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Sunday, 15 September 2013

Autism Flare-Ups & Leaky Blood Brain Barrier


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

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.

A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders

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.

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.

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.

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.




4 comments:

  1. Your proposed explanations for "autism flare-ups" have been particularly interesting to me, as my daughter's symptoms have always presented in "phases". These are more than the good days/bad days that you frequently hear about in autism, and they prevented us from getting a diagnosis for some time because our pediatrician dismissed my concerns by stating that autism doesn't come in phases. Approximately two-thirds to three-quarters of the time, my daughter presents with mild symptoms. People with knowledge of autism are able to identify her as someone on the spectrum, but the rest of the population generally views her as "quirky". However, she periodically goes through phases, usually lasting a couple of weeks but up to a couple of months, during which her symptoms are more pronounced. She becomes extremely spacey, even more socially withdrawn, her speech sometimes becomes less fluent and more odd, and her mood declines. We have never been able to reliably tie these phases to a specific biological and environmental event, and up to now, no one has been able to offer an explanation. Now I at least have some theories to test.

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    1. You will see later in my blog that I traced my son's flare up's to a mild pollen allergy and also to the inflammatory cytokine (IL-6) that results from allergy and when the roots of milk teeth dissolve. This has now been 90+% solved and we no longer have flare-ups, they can be anticipated, treated and so avoided.

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  2. i am an autistic person. high functioning. but i do get regressions in early spring and before winter. i am on NAC 1800 mg divided/ ranitidine 300mg / divaloproex 500mg/methyl b12 subcut/ methyl folate. i take magnesium, but it makes me very cool and unfocussed. i tried verapamil but it was also making me too relaxed. is there anything you can suggest to prevent regressions and improve brain fog.

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    1. The drug that seems to help the majority of Asperger's is baclofen, say 5mg three times a day. I would think that well worth a try. For flare-ups ibuprofen can really help some people. People with immune system issues do seem to respond to some probiotic bacteria, this dampens their immune response. Biogaia probiotics seem to help, but are not cheap. Simple to make a trial.

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