Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429

DOI 10.1007/s10096-009-0799-0

ARTICLE

Anti-NMDA receptor encephalitis: report of ten cases

Received: 9 May 2009 / Accepted: 1 August 2009 / Published online: 29 August 2009
# The Author(s) 2009. This article is published with open access at Springerlink.com

Abstract The California Encephalitis Project (CEP), estab- simplex-1 (HSV-1) origins. Sixteen cases with confirmed
lished in 1998 to explore encephalitic etiologies, has identified viral etiologies were all negative on NMDAR antibody
patients with N-methyl-D-aspartate receptor (NMDAR) anti- testing. Ten anti-NMDAR+ patients were profiled with a
bodies, the likely etiology of their encephalitis. This study median age of 18.5 years (range 11–31 years). None were
compares the presentation of such patients to those with viral Caucasian. They had a characteristic progression with
encephalitis, so that infectious disease clinicians may identify prominent psychiatric symptoms, autonomic instability,
individuals with this treatable disorder. Patients were significant neurologic abnormalities, and seizures. Two had
physician-referred, and standardized forms were used to a teratoma, and, of the remaining eight, four had serologic
gather demographic, clinical, and laboratory data. Features of evidence of acute Mycoplasma infection. The clinical and
anti-NMDAR+ patients were compared with the viral imaging features of anti-NMDAR+ patients served to
encephalitides of enteroviral (EV), rabies, and herpes differentiate this autoimmune disorder from HSV-1, EV,

M. S. Gable A. Collins
Department of Psychiatry, University of California San Francisco, Department of Pediatrics, Section of Child Neurology,
Fresno, CA, USA University of Colorado,
Denver, CO, USA
S. Gavali : C. A. Glaser
Viral and Rickettsial Disease Laboratory,
Division of Communicable Disease Control,
Center of Infectious Disease, A. Dengel
California Department of Public Health, Loma Linda University Medical Center,
Richmond, CA, USA Loma Linda, CA, USA

A. Radner
Salinas Valley Memorial Hospital,
Salinas, CA, USA J. Dalmau
Department of Neurology, Division of Neuro-oncology,
D. H. Tilley University of Pennsylvania,
Division of Infectious Disease, Naval Medical Center San Diego, Philadelphia, PA, USA
San Diego, CA, USA

B. Lee
Division of Infectious Disease, M. S. Gable (*) : C. A. Glaser (*)
Children’s Hospital and Research Center Oakland, Viral and Rickettsial Disease Laboratory,
Oakland, CA, USA California Department of Health Services,
850 Marina Bay Parkway,
L. Dyner Richmond, CA 94804, USA
Lucile Packard Children’s Hospital, e-mail: [email protected]
Palo Alto, CA, USA e-mail: [email protected]
1422 Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429

