Paraneoplastic AntiN-methyl-D-aspartate Receptor Encephalitis

Associated with Ovarian Teratoma

Josep Dalmau, MD, PhD
1
, Erdem Tzn, MD
1
, Haiyan Wu, PhD
1
, Jaime Masjuan, MD
2
,
Jeffrey E. Rossi, BA
1
, Alfredo Voloschin, MD
3
, Joachim M. Baehring, MD
4
, Haruo Shimazaki,
MD, PhD
5
, Reiji Koide, MD
6
, Dale King, MD
7
, Warren Mason, MD
8
, Lauren H. Sansing, MD
1
,
Marc A. Dichter, MD, PhD
1
, Myrna R. Rosenfeld, MD, PhD
1
, and David R. Lynch, MD, PhD
1
1Department of Neurology, Division of Neurooncology, University of Pennsylvania, PA
2Department of Neurology, Hospital Ramn y Cajal, Madrid, Spain
3Department of Neurosurgery, Medical College of Georgia, Augusta, GA
4Department of Neurology, Yale University School of Medicine, New Haven, CT
5Jichi Medical School, Tochigi, Japan
6Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
7Childrens Hospital of Pittsburgh, Pittsburgh, PA
8Department of Neurology, Princess Margaret Hospital, Toronto, Ontario, Canada
Abstract
ObjectiveTo report the autoantigens of a new category of treatment-responsive paraneoplastic
encephalitis.
MethodsAnalysis of clinical features, neuropathological findings, tumors, and serum/
cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing
subunits of the N-methyl-D-aspartate receptor (NMDAR).
ResultsTwelve women (14 44 years) developed prominent psychiatric symptoms, amnesia,
seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often
requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly
immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal
neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B
binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially
expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single
subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature)
and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue
that strongly expressed NR2 subunits and reacted with patients antibodies. Tumor resection and
immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by
decreased antibody titers); two of three patients without tumor resection died of neurological
deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal
degeneration predominantly involving, but not restricted to, the hippocampus.
InterpretationAntibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate
with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and
Address correspondence to Dr Dalmau, Department of Neurology, 3 W. Gates, Division Neurooncology, 3400 Spruce Street, University
of Pennsylvania, Philadelphia, PA 19104., E-mail: josep.dalmau@uphs.upenn.edu.
This work was first presented at the 131st Annual Meeting of the American Neurological Association, Chicago, IL, Oct 10, 2006.
NIH Public Access
Author Manuscript
Ann Neurol. Author manuscript; available in PMC 2008 J une 18.
Published in final edited form as:
Ann Neurol. 2007 January ; 61(1): 2536.
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suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other
immune-mediated disorders of memory, behavior, and cognition.
Disturbances of memory, behavior, cognition, and seizures can result from immune-mediated
encephalitis. One cause of autoimmune encephalitis is the paraneoplastic manifestation of a
neoplasm.
1
Until now, most paraneoplastic encephalitides have been associated with
antibodies to intracellular onconeuronal proteins and cytotoxic T cells presumably against the
same proteins.
2
These disorders usually associate with malignant tumors and are poorly
responsive to immunotherapies or treatment of the cancer.
3
In a previous study, we described
a disorder that appeared to represent a new category of severe, potentially lethal, but treatment-
responsive paraneoplastic encephalitis.
4
The affected patients were women who developed
prominent psychiatric symptoms, seizures, memory deficits, and decreased level of
consciousness often requiring ventilatory support. Three salient features included the young
age of the patients, the association with ovarian teratomas, and the detection of antibodies to
unknown antigens predominantly expressed in the cell membrane of hippocampal neurons
(also referred to as a subgroup of neuropil antigens).
5
Since then, we have studied eight
additional patients and now report the identification of the target autoantigens, which are
heteromers containing NR1 and NR2 subunits of the N-methyl-D-aspartate receptor
(NMDAR), also expressed by the associated tumors.
Patients and Methods
Patients include 12 women with paraneoplastic encephalitis associated with teratomas. The six
most recently identified patients and neuropathological findings (two cases) are described in
detail in the Supplementary materials; the clinical features of the other six patients have been
reported previously by us and others.
4 8
Frozen serum or cerebrospinal fluid (CSF) was
available from all 12 patients. Tissues for immunological studies included tumors from five
patients (one frozen tissue, four embedded in paraffin), and brain obtained at autopsy of one
patient and two neurologically normal individuals. Sera or CSF of 200 individuals, including
blood donors and patients with diverse paraneoplastic and nonparaneoplastic encephalitis
served as controls. Studies were approved by the University of Pennsylvania Institutional
Review Board.
Animal Tissue, Antibodies, and IgG Biotinylation
Wistar rats were killed omitting perfusion with saline or fixatives; the brain was removed,
immersed in 4% paraformaldehyde at 4C for 24 hours, cryoprotected with 40% sucrose,
sagittally sectioned, and snap frozen in isopentane chilled with liquid nitrogen. The following
antibodies were used at the indicated dilutions: chicken anti-MAP2 (1:20,000; Covance,
Princeton, NJ ); rabbit anti-NR1 (1:50; amino acids 120) and rabbit anti-NR2A (1:50; amino
acids 12651464) (both from Upstate Biotechnology, Lake Placid, NY); rabbit anti-NR2B
(1:50; 251-amino acid sequence from N-terminal portion of NMDAR; Zymed, San Francisco,
CA); and CD3, CD19, and CD68 (all 1:100; Dako-Cytomation, Carpinteria, CA).
All immunohistochemical studies with tumor tissue utilized IgG purified from patients sera
and labeled with biotin to avoid reactivity with endogenous IgG.
9
Immunohistochemistry
Paraffin-embedded tissue was deparaffinized and the antigens retrieved, as reported elsewhere.
10
Seven-micrometer-thick frozen (or 4m-thick paraffin) tissue sections were
seriallyincubated with 0.3% H
2
O
2
for 20 minutes, 10% goat serum for 1 hour, and patients
serum (1:250), CSF (1:10) or biotinylated IgG (0.2mg/ml), or the indicated purchased
antibodies overnight at 4C. After using the appropriate secondary antibodies (all 1:2,000),
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reactivities were developed with the avidin-biotin-peroxidase method. The secondary antibody
was omitted when patients biotinylated IgG was used. Normal human serum and biotinylated
IgG and also normal goat serum served as controls. Double immunolabeling with patients
IgG, MAP2, and NR2 antibodies was performed using the appropriate Alexa Fluor secondary
antibodies diluted 1:2,000 (Molecular Probes, Eugene, OR); results were photographed under
a fluorescence microscope using Zeiss Axiovision software (Zeiss, Thornwood, NY).
Immunocytochemistry
Rat hippocampal neuronal cultures were prepared as reported elsewhere.
11
Live neurons
grown on coverslips were exposed for 1 hour at 37C to the patients or control serum (final
dilution 1:400) or CSF (1:10). After removing the media and extensive washing, neurons were
fixed with 4% paraformaldehyde, and single or double immunolabeling was performed, as
indicated earlier. The reactivity of commercial antibodies to NR1 and NR2 subunits was best
seen with cell permeabilization (0.1% Triton X-100) after paraformaldehyde.
HEK293 cells were transfected with plasmids containing rodent NR1, NR2A, or NR2B
subunits of the NMDAR (>90% homologous to the human subunits in the extracellular
domains) or plasmids without insert (control), as reported previously.
1214
In other
experiments, cells were co-transfected with NR1 and NR2A (or NR1 and NR2B) in equimolar
ratios.
1214
Cells were grown for 24 hours after transfection before assessment. All cells were
routinely grown in the presence of NMDAR antagonists (500M ketamine) to prevent cell
death after transfection.
15
Transfected cells were then incubated with patients serum (1:400)
or CSF (1:10) overnight at 4C and the appropriate Alexa Fluor secondary antibodies, as
described earlier.
Results
Neurological Findings
The median age of the patients was 27 years (range, 14 44 years). In 11 patients, the
neurological symptoms preceded the diagnosis of the teratoma by 3 weeks to 4 months (median,
2 months), and in one patient occurred after an ovarian cyst had been radiologically detected
1 month earlier. Ten patients had a viral-like prodromic syndrome with hyperthermia (seven
cases) and frequent headache (six cases) (Table 1).
Three of the 12 patients presented with short-term memory loss, followed by psychiatric
symptoms or confusion and decreased level of consciousness (see Table 1). The other nine
patients presented with an acute psychiatric syndrome, including personality and behavioral
change, agitation, or paranoid thoughts. Overall, six patients were initially evaluated by
psychiatrists and five admitted to psychiatric units. Eleven patients developed generalized or
partial complex seizures. After controlling the seizures, 10 patients required mechanical
ventilation because of the decreased level of consciousness and hypoventilation in 9 cases and
a pulmonary embolism in 1 case; the median time that patients were receiving mechanical
ventilation was 12 weeks (216 weeks). During that time multiple electroencephalograms
showed diffuse general slowing in seven patients and generalized slowing with occasional
epileptic activity in the other three.
During the course of the disease, eight patients developed episodes of hyperthermia, alternating
in one case with hypothermia (see Table 1). Seven patients developed abnormal movements
that included one or more of the following: choreoathetosis, myoclonic and ballistic
movements, dystonic movements, dyskinesias in face and arms, rhythmic contractions of the
abdominal wall, opisthotonos-like postures, and catatonic-like episodes. Five patients had signs
of autonomic instability, including episodes of mydriasis, tachycardia, tachypnea, diaphoresis,
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or hypertension, which in one case alternated with hypotension. Four patients developed
transient sleep dysfunction while recovering from the encephalitis.
Ancillary Tests
All patients underwent several brain magnetic resonance imaging (MRI) at the early stage of
the disorder (Table 2): three had bilateral medial temporal lobe fluid-attenuated inversion
recovery hyperintensities (one with right frontal cortex involvement; Fig 1), five had small or
punctuate areas of fluid-attenuated inversion recovery or T2 hyperintensity in the frontal or
parietal cortex (two with cerebellar involvement) and subtle enhancement of overlying
meninges, one had transient T2 hyperintensity in the medulla and spinal cord, and three had
normal or nonspecific findings.
CSF lymphocytic pleocytosis was identified in all patients (9 219 cells/l; median, 24 cells/
l), and seven also had increased protein concentration (56 129mg/ dl; median, 67mg/dl); the
glucose concentration was normal in all instances (see Table 2). Oligoclonal bands were
identified in three of six patients examined. All patients had extensive serum and CSF
diagnostic tests with negative or normal results for viral, bacterial, and fungal infections;
collagen-vascular autoimmune disorders; thyroid autoimmunity; and comprehensive panels of
paraneoplastic and voltage-gated potassium channel (VGKC) antibodies.
Associated Tumors
Computed tomography of the chest, abdomen, and pelvis demonstrated an ovarian mass in 10
patients, a tumor in the anterior mediastinum in 1, and no evidence of tumor in 1 (the tumor
was demonstrated at autopsy). The radiological size of the tumors ranged from 1.5 to 22cm
(median largest diameter, 6.5cm) (see Table 1). Two patients (Cases 1 and 7) had significant
tumor growth during the encephalitic process (Figs 2A, B). Only one patient had increased
levels of carcinoembryonic antigen (CEA), CA125, and -fetoprotein. One patient had a history
of a resected contralateral teratoma (without accompanying encephalitis), and another patient
had three episodes of neurological symptoms, each heralding a new or recurrent mature
teratoma (NR2 antibodies were measured at the last recurrence).
Nine patients had complete tumor resection and three did not have surgery (the tumor of two
of these cases was studied at autopsy). Overall, pathological studies showed that seven patients
had mature teratoma (six ovary, one mediastinum) and four immature teratoma. Review of
slides from eight of the ovarian teratomas demonstrated in all instances nervous tissue
intermixed with tissues derived from the other germinal layers; tissue was available from five
of these tumors for immunological studies (described later).
Treatment and Outcome
Seven patients were treated with tumor resection and immunosuppressants (one with additional
chemotherapy); six recovered and one died unexpectedly in a chronic care facility after mild
improvement
8
(see Table 2). Five of the six patients who recovered returned to work, and the
follow-up MRIs were normal; the sixth patient had partial recovery (Mini-Mental State
Examination score =24/30) and developed mild frontotemporal atrophy.
The other five patients were treated with surgery alone (two cases) or immunosuppressants
(three cases). Three patients recovered (two returning to work; one partial recovery Mini-
Mental State Examination score =28/30) and the other two died of neurological progression
(both without tumor removal). In one of these patients (Case 2), corticosteroids, plasma
exchange, and intravenous immunoglobulin (IVIg) had no effect on the symptoms and CSF
pleocytosis; multiple MRIs showed progressive atrophy, mainly in the temporal lobes and
hippocampi. Seven weeks before her death, she received cyclophosphamide that resulted in
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normalization of the CSF but no clinical recovery. In the other deceased patient (Case 6), the
ovarian teratoma was discovered at autopsy; among many diagnostic tests, this patient had
undergone brain biopsy. The neuropathological findings of these two patients are described in
the Supplemental information.
Patients Antibodies React with Neuronal Cell Membrane Antigens Preferentially Expressed
in the Hippocampus
The CSF and serum of all 12 patients, but not control subjects, showed a distinctive pattern of
reactivity with the neuropil of rat hippocampus; the reactivity with other forebrain regions was
less intense, and hardly visible in the cerebellum (Fig 3A). The immunolabeling predominantly
occurred with the cell membrane of neurons and was intense in the molecular layer of the
hippocampus (see Fig 3B), as reported in a previous study.
4
The addition of CSF or serum of
patients, but not control subjects, to cultures of live rat hippocampal neurons produced striking
immunolabeling of the cell surface and dendrites (see Fig 3C). Control antibodies to
intracellular antigens (ie, HuD) produced no reactivity with live neurons, but showed
intracellular reactivity with permeabilized neurons (data not shown). These findings indicate
that the patients antibodies recognize epitopes exposed on the cell surface.
Using rat brain tissue and serial dilutions of normalized total IgG in paired serum and CSF
samples, we noted that 8 of 11 patients had evidence of intrathecal synthesis of antibodies (in
2 patients, the antibodies were barely detectable in serum). Serum antibody titers were followed
in eight patients: all seven patients with neurological improvement had a decrease of titers (five
became undetectable), and one who died of neurological progression had an increase of titers
(from 1:200 to 1:1,600).
The Main Autoantigens Are Functional Heteromers of N-methyl-D-aspartate Receptors
Double immunolabeling of brain and hippocampal rat neurons using patients antibodies and
diverse markers of candidate autoantigens demonstrated significant co-localization with the
NR2B subunit of the NMDAR (see Figs 3CE). Because this subunit is preferentially expressed
in the hippocampus and forebrain (and absent from the cerebellum) forming heteromers with
NR1 or with NR1 and NR2A, we subsequently examined the reactivity of patients antibodies
with HEK293 cells expressing individual subunits (NR1, NR2A or NR2B) or a combination
of subunits required for a functional receptor (NR1/NR2B or NR1/ NR2A heteromers). These
studies showed that all 12 patients CSF and serum reacted with NR1/NR2 heteromers
containing NR2B; sera and CSF from eight patients also recognized heteromers containing
NR1/ NR2A (Fig 4). Sera did not react with cells transfected with individual subunits (NR1,
NR2A, or NR2B). These antibodies were not identified in an extensive group of control sera
and CSF, including among others six patients with testicular teratomas and paraneoplastic anti-
Ma2 encephalitis.
Immunoblots of membrane proteins isolated from hippocampal neurons or HEK293 cells
expressing NR1/NR2B or NR1/NR2A heteromers showed reactivity with commercially
available antibodies (NR1, NR2A, NR2B) but did not react with patients CSF or serum (data
not shown). Overall, these findings indicate that patients antibodies recognize NR1/NR2
heteromers containing the NR2B (and at a lesser degree NR2A) subunit of the NMDAR and
suggest that the epitopes are conformational.
We subsequently examined whether patients tumors contained nervous tissue expressing
NMDARs and whether these receptors were recognized by patients antibodies. Five of five
tumors examined showed mature- and immature-appearing neurons together with a variably
dense network of fibers expressing MAP2 (a marker of neurons and dendritic processes) (Figs
5A, B). This atypical nervous tissue had intense expression of NR2 subunits of NMDAR;
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colocalization of reactivities was observed when tumors were incubated with commercially
available antibodies to NR2B or NR2A and patients antibodies (see Figs 5CH).
Discussion
This study facilitates the recognition of a severe form of autoimmune encephalitis that is often
responsive to treatment. In addition, the results emphasize the idea that autoimmunity can affect
behavior, and particularly that antibodies to heteromers containing the NR2B and NR2A
subunits of the NMDAR may alter emotion, memory, and consciousness.
16
The frequency of this disorder (which we call paraneoplastic anti-NMDAR encephalitis) is
unknown. Before our description of five patients in 2005,
4,5
only five other possible clinical
cases had been reported in the English literature (reviewed in Vitaliani and colleagues
4
). Thus,
the identification of seven additional patients in the few months after those publications
suggests that the disorder is frequently unrecognized. This may be due to several features that
make this disorder unique among paraneoplastic encephalitis including: (1) involvement of
relatively young women between the second and fifth decades of life; (2) the unusual
presentation with prominent psychiatric manifestations; (3) normal or atypical MRI findings,
which in 75% of cases consist of mild, transient T2 or fluid-attenuated inversion recovery
abnormalities outside the medial temporal lobes, sometimes with cortical enhancement; and
(4) the benign appearance of the ovarian tumors.
The clinical picture of all 12 patients shows a recognizable syndrome in most instances. At
presentation, a psychiatric disorder is usually considered and patients are often admitted to
psychiatric centers. Most patients appear confused, restless, agitated, with frequent paranoid
or delusional thoughts sometimes alternating with quiet staring and dystonic or catatonic
postures. In addition, most patients develop seizures and a subsequent decrease of level of
consciousness, requiring antiepileptic medication, sedation, frequent mechanical ventilation,
nutritional support, and management of episodes of autonomic instability and dyskinesias.
After controlling the seizures, attempts to decrease the sedation or wean patients from the
ventilator demonstrate limited recovery of consciousness and spontaneous breathing, and
reappearance or worsening of abnormal movements (often with diffuse slowing of the
electroencephalogram). As a result, ventilatory support was required for a median of 12 weeks
in 9 patients.
A constant abnormality is the presence of CSF pleocytosis or increased protein concentration
that suggests an inflammatory or immune-mediated neurological process. Otherwise, extensive
evaluations to identify the cause of the encephalitis are normal or unrevealing, and the
associated tumors (usually appearing as benign ovarian cysts) are frequently considered
unrelated to the disorder.
A remarkable finding is that all patients had antibodies to NMDARs containing the NR2B, and
at a lesser degree, the NR2A subunit. NMDARs are usually formed from heteromers of NR1
(which bind glycine) and NR2 subunits (which bind glutamate).
17,18
Both subunits are
required to create a functional receptor that likely contains two NR1 and two NR2 subunits.
19
There are four NR2 subunits (NR2AD) that have 50 to 70% sequence identity in the
extracellular domain (NR2B is 70% identical to NR2A, and 5558% identical to NR2C and
NR2D). These NR2 subunits are coded by four different genes and show developmental and
regional variability. NR2B is expressed at high levels prenatally and declines postnatally.
20,
21
During its decline, expression levels of NR2A and NR2C increase. In adults, NR2A is found
in most brain regions, NR2B in the hippocampus and forebrain, NR2C in cerebellum, and
NR2D in limited subsets of neurons.
20,21
NR1 is ubiquitously distributed in the brain.
19
21
With maturity, many NR1/NR2B receptors become largely extrasynaptic in hippocampal
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neurons and NR1/NR2A/NR2B becomes the major synaptic receptors in the hippocampus and
forebrain. Thus, the predominant reactivity of all patients antibodies with hippocampus and
forebrain correlates with the distribution of heteromers containing NR2B.
22
Furthermore, the
antibodies readily access cell-surface epitopes of live neurons and react only with HEK293
cells expressing functional receptors (heteromers of NR1/NR2B or NR1/NR2A). No reactivity
is identified when each subunit is expressed individually (even though NR1 in particular
assembles in stable but inactive homomeric receptors in HEK293 cells)
12
or with immunoblots
of cells expressing the functional receptor. These findings suggest that the main epitopes are
in the extracellular domain of NR2B and NR2A subunits and are likely conformational.
Preliminary studies indicate that some patients also harbor antibodies to functional heteromers
of NR2C and NR2D (consistent with the 5558% homology between these subunits and
NR2B); however, no increase of cerebellar immunolabeling was seen in sera or CSF from these
patients, suggesting that these antibodies occur at low titers (data not published).
The discovery of NR2B-related antibodies in the serum and CSF of all patients provides a
potential diagnostic test for the disorder and suggests a novel immune-mediated mechanism
of NMDAR dysfunction. Critical roles of NMDARs include synaptic transmission and
remodeling, dendritic sprouting, and hippocampal long-term potentiation, one paradigm of
memory formation and learning.
19
However, NMDARs are also the major mediator of
excitotoxicity, and their dysfunction has been associated with schizophrenia, epilepsy, and
several types of dementia. Drugs interacting with NMDARs may result in paranoia,
hallucinations, and dyskinesias, all frequent symptoms in our patients.
23
Antibodies to NR2
subunits have been identified in patients with neuropsychiatric lupus
24,25
and diverse seizure
disorders, but the target epitopes (recognized by immunoblot)
26,27
and syndromes are
different from those of our patients. The antibodies of patients with lupus are antidouble-
stranded DNA that cross-react with a single epitope present in NR2A and NR2B
28
; these
antibodies can cause neuronal death by excitotoxicity and apoptosis and result in behavioral
abnormalities in an animal model of the disorder.
29
None of our 12 patients had symptoms of
lupus, and all were negative for antidouble-stranded DNA; furthermore, the target NR2
epitopes in our patients appear to be multiple and are not always present in receptors that contain
NR2A.
Although the mechanisms that triggered the immune response are unclear, we postulate the
ectopic expression of NR2 subunits by nervous tissue contained in the teratomas contributes
to break immune tolerance. All five tumors available for immunological studies showed intense
reactivity with patients antibodies that colocalized with dramatic expression of NR2 subunits
(more robust than that observed in normal hippocampus; data not shown). A combination of
factors such as an adjuvant effect of the prodromal viral-like illness
30,31
that occurred in most
patients, and perhaps a genetic predisposition, could play additional roles in the initiation of
the immune response.
The mechanisms of how antibodies breach the bloodbrain barrier have been explored in
models of lupus. These studies showed that infection or hypertension significantly enhanced
antibody entrance to the central nervous system.
29,32
Interestingly, the amygdala and
hippocampus that have the highest levels of NR2B and NR2A are also the regions where the
bloodbrain barrier is more vulnerable to these mechanisms. During the course of the disease
of our patients, hypertension and symptoms of sympathetic overactivity occurred frequently,
possibly enhancing bloodbrain barrier leakiness. Furthermore, intrathecal production of
antibodies was identified in eight patients.
A possible pathogenic role of NR2 antibodies in paraneoplastic anti-NMDAR encephalitis is
suggested by the following factors: (1) the indicated animal models of neuropsychiatric lupus
(although the epitopes are different)
28,33
; (2) the correlation between patients symptoms and
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antibody titers; and (3) the demonstration of deposits of IgG in the hippocampus and amygdala
of a patients autopsy, in a pattern that showed striking resemblance to the rat brain
immunolabeling by patients antibodies (see Supplemental data for Case 2 and Supplemental
Fig 6). Whereas in other paraneoplastic encephalitis cases (ie, Hu, Ma2) the perivascular and
interstitial infiltrates of T cells are prominent,
34,35
the encephalitis with NR2 antibodies
associates with extensive microglial proliferation, variable neuronal degeneration, and rare
inflammatory infiltrates (see Supplemental data for Cases 2 and 6 and Supplemental Fig 7). In
these patients and a previously reported case (Case 10),
8
the abnormalities predominated in
the hippocampi, amygdala, and at a lesser degree, other areas of the neuraxis.
Despite the severity of the symptoms, paraneoplastic anti-NMDAR encephalitis has a better
prognosis than most other paraneoplastic encephalitides.
3,36
Nine of 12 patients significantly
recovered and 7 returned to their jobs. Because most patients had tumor resection and
immunotherapy in close temporal association, the relative contribution of these treatments to
neurological recovery is difficult to assess in this study. In general, resection of the tumor
appeared important to attain final recovery or sustain the improvement that in some cases
started soon after immunotherapy (corticosteroids, IVIg, or plasma exchange). Two patients
had only tumor resection and both improved, but two of the three patients who did not have
tumor resection died of neurological progression. The importance of removing the tumor is
also suggested by one patient who developed recurrent neurological symptoms, each heralding
a tumor recurrence. We were surprised by the dramatic and rapid recovery of some patients,
suggesting a potentially reversible antibody-mediated neuronal dysfunction. The deterioration
or partial recovery of a few patients may reflect a more sustained disruption or involvement of
other critical epitopes of the NMDAR, or a secondary effect of the prolonged seizures, leading
to neuronal degeneration.
While preparing this article, four patients with a similar syndrome, antibodies to NR2B-
containing heteromers, and ovarian teratoma (one immature; three mature, in one case bilateral)
have been identified (currently under study). These patients, as well as most of those in this
study, were initially considered to have a psychiatric illness or viral encephalitis. Because some
patients have transient (usually partial) improvement with the empiric use of corticosteroids,
IVIg, or plasma exchange, they may be discharged from hospitals without a final diagnosis,
and subsequently deteriorate or die if the ovarian mass is not removed. For example, 10 of our
patients were seen at several institutions, some with multiple hospital transfers or discharges,
before the tumor was diagnosed and removed. This raises the concern that this disorder is more
frequent than our current experience suggests. In addition to clinical implications, further
studies may provide an important model of immune-mediated dysfunction of NMDARs, with
relevance to multiple disciplines.
19
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgements
This work was supported by NIH/NCI (RO1CA89054, J .D.; RO1CA107192, J .D.), and NIH (RO1 NS45986, D.R.L.).
We thank Drs F. Lieberman T. Zwerdling for providing clinical information, and M. Maronski for excellent technical
assistance.
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Fig 1.
Brain magnetic resonance imaging (MRI) findings in three patients. (A, B) MRI of Patient 1
at symptom presentation (A) and after partial clinical improvement and cerebrospinal fluid
normalization with immunotherapy (B); note that the clinical and MRI improvement started
to occur before tumor resection. (C, D) MRI of Patient 2 at symptom presentation (C) and 4
months later (D); this patient developed rapidly progressive neurological deterioration that did
not respond to immunotherapy. The autopsy demonstrated that the ovarian cyst was a mature
teratoma of the ovary. (E, F) MRI of Patient 3 at symptom presentation; note the mild fluid-
attenuated inversion recovery hyperintensity in medial temporal lobes and right frontal cortex.
After immunotherapy and tumor resection, the MRI was normal (not shown).
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Fig 2.
