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Physiopathology of anti-NMDA
receptor encephalitis
Students: Felix Gassert - Universität Ulm, Germany Sara Mahmoud – Université d'Angers, France Sindy Sim – Université de Nantes, France Borbàla Szepes – University of Szeged, Hungary César Terán Zea – Universidad Espíritu Santo, Ecuador
Tutor: Franck Letournel – Université d'Angers, France
ACKNOWLEDGMENT
We would like to express our deep gratitude to professor Franck Letournel, our tutor for his
guidance, encouragement and useful critiques on this research work.
We would also like to thank professor Guillaume Lamirault for supervising this project.
LIST OF ACRONYMS
• ABD: agonist-binding domain
• AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
• CNS: central nervous system
• CSF: cerebrospinal fluid
• EEG: electroencephalography
• LTD: long term depression
• LTP: long term potentiation
• MRI: magnetic resonance imaging
• NMDA: N-methyl-D-aspartate
• NMDAR: NMDA receptor
• NTD: N-terminal domain
• TMD: transmembrane domain
INDEX
Introduction......................................................................................................................................1
I. NMDA-receptor.....................................................................................................................1
I.A Subtype composition...................................................................................................1
I.B Subunit architecture....................................................................................................2
I.C Different subunit composition/NMDAR subunit composition is plastic........................2
I.D Long term changes in mature synapses.....................................................................3
I.E NMDAR and diseases.................................................................................................3
II. Clinical features....................................................................................................................3
II.A General clinical and paraclinical features..................................................................3
II.B Children and adolescent (less than eight years old)..................................................4
II.C Paraneoplastic and non-paraneoplastic anti-NMDAR encephalitis...........................5
III. From the discovery of the antibodies to the diagnosis...................................................5
IV. Physiopathology of this immune-mediated disease........................................................7
IV.A Antibody-induced receptor internalisation................................................................7
IV.B mEPSC decrease due to NMDA-R internalisation..................................................7
IV.C Immunological trigger..............................................................................................8
IV.D Source of antibodies...............................................................................................9
IV.E Cellular alterations-symptom correlation.................................................................10
V. Treatment...........................................................................................................................10
Conclusion.....................................................................................................................................10
References......................................................................................................................................12
Introduction
Anti-NMDA encephalitis is a recently described disorder that is mediated by antibodies to
the NR1 subunit of the receptor. Indeed, the NMDA receptor is composed of two main subunits :
NR1 that binds glycine and NR2 that binds glutamate. It is often paraneoplastic, treatable and can
be diagnosed by CSF samples. However, it can also be non-paraneoplastic.
Most patients are children or women, but men can also be affected.
It is a neuropsychiatric immune-mediated disease.
I. NDMA-receptor
The NMDA receptor, named by its selective agonist N-methyl-D-aspartate, is a ligand
gated cation channel with crucial roles in synaptic transmission allowing the passage of Ca2+ and
Na+ into the cell and K+ out of the cell. The NMDAR is an essential mediator of brain plasticity
and is capable of converting specific patterns of neuronal activity into long-term changes in
synapse structure and function that are thought to underlie higher cognitive functions (Lee et al.,
2014; Paoletti et al., 2013; Dalmau et al., 2008). It is ubiquitously expressed in the brain but shows
stronger expression in certain regions, e.g. the hippocampal neuropil. NMDARs exhibit remarkable
properties that distinguish them from other types of ligand-gated ionotropic receptors. First, their
ion channel is subject to a voltage- dependent block by Mg2+; second, NMDAR channels are
highly Ca2+- permeable; third, they display unusually slow kinetics owing to slow glutamate
unbinding; fourth, their activation requires the presence not only of glutamate but also of a co-
agonist (glycine or d- serine) (Paoletti et al., 2013).
I.A Subtype composition
Many different NMDAR subtypes coexist in
the CNS. The receptors are tetrameric complexes
mostly consisting of two obligatory glycine binding
GluN1 subunits combined with two glutamate binding
GluN2 subunits (Dalmau et al., 2008; Moscato et al.,
2010; Laube & Kiderlen, 1997). This combination
forms the so-called di-heteromeric receptors.
Combination of two GluN1 subunits and a mixture of
1
Figure 1: Seven NMDA receptor subunits have been identified: GluN1, GluN2A– GluN2D and GluN3A and GluN3B. Subunit heterogeneity is further enhanced by alternative splicing of GluN1 and GluN3A subunits. M1–M4 indicate membrane
one GluN2 and one GluN3 subunit leads to so-called tri-heteromeric receptors. The GluN2 subunit
is subdivided into GluN2A-D, whereas the GluN3 subunit is subdivided into GluN3A and GluN3B
(Moscato et al., 2010). The GluN1 subunit is encoded by a single gene but has eight distinct
isoforms (GluN1-1a–GluN1-4a and GluN1-1b–GluN1-4b) owing to alternative splicing (Paoletti et
al., 2013).
I.B Subunit architecture
NMDAR subunits consist of four discrete modules: Two large
globular bilobate extracellular domains: the amino (N)-terminal domain
(NTD), which is involved in subunit assembly and allosteric regulation, and
the agonist-binding domain (ABD), that is formed by two discontinuous
segments (S1 and S2), binding glycine or glutamate depending on the
GluN subunit. Furthermore there is one transmembrane domain (TMD)
consisting of three transmembrane helices (M1,3,4) and a pore loop (M2)
that lines the ionselectivity filter. The TMD connects the extracellular
domains to the intracellular domain (CTD), which is involved in receptor
trafficking, anchoring and coupling to signaling molecules (Paoletti et al.,
2013, Lee et al., 2014).
I.C Different subunit composition/NMDAR subunit composition is plastic
Due to different subunit compositions NMDARs show different subtypes with distinct
pharmacological properties, localization, and ability to interact with intracellular messengers.
NMDARs are mobile (at least in cultured neurons), particularly the GluN2B-containing ones, and
probably exchange through lateral diffusion between synaptic and extrasynaptic sites. Typically,
NMDARs are found at postsynaptic sites, but as well can be found in pre-, peri- and extrasynaptic
sites and then are enriched in GluN2A-containing receptors (Paoletti et al. 2013).
Thus the subtype composition in the CNS varies in different areas and throughout a life, not
only concerning number and density but as well the subunit composition (Paoletti et al., 2013).
Reasons for change may be aging, learning and diseases. Mainly diheteromeric GluN1/GluN2B
but as well diheteromeric GluN1/ GluN2A receptors represent an important fraction of juvenile
NMDARs. During early postnatal development, NMDARs switch their subunit composition from
primarily containing GluN2B subunits to predominantly containing GluN2A subunits leading to
predominantly diheteromeric GluN1/GluN2A and triheteromeric GluN1/GluN2A/GluN2B receptors
in the adult forebrain, especially populating the hippocampus and cortex.
2
Figure 2: All GluN subunits share a modular architecture that is made of four distinct domains: the NTD, the ABD, TMD and an intracellular C-terminal domain (CTD).
I.D Long term changes in mature synapses
NMDARs are essential mediators of brain plasticity and are capable of converting specific
patterns of neuronal activity into long-term changes (LTP and LTD) important for learning
processes. Nevertheless LTP due to NMDA receptors require a stronger induction protocol and
develop slower than similar processes triggered by AMPAR for example. LTD due to NMDA is well
established also the underlying processes are poorly defined. (Paoletti et al., 2013).
I.E NMDAR and diseases
The NMDAR is involved in various neurological and psychiatric disorders. The subunits
mainly affected are the GluN1 leading to Anti-NMDA receptor encephalitis, behavioral and memory
deficits, dyskinesias, language reduction (in children), seizures and autonomic instability and the
GluN2A/B leading to neuropsychiatric systemic lupus erythematosus, cognitive deficits, psychosis,
memory deficits, mood disorder, seizure and headache (Moscato et al., 2010; Paoletti et al., 2013;
Damlau et al., 2008).
II. Clinical features
II.A General clinical and paraclinical features
Patients show mostly psychiatric and neurologic symptoms, but they can also present
other kind of signs.