and rabies. Unlike classic paraneoplastic encephalitis, anti- patients must be hospitalized with encephalopathy with at
NMDAR encephalitis affects younger patients and is often least one of the following: fever, seizure, focal neurologic
treatable. The association of NMDAR antibodies in patients findings, cerebrospinal fluid (CSF) pleocytosis, or electro-
with possible Mycoplasma pneumoniae infection warrants encephalographic or neuroimaging findings consistent with
further study. encephalitis. A standardized case history form is submitted by
the referring physician with patient information on exposures,
travel, laboratory findings, and clinical and demographic
Introduction characteristics. This study was approved by an ethical stand-
ards committee, and subjects signed a consent form prior to
The causes of encephalitis are numerous, and most patients NMDAR antibody testing.
undergo extensive testing to identify infectious etiologies.
However, other etiologies need to be considered. In the late CEP core testing
1960s, an association between limbic encephalitis and malig-
nancy was made, and, since then, a number of antineuronal CSF, respiratory specimens, and acute- and convalescent-
antibodies, such as the intracellular anti-Hu and anti-Ma, have phase serum specimens are submitted and tested for 16
been discovered and found to be associated with a specific potential infectious agents of encephalitis, including her-
array of cancers, as well as neuropsychiatric symptoms [1, 2]. pesviruses, enteroviruses, arboviruses, respiratory viruses,
More recently, antibodies to neuronal extracellular membrane and Mycoplasma pneumoniae [3].
antigens have been recognized. One of these is the NR1 Once the CEP became aware of the occurrence of anti-
subunit of the N-methyl-D-aspartate receptor (NMDAR), NMDAR+ encephalitis, collaboration with the University
which was first identified in 2007. Unlike its classic of Pennsylvania was established to facilitate the recognition
paraneoplastic counterparts, patients with this antibody may and testing of anti-NMDAR+ cases within the CEP, as
or may not have an associated neoplasm, and often respond follows: retrospective testing of patients who had idiopathic
to immunotherapy and tumor removal, if present [2]. encephalitis, along with dyskinesias or movement disor-
The California Encephalitis Project (CEP) was initiated ders; and prospective referral of cases based on similar
in 1998 to identify the etiologic agents and define the syndromic features. Testing for NMDAR antibodies was
clinical and epidemiologic characteristics associated with performed as previously described [6]. Samples from a
encephalitis. Over 3,000 cases have been referred to the limited number of patients with confirmed viral etiologies
CEP, and many have been characterized into clinical including enteroviral (EV), rabies, and herpes simplex-1
profiles [3]. In 2007, the CEP was notified that one referred (HSV-1), varicella zoster virus, and rabies were selected
patient was diagnosed with an ovarian teratoma associated and tested for NMDAR antibodies.
with NMDAR antibodies. This case, in combination with
previous experience with cases of a similar phenotype and Data analysis
unclear etiology, as well as the increasing recognition of
anti-NMDAR encephalitis worldwide, led us to a collabo- Demographic, clinical, and laboratory data from anti-
rative work with the University of Pennsylvania focused on NMDAR+ patients were compared with data from enceph-
the identification of similar cases within the context of CEP alitis patients with confirmed EV and HSV-1, since these
referrals [2, 4–7]. The purpose herein is to describe patients are the most commonly identified viral etiologies within the
within the CEP that tested positive for the NMDAR CEP. Rabies virus cases were also included for comparison
antibody and compare them with patients that had a because this diagnosis was strongly suspected by referring
confirmed viral etiology, so that infectious disease physi- physicians in several cases that were ultimately found to be
cians can more readily identify those affected with this new, NMDAR antibody positive. Categorical data were analyzed
potentially treatable, immune-mediated disorder. using the Chi-square test, and continuous data were
subjected to the Kruskal-Wallis test. Statistical significance
was defined as P<0.05.
Methods

Patient selection/enrollment Results

Specimens are referred to the CEP by their treating Characteristics of anti-NMDAR+ cases
physicians for diagnostic testing. Patients are required to
be immunocompetent, at least 6 months of age, and must Of the 20 cases tested, ten anti-NMDAR+ cases were
meet the CEP case definition of encephalitis, by which identified; two patients were identified by retrospective
Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429 1423

