As I discussed in an earlier post, autism flare-ups occur regularly in the lives of many autistic children. The cause might be a pollen allergy, food allergy or indeed an illness that does not cause a fever.
That last part might sound odd,
but fever actually reduces autistic behaviours.
This has been noted and documented by many, but never conclusively
explained. Lots of parents have noticed
and one even created a blog about it, but they have not explained it.
To investigate the fever effect, you first need to understand
thermoregulation, the process by which the body sets and maintains its
temperature and the role played by of the HPA axis (hypothalamic-pituitary-adrenal axis). The simplified explanation is that the body initiates a fever as part of its defence mechanism to the threat that has
been detected, like an infection of some kind.
Certain hormones are released so as to raise and then maintain a steady higher
temperature; they include TRH, ACTH, AVP, PRL and TSH. It occurred to me that
if you could identify which hormone increase was behind the reduction in
autistic behaviours during fever, you would be on to something really
useful. This is something that is very poorly
covered in the literature and so it is very difficult to prove anything. My hunch is that TRH is the one and I am
looking into ways to prove it. I wrote
an early post all about TRH, which I believe, for other reasons could have
great therapeutic value in autism.
The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism
Back to flare ups …
Sickness involving
stress/inflammation, but without fever, makes autistic behaviours worse. Stress and inflammation have been shown in
research to make the Blood Brain Barrier (BBB) more permeable. In an earlier post we discovered that
histamine itself increases the permeability of the BBB.
If you want to read up on the BBB,
here is some heavy reading:-
The other observation that seems
not to get documented in the literature is the effect of a new cause of
stress/inflammation on any previously existing or dormant ones. This is very relevant in autism since part of
the brain is known to be in a near permanent state of inflammation/stress. So if a new site of inflammation/stress
elsewhere in the body will “re-ignite” other weak sites around the body
(including the brain) then we have a problem.
Just as we showed that pollen and food allergies sparked autism flare
ups, so can a viral infection.
Because there is no temperature,
you may hardly notice the virus. Most parents think their kids are only really sick
if they have a temperature.
These observations actually apply
to all of us. My son Monty, aged 10 with
ASD, currently has a virus that does not cause a fever. I know all about it, because I subsequently
caught it from him. Having caught it
myself, I see why it would affect Monty’s behaviour. It goes on far longer than a common cold, but
outwardly after a day sneezing and a runny nose there is little to notice. Since I am now focused on autism flare up and
comorbidities, I am taking a lot of notice.
I can see that in my own body sites of previous inflammation do indeed
flare up. Like many people, I occasionally
suffer from GERD, which you might know better as “heartburn”. This causes inflammation to the oesophagus
and when it occurs you can actually feel it, as I can while writing this.
Imagine you have a brain with
chronic neuroinflammation, even if you are taking steps to put out that fire
(NAC and statins) along comes a wave of inflammatory cytokines released
elsewhere in the body and they act to reignite the inflammation in the brain
again.
In healthy neurotypical people
the brain is better protected from such inflammatory cytokines due to a more
effective Blood Brain Barrier (BBB). In
autism there is plenty of evidence pointing to a more permeable BBB.
You cannot stop your child
getting pollen allergies, though you might well adjust diet to avoid food
allergies; but can you do anything to keep those pro-inflammatory cytokines out
of the brain?
We know for a fact that certain
substances weaken the BBB; we just need to find the neuro-protective ones that
can strengthen the BBB. Such substances
do indeed exist. A common issue than arises
is that what works in the test tube (in vitro) does not always work in humans
(in vivo) and also what works in rodents (the typical laboratory test subject)
may not apply to humans.
Other diseases linked to leaky BBB - Multiple
Sclerosis & Alzheimer’s
The best known disease long thought
to be caused by a breakdown in the BBB is multiple sclerosis. People with MS and those trying to help them
have a big interest in what might protect the BBB.
I found it interesting that
recent research shows that Alzheimer’s disease is also triggered by a failure
in the BBB.
Alzheimer's protein damages blood brain barrier
Alzheimer's disease: A breach in the blood–brain barrier
Alterations
in brain blood vessels in mice precede the neural dysfunction associated with
Alzheimer's disease. The finding highlights potential targets for drug
development.
Alzheimer’s disease (AD) is well
researched/funded since it is the leading cause of dementia. It is characterised by both oxidative stress
and neuroinflammation, as is autism.
Drugs developed for AD that target strengthening the BBB or reducing
stress/inflammation in the brain would be good targets to trial in autism.
Substances neuro-protective to the BBB.
If you look in the literature you
struggle to find much research on strengthening the BBB. Much more frequent reference is made to
“neuro-protective” ,which is something good but subtly different.
Mast cell stabilizers.
Mast cell stabilizer drugs
work to prevent allergy cells called mast cells from breaking open and
releasing chemicals that help cause inflammation.
Commonly used mast cell stabilizers
in medicine include the drugs Cromoglicic acid and Ketotifen. These drugs are used in treating
allergies and asthma. Both these drugs have been covered in earlier posts and
at least Ketotifen is used in autism. Some researchers suggest that
truly effective mast cell stabilizers for humans do not exist. It is suggested that mast cell
stabilizers would be highly protective of the BBB.
Lipoic Acid
It has been stated that Lipoic acid is protective of the BBB, also known as
Alpha lipoic acid and thioctacid; it is another antioxidant. I have also mentioned it previously in this
blog.
Thioctacid is prescribed by doctors to patients
with diabetic polyneuropathy in Germany and most East European countries. It not only reduces symptoms of neuropathy
but it also reduces the amount of insulin patients require. It is given both intravenously and
orally. I am told that oral
administration is effective, but research showed that IV has the strongest
effect.
In autism some people in the US
take advantage of its metal-chelating properties. All anti-oxidants have should have metal-chelating
properties, by the way.
Here is a study from the world of
Multiple Sclerosis, into the protective properties of Lipoic Acid.
Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity
In the following research NAC was
combined with Lipoic Acid to reverse memory impairment and oxidative stress in
the brain.
The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice
These
results support the hypothesis that oxidative stress can lead to cognitive
dysfunction and provide evidence for a therapeutic role for antioxidants
From Iran, I found a hypothesis
about lipoic acid reducing inflammation in autism.
Gold nanoparticles and lipoic acid as a novel anti-inflammatory treatment for autism, a hypothesis
Gold nanoparticles and lipoic acid as a novel anti-inflammatory treatment for autism, a hypothesis
Anti-oxidants as neuroprotectors
Anti-oxidants will indirectly
strengthen the BBB, since they reduce the oxidants that damage the BBB. Are all anti-oxidants equal? There is an argument that you should match
the anti-oxidant to the oxidant. The
most powerful anti-oxidant available seems to be NAC, and I am already using
it. My second choice would be
L-carnitine, since there has been at least one positive clinical trial in
autism.
It works in a quite different way to NAC and it also has an effect on the mitochondria. As you saw above, there is also a case to be made for alpha lipoic acid (ALA), as an antioxidant. In the research combinations of antioxidants have been trialled, just not for autism. In an ideal world, some research would be carried out comparing the effectiveness of different combinations of NAC, Carnitine and ALA.A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders
Interestingly as with lipoic
acid, L-carnitine improves insulin response in diabetics.
I found this Alzheimer’s research
interesting. It tested NAC, carnitine
and SAMe. SAMe is used in to treat many
neurological conditions, including ADHD, which I view as autism-lite. It is also used to treat seizures, a major
comorbidity of autism.
Effects ofdietary supplementation with N-acetyl cysteine, acetyl-L-carnitine andS-adenosyl methionine on cognitive performance and aggression in normal miceand mice expressing human ApoE4.
In addition
to cognitive impairment, behavioral changes such as aggressive behavior,
depression, and psychosis accompany Alzheimer's Disease. Such symptoms may
arise due to imbalances in neurotransmitters rather than overt
neurodegeneration. Herein, we demonstrate that combined administration of
N-acetyl cysteine (an antioxidant and glutathione precursor that protects
against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels,
protects mitochondria, and buffers A beta neurotoxicity), and
S-adenosylmethionine (which facilitates glutathione usage and maintains
acetylcholine levels) enhanced or maintain cognitive function, and attenuated
or prevented aggression, in mouse models of aging and neurodegeneration.
Enhancement of cognitive function was rapidly reversed upon withdrawal of the
formulation and restored following additional rounds supplementation.
Behavioral abnormalities correlated with a decline in acetylcholine, which was
also prevented by this nutriceutical combination, suggesting that
neurotransmitter imbalance may contribute to their manifestation. Treatment
with this nutriceutical combination was able to compensate for lack of dietary
folate and vitamin E, coupled with administration of dietary iron as a
pro-oxidant (which collectively increase homocysteine and oxidative damage to
brain tissue), indicating that it provided antioxidant neuroprotection.
Maintenance of neurotransmitter levels and prevention of oxidative damage
underscore the efficacy of a therapeutic approach that utilizes a combination
of neuroprotective agents.
Statins
Statins are claimed to increase
the integrity of the BBB. I am already
convinced of the benefit of Atorvastatin, for other reasons.
Flavonoids: luteolin, Quercetin, Rutin
Dr Theoharides from Tufts
University in Boston where he is Professor of Pharmacology, Internal Medicine
(Allergy) and Biochemistry is a proponent of flavonoids to stabilize mast
cells, He favours a mix of luteolin, Quercetin,
Rutin all mixed up in olive kernel oil.
He says it works far better than Ketotifen and cromolyn. His mixture is marketed under the
name Neuroprotek.
Mast stabilizers are claimed to
reduce BBB permeability, so as a consequence these flavonoids should help
I initially found it odd that
such a scientist was favouring natural extracts, so I thought I would see what other
neuro-protective extracts might be out there.
Naturally occurring neuro-protectants
The internet is full of natural
remedies and most have little supporting evidence. Here are two that I found interesting.
