Molecular classification of pediatric brain tumors

Speaker: Marcel Kool

Department: JNI Oncology

Subject: Molecular classification of pediatric brain tumors

reveals new entities

Location: Erasmus MC

Date:23-9-15

Author: Hielke Walinga

Times that only surgery was a treatment for cancer are long over. Very different treatments have been developed and knowing which one to use for a patient can be crucial for the survival of the patient or can prevent severe damage to other tissues near the tumour. Especially very vulnerable tissues like the brain must be treated with the exact right treatment. Therefore some researchers focus on the classification of these tumours. Just like Marcel Kool whose seminar I listened to at 2 September. Marcel Kool tries to classify paediatric (children’s) brain tumours using molecular methods. He gave an overview of the latest discoveries of the field.

Cancer types always used to be classified by their histology (their appearance when viewing it under a microscope). This makes sense, since the way a cancer looks is usually a result from the specific mutations it has. However molecular research has shown that this classification isn’t always correct for guessing the type of cancer.

For example oligo astrocytoma, which looks like a bunch of star like structures, doesn’t exist on the molecular level. It is actually at the molecular level either astrocytoma (star like structure) or oligodendroglia (a bunch of tree like structures).

Another way to distinct different cancer types is to look at the clinical outcome. The survival rate should be a good sign on the different mutations of the tumour, and might be later be linked to something that good help to set a good diagnosis. This classification is done using grades. Higher grades (from one to three) stand for a worse outcome. However molecular research has shown that there is actually no difference between two and three of most types.

To reveal the gene expression the molecular methods that could be used for this research are for example Northern or Southern blotting, however it’s quite hard to obtain enough sample from the tumour, especially because it’s in the brain, to do these kind of research. A better method might be to use NanoString to reveal certain fragments RNA. A method, that’s better to be done, and also studies by Marcel Kool, is actually to reveal DNA methylation. However, it’s left to discussion on how this actually relates to the nature of the tumour.

DNA methylation

An example of a methylation heat map created in a research in which Marcel Kool has cooperated. (Source: Hendrik Sturm, Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma, Cancer Cell: Volume 22, Issue 4, 16 October 2012, Pages 425–437)

The research shows a lot of new entities of brain tumours, and the researchers also have been able to link the results to different causes of the cancer. Their distinction almost always came from different pathways that are affected by some kind of mutations. Sometimes they were able to link these together to one certain factor, like the MITF TF of the AT RT tumours. But it also revealed that glioblastoma is a cancer caused by a histone gene mutation. They also were able to link their results to the clinical outcome of the disease. For example, medulastoma has a molecular subgroup (Wnt) which almost always meant a survival for the patient.

To use all these result for the benefit of the patient, the next step would be to create a worldwide database of some sort, which doctors could use by their diagnosis of the patients. Therefore this will be the next step in molecular neuropathology. Actually this has partly already begun and it is called INFORM (INdividualized therapy FOr Relapsed Malignancies in childhood). Still this only focusses on the relapse cases, because they usually have a dismal prognosis.

 

Molecular classification of pediatric brain tumors reveals new entities

Speaker: Marcel Kool
Department: Division of pediatric neuro-oncology, DKFZ Heidelberg
Subject: Molecular classification of pediatric brain tumors reveals new entities
Location: JWI-Oncology, Erasmus MC Rotterdam
Date: 23-9-2015
Author: Mirte Golverdingen

A very important part of finding a cure to cancer is to know which medicine you need to use. Marcel Kool is a researcher of the division of pediatric neuro-oncology in Heidelberg. He is currently working on the classification of brain tumors. If you know which tumor causes the cancer, you can find more easily a treatment for this tumor.

There are a lot of different brain tumors, and almost all have different treatments. Tumors are graded in a grading system with four levels, if the grading is higher, the tumor will be more aggressive and harder to treat. Moreover, tumors are classified in different groups by looking at the morphology and the way they develop. Research gives that this classification is not complete, there are more and/or different subgroups that not yet have been revealed.

The DKFZ in Heidelberg uses DNA methylation to classify brain tumors, this is a very robust technique that is very useful for molecular profiling of tumors. They found first of all 2 new subgroups in the Glioblastoma group. This research resulted in new target therapies for patients.

Moreover, their research revealed that there are not 2 but 9 subgroups in Ependymal tumors. In these group there was no distinction between grade II and grade III. This resulted in the conclusion that the current grades of tumors are not accurate. A very interesting result because patients are currently treaded by their grades.

The research group also concluded that there are 3 subgroups in the ATRT group. However, the most special result of this group is that the CNS-PNET group doesn’t exist. It was considered as a grade IV heterogeneous tumor group and hard to treat. The research gives that 70% of the sub-groups can be reclassified in known entities. The remaining subgroups form 4 new groups that all have specific processes that drive the forming of the tumor. Above that unclassified tumors could be classified in this new groups. It results in better and more specific treatments than before.

I did know that tumors where classified in different groups, but I didn’t realize that it was so important for the treatment of the tumors. This research results in better and more effective treatments for patients. The lecture was a good insight into the current research of cancer, and how important DNA research is in this process. The plans of the research group to start algorithms to classify brain tumors and start a database are very exciting. This is a good way to share the knowledge they gain at the lab.

Figure 1: Microscopical appearance (a, d, g), FISH analysis of the 19q13.42 locus (b, e, h), LIN28A immunohistochemistry (c, f, i) of ETANTR (a–c), EBL (d–f) and MEPL (g–i). Amplification of 19q13.42 (b, e, h) and LIN28A immunoexpression (c, f, i) was detected in all three histological ETMR subtypes. For the FISH analysis the C19MC 19q13.42 probe (green signals) and a reference 19p13 probe were used (red signals) (Source: Korshunov A, Sturm D, Ryzhova M, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathologica. 2014;128(2):279-289. doi:10.1007/s00401-013-1228-0)

Figure 1: Microscopical appearance (a, d, g), FISH analysis of the 19q13.42 locus (b, e, h), LIN28A immunohistochemistry (c, f, i) of ETANTR (a–c), EBL (d–f) and MEPL (g–i). Amplification of 19q13.42 (b, e, h) and LIN28A immunoexpression (c, f, i) was detected in all three histological ETMR subtypes. For the FISH analysis the C19MC 19q13.42 probe (green signals) and a reference 19p13 probe were used (red signals) (Source: Korshunov A, Sturm D, Ryzhova M, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. Acta Neuropathologica. 2014;128(2):279-289. doi:10.1007/s00401-013-1228-0)

Molecular classification of paediatric brain tumours reveals new molecular entities

Speaker: Dr. Marcel Kool

Department: Paediatric neuro-oncology

Subject: Molecular classification of paediatric brain tumours reveals new molecular entities

Location: Erasmus MC, Rotterdam

Date: 2015-09-23

Author: Romano van Genderen

The talk about Dr. Kool started with a small piece of background information on brain tumours. Some of the key characteristics of these are that there are extremely many types, compared to for example breast cancers. These types differ in “grade”, which is a number varying from 1 to 3, which experts use to determine the intensity of therapeutic treatment. Another thing they differ in is morphological structure. But Dr. Kool claimed that these distinctions are not enough. Even tumours that appear morphologically similar, differ a lot on the molecular scale.

To investigate the tumours on this scale, multiple techniques were used in the past, but each one of them has a specific shortcoming. Identifying a molecular subgroup based on mRNA expression is accurate, but it needs very fresh and undamaged samples of mRNA. For immunohistochemistry, very specific and accurate antibodies are needed, making this method useless in the case of rare sorts of tumours. Nanostring methods are accurate and can even use broken strands of mRNA, but the morphological type of the cell must be pinpointed perfectly, and you wouldn’t risk treating a patient with the wrong medicine based on an oversight by a pathologist. But now the scientific community has finally identified a method which seems to have no drawbacks. This method is based on identifying the tumours based on the DNA methylation pattern. Methylation is the process of adding -CH3 tags to the DNA in order to change the intensity of non-covalent interactions with the DNA.