testing and eight cases were identified prospectively. All ten presentation. The median CSF protein concentrations were
patients were negative for viral studies, but four had a elevated, but the CSF glucose was often within normal
positive serum Mycoplasma IgM. The demographic, clin- limits. EEG monitoring revealed diffuse slowing almost
ical, laboratory, and imaging findings of the ten cases are universally. Focal epileptic activity was uncommon (10%)
summarized in Table 1, while the frequencies are found in and paroxysmal discharges were not observed (Table 1).
Table 2. The median age was 18.5 years (range 11–31 years), Computed tomography (CT) rarely revealed abnormalities.
and none were of Caucasian descent, while there was a While magnetic resonance imaging (MRI) was normal on
predilection for Asians/Pacific Islanders (50%). Although admission in all patients, changes were demonstrated in 40%
60% of patients presented with apparently benign symptoms, of subjects on follow-up studies. However, the findings on
all had returned with more severe symptomatology within MRI, for both fluid-attenuated inversion recovery (FLAIR)
days. Nearly all patients demonstrated personality changes, and T2-weighted images, were not consistent from patient to
and the majority (70%) displayed extreme irritability. Psychi- patient. Periventricular white matter demyelination and other
atric symptoms were common and manifested earlier in the nonspecific findings were observed in one case, and temporal
course of the illness, often at presentation. Psychotic lobe abnormalities were notable in others. Nonspecific
symptoms were noted in 68% of subjects, with all of these abnormalities, or, often, no abnormality at all, appeared to be
patients experiencing hallucinations, particularly of the the standard for these patients.
auditory nature. Other schizophrenia-like symptoms, includ-
ing flat affect and disorganized thinking, were reported in Comparison of anti-NMDAR encephalitis with viral
three patients. Two subjects presented with seizures, and an encephalitis
additional 60% developed seizures after hospitalization, often
of the tonic-clonic type, but sometimes in combination with Samples from 16 cases with confirmed viral etiologies were
focal episodes. Mental status changes were nearly universal, all negative upon testing for anti-NMDAR antibodies.
and care in the intensive care unit (ICU) was required; patients Comparison of anti-NMDAR+ patients to those with viral
had a median Glasgow Coma Scale (GCS) score of 8. etiologies of encephalitis revealed significant differences
Choreoathetoid movements, ataxic gait, cranial nerve (Table 2). Viral cases were not disproportionately common
abnormalities, repetitive orofacial movements, and aphasia among Asians or Pacific Islanders (P<0.05 for HSV-1, EV,
were each reported in around half of the patients. Subjects and rabies-associated encephalitides). Psychosis was signif-
suffered from various combinations of neurologic findings, icantly less common in all viral groups with frequencies of 0
but 90% of patients experienced at least two or more to 2% (P<0.0001), and the presence of hallucinations was
abnormalities, while 60% demonstrated three or more also less likely (P<0.05 for all groups). Personality changes,
abnormal neurologic findings. Sixty percent of those with though more frequent in HSV-1 and rabies virus patients,
orofacial dyskinesias had movements limited to the mouth were seen significantly less often in encephalitic subjects
alone, including lip smacking, tongue protrusion, and with a viral etiology (P<0.0001 for all groups). Seizure
bruxism, each unassociated with a seizure focus on EEG activity was observed less often among virus-infected
when concurrent motor activity was present. None of the individuals, though not statistically less so among those with
patients were believed to acquire these findings as a result of HSV-1 encephalitis (P<0.001 for EV and rabies cases).
anti-psychotic medications, but, in one case, the medication Laboratory studies revealed that the CSF WBC median
did precede the development of symptoms. Choreoathetoid was higher in those with EV and HSV-1 (90 and 56 cells
movements and dyskinesias were also highly variable from per μl, respectively) than in those with anti-NMDAR+
patient to patient, with no distinct pattern in terms of rate or encephalitis (22 cells per μl). Rabies virus cases rarely
rhythm (Table 1). Dysautonomia was nearly ubiquitous in demonstrated CSF pleocytosis, with a median count of 3.5
anti-NMDAR+ patients, observed in 89% of cases. Tachycar- cells per μl (P<0.05). The median CSF protein concen-
dia and bradycardia, blood pressure lability, hyperthermia, trations were significantly higher in those with viral causes,
hypoventilation, and/or apnea were each reported in most with the exception of those with rabies (65 mg/dl in HSV-1
patients with autonomic instability. Many patients experienced and 54 mg/dl in EV vs. 28 mg/dl in anti-NMDAR+ patients;
three or more types of instability, making these symptoms P<0.05 for both), but the CSF glucose concentrations did
prominent clinical manifestations (Table 1). not differ. Temporal lobe changes on neuroimaging were
more common in patients with HSV-1 (27 and 69%,
Laboratory, EEG, and neuroimaging findings respectively; P<0.05).
Overall, viral causes, and especially EV encephalitis,
The majority of anti-NMDAR+ patients (89%) demonstrated appeared to cause fewer severe complications, including a
a lymphocytic pleocytosis during the course of illness, with a lower rate of alteration in consciousness (36 vs. 50%), ICU
median CSF white blood cell (WBC) count of 26/μl on admission (33 vs. 80%), and intubation (5 vs. 60%).
Table 1 Listing of California Encephalitis Project (CEP) patients with N-methyl-D-aspartate receptor (NMDAR)-positive encephalitis
1424

Age Race/ Reason for initial Neurologic Autonomic Aggression/ Hallucinations Personality Seizures Lowest Neoplasm Lumbar puncture MRI EEG
Gender ethnicity presentation abnormalities instability irritability change GCS (LP) results
CSF WBC
CSF protein
CSF glucose

