Adult-sized people with autism can cause property damage and much worse.
I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.
The most
common worry for parents of toddlers diagnosed with severe autism is their lack
of speech.
By the time
these children reach adulthood, the biggest worry for parents is often
aggression and self-injury. Often it is the mother who faces the worst episodes
of aggression, which is a really cruel turn of events.
Aggression
is usually not present in young children with autism, in some people it never
develops, but in others it later becomes established as a learned behavior and
then you are stuck with how to deal with it.
One of my
own therapy targets has long been to improve cognitive function; this can indeed be
achieved and then you can improve important daily living skills (adaptive function). Some
steps that you can take to improve cognition, and indeed speech, have a
downside in that they increase anxiety, which may lead to aggression. Calcium
Folinate (Leucovorin) does cause aggression in a significant minority of
people. I think that low dose
Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but
it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases
alertness, which is a good thing, but too much alertness will make you anxious.
When dealing
with a full sized adult, which is more important, increased cognition/speech or
avoiding explosive aggression?
Clearly
there is a need for a compromise.
In adults
with severe autism, living at home, entirely extinguishing aggressive behavior
looks like the number one treatment goal.
For children
in mainstream school, following the regular curriculum, cognitive function has
to be a top priority. Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.
It looks
like you can potentially have the best of both worlds - increased IQ and
adaptive function, but without aggressive behavior. That is my own experience,
but it was not simple.
Pioglitazone
has been covered quite extensively in this blog and it is again featuring in
the research. Pioglitazone is an interesting old drug used to treat people with
type 2 diabetes; the phase 2 trial for autism has been completed. I doubt there will be a phase 3 trial due to
the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the
pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine
IL-10.
We have seen
in early posts how important is IL-6 and that it plays a key role in both
allergy and even how milk teeth roots “dissolve” and then permanent teeth
erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging.
IL-6, either
directly or indirectly, seems to negatively affect behavior.
PPAR gamma
In earlier posts there was a lot about
the various PPARs. These are used in medicine as targets to treat conditions
like high cholesterol and type 2 diabetes.
Resveratrol and Pterostilbene are the OTC supplements that some
readers are using. Sytrinol is another such supplement, but its cognitive
benefit unfortunately just lasts a few days.
Here is a relatively recent paper on the subject, for those seeking the details.
Nuclear Peroxisome
Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol
for Autism Spectrum Disorder
Or just look up the old posts in this blog:-
https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3
PPARs are
rather complicated, but do seem to be very relevant. For example, the master regulator of
mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR
gamma. If you have mitochondrial dysfunction that included a reduced number of
mitochondria, you might want to make more mitochondria. A PPAR gamma agonist
might be beneficial.
Dysregulation of PGC-1 alpha is
associated with neurodegenerative and metabolic
disorders including Parkinson's, Alzheimer's and Huntington's.
Outside this blog, there is some interest in PGC-1 alpha
and autism, particularly in connection with oxidative stress and mitochondrial
dysfunction.
“In conclusion, we demonstrated mitochondrial
oxidative stress may affect a significant subgroup of ASD children and that the
SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”
Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder
It does look
like PPARs can be targeted and provide a benefit for at least some types of
autism. My choice is Pioglitazone.
Dumber in the Summer
In parallel
with summertime raging comes the phenomenon I called “Dumber in the Summer”,
where cognitive function regresses.
Monty’s
assistant told me recently there is no “Dumber in the Summer” this year, and I
opened my medicine cupboard and explained why this is indeed the case.
At least in
our case, when you resolve summertime raging, you also protect against cognitive
regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.
Pioglitazone Side effects
In the stage
2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found
to be safe and well tolerated.
As a
summertime add-on therapy it appears very well tolerated.
In adults
with type 2 diabetes, who will tend to be overweight and not so healthy, there
are common side effects. At one point,
it was thought that there was an association between this drug and bladder
cancer. Now this is thought not to be the case.
For adults
with severe untreated autism, who are aggressive and self-injure, these behaviors
very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If
Pioglitazone can help control these behaviors, some side effects are likely a
price worth paying.
Conclusion
Pioglitazone,
by the standards of autism drugs, has plenty of evidence in the literature,
regarding both mouse models and humans, to support an n=1 trial. It addresses neuro-inflammation, one key
feature of autism and it has beneficial effects on mitochondria.
Pioglitazone abolishes autistic-like behaviors via
the IL-6 pathway
In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects
pioglitazone treatment inhibits the
secretion of proinflammatory factors, such as nitric oxide and IL-6, and
enhances the levels of the secretion of anti-inflammatory factors IL-4 and
IL-10. Therefore, considering the results of Qiu and Li and our present
findings, pioglitazone acted to benefit autistic-like behaviors possibly via
the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which
inhibited the neuroinflammatory response.
I think for
people whose child with autism has a behavioural or cognitive regression in
summer, there is good reason to expect a benefit. They very likely have allergies or other autoimmune conditions.
For people
who deal with aggression and self-injury in a person who responds partially,
but not 100%, to Verapamil, they may find that Pioglitazone helps to complete
their anti-aggression therapy.
Our doctor
reader Agnieszka did her best to collect case studies of people with autism responsive
to Verapamil, but not enough parents wanted to participate.
Based on the
comments section in this blog, it would look like our reader George in Romania
has a son whose son’s aggression is reduced by Verapamil. If some aggression persists in summer, I
think there is a very good chance that Pioglitazone will help reduce it. George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.
Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute). There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.
The research
proposes Pioglitazone as a year round therapy for idiopathic autism. In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a
summertime add-on therapy. We used it last summer and now again this summer.
People with
a diagnosis of mitochondrial disease, who also present with lethargy, might be
another target group because of PGC-1 alpha.