Afterwards, he dealt with the results of this method. The first was medulloblastoma, a form of cancer located in the lower back of the brain, which appeared to have not 1, but 4 types. The type 1 was usually over-treated, leading to unnecessary brain damage, while type 3 was usually undertreated. Afterwards, he showed that pilocytic astrocytoma’s, which are a cancer in the astrocytes (star-shaped cells responsible for transferring nutrients from capillaries to neurons), have 2 pathways associated with them instead of one. Then he showed that glioblastomas (cancers in the glial cells, a cell group that supports and assists neurons in the central nervous system) can be caused by 2 different mutations in the same gene. Then he showed evidence that ependymal tumours (tumours in ependymal cells, the cells that produce the cerebro-spinal fluid that fills the cavities in the brain) have 9 subtypes and that in this case the usual type II and type III tumours are identical. Then he mentioned that all different classes of atypical teratoid rhabdoid tumours are in fact identical and that the differences were caused by varying degrees of expression.

gliageek_True ependymal rosettes x400 
Fig 1. Ependymal tumours (note the fluid-filled cavities), Haematoxylin & Eosin stain, 400x magnification

Radiographics. 2005 Mar-Apr;25(2):486-90.
Best cases from the AFIP: supratentorial ependymoma.
Mermuys K, Jeuris W, Vanhoenacker PK, Van Hoe L, D’Haenens P.
(PMID:15798065)

The final type of tumour he mentioned was the CNS-primitive neuroectodermal tumour, which is caused by a mutation in the common progenitor of neurons, glial cells and ependymal cells (neuroectodermal cells). These cells look like poorly differentiated mature cells. After investigating their genome, he came to a very surprising result, namely that these tumours, based on their methylation pattern, almost all belong to other classes of tumours.

Finally he talked about his future plans, which were to make methylation databases to identify these tumours much more easily, as he mentioned, in a span of weeks.

This talk really showed very well how the collaboration between pathologists, oncologists and molecular biologists can help us learn more about cancer and work to come closer to better and faster treatments.

Molecular classification of pediatric brain tumours

Speaker: Marcel Kool
Department: Pediatric neuro-oncology
Subject: Molecular classification of pediatric brain tumours reveals new entities.
Location: Erasmus MC Room Ae-406
Date: 23-09-2015

Author: Kristian Blom

Brain tumours, one of the worst types of cancer. In 2007 the WHO (World Health Organization) came with a classification of brain tumours on histological aspects and grades, called the World Health Organization Classification of Tumours. These classifications are important for clinical treatment of brain tumours, since every brain tumour needs a different treatment. Unfortunately, just by looking at brain tumour tissue under the microscope isn’t enough for proper classification, we also have to look to the brain tumour tissue at molecular level. Marcel Kool, the speaker of this seminar, is one of the researchers of the German Cancer Research Center (DKFZ: Deutsches Krebsforschungzentrum). In his research group he classifies pediatric brain tumours – tumours that occur in children – at the molecular level.

There are different ways to identify molecular subgroups (mRNA expression, immunohisto chemistry), but the most used and successive one is looking at the DNA methylation profile. DNA methylation is a cellular process whereby methyl groups are binding to the DNA. This binding alters the structure of the DNA itself (not the DNA sequence), whereby the function of the DNA gets modified. DNA methylation is very important in gene regulation; the process where external factors switches a gene on/off. When a mutation in DNA methylation occurs, it is possible that a cell will become a tumour cell.

