [68,2,28]. Furthermore, B
cells and plasma cells outnumber T cells within the CNS of patients
with anti-NMDAR encephalitis [68,28], emphasizing the important
role of autoantibodies in disease pathogenesis. Future research will
address whether an anti-NMDAR encephalitis-like disease can be in-
duced in rodents using active or passive immunization strategies.
Similar studies have already been performed in animal models of
MG and NMO. Following immunization of mice with puried AChR
mixed with Complete Freund's Adjuvant, a MG-like condition is pro-
duced through deposition of anti-AChR antibodies at the neuromus-
cular junction leading to receptor degradation [69]. In models of
NMO active immunization with aquaporin-4 plus adjuvant does not
trigger disease in rodents [70]; however, intrathecal delivery of pa-
tient anti-aquaporin-4 antibodies into the mouse brain does induce
NMO-like lesions [71]. This observation emphasizes the important
role of the intact blood brain barrier (BBB) in pathogenesis of disease
in which the autoantigen is localized within the CNS. Invariably, any
disease model of anti-NMDAR encephalitis must account for the BBB.
2.3. How might anti-NMDAR encephalitis be initiated?
2.3.1. Scenario: paraneoplastic autoimmunity and the role of non-
specic infections in triggering anti-NMDAR encephalitis
2.3.1.1. A tumor by itself is not an initiator of autoimmunity. A teratoma
or other tumor type has been described in 59% (58/98) of cases of
anti-NMDAR encephalitis. In these cases, removal of the tumor
resulted in improvement of the disorder [9]. Subsequently, it was pre-
sumed that the tumor provided the source of an unknown self-
antigen that would induce the initial expansion of the T and B cells
and production of the tumor-specic antibodies that cross-react
with NMDARs [72]. This mechanism of molecular mimicry thus re-
sembles that which occurs in NP SLE. In NP SLE the mimotope (epi-
tope mimicry) is a consensus pentapeptide (DWEYS) in NR2 and
DNA [73]. Subsequently, circulating antibodies cross the BBB and
react with the NR2A and NR2B subunits in the hippocampus and neo-
cortex, increasing the time the calcium channel is open. Increased cal-
cium inux is associated with excitotoxic death of target neurons, and
clinically measurable learning and memory dysfunction [64,73,74].
 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872
If the established rules of T cell engagement and tumor mutation
apply [75], the presence of a tumor itself should be insufcient to
trigger autoimmunity. An antigen presenting cell (APC) presenting
a self tumor antigen (signal 1) in the absence of a co-stimulatory
signal (signal 2) in the form of upregulated CD80 or CD86 (normally
triggered by a microbial stimulus), should either induce anergy or
cause the deletion of tumor-specic T cells, or expansion of T regu-
latory cells [75]. In a similar fashion, self-reactive B cells are deleted
or rendered anergic if they encounter a self-antigen in the absence
of T cell help [76]. In addition, the tumor environment itself is tol-
erogenic [77]. Tumors produce immunosuppressive cytokines such
as IL-10 and TGF-beta that induce expansion of T regulatory cells,
as well as soluble Fas ligand that can induce apoptosis of autoreac-
tive T cells. Tumors also exhibit a high activity of indolamine-23-
dioxygenase, which depletes tryptophan locally, preventing T cell
expansion [77].
2.3.1.2. A pathogen interacts with a tumor. We postulate that a pathogen-
ic trigger interacting with a tumor remains central to the initiation of
this disorder. Numerous pathogens have been detected in the serum
of affected patients, including Mycoplasma pneumoniae [3], inuenza
virus A and B, Chlamydophilia pneumoniae, Bordetella pertussis, Borde-
tella parapertussis [8], and EpsteinBarr virus [78]. We also suggest
that human endogenous retroviruses, which account for 18% of the
human genome [79], should be explored as possible triggers or adju-
vants, as they are readily found in teratomas [80], and have been
shown to be reactivated during autoimmune disease and cancer
[8083]. These features suggest that this disorder could be classied
with other conditions as an autoimmune syndrome induced by adju-
vants (ASIA) [84,85].
2.3.1.3. The innate immune system is triggered rst. If non-specic infec-
tious agents infect the tumor or the tumor-inltrating dendritic cells,
it would offer a source of ligands for the toll like receptors (TLRs), nu-
cleotide oligomerization domain (NOD)-like receptors, or retinoic
acid-inducible gene-1(RIG-1) or melanoma differentiation-associated
protein-5 (MDA-5) helicases, which are innate immune system pat-
tern recognition receptor proteins [86]. Activation of these innate mol-
ecules and their downstream signaling pathways would trigger the
adaptive immune system as manifested by the upregulation of the
major histocompatibility complex (MHC) Class I and II receptors,
along with CD80 and CD86 (signal 2) on APCs, leading to the presen-
tation of tumor antigens and subsequent breakdown of T cell tolerance
mechanisms [86].
