Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis and autistic regression

Regression as part of the presentation of autism is still a topic which has the ability to create discussion and fuel controversy. I've talked about it a few times on this blog (see here and here) and how, after a bit of a laboured start, modern day autism research has finally come around to acknowledging that regression can occur in cases of autism.

Fire @ Wikipedia  

The cause(s) of regression associated with autism has been where a lot of the debate has been had over the years. I've talked for example, about how vitamin B12 deficiency has been associated with cases of Childhood Disintegrative Disorder (CDD) (see here). This being one of the less 'controversial' theories put forward for regression in autism or in an autistic-like presentation as per other papers analysing factors such as thimerosal (thiomersal) exposure* and that-which-should-not-be-mentioned**.

What I take from the collection of literature on this topic is that (a) autism is probably better defined as the autisms insofar as the regression being present or not for example, and (b) there probably isn't just one factor influencing regression where and when it occurs in relation to those autisms. Oh and (c) getting to the bottom of the causes of regression in cases of autism is a mighty difficult task.

For today's post I'm talking about the paper by Ori Scott and colleagues*** describing a case report of a child where anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis was suspected "as the cause of autistic regression".

From the top, anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune condition whereby a person generates antibodies against self, in particular, antibodies that target NMDA receptors in the brain. As per the paper by Florance and colleagues**** (open-access here) the presentation of the anti-NMDA receptor encephalitis in children and adolescents is not wholly dissimilar from that in adults including behaviour and personality changes albeit including "temper tantrums, behavioral change, agitation, aggression, and progressive speech deterioration as initial symptoms". For those more interested in the adult presentation of the condition, the book 'Brain on Fire' by Susannah Cahalan is probably a good starting point.

Scott and colleagues chart the clinical course of a young boy following "an upper respiratory tract infection" into what would eventually "fit the diagnostic criteria for autistic spectrum disorder". Said anti-NMDA receptor antibodies were detected in cerebrospinal fluid (CSF) and treatment with "intravenous immunoglobulins and steroids" brought about a resolution of some of the behavioural issues. I might add that this is not the first time that anti-NMDA receptor encephalitis has been mentioned with autism in mind***** including that cross-over with CDD.

Taking into account the Scott paper and the writings of Cahalan, I get the impression that luck played a big role in the resolution of both cases. As per the Grauniad (sorry, Guardian) write-up of her book "Cahalan is never in any doubt about the extent of her luck: the luck in finding a sensitive doctor who listened to her, and took her case on its own merits". One can perhaps see that other medics might have not offered a similar diagnosis to the one she was eventually given and upon which treatment was commenced.

The Scott paper also brings into sharp focus how, when presented with cases of "autistic regression", it may be worthwhile undertaking some pretty detailed medical examination to determine whether the source of the regression might just fall into the jurisdiction of something like anti-NMDA receptor encephalitis. This accepting that getting a sample of CSF is not the nicest of procedures although as per other case studies, a full medical work-up is indicated****** (open-access).

That there also may be a medical reason for such a regression to occur is another lesson for autism research as and when it is confronted by children presenting with a fairly rapid regression into autism or autistic-like symptoms. It for example, strikes me that there is a growing respect for anti-NMDA receptor encephalitis when it comes to the presentation of something like delerium******* or even some cases of schizophrenia******** (open-access here) even without seizures being present. So when such a regression occurs in younger children, are they any less deserving of such medical consideration too? Exactly how the Scott report might play into the blanket 'autism is a lifelong condition' is another consideration.

Finally, I have to point out that the Scott paper was a case report and before anyone gets too carried away, does not necessarily mean that every case of regression in autism is due to this factor. That being said, the use of something like IVIg as the chosen treatment method for anti-NMDA receptor encephalitis is not necessarily a stranger to autism research (see here). The use of steroids as immunosuppressive agents, indicated for certain autoimmune conditions, might also offer some clues about certain parts of those autisms (see here) too bearing in mind my caveat on this blog about not giving medical or clinical advice.

Some music to close this post I think. Oasis and Don't Look Back in Anger. "Please [Mr McGee], don't make me angry, you wouldn't like me when I'm angry" (he says hiding behind the sofa).

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* Kern JK. et al. Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Int J Environ Res Public Health. 2013 Aug 20;10(8):3771-800.

** Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

*** Scott O. et al. Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler. J Child Neurol. 2013 Oct 3. [Epub ahead of print]

**** Florance NR. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009 Jul;66(1):11-8.

***** Creten C. et al. Anti-NMDA-receptor encephalitis: a new axis-III disorder in the differential diagnosis of childhood disintegrative disorder, early onset schizophrenia and late onset autism. Tijdschr Psychiatr. 2012;54(5):475-9.

****** Chapman MR. & Vause HE. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychaitry. 2011; 168: 245-251.

******* Punja M. et al. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila). 2013 Sep;51(8):794-7.

******** Tsutsui K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry. 2012 May 8;12:37.

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Scott O, Richer L, Forbes K, Sonnenberg L, Currie A, Eliyashevska M, Goez HR. (2013). Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler Journal of Child Neurology DOI: 10.1177/0883073813501875