Review

pubs.acs.org/chemneuro

Anti-NMDA-Receptor Encephalitis: From Bench to Clinic

Arun Venkatesan* and Krishma Adatia
Johns Hopkins Encephalitis Center, Division of Neuroimmunology and Neuroinfectious Diseases, Department of Neurology, Johns
Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
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ABSTRACT: NMDAR encephalitis is a common cause of autoimmune encephalitis, predominantly affecting young adults.
Current data supports the idea that autoantibodies targeting NMDARs are responsible for disease pathogenesis. While these
autoantibodies occur in the setting of underlying malignancy in approximately half of all patients, initiating factors for the
autoimmune response in the remainder of patients are unclear. While there is increasing evidence supporting viral triggers such as
herpes simplex encephalitis, this association and the mechanism of action have not yet been fully described. Although the
majority of patients achieve good outcomes, those without an underlying tumor consistently show worse outcomes, prolonged
recovery, and more frequent relapses. The cloning of patient-specific autoantibodies from affected individuals has raised
important questions as to disease pathophysiology and clinical heterogeneity. Further advances in our understanding of this
disease and underlying triggers are necessary to develop treatments which improve outcomes in patients presenting in the
absence of tumors.
KEYWORDS: NMDA, autoimmune encephalitis, plasma cells, receptor internalization, immunotherapy

■ INTRODUCTION
Encephalitis is a neurological disorder caused by inflammation
but cases have been reported across a wide age range, from 2
months16 to the ninth decade of life.7,13,16−21
of the brain parenchyma.1 Its incidence is approximated at 5− The traditional association of NMDAR encephalitis with an
underlying tumor has been shown to be less common than first
10 per 100 000 people per year, though this is likely an
thought. In various reports, 20−59%7,8,14,22 of cases are seen in
underestimation.2,3 Although encephalitis is most commonly
the presence of an underlying tumor, occurring less frequently
attributed to underlying viral infection, autoimmune conditions
in younger and male patients.7,8,10,22,23 While coexisting tumors
have become increasingly appreciated as causes of encephalitis.4
were seen in 52% of females, this was only found to be the case
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis
in 6% of children and male patients.23 NMDAR encephalitis
was first described by Dalmau et al. in 2007 as a disease in
additionally not only appears to be more prevalent among non-
which antibodies to the NMDAR are associated with ovarian
Caucasians, but also shows a greater association with teratomas
teratomas in young women.5 In the time since this initial
in African Americans compared to any other ethnic
description, our understanding of the mechanisms and clinical
group.7,14,15,18,24,25
features associated with this disorder has greatly increased.
Ovarian teratoma is the tumor most commonly implicated

■ EPIDEMIOLOGY
Initially described as a disease of young females with ovarian
teratomas,5,6 NMDAR encephalitis has since been identified in
males, children, and in the absence of tumors.7−13 There
remains a female predominance, however, with approximately
80% of cases occurring in women,7 though this percentage is
lower in patients younger than 12 and older than 45. Young
adults in their third decade of life are primarily affected,5,8,14,15
with NMDAR encephalitis;7,8,22 a large series demonstrated
that of all cases associated with an underlying malignancy, 98%
were due to ovarian teratomas.7 Other malignancies seen in
NMDAR encephalitis include mediastinal teratomas, sex cord
stromal tumors, small cell lung cancer, testicular teratomas,
Received: August 21, 2017
Accepted: October 27, 2017
Published: October 27, 2017

© 2017 American Chemical Society 2586 DOI: 10.1021/acschemneuro.7b00319

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Figure 1. Model of receptor internationalization following binding of NMDAR antibody. (A) NMDARs (dark blue) are associated with EphB2Rs
(purple) in the extrasynaptic region. Glycine and glutamate binding to the GluN1 and GluN2 subunits, respectively, leads to receptor activation and
Na+ and Ca2+ entry, causing depolarization. (B) In patients with NMDAR encephalitis, antibody attachment, capping, and cross-linking occur on the
GluN1 subunit. This disrupts the interaction between NMDAR and EphB2R, reducing NMDAR stability and clustering. (C) Receptor
internalization occurs, resulting in reduced NMDAR density and decreased currents.