First, after showing prodromic symptoms of mild hyperthermia, headache or a viral-like
process, patients develop sudden behavioral and personality changes which explain why they
are mostly initially seen by psychiatrists or admitted to psychiatric centers (Dalmau, et al.,2007).
Patients appear confused, restless, agitated, with frequent paranoid or delusional thoughts.
In addition of this clinical presentation, seizures, decreased level of consciousness,
abnormal movements (orofacial and limb dyskinesias, dystonia, choreoathetosis) or catatonia
which is a lack of movement, activity and expression are noted. Furthermore, autonomic
instability (tachycardia, hyperthermia, hypertension) and sometimes hypoventilation are also
observed.
Finally, MRI findings (figure 3) are mostly normal but can be abnormal which usually
consist of mild, transient T2 or fluid-attenuated inversion recovery abnormalities.
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II.B Children and adolescent (<18 years old)
In patients younger than 18 years old, differences in tumor association, neurological
presentation and frequency of symptoms (Florance, et al., 2009) are observed compared to adult
patients. The younger the patient is, the less likely a tumor is to be identified (figure 4).
Clinical picture of pediatric patients with anti-NMDAR encephalitis is similar to the adult's
one. But several differences can be noted in the frequency and manifestation of some symptoms.
Indeed, most of adults initially show obvious psychiatric signs such as anxiety, agitation, paranoia,
visual or auditory hallucinations... Whereas the recognition of psychosis in young children is
neglected. Furthermore, the autonomic manifestations can occur during the course of the disease
in children but they are less severe than in adults.
Anti-NMDAR encephalitis should be suspected in children with acute behavioral changes,
seizures, dystonia or dyskinesia. Usually these signs are accompanied by :
➢ CSF lymphocytic pleocytosis (presence of more than the normal number of lymphocytes
in the cerebrospinal fluid).
➢ EEG with infrequent epileptic activity, but frequent slow, disorganized activity.
➢ Brain MRI that is often normal or shows transient fluid attenuation inversion or contrast-
enhancing abnormalities.
4
Figure 4: Distribution of age and tumors in 81 patients with anti-NMDAR encephalitis.
Black bars: number of patients with tumors (ovarian teratomas).
Younger patients were less likely to have a tumor.
Figure 3 (Dalmau, et al.2008) Brain magnetic resonance imaging (MRI) in three patients.
(A,B) : patient 1 at symptom presentation (A) and after partial clinical improvement and CSF normalization (B)
(C,D) : patient 2 at symptom presentation (C) and 4 months later (D) showing a neurological deterioration that didn't respond to immunotherapy.
(E,F) : patient 3 at symptom presentation with mild fluid-attenuated inversion recovery hyperintensity in medial lobes and right frontal cortex. After immunotherapy and tumor resection, the MRI was normal (not shown).
The diagnosis is confirmed by detection of antibodies to NR1 subunits of the NMDAR.
II.C Paraneoplastic and non-paraneoplastic anti-NMDAR encephalitis
Most of the times, the anti-NDMA-receptor encephalitis in adults, mostly women, are
associated with tumors. In this case, we talk about paraneoplastic syndrome. Patients usually
develop neurological symptoms before the tumor diagnosis. Indeed, an immune response resulting
in antibody synthesis may decrease the size of the tumor at its initial stage (Moscato, et al.,2010)
or even completely eliminate it.
The frequency of ovarian teratoma is higher in women older than 18 years. Ovarian
teratoma is identified in women by CT scan, MRI or ultrasound. This is a tumor, often benign, that
contains a diversity of tissue and that develops from a totipotential germ cell. Men can also be
affected and often show testis teratomas, and sometimes small-cell lung cancer which is more
difficult to cure.
Patients with paraneoplastic anti-NMDAR encephalitis present teratomas which contain
nervous tissue that are positive for expression of NMDA receptors (Dalmau, et al., 2008). Thus, the
presence of this tumor contributes to breaking immune tolerance.
