Research
Brains
‘on fire’
More research is needed into why children
can tip into autism when their immune
system goes wrong. Dr Ben Marlow, a
paediatrician and father to Freddie, who
has the condition, describes how their
developing brains can be badly affected
Autism is an umbrella term with
many subtypes. The heterogenous
nature of the phenotype (in other
words, the way that it manifests in
an individual) is further
complicated by the unpredictable
way that it affects the body and the
nervous system.
Dr Ben Marlow is a There are frequent associations
neurodevelopmental with certain syndromes and many
paediatrician working ‘risk genes’ have been identified.
across Luton and Nevertheless, there is emerging
Cambridge for the NHS evidence that a dysregulated
immune system can have
devastating effects on the
developing brain.1
Medicine is entering a new age
of neuropsychiatry, which is the
branch of medicine dealing with
diseases involving the mind and
www.autismeye.com
nervous system. It is challenging
traditionally held beliefs about the
underlying causes of behaviour. In
turn, this is leading to a range of
new therapies that have not
previously been explored.
My particular interest is in
Microglia start to
cause trouble –
attacking neurons and
synapses within the
brain that shouldn’t be
broken down. This
creates a toxic soup”
looking at the association
between the immune system and
the nervous system, and in
particular at a cohort of children
with autism where the immune
system has become dysregulated
and hyperactive.
The children with this ‘immune
subtype’ of autism tend to be more
on the severe end of the spectrum.
They have difficulties with
language and stereotypical
behaviour. They also have
abnormal conditions resulting from
a previous disease.
This can be mitochondrial
dysfunction (which affects the
body’s use of energy), bowel
problems and marked
hypersensitivities.
A ‘hyperactive’
immune system
Epidemiological studies (the
branch of medicine dealing with
the incidence and prevalence of
disease in large populations) have
shown there is an association
between certain inflammatory
disease in the mother or child and
the risk of autism, especially with
regression.2 The maternal immune
system can be activated via
Au t i s m | e y e I s s u e 3 0 2 0 1 8 13
 Research
infection or other pathways and
trigger an inflammatory response.
This can lead to an increase in
inflammatory molecules such as
Interleukin 1B, IL-6, IL-17 and TNF.1
It can also increase the number
of other cells. Among these are
mast cells, which are present in
connective tissue and release
heparin, histamine, seratonin and
other molecules during
inflammation and allergic reactions.
These cell-derived messengers,
called inflammatory mediators, act
on blood vessels, inflammatory
cells or other cells to contribute to
an inflammatory response.
Mast cells can also increase the
permeability of the blood-brain
barrier. This can cause the
inflammatory mediators to enter
the brain.
‘Brain fire’
Once these inflammatory mediators
are in the brain, there are immune
surveillance molecules called
microglia that start to increase in
number. Normally, microglia police
the body’s cerebrospinal
fluid within the brain looking for
signs of infection – they are part of
the innate immune system.
If they find anything that
shouldn’t be there they can
manufacture chemicals to kill the
offending bacteria or invader.
The M1 subtype can be
particularly destructive.
In this inflammatory subtype of
ASD, it is thought that these
microglia start to cause trouble –
attacking neurons and synapses
within the brain that shouldn’t be
broken down. This creates a toxic
soup of inflammatory mediators
and abnormal neuronal firing.
Professor Theoharides (Tufts
University in Boston) refers to this
as ‘brain fire’.
It results in disorganised,
ineffective neural connectivity and
neuronal loss.
The systemic fallout
As a consequence of the
microglial overactivity, the
production of nitric oxide
increases. This can have an
impact on a variety of organ
systems. Systemic features in this
cohort of children include
headache, higher rates of infection
14 Au t i s m | e y e I s s u e 3 0 2 0 1 8
Features in
this cohort
of children include
headache, higher
rates of infection …
seizures and abnormal
brain waves …
food allergies and
gut problems”
due to the reduction and
impairment of specific cells within
the immune system called ‘Natural
Killer’ (NK) cells, seizures and
abnormal brain waves called
Subepileptiform Discharges, or
SEDs.3 Other features can be an
increased incidence of food
allergies and gut problems.
Nitric oxide in high levels has
also been shown to impact the
function of mitochondria, which
are organelles responsible for
the generation of energy within
the body.
Future directions:
putting the fire out
The time has come for the
scientific community and clinicians
to acknowledge that there is a
large proportion of children with a
diagnosis of ASD whose
symptoms and other co-existing
conditions could be greatly
improved by addressing the issue
Time to reTHINK autism
❝
“The gluten and casein free diet changed me within two weeks from a brain-dead, depressed,
anxious wreck into someone free of all of those struggles. Once I had that experience and I read
literature of well-funded studies telling me I was obviously mistaken when it was clearly so powerful for
me I knew something was seriously amiss with some of our institutions. The research I conducted
since has helped fuel a total life transformation. A year from now I expect to be able to totally
relinquish the label of ASD.” An adult with ASD
“The introduction of this intervention by our doctor (thanks in great part to information collected and
passed on by TA!) meant that in just five days our child showed a marked improvement in behavioural
responses, a reduction in OCD rituals and rigidity, reduction in oral defensiveness enabling new foods
to be introduced on their first attempt. This intervention has given the whole family a better quality of
life and more social opportunities to help develop our child, giving our child the opportunity to just be a
child like any other!” Parent of a child with ASD
“Our son has improved and been transformed from a non-verbal, non-toilet-trained, leaky gut child
into a healthy mainstream grade 4 pupil. All of this results from efforts in diet and education that we
learned from your charity and practitioners associated with it.” Parent of a child with ASD
of immune dysfunction. Dampening Neuro-
down this inflammatory cascade inflammation:
should be seen as a target in this Dr Ben Marlow “There is a pressing need for “Children with ASD with “Treatment began with a
cohort of children. is calling for all clinicians to approach increased inflammation are special vitamin/mineral
Other specific targets could be more scientific
ASD as a chronic health often those who exhibit the supplement, and additional
modulating microglial function, work on the
correcting the excitatory/inhibitory way this can condition requiring regular most severe behaviors... treatments were added
imbalance within the nervous affect some
follow-up and routine screening This immune activation is sequentially...There was a
system, or treating subepileptiform children with
discharges (SEDs). autism – and and treatment of medical and not helping these children. It significant improvement
The presence of SEDs is for it to lead psychiatric issues.” might not be causing autism – in nonverbal intellectual
widespread and may be a to action
Davignon et al., 2018 we don’t know that yet – ability in the treatment group
precursor to seizures. Studies now
show treating SEDs before they but it’s certainly making compared to the non-treatment
progress to seizures may mark a “For many children, the things worse.” group (+6.7 ± 11 IQ points
significant change in traditional
views held about epilepsy.3
symptoms of autism are Paul Ashwood, Ph.D. vs. −0.6 ± 11 IQ points, p =
Many other neuropsychiatric not permanent and can be 0.009) based on a blinded
diseases such as schizophrenia, improved dramatically with “Many individuals with ASD clinical assessment. Based
multiple sclerosis and Parkinson’s
have more funding and research the right treatment.” have symptoms associated on semi-blinded assessment,
motivation. This research involves Robert Naviaux MD, PhD with underlying medical the treatment group,
similar fields of chronic conditions, including compared to the non-treatment
neuroinflammation and microglial
activation. Autism deserves to have “Whether we like it or not, there seizures, sleep problems, group, had significantly
the same spotlight and scientific is a piling up of evidence gastrointestinal (GI) disorders, greater improvement in
interest, translating scientific work
that the immune system has psychiatric conditions, nutritional autism symptoms and
into action.
a major impact on brain deficiencies, and metabolic developmental age.”
function: The brain is not conditions; when left untreated, James et al., 2017
REFERENCES
1
Theoharides et al: ‘Atopic diseases and inflammation
isolated from the rest of the these conditions may not only
of the brain in the pathogenesis of autistic spectrum body,” compromise general health
disorders’, Translational Psychiatry, 2016 Jonathan Kipnis, Ph.D but also have clear effects on
2
Scott et al, 2017: ‘Clinical cues for autoimmunity and
neuroinflammation in patients with autistic regression’, behavior, development, and
DMCN 59 (9) 947-51 educational outcomes for
3
Wang et al: ‘Levetiracetam is associated with
individuals with ASD.”
decrease in subclinical epileptiform discharges and
improved cognitive functions in pediatric patients Lajonchere et al,. 2012
with autism spectrum disorder’, Neuropsychiatr Dis
Treat 13:2321-26, 2017
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