Anti-NMDA Receptor Encephalitis

Overview

Anti-NMDA receptor (NMDAR) encephalitis is a newly identified autoimmune disorder that targets NMDARs, causing severe neurological symptoms including hallucinations, psychosis, and seizures, and may result in death. The disease was first characterized in 2007. It is the most common and best characterized antibody-related encephalitis.

N-Methyl-D-aspartate (NMDA) receptors play a key role in the plasticity of synapses (structures in nerve cells participating in signal transduction in the nervous system), which is believed to underlie memory and learning, as well as the development of the nervous system.

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against NMDA receptors.

The condition is associated with tumours, mostly teratomas of the ovaries, and thus can be considered a paraneoplastic syndrome. However, there are a substantial number of cases with no detectable tumour, and in fact it appears that most patients do not have a tumour.

Symptoms

Symptoms range from psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, to decreased levels of consciousness and breathing, autonomic instability (unstable blood pressure level or pulse rate, hypersalivation, central hypoventilation, etc.). Within the first month, movement disorders and ataxia were more frequent in children, while memory problems and decreased breathing predominated in adults. Very often headache, fever and flu-like symptoms preceded other encephalitis features.

The most frequent initial symptoms in children include:

  • Abnormal behavior
  • Seizures
  • Movement disorders/involuntary movements

In adults the most frequent initial symptoms were:

  • Abnormal behavior
  • Memory problems

Causes

Patients with anti-NMDA receptor encephalitis produce antibodies against one of the components (subunits) of the NMDA receptor. These antibodies crosslink the receptor, causing it to be internalized and destroyed.

The initial patients diagnosed with anti-NMDAR encephalitis were mainly adult women in whom the presence of anti-NMDAR antibodies coincided with an ovarian teratoma or cyst that expressed NMDA receptors. However, these types of tumors are not the cause of NMDAR encephalitis. Later studies showed that also men and children without tumors can develop NMDAR encephalitis.

It is known that the vast majority of encephalitis patients have prodromal infection before onset of the disease. If this infection affects either normal ovaries or ovarian teratomas, it may trigger the expression of NMDAR-related epitopes (regions on receptor molecules, where antibodies bind) in oocytes. Therefore, ovarian teratomas that consist of large amounts of neural tissue might indicate an increased risk for development of this type of intractable encephalitis.

Diagnosis

If you develop the aforementioned symptoms, you should contact your healthcare provider as soon as possible. Quicker diagnosis and early treatment can improve outcomes for this severe disease.

If you have an ovarian teratoma or cyst, you are at higher risk of developing this type of encephalitis.

Tests for anti-NMDAR encephalitis include:

  • Analysis of cerebrospinal fluids (CSF) and sera for antibodies against NMDA receptors (a-NMDAR ab). Usually higher concentrations of a-NMDAR ab is detected in the CSF*
  • Sometimes brain MRI is performed to reveal possible abnormalities
  • Tests for tumors, like ovarian teratoma and others (ultrasound, computer tomography, MRI etc)

Prognosis

The condition occurs most frequently in women and predominately in younger people (age 17-30). It is very often associated with ovarian teratoma or cyst. In most of the cases it is treatable, if diagnosed promptly.

Treatment

If people are found to have a tumour, the long-term prognosis is generally better and the chance of relapse is much lower. This is because the tumour can be removed surgically, thus eradicating the source of autoantibodies. In general, early diagnosis and aggressive treatment is believed to improve patient outcomes, but this remains impossible to know without data from randomized controlled trials. Given that the majority of patients are initially seen by psychiatrists, it is critical that all physicians (especially psychiatrists) consider anti-NMDA receptor encephalitis as a possible cause of acute psychosis in young patients with no past neuropsychiatric history.

  • If a tumour is detected, its removal should occur in conjunction with first-line immunotherapy. This involves steroids to suppress the immune system, intravenous immunoglobulin, and plasmapheresis to physically remove autoantibodies. A study of 577 patients showed that over four weeks, about half the patients improved after receiving first-line immunotherapy.
  • Second-line immunotherapy includes rituximab, a monoclonal antibody that targets the CD20 receptor on the surface of B cells, thus destroying the self-reactive B cells. Cyclophosphamide, an alkylating agent that cross-links DNA and is used to treat both cancer and autoimmune diseases, has sometimes proven useful when other therapies have failed.
  • Other medications, such as alemtuzumab, remain experimental.