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.

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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.

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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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