11 Pacific Left facial twitching Choreoathetoid movements, Tachycardia N Y Y Y 8 Y, ovarian 6b Abnormal; focal Right hemisphere
F Islander with choreoathetoid ataxia, cranial nerve abn., teratoma 23 cerebritis of right, slowing; no
movement of the tongue thrusting, facial 55 posterior frontal lobe epileptiform
arm and leg, headache twitching, aphasia activity
11 Asian Mental status changes, Ataxia, mouth twitching, Tachycardia, Y Yes, auditory Y N 14 N 16b Normal Diffuse slowing, no
M psychosis, mouth aphasia hypertension, and visual 23 epileptiform activity
twitching and hyperthermia Unk
muscular spasticity
11 Asian Headaches, fever, Ataxia N Y Y, olfactory Y Y 15 N 26 (94%L) Normal Diffuse slowing; no
M psychosis 29 epileptiform activity(?)
66
12 Pacific Mental status changes Choreoathetoid movements Tachycardia, Y N Unk Y 8 N 170 (92%L, 2%M) Abnormal; dural Diffuse slowing; some
F Islander hypertension, 67 and meningeal left frontal spikes
hyperthermia 66 enhancement

18 Black Behavioral problems Ataxia, cranial nerve Blood pressure Y Y Y Y 4 N 100 (94%L, 6%M) Normal Unk
F abnormalities, aphasia lability 220
72
19 White- Involuntary rightarm Choreoathetoid movements, Y N N Y N 15 N 3 (89%L, 10%M, Abnormal; Polymorphic bilateral
Hispanic and shoulder left facial droop 1%P) basal ganglia frontopolar and
F movements 27 hyperintensity, frontal slowing
58 bilaterally

19 Black Headache, personality Orofacial dyskinesias Tachycardia, Y Y, auditory Y Y 3 N 18 (93%L, 4%M, Abnormal; white Diffuse slowing; no
change, nonsensical hypertension, 3%P) matter demyelination epileptiform activity
M speech hyperthermia, 28 (periventricular,
tachypnea, 62 thalamic,corpus
hypoventilation callosum lesions)
22 Asian Psychosis Choreoathetoid movements, Tachycardia, Y Y, auditory Y Y 8 N 13 (84%L, 3%M, Normal Temporal epileptiform
orofacial dyskinesias, hypertension, 11%P) activity with left>right
M aphasia hyperthermia, 21
tachypnea, 57
hypoventilation
27 Hispanic Headaches, confusion, Ataxia, bruxisms, lingual Tachycardia, N N Y Y Unk Y, ovarian 118 (85%L, Normal Diffuse slowing; no
psychosis dyskinesias, tongue biting, hypertension, teratoma 10%M, 5%P) epileptiform activity
F aphasia hyperthermia, 30
hypoventilation 63
31 Black Headache, fever Choreoathetoid movements, Tachycardia, Y Unka Y Y 3 N 34 (93%L, 7%M) Normal Diffuse slowing; no
F ataxia, cranial nerve abn., hypertension, 33 epileptiform activity
with left eyedeviation hyperthermia, 58
tachypnea

Y = yes; N = no; F = female; M = male; GCS = Glasgow Coma Scale; CSF = cerebrospinal fluid; WBC = white blood cell; abn. = abnormalities; MRI =magnetic resonance imaging; EEG =
electroencephalogram; L = lymphocytes; M = monocytes; P = polymorphocytes
a
Severely altered, unable to report
b
Differential not done or unknown
Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429
Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429 1425

