Mental health clinicians should be mindful that numerous physical illnesses can present with psychiatric symptoms. A case in point is a recently described autoimmune disorder in which antibodies target glutamate NMDA receptors within the brain. Acute psychosis and cognitive dysfunction are so prominent in this condition, Anti-NMDA receptor encephalitis, that many patients are initially referred to psychiatry. Swift and accurate diagnosis is essential, as the appropriate therapy is immunological rather than psychiatric.

The antibody targets the extra-cellular portion of the NMDA receptor. Initially, there is an increase of NMDA mediated currents. But hypofunction emerges, the receptor appears to be internalised and vital functions such as long-term potentiation (LTP), which are essential for cognition, are lost. [see link]

Anti-NMDA receptor encephalitis

Symptoms and signs

Anti-NMDA receptor encephalitis was first described in young women with underlying ovarian tumours. But cases in males, in children and non-tumour cases are well documented. In about 20% of presentations, neuropsychiatric symptoms are preceded by a flu-like illness. Early symptoms in adults are psychosis (hallucinations, delusions and bizarre behaviour), cognitive impairment (confusion, memory dysfunction, dysphasia), and seizures. Over days to weeks additional neuropsychiatric features emerge; movement disorder (choreoathetoid, myoclonus, parkinsonism, rigidity), autonomic instability (tachy/bradycardia, labile BP, hypersalivation, central hypoventilation) and reduced levels of consciousness [full paper].

Investigations

In terms of investigation, CSF lymphocytosis, CSF oligoclonal bands, EEG slowing and epileptiform potentials can be found. The MRI scan is usually normal. The diagnosis is clinched by the presence of CSF IgG antibodies against the NR1 subunit of the NMDA receptor.

Treatment

The treatment of choice is immunotherapy (IV steroids, IV immunoglobulin, plasma exchange) – as well as tumour resection. A good outcome is associated with a decrease in NMDA receptor antibody levels. In some patients the recovery is prolonged, and 2nd line immunotherapies are required. Interestingly, many patients have also responded well to modified ECT.

NMDA receptor autoantibodies & Schizophrenia?

There has been recent interest in the possibility that many cases of diagnosed schizophrenia may actually be alternative forms of anti-NMDA receptor encephalitis. But the evidence for this is not convincing. In a Spanish study of 80 patients, no cases were positive for anti-NMDA receptor IgG antibodies. In a larger study from Germany (approx 450 acute patients), there was an excess of anti-NMDA receptor antibodies in acute schizophrenia (10%) versus major depression (3%). But these were not the IgG antibodies against the NR1 subunit, which is the defining feature of NMDA receptor encephalitis. Instead there were IgA and IgM antibodies against the NR1 and NR2 subunits. The significance of these antibodies is not entirely clear, especially as they were also found in healthy controls (0.4%). Are they a marker of a prior insult against the NMDA receptor or an incidental finding? – A question which will now attract much research.

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