Blueberries
These are both very tasty,
available and remarkably good for you; nobody is exactly sure why. They seem to slow down cognitive decline in
older people, reduce neuroinflammation and promote cell survival.
Antioxidant and neuroprotective properties of blueberry polyphenols: a critical review
Over the
last 10 years an increasing scientific interest has developed about
polyphenols, which are very abundant in blueberries, as they have been seen to
produce favourable effects related to neuroprotection and linked to a possible
decrease of age-related cognitive and motor decline, as shown by the
improvement of such functions in animal models with a supplemented diet. Such
effects could not only be explained through a purely antioxidant action but
also through more complex mechanisms related to inflammation, genic expression,
and regulation of cell survival
Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.
Withania Somnifera, also known as Ashwagandha
On the surface, this ages old
Indian medical remedy looks interesting, not least because one study
showed it could reverse Alzheimer’s Disease. It is claimed to do many things, including protecting the BBB.
Withania somnifera reverses Alzheimer's disease pathology
Indeed it is an ingredient used
in some supplements used for autism and if you Google it, you will parents
recommending it.
Not being a regular to such types
of “medicine” I did some research and found that you should buy the actual root
rather than the ground up bits available in capsules. The logic being that they put the leftovers
in the capsules and that the capsules may give an overly concentrated dose, as
compared to the tea version.
With root you make a kind of
herbal tea. It is actually very easy and
quite inexpensive; indeed the root seems easier to find than the capsules. In keeping with my self-experimentation
approach, I brewed up a batch of Withania somnifera tea and gave it a try. Well there genuinely is an effect; you do
feel different, although I would not call it “better”. The problem is, as I learnt a couple of hours
later, that it can, and does, irritate the gastrointestinal tract. Maybe my brew was too strong or maybe I am
just sensitive to it. On WEBMD they list
the following side effects:-
ASHWAGANDHA Side Effects & Safety
Ashwagandha
is POSSIBLY SAFE when taken by mouth short-term. The long-term safety of
ashwagandha is not known. Large doses of ashwagandha might cause stomach upset, diarrhoea, and vomiting.
It’s not known whether it’s safe to apply ashwagandha directly to the skin.
It’s not known whether it’s safe to apply ashwagandha directly to the skin.
Special Precautions & Warnings:
Pregnancy and breast-feeding: Do not use ashwagandha if you are pregnant.
It is rated LIKELY UNSAFE during pregnancy. There is some evidence that
ashwagandha might cause miscarriages. Not enough is known about the use of
ashwagandha during breast-feeding. Stay on the safe side and avoid use.
Stomach ulcers: Ashwagandha can irritate the gastrointestinal (GI) tract. Don’t use ashwagandha if you have a stomach ulcer.
“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Ashwagandha might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using ashwagandha.
Surgery: Ashwagandha may slow down the central nervous system. Healthcare providers worry that anaesthesia and other medications during and after surgery might increase this effect. Stop taking ashwagandha at least 2 weeks before a scheduled surgery.
Stomach ulcers: Ashwagandha can irritate the gastrointestinal (GI) tract. Don’t use ashwagandha if you have a stomach ulcer.
“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Ashwagandha might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using ashwagandha.
Surgery: Ashwagandha may slow down the central nervous system. Healthcare providers worry that anaesthesia and other medications during and after surgery might increase this effect. Stop taking ashwagandha at least 2 weeks before a scheduled surgery.
Since Ashwagandha can make the immune system more active, it would seem unsuitable
for autism, which we have established in this blog is linked to an already
overactive immune system.
Conclusion
Finding a remedy to permeability
of the blood brain barrier (BBB), was never going to be simple, if it was, then
multiple sclerosis and Alzheimer’s disease would have already become curable. But, knowing what weakens the BBB does help
explain why autism flare-ups occur, and in turns this helps us to minimize
them.
I think I will stick with the
blueberries and steer clear of the Ashwagandha, at least until I have to worry
about Alzheimer’s. The L-carnitine is
getting a trial as a supplemental anti-oxidant and mitochondria protector, as
will Dr Theoharides’ somewhat expensive Neuroprotek. Alpha lipoic acid is now in third position in
my anti-oxidant league table and will be studied further. NAC remains in pole position as antioxidant proven to reduce autistic behaviours. The very inexpensive Ketotifen may have
capabilities above and beyond those accepted by Theoharides, as suggested by
the fact that it has the remarkable ability to prevent the onset of asthma in
the at risk group.
I wrote an earlier post on
flavonoids. These are good parts of
fruits that you usually miss out on in juices, since they are concentrated in
the skins. Indeed though olive oil contains
beneficial flavonoids, many remain in the stone/kernel in the centre, It was of interest to me that Theoharides
uses olive kernel oil rather than regular olive oil to bind his Neuroprotek
together. All berries seem to be
particularly good for you, including cranberries, blackberries, blueberries, billberries and
raspberries. I think these flavonoids are likely more about promoting your
general health than any autism breakthrough.