Methylation profile of 500 ependymal tumours
Image 1: A. The methylation profile from the 500 ependymal tumour samples. We can distinct nine different subgroups of ependymal tumours. Red indicates a high level of DNA methylation. B. The methylation profile in primary ependymal tumours and corresponding diseases. The first two profiles (from the left) are from the most aggressive ependymal tumours. (Source: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Cancer Cell volume 27)

An example of pediatric brain tumours classification are the ependymal tumours. These kind of tumours occur in different regions of the central nervous system at different ages. Marc and his research group collected 500 ependymal tumour samples, classified them by looking at the DNA methylation profile, and they concluded that there are 9 subgroups (see image 1-A) in the ependymal tumours.
A remarkable observation was that at the molecular level there wasn’t any distinction between the DNA methylation profile of grade II and grade III (more aggressive) ependymal tumours. This intended that based on molecular distinction, the clinical treatment of both grade II and grade III ependymal tumours should be the same. Of course this assumption must be verified by doing more research, because not everything can be said by only observing the molecular nature of a tumour.
Another important discovery of the ependymal tumour is that when it reoccurs, it will remain in the same molecular subgroup as first. For clinical aspects this is very useful, since unfortunately relapses in brain tumours occur a lot.
Last, Marc and his group found out that there are two highly aggressive subgroups of the ependymal tumour: PF-EPN-A and ST-EPN-RELA (see image 1-B). Patients with one of these tumours should get the maximum treatment. Remarkable is that both have very distinct methylation profiles, which suggest that different mutations can cause highly aggressive ependymal tumours.

The ideal view for the future is that every patient with a brain tumour can be healed without relapses. But to reach this goal, we have to know the classification of a tumour to give every patient an optimized treatment. That’s why the research of Marc Kool is very important, since they are making an algorithm for brain tumours classification. Imagine in the future that neuroscientist make a methylation profile of a patient’s tumour, upload it onto a website/app, and in just a few minutes they receive information about the kind of tumour they are dealing with. This will definitely increase the success rate of brain tumour treatment.

Since a DNA methylation profile only express one part of the molecular nature of a tumour, I think it is really important for future research to combine different aspects of the molecular nature for more accurate tumour classification. Think about physical features like heat, forces, pressure etc. These factors could vary for different tumours. The more differences we can find in different aspects of a tumour cell (histological, physical, biological), the more accurate the tumour classification would be.

Autoimmune encephalitis

[Cleo Bagchus]

[cleo.bagchus@hotmail.com]

[4386736]

Seminar 1:

Speaker:      Josep Dalmau

Department: neuroscience                                                                                                                              

Subject: Autoimmune encephalitis                 

Location: Rotterdam            

Date: 07-09-2015   

Autoimmune encephalitis is a disease in which the immune system attacks the brain. Antibodies often bind to the synapses of the patients, leading to impaired brain function. The earliest symptoms are agitation and problems with information processing. But as the disease progresses this leads to inability to control movement and eventually some patients even fall into a coma. Next to these symptoms the disease is often accompanied by tumours. In the US 20 000 patients were hospitalized in 2010 because of encephalitis. In 50% of these cases the cause of the disease was unknown. A recovery can be (almost) complete, but often takes years, which makes it a very costly disease. In many cases the patient has no recollection of the disease or the recovery.

The disease is divided into three categories: intracellular, synaptic intracellular and synaptic surface. Dr. Dalmau’s research focuses on anti-NMDAR encephalitis. which falls under synaptic surface encephalitis. Anti-NMDAR encephalitis most often occurs in young females. In young, male cases the disease is often not accompanied by tumours.

In anti-NMDAR disease antibodies attack proteins on the surface of synapses. The NMDAR receptor and the ephrin B2 receptor are attacked. Antibodies of patients decrease the number of NMDAR clusters. These clusters become internalized. The clusters can recover if you remove the antibody. Antibodies disrupt the cell surface interaction between NMDAR and Ephrin-B2 receptors. This leads to a lower current running through the synapses. Patient’s antibodies cause a homeostatic decrease of inhibitory synapse density. Because of this the synapses start to dysfunction.

gr5

image 1: the amount of  NMDAR-receptors related to the progress of the disease (from: Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis written by Prof Josep Dalmau, MD Eric Lancaster, MD, Eugenia Martinez-Hernandez, MD, Prof Myrna R Rosenfeld, MD, Prof Rita Balice-Gordon, PhD, http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(10)70253-2/fulltext?rss=yes)

As you can see in image 1 the clinical worsening of the disease is directly linked to the amount of NMDAR-receptors still present on the synaptic surface.