Table 2 CEP NMDAR cases vs. confirmed viral cases

NMDAR (n = 10) Confirmed HSV-1 Confirmed enterovirus Confirmed rabies

Demographics
Age, median, years 18.5 (range 11–31) 46.0 (range 0–89) 14.0 (range 0–75) 38.5 (range 11–72)
Gender
Male 4 (40%) 26 (50%) 52 (61%) 6 (100%)
Female 6 (60%) 26 (50%) 33 (39%) 0
Ethnicity
White, Hispanic 2 (20%) 8 (15%) 26 (31%) 1 (17%)
White, non-Hispanic 0 27 (52%) 30 (35%) 1 (17%)
Black 3 (30%) 2 (4%) 7 (8%) 0
Asian/Pacific Islander 5 (50%) 3 (6%) 10 (12%) 2 (33%)
Other/unknown 0 12 (23%) 11 (13%) 2 (33%)
Clinical findings
General symptoms
Fever 7 (70%) 46 (88%) 63 (74%) 4 (67%)
GI 5 (50%) 19 (36%) 35 (41%) 5 (83%)
URI 1 (10%) 11 (21%) 24 (28%) 4 (67%)
Rash 0 3 (6%) 15 (18%) 0
Intubation 6 (60%) 8 (15%) 4 (5%) 5 (83%)
ICU admission 8 (80%) 30 (58%) 28 (33%) 4 (67%)
Seizures 8 (80%) 30 (58%) 24 (28%) 2 (33%)
Coma 3 (30%) 8 (15%) 5 (6%) 5 (83%)
Died 1 (10%) 9 (17%) 5 (6%) 6 (100%)
Neurologic symptoms
Altered consciousness 5 (50%) 32 (62%) 31 (36%) 4 (67%)
Ataxia 6 (60%) 7 (13%) 23 (27%) 0
Focal neurologic signs 6 (60%) 17 (33%) 24 (28%) 2 (33%)
Stiff neck 3 (30%) 16 (31%) 27 (32%) 0
Cranial nerve abnormality 3 (30%) 0 3 (4%) 0
Psychiatric symptoms
Hallucinations 6/9 (67%) 8 (15%) 9 (11%) 1 (17%)
Psychosis 6/9 (67%) 1 (2%) 2 (2%) 0
Personality change 10 (100%) 15 (29%) 7 (8%) 2 (33%)
Irritability 7 (70%) 11 (21%) 29 (34%) 1 (17%)
Laboratory dataa
CSF
WBC, median (range), per mm3 22 (range 3–170) 90 (range 0–110) 55.5 (range 0–1,332) 3.5 (range 0–10)
Protein, mg/dL 28.5 (range 21–220) 65 (range 6–297) 54 (range 16–881) 35 (range 32–172)
Glucose, mg/dL 62 (range 55–72) 68 (range 39–112) 66 (range 27–159) 65 (range 60–110)
Neuroimaging abnormalitya
MRI
Temporal lobe 0 36 (69%) 4 (5%) 0
Hydrocephalus 0 1 (2%) 0 0
White matter involvement 1 (10%) 4 (8%) 4 (5%) 0
Cerebral edema 0 1 (2%) 0 0
CT
Temporal lobe 0 14 (27%) 0 0
Hydrocephalus 0 1 (2%) 3 (4%) 0
White matter involvement 0 1 (2%) 2 (2%) 0
1426 Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429

Table 2 (continued)

NMDAR (n = 10) Confirmed HSV-1 Confirmed enterovirus Confirmed rabies

Cerebral edema 0 0 0 0
EEG
Slowing 8 (80%) 9 (17%) 7 (8%) 2 (33%)
Epileptiform activity 1 (10%) 7 (13%) 2 (2%) 0
PLEDs 0 4 (8%) 1 (1%) 0

CSF = cerebrospinal fluid; WBC = white blood cell; MRI =magnetic resonance imaging; CT = computed tomography; EEG =electroencephalogram;
PLEDs = periodic lateralized epileptiform discharges; ICU = intensive care unit
Denominators used in the calculations may vary, depending on the available data
a
Data are from initial neuroimaging studies or initial lumbar puncture