breast cancer, lung cancer, thymic carcinoma, pancreatic cancer,
neuroblastoma, and Hodgkin’s lymphoma.7,8,18,23,26
■ CLINICAL PICTURE
The presentation of NMDAR encephalitis has been well-
defined in adults, with disease progression consisting of four
distinct stages: the prodromal phase, psychotic phase,
unresponsive phase, and hyperkinetic phase.7,15,27 A viral
prodrome is experienced by up to 86% of patients;7 the
remaining phases are more variable in presentation, severity,
and sequence in which they occur.28 During the prodromal
phase, patients typically experience a flulike illness for 1−21
days, consisting of low grade fever, malaise, headache, upper
respiratory tract symptoms, fatigue, nausea, vomiting, and
diarrhea.10,17,20,29 Delusions, auditory and visual hallucinations,
depression, paranoia, agitation, and insomnia occur with
progression to the psychotic phase.28 Most patients present
to medical attention at this stage, with numbers quoted in the
range of 72−84%.8,10,29,30 Approximately 40−42% are initially
misdiagnosed as having a psychiatric disorder.29,31−35 Further
progression may lead to seizures (commonly generalized tonic-
clonic), dyskinesias (predominantly perioral such as lip-
smacking and grimacing), catatonia, impaired attention, and
episodic memory loss.7,20,27,28 Seizures are a common
manifestation of this disease, and are experienced by 76−82%
of patients.8,10 Although they may occur at any time throughout
the course of illness, males tend to present with seizures
earlier.9 Mutism or akinesia is typically seen in the unresponsive
phase, but athetosis may also occur.8,27 Autonomic instability is
a hallmark of the hyperkinetic phase, and may manifest as
hypotension, hypertension, cardiac arrhythmias, hypoventila-
tion and hypo- or hyperthermia. Hypoventilation is a significant
feature of the illness and patients who progress often require
ventilatory support.5,8,10,12,22,23
In children, seizures often mark the onset of the disease, with
behavioral problems such as inattention, aggression, temper
tantrums, hyperactivity, or irritability occurring subse-
quently.8,22 These behavioral symptoms play a more significant
role compared to adults, and may make diagnosis more
difficult.7,36 The typical presentation of seizures or abnormal
movements15,37−39 are in contrast to the predominance of
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psychiatric presentations, such as anxiety, paranoia, and
hallucinations, seen in adults.8,15,23 Additional differences
include a greater incidence of atypical symptoms, such as
cerebellar ataxia or hemiparesis in children, and a greater
incidence of memory deficits and autonomic instability in
adults; 66% of adult cases suffer from central hypoventilation in
contrast to only 23% of pediatric cases.8,22,38,40 Although initial
presentations differ between children and adults, in most cases
the clinical picture for all age groups converges at 3−4 weeks
following symptom onset; behavioral symptoms, for example,
occur in 90% of patients at 1 month regardless of age group.23
■ PATHOPHYSIOLOGY
NMDARs are heterotetrameric ionotropic receptors 41,42
composed of two GluN1 subunits and combinations of two
GluN2 or GluN3 subunits.43 The subunit composition of the
receptor depends upon brain location and drives receptor
function; GluN2A and GluN2B subunits, for example, are
commonly seen in the forebrain, compared to GluN2C in the
cerebellum.44 NMDARs are predominantly found in the
forebrain and limbic system, most notably the hippo-
campus,8,15,45 and play a significant role in learning, memory,
cognition and behavior.41,46−48
The available data suggests that IgG antibodies that target the
GluN1 subunit of the NMDAR are responsible for disease
pathogenesis.49 Three mechanisms for the resulting symptoms
have been proposed in the literature: (i) receptor internal-
ization, (ii) antibody blockade of ion entry, and (iii)
complement mediated cell lysis.41 Receptor internalization is
the mechanism most supported by current literature. Here,
antibody attachment, capping and cross-linking of NMDARs
induces their endocytosis and lysosomal degradation22,40,50,51
(Figure 1). Internalization of NMDARs is also facilitated by
antibody-mediated disruption of NMDAR and ephrin B2
receptor (EphB2R) interactions; EphB2Rs normally aid
stabilization of NMDARs at the membrane.51 Receptor
internalization similarly occurs for both excitatory and
inhibitory NMDARs.40
Electrophysiological studies have demonstrated reduced
NMDAR-mediated currents due to decreased receptor density,
the magnitude of which is related to antibody titers.40,41,50,52 By
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Figure 2. Cloning of patient-specific autoantibodies from individuals with NMDAR encephalitis. Individual antibody secreting cells are isolated by
flow cytometry from the CSF, followed by cloning and expression of patient-specific antibodies. These antibodies were found to bind multiple cell
types in the CNS.

Figure 3. Model of antibody cross-reactivity in the setting of tumor. (1) NMDARs are expressed by ovarian teratomas. Where apoptosis occurs,
these are released and taken up by antigen presenting cells, predominantly dendritic cells. (2) These dendritic cells migrate to regional lymph nodes,
where activation of B, CD4+, and CD8+ cells occurs. (3) Immune cells migrate back to the ovary, where they target NMDARs. (4) In the presence of
impaired blood brain barrier permeability, these cells are also able to enter the brain and cross-react with NMDARs found on neurons.

the time internalization of receptors becomes microscopically
visible at 2 h after exposure in vitro, receptor density has
already fallen by 19%,51 continuing to fall until a nadir at 12 h,
after which a plateau is seen that persists for the duration of
antibody exposure.40 Total loss of NMDAR density in vitro
may be greater than 45%.52 Importantly, this process is
reversible with removal of antibodies; return to baseline
NMDAR density occurs within 4 days in in vitro models.50
Animal studies have supported the concept that antibodies can
drive disease pathogenesis; mice develop symptoms of
depression, anhedonia, and memory deficits following the
intrathecal injection or infusion of CSF from affected
humans.8,53 Symptoms in mice show increasing severity with
infusion time, and resolve upon stopping the infusion,
demonstrating similar titer-dependence and reversal as seen
in electrophysiological studies.53 Subsequent histopathological
2588
analysis of brain tissue demonstrates binding of human IgG to
NMDARs, predominantly in the hippocampus.8,53
Brain tissue samples also show a notable absence of
complement.8 Reduction of NMDAR density to similar extents
following administration of either heat inactivated CSF or
nonheat inactivated CSF provides further evidence that
pathogenesis is not complement-mediated.40,41,50 Moreover,
Kreye et al. have demonstrated NMDAR downregulation in
vitro in the presence of the GluN1 antibody alone.52
More recently, patient-specific antibodies have been cloned
from individual antibody-secreting cells in the CSF of affected
patients. Notably, these antibodies were observed to bind to
additional epitopes in the brain, such as endothelium, glial cells
and Purkinje neurons, the significance of which remains to be
determined52 (Figure 2).
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Triggers. Malignancies and infections have been proposed
as triggers for NMDAR encephalitis. Ectopic expression of
NMDARs in ovarian teratomas, for example, is thought to
trigger the immune response in NMDAR encephalitis8,54
(Figure 3). A likely oversimplified model is as follows: antigens
are released by these tumor cells when undergoing apoptosis,
and are taken up by antigen-presenting cells which travel to
regional lymph nodes. Here, plasma cells produce antibodies
which later cross-react with NMDARs in the brain following
impaired blood-brain barrier (BBB) permeability.49 While
ovarian teratomas are the most widely recognized tumor
associated with NMDAR encephalitis, other tumors and tumor
cell lines have been shown to express the NMDAR, potentially
explaining the association of such tumors with NMDAR
encephalitis albeit at lower frequencies.55−58 In up to 80% of
cases, no underlying tumor is found.22 Recent evidence has
suggested the presence of NMDARs on a variety of peripheral
blood cells, including red blood cells and immune cells,59,60
which could potentially play a triggering role in NMDAR
encephalitis were self-tolerance to these antigens broken.
The viral prodrome seen with this disease may support the
idea of an infectious trigger. However, it is unclear whether this
prodrome is merely a consequence of the early immune
response or due to an infection which then facilitates antibody
passage across the BBB.8 Herpes simplex has been the virus
most commonly implicated in the development of NMDAR
encephalitis.14,61−71 Up to 20−30% of patients with herpes
simplex encephalitis (HSE) have been reported to develop
NMDAR antibodies,61,66,69 occurring in the CSF before
serum.62 These antibodies are not usually present at the
onset of HSE, instead developing over the course of infection,
suggesting that HSE triggers B cell and plasma cell generation.
Development of antibodies, however, does not always lead to
progression to NMDAR encephalitis.69 In those who do go on
to develop NMDAR encephalitis, this may be seen as
behavioral change and choreoathetosis in children,61,66 or
psychiatric and cognitive abnormalities in adults.62 Identifying
post-HSE NMDAR encephalitis may have significant prognos-
tic implications, as these patients do not appear to be as
responsive to treatment as those with other triggers such as
teratoma.61 Although post-HSE NMDAR encephalitis has been
the most widely reported, there have been a few reported cases
where NMDAR encephalitis has occurred following mycoplas-
ma, Epstein−Barr, varicella zoster, or influenza infec-
tions.14,72−74
Molecular mimicry, altered self-antigens, and dysregulation of
immunoregulatory pathways are some of the mechanisms
proposed for the link between infections and induction of CNS
autoimmunity.75 In molecular mimicry, antibody cross-
reactivity with self-antigens occurs when there is sufficient
structural similarity between epitopes on foreign and self-
proteins. Self-antigens may also induce immune activation
themselves, through alterations via expression level changes, or
post-translational modification, thereby contributing to break-
ing of immune tolerance. Notably, the immune response
resulting from an altered antigen may potentially be persistent
even in the absence of further altered antigens, thus resulting in
chronic neuroinflammation.75
■ DIAGNOSIS
Identification of NMDAR antibodies in CSF or serum is the
mainstay of diagnosis.8,11,76 Some studies have suggested lower
specificity of serum testing, which occasionally demonstrates
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presence of antibodies in patients without NMDAR encepha-
litis.9,77−82 When compared with CSF testing, serum testing
also demonstrates a lower sensitivity than CSF testing
(approximately 85%).23,83,84 Although testing of CSF titers
alone is generally considered to be sufficient for the diagnosis of
NMDAR encephalitis, some propose testing both CSF and
serum to reduce the risk of false positive and false negative
results.7,76,84
Antibody titers show temporal increase with disease
progression, and appear to correlate with clinical symptoms;
patients with more severe symptoms and associated malig-
nancies have been reported to have higher titers.8,50 Other CSF
abnormalities seen include lymphocytic pleocytosis (in 89−
90%), increased protein levels (33%), and oligoclonal bands
(60%).5,8,14,23,85 Again, temporal changes in these abnormalities
are seen throughout the course of the disease; lymphocytic
pleocytosis has been reported to be present in early CSF
samples while oligoclonal bands are typically not, and the
reverse is more often observed later in the disease.10
Routine imaging techniques are not typically useful in aiding
diagnosis, as CT very rarely reveals abnormalities14 and normal
MRIs are seen in 50−70% of cases.5,7,8,10,11,14,86 When MRI
abnormalities are present, changes are seen in the hippocampi,
cerebellar or cerebral cortex, frontobasal and insular regions,
basal ganglia, brainstem, or spinal cord.5 These findings may be
transient, can be nonspecific, and do not correlate with
symptom severity.8 Whether follow up MRIs demonstrate any
abnormalities is not agreed upon. Dalmau et al. reported
normal or minimal changes regardless of symptom severity and
duration,7 while Gable et al. reported changes in 40% of follow
up MRIs, though these changes were inconsistent between
patients.14 Some abnormalities that have been reported on
serial imaging include periventricular white matter demyelina-
tion, temporal lobe hyperintensity, and frontotemporal or
medial temporal lobe atrophy.5,14 Thus, due to the large
variability in findings between patients, currently utilized
routine imaging techniques show little usefulness as diagnostic
tools in NMDAR encephalitis. Recent work has suggested that