Although the presence of a tumor that expresses NMDA receptors is a great explanation for
the mechanism of this immune-mediated disease, other immunological mechanisms that are still
not fully understood are involved since patients can be affected even without presenting a tumor,
mostly young patients. In these cases, we'll talk about an auto-immune anti-NMDAR
encephalitis.
III. From the discovery of the antibodies to the diagnosis
The anti-NMDAR encephalitis seems to be mediated by antibodies, because patients often
recover after tumor removal and immunotherapy. If the antibodies were pathogenic, we reasoned
that their effects on NMDA receptors would be reversible because most patient recover.
5
Figure 5: Immunohistochemical criteria for the presence of NR1-NR2B antibodies! Serum and CSF were tested for antibodies for the NMDA receptor, and considered positive if three immunohistochemical criteria were fulfilled.
NMDA receptor is expressed in the hippocampus. Indeed, coronal section of a rat brain incubated
with a representative CSF shows intense reactivity predominantly involving this region (A).
Studies have suggested that the target epitopes were located in extra-cellular region of
NR1-NR2B NMDA receptor. Cultures of non-permeabilized live rat hippocampal neurons incubated
with the same CSF showed extensive cell-surface immunolabelling (B).
HEK293 cells (Human Embryonic Kidney 293 cells) ectopically expressing single or
assembled NR1-NR2 subunits were used to determine the epitope targeted by the antibodies.
These cells, transfected with NR1 and NR2B (forming NR1-NR2B heteromers of the NDMA
receptors), showed intense reactivity with patients’ CSF. Thus, we can say that the encephalitis is
associated with antibodies against NR1-NR2 heteromers of the NMDA receptor (C).
The HEK293’s reactivity co-localizes (D) with the reactivity of a monoclonal rabbit antibody
against NR1 (E). To sum up, the crucial epitopes were present in the more widely expressed NR1
subunit. As an addition, selective disruption of receptors containing NR2B, which are
predominantly expressed in the forebrain and hippocampus, would not explain the extensive
deficits of patients (Dalmau, et al., 2008).
Studies have also shown that antibody titers were higher in CSF than in the serum for
patients with anti-NMDA-receptor encephalitis, this is why the diagnosis is made by a CSF
sample. Moreover, those with tumors had higher titers than those without. The serum NR1
antibody titer is positively correlated to neurological outcome, and negatively correlated to the
follow-up.
Analysis of the reactivity of patients’ sera or CSF against the indicated NDMA-receptor
subunits or heteromers showed that the antibody reactivity was not modified by changing the
NR2 subunit (A, B, C or D) and was retained by homomers of NR1. As a conclusion, antibodies in
CSF or serum react with extracellular epitopes of NR1 (Graus, et al., 2010).
IV. Physiopathology of this immune-mediated disease
The underlying cellular event behind the previously listed clinical signs is the prominent
decrease of NMDA-Rs on post synaptic neuronal surfaces. Self-reactive IgG autoantibodies
recognize NR-1 subunits of the receptors as antigens, then induce cross-linkage and
internalization of NMDA-receptors (Dalmau, et al. 2008).
IV.A Antibody-induced receptor internalisation
As neurotransmitter receptors are capped with IgG antibodies receptor cross-linking
occurs by creating covalent bonds between adjacent protein chains of the receptors. Cell-surface
receptor NR-1 subunits tagged by autoantibodies are subsequently taken up and internalized via
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synaptic vesicles. Reduction is restricted to post dendritic sites, dendritic spines, branches as
well as, cell viability remain intact. Two synaptic markers VGlut and PSD-95 were used to monitor
the changes in cell membrane integrity (VGlut for pre-, PSD-95 for post-synaptic sites), both of
which were found to be present even after antibody activation, thus indicating that antibodies are
exclusively targeted against NMDA-Rs (Moscato, et al.,2010; Hughes, et al.,2010) The elimination
is selective and titer-dependant : the more IgGs are synthetized, the more receptors are
internalized, and the clinical manifestations are the more severe (Vincent, et al.,2010).
