Showing posts with label Barnes. Show all posts
Showing posts with label Barnes. Show all posts

Saturday 31 August 2013

Asthma-Autism Hypothesis and Immunomodulatory Therapy for Autism

You may be aware that about a third of people with autism also have asthma; this is not a coincidence, just as the finding that autistic people have elevated cholesterol was not a coincidence. 

Since Monty, aged 10,  has both autism and asthma, I have had to become informed on both conditions.  Having now read the research on both autism and asthma, it is somewhat shocking that there are so  many parallels.  I would now go so far as to make my own hypothesis:-
The causes of Autism and Asthma are overlapping; so much so, that some drug treatments for the core symptoms of one may be effective in the other.
This may sound a strange, even bizarre proposition, but I will show that it is at worst plausible and at best proven.  Note that it was the observation that bumetanide was an effective treatment in neonatal non-convulsive seizures ,that led to the idea of trialling that drug on autistic children.  Many children with autism subsequently develop epilepsy or other forms of seizure.  So investigating the so-called comorbidities is not such a novel idea.
Drugs effective in both Asthma & Autism
·         NAC (N-acetyl cysteine) – reduces oxidative stress

·         Prednisone – powerful steroid for short term use to supress immune system

·         Statins – reduce neuroinflammation

·         Ketotifen – mast cell stabilizer and anti-histamine

In case you are not familiar with asthma, there are some remarkable similarities between asthma and autism, just take a look:-

·         Both affects boys much more than girls

·         Both involve neuroinflammation

·         Both are linked to defects in the auto-immune system

·         Exact cause of both is not known, but is seen as a combination of genetic and environmental factors

·         Both were thought of as a psychological disorders and were unsuccessfully treated as such

·         Both are usually lifelong conditions, though functional recovery is much more common with asthma than autism, often occurring after puberty with asthma

·         In recent decades there has been an “epidemic” increase in prevalence of both. 

Asthma is much more prevalent among those with autism the general population and is frequently cited as a comorbidity, along with epilepsy and GI disorders.
Left untreated, asthma can easily be fatal, so it has been well studied and numerous drugs have been specially developed.  I thought that perhaps there are insights for autism to be gained by looking at how asthma is treated;   indeed there are.

Asthma Prevalence

There is a lot of research into the prevalence of asthma.  After increasing for several decades, there are some reports of it plateauing or even declining.


It is generally accepted that asthma is a disease of the developed world and the apparently the English-speaking world in particular.

Asthma Statistics
The American Academy of Allergy Asthma & Immunology (AAAAI) has an eye-opening summary of asthma statistics showing:-

·         The prevalence of asthma in different countries varies widely, but the disparity is narrowing due to rising prevalence in low and middle income countries and plateauing in high income countries.

·         An estimated 300 million people worldwide suffer from asthma, with 250,000 annual deaths attributed to the disease.

·         It is estimated that the number of people with asthma will grow by more than 100 million by 2025.

·         Workplace conditions, such as exposure to fumes, gases or dust, are responsible for 11% of asthma cases worldwide.

·          About 70% of asthmatics also have allergies.

·         Approximately 250,000 people die prematurely each year from asthma. Almost all of these deaths are avoidable.

·         Occupational asthma contributes significantly to the global burden of asthma, since the condition accounts for approximately 15% of asthma amongst adults.

Asthma Treatment

To learn more about asthma and how it is treated the University of Maryland have a helpful summary, just click the link.
There are generally three lines of treatment.  The well-known first line of treatment is the “rescue” inhaler that children are seen with at school, this is to treat acute attacks.  These are bronchodilators, like Ventolin, that open the airways in moderate to severe attacks.

If acute attacks become frequent, then typically an anti-inflammatory steroid inhaler is prescribed.  Long-term control medications are essential to minimize long-term damage of the inflammatory response, to reduce the risk of serious exacerbations.  This is used daily in the hope of preventing future attacks.
In case of an acute attack that does not respond to the rescue inhaler, an oral corticosteroid can be given .  These are powerful drugs that because they are administered orally will affect the whole body;  the steroid inhaler substantially avoids this drawback.  The corticosteroid  works by deactivating the immune system.
There are many other therapies used by allergists, in particular the use mast cell stabilizers and anti-histamine drugs.

Ketotifen is mast cell stabilizer, which means it blocks mast cells from releasing histamine it is also an H1 antagonist, which means it blocks H1 histamine receptors.  It is primarily used as a long term treatment of asthma.  It will not stop an acute asthma attack, but it should reduce their frequency.  If given to high risk children, its use can avoid the initial onset of asthma.
Prevention of asthma by Ketotifenin infants with atopic dermatitis.

It is used in irritable bowel syndrome and it is by DAN doctors to treat GI problems in autism.  If have read about mast cells and Dr Theoharides, then you can see how mast cells may play a key role in autistic behaviour and as such Ketotifen could be a prime therapy.
Autism and the auto immune system
There is a substantial body of opinion that autism is itself a disease linked to the auto immune system, like asthma and indeed type 1 diabetes.  The over active immune system is destroying certain important body functions.

The logical conclusion would be to find a way to down rate the immune system so that the unwanted affects were minimized, without leaving the body open to attack.  This strategy is indeed followed in asthma therapy where the emergency treatment is oral corticosteroid Prednisone
If all this sounds familiar, it should do.  The hygiene hypothesis has also been used to  link asthma, autism and the overactive immune response. 

