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Wednesday, 28 August 2013

Potassium may play an important role in Autistic Behaviours

This is not the kind of post that I expected to be writing.  How can the effect of something so simple as a mineral, not have been noticed by others and researched in depth?

Potassium (K+),  is one of several electrolytes that occur in humans, the others being sodium(Na+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl), hydrogen phosphate (HPO42−), and hydrogen carbonate (HCO3)

Electrolyte balance or homeostasis is regulated by specific hormones.  These electrolytes are used to control many aspects of your body.  The concentration of each electrolyte varies across the boundary of each cell.  Electrolytes pass through the cell wall/membrane through so called ion channels.  These are like special valves that open and close based on particular pre-programmed circumstances.  When these ion channels malfunction, often due to a genetic fault, disease occurs.  Ion channel diseases have a special name - channelopathies.  This is still an emerging area of science.

In autism the brain has developed in an unusual way and although it is thankfully not a degenerative disease, the biological equilibrium it has evolved to is not the one originally intended.  There are both channelopathies and hormonal irregularities; indeed the two are interrelated.

Many hormones are interrelated and have multiple functions and therefore a change in one may have a cascading effect on others.  The same applies to the electrolytes, for example a deficiency in magnesium will trigger a deficiency in potassium.

Choride (Cl-)

I started my blog when I read about a successful clinical trial that set out to prove whether an imbalance in chloride between the extra/intra cellular fluid could cause one of the brain’s main neurotransmitters (GABA) to malfunction.  A clever Frenchman called Ben-Ari, had been researching neonatal seizures and proposed to trial the drug Bumetanide.    Bumetanide is known to block the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing.  Do not be put off if this does not make sense to you.

The trial showed the positive effect on autistic behaviours of this long established and inexpensive drug.
 
A randomised controlled trial of bumetanide in the treatment of autism inchildren


Potassium (K+)

Not long after making a trial of bumetanide on Monty, then aged 9 years, I started this blog and my own research.  I soon came across a condition called Hypokalemic Sensory Overstimulation.  In this condition, the subject becomes overwhelmed by his senses of sound, light, smell etc.  After taking oral potassium, the symptoms disappear within 20 minutes.  It is claimed that this is also a characteristic of ADHD (attention deficit hyperactivity disorder).  Well sensory overload is pretty common in autism, and, as I have learnt, ADHD is really just a light case of autism.

There is almost no research into this condition, which is odd since it is linked to the very common ADHD condition.  The paper below  was only ever cited 3 times in other research, and only once in English.

I then did my own experiment using a small dose of K+  supplement (equivalent to one banana) to see if by any chance I could see a reduction in sensory overload.  I tested both my sons, and only in the ASD son did the potassium have any impact; and it was a marked impact.  I wrote this up in a blog post.

I kept potassium and channelopathy on my list of things to research and left it at that.

 
Ion Channels & Ion Channel Diseases (Channelopathies)

Ion channels are an emerging area of science all about how signals are sent throughout your body to control it.  It gets very complicated and is still far from fully understood.  So you may want to skip this part.

So far 300 types of ion channel have been identified.  The main types are:-

·         Chloride (Cl-) channels

·         Potassium channels

·         Sodium channels

·         Calcium channels

·         Proton channels

·         Non-selective cation channels

 Then there are differing ways in which the channels open and close such as:-

·         Voltage gated

·         Ligand gated

And odd ones like
 
·         Light gated

·         Temperature gated

·         Calcium activated potassium channels

When the ion channel and/or its gating does not work properly then a disease called a channelopathy may result.  Examples of well know disease are cystic fibrosis, various types of epilepsy and ataxia.

 
Puberty and Epilepsy  

As a result of the changes in hormones triggered by puberty it is therefore not surprising that around this time other changes occur in the body.  In some children with asthma, their symptoms become more mild or even appear to disappear.  In autism the hormonal changes often trigger an improvement, but may be the trigger of the onset of epilepsy.  When you consider the importance of all these electrolyte levels, and the variation of each across one each cell boundary in the body and how this is intertwined with how the neurotransmitters function, it is not surprising that a shift in Homeostatis occurs.

That shift in Homeostatis could be reflected in a mellowing of autistic characteristics.  But if you can now make some small adjustments in these levels via diet and mild drugs, why not investigate it?  You will not be able to achieve perfection, but you might be able to shift from one stable equilibrium to another one, with milder autism and no troubling side effects.

This would also imply that those children developing epilepsy during puberty might be able to treat it using the diuretic bumetanide.  By blocking the NKCC1 transporter, the level of Cl- is blocked and GABA becomes more inhibitory and thus the risk of an epileptic attack might be reduced, or perhaps eliminated.  This is surely worth some research?

 
K+ ion channel disease – Epilepsy & Autism

There is existing research linking potassium ion channels to both epilepsy and autism





ADHD & Ritalin

I read some research about a stimulant drug used to calm children with ADHD.  It seemed odd to use a stimulant to produce calm.  Here again potassium (K+) and sodium (Na+) levels are at the centre of argument.
 
Then I noted a very recent article (July 2013) reporting a study of Ritalin on children with ASD and/or ADHD.

In the world of alternative medicine there is talk of Ritalin helping in ADHD due to it altering the level of potassium:-


This inverted ratio of Na/K may be helpful in explaining why a stimulant drug like Ritalin would have a calming effect on hyperactive children and adolescents. Ritalin does, indeed, have a stimulating effect on these children, but its stimulating mechanism is neuroendocrine and biochemical, not behavioural. More specifically, its stimulating effect is on the adrenal glands and the retention of sodium in the tissues relative to potassium. It is critical for normal cellular functioning that sodium and potassium (Na and K) be in balance for the optimal operation of the Na/K pump at the cellular level. It is also critical for efficient neurotransmissions that there be a proper balance between sodium and potassium (Na and K) for neuronal conductance.

 
Measuring electrolyte (Ka, Na, Mg, Cl etc.) levels

I would have expected that it was easy to check the level of electrolytes and indeed to check the levels in blood is very easy.  I have done this and all was normal.  When you read further in the literature, you will realize that the level of electrolytes at the extra/intra cellular level is not so easy to measure.  A whole business has been created by people analyzing hair samples for clues as to the balance or imbalance of various minerals in the body.

Hair analysis is used in forensic toxicology and  drug testing to detect the presence of various chemicals in the body.  The method has been adopted by the complementary and alternative medicine (CAM) community to try to predict food intolerance and dietary deficiency.  It is viewed by the scientific community that much of the CAM use of the technology is not valid and potentially fraudulent,

So there is no certain way of checking the cellular level of electrolytes.  You can only measure what you eat and you can measure what is in your blood.


Other suspected electrolyte imbalances in Autism

There have been several studies regarding Magnesium and autism, but the peer reviews of these studies are highly critical of the methodologies used and conclude that nothing has been proven.

Vitamin B6-magnesium treatment for autism: the current status of the research

Calcium has also been put forward as an intervention.  One mother spent a great deal of time collecting supporting information in her paper below.


 
DAN doctors and Spironolactone

Having come across a “bible” of therapies proposed by DAN (Defeat Autism Now) doctors I noted the use of a potassium-sparing diuretic called Spironolactone.  For a change, there is actually a published paper setting out their case for this drug.  The case made has nothing to do with potassium, even though the intended purpose of the drug is to raise potassium levels.

Bradstreet et al wrote a paper on this in 2006.  It has been cited only 7 times up until 2013 and two of these times by the authors themselves.  This tells you that other researchers were either skeptical or just disinterested.
 


Potassium Supplements
 
There are many hundreds of types of mineral and vitamin supplements; these days many contain far more than recommended daily amount (RDA).  This is not the case with potassium.  Even though the RDA for adults is 3,500 – 4,700 mg, in the US supplements by law may not contain more than 100 mg of potassium.  In Europe potassium supplements with 500mg are common.

A typical banana contains over 400mg of potassium, which would seem to make a 100mg supplement pretty pointless.

In the US it seems that there is a perceived fear of potassium poisoning.  It is indeed the home of the lethal injection.  Potassium chloride in a very high dose will stop your heart.

You will even find people debating whether you can poison yourself with bananasIt would seem that while you can reduce your high blood pressure with bananas, it does not kill you.  One person was even eating 30 bananas a day!!

The fear of potassium though remains and it is all over the American internet.
 
But, in the UK, the National Health Service advises:-

You should be able to get all the potassium you need by eating a varied and balanced diet. If you take potassium supplements, do not take too much because this could be harmful.

Taking 3,700mg or less of potassium supplements a day is unlikely to cause any harm.

That amount of potassium would require 37 American supplement tablets each and every day!

In reality, a concentrated dose of potassium may indeed upset your stomach and this is why it is better to get it from a healthy mix of fruit and vegetables.  The average American apparently consumes about 1,000mg of potassium per day.

Internet Chatter

If, like me, you use Google to see what other people are up to, you will come across talk of potassium and autism.  The discussions in forums never get far, because someone starts talking about lethal injections, and then fear prevails.

Sodium Potassium Pump  (Na+/K+-ATPase)

The sodium-potassium pump was discovered in the 1957 by a Danish Scientist, who later went on to win a Nobel prize for his discovery in 1997.  Its main application has been in the understanding and treatment of heart disease, but it is now thought to be directly involved in a critical part of the brain already known to be damaged in autism. 


As I have already mentioned in my blog, the comorbidities of autism (asthma, high cholesterol etc.) mean that much of the work has already been done by others.

Those many people with hypertension (high blood pressure) are suffering due the way the sodium potassium pump works.  They eat too much sodium and far too little potassium and the end result is high blood pressure.

An author and researcher, Dr Richard Moore, has a simple explanation on his website and a link to his book showing how diet can indeed control your blood pressure.  If you check the book on Amazon you will see many very favourable comments from people who have indeed lowered their blood pressure with bananas.

His book is called: The High Blood Pressure Solution: A Scientifically Proven Program for Preventing Strokes and Heart Disease.

 
Sodium Potassium Pump and Autism

I was looking for evidence (other than my own) that potassium levels affect the autistic brain.  Potassium plays a key role in how most ion channels function, but I was looking for something really tangible.  I think I have found it.

In my earlier posts I introduced readers to a part of the cerebellum called the Purkinje Cell Layer (PCL).  This is a critical part of the brain and unfortunately in autism, half of the cells are dead and this then manifests itself in altered brain functioning and hence behaviour.  

As recently as 2012, scientists in England showed that the neurons in the PCL are controlled by the Sodium Potassium Pump.


The paper’s summary concludes “We propose that Na+/K+ pump activity controls the intrinsic firing mode of cerebellar Purkinje cells”
 
Our new friend Dr Richard Moore puts it very simply:-

For the Na-K-pump to operate normally, the diet must have a ratio of potassium to sodium ratio (the K/Na ratio, or "K Factor") that is above a threshold that is somewhere between 2 and 4. Our ancestors ate a diet with a K/Na ratio ranging between 12 and 16. However, the average American white eats a diet with a K/Na ratio of less than 1 - about 0.6 - and the average American black eats a diet with an average K/Na ratio of about only 0.38! Obviously, the American diet generally has a very deficient K/Na ratio.

A low dietary K/Na ratio causes a low K/Na ratio in each and every cell in your body. This has been known since the end of World War II when whole body radio-active counters were used to determine the amount of potassium (a small part of which is naturally radioactive) in the human body. Almost universally, to their surprise, it was found that people with hypertension have a deficient amount of potassium in their body.

By 1983, several scientists including myself had worked out the vital role of the Na-K-pump in cell function to the point where our understanding predicted that other dysfunctions, or disease states, of the body's cells would occur. Not until the mid 1990's did anyone bother to look for these other conditions. Since then, it has become well established that in the U.S., our typical diet with its low K/Na ratio is the cause of:

About 95% of the cases of high blood pressure.
At least 90% of strokes whether or not high blood pressure is involved.
Much of the osteoporosis and kidney stones.
An increased likelihood of h-pylori infection with resulting stomach ulcer and stomach cancer.
An increase in the severity of asthma.
An increased likelihood of mental decline with aging.

