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Monday 4 August 2014

Allergies, Autism and Cognitive Impairment

Previous posts showed how pollen allergies can lead to summertime flare-ups in autism; most noticeable are violent/aggressive behaviours, but there is actually much more going on.

I established that Verapamil, the calcium channel blocker, and surprisingly also a mast cell stabilizer, can very effectively extinguish the aggression, but without really solving the usual allergy symptoms like itchy eyes.  As a result, you need to use a convention anti-allergy treatment as well.


Asthma/Pollen Hot Spots

Any asthma suffer will be able to tell you about the places that make them feel worse and the places that places that reduce their symptoms.  It seems that pine forests high in the mountains and on certain coastlines are best.

Forested areas around cities are not good for asthma, Berlin being an example. So you can easily check if you live in an asthma hot spot, or in a better place.


Cognitive Impairment

We just spent two weeks under the olive trees beside the sea in Greece, which I would classify as a low pollen location.  Having returned home to a big city and a house directly opposite a forest, we could see the effect of an asthma/pollen hot spot.

Monty, aged 11 with ASD, mild pollen allergy and mild asthma, did change his behaviour almost immediately.

The Verapamil does continue to block aggressive behaviour, but what changed was an immediate return of mild atopic dermatitis (red patches behind knees) and what Monty’s brother Ted, aged 14, described as Monty became “more stupid”.  It is not a nice way to describe it, but when you look closely, it is there.  The allergy has effectively lowered his cognitive function.  It is very easy to check, just ask some simple maths questions or memory questions (what did you have for breakfast?).  It is as if he is very mildly intoxicated (drunk), he is not staggering around, but he is not as sharp as he was in Greece, or at home in the spring.

Faced with an aggressive child, the last thing you would bother about is how good he is at mental maths, and so you would probably never notice it.  But having solved the aggression we are left with the observation that the allergy causes some temporary cognitive impairment.  I say temporary, because if you take away the allergens, everything improves and returns to where it was.


What is going on?

We know that allergens cause mast cell degranulation, which releases histamine, IL-6, and other pro-inflammatory substances in a chain reaction.  We know that these cross the BBB (blood brain barrier) where there are several types of histamine receptor.  The body has at least 4 types: - H1, H2, H3 and H4, and maybe more not yet identified.

Typical anti-histamines only block H1, and the newer ones are specifically designed not to cross the BBB, so as not to make you drowsy.  We later discovered that most H1 anti-histamines have moderate mast cell stabilizing properties, meaning they do reduce the release of histamine itself.

Calcium channel signaling is known to be disturbed in autism and there is excess physical calcium found in the autistic brain.  This did suggest that modifying calcium channel behaviour might be of benefit.  A known genetic variation in autism does affect the L-type calcium channels.  This suggested that blocking the L-channels might be helpful.  This was shown to be true in Timothy syndrome and I showed it to be true in Monty.

Other research has shown that Verapamil is an effective mast cell stabilizer, which did come as a surprise.

Now we come back to the effect of the allergy.  If untreated, it will “dumb down” the child and also lead to extreme behaviours like aggression, but also even odd physical tics, like moving the head forwards and backwards like a pigeon.

Perhaps there is a two stage process going on, which ultimately leads to the aberrant signaling of the L-type calcium channels and aggression.  Or is it just a progression from mild to severe?

Is it a coincidence that a calcium channel blocker can stabilize mast cells?  I think it unlikely.


Autism as an Allergy of the Brain

The idea put forward by Professor Theoharides, that autism is, at least in part, an allergy of the brain, looks more and more valid.  It was the subject of an earlier post.


I do wonder how much mental retardation (MR) / cognitive impairment is also caused by the same mechanism.  Depending on how you define “autism” and whose figures you use, between 20% and 50% of people with autism have MR.  MR is defined as an IQ of 70 or less.

·        Mild retardation: Mild retardation: IQ level 50-55 to approximately 70 (85% of people with mental retardation are in this category)
·        Moderate retardation: IQ level 35-40 to 50-55 (10% of people with mental retardation)
·        Severe retardation: IQ level 20-25 to 35-40 (3 - 4% of people with mental retardation)
·        Profound retardation: IQ level below 20 or 25 (1 - 2% of people with mental retardation)

I would suggest that many people with autism might be “cognitively impaired” by allergies, be they caused by pollen, cats, dust, food, detergents, pollution or anything else.  Maybe they just dropped from a potential IQ of 120 to 110, or maybe they dropped from 80 to 35 and are now known as severely retarded.


Verapamil treats more than aggression and SIB

Based on my sample of one, it would be conceivable that Verapamil merely treats aggression and self-injurious behaviour (SIB), and that allergies are a side issue.  But thanks to the feedback on this blog, it is clear that Verapamil is treating the allergy.  One reader gave very extensive feedback showing how Verapamil greatly reduced her child’s GI problems (caused by food intolerance/allergies) and improved behaviour.  So based on a sample of two, Verapamil’s effect does seem to be related to mast cell degranulation and allergies.


Conclusion

I am very happy to have discovered the benefits of Verapamil, but I will continue to look into how further to reduce the “brain allergy effect”.  Perhaps the allergy is somehow affecting the excitatory/inhibitory balance of the Neurotransmