DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY COMMENTARY

Autistic regression and central nervous system autoimmunity

RUSSELL C DALE
Paediatric Neurology, Children’s Hospital at Westmead, University of Sydney,
Sydney, NSW, Australia.
doi: 10.1111/dmcn.13185
This commentary is on the case report by Hacohen et al. To view this
paper visit http://dx.doi.org/10.1111/dmcn.13169.
A proportion of patients with autism, some of whom
appear neurodevelopmentally normal before onset, can
regress in the first years of life. This autistic regression is
an important but poorly understood entity that may have a
genetic aetiology and/or an acquired aetiology. There is an
emerging literature suggesting that some patients with aut-
ism have immune activation in the central nervous system
(CNS), and there is increasing interest in modulation of
the immune system which could result in clinical benefits.1
Hacohen et al.2 describe two cases with an autistic
regression who had confirmed anti-NMDAR (N-methyl-D-
aspartate receptor) encephalitis. Part of the diagnostic chal-
lenge in these cases was the young age at onset, as both
children were 2 years old. Anti-NMDAR encephalitis is an
autoimmune encephalitis with acute or subacute onset of
encephalopathy, behavioural change, seizures, and move-
ment disorders. The encephalopathy in anti-NMDAR
encephalitis is different to the reduced consciousness
observed in most children with viral encephalitis and
acute disseminated encephalomyelitis. In anti-NMDAR
encephalitis (NMDAR-E), the patients are typically ‘awake
but unresponsive’, and typically unable to recognize their
parents and are unresponsive to their environment. Fur-
thermore, patients with NMDAR-E have loss of language,
referred to as aphasia or mutism. In the two described
cases, this combination of loss of reactivity to the environ-
ment, loss of social reciprocity, and loss of language
resulted in the initial suspicion that the patients had an
autistic regression. The occurrence of possible seizures
(n=1), gait disorder (n=1), and movement disorder (n=1)
resulted in testing for NMDAR antibodies in cerebrospinal
fluid (CSF) and serum, and consequent diagnosis.
However, these additional features were relatively subtle,
adding to the diagnostic challenge. The movement disorder
in one of the patients was relatively mild and had repetitive
and stereotypical features. There is a very broad spectrum
of movement disorders associated with anti-NMDAR
encephalitis (including chorea, dystonia, and akinesia),
although perseverative and stereotypical phenomena seem
to discriminate NMDAR-E from other autoimmune move-
ment disorders.3 The video accompanying the case is inter-
esting and adds to the challenge. The movements were not
clearly extrapyramidal (as seen in chorea or dystonia), but
instead there was a restless nature to the movements with
repetitive, stereotypical, and semi-purposeful features such
as chewing movements, repetitive touching of the arm and
hair, and pulling at the shirt. The perseverative and stereo-
typical nature of the movements was reminiscent of
NMDAR-E, but stereotypical movements are also observed
in young children with autism.
Once the diagnosis of NMDAR-E was made, the patients
received immune therapy and made good recoveries.
The cases are thought-provoking for a number of rea-
sons. First, these cases reinforce the challenge in making
a diagnosis of anti-NMDAR encephalitis in young chil-
dren, which can result in late diagnoses and worse out-
comes. Second, neither child in the report by Hacohen
et al. had CSF pleocytosis, highlighting the need to test
for other markers of CNS inflammation such as oligo-
clonal bands, CSF NMDAR antibodies, and CSF neop-
terin.4 Thirdly, these cases raise the possibility that a
minority of children with autistic regression could have
CNS autoimmunity.5
There is evidence from studies of amniotic fluid, serum,
CSF brain parenchyma, and neuroimaging that there is
CNS immune activation in some children with autism.1 It
is unclear whether this CNS immune activation observed
in autism is primary and causal (as seen in autoimmune
diseases), or secondary. However, regardless of this distinc-
tion, identifying modifiable and treatable neuroinflamma-
tion could result in improved functioning. There is a need
for more sensitive biomarkers of CNS immune activation
to alert the clinician to patients with autistic regression
who may, in theory, benefit from immune modulation.
The cases described by Hacohen et al. remind us to
remain vigilant and not miss treatable causes of neurologi-
cal impairment.

REFERENCES
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2. Hacohen Y, Wright S, Gadian J, et al. N-methyl-D-aspar-
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an autistic regression. Dev Med Child Neurol 2016; doi:
10.1111/dmcn.13169. [Epub ahead of print].
3. Mohammad SS, Fung VS, Grattan-Smith P, et al. Move-
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