In addition, there is some evidence that this low K/Na ratio in the American diet contributes to insulin resistance, to obesity, and to adult diabetes

  
So since in autism a critical part of the brain is already damaged and has been shown to be subject to oxidative attack and neuroinflammation, it is not surprising that it is particularly susceptible to further interference.  As a result whereas, in a typical childlike Ted, aged 13 with an aversion to fruit and vegetables, can function perfectly well and additional potassium made no measurable difference to his sensory behaviour, the same was not true of Monty, aged 10 with ASD, and with a diet full of fruits and vegetables.  The additional potassium actually changed his sensory behavoiur.  Now I have a plausible explanation

Electrolytes etc.

 If you really want to go into the biology and understand intercellular/extra cellular fluid, role of hormones vasopressin and aldosterone and all about sodium and potassium balance, then take 10 minutes to carefully read the following link:-
 

 
Autism and Heart Disease, Diabetes and Cancer

On this blog I have already shown that several strategies for cardiac health also help autism.  Since in autism there is proven high cholesterol and high neuroinflammation and most likely also hypertension, it would make great sense reduce these risks regardless of the fact that those steps may likely also reduce autistic behaviours and improve functioning.

I made a study into omega 3 and conclude “eat fish”, it is cheaper than omega 3 oil, and it definitely will help cardiac health, but probably will do little to nothing for the autism.


A high potassium diet, particularly if it is based on food rather than supplements, will protect your child from heart disease later in life.  He/she is already in an at risk group.

 So there are two very good reasons increase potassium and reduce sodium in his/her diet.  If you are not aware of the health issues surrounding autism, take a look at this:-


Without intervention, adults with autism spectrum disorder appear to be at significant risk for developing diabetes, coronary heart disease, and cancer by midlife.

For a general discussion on these and other health issues, there is a well-researched paper called:
 

  
Conclusion

In the case of Monty, aged 10 with ASD, incremental potassium in diet and via an over the counter potassium supplement (that also contains magnesium and B vitamins) has a positive effect on autistic behaviours.  The total daily potassium ingested (1g as supplement, plus banana, orange juice, potato etc.) is still probably below the adult RDA of 3.5g, but much higher than most 10 year olds with ASD.

There is a scientific logic to show why potassium might produce beneficial effects due to better functioning of the sodium-potassium pump, particularly in the Purkinje cell layer of the brain, which is a known to be damaged in ASD.

It may also be that the magnesium, that is also present in the potassium supplement, is having a beneficial effect.  This could easily be investigated by some further research, should anyone be so inclined.

In any case, a relatively high potassium diet is well established to be very healthy and, along with strategies to lower cholesterol, will promote a healthy heart.  The literature shows that autistic people have elevated cardiac risk and so already have a good reason to be following this kind of diet;  I have just added another good reason.

 

Thursday, 22 August 2013

Autism - A Neurodevelopmental Journey from Genes to Behaviour

I am getting a little behind in writing up the findings of my research; I have several posts in preparation.  Here today is a link for those scientists among you:-

Autism - A Neurodevelopmental Journey from Genes to Behaviour


This is a free e-book with 24 scientific papers.  You can download the entire book or just individual chapters.  The book is from 2011, so it is quite up to date.

In the meantime I am looking at ion channels and transporters; and a new term to me "sensory gating".  This is all connected to an earlier observation I have noted about the effect of potassium (K+) on behaviour and a paper I found about the use of spironolactone (a potassium-sparing diuretic) as a therapy in autism.  The paper claims the benefits are do to a secondary anti-inflammatory effect of the drug; I am not so sure they got their science right.  This all goes back to the role of the neurotransmitter GABA, its role in how the brain develops as it grows and then how it functions thereafter; this is all affected by transporters NKCC1 and KCC2.