fluorodeoxyglucose positron emission tomography scanning
(FDG-PET) may serve a role in the assessment of patients with
autoimmune encephalitis, as abnormalities are observed more
frequently than in MRI.87,88 Interestingly, a pattern of occipital
lobe hypometabolism has emerged as a biomarker that appears
to distinguish NMDAR encephalitis from other autoimmune
encephalitides.87
EEG monitoring is abnormal in 90% of patients with
NMDAR encephalitis, where nonspecific slowing of brain
activity is typically seen.8,14,15,22,23 Focal electrographic seizures
may also be seen in 10%14 and extreme delta brush (EDB)
pattern in 16−33%.89−91 EDB is manifested as delta waves (1−
3 Hz) upon which beta waves (20−30 Hz) are superimposed,
and is named such due to the resemblance to the “delta brush”
EEG pattern seen in premature infants. EDB is distinct from
this neonatal pattern as it is typically synchronous and does not
vary with sleep--wake cycles or level of arousal, and is thus a
relatively unique feature of NMDAR encephalitis.90 It is
typically seen as a continuous pattern, unrelated to symptoms
such as dystonia, choreoathetosis or orofacial dyskinesias.90,92
Whether the presence of EDB reflects greater disease
severity90,92−94 and worse outcomes90,93,94 remains controver-
sial.91 Importantly, EDB is an early finding which may guide
investigations and facilitate diagnosis of NMDAR encephali-
tis.94
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An overview of diagnostic findings in patients is given in
Figure 4.
Figure 4. Frequency of common diagnostic findings in patients with
NMDAR encephalitis. Findings from 577 patients with NMDAR
encephalitis are depicted. N, normal; A, abnormal; U, unknown.
It is also necessary to screen for underlying malignancies if
NMDAR encephalitis is suspected. MRI, CT, and pelvic and
transvaginal ultrasound are useful for identifying tumor
presence. Serological tumor markers, on the other hand, tend
to be negative in most patients.7
■
TREATMENT
In patients with underlying malignancies, removal of the tumor
improves symptoms in 75% of cases;7,8,24,95,96 this rises to 80%
with the addition of immunotherapy.23 Where tumors are not
present, first line treatment comprises corticosteroids, intra-
venous immunoglobulins, and/or plasma exchange.7,11,23,41,96,97
Good responses are usually seen following these treat-
ments,5,8,22 but in patients who are unresponsive to or relapse
after first line therapy, rituximab or cyclophosphamide are
useful as second line treatments.7,11,23,41,96,97 Patients without
tumors are usually less responsive to first line therapy, and thus
more often require these second line therapies.7 In patients
Figure 5. Outcomes following NMDAR encephalitis.
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who also show inadequate response to rituximab, tocilizumab
(monoclonal antibody against the interleukin-6 receptor) and
bortezomib (a proteasome inhibitor) may have some additional
benefit.98,99 In a recent nonrandomized study, tocilizumab
resulted in better long-term outcomes compared to those given
further rituximab or no subsequent treatment.98 Bortezomib
therapy in refractory anti-NMDAR encephalitis patients
demonstrated a fall in CSF antibody levels, with corresponding
clinical improvement.99 Of note, while there have been few
reported cases of recovery occurring in the absence of any
targeted therapy, the natural history of NMDAR encephalitis
remains to be defined.15,100
Symptom specific pharmacological management has been
reported in few studies, though this has not been investigated in
great detail.32 Catatonia is frequently managed with benzodia-
zepines. In some patients, sufficient control is only achieved
with up to 20−30 mg of lorazepam per day.101−104 In such
cases, electroconvulsive therapy (ECT) may be beneficial,
though current literature provides inconsistent reports on its
efficacy;42,101−104 it has been quoted in the range of 80−96%
compared to lorazepam at 80−100%.101 Some case reports
have demonstrated full recovery after ECT in patients with
disease refractory to first and second line therapies.32,102−105
The mechanism by which ECT is able to exert symptomatic
benefits in NMDA encephalitis is still unclear, but it has been
proposed that it is able to increase the number of GluN2A and
GluN2B subunits.106
■ PROGNOSIS
NMDAR encephalitis tends to show a better prognosis
compared to most other causes of encephalitis;11 over 75%
recover to at or near baseline neurological function-
ing,7,9,23,29,97,107 and only 25% suffer significant morbidity or
mortality.7,23,34,107 Although there has yet to be a randomized