Despite a good outcome for most patients with anti- healthy individuals to develop schizophrenia-like symp-
NMDAR encephalitis, this is a severe disorder that may toms [19–21]. A newly published study also revealed that
result in death. In the current study, 10% of anti-NMDAR+ antibodies from patients with anti-NMDAR receptor en-
patients died of this disorder, a number that is higher than cephalitis cause a dramatic decrease in the number of
those who died of EV (6%), although lower than the NMDAR postsynaptic clusters in neuronal cultures, sug-
mortality associated with HSV-1 (19%) and rabies (100%). gesting a decrease in NMDAR function [22]. Behavior and
personality changes, sometimes with notable aggression,
appear to be additionally remarkable in patients with this
Discussion form of encephalitis [2, 10–18, 22]. Continued decompen-
sation is the norm in these patients, with most requiring
When patients present with clinical features of encephalitis, intensive care monitoring and possibly ventilatory support.
viral etiologies are among the primary considerations in Hypoventilation, in particular, has been described as a
establishing a diagnosis, with HSV-1 and EV being among significant feature of this illness, affecting 66% of those in a
the most common offending agents [3, 8, 9]. Viral testing 100-patient series [22]. Other neurologic symptoms also
can be time consuming and, if it is unable to reveal the develop in nearly every patient, including dystonias, orofacial
cause for the patient’s condition, can leave clinicians movements, particularly oral dyskinesias, and choreoatheto-
confounded as to how to proceed with further testing or sis; none of these have epileptic origins. However, seizures
treatment. Autoimmune etiologies should be considered in themselves, often of a tonic-clonic nature, are common,
the differential diagnosis, even at initial presentation. with no correlative epileptiform discharges that permitted
Despite the small sample of anti-NMDAR+ patients, localization on EEG [2, 16–18, 22]. Mental status changes,
there are clinical features that appear to be common in though seen in some patients at presentation, consistently
patients with anti-NMDAR+ encephalitis, and which developed later in the course of illness, with many patients
correlate with those reported in other case series describing becoming non-responsive and non-verbal, and displaying
similar encephalitic patients. While prodromal symptoms low GCS scores. Autonomic instability is almost always
were not highly patterned in the patients in this study, observed.
others have noted a consistent ‘flu-like’ viral illness prior to Specific demographic characteristics were notable
or with initial presentation, though most patients herein did among our cases and, at times, possibly as a result of the
report fever and headache [2, 10–18]. The progression of small anti-NMDAR+ sample size, at odds with previous
illness noted in this series did, however, resemble that reports. There were a larger number of males in our series,
described in other studies. which is likely a result of the selection process. However, it
Anti-NMDAR+ encephalitic patients appear to develop a may also be that males have been less readily recognized
somewhat predictable course of illness, during which a with this diagnosis, as there have been inconsistent
number of symptoms are frequently observed. Psychiatric associations with concurrent neoplasms, making clinicians
symptoms manifest early in the course of illness, and hesitant to attribute symptoms to this specific cause. It is
patients are likely to display schizophrenia-like behaviors, not clear whether or not these individuals would ultimately
such as psychosis and hallucinations. This is consistent be found to have tumors, or whether, as with other
with the observation that NMDAR antagonists can cause autoimmune encephalitides (e.g., that are associated with
Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429 1427