Asthma - Autism Hypothesis
 

Friday, 16 August 2013

Autism flare ups and comorbidities



Anyone familiar with autism will know that it seems to go in waves of good and not so good.  Generally this gets accepted as just the way it has to be.

I chanced upon an unusual paper recently, it was all about comorbidities in autism.  As you may know, comorbidities are other diseases that seem to frequently occur alongside autism.  The main point of the paper and the charity behind it, is that comorbidities should be diagnosed and treated, rather than ignored, just because the person has ASD.

The paper was produced by Treating Autism, a UK charity that follows a biomedical approach similar to the American DAN organisation.  They have a link to a very comprehensive summary of what DAN actually recommends. The DAN paper is by a Dr Jepson.

The idea of treating the comorbidities as they crop up, seems entirely logical to me; but it seems to miss the bigger issue of what the comorbidity might help tell us about the autism itself.

Their list of comorbidities to keep a look at for:-

·         Allergic disorders in ASD: effects of allergies on behaviour, cognition and anxiety. Food and inhalant allergies, allergic rhinitis.
·         Autoimmunity in ASD. 
·         Autonomic nervous system dysfunction (dysautonomia) in ASD
·         Seizure disorders in ASD

Allergic rhinitis was of course the one that caught my eye.  This is the medical name for the itchy red eyes and runny nose caused by summertime pollen and pollution.  This reinforced by own observation that histamine can have a major negative impact on behaviour in ASD.  This was presented in my recent posts on histamine and antihistamine drugs.

Also of note to me was the observation that atopic dermatitis (itchy skin) and asthma are comorbidities.  Asthma was one of the comorbidities I choose to investigate myself.  An interesting observation I came across was that atopic dermatitis is actually a good predictor of developing asthma and, in fact, that by effectively treating it with a particular drug (ketotifen), you can actually halt the progression to asthma.  There is a study investigating exactly this issue; one half of the trial were itchy toddlers with a placebo and the other itchy toddlers had ketotifen.  A year later the group with ketotifen had a far lower percentage that had developed asthma than the placebo group.  I call that interesting but how many family doctors, let alone parents, are aware of that?



Also, another interesting paper all about childhood allergies is called The Allergic March.


Conclusion

Autism flare ups seem to be common and a little investigation may well lead to a better understanding of your child’s type of autism.  By recording data on bad behaviours, as in an ABA programme, or my preference, by just be keeping a watchful eye, you may well identify the cause and then find a remedy.  It might be a wobbly tooth, or it might be something more subtle like histamine.

I also believe that a detailed understanding of the comorbidities will ultimately lead to some effective therapies for autism itself.  Since it is clear that different people have different types of autism, knowing what triggers your child's flare ups may well help define what type of autism he/she has and therefore what therapies may or may not prove effective.


Saturday, 27 July 2013

More on anti-histamines in Autism and introducing H4

In my previous posts on histamine, you would have read that I found that Claritin appeared to reduce autistic behaviours.  Once I had got to the bottom of what was going on, I found out that histamine has a long record of stimulating challenging behaviour in all children.  It also became clear that typical anti-histamines (H1 antagonists) are all slightly different and one may be effective in one person and ineffective in another.  Each one tends to have additional secondary effects.

It now appears that the secondary effect of certain H1 antagonists may actually be more important than the primary intended effect of reducing itchy eyes and runny noses.
There are three generations of H1 drugs.  The fastest working and most potent is still the first generation, the second generation are non-drowsy derivatives of the first generation.  The third generation are the active metabolite of the second generation.  As you will see in today’s central paper, the third generation probably does not warrant the tittle.  For many users they may be just expensive versions of the second generation drug.