In the case of autism at least one therapy is also based on this approach.
There is the case of Stewart Johnson in America, who trawled through the research looking for ways to help his autistic son.  He became convinced that the immune system was the key and looked into ways to down rate it.  He came upon the idea of using the TSO parasitic worms.  These parasites live in pigs(?) and in order to preserve themselves they evolved a method of reducing the immune system of their host so that they would not be expelled.  Treatment with such worms has been tried with other conditions, such as Crohn’s disease.  Mr Johnson ordered some TSO from Germany and fed them to his son.  He found that initially there was no impact on his son’s autism, but when he increased the dose there was a marked reduction in autistic behaviours.

Every couple of weeks or so, he gave his son another dose of TSO.

A clinical trial is being carried out at the Albert Einstein medical school to test the effectiveness of the treatment.  Mr Johnson created a website to document his experiences.  
It appears that not all people with autism respond to TSO; perhaps this is not surprising, not all people with autism have asthma either.

Perhaps Mr Johnson should see if a mild dose of Prednisone has the same effect as the worms?

Prednisone & Autism
It turns out that some doctors have indeed been prescribing prednisone for autism.  Most are DAN doctors, but not all.

You will even see on autism forums that when kids were given prednisone for their asthma, they suddenly had a big improvement in their autism.

While extended use of steroids causes side effects, it seems some doctors used them to try to proactively reverse regressive autism and to get non-verbal kids to speak.  This would seem entirely logical.

Immunomodulatory Therapy in Autism

An truly excellent review paper of Immunotherapy in Autism has been written by Dr Michael Chez, a respected mainstream specialist from Sacramento.  He also seems to be endorsing the use of the prednisone steroid in autism therapy

 Here are two important paragraphs:-

Experience with EEG abnormalities and autistic regression cases that respond to steroids have been described in various case reports. Treatment was usually prescribed with daily prednisone doses of 2 mg/kg/day for 3 to 6 months. Limitations to therapy were usually Cushingoid side effects. As in other chronic conditions requiring steroids, pulse dosing was tried with steroids in the form of prednisone or prednisolone at 5 to 10 mg/kg twice per week. Long-term success with no dependence or minimal Cushingoid effects has been noted in several hundred patients treated in this manner.

In summary, among the current studies of immune targeted therapies, the most collective data on steroid effects on autism is probably the largest. Clear clinical improvements are consistent between different groups that had peer-reviewed assessments. In addition, all reported similar outcomes and side effects were made with the use of steroids. As in IVIG treatment, there has been no report of cure or elimination of all autism features. In the majority of cases, steroid effects did not permanently alter an autism diagnosis in these patients. Clinical concerns about steroid dependency and side effects, such as Cushingoid or long-term, well-known steroid effects have limited more randomized or controlled studies of steroid medications in autism. This is unfortunate, as there may be a potential for significant improvement from steroid treatment on cytokine and chronic immune dysregulation in autism.

Oxidative Stress, Nitrative Stress and Inflammation in Asthma
Much has been written about oxidative stress and inflammation in autism, well it turns out these are key issues in asthma.  In asthma, fortunately, they have been looked into very seriously and all is well documented.

Another superb paper, this time by Professor Peter Barnes, from Imperial College in London is:- 

Histone acetylation and deacetylation: importance in inflammatory lung diseases
 This paper should be read from cover to cover, it is full of interesting information.  For example cigarette smoking in asthma causes oxidative stress.  That stress continues even after the patient has given up smoking, so it is chronic.  To treat this oxidative stress, guess what? He uses NAC just like I using for oxidative stress in my son’s autism.

Also, oxidative Stress causes steroid resistance, so steroids that work in asthma do not work well in COPD.

Cytokines in asthma
Because asthma affects so many people and can be fatal, there is a considerable research effort and drug pipeline.
Cytokines play a key role in all inflammation.  The keys ones have been identified in both autism and asthma; the difference is that in asthma they are being studied in great detail.

Also several cytokine modulators are in various stages of development, but tested on asthma sufferers.

For the scientists among you, this subject is covered in depth by Professor Barnes, from Imperial College.

How Corticosteroids control inflammation
If you are tempted to make a trial of Prednisone, then you should be interested a read how such steroids control inflammation.  Here is an excellent paper that explains how corticosteroids control inflammation:-
Asthma and statins 
I have established that the anti-inflammatory properties of statins, already applied neuroscientists in other fields, are very helpful in treating autism.

Researchers are also looking to see whether these properties of statins can be helpful in treating asthma.  Here is a recent paper:-
The paper concludes -
The findings suggest beneficial effects of statins in asthma management.
 Yet again the same drug has a positive effect in both conditions.

If you have made it this far in my post, congratulations!
So far from asthma, the autism world has taken Prednisone, Ketotifen and NAC.  I suspect that as new anti-inflammatory drugs are developed for asthma, other little gems will become available.  Also new stronger anti-oxidants are likley to be developed for asthma, since they find NAC not powerful enough. 

Prednisone clearly has drawbacks, but in the case of a sudden regression in autism, it might well be a very smart short term intervention.  Perhaps also in kick-starting development where it has stalled/plateaued.
Quite remarkably, statins not only reduce autistic behaviours but also help control asthma.

I think I have proved my hypothesis
The causes of Autism and Asthma are overlapping, so much so, that some drug treatments for the core symptoms of one may be effective in the other.
Also, we learned from Professor Barnes that corticosteroids do not work well in the presence of oxidative stress.  In asthma he reduces this stress using NAC; I do the same in autism with NAC.  This means that if you are going to trial prednisone, it would be very wise to start with NAC first.  It also means that if your child has both autism and asthma, their inhaled steroid will work better if you  are also using both NAC and statins.   

In case you were wondering, prednisone, Ketotifen and statins are all off-patent and very cheap.  NAC is an OTC supplement and inexpensive if you buy it online.