voltage-gated potassium channels), a substantial percentage the temporal lobe may also point to a viral etiology and, of
of patients simply did not harbor neoplasms [23, 24]. This course, a positive HSV PCR in the CSF is a defining feature
is often difficult to ascertain, as many paraneoplastic of herpes simplex encephalitis [3, 9, 30, 31].
syndromes can precede the discovery of associated tumor EV encephalitis, like HSV-1 encephalitis, is generally
by years [2]. associated with a higher WBC count and protein concentration
Patients were also more likely to be of Asian or Pacific in the CSF when compared to patients with anti-NMDAR+
Islander descent, a finding suggested by a recent publication encephalitis. Neuroimaging is nonspecific in these patients, but
from Japan [15]. This was surprising, given that teratomas, symptomatology can play a substantial role in differentiating
which are the most common tumors associated with anti- these two etiologies because psychiatric and focal neurologic
NMDAR encephalitis, demonstrate no racial bias, though findings will be much less likely. Patients with EV-associated
malignant ones are more common among Asians [25]. encephalitis are less apt to decompensate and become non-
In the present series, the median age was younger than responsive and unable to verbally communicate. Autonomic
that in prior studies, in which a higher percentage of instability with subsequent ventilatory support plays a much
patients with teratomas were identified [2, 7, 10–18, 22]. more subtle role in EV-affected individuals and, as with HSV-1
Given the small number of subjects, it is difficult to encephalitis, EV can be detected in the CSF [31, 32].
ascertain whether the true median age for this entity is as Rabies virus cases pose a particular diagnostic challenge
low as 18.5 years, but it is notable that a number of subjects because behavioral symptoms can be as prominent as they
in the current series were children. Those as young as are with anti-NMDAR encephalitis. Exposure history, along
5 years of age have been described elsewhere, and the with diagnostic testing for rabies, is of great value. Typically,
median age appears to be distinctly younger than that seen more than one diagnostic test will be required to diagnose
among those with classic paraneoplastic syndromes [2, 14, rabies encephalitis in antemortem patients, while a brainstem
16]. Only 20% of those examined herein had ovarian biopsy alone is required in post-mortem individuals [33].
teratomas, and, interestingly, of those without tumors, 50% The study results do merit a few additional considerations.
had positive Mycoplasma IgM serologies. As previously Reports of cranial nerve abnormalities, ataxic gait, and
reported, the significance of an isolated positive M. aphasic findings, obtained from CEP questionnaires, can be
pneumoniae serum IgM, especially without signs of subjective in their interpretation. For example, it may be that
Mycoplasma IgG change or polymerase chain reaction facial nerve dysfunction and ocular deviations were, in
(PCR) positivity is unknown [26]. On average, only about reality, of central origin, as oculogyric crises and facial
10% of CEP patients have positive serology for M. dystonias have been reported to occur in anti-NMDAR+
pneumoniae, making this percentage higher than generally patients [16, 22]. Yet, despite their variable interpretation,
expected. This observation lends itself to the speculation that gait, facial, and verbal abnormalities, whether of central
anti-NMDAR+ patients may develop encephalitis as a result origin or not, are noted in many cases and can assist in
of a post-infectious, antibody-mediated process such as that suggesting a diagnosis. Furthermore, though many of our
observed in Sydenham’s chorea or other pediatric autoim- positive confirmed viral cases were not tested for the
mune neuropsychiatric disorders associated with streptococcal presence of NMDAR antibodies, samples from 16 patients
infections (PANDAs) in which antistreptococcal-antineuronal within the CEP cohort with confirmed viral etiologies were
antibodies are thought to destroy healthy nervous system cells negative for NMDAR antibodies, and based on previous
which serve as molecular mimics [27–29]. Because the work by Dalmau et al. [22], the antibody is both highly
association with M. pneumoniae is not fully understood, sensitive and specific. It binds to a distinct region of the
clinicians should be cautioned against accepting M. pneumo- NMDAR. Although viral encephalitis, stroke, chronic
niae as the sole explanation for an encephalitic illness, epilepsy, and lupus have been associated with NMDAR
especially if this diagnosis is based on a single IgM test. antibodies, the region of the NR1 portion of the receptor to
The differentiation of anti-NMDAR+ associated encepha- which the NMDAR antibodies bind appears to be uniquely
litis from encephalitis of viral origin on clinical grounds alone associated with anti-NMDAR encephalitis, as opposed to
is difficult, although our study reveals that there may be some other conditions.
useful clues. HSV-1 patients will typically be older than anti- The management of anti-NMDAR+ encephalitis can
NMDAR+ patients, and are less likely to display severe prove to be very effective and involves the identification
psychiatric disturbances and schizophrenia-like symptoms. and treatment of the tumor, along with immunotherapy. In a
HSV-1 encephalitis patients are also not as likely to display series of 100 cases, 91 were women, and 63% had a tumor,
combinations of movement disorders, such as choreoathetosis primarily an ovarian teratoma. Only 2 of the 9 men had a
and orofacial dyskinesias, as those with anti-NMDAR tumor (one teratoma of the testis and one small-cell lung
encephalitis [28, 29]. Autonomic instability is not a cancer). Patients with prompt tumor removal and immuno-
predominant feature of HSV. Focal EEG abnormalities of therapy (e.g., steroids) had better outcomes and fewer
1428 Eur J Clin Microbiol Infect Dis (2009) 28:1421–1429

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Clinicians must be aware of this condition, especially when female and presenting with psychosis with minimal changes on
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Acknowledgments We thank the laboratory staff of the Viral and an adolescent girl. Acta Paediatr 92:506–509
Rickettsial Disease Laboratory and Microbial Disease Laboratory for 18. Muni RH, Wennberg R, Mikulis DJ et al (2004) Bilateral
performing the diagnostic testing. We also thank the clinicians who horizontal gaze palsy in presumed paraneoplastic brainstem
referred cases to the California Encephalitis Project (CEP). encephalitis associated with a benign ovarian teratoma. J Neuro-
Financial support was obtained from the Centers for Disease ophthalmol 24:114–118
Control and Prevention Emerging Infections Program *U50/ 19. Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor
CCU915546-09).09 (CG), and there was additional support, in part, hypofunction model of schizophrenia. J Psychiatr Res 33:523–533
from the National Institute of Health 2RO1CA89054-06A2 (JD). 20. Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA
There are no conflicts of interest. receptor hypofunction in the pathophysiology of schizophrenia.
Ann N Y Acad Sci 1003:318–327
Open Access This article is distributed under the terms of the 21. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of
Creative Commons Attribution Noncommercial License which per- phencyclidine: from NMDA receptor hypofunction to the dopamine
mits any noncommercial use, distribution, and reproduction in any hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225
medium, provided the original author(s) and source are credited. 22. Dalmau J, Gleichman AJ, Hughes EG et al (2008) Anti-NMDA-
receptor encephalitis: case series and analysis of the effects of
antibodies. Lancet Neurol 7:1091–1098
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