Interval increase of tumor size during encephalitis. (A) Computed tomography of Patient 1
shows a 5cm cystic ovarian lesion (arrow) that doubled in size over 2 months (B). The lesion
was not initially removed because of the poor clinical condition of the patient and benign
appearance of the ovarian mass. After partial clinical improvement with immunotherapy, the
mass was removed (immature teratoma).
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Fig 3.
Reactivity of patients antibodies with hippocampus and forebrain, and colocalization with the
NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR). (A) Sagittal section of rat
brain immunolabeled with a patients cerebrospinal fluid. Note the robust reactivity with the
hippocampus and milder reactivity with forebrain. The cerebellum is largely spared. (B) Higher
magnification of the molecular layer of the hippocampus (arrow in A); this pattern of reactivity
is identical to that previously reported in patients with paraneoplastic encephalitis and ovarian
teratoma.
4
(CE) Double immunolabeling of cultures of rat hippocampal neurons using a
patients antibodies (C, green) and an antibody against NR2B of the NMDAR (E, red); note
the significant colocalization of reactivities (D, yellow). These findings suggested that patients
antibodies were directed against the NMDAR. Subsequent studies demonstrated that the patient
also had antibodies against NR2A (not shown), which explains, in part, the partial
colocalization of reactivities. Original magnification 2.5 (A) and 400 (B), both
counterstained with hematoxylin; 800 (oil lens), immunofluorescence (CE).
Dalmau et al. Page 13
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Fig 4.
Patients antibodies react with heteromers of NR2B and NR2A subunits of the N-methyl-D-
aspartate receptor (NMDAR). HEK293 cells expressing heteromers (NR1/NR2B or NR1/
NR2A) or transfected with single subunits NR1 or NR2B of the NMDAR were incubated with
patients serum or cerebrospinal fluid (CSF). (top row) Panels demonstrate that the CSF of
Patient 7 reacts with cells expressing heteromers (functional receptors) of NR1/NR2B and
NR1/NR2A, but not with cells transfected with single subunits (NR1; NR2B). Cells transfected
with single NR2A or plasmid without insert were not reactive with patients antibodies (not
shown). (bottom row) Panels demonstrate the reactivity of the CSF of Patients 1 and 3 with
NR1/NR2B. In the third panel (#7 +NR2B), the cells were coincubated with CSF of Patient
7 and an antibody specific for NR2B, showing colocalization of reactivities. The fourth panel
(C ()) corresponds to the CSF of an individual without paraneoplastic encephalitis (negative
control). Original magnification 800, immunofluorescence; nuclei of cells demonstrated with
4,6-diamidino-2-phenylindole (DAPI), except #7 +NR2B, in which no DAPI was used.
Dalmau et al. Page 14
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Fig 5.
Patients antibodies react with NR2 subunits of the N-methyl-D-aspartate receptors
(NMDARs) expressed by nervous tissue present in the tumor. (A, B) Panels correspond to the
ovarian teratoma of Patients 3 and 5 immunolabeled with MAP2 (brown staining), a marker
specific for neurons and dendritic processes. Note the intense reactivity with neuronal-like cells
and a network of cell processes that are better developed in A. (B, inset) Some immature
neuronal cells at higher magnification. (CE) Panels correspond to the tumor of Patient 3
immunolabeled with the patients antibodies (C, green) and a specific antibody for NR2B (E,
red). Note that there is colocalization of reactivities (D, yellow), indicating that the patients
antibodies react with NR2B expressed in the tumor (similar findings were observed with
NR2A, not shown). (FH) Panels correspond to the tumor of Patient 5 immunolabeled with
the patients antibodies (F, green) and a specific antibody for NR2B (H, red). There is also
colocalization of reactivities (G, yellow), indicating that the patients antibodies recognize
NR2B expressed in the tumor (similar findings were observed with NR2A, not shown).
Original magnification 200, counterstained with hematoxylin (A, B); 400,
immunofluorescence (CH).
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m
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n
.
Ann Neurol. Author manuscript; available in PMC 2008 J une 18.