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NIH Public Access
Author Manuscript
Lancet Neurol. Author manuscript; available in PMC 2011 August 19.
Published in final edited form as:
NIH-PA Author Manuscript
Lancet Neurol. 2011 January ; 10(1): 63–74. doi:10.1016/S1474-4422(10)70253-2.
Clinical experience and laboratory investigations in patients with

anti-NMDAR encephalitis
Prof Josep Dalmau, MD, Eric Lancaster, MD, Eugenia Martinez-Hernandez, MD, Prof Myrna
R Rosenfeld, MD, and Prof Rita Balice-Gordon, PhD
Department of Neurology (Prof J Dalmau, MD, E Lancaster, MD, E Martinez-Hernandez, MD,
Prof M R Rosenfeld, MD) and Department of Neuroscience, University of Pennsylvania School of
Medicine (Prof R Balice-Gordon, PhD), Philadelphia, PA, USA
Abstract
Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-
aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most
patients with anti-NMDAR encephalitis develop a multistage illness that progresses from
psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness
with catatonic features often associated with abnormal movements, and autonomic and breathing
instability. The disorder predominantly affects children and young adults, occurs with or without
tumour association, and responds to treatment but can relapse. The presence of a tumour (usually
an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older
than 18 years, and slightly more predominant in black women than it is in white women. Patients
treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin,
or plasma exchange) respond faster to treatment and less frequently need second-line
immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who
receive similar initial immunotherapy. More than 75% of all patients have substantial recovery
that occurs in inverse order of symptom development and is associated with a decline of antibody
titres. Patients’ antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a
mechanism of crosslinking and internalisation. On the basis of models of pharmacological or
genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation
between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.
Introduction
In 2005, a syndrome of memory deficits, psychiatric symptoms, decreased consciousness,

and hypoventilation was reported in four young women with ovarian teratomas.1 Specific
autoantibodies to the N-methyl D-aspartate receptor (NMDAR) were soon detected in these
and eight other patients with similar neurological symptoms, seven of whom also had
ovarian teratomas.2 During the following 3 years we identified 419 other patients with this
syndrome, many of them children and young adults with or without an associated tumour.
Correspondence to: Prof Josep Dalmau, Division of Neuro-Oncology, Department of Neurology, 3 West Gates, University of
Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA, [email protected].
Contributors
JD examined patients, and interviewed physicians and families. JD and RB-G provided synaptic and cell-based experimental data.
EM-H collected and analysed clinical data. EL and MRR did the literature search and examined the mechanisms related to genetic and
pharmacological alterations of NMDAR. JD, EL, MRR, and RB-G wrote the paper.
Conflicts of interest
A patent application for the use of NMDAR antibody determination in patients’ serum samples and CSF as a diagnostic test has been
filed in USA and Europe by JD. EL has a training grant from Talecris, a company that sells human immnoglobulin. None of the other
authors declare any conflicts of interest.
Dalmau et al. Page 2
The discovery of this disorder, termed anti-NMDAR encephalitis, has changed the
diagnostic approach to clinical problems as diverse as catatonia, subacute memory
disturbance, seizures, abnormal movements, and limbic encephalitis.3 It has also led to the
discovery of other autoimmune synaptic encephalitides mediated by antibodies against the

AMPA receptor (AMPAR);4 the γ-amino-butyric acid-B receptor (GABAB-R);5 and
leucine-rich, glioma-inactivated 1 (LGI1), which is the main autoantigen of limbic
encephalitis previously attributed to voltage-gated potassium channels.6 In addition to their
clinical significance, these immune responses provide insights into the function of the
neurotransmitter receptor targeted by the antibodies.7
In this Review we present our clinical experience in the diagnosis and management of
hundreds of patients with anti-NMDAR encephalitis and also discuss reports from other
investigators. We address the clinical presentation, differential diagnosis, frequency of
tumour association, the cellular and synaptic mechanisms of the disease, and the process of
recovery. We also discuss several confounding factors that often delay the recognition of
this disorder, and propose an algorithmic strategy to guide treatment.
Frequency
The exact incidence of anti-NMDAR encephalitis is unknown, but on the basis of the rapid
accrual of patients and increasing number of case reports, it seems to be more frequent than
any other known paraneoplastic encephalitis. Evidence from intensive care,9–11
paediatric,12,13 and neurology departments8 lend support to this idea. In one retrospective
analysis of encephalitis of unknown origin,10 NMDAR antibodies were identified in 1% of
patients (aged between 18 and 35 years) admitted to an intensive care unit. A multicentre,
population-based prospective study of causes of encephalitis in the UK14 showed that 4% of
patients had anti-NMDAR encephalitis; the disorder was the second most common immune-
mediated cause, after acute disseminated encephalomyelitis and before all antibody-
associated encephalitis, including encephalitis attributed to voltage-gated potassium
channels. In another study,15 a series of 200 patients with anti-Hu-antibody-associated
encephalomyelitis was accrued over 13 years, and 500 cases of autoimmunity to proteins
that interact with voltage-gated potassium channels were identified over a 6-year period.16
Thus, by comparison, our experience of 400 patients with anti-NMDAR encephalitis in just
3 years suggests a relatively frequent disorder.
The syndrome
Antibodies against the NR1 subunit of the NMDAR (NMDAR antibodies) are associated
with a characteristic syndrome that develops in several stages of illness and recovery, as first
reported by Iizuka and colleagues17 and Sansing and colleagues.18 About 70% of patients
have prodomal symptoms consisting of headache, fever, nausea, vomiting, diarrhoea, or

upper respiratory-tract symptoms. Within a few days, usually less than 2 weeks, patients
develop psychiatric symptoms and many are seen initially by psychiatrists. Anxiety,
insomnia, fear, grandiose delusions, hyper-religiosity, mania, and paranoia are frequent
manifestations; social withdrawal and stereotypical behaviour are sometimes seen. Short-
term memory loss is common but underestimated because psychiatric symptoms and speech
problems often interfere with the assessment of memory.8 A rapid disintegration of
language, from reduction of verbal output and echolalia (usually with echopraxia) to frank
mutism, is frequent and cannot be attributed to cortical aphasia.
In young children, the behavioural change can be difficult to detect because they often
present with temper tantrums, hyperactivity, or irritability as opposed to frank psychosis. In
children, the first symptom to be recognised is often non-psychiatric—eg, seizures, status
epilepticus, dystonia, verbal reduction, or mutism. Some behaviours are hypersexual and

violent (for instance, kicking and biting caregivers and parents). Because of anxiety and
insomnia, some children need intense sedation.12
This initial phase of the illness is usually followed by decreased responsiveness that can
alternate between periods of agitation and catatonia. At this stage, abnormal movements and
autonomic instability are usual manifestations. Oro-lingual-facial dyskinesias are the most
characteristic movements, but other types might occur simultaneously or alternate with limb
and trunk choreoathetosis, elaborate motions of arms and legs, oculogyric crisis, dystonia,
rigidity, and opisthotonic postures (see video recordings19–23). The most frequent autonomic
manifestations include hyperthermia, tachycardia, hypersalivation, hypertension,
bradycardia, hypotension, urinary incontinence, and erectile dysfunction.8 Two women
(aged 16 and 17 years) were thought to have Takotsubo cardiomyopathy (or stress
cardiomyopathy) due to high blood pressure (JD, unpublished). Hypoventilation, requiring
respiratory support, occurs as the patient becomes comatose but can occur earlier when the
level of consciousness is relatively preserved. In some cases the central origin of
hypoventilation is noted when patients cannot be weaned from mechanical ventilation.
While recovering, one patient needed nocturnal ventilatory support for 3 months. Autonomic
storms can fluctuate from tachycardia to bradycardia and longlasting cardiac pauses, which,
in some patients, require a temporary pacemaker.18 A transient increase of intracranial
pressure has been recorded in a few patients (JD, personal observation).
Motor or complex seizures develop at early stages of the disease. The overlap of abnormal
movements and epileptic seizures can lead to under-recognition of the seizures or
unnecessary escalation of antiepiletics for dyskinesias that are interpreted as seizures.24 In
general, the frequency and intensity of the seizures decrease as the disease evolves.
However, seizures and status epilepticus can resurface at any time during the illness.
Attempts to wean patients from sedation can result in status epilepticus.2
During such stages, in which patients are usually managed in intensive care units,
dissociative responses to stimuli are noted. For example, patients often resist eye opening
but show little or no response to painful stimuli.17 This dissociative state is similar to that
caused by NMDAR antagonists, such as phencyclidine or ketamine, which are called
dissociative anesthetics.25,26
Oversimplification of the disease into cortical and subcortical stages and the suggestion that
patients without a tumour have a less impaired level of consciousness than do patients with a
tumour27 is (in our experience) highly inaccurate. Many symptoms with which a patient
presents (such as anxiety, fear, bizarre or stereotypical behaviour, insomnia, and memory
deficits) cannot be classified as cortical. Clinical examination of patients reveals a diffuse
encephalopathy indicating dysfunction of subcortical structures, limbic regions, amygdalae,

and frontostriatal circuitry. Patients without tumours have periods of unconsciousness and
confusion that can be longer or worse than are those of patients with tumours.8,12,28
Diagnostic tests
Brain MRI is unremarkable in 50% of patients, and in the other 50%, T2 or FLAIR signal
hyperintensity might be seen in the hippocampi, cerebellar or cerebral cortex, frontobasal
and insular regions, basal ganglia, brainstem, and, infrequently, the spinal cord.2 The
findings are usually mild or transient and can be accompanied by subtle contrast
enhancement in the affected areas or the meninges.8 Follow-up MRIs either remain normal
or show minimum change despite the severity and duration of symptoms. Earlier reports2,17
of patients who had refractory seizures, or who did not recover or died, showed pronounced
brain atrophy. Lesions can occur that appear demyelinating, do not usually enhance, and are
transient. One patient with severe, relapsing symptoms, attributed to atypical antibody-

negative neuromyelitis optica, had anti-NMDAR encephalitis that substantially improved

after aggressive immunotherapy.29 A few studies that used MR spectroscopy,30 fluoro-2-
deoxy-d-glucose-PET,17,31,32 or 99mTc-d,l-hexamethyl-propyleneamine oxime (HMPAO)
single photon emission computed tomography (SPECT)17,33 have shown variable multifocal
cortical and subcortical abnormalities that change during the course of the disease, although
in some cases early SPECT studies were normal.17 Reversible frontotemporal hypoperfusion
and brain atrophy, not due to corticosteroid treatment, have been reported in two patients
with follow-up of 5–7 years.34
Electroencephalograms (EEG) are abnormal in most patients, usually showing non-specific,

slow, and disorganised activity sometimes with electrographic seizures.8 Slow, continuous,
rhythmic activity in the delta-theta range predominates in the catatonic-like stage.12 This
activity is not associated with abnormal movements and does not respond to antiepileptic
drugs. Monitoring with video EEG is important to diagnose and treat seizures
appropriately.24 One patient had non-convulsive status epilepticus that lasted for 6 months
and required a pentobarbital-induced coma.35 A prophylactic oopherectomy was done and a
microscopic ovarian teratoma was detected; the patient recovered afterwards.
The cerebrospinal fluid (CSF) is initially abnormal in 80% of patients and becomes
abnormal later in the disease in most other patients.8 Findings include moderate lymphocytic
pleocytosis, normal or mildly increased protein concentration, and, in 60% of patients, CSF-
specific oligoclonal bands. Most patients have intrathecal synthesis of NMDAR

