Limbic encephalitis

Symptoms of Limbic Encephalitis

The symptoms of LE can vary, but common signs include:

• Memory loss: Difficulty remembering recent events or learning new information.
• Seizures: Sudden, uncontrolled electrical disturbances in the brain, which may vary from minor to severe.
• Confusion: Often, people with LE experience episodes of disorientation or a lack of mental clarity.
• Sleep disturbances: Disrupted sleep patterns or insomnia.
• Personality or behavioural changes: Anxiety, irritability, aggression, or depression are common psychological symptoms.

These symptoms often develop over days or weeks, but in some cases, they may appear more gradually. Early recognition is key, as the condition can progress quickly if not treated.

Causes of limbic encephalitis

Limbic encephalitis can be caused by different factors, generally grouped into two main categories:

1. Infectious encephalitis – caused by direct invasion of the limbic area of the brain by a bug, usually a virus.
2. Autoimmune encephalitis – caused by the person’s own immune system reacting against parts of the limbic system.

1. Infectious causes

Infectious limbic encephalitis occurs when a virus, bacteria, or another pathogen causes inflammation in the limbic areas. The herpes simplex virus (HSV) is one of the most common infectious causes, particularly affecting the hippocampus and amygdala. Some patients may be diagnosed with HSV encephalitis, while others are diagnosed with limbic encephalitis if the infection primarily affects these areas.

Other viruses, such as varicella-zoster (the virus that causes chickenpox and shingles), and mosquito-borne viruses like West Nile virus, can also cause infectious LE. Quick treatment with antiviral medications is essential to prevent long-term damage.

2. Autoimmune causes

Autoimmune limbic encephalitis occurs when the body’s immune system mistakenly attacks the limbic areas of the brain. 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 tumour in their body which activates the immune system. This activated immune system can, in turn, attack the brain. Doctors call this paraneoplastic limbic encephalitis as the tumour (neoplasm) affects the brain from a distance, via the immune system.

In many cases, PLE can be diagnosed by testing for one of paraneoplastic autoantibodies in the patient’s blood and spinal fluid. Most individuals with PLE have a cancer of the lung, thymus gland, ovary, breast or testes. More rarely, other cancers can initiate the condition. The outcome is very dependent on the underlying tumour and the precise condition, often classified by the antibody. In some cases, 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 and the tumour cannot be controlled successfully.

b) Non-paraneoplastic limbic encephalitis (NPLE)

NPLE has only been clearly recognised in the last few years when doctors began to identify patients with symptoms similar to those with PLE but who did not have any of the marker paraneoplastic antibodies in their blood and never developed a tumour. NPLE is far 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, plasma exchange and rituximab.

Types of Autoimmune Limbic Encephalitis and Antibodies

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:

• LGI1/CASPR2 (previously termed voltage-gated potassium channel complex antibodies)

These two forms of encephalitis associated with LGI1 (leucine-rich-glioma inactivated 1) and CASPR2 (contactin-associated protein 2) antibodies are described in a different factsheet called LGI1/CASPR2 antibody encephalitis.

• AMPAR and GABA_B/AR antibodies

Antibodies against two other receptors in the brain, AMPA and GABAA/B, 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 PLE).

• NMDAR-antibodies

Another antibody that can cause PLE or NPLE is the NMDAR antibody. This disease may be associated with a growth such as a cancer, particularly ovarian teratoma in around 30% of cases. This antibody usually causes encephalitis involving several brain regions, but it can sometimes cause a pure LE (Please see the anti-NMDAR encephalitis factsheet for further details).

It should be noted that the brain imaging and the routine lumbar puncture results may be normal in autoimmune limbic encephalitis.

Diagnosis and Treatment

Diagnosing limbic encephalitis can be challenging, especially in cases where routine tests like MRI scans or lumbar punctures do not reveal clear abnormalities. Often, the diagnosis is confirmed through blood or spinal fluid tests that detect specific antibodies.

Treatments for Infectious Limbic Encephalitis

For infectious LE, treatment typically involves antiviral or antibacterial medications. Herpes simplex virus encephalitis, for example, is treated with acyclovir, an antiviral drug. Prompt treatment is critical to prevent permanent brain damage.

Treatments for Autoimmune Limbic Encephalitis

For autoimmune LE, treatments aim to reduce the immune system’s attack on the brain. Common treatments include:

• Steroids: These reduce inflammation and suppress the immune system.
• Intravenous immunoglobulin (IVIg): A blood product that helps block harmful antibodies.
• Plasma exchange: A procedure that removes harmful antibodies from the blood.
• Rituximab: A medication that targets the immune cells responsible for producing antibodies.

The earlier the treatment is started, the better the chance of recovery. In some cases, patients may require long-term therapy to manage their symptoms and prevent relapse.

Prognosis and Future Outlook

The outlook for individuals with limbic encephalitis depends on the underlying cause, the speed of diagnosis, and the effectiveness of treatment. For some, particularly those with autoimmune LE, treatment can lead to significant improvement, though it may take time. Unfortunately, for others, especially those with paraneoplastic LE, the prognosis can be poorer if the underlying cancer cannot be effectively treated or the brain damage is extensive.

As research continues, the hope is to develop more targeted therapies that can improve outcomes for all forms of limbic encephalitis. Raising awareness among healthcare providers is also crucial for improving early diagnosis and treatment.

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By Prof Sarosh, University of Oxford and John Radcliffe Hospital, Oxford, UK and reviewed by Dr Sophie Binks, Oxford Autoimmune Neurology Group, Oxford, UK

FS013V4 Limbic encephalitis

Date created: March 2007/Last updated: December 2021/ Review date: December 2024

Disclaimer: We try to ensure that the information is easy to understand, accurate and up-to-date as possible. If you would like more information on the source material and references the author used to write this document please contact the Encephalitis International. None of the authors of the above document has declared any conflict of interest, which may arise from being named as an author of this document.