IV.B mEPSC decrease due to NMDA-R internalisation
Not only receptor number and distribution alterations occur in anti-NMDA-R-encephalitis
patients but the decrease of miniature excitatory end-plate current (mEPSC) can also be
examined. This so-called mEPSC has an AMPA-R mediated fast and NMDA-R induced slow
component, both of which is caused by the random release of neurotransmitters from the pre-
synaptic axon terminal. mEPSCs may contribute to maintain synaptic integrity and may play a role
in LTP/LTD altering in the hippocampus (Zhang, et al.,2005). Studies indicate that NMDA-R loss
could lead to psychosis and memory deficit by reducing mEPSCs (Gable et al., 2009), which
finding could explain some of the most prominent symptoms of anti-NMDA-R-encephalitis.
However, it is important to underline that the overall cellular structure remains intact as well as
the synaptic density is unchanged, so the pathologic neuronal function is reversible.
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Figure 6: Flow diagram showing steps of IgG mediated NMDA-R internalization (A-C). Also, rodent neuronal N1 subunit, VGlut and PSD-95 were stained to examine changes in synaptic integrity due to antibodies (D,E). Whole-cell patch recordings showing fast AMPA-R (F) and slow NMDA-R (G) component of miniature excitatory post synaptic current (mEPSC) which play a role in LTP and LTD.
IV.C Immunological trigger
In a subset of anti-NMDA-R-encephalitis cases the disease occurs as a paraneoplastic
syndrome, the ectopic expression of receptors leads to the breakdown of immunological tolerance
towards NMDA-Rs (by antigen presentation by T cells or dendritic cells which promotes generation
of antibody producing plasma cells and memory B-cells). In other cases the immunological trigger
is unknown. (Moscato, et al.,2010)
IV.D Source of antibodies
Comparing the IgG titer in blood serum and CSF might bring to light the localisation of
antibody production, which could serve as an effective treatment target. Two, not mutually
exclusive mechanisms may underlie this topic: peripherally synthetized IgGs either enter the
CNS through a disrupted blood-brain-barrier (BBB) or are produced intrathecally. (Martinez-
Martinez, et al.,2013)
The first possibility implies that antibodies enter the brain through a pathologically broken
BBB (could be caused by the acute inflammation of the NS), or circumventricular organs (which
lack the integrity of the BBB and are physiologically leaky) or through regions more susceptible
to systematic changes (such as elevated blood pressure). It is interesting to note that the BBB is
more predisposed to disruption around the hippocampus, the organ primarily affected in
ANRE. This passive intrusion would normally be inhibited by the highly selective permeability
function of astrocytes and capillary endothelial cells.
An elevated concentration of IgGs in the CSF compared to the serum level gives base to
the other possible explanation, notably that antibodies are synthetized by local plasma cells
found within the thecal space. However, extensive clinical and immunological data suggests that
both passive entering of the BBB and intrathecal synthesis occurs, a phenomenon already
examined in sclerosis multiplex.
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Figure 7: Image showing the possible sources of anti-NMDA-R antibodies in the CNS (A:paraneoplastic, B:unknown origin). Antibodies can either directly infiltrate the CNS via leaky blood-brain-barrier (BBB) (3) or as products of plasma cells having entered the brain by a similar way (5). Even though intrathecal antibody synthesis may be the underlying source of autoreactive IgGs.
IV.E Cellular alterations-symptom correlation
For normal synaptic transmission and plasticity; especially in learning, memory and
behaviour; the integrity of NMDA-Rs for proper glutamate binding is crucial. Based on both animal
and human experiments changes in synaptic and circuit function are strongly related to the
apparent clinical symptoms (Hughes, et al.,2010). It is an intriguing phenomenon why anti-NMDA-
R-encephalitis patients develop a complex syndrome. Understanding the key mechanisms in the
pathophysiology of the disease will provide the most effective target points for therapy.