The excellent paper  New anti histamines: a critical view is from Brazil, but it has an English version.  It is highly readable.  It tells of the specific secondary effects of certain second generation  H1 antagonists.   (She omits to mention the secondary effects of the first generation. Some people say Ketotifen is 1st generation and other people say 2nd generation, anyway it appears not to be sold in Brazil).  I suggest you read the paper, if you have a child with an ASD. The key section is this:

Antiallergic/anti-inflammatory effects

Originally, studies of the relative potencies of H1 antihistamines were based on the capacity of different compounds to competitively inhibit the H1 receptor binding of histamine, i.e. on their blocking effect on the receptor.8 Nevertheless, it has already been known for some time that, in addition to acting on H1 receptors, many H1 antihistamines, at appropriate doses, are capable of inhibiting not only the release of histamine by mast cells,9,10 but also mast cell activation itself.11 Some of them can even regulate the expression and/or release of cytokines, chemokines, adhesion molecules and inflammatory mediators.5,8

Therefore, the antiallergic properties of H1 antihistamines are generally a reflection of their capacity to affect mast cell and basophil activity, inhibiting the release of preformed mediators such as histamine, tryptase, leukotrienes and others.8 Several second-generation H1 antihistamines have demonstrated antiallergic properties, irrespective of their interaction with the H1 receptor.5,8

Chronic allergic inflammation resulting from the late-phase reaction, exhibits components that are similar to other forms of inflammation, including chemotaxis of inflammatory cells followed by activation and proliferation, with subsequent production and release of many chemical mediators. Among cells involved in allergic inflammation are: antigen-presenting cells (for example, macrophages), mast cells, basophils, T lymphocytes, epithelial/endothelial cells and eosinophils - major effectors of chronic inflammation. Cytokines, chemokines, inflammatory mediators and adhesion molecules also contribute to this process which ultimately leads to dysfunction of the affected organ.8

Many second-generation H1 antihistamines (particularly cetirizine) are capable of inhibiting the influx of eosinophils to the site of allergen challenge in sensitized individuals.5,8 Studies have demonstrated that some of them can also alter adhesion molecules expression on epithelium and eosinophils, and reduce in vitro survival of eosinophils. Finally, some second-generation H1 antihistamines are capable, in vitro and in vivo, of altering the production of inflammatory cytokines (for example, TNF-a, IL-1b and IL-6) and the Th1/Th2 balance regulation cytokines (for example, IL-4 and IL-13).5,8

Therefore, it is well established that, in addition to their effects on H1 receptors, many second-generation H1 antihistamines also manifest antiallergic and anti-inflammatory properties which differ depending upon their molecules and the experiments used for their evaluation.5

 
From my own experience, I have already replaced Claritine (Loratadine) with Cetirizine to see if it will remain active for longer.  Rather than working for 24 hours, Claritine is working for about 5 hours.
I thought Cetirizine might remain active for longer, but the main difference seems to be in how it works, rather than for how long it works.  With Cetirizine autistic behaviour has pretty much returned to where it was at the start of summer, before the allergy season.  With Claritine things improved greatly, but not all the way back to "normal".

Reading the paper and one of its references -
makes me think that the expensive new  version of Cetirizine, called Levocetirizine, might be even better.  It happens to be available locally, but it is seven times as expensive.

The Brazilian paper does rather contradict some of what Dr Theoharides says about stabilizing mast cells.  You can choose who you think has got it right.  The good thing is that both Dr Inês Cristina Camelo-Nunes and Dr Theoharides seem very serious, objective people, which cannot be said about all the people offering their advice on the internet.

In fact, I found an interesting paper on the anti-inflammatory effects of the new version of Claritin, called Aerius/Clarinex (Desloratadine).


It really seems to be the case of trying several antihistamines and selecting the one that works best for you.
 
The H4 Histamine Receptor and Inflammation
You may recall that there is a fourth histamine receptor, naturally called H4.

It was only recently discovered, as you might guess from the short entry in Wikipedia.  It seems that the H4 receptor plays a substantial role in the inflammatory response.  It is seen as playing a key role in conditions ranging from arthritis to asthma.
Here is a full text paper for those interested in the science:-

The role of histamine H4 receptor in immune and inflammatory disorders

 Here is a graphic from that paper:-

I wonder if that H4 is a ticking bomb in autism as well ?

Those more peaceful people among you will be less aware of what C4 is, and hence the sticks of H4 dynamite.