Josep Dalmau wants to answer two questions with his research. Why is the recovery of anti-NMDAR encephalitis so slow? What can we learn from the pathology of this disease to help speed up its recovery?

To answer these questions he made a mouse-model of the effects of NMDAR antibodies. They injected mice with cerebrospinal fluid from patients that contained NMDAR antibodies. After eighteen days a dramatic drop in memory was seen. Also the infected mice showed signs of depression. There was a progressive detection of brain-bound antibodies that cause the synapses to dysfunction. Some of these symptoms are prevented by ephrin B2. Ephrin B2 protects synapses from the antibody. When the antibodies were removed the symptoms slowly disappeared. Possible medicines can also be tested on these mice.

I had never heard of encephalitis, so the entire subject of the lecture was new for me. I learned about the disease, the symptoms and the way researchers try to find out more about this disease. The fact that patients could recover almost fully after brain function was impaired so drastically, made this subject very exciting to me.

I believe it is important that the reason patients get encephalitis is discovered. Now in 50 % of the cases the cause of the disease is unknown. I believe you can treat a disease much better if you know what causes it and this might also prevent relapses. So I believe research should focus on discovering the cause of encephalitis. For this will lead to a better understanding of the disease and eventually a better treatment of the disease.

Autoimmune encephalitis: from human disease to animal models

Speaker: Dr. Josep Dalmau

Department: Neuroscience

Subject: Autoimmune encephalitis: from human disease to animal models

Location: Erasmus MC, Rotterdam

Date: 2015-09-07

Author: Romano van Genderen

Dr. Josep Dalmau began to talk about an illusive disease in the brain, called autoimmune encephalitis. This is a disease of which in many cases the cause is unknown. A patient with a form of this disease has a certain mutation which makes his or her immune cells produce antibodies against their own neurons. There are three different types of this disease.:

1. Intracellular, in which the antibodies attack the intracellular proteins. This almost always causes the formation of tumours.

2. Synaptic intracellular, in which not the main cell body of the neuron, but only the synapses are affected.

3. Synaptic/surface, in which there are antibodies produced against proteins on the cell surface. This is the form with the most intense sickness, but often spontaneous recovery.

The one Dr Dalmau talked about was a synaptic form with antibodies against the NMDA receptor, a glutamate receptor on the synapse. Glutamate is the most common excitatory neurotransmitter in the human nervous system.


Image 1: The position and function of the NMDA receptor

Source: http://www.euroimmun.us/recent-news/anti-nmda-receptor-encephalitis-recombinant-immunofluorescence-test-for-determination-of-antibodies-against-glutamate-receptors

This is why it has such massive clinical effects, such as psychosis and seizures. In extremely heavy cases this can lead to the patient entering a coma. But upon recovery the patient surprisingly enough remembers next to nothing about the period they had the disease. Sampling the patient database showed a few significant trends, such as the fact that the most common patients are adolescent females, which in 50% of the cases develop visible tumours. Another fact is that for younger patients there is no correlation between gender and the number of patients, and that young individuals never develop tumours.

One part of the talk that was interesting for me as a nanobiologist was how the changes in neuron function are caused by the anti-NMDA antibodies. It targets the post-synaptic glutamate receptors and removes them without having any effect on the voltage-gated potassium channels. Let me compare this to a power cable. You can stop the electricity from running through said cable in 2 ways, by pulling out the plug and by cutting the wire. The anti-NMDA antibodies do the first. They stop the incoming signal, but do not prevent the conduction.

One of the potential causes of the disease is the Herpex simplex virus. In order to investigate this, they used PCR to check for viral DNA in the patient’s brain, but this was not found. Therefore they concluded that the disease follows the viral infection, and is not a symptom of the infection.

The final part of his talk was how he used mouse models to investigate the disease. He slowly injected patient CSF (cerebral spinal fluid, the fluid that surrounds the brain) into mice. He used mice which were slowly injected with healthy patient CSF as a control. These results showed that the mice which were injected with patient CSF had memory loss, were anhedonic (unable to experience pleasure) and depressed, all checked using the standard procedures for mouse models. It also showed that ephrin-B2 prevented most of the symptoms. Using single molecule methods he found that it does not prevent the binding of the antibody, but it does prevent the effects.

This talk has shown me how modern experimental approaches, like PCR and single-molecule investigations, can shed light on unknown details of diseases, bringing mankind closer to finally discovering a cure.

Autoimmune encephalitis: from human disease to animal models

Speaker:         Dr. Josep Dalmau

Department:    Neuroscience

Subject:          Autoimmune encephalitis: from human disease to animal models

Location:         Rotterdam

Date:               7 september 2015

Author: Carolien Bastiaanssen

Autoimmune encephalitis is a disease where the immune system of the patient attacks the brain. It can cause a wide range of neuro-psychiatric symptoms, beginning with changes in behaviour like agitation and mood swings but when the disease worsens it can cause memory deficit, seizures and the patient could fall into a coma. It may even be lethal. In the USA there are about 20.000 hospitalizations per year concerning autoimmune encephalitis, yet the cause of this disease is often (±50%) not clear.

There are several types of autoimmune encephalitis, classified by the localization of the disease. The three main groups are: intracellular, synaptic intracellular and synaptic surface. In this seminar Dr. Josep Dalmau focussed on anti-NMDAR encephalitis from the synaptic surface subgroup. In this type of autoimmune encephalitis the antibodies attack proteins on the surface of synapses. With a decreasing number of working proteins the synapses start to dysfunction and neural signals are blocked. In anti-NMDAR encephalitis the NMDA receptor and the ephrin B2 receptor are targeted.

Model of impact antibodies on NMDA receptor

Source: L. Mikasova et all. , Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis, Brain a journal of neurology, 28 April 2012

The first figure shows the basal situation where the NMDA receptors are anchored on the surface of the synapse. In the second figure antibodies target the parts of the NMDA receptors extending from the receptors surface, reducing the number of receptors on the surface and promoting their degradation.

Besides the symptoms mentioned before this disease also changes the way patients see the world. When asked to draw basic things like a tree, the patient makes drawings like a toddler would make. After treatment the drawings gradually become less childish. Patients can be treated with intense immunotherapy but full recovery sometimes takes years. Afterwards patients have no memory of the disease.

Drawings from anti-NMDA encephalitis patient

Source:  Esseveld MM et all. , Drawings during neuropsychiatric recovery from anti-NMDA receptor encephalitis, The American journal of h, 2013

The above figure depicts four drawings made by an anti-NMDAR ancephalitis patient. When asked to draw a dog and a cat the young adolescent did not know how to start. The researchers told her what the animals look like and the result is shown in figure 1. After two weeks of therapy the dog was already more i but it looks more like a human. Figure 3 shows a drawing which was made two months after treatment started and the last figure was made after 5 months of rehabilitation.

A study by Dr. Titulaer of the Erasmus MC shows that this type of autoimmune encephalitis differs from the other types. First of all anti-NMDAR encephalitis patients are often children or young adults while patients of the other types are mainly adults or elderly people. Furthermore this disease has more female than male patients and in 50% of the female cases it goes paired with tumours while in most male cases no tumours are present. A striking fact is that among the youngest patients this sex difference levels off and these patients are less likely to have tumours. It is often not clear what the cause of the disease is, it could be that a tumour triggered an immune reaction which got out of hand. Another suspect is the herpes simplex virus.

There are a lot of questions about anti-NMDAR encephalitis. A way to answer (some of) these questions is using a mouse model. Mice were infused with cerebrospinal fluid from patients, which contained NMDAR antibodies, after which their behaviour was monitored. An increase in brain-bound antibodies was detected and deficits in memory and depressive like behaviour were observed. When the antibodies were removed the effects were reversed. The effect of ephrin B2 was studied as well. Some of the effects were partially prevented by ephrin B2 but others were unaltered.

Mouse models can contribute to explaining the questions that remain about anti-NMDAR encephalitis. They could reveal a strategy to counteract the pathogenic effects of the antibodies that may lead to novel therapies.

Autoimmune encephalitis: from human disease to animal models

Speaker:                     Josep Dalmau

Department:             Neuroscience

Subject:                      Autoimmune encephalitis: from human disease to animal models

Location:                    Erasmus MC Rotterdam

Date:                           07-09-2015

Author: Katja Slangewal

A shaking woman, her eyes wide open, she doesn’t respond at all to the touch of a doctor. We look at a short movie of a woman with autoimmune encephalitis. With 20.000 hospitalizations a year in the USA, this is a very serious disease. The disease is caused by autoimmunity; which means that antibodies are produced that attack the own body cells. Josep Dalmau specifically focuses on Anti-NMDAR encephalitis, in this specific disease the antibodies attack the NMDA receptor on the synapse. See figure 1. The antibodies disrupt the interaction between the NMDA receptor and another receptor called ephrin B2. This causes a decrease of inhibitory synapse density and it impedes signaling between neurons. Patients will notice this in form of the following symptoms: headaches, behavior changes, increased agitation, paranoia, seizures, abnormal movements, impaired cognition, memory loss and speech problems. When it gets worse patients will get in coma and suffer hypoventilation and dysautonomia. So anti-NMDAR encephalitis is truly a disease you would rather avoid.

Figure 1

Figure 1: Antibodies attack the NMDA receptor, NR1 and NR2 are subunits of the NMDA receptor.

http://www.lcsciences.com/news/new-evidence-suggests-let-7b-may-be-a-potential-diagnostic-marker-and-indicator-that-reflects-the-molecular-mechanism-of-anti-nmdar-encephalitis/

Anti-NMDAR encephalitis is part of the synaptic surface subgroup of autoimmune encephalitis, which means the affected proteins are localized on the synaptic surface. In contrary to other more researched subgroups, the patients in the synaptic surface group don’t always carry tumors in their heads and are relatively young. This is useful to know while determining a cure. The search for a tumor would be a waste of time for these people for instance.

The precise cause of anti-NMDAR encephalitis is not entirely clear, though infection with the herpes simplex virus 1 (HSV1) could start the disease. Patients with HSV1 encephalitis (HSE) can produces antibodies against the NMDA receptor. These patients develop choreathetosis post-HSE which is seen as the same disease as anti-NMDAR encephalitis. Though HSE and anti-NMDAR encephalitis succeed each other, there are a lot of differences in detecting the disease. See table 1.

Tabel 1: difference between HSE and post-HSE

  Viral relapse of HSE Choreathetosis post-HSE
PCR Positive Negative
Abnormalities at MRI Yes No
Etiology Viral antibody

There are more uncertainties about anti-NMDAR encephalitis; one other question is for instance: how do the antibodies exactly start the disease? This is tested by using animal models, mice in this case. Antibodies are injected in a mouse and afterwards the effect is determined. These tests have shown that the antibodies are mostly found in the cerebrospinal fluid. A few days after the antibody injection, there is a clear loss of clustered NMDA receptors. The mice also show memory loss and depressive-like behavior, which is connected to the ephrin B2 receptor. Furthermore the tests show that the ephrin B2 doesn’t affect the binding of the antibodies. These facts gain by using animal models are import for the search to novel therapies.

Better therapies are needed not only for the people who suffer from anti-NMDAR encephalitis, but also for animals like polar bear Knut who also suffered from the disease. The work of Josep Dalmau hopefully helps to find those improved therapies.