Limbic Encephalitis

The brain could be regarded as being in three parts. The brain stem is the most primitive part and sits above the spinal cord at the base of the rest of the brain. The brain stem plays a vital role in basic attention, arousal, and consciousness. All information to and from our body passes through the brain stem on the way to or from the brain. The brain stem is responsible for many of the functions that give us life such as breathing, heart function, sleep wake cycle, temperature control.

Wrapped around this basic brain is the “limbic brain” or intermediate brain. It includes the hippocampus, thalamus, hypothalamus and amygdala which are involved in memory and much of the behaviour related to sex, hormones, food, fight or flight responses, the perception of pleasure and competition with others. The limbic brain is the seat of higher emotions including the protection of the young and feelings such as love, sadness and jealousy.

The third and major part of the brain is the neocortex, the rational brain. The neocortical brain provides logic and thought, it is the seat of processes such as speaking, planning and writing.

Limbic encephalitis, implies inflammation in the limbic system. It is therefore an anatomical diagnosis and not all cases share the same cause.

Causes of Limbic Encephalitis

All types of encephalitis fall into 2 main categories:

Infectious encephalitis – caused by direct invasion of the brain by an infectious agent, usually a virus.

Auto-immune encephalitis – caused by the persons own immune system reacting against itself.

Infectious causes

Any infection of the brain can potentially cause an inflammation of the limbic area of the brain. A number of viruses appear to target this area and can, but not always, include the herpes simplex virus. Some people may therefore be given the diagnosis of “limbic encephalitis” whilst others may be given the diagnosis “herpes simplex encephalitis” for the same condition. It would be clearer for people affected by encephalitis affecting the limbic system if both terms were used – “herpes simplex encephalitis affecting mainly the limbic area of the brain” – but that is rather long winded!

Autoimmune causes

Autoimmune encephalitis presents with many of the same symptoms (e.g. memory loss, seizures and confusion) as infectious encephalitis but a causative virus, such as herpes simplex, is not present. In fact, the cause is an antibody - made by the immune system.

Antibodies are made by all healthy individuals in response to infections or after vaccination. The antibodies attack the infectious agent (such as a virus) and help the body’s immune system get rid of the infection. The immune system has to make literally millions of different antibodies in order to combat effectively different infections. It also makes antibodies to damaged or abnormal tissue, such as cancer tissue. Unfortunately, a few of these antibodies may “cross-react” with the patient’s healthy tissue proteins, attacking the tissue and causing an autoimmune disease.

There are two forms of autoimmune limbic encephalitis, paraneoplastic limbic encephalitis (PLE) and non-paraneoplastic limbic encephalitis (NPLE).

Paraneoplastic limbic encephalitis (PLE)
Paraneoplastic limbic encephalitis (PLE) occurs in a small proportion of people with particular cancers. Most individuals with PLE will turn out to have a cancer of the lung, thymus gland, the breast or the testis. In many cases, PLE can be diagnosed by testing for one of a group of paraneoplastic autoantibodies in the patient’s blood. These antibodies are made by the patient in their attempt to attack the cancerous tissue. The condition may improve or at least stabilise if the cancer is detected and treated effectively, but unfortunately in many cases the tumour proves difficult to identify or the treatment does not cure the patient’s neurological symptoms.

Non-paraneoplastic limbic encephalitis (NPLE).
NPLE has only been clearly recognised in the last five years. 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. Moreover, some of these patients got better if they were treated with drugs that suppress the immune system 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 tissue, particularly the hippocampus and other limbic areas. The antibody binds to a protein, present in all brain tissue: the potassium channel. This causes a reduction in the number of potassium channels, decreasing the control over electrical signals operating in the brain. Potassium channels are proteins that lie in the surrounding membrane of nerve cells in the brain and in the nerves that lead to the muscles of the skeleton, the gut and the heart. They are particularly common in the hippocampus and other limbic areas of the brain.

Voltage-gated potassium channel (VGKC) antibody-associated encephalitis
This syndrome has been called voltage-gated potassium channel (VGKC) antibody-associated encephalitis. It is thought that this type of autoimmune encephalitis is currently under-diagnosed and, hence, under-treated. The main reason for this under-diagnosis is the current lack of awareness of the condition. Also, it does show marked similarities to infectious encephalitis, in its symptoms and brain imaging features, making differentiation difficult.

The diagnosis of autoimmune encephalitis is particularly important because the disease is potentially treatable, using immunosuppressive drugs such as steroids. As this syndrome was only described in 2001, 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 potassium channels, and hence causes disease. Researchers also hope to discover further antibodies which may allow other autoimmune encephalitides to be diagnosed.

This article has been compiled by the Encephalitis Society in conjunction with Dr Sarosh Irani, Prof. Angela Vincent and Dr Camilla Buckley from Oxford NHS Trust.

Last modified: 25 March 2008