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by Dr Sarosh R Irani and Prof Angela Vincent, John Radcliffe Hospital, Oxford
The limbic areas of the brain control many functions including memory, learning, and emotions such as aggression. The main regions of the limbic system include the hippocampus, and amygdala.
The term “Limbic Encephalitis” (LE) is used when the limbic areas of the brain are inflamed (swollen) or not functioning properly. The symptoms of Limbic Encephalitis include memory loss, seizures, confusion, disturbances of sleep and psychological disturbances such as altered personality or behaviour.
There are several known causes of Limbic Encephalitis.
Causes of Limbic Encephalitis
Most forms of Limbic Encephalitis fall into 2 main categories:
- Infectious Encephalitis – caused by direct invasion of the limbic area of the brain by a bug, usually a virus.
- Autoimmune Encephalitis – caused by the person’s own immune system reacting against parts of the limbic system
- Infectious causes
Many infections of the brain can potentially cause inflammation of the limbic areas. A number of viruses seem to preferentially target this area, such as the herpes simplex virus (HSV). Some people may therefore be given the diagnosis of “Limbic Encephalitis” whilst others are given the diagnosis “Herpes Simplex Encephalitis” for the same condition. A clearer way for people would be to say that the person has “Herpes Simplex Virus Encephalitis affecting mainly the limbic areas of the brain”, but this is rather long-winded.
- Autoimmune causes
A major role of our immune system is to recognize and get rid of infection. But sometimes parts of the immune system – called “Antibodies” - may instead react with proteins of our own body to cause autoimmune diseases. When this reaction is against proteins of the limbic areas of the brain, this is called “Autoimmune Limbic Encephalitis”.
There are broadly two forms of Autoimmune Limbic Encephalitis: Paraneoplastic Limbic Encephalitis (PLE) and Non-paraneoplastic Limbic Encephalitis (NPLE).
a) Paraneoplastic Limbic Encephalitis (PLE)
Sometimes when the immune system starts to react with the limbic areas, this happens because the person has a growth, such as a cancer (tumour), which ‘activates’ the immune system. In this case the antibodies made by the patient in response to the growth will attack the brain. Doctors call this “Paraneoplastic” Limbic Encephalitis (PLE)”.
In many cases, PLE can be diagnosed by using a blood test (testing for one of paraneoplastic autoantibodies in the patient’s blood). Most individuals with PLE will turn out to have a cancer of the lung, thymus gland, breast or testes. The condition may improve or at least stabilise if the cancer is detected and treated effectively. However, unfortunately in many cases treatment does not improve the patient’s neurological symptoms, probably because the immune system has irreversibly damaged the brain cells.
b) Non-paraneoplastic Limbic Encephalitis (NPLE) has only been clearly recognised in the last few years when doctors began to identify patients who had the symptoms of Paraneoplastic Limbic Encephalitis but who did not have any of the marker paraneoplastic antibodies in their blood and never developed a tumour. NPLE appears to be more common than PLE.
It is becoming increasingly clear that NPLE is caused, at least in part, by specific antibodies in the patient’s blood that target the patient’s brain, particularly the hippocampus and other limbic areas.
Many of these patients improve if they are treated with drugs that suppress the immune system and reduce the levels of the antibodies. These drugs include steroids, intravenous immunoglobulins and plasma exchange.
A number of specific brain protein targets for these antibodies have been discovered over the last years and this variety may explain why people have different symptoms. The main established antibodies and their associated features are described below:
- Voltage-gated potassium channel complex antibody
This antibody targets proteins that are tightly linked in with the potassium channels in brain. The two commonest target proteins are LGI1 (leucine-rich-glioma inactivated 1) and CASPR2 (contactin-associated protein 2). It is thought that this type of Autoimmune Encephalitis is currently not tested for enough and therefore may be under-recognised. The main reasons for this include the current lack of awareness of the condition and because the symptoms and the brain scans can look very similar to people with Infectious Encephalitis.
Other than the definitive test of the presence of the antibody in blood or spinal fluid, two other tests that can assist doctors to try and tell the difference between Infectious Encephalitis and Voltage-gated Potassium Channel Complex antibody Limbic Encephalitis include
- The Lumbar Puncture (the lumbar puncture results are often abnormal -typically high white cells in infection)
- A blood test checking for the blood salt (sodium) level (A low level is often seen in Voltage- gated Potassium Channel Complex Antibody Associated Encephalitis but can also be seen in infectious causes).
Voltage-gated Potassium Channel Complex antibodies have recently been found in people with a particular type of seizure problem (termed faciobrachial dystonic seizures), which may start before the start of Limbic Encephalitis. This might mean that doctors could start treatment sooner and try to improve the outcomes for patients, such as trying to reduce amnesia and confusion that may develop after this type of Encephalitis.
- AMPAR and GABABR antibodies
Antibodies against two other receptors in the brain, AMPA and GABAB, are less common causes of Autoimmune Limbic Encephalitis. Although the majority of these patients have an underlying tumour, this is a form of Paraneoplastic Limbic Encephalitis that can often respond to treatment relatively well (see above).
Another antibody that can cause Paraneoplastic Encephalitis is the NMDAR antibody. This disease may be associated with a growth such as a cancer. This antibody usually causes Encephalitis involving several brain regions, but it can rarely cause a more pure Limbic Encephalitis (Please see the NMDAR-antibody factsheet for further details)
Treatments of Autoimmune Encephalitis
The diagnosis of Autoimmune Encephalitis is particularly important because the disease is potentially treatable with medicines that dampen down the immune system. These medications are called immunosuppressive and include steroids, immunoglobulins (a blood product given into the vein in a drip) and plasma exchange (when some of a person’s blood is taken out from a vein, washed and then put back into the vein in a drip). All these drugs have known side-effects but their benefits are generally felt to outweigh possible side-effects in these conditions.
As these diseases have only been recently described, there is still much to be done to raise awareness amongst clinicians. Future research aims to understand the biological mechanisms by which this antibody affects the excitability of the brain, and hence causes disease. Researchers also hope to discover further antibodies which may allow other Autoimmune Encephalitis forms to be diagnosed.
FS013V2 Limbic Encephalitis Page Created: March 2007/Last Update: August 2013/ Review date: August 2015