Anti-NMDA Receptor Encephalitis #illumedati

Hi guys! It’s Medicine Mondays again and I’m here to talk about Anti-NMDA Receptor Encephalitis.

A good friend of mine from fellowship is out here visiting me and we were talking over some coffee yesterday. I asked him what he thought I should talk about for Medicine Mondays. He’s a neuroradiologist like me. However, he recently he had developed an interest in auto-immune syndromes and the intersection between immunology and other disease processes.

Stock Photo from: Pixabay

For example, there is a growing body of research with links toward auto-immune disorders of the gut, such as Crohn’s Disease or Ulcerative Colitis may have ties to Anxiety and Depression. Source This  reminded me of a diagnosis my wife always tries to keep in the back of her mind, which is Anti-NMDA Receptor Encephalitis... and that’s why I’m writing this post.

What is Anti-NDMA Receptor Encephalitis?

Like its name suggests, it is an auto-immune response to the NR1 subunit of the NMDA receptor (N-methyl D-aspartate receptor). Originally, it was first associated with younger female patients who had ovarian teratomas. However, it is becoming increasingly more common in patients who do not have a tumor.

What is the presentation?

In retrospective studies, patients have described a pro-dromal phase with the nonspecific symptoms of headaches, flu-like illness, or symptoms similar to an upper respiratory infection. The most interesting aspect of this disease is that first symptoms are usually psychiatric. The most prominent symptoms included delusional thinking, aggression, and mood disturbances, which were usually manic. (JAMA 2013)

The take home point here is that any young patient (around or less than 30 years of age) with a new onset of psychosis and no past neuropsychiatric history, could potentially have this disease and it should be considered.

Unfortunately, the diagnosis is not an easy one to make and it requires a skilled psychiatrist to tease out this diagnosis and separate it from any underlying pre-existing psychiatric condition. As such, patients with this disease may progress past the earlier psychiatric presentation into a more neurologic presentation.

Progression of disease may include:

Autonomic disturbances such as tachycardia, fever, or hypertension.

Mild neurologic symptoms such as facial twitching, as well as catatonia, seizures, mutism, or development of extrapyramidal symptoms when placed on an antipsychotic agent. (emphasis mine)

The development of extrapyramidal symptoms (EPS) when placed on antipsychotics should alert the team to consider this diagnosis. Of course, EPS is a known side effect of antipsychotics anyways, but it just another reminder to consider the possibility of Anti-NMDA Receptor Encephalitis. A new onset of possible Neuroleptic Malignant Syndrome should also make the team consider the possibility of Anti-NMDA Receptor Encephalitis (especially if the Creatine Kinase (CK) is normal, or CK normalizes after treatment, but without improvement.)

What is the best way to work-up/confirm the diagnosis?

The best way to confirm the diagnosis is finding the Anti-NMDA antibodies in the serum or cerebrospinal fluid (CSF).

However, the sensitivity of finding Anti-NDMA antibodies in serum is only ~75% with a 97%+ specificity. This means you may miss about 25% of cases. So, if there is a high index of suspicion, even if the serum test is negative, a CSF sample should be acquired and evaluated. Demonstration of antibodies in the CSF is 100% sensitive and 100% specific.

Another specific finding are extreme delta brushes on EEG: “Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome.” – Source

What makes the diagnosis unlikely (ruled out)?

Time. If the patient doesn’t develop neurologic symptoms within 4 weeks after onset of psychiatric symptoms, as discussed above, then the diagnosis becomes very unlikely.

What is the treatment?

Once diagnosis is confirmed, a search for an underlying tumor should be performed. As stated above, there is an association with ovarian teratomas and other tumors. Removal of these tumors, which could be producing the antibody is important in addition to first-line immunotherapy, which includes:

Steroids, Intravenous Immunoglobulin (IVIG), and plasmapheresis.

Second-line immunotherapy includes:

Rituximab, a monoclonal antibody that targets the CD20 receptor on the surface of B cells, destroying the self-reactive B cells.

Cyclophosphamide, an alkylating agent that cross-links DNA and is used to treat both cancer and autoimmune diseases.

What is the prognosis?

Overall prognosis is pretty good. However, the earlier the diagnosis, the better the prognosis, which is why it is so important to be aware of this syndrome during its earlier psychiatric presentation. As it progresses into the the later neurologic stages, the potential for a long term deficit increases.

“Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months.” – Lancet 2013

“Physicians should be aware that isolated psychiatric symptoms can last for months before neurological symptoms and should remain hopeful for a good prognosis because continuous IT can achieve a favorable outcome despite delayed diagnosis of anti-NMDAR encephalitis.” Movement Disorders Clinical Practice 2014

Why did you decide to write about this disease today?


this is from a meme btw – Overconfident Alcoholic (Depression Guy)


Anti-NMDA Receptor Encephalitis is an auto-immune disease which walks the line between psychiatry/neurology.

Awareness of this disease and the relatively young population it affects as well as knowledge of its earlier psychiatric and later neurologic presentation is the key.

A new onset of psychosis in a young patient without a past neuropsychiatric history should make this diagnosis a consideration.

A diagnosis of Neuroleptic Malignant Syndome without an increased CK, or no improvement after treatment and normalization, also should make this diagnosis a consideration.

Anti-NMDA antibodies in the serum and CSF are the best way to confirm diagnosis.

Extreme delta brush waves on EEG, when present, are characteristic.

Treatment revolves around finding a possible underlying tumor and immunotherapy.

Recovery can be slow, but overall prognosis is good. However, the earlier the diagnosis, the better the outcome.

You don’t know what you don’t know.



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