controlled trial of therapies in NMDAR encephalitis, large
retrospective studies suggest that good prognosis, including
fewer relapses, is associated with early diagnosis and treat-
ment,23 milder symptoms, and removal of tumor when
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present.5,8,15,22,108−110 Presence of tumor itself, however, is not
a prognostic indicator; final outcomes are similar between
patients with and without tumor (Figure 5).7,10
Long-term outcome is associated with treatment responsive-
ness: 97% of patients responsive to first line therapy show good
outcome at 2 year follow up (modified Rankin Score 0−2).23 In
patients who do not respond to first line therapy, subsequent
treatment with second line therapies confers better long-term
outcome compared to patients who have no further treat-
ment.7,23,107 Improvements in symptoms begin within a few
weeks after initiating treatment,24 but return to baseline
functioning may only be achieved up to 3 years
later.4,8,22,37,95 Patients without tumors typically show a slower
course of recovery and some patients do not ever recover
fully.8,111
Serum and CSF antibody titers can be measured to
demonstrate control of the immune response. Although
serum levels tend to show a faster rate of decline than CSF
titers,8 CSF antibody titers show better correlation with long-
term clinical outcome and relapses.8,10,76,108,112 Lower initial
CSF titer and early decline in antibody levels are associated
with better outcome; however, patients may have persistent
positive titers even in the setting of recovery.8,10,76,108,112
Despite achieving medical recovery, rehabilitation is required
in around 85% of patients upon discharge; deficits in attention,
memory, and executive functions may persist for many
years.8,10,107 Persisting amnesia of the entire duration of illness,
in particular, is a characteristic feature.29 Memory deficits seen
following NMDAR encephalitis have recently been demon-
strated to correlate with degree of hippocampal atrophy, which
in turn are associated with symptom duration and severity.113
Diffuse cerebral atrophy (DCA) and progressive cerebellar
atrophy (PCA) have also been reported in patients with
NMDAR encephalitis. Where DCA occurs, although full
recovery may take a number of years, follow up MRIs may
demonstrate some reversal of brain atrophy.111 In patients with
PCA, however, only partial clinical improvement is seen, with
persisting atrophy.114
Residual visual impairments following NMDAR encephalitis
have also been reported.115 Here, deficits in both high and low
contrast acuity are reported, with extent of high contrast deficit
associated with disease severity.115 NMDARs can be found in
the retina, so such visual dysfunction may originate here. With
use of optical coherence tomography, Brandt et al. failed to find
any structural retinal damage in patients with NMDAR
encephalitis, suggesting that cortical deficits may be respon-
sible.115
Relapses have been reported in approximately 10−29% of
cases,7,10,23 being more common in patients without tumors.7,23
Death has been reported in 4−10% of patients;8,14 this is
usually seen within months following disease onset.7,13
■
CONCLUSIONS
Over the past 10 years, it has become well-established that
NMDAR encephalitis is a common cause of autoimmune
encephalitis. The available data from in vitro and in vivo studies
demonstrate that autoantibodies targeting NMDARs can result
in receptor internalization, perturbation of NMDAR currents,
and behavioral alterations. While both malignancy and
infections can trigger NMDAR encephalitis, the mechanisms
by which infections in particular may do so remain to be
explored. The recent cloning of patient-specific autoantibodies
from patients with NMDAR encephalitis may facilitate studies
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of disease pathogenesis and may shed light on some of the
clinical heterogeneity of the disease. In addition, such studies
may contribute to the development of new targeted therapies
for individuals afflicted by this condition.
■
AUTHOR INFORMATION
Corresponding Author
*Mailing address: Johns Hopkins Hospital, 600 N. Wolfe St.,
Meyer 6-113, Baltimore, MD 21287, USA. E-mail: avenkat2@
jhmi.edu.
ORCID
Arun Venkatesan: 0000-0002-9335-7361
Funding
This work was supported by the National Institutes of Health
(NINDS R21 NS098229 to A.V.).
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Figures 4 and 5 represent new figures created from data
presented by J. Dalmau and colleagues in prior publications.
■
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