2.3.1.4. B-lymphocytes (B cells) become autoreactive. Following presenta-
tion of tumor antigens through usual means, autoreactive T helper cells
would be expected to provide help (via CD40CD40L interactions) to
tumor-specic B cells, breaking B cell tolerance and inducing CSR and
somatic hypermutation in target B cells. These latter processes are cen-
tral to driving antibody diversication and afnity maturation during
autoimmunity. In CSR, the mature B cell switches from producing the
chain of IgM to an alternate heavy chain, 1 for IgG1, for IgA, and
for IgE in a T cell-help-dependent way [87]. In anti-NMDAR enceph-
alitis, the antibodies detected in patients are class-switched to IgG1
and IgG3, indicating that T and B cell tolerance is broken in this disease.
In addition to effects on T cells, TLR ligands have the potential to
induce the clonal expansion of a pre-existing autoimmune B cell rep-
ertoire independent of T cell help [86], as well as initiate the release of
pro-inammatory cytokines (IL-1, IL-6, IL-12 and TNF), chemokines,
and nitric oxide from cells within the peripheral and CNS [88]. The in-
nate cytokine IL-1 can act on the hypothalamus to induce fever [72],
while IL-1, together with IL-12 (Th1) or IL-6 and TGF-beta (Th17),
trigger the TH1 or TH17 differentiation of autoreactive T cells, making
these CD4 + T cells [72] more effective B cell helpers [89,90].
869
2.3.1.5. The blood brain barrier becomes permeable to B cells. Innate
cytokines or TLR ligands can activate transport systems within the
BBB endothelium [88], while IL-17 produced by autoreactive Th17
cells can also induce disruption of tight junctions between endotheli-
al cells making the BBB more permeable [89,91], and allowing auto-
reactive memory B cells and plasma cells to enter the CNS (Dalmau,
2011, personal communication). Having crossed the BBB, B cells are
expected to thrive due to the constitutive production of the B cell ac-
tivation factor (BAFF) of the TNF family [92], leading to clonal expan-
sion and phenotypic oligoclonal immunoglobulin production that is
detected within the CSF of affected patients. With resolution of the
prodromal infection, BBB healing is expected, while constitutive pro-
duction of B cells continues within the immune-privileged CNS. The
persistence of antibody production within the immune-privileged
CNS may explain both the rapid clinical deterioration observed in
subsequent illness phases, and the poorer outcome/response to ther-
apeutic interventions later in the illness course.
2.3.2. Scenario: infection-induced molecular mimicry
Forty-one percent of patients have no tumor, possibly because it
went undetected. Alternatively, a tumor may not be essential for
development of anti-NMDA encephalitis. Instead, the prodromal
infection may act as the antigenic trigger for the initial expansion of
anti-NMDAR-specic lymphocytes via molecular mimicry [4], in addi-
tion to acting as an adjuvant. A classic example of microbial-induced
molecular mimicry is rheumatic fever, in which the formation of anti-
bodies against connective tissue antigens occurs because these antigens
are similar to those found on Lanceeld group A beta hemolytic
Streptococci. The resulting antibodies cross-react with peripheral con-
nective tissue, leading to arthropathies and cardiac valvulopathies
[93]. More rarely, these cross-reactive autoantibodies target CNS tissue,
producing a variety of syndromes including hyperkinetic movement
disorders (Sydenham's chorea), tics, abrupt-onset Tourette syndrome,
some cases of pediatric obsessive-compulsive disorders and pediatric
autoimmune neuropsychiatric disorder associated with streptococcus
(PANDAS) [9496]. Another disorder with a possible microbial associa-
tion is primary biliary cirrhosis [97].
2.3.3. Scenario: extra-CNS NMDA receptor-induced autoimmunity
NMDARs or functional subunits, most often paired NR1s, are also
found outside of the CNS in locations including the kidney [98],
parathyroid glands [99], bone osteoclasts and osteocytes [100], pan-
creatic beta cells [101], myocardium [102], lung [103], megakaryo-
cytes [104], lymphocytes [105], erythrocytes [106], peripheral
myelinated and unmyelinated axons [107], and myenteric plexus
[108]. Normally, these self-antigens should not be sufcient to trig-
ger autoimmunity due to the peripheral T and B cell tolerance mech-
anisms discussed above. However, if the tissue expressing these
receptors becomes infected and damaged, these proteins and
pathogen-associated molecular patterns from the infected tissue
would be taken up by APCs, most likely macrophages. These APCs
would then have the capacity to break T cell tolerance in a similar
way as described in the paraneoplastic initiation of this disorder.
The possible development of nervous system autoimmunity from
extra-CNS tissue exposure is supported by recent reports of a mono-
phasic inammatory polyradiculopathy developing in swine abat-
toir workers [109] in contact with aerosolized swine brain
proteins. When patient serum was extracted, IgG binding to mouse
brain sections was demonstrated. Further analysis conrmed pres-
ence of voltage-gated potassium channel (VGKC)-complex anti-
bodies in most cases. Mice exposed intranasally to liqueed brain
tissue showed a remarkably similar clinical and serological pheno-
type, including the generation of VGKC-complex antibodies [110].
In a similar way, it is possible that extra-CNS NMDAR might induce
autoimmunity when presented at respiratory or intestinal surfaces
or in lesioned tissue. In this scenario, it is possible that both the
870 H.E. Peery et al. / Autoimmunity Reviews 11 (2012) 863872

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