V. Treatment
It is really unlikely for patients with this or any CNS disease, to have a quick response to
treatment. Nevertheless, there are cases in which improvements occur within a week. It is believed
that the explanation for this condition is the fact that the CNS does not recover as quick as other
tissues do. The used methods for this disease are:
➢ Tumor resection
➢ Immunotherapy: corticosteroids, intravenous immunoglobulin, plasma exchange,
rituximab, cyclophosphamide, azathioprine
Several studies reveal that those subjects who received both methods are more likely to have a
better outcome and fewer neurological relapses as well.
There are cases in which even though the patients have recovered from the disease, they
remain with amnesia of the entire process; this may be due to the fact that the mechanisms of
synaptic plasticity are disrupted.
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One of the theories that could explain the slow recovery is that most components of the
immunotherapy are incapable of resulting in a rapid and sustained control of the immune response
within the CNS.
In a study made by (Titulaer, et al., 2013), in the cases where immunotherapy and tumor
removal are applicable, there is a substantial neurological improvement in patients with anti-NMDA
encephalitis after a median follow-up of 24 months. In addition, second-line immunotherapy with
rituximab, cyclophosphamide, or both, helped to the improvement of the outcome of patients who
did not respond positively to first-line treatment and decreases the occurrence of relapses as well.
The decisions taken for the type and duration of immunotherapy should be based on clinical
symptoms, not antibody titers.
Other studies show that the usage of Alemtuzumab, an anti-CD52 monoclonal antibody that
affects memory B cells and T cells and that has been used in oncology, in patients receiving
transplants and in clinical trial in adults with multiples sclerosis; also has positive effects in the
condition of the subjects (Liba , Sebranova, Komarek, Sediva, & Sedlacek, 2013
Conclusion
Anti-NMDA encephalitis is a newly characterized disease associated with antibodies
against the NR1 subunit of the NMDAR, that has a progressive and predictable clinical course,
which can be improved with an effective choice of treatment. There are several ways in which this
disease can be diagnosed such as diagnostic immunoassays or analytical chemistry techniques
like immunoprecipitation and mass-spectometry, respectively; with the ability to detect NMDA
receptor autoantibodies.
Although this is a serious life-threatening disease, a prompt diagnosis and treatment can
lead to a very positive outcome. Nevertheless, the recovery is generally slow and may take a few
months or even years and unfortunately, not all the subjects recover from the disease.
Once the treatment is established and its efficiency is proven, routine medical assessments
have to remain, including repeat imaging to ensure that no tumor is found.
More research is required as far as this disease is concerned, considering the fact that
sometimes there is no treatment that can improve the condition of the patients leading them to
death.
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ABSTRACT
The Anti-NMDA receptor encephalitis is a recently described immune mediated neuropsychiatric
disease. Seizures, decreased level of consciousness, abnormal movements and autonomic
instability are the most prominent symptoms. The heterotetrameric NMDA receptor (NMDAR),
which is a ligand gated cation channel, is affected in this disease. It plays a crucial role in synaptic
transmission and is essential for inducing long-term changes in the brain. The receptor consists of
various combinations of the subunits GluN1, GluN2 and GluN3. The GluN1 subunit, expressed
ubiquitously in the CNS, is selectively targeted by IgG antibodies. This binding is thought to induce
the cross-linkage and reversible internalization of the receptors at the post-synaptic site.
Consequently there is a reduced level of receptors in the brain leading to impaired neuronal
function. The antibodies can either be synthesized in the periphery and enter the CNS through a
ruptured blood-brain-barrier or be produced intrathecally. In a subset of patients it occurs as a
paraneoplastic syndrome, meaning that the production of antibodies is enhanced by the
expression of tumor NMDA receptors. IgG titering in the CSF is used for diagnose and can serve
as a prognosis factor. As receptor internalization is antibody titer dependent and reversible, the use
of immunotherapy is aimed to restore the amount of NMDAR by diminishing the IgG concentration
in the CSF. Furthermore, tumor resection can be used as a treatment in patients with
paraneoplastic disease. Even though Anti-NMDAR encephalitis is a life-threatening disease,
prompt diagnosis followed by efficient treatment can lead to a positive outcome.
Keywords: Encephalitis, Autoimmunity, NMDA receptor, Paraneoplastic
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