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Overview of the Anti-NMDA receptor encephalitis mimicking schizophrenia: diagnosis and treatment

Interview with Dr. Maarten Titulaer, recorded at ECNP Congress 2016, Vienna

PROF_ Titulaer | V1-HD 1080p

Discovered in 2007, anti-NMDA receptor encephalitis is a disorder that features a lot of psychiatric symptoms – patients become psychotic, have insomnia, seizures, mutism, autonomic dysfunction and ICU admission. Many patients were not treated properly and left with deficits or died before 2007. If you diagnose such a patient, treatment might take months but the outcome is rewarding in almost all patients, who may end up going home instead of staying in an institute. Studies have approached the disorder in two ways: starting with the NDMA receptor and go back to the symptoms or looking for antibodies, receptor and encephalitis. There are many limitations, from potentially inaccurate use of high throughput screening to unchecked wrongly positive results. In patients with long-term schizophrenia, the chance of finding pathogenic antibodies is virtually zero. Symptoms can be mild – less speaking, less memory, tachycardia, fever; psychosis with catatonia. Serum testing can miss a diagnosis; a lumbar puncture is needed to be sure.


Q. Could you give the background to your presentation on anti-NMDA receptor encephalitis mimicking schizophrenia?

A. Of course, I am happy to talk.  Anti-NMDA receptor encephalitis was discovered only in 2007, so less than 10 years ago.  It is a disorder which features many psychiatric symptoms, where patients become psychotic, but also have insomnia.  They can have many symptoms including seizures, mutism, autonomic dysfunction, ICU admission and, until 2007, many patients were not treated and remained with severe deficits or died.  The good thing is that we know that this disorder is treatment-responsive: although treatment might be difficult, recovery is very good in most patients, once you treat them adequately. In 2011, it was suggested that patients with schizophrenia could also have NMDA receptor encephalitis and this caused a great deal of interest from the psychiatric field into these diseases.  There was the question like, are many patients with schizophrenia treated wrongly in institutions, while they could have been treated and recovered?  That is the basis of why psychiatry is interested in NMDA receptor encephalitis.

Q. What flaws have there been with previous studies looking at anti-NMDA receptor encephalitis and psychotic behaviour?

A. There are two ways of looking into it.  One way is that you start with NMDA receptor encephalitis and you go back to psychiatric symptoms.  This has been done quite extensively and we know that 97 per cent of all patients will develop psychiatric symptoms – so almost all – and we also know that, especially in adults and adolescents, about two-thirds of patients will present initially with psychiatry.  [Having] psychiatric symptoms by themselves, only without any neurological or internal symptoms, is rare, but studies the other way around, from schizophrenia or psychosis into whether the patients have antibodies, and do the patients have NMDA receptor encephalitis, are much more dispersed. There is a great deal of variety in techniques of testing and many studies only use high throughput screening which, of course, is useful and easy, but the problem is that you have to check whether your screening is adequate by additional techniques.  If you test thousands of patients, and you have a test which is 99 per cent sensitive/specific, then you get some wrongly positive results, and you have to check these.  These checks of the balance are often lacking.  Another problem is that antibodies are of one specific subtype in this disease and some studies lump all types of antibodies you can find [together] and say ‘We find these in everyone – stroke, healthy controls, dementia, Parkinson’s, but also schizophrenia.’  They have spent tens of papers, explaining that these antibodies are in everything and that they are useless, but that is a really flawed method and, unfortunately, they are still published.

Q. In what situations should anti-NMDA receptor encephalitis be screened for, and how?

A. We know that, in patients with schizophrenia, long-term schizophrenia, the chance of finding pathogenic antibodies is virtually zero.  In patients with first episode psychosis, the chances are still low, at about one per cent or perhaps two per cent, but if you look for specific red flags, these chances are higher.  Some things are atypical – first psychosis, neurological symptoms, although those can be quite mild, such as less speaking, or less memory, or tachycardia or fever.  [There are] patients with autoimmune disorders, psychosis with catatonia, and patients with a severe response to typical antipsychotic medication low dose – such as patients who develop severe dyskinesias due to a small dose of haloperidol.  Those are the ones you should be looking into, and it can mimic malignant neuroleptic syndrome, and so every patient with malignant neuroleptic syndrome following first-episode psychosis should be screened. One caveat is that serum testing can miss the diagnosis.  If you have a suspicion, you need CSF: you have to do a lumbar puncture.  The other way round, if your result is positive but if you only have psychiatric symptoms, you should screen the CSF to know for sure that it is a real result and not a false positive result.

Q. What is your take-home message?

A. Anti-NMDA receptor encephalitis as a mimic of psychosis, more than schizophrenia, does exist, but it is rare.  If you remember the red flags, the neurological symptoms, although mild, or internal symptoms, although mild, catatonia, severe side effects of low dose antipsychotics – if you know the red flags, then you know when to screen.  Definitely, and importantly, know the caveats of serum and CSF testing.  Although rare, it is very rewarding because, if you diagnose such a patient, treatment might be long and it might take months but in the end, in almost all patients, the outcome is rewarding and your patients will go back to their own lives without being in an institute or on psychiatric medication for the rest of their lives.