Anti-NMDA Receptor Encephalitis

What Causes Anti-NMDA Receptor Encephalitis?

Anti-NMDAR encephalitis occurs when the immune system attacks nerve-cell proteins called N-methyl-d-aspartate (NMDA) receptors. This type of encephalitis sometimes follows cases of herpes simplex encephalitis. It is also commonly associated with the presence of an ovarian tumor called a teratoma.

Scientists don’t yet know what causes the inappropriate immune-system response that triggers anti-NMDAR encephalitis. Likely, a combination of genetic predisposition and environmental factors come together to cause the immune system to react abnormally.

Is Anti-NMDA Receptor Encephalitis Hereditary?

In most cases, anti-NMDAR encephalitis does not seem to be an inherited condition. Some studies have found an association between the disease and specific genetic mutations, but these changes usually occur during sperm or egg development and are not carried by a child’s parents. However, the studies have found a small number of cases in which the disease-associated mutations have run in families. Therefore, more research is necessary to determine if the disease has a significant inherited component.

How Is Anti-NMDA Receptor Encephalitis Detected?

Anti-NMDAR encephalitis often begins with relatively mild neurological symptoms, including behavior changes and speech difficulties. Psychological symptoms may include:

• Aggression
• Depression
• Anxiety
• Insomnia
• Disorganization
• Mania
• Hallucinations, paranoia, or psychotic symptoms

The disease usually progresses rapidly, and symptoms typically become more severe until hospitalization is required.

How Is Anti-NMDA Receptor Encephalitis Diagnosed?

If you exhibit symptoms consistent with anti-NMDAR encephalitis, your healthcare provider will perform a series of diagnostic steps to see if you have the condition.

• Physical exam and medical history. The doctor will look for signs of encephalitis.
• Laboratory tests. Tests of your blood can determine whether or not antibodies associated with anti-NMDAR encephalitis are present.
• Spinal tap. This procedure removes and tests a small amount of the fluid that protects your brain and spinal column for the presence of antibodies.

How Is Anti-NMDA Receptor Encephalitis Treated?

Treatment for anti-NMDAR encephalitis involves controlling the inflammation and swelling of the brain, which can cause long-term damage and death, and treating any underlying condition, such as a tumor, associated with the encephalitis.

Treatment may include:

• Corticosteroids such as prednisone or methylprednisolone
• Transfusions of blood plasma to remove abnormal antibodies and replace them with normal plasma
• Intravenous immunoglobulin (IVIg), the intravenous administration of normal antibodies
• Immunosuppressive drugs such as CellCept, Rituximab, or Cytoxan

How Does Anti-NMDA Receptor Encephalitis Progress?

Anti-NMDAR encephalitis progresses quickly after the initial onset of symptoms, but most people recover fully when the disease is treated promptly and correctly. The most severe neurological symptoms typically resolve most rapidly, while behavioral and cognitive symptoms tend to linger longer. However, most patients have fully recovered within two years after treatment begins.

Full recovery is more likely under several conditions, including:

• The disease is associated with a tumor, and the tumor is removed.
• The disease is diagnosed early, and treatment begins promptly.
• Treatment is aggressive and includes immunosuppressants.

How Is Anti-NMDA Receptor Encephalitis Prevented?

Because the specific causes of the disease are unclear, there is no known way to prevent anti-NMDAR encephalitis.

Anti-NMDA Receptor Encephalitis Caregiver Tips

After surviving a severe case of encephalitis, patients are often forced to deal with complications that may last for years. Although the disease is gone, its lingering effects can make everyday life difficult, and caregivers can help sufferers to return to their daily routines as much as possible.

• Learn as much as you can about the disease and its long-term effects. The sufferer may need help with ongoing therapies, such as physical therapy, occupational therapy, speech therapy, or psychotherapy.
• 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 such as paying bills may be difficult, leading to financial missteps. As a caregiver, be aware that these seemingly 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 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.

Anti-NMDA Receptor Encephalitis Brain Science

NMDA receptors are sites on the surface of nerve cells that interact with an amino acid called N-methyl-D-aspartate. This interaction is part of a mechanism that allows calcium and sodium to flow into the cells and potassium to flow out. This mechanism, in turn, is part of a signaling process between nerve cells that is vital to brain function. In particular, NMDA receptors play an essential role in memory and learning.

Dysfunction of the receptors has been associated with memory deficits, learning impairment, and psychotic symptoms. In addition, some researchers have suggested that NMDAR-related gene mutations form a connection between anti-NMDAR encephalitis, other types of autoimmune encephalitis, and certain types of epilepsy.

One current study examines the early symptoms of anti-NMDA receptor encephalitis, specifically psychiatric and speech symptoms that occur in the early phases of the condition. Unfortunately, these early symptoms often progress to more severe symptoms such as seizures and movement abnormalities. The study hopes to help practitioners better recognize the very early signs so that treatment can begin before the condition becomes more severe.

Another study is looking at the recovery obstacles faced by survivors of autoimmune encephalitis and their caregivers. Researchers hope that practitioners will develop more effective therapies and support systems by having a more thorough understanding of what it means to live with the effects of encephalitis.

Anti-NMDA Receptor Encephalitis Research

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-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.

Title: Autoimmune Encephalitis With Anti-NMDA Receptor Antibodies Following Herpetic Encephalitis (NMDARE-HSE)

Stage: Recruiting 

Study director: Jérôme Honnorat    

Hospice Civils de Lyon

Bron, France

Herpes Simplex Virus encephalitis is the most common infectious encephalitis, with an estimated annual incidence of 1 / 250,000 to 1 / 500,000 in industrialized countries. Despite a widely used antiviral treatment, the prognosis remains poor, with 5 to 20% mortality and a considerable morbidity rate.

One contributing factor to unfavorable prognosis is the development of encephalitis mediated by autoantibodies, most often directed against NMDA receptors, in the weeks following viral encephalitis.

The description of this pathology is recent, the pathophysiology of this process remains poorly understood, and the management of these patients is not yet codified.

Title: Autologous Peripheral Blood Stem Cell Transplant for Neurologic Autoimmune Diseases

Stage: Recruiting 

Contact: George E. Georges

Fred Hutch/University of Washington Cancer Consortium

Seattle, WA

This phase II trial studies the side effects and how well carmustine, etoposide, cytarabine, and melphalan together with antithymocyte globulin before a peripheral blood stem cell transplant works in treating patients with autoimmune neurologic disease that did not respond to previous therapy. In autoimmune neurological disorders, the patient’s immune system ‘attacks’ the nervous system, including the brain/spinal cord and/or the peripheral nerves. Before a peripheral blood stem cell transplant, giving high-dose chemotherapy, including carmustine, etoposide, cytarabine, melphalan, and antithymocyte globulin weakens the immune system and may help stop the immune system from ‘attacking’ a patient’s nervous system. When the patient’s own (autologous) stem cells are infused into the patient, they help the bone marrow make red blood cells, white blood cells, and platelets so the blood counts can improve.