Speaker: Dr. Josep Dalmau
Subject: Autoimmune encephalitis: from human disease to animal models
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.
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.
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.