Limbic Encephalitis

What Causes Limbic Encephalitis?

LE is the result of an abnormal immune system response. In this case, the immune system mistakes proteins in nerve cells for infectious invaders, causing the immune system to attack the healthy nerve cells. This type of encephalitis is called autoimmune encephalitis.

LE is often associated with the presence of a cancerous tumor, suggesting that in many cases, the immune system reaction may be triggered by the tumor. Often, the symptoms of LE precede detection of the cancer. This type of LE is called paraneoplastic limbic encephalitis (PLE). The disorder may be associated with nearly any kind of tumor, but types of cancer commonly involved in PLE include:

• Small cell lung cancer (SCLC)
• Breast cancer
• Testicular cancer

In some cases of LE, no tumor is present. In these cases, the disorder is likely caused by a viral infection, such as herpes simplex, or autoimmune disorders. This kind of LE is known as non-paraneoplastic limbic encephalitis (NPLE).

Is Limbic Encephalitis Hereditary?

LE is not an inherited disorder.

How Is Limbic Encephalitis Detected?

Early detection of LE is essential because the disorder and its underlying causes are often treatable if caught in their early stages. Unfortunately, the defining characteristics of LE can be challenging to spot, and diagnosis is often overlooked and delayed.

In some cases of PLE, the signs of encephalitis appear before a tumor is detected. In these cases, regular screening for cancer is important.

Common early signs of LE include:

• Severe short-term memory loss that comes on suddenly or develops over a period of weeks
• Moodiness
• Problems sleeping
• Sudden sensations of a foul smell or taste
• Periods of confusion

How Is Limbic Encephalitis Diagnosed?

If you exhibit symptoms consistent with LE, your healthcare provider will move through a series of diagnostic steps to see if you have the condition.

• Physical exam and medical history. The doctor will look for signs that you may be at risk for encephalitis. For example, they may ask if you’ve recently had a gastrointestinal or respiratory illness (cold or flu).
• Spinal fluid tests. These tests can detect the presence of antibodies associated with autoimmune encephalitis.
• Electroencephalogram (EEG). This test monitors your brain’s electrical activity and can help detect abnormalities in brain function.
• Imaging tests. Magnetic resonance imaging (MRI) and computed tomography (CT) scans can detect brain swelling caused by LE.

To confirm a diagnosis of LE, a doctor will look for the disorder’s distinguishing characteristics, including:

• Short-term memory loss or psychiatric symptoms that have progressed rapidly
• Seizures not associated with another seizure disorder
• Imaging results that suggest encephalitis
• Evidence of an immune response in the spinal fluid
• No other explanation for symptoms

How Is Limbic Encephalitis Treated?

The first line of treatment for limbic encephalitis is usually aimed at the disorder’s underlying cause. In the case of PLE, removal or treatment of the triggering tumor is typically addressed first. In the case of NPLE caused by a viral infection, antiviral medications may be administered.

In addition to treating the underlying cause, doctors may also prescribe immunotherapy, which uses antibodies or other agents to control the immune system. If immunotherapy isn’t effective, immune-suppressive medications such as rituximab or cyclophosphamide may be an option.

How Does Limbic Encephalitis Progress?

The long-term outlook for people with LE depends on the disorder’s underlying cause and its responsiveness to treatment. In general, the prognosis for people with NPLE is better than the outlook for cases of PLE. Even within the category of PLE, the prognosis can vary depending on the type of tumor involved. For example, cases associated with some types of small cell lung cancer often do not respond well to treatment. In contrast, cases involving an ovarian tumor called a teratoma typically do respond well.

How Is Limbic Encephalitis Prevented?

There is no known way to prevent limbic encephalitis.

Limbic Encephalitis Caregiver Tips

The brain-related complications of LE are challenging for both patients and their caregivers. If your loved one suffers from LE, keep these tips in mind:

• Understand that although your loved one may look as if everything is fine, they may be struggling with subtle, unseen complications. Depression and anxiety often result from these struggles, and daily tasks may be difficult. As a caregiver, be aware that these apparently unrelated problems result from the disease, and be alert for warning signs.
• Create an environment free of distraction and confusion to help the sufferer cope with any problems with memory, concentration, or focus.
• Find a support group for both the sufferer and yourself as a caregiver. It always helps to know that you’re not alone in what you’re going through.

Many people with LE also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with LE:

• Limbic encephalitis can cause anxiety or depression.
• Seizures and epilepsy are common symptoms of LE.

Limbic Encephalitis Brain Science

LE can affect many different parts of the brain, but it is typically associated with inflammation in the limbic system. This brain network includes the hippocampus and the amygdala. Other structures, including the thalamus, hypothalamus, and basal ganglia, also contribute to the limbic system.

Together, these structures are responsible for regulating emotions and behaviors, especially those vital to our basic survival. For example, the hippocampus helps us to form and store memories. It also associates sensory inputs with memories, assists in spatial perception, and aids in learning new things. The amygdala is responsible for our emotional responses and connections between memories and emotions. The other parts of the limbic system play a role in fundamental survival functions such as hunger, thirst, sleep regulation, and reproductive drives.

Because LE disrupts the function of the limbic system, the disorder causes symptoms related to limbic functions, including:

• Memory loss
• Confusion
• Mood swings
• Sleeplessness
• Loss of or increased appetite
• Problems with body temperature regulation
• Hormonal abnormalities

Limbic Encephalitis Research

Title: Immunotherapy in Autoimmune Encephalitis (PE)

Stage: Recruiting 

Study Chair: Yan Zhang, PhD   

Xuanwu Hospital of Capital Medical University

Beijing, China

The study is to explore the treatment effects and long-term prognosis (12 months and 24 months after immunotherapy) by comparing the early plasma exchange (PE) combined with medication therapy with the PE after medication immunotherapy in autoimmune encephalitis (AE) patients to make clear that the early PE can be more effective than the treatment of PE after medication immunotherapy. The study also explores whether PE is also effective in AE with autoantibody synthesis in the sheath, positive cerebrospinal fluid antibody, and seronegative.

Patients with AE will be randomly divided into the early PE group and the non-early PE group according to the random table. All patients will receive tumor screening, symptomatic supportive treatment, and immunotherapy. The immunotherapy includes high-dose corticosteroid, intravenous gamma immunoglobulin (IVIG; 0.4 g/kg/d for each course for 5 d), PE, and immunosuppressants. The immunosuppressants will be given after enrolled four weeks. High-dose corticosteroid and PE will be given before IVIG in the early PE group. PE will be given after high-dose corticosteroid and IVIG 2 weeks in the non-early PE group. The mRS will be used for outcome evaluations. The outcomes will be evaluated after 2, 3, 6, 12, and 24 months respectively, following immunotherapy. The evaluation standards were as follows: an mRS of 0-2 points is favorable, and 3-6 points is unfavorable. Statistically, analyses will be employed to examine the differences in outcomes between the severe and non-severe groups.

Title: Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis (Generate-Boost)

Stage: Recruiting 

Study Director: Christian Geis, Prof.

Jena University Hospital

Jena, Germany

Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming to reduce pathogenic antibodies and contain the autoimmune process. In the first line, patients are treated with plasmapheresis and cortisone. In the second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments is, however, often delayed and insufficient.

Therefore, we need a specific therapy aiming at the antibody-producing plasma cells.

Bortezomib is a proteasome inhibitor that interferes with NF-kB (nuclear factor kB) and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis – like plasma cells – and induces cell death in these cells. Bortezomib has been used for more than a decade in multiple myeloma chemotherapy. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells, reducing the number of pathogenic antibodies and improving clinical outcomes. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with five patients.

Title: The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis (ExTINGUISH)

Stage: Not Yet Recruiting 

Contact: Stacey L. Clardy, MD, PhD

University of Utah

Salt Lake City, UT

N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients aged 10-50, causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders, and life-threatening dysautonomia. Intensive care, including cardiorespiratory support, is required in 75% of cases. The diagnosis is confirmed by detecting IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, ~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as “second-line” treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood-brain penetrance and efficacy and poor consensus on the timing, dose, and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in treating neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off-label B-cell depleting therapies, such as rituximab, inebilizumab depletes not only CD20+ B-cells but also CD20- plasmablasts and plasma cells resulting in robust and sustained suppression of B-cell expression. The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive, validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, determine more meaningful cognitive endpoints, and identify better biologic biomarkers to predict the outcome.