antibodies.3,8,27 Of 431 patients studied (412 with paired serum and CSF), we have not
encountered a patient in whom antibodies were only present in serum. If diagnosis is
delayed or patients have received treatment with plasma exchange or IV immunoglobulin,
antibodies might be detected only in CSF.10,12 Similarly, patients with a protracted clinical
course or persistent symptoms might be seronegative and have persistently raised CSF titres
until symptoms improve (figure 1; JD, unpublished). Less frequently, long-term follow-up
reveals patients who, after recovery, still have high serum titres and absent or barely
detectable titres in the CSF (any antibodies in the CSF would probably have leaked from the
serum).20 These findings are consistent with a disease in which the immune response is
initially triggered systemically by a tumour or other unknown causes and is reactivated and
expanded in the CNS.
Brain biopsy does not provide a diagnosis of anti-NMDAR encephalitis. Biopsies in 15

patients showed normal or non-specific findings, including perivascular lymphocytic cuffing
(predominantly of B cells), sparse parenchymal T-cell infiltrates, or microglial
activation.8,36 Data from autopsy studies show similar findings along with plasma cells and
rare or absent neuronophagic nodules.2,37
Sex, tumour association, and potential triggers of the immune response

About 80% of patients with anti-NMDAR encephalitis are women. The detection of an
underlying tumour is dependent of age, sex, and ethnic background.8,12 Figure 2 shows the
distribution of 400 patients grouped by age and the presence or absence of a tumour. When
compared with a previous series,8 these data show that, with increased awareness of this
disorder, the disease is being more frequently recognised in younger teenagers and children.
Analysis of these 400 patients confirms that the younger the patient, the less likely that a
tumour will be detected, and that in female patients older than 18 years, the frequency of an
underlying teratoma is much the same as we initially reported (webappendix p 1).8 Black
women are more likely to have an underlying ovarian teratoma than are patients of other
ethnic groups (webappendix p 2)

Only 5% of male patients older than 18 years had an underlying tumour. Detection of
tumours other than teratoma is not very common—eg, of 400 patients studied, only 7 (2%)
had a tumour other than an ovarian teratoma (webappendix p 1). One patient with
neuroblastoma and another with Hodgkin’s lymphoma have been reported.38,39 The ovarian
teratomas of 25 patients showed expression of NMDAR in all cases.37 The expression of
NR1 by other tumours has been examined in only one patient with breast cancer and proved
positive (unpublished). Whether tumours other than teratomas are true associations or
unrelated coincident disorders is unknown.
On the basis of these data, the first concern in female patients should be screening for an
ovarian teratoma. The most useful screening tests include MRI, CT scan, and pelvic and
transvaginal ultrasound (if age appropriate). Serological tumour markers (CA125, β-HCG,
α-fetoprotein, or testosterone) have not been systematically assessed but are negative in
many patients. High serum concentrations of testosterone and signs of virilisation were
identified in a 15-year-old girl who, for 16 months, had relapsing episodes of encephalitis
and psychosis. Her serum was positive for NMDAR antibodies and a large mature teratoma
containing 6 L of fluid was removed, resulting in full recovery.40 In some patients,
exploratory laparoscopies and blind oophorectomies showed ovarian tumours,8,35 but in
others no tumour was detected.28
Because the presentation of anti-NMDAR encephalitis often suggests an infectious process,

many patients undergo extensive blood and CSF assessments. A few patients had positive
serological tests suggesting an infection (eg, positive serum mycoplasma usually in
children),41 or direct evidence of a concomitant infection (eg, two patients with herpes
zoster; JD, unpublished). In four patients with neurological complications attributed to
influenza H1N1, one had NMDAR antibodies.42 The clinical picture of this patient, but not
the other three, was typical of anti-NMDAR encephalitis. Moreover, none of the above
mentioned patients had CSF findings indicating direct viral involvement of the CNS. The
absence of detection of a consistent infectious agent makes an immune response by
molecular mimicry unlikely.
Two patients developed the disorder after vaccination against H1N1 influenza (JD, personal
observation), and one patient after a booster vaccination against tetanus, diphtheria,
pertussis, and poliomyelitis.43 A 3-year-old child had a microdeletion in the short arm of
chromosome 6 that involved the HLA cluster, leading investigators to suggest a
predisposition to autoimmunity.44 A similar propensity to autoimmunity has been suggested
in patients, mostly children, who had, in addition to NMDAR antibodies, antinuclear or
thyroid peroxidase antibodies, or both.12 These findings suggest that racial and genetic
factors might predispose individuals to this type of autoimmunity, as shown in myasthenia
gravis and Lambert-Eaton syndrome, which also occur as paraneoplastic or non-

paraneoplastic syndromes.45–47 In this context, non-specific systemic infections or
vaccinations can act as an adjuvant of the autoimmune response.
Treatment, outcome, and relapses

About 75% of patients with NMDAR antibodies recover or have mild sequelae; all other
patients remain severely disabled or die.8 Management of anti-NMDAR encephalitis should
initially focus on immunotherapy and the detection and removal of a teratoma. Most patients
receive corticosteroids, intravenous immunoglobulins (IVIg) or plasma exchange as first-
line of immunotherapy. These treatments have enhanced effectiveness and speed of action
when patients have an underlying tumour that is removed.8,12,27 In patients without a
tumour or with delayed diagnosis, additional treatment with second-line immunotherapy (a
rituximab or cyclophosphamide, or both) is usually needed.12,21,48 Our experience with 105

consecutively diagnosed patients in 2009 accord with these findings (figure 3). Although
80% of patients with a tumour (mostly teratomas) had substantial improvement after tumour
removal and first-line immunotherapy, only 48% of those without a tumour had a similar
degree of improvement after first-line immunotherapy (p=0·001; unpublished) and needed

second-line immunotherapy more often. Overall, second-line immunotherapy resulted in
substantial improvement in 15 of 23 (65%) patients. The final outcome, substantial
improvement (as previously defined8), was much the same in patients with or without
tumour (84% vs 71%, p=0·16), but the five patients who died did not have a tumour and did
not receive second-line immunotherapy.
Reports exist of patients with predominant psychiatric manifestations that were given
electroconvulsive treatment (JD, unpublished).12 One patient’s disorder resolved without
further treatment,49 but the other patients only had a definitive improvement after
immunotherapy or removal of an underlying teratoma.50
Infrequently, the neurological response to tumour removal can be seen in a matter of

hours,51 suggesting an effect of anaesthetics on NMDAR function. In one patient, induction
of anaesthesia with propofol for a spinal tap produced pronounced hypotension; a repeat
procedure several months later with a reduced dose of propofol was well tolerated.52 We are
not aware of other complications related to anaesthetics.
Spontaneous neurological improvement has been reported, but usually occurs at the expense
of longer hospital stay and slower recoveries. Iizuka and colleagues17 described four women
with NMDAR antibodies identified in serum and CSF collected 4–7 years before the study,
providing the best natural history we have of this illness. Despite an absence of consistent
immunotherapy or tumour removal (tumours being identified in three patients several years
after recovery), all had gradual recovery (mean 7 months in hospital, recovery of more than
3 years for two patients). By contrast, one patient who developed the disorder before it was
described as a clinical entity had medical support withdrawn 3 months after the onset of
symptoms because their symptoms were judged to be irreversible. Analysis of the patient’s
serum and CSF and a review of autopsy material showed anti-NMDAR antibodies and an
ovarian teratoma.2 In another case, medical support was going to be discontinued when anti-
NMDAR antibodies were identified; treatment was continued and the patient recovered after
treatment with rituximab and cyclophosphamide (JD, unpublished). Relapses occur in 20–
25% of patients.8,12,27 They can be separated by intervals of months or years, usually with
substantial recovery between relapses. Patients’ symptoms can worsen when treatments are
tapered or discontinued.
The process of recovery

Recovery from anti-NMDAR encephalitis occurs as a multistage process that happens in the
reverse order of symptom presentation. Patients slowly wake from coma as their autonomic
functions stabilise, respiration recovers, and dyskinesias subside; they are able to follow
simple commands and can have appropriate interactions before they recover verbal
functions. During this period patients can become psychotic and agitated again, calming as
they recover further (JD, unpublished observations). Social behaviour and executive
function symptoms are usually the last to improve, and recovery can be incomplete or
delayed by many months.
For the acute stage of the disease, many patients need to be hospitalised for at least 3–4
months, followed by several months of physical and behavioural rehabilitation.8,12,17
Patients need close supervision to prevent incidents caused by inappropriate behaviour,
impulsivity, disinhibition, and sometimes hyperphagia, hypersexuality, and hypersomnia.
Patients’ symptoms might resemble those of patients with Klüver-Bucy syndrome (bulimia,

hypersexuality, flat affect, memory loss, visual agnosia), Kleine-Levin syndrome

(hypersomnia, compulsive hyperphagia, hypersexuality, apathy, child-like behaviour) or a
persistent encephalitis lethargica (JD, personal observation).49,53 Counselling about long-
term prognosis, even in the most disabled patients, should be done with caution.
Anti-NMDAR encephalitis during pregnancy

Three patients were diagnosed with anti-NMDAR encephalitis while pregnant, and two of
them had ovarian teratomas.54 The pregnancy was terminated in one patient who had
recurrent bilateral ovarian teratomas. The two other patients carried the pregnancy to term
and delivered healthy babies. One baby was thoroughly tested for antibodies in serum, cord
blood, and CSF, and was shown to be negative; at diagnosis the mother had antibodies
detectable only in CSF, which probably explained the absence of transfer to the fetus.
During pregnancy, patients were treated safely with methylprednisolone, IVIg, or plasma
exchange with mild or questionable improvement. In all three patients, recovery seemed to
accelerate after delivery or termination of the pregnancy.
Milder or incomplete forms of the disorder (formes frustes)

Milder or incomplete forms of the disorder in which patients develop predominant or
apparently isolated psychiatric symptoms, seizures,55 or dystonia56 can occur. Some of these
forms represent a referral bias—eg, 5 of 6 patients with new onset epilepsy55 also had other
neurological or psychiatric symptoms. In our experience, pure monosymptomatic syndromes

are uncommon and arise in less than 5% of patients.8 The most common scenario is that of
patients with a predominant symptom and milder manifestations of other elements of the
syndrome, or those who later develop other symptoms. For example, the parents of a 19-
year-old man who had been diagnosed with pure mania indicated that for several weeks he
had had memory problems at school. They denied abnormal movements, but when showed
several forms of oculofacial dyskinesias, they indicated that, along with memory problems,
the patient had profuse eye blinking, a symptom they attributed to being anxious.
Mortality and causes of death

On the basis of data for 360 patients with clinical follow-up longer than 6 months, the
estimated mortality for anti-NMDAR encephalitis is 4% (15 patients died; seven of them
previously reported8). The median time from disease onset until death was 3·5 months
(ranging from 1 to 8 months). 14 patients died in intensive care units: three died of sepsis,
two of sudden cardiac arrest, two of acute respiratory distress (one associated with renal
failure, and one with atrial fibrillation and hyponatraemia), two of refractory status
epilepticus, two of tumour progression, one after withdrawal of medical support, and two of
an unknown cause. The only patient who did not die in an intensive care support unit died of
unclear cause in a nursing home facility.
Differential diagnosis
The constellation of symptoms in anti-NMDAR encephalitis results in a characteristic
syndrome that can suggest alternative diagnoses at different stages. Patients, particularly
adults, are often diagnosed with new onset psychosis. Many patients are treated with
antipsychotic medication, such as haloperidol, and then when they develop rigidity,
autonomic instability, increased concentrations of muscle enzymes, or rhadomyolysis are
thought to have neuroleptic malignant syndrome.18 However, these symptoms also occur in
patients who do not receive neuroleptics. Drugs that block NMDAR function, such as
phencyclidine, can produce similar symptoms.26,57

Rhabdomyolysis can also occur as an adverse side-effect of high-dose and long-term use of
propofol (propofol infusion syndrome). Additional manifestations of propofol infusion
syndrome include severe metabolic acidosis, hyperkalaemia, lipaemia, renal failure,
hepatomegaly, and cardiovascular collapse.58 We are not aware of any patient with anti-
NMDAR encephalitis who developed this syndrome, but since many of these patients need
protracted sedation with propofol, and also receive corticosteroids (a risk factor for propofol
infusion syndrome), the possibility of this complication should be kept in mind.
Viral encephalitis is an early presumptive diagnosis, suggested by the acute neurological

change, CSF pleocytosis, and occasional hyperthermia.59 Three of our patients were
suspected to have rabies because of the development of psychiatric symptoms, decreased
consciousness, dystonic facial movements, hypersalivation, and autonomic instability (JD,
unpublished). Ten of 20 children who had previously been enrolled in the California
encephalitis project with a diagnosis of idiopathic encephalitis with psychiatric
manifestations and dyskinesias had NMDAR antibodies.41 In a study53 that examined
patients who had previously been diagnosed with encephalitis lethargica, many with
dyskinesias were shown to have NMDAR antibodies. There are several reported disorders,60
mainly in paediatric studies,13,61–65 that were probably cases of anti-NMDAR encephalitis.
Pathogenic mechanisms and effects of antibodies

Compelling clinical and laboratory evidence exists that anti-NMDAR antibodies are
pathogenic. As previously discussed, antibody titres in CSF and, less often, in serum relate
with clinical outcome. Furthermore, the reversibility of the disorder, irrespective of the
duration of symptoms, suggests an immune-mediated neuronal dysfunction rather than
irreversible degeneration. These features, coupled with the paucity of brain T-cell infiltrates,
places this disorder in a category distinct from those that are mediated by complement or
cytotoxic T-cell mechanisms.66,67 Although patients’ antibodies are of the IgG1 and IgG3
classes,37 and therefore capable of activating complement, autopsy and biopsy studies show
deposits of complement in the tumour, but not in the brain, despite the presence of IgG in
brain (EM-H, unpublished).2 This occurrence is probably attributable to preservation of the
blood–brain barrier and low concentrations of complement in the CNS.
The first study8 showing that patients’ antibodies altered the density of NMDAR used rat
hippocampal neurons treated for 3 or 7 days with CSF or with IgG isolated from serum. The
antibodies caused a pronounced decrease of surface NMDAR clusters that was reversible on
removal of patients’ antibodies from the culture. Subsequently, Hughes and colleagues68 did
a comprehensive assessment of the effects of patients’ antibodies on synaptic NMDAR with
in vitro and in vivo experiments. They showed that anti-NMDAR antibodies cause a
selective and reversible decrease in NMDAR surface protein, cluster density, and synaptic
localisation that is associated with CSF and serum antibody titres. The mechanism of this
decrease was selective antibody-mediated capping and internalisation of surface NMDARs,
because monovalent Fab fragments prepared from patients’ antibodies did not decrease
surface receptor density, whereas crosslinking with anti-Fab antibodies (linking two Fab
fragments in a conformation much the same as unmodified antibodies from patients)
recapitulated the decrease caused by patients’ antibodies that were intact (figure 4).
Additionally, whole-cell patch clamp recordings to assess miniature excitatory postsynaptic
currents in cultured rat hippocampal neurons showed that patients’ antibodies specifically
decreased synaptic NMDAR-mediated currents, but did not affect AMPA receptor-mediated
currents (figure 4). By contrast with these robust effects on NMDARs, patients’ antibodies
did not alter the localisation or expression of other glutamate receptors or synaptic proteins,
the number of synapses, dendritic spines, dendritic complexity, or cell survival. Results from
in-vivo experiments showed that infusion of patients’ antibodies into rat hippocampus

substantially reduced NMDAR density, much the same as the decrease of these receptors
seen in the hippocampi of patients on autopsy (figure 4).
These studies show that antibodies from patients with anti-NMDAR encephalitis lead to the
rapid and reversible loss of surface NMDAR by antibody-mediated capping and
internalisation, resulting in abrogation of NMDAR-mediated synaptic function. Our insights
are based on studies by Drachman and colleagues,69 which show that acetylcholine receptor
antibodies from patients bind, cap, and internalise receptors at neuromuscular junctions as a
mechanism underlying myasthenia gravis. Our studies further imply that synaptic loss of this
subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in
patients’ symptoms.
Prüss and co-workers10 reproduced the antibody-induced decrease of NMDAR

concentrations in cultured hippocampal neurons. Results from a study measuring NMDA-
mediated calcium internalisation in cultured granular cerebellar neurons showed that after 1
h of treatment with a patient’s CSF, calcium entry substantially decreased.56 In another
study,70 patients’ antibodies were injected in the prefrontal area of rodents and the effects on
the afferent facilitation for corticomotor responses were assessed in a conditioning
paradigm. Patients’ antibodies substantially enhanced the excitability of motor cortex,
suggesting overactivity of glutamatergic pathways.70 This glutamatergic hyperactivity has
been shown in models of pharmacological or genetic reduction of NMDAR, and is the basis
of the NMDAR hypofunction theory of schizophrenia discussed below.71
Patients phenotype resembles those of genetic or pharmacological

disruption of NMDAR
Studies investigating the effects of phencyclidine and ketamine (non-competitive antagonists
of NMDARs) in human beings show that these drugs induce behaviours that are much the
same as the positive and negative symptoms of schizophrenia, along with repetitive orofacial
and limb movements, autonomic instability, and seizures.25,72–75 In rodents, drugs that
antagonise NMDAR function induce cataleptic freeze and locomotor and stereotypical
behaviours.76–79 Mice with decreased expression of NR1 also have such behavioural
deficits, whereas mice that do not express NR1 develop breathing problems and die in the
perinatal period.80 A mouse strain in which 40–50% of NMDARs in cortical and
hippocampal neurons were selectively eliminated showed schizophrenia-related symptoms
and social and spatial working memory deficits that emerged after sexual maturity.81
The profile of symptoms caused by antagonists of NMDAR is dose dependent and varies in
much the same way as the multistage clinical course of anti-NMDAR encephalitis does
(figure 5). At low doses, NMDAR antagonists cause psychosis, agitation, memory
disturbance, and decreased responsiveness to pain, and at higher doses they cause
dissociative anaesthesia, a state of profound unresponsiveness with catatonic features, and
coma.82 NMDAR blockade disrupts the control of brainstem respiratory centres by higher
brain regions83 and the perception of pain.84 Therefore, progressive decrease of NMDAR by
patients’ antibodies and gradual restoration of NMDAR after a decline in antibody titre
might probably result in the multistage process of illness and recovery seen in patients with
anti-NMDAR encephalitis.
All steps and resulting clinical features of anti-NMDAR encephalitis outlined in figure 6
have been shown in animal models with a pharmacological or genetic decrease of NMDAR
expression.26,80,83 In these models, inactivation of GABAergic neurons, which express
higher concentrations of NMDAR than do other neuronal subtypes, has a central role in
clinical manifestations of the disease. Keeping in mind that in anti-NMDAR encephalitis the

effects of patients’ antibodies on GABAergic neurons have not been studied, we postulate
that an antibody-mediated decrease of NMDAR predominantly inactivates GABAergic
neurons and leads to most of the clinical features of the disorder. The complexity of some
abnormal movements could be explained by disinhibition of a brainstem central pattern

generator.85 Facial movements including rooting, sucking, and limb movements can occur in
anencephalic newborn babies.87 Other abnormal movements that manifest as learned
sequences of motions (eg, piano playing or dancing-like motions) are probably caused by
basal ganglia dysfunction. Taken together, these studies and the NMDAR-depleting effects
of patients’ antibodies in neurons in vitro and in the hippocampi of rats after infusion in
vivo,68 strongly suggest that an antibody-mediated decrease of NMDAR in the entire brain
will probably provide a behavioural animal model that is much the same as those obtained
by use of pharmacological or genetic reduction of NMDAR.
Approach to diagnosis and proposal of a treatment strategy

Anti-NMDAR encephalitis should be suspected in any individual, usually younger than 50
years and especially a child or a teenager, who develops a rapid change of behaviour or
psychosis, abnormal postures or movements (mostly orofacial and limb dyskinesias),
seizures, and variable signs of autonomic instability, hypoventilation, or both. Supportive
findings include CSF lymphocytic pleocytosis or oligoclonal bands; electroencephalogram
with infrequent spikes, but frequent, slow, disorganised, sometimes rhythmic activity that
does not relate with most abnormal movements; and brain MRI that is often normal or
shows transient FLAIR or contrast-enhancing abnormalities.
Antibody studies should be done in both serum and CSF. Such tests allow comparison of
antibody concentrations during the course of the disease. Periodic screening of serum and
CSF is useful to assess the effects of treatment, especially in the CNS. All patients should be
examined for the presence of an underlying tumour, mainly an ovarian teratoma or a
testicular germ-cell tumour. The very low frequency of other tumours suggests that periodic
whole-body screening, as recommended for classic paraneoplastic syndromes, is
unnecessary.88 However, we do recommend periodic screening for ovarian teratomas for at
least 2 years, even if patients have recovered from encephalitis.17
On the basis of previous experience and data from this Review, a proposal for treatment is
shown in figure 7. Although no standard of care exists, we prefer concurrent IVIg (0·4 g/kg
per day for 5 days) and methylprednisolone (1 g/day for 5 days) to plasma exchange. Plasma
exchange is more difficult to do in children, poorly cooperative patients, or patients with
autonomic instability. If no response is seen after 10 days, we start second-line therapy. In
adults, we use rituximab (375 mg/m2 every week for 4 weeks) combined with
cyclophophamide (750 mg/m2 given with the first dose of rituximab), followed by monthly
cycles of cyclophosphamide. This treatment is discontinued when patients have had

substantial clinical recovery, which is usually accompanied by a decrease of CSF and serum
antibody concentrations. Paediatricians often use only one of these drugs—mostly
rituximab. After substantial improvement, antiepileptics are not needed in most patients.
Because relapses occur in 20–25% of patients, often in those without teratoma, in such
patients we recommend continued immunosuppression (mycophenolate mofetil or
azathioprine) for at least 1 year after initial immunotherapies are discontinued.
Future studies
In this Review we have shown that anti-NMDAR encephalitis defines a new syndrome,
reclassifies poorly defined disorders, and strengthens previous hypotheses, such as
hypofunction of NMDAR in schizophrenia. Future studies should clarify the mechanism and
timing of how the immune response is expanded in the CNS, the best treatment approach,

and strategies to accelerate the process of recovery. The frequency of the disorder suggests
that multicenter clinical trials are feasible. The idea that GABAergic inactivation occurs not
only in pharmacological and genetic models of decrease of NMDAR but also in patients
with anti-NMDAR encephalitis needs to be confirmed. Further studies on the effects of

antibodies at the cellular, synaptic, and circuit levels in animal models that recapitulate the
disease and the process of recovery are necessary to fully understand how these and other
synaptic antibodies affect brain function.
Acknowledgments
We thank physicians, patients, and families for providing information, and patients and family members who
volunteered to come to our institution for clinical assessment; Lindsey McCracken for her excellent job collecting
data; and Francesc Graus for critical review of the manuscript. This work was supported in part by grants from the
National Institutes of Health and National Cancer Institute RO1CA89054 (JD), 1RC1NS068204-01 (JD and RB-G),
and a McKnight Neuroscience of Brain Disorders award (JD and RB-G), Fondo de Investigaciones Sanitarias
F108100285 (EM-H), and a Dana Foundation Neuro-imunology Award (EL).
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Search strategy and selection criteria

References for this Review were identified by searches of PubMed from 1966 to October,
2010, with the search terms “NMDA receptor encephalitis”, “anti-NMDAR
encephalitis”, and “N-methyl-D-aspartate receptor encephalitis”. Articles were also

identified through searches of the authors’ own files. Papers published in English,
German, and Spanish were reviewed. Data from 400 patients were obtained from clinical
examination (72 cases seen by JD) and information provided by patients, their families,
and physicians. Serum and CSF samples from these patients were examined by the
authors by use of previously reported techniques.8

Figure 1. Antibody studies in a patient without tumour and extended clinical course
An 18-year-old man was transferred from another hospital after 4 weeks’ of being in coma.
At admission, his CSF and serum were assessed at dilution 1 in 40 for reactivity with
HEK293 cells that recombinantly expressed NR1/NR2 heteromers of the NMDAR. Only the
patient’s CSF was positive (A). B shows the reactivity of a monoclonal antibody against
NR1, and co-localises with patient’s CSF reactivity (merged immunolabelling in C). D
shows that the patient’s serum did not react with cells expressing NR1/NR2; in E these cells
are immunolabelled by use of a monoclonal antibody against NR1. F shows the merged
reactivities. In C and F the nuclei of the cells are stained with DAPI. The graph shows
NMDAR antibody titres in CSF over time. Titres were measured by ELISA for 13 months.
CSF from control individuals with disorders other than anti-NMDAR encephalitis (eg,
stroke, encephalitis suspected to be autoimmune, cerebellar degeneration, and viral
encephalitis) were less than 500 relative fluorescence units (RFU; data not shown). The
patient was treated initially with corticosteroids and intravenous immunoglobulin (IVIg)
without improvement, and subsequently with rituximab and monthly cyclophosphamide.
During the clinical course the brain MRI showed mild generalised atrophy. He is currently at
home and able to take care of himself, have normal conversations, and play computer
games, but is still recovering from symptoms of frontotemporal dysfunction. All techniques
have been described elsewhere.8 CSF=cerebrospinal fluid. NMDAR=N-methyl-D-aspartate
receptor.

Figure 2. Distribution of patients by age and presence or absence of tumours

Data are for 400 patients with anti-NMDAR encephalitis.

Figure 3. Treatment and outcome in 105 patients comparing presence and absence of tumour
and the use of second-line immunotherapy
First-line immunotherapy consists of corticosteroids, IVIg and plasma exchange given alone
or in combination (detailed below). *Second-line immunotherapy, consists of rituximab or
cyclophosphamide, or both. Substantial improvement is defined as previously reported,8 and
includes full recovery or minimum deficits estimated by physicians and family members as
recovery of more than 90% of function. All other patients are judged to have little
improvement or no change. In patients with tumour, first-line treatment indicates tumour
removal and in most cases first-line immunotherapy. Although there was no difference
between the proportion of patients who achieved substantial recovery with or without
tumour (Fisher’s exact test, p=0·16), patients with tumour responded to first-line treatment
more often than did patients without tumour (p=0·001). Those without tumour required
second-line immunotherapy more often and the 5 patients who died were in this group.
Whether these patients had occult tumours is unknown.

Figure 4. Association between patients’ antibodies and internalisation of NMDAR receptors and
abrogation of NMDAR currents
(A) Hippocampal neurons immunostained for surface and internal (total) N-methyl-D-
aspartate receptor (NMDAR) clusters (top row, stained with commercial NR1 subunit
antibody), surface NMDAR clusters only (middle row, stained with patients’ cerebrospinal
fluid [CSF]) and their co-localisation (bottom row, surface NMDAR clusters in yellow).
Treatment with patients’ IgG for 1 day decreases surface and total NMDAR cluster density
compared with control IgG. Treatment with patient Fab fragments does not affect surface or
total NMDAR cluster density, whereas treatment with divalent patient Fab fragments (Fab
fragments and anti-Fab secondary antibodies) decreases surface and total NMDAR cluster
density to an extent similar to patients’ IgG. (B) Effects of patients’ IgG, Fab fragments, and
divalent Fab fragments on surface and total NMDAR cluster density. (n=30 cells, four
independent experiments; two samples from patients, two samples from control patients
with unrelated neurological disorders with no immune system involvement). All values are
mean ± SE. *=significant difference (one-way ANOVA test followed by Bonferroni’s
multiple comparison test, p<0·00071). (C) Graphic representation of the effect of each
treatment on surface receptor clusters. (D) Representative average miniature excitatory
postsynaptic currents (mEPSCs) recorded in magnesium (Mg2+)- free physiological saline
with tetrodoxin (TTX) and picrotoxin to isolate synaptic NMDAR-mediated currents. In
neurons treated with IgG from controls for 1 day, 2-amino-5-phosphonovaleric acid (APV),
an NMDAR antagonist, blocks the slow decay of the mEPSC (dark green trace). The
difference between the dark green traces is the slow NMDAR-mediated current. Neurons
treated for 1 day with CSF from a patient (right) have no APV sensitive, NMDAR-mediated
current (ie, no difference between the dark green traces). (E) Brain sections from rats
infused with CSF from controls (top left) contain many NMDAR clusters in the cornu
ammonis (CA1) of the hippocampus, whereas brain sections from rats infused with a
patient’s CSF (top right) contain substantially fewer NMDAR clusters. Presynaptic synapsin
immunostaining is similar between groups (bottom left, right). (F) Effect of 2-week-infusion
of patients’ CSF with different antibody titres on NMDAR cluster density in CA1. Each
point represents the mean NMDAR cluster density from three to five images from an
infused rat, ±SE. Patients’ CSF with higher antibody titres reduced NMDAR cluster density
to a greater extent than did lower titre samples. These findings indicate that infusion with
patients’ CSF results in a titre-dependent decrease in NMDA cluster density (linear
regression analysis; R2=0·32, p<0·03). All values are mean±SE. Data are for nine rats killed
after 14 days of infusion; five CSF samples from patients, and four CSF samples from
controls. (G) Hippocampal section from a healthy individual (left) and from a patient with
anti-NMDAR encephalitis (right) immunostained with a commercial NR1 antibody. (H)
Intensity of NR1 immunostaining is substantially reduced in the hippocampi of anti-
NMDAR encephalitis patients (n=2) compared with hippocampi of controls (3). The

distribution of both patient values for NR1 intensity differed significantly from the
distribution of control values (paired Komolgorov-Smirnov test, p<0·03). All data adapted
from Hughes and colleagues,68 with permission from the Society for Neuroscience.

Figure 5. Stages of illness and recovery

In patients with anti-NMDAR (N-methyl-D-aspartate receptor) encephalitis, the processes of
symptom presentation and recovery develop in opposite directions (A). The clinical picture
is much the same as that caused by phencyclidine, in which the profile of symptoms
correlates with the circulating concentration of drug (B). Since NMDAR antibodies cause a
decrease of receptors that directly correlates with the titres, we postulate that the profile of
symptoms during illness and recovery depends on the intensity of antibody-mediated
decrease of NMDAR (C). The green receptors are NMDAR. The blue receptors are α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). The small round
vesicles that are released in the synapse are glutamate. PCP=phencyclidine.

Figure 6. Clinical correlates of antibody-mediated decrease of NMDAR

The figure is based on data from animal models of pharmacological or genetic decrease of
NMDAR (N-methyl-D-aspartate receptor). Each step has been shown in these models or in
individuals treated with antagonists of NMDAR. The pronounced resemblance with the
clinical features of anti-NMDAR encephalitis leads us to postulate that an antibody-
mediated decrease of NMDAR predominantly inactivates GABAergic neurons (which are

rich in NMDAR), leading to disinhibition of excitatory pathways and increase of
extracellular glutamate. As a result patients develop a frontostriatal syndrome, which is
characteristic of anti-NMDAR encephalitis. The complexity of orofacial and limb
movements in patients with this disorder is probably explained by disinhibition of a
brainstem central pattern generator that under normal conditions is tonically inhibited by the
GABAergic system.85 Because genetic disruption of NR1 causes hypoventilation,80 a direct
effect of the antibodies on the medullary-pontine respiratory network (nuclei of Kölliker-
Fuse) might result in breathing dysfunction.83 The presence of NMDAR in dopaminergic,
cholinergic, and noradrenergic systems probably explains the autonomic manifestations
(hypersalivation, hypertension, hyperthermia, cardiac dysrhythmia) that are also typical of
NMDAR antagonists.26 Figure adapted from Florance-Ryan and Dalmau86 with permission
from Wolters Kluwer Health. GABA= γ-amino-butyric acid.

Figure 7. Proposed algorithm for the treatment of anti-NMDAR encephalitis

*In women, ultrasound of abdomen and pelvis, or transvaginal unltrasound (if age-
appropriate); in men, testicular ultrasound. †Mycophenolate mofetil or azathioprine for 1
year.‡Consider oral or intravenous methotrexate as an alternative immunosuppressant.10
Figure adapted from Florance-Ryan and Dalmau 86 with permission from Wolters Kluwer
Health.

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Lancet Neurol. 2011 January ; 10(1): 63–74. doi:10.1016/S1474-4422(10)70253-2.

Clinical experience and laboratory investigations in patients with

In 2005, a syndrome of memory deficits, psychiatric symptoms, decreased consciousness,

discovery of other autoimmune synaptic encephalitides mediated by antibodies against the

have prodomal symptoms consisting of headache, fever, nausea, vomiting, diarrhoea, or

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

encephalopathy indicating dysfunction of subcortical structures, limbic regions, amygdalae,

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

negative neuromyelitis optica, had anti-NMDAR encephalitis that substantially improved

Electroencephalograms (EEG) are abnormal in most patients, usually showing non-specific,

specific oligoclonal bands. Most patients have intrathecal synthesis of NMDAR

Brain biopsy does not provide a diagnosis of anti-NMDAR encephalitis. Biopsies in 15

Sex, tumour association, and potential triggers of the immune response

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Because the presentation of anti-NMDAR encephalitis often suggests an infectious process,

gravis and Lambert-Eaton syndrome, which also occur as paraneoplastic or non-

Treatment, outcome, and relapses

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

degree of improvement after first-line immunotherapy (p=0·001; unpublished) and needed

Infrequently, the neurological response to tumour removal can be seen in a matter of

The process of recovery

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

hypersexuality, flat affect, memory loss, visual agnosia), Kleine-Levin syndrome

Anti-NMDAR encephalitis during pregnancy

Milder or incomplete forms of the disorder (formes frustes)

neurological or psychiatric symptoms. In our experience, pure monosymptomatic syndromes

Mortality and causes of death

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Viral encephalitis is an early presumptive diagnosis, suggested by the acute neurological

Pathogenic mechanisms and effects of antibodies

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Prüss and co-workers10 reproduced the antibody-induced decrease of NMDAR

of the NMDAR hypofunction theory of schizophrenia discussed below.71

Patients phenotype resembles those of genetic or pharmacological

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

abnormal movements could be explained by disinhibition of a brainstem central pattern

Approach to diagnosis and proposal of a treatment strategy

cycles of cyclophosphamide. This treatment is discontinued when patients have had

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

with anti-NMDAR encephalitis needs to be confirmed. Further studies on the effects of

2. Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

15. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

encephalitis lethargica. Ann Neurol. 2009; 66:704–09. [PubMed: 19938173]

of obscure origin. J Pediatr. 1992; 121:845–51. [PubMed: 1447643]

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Search strategy and selection criteria

encephalitis”, and “N-methyl-D-aspartate receptor encephalitis”. Articles were also

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Figure 2. Distribution of patients by age and presence or absence of tumours

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.

Lancet Neurol. Author manuscript; available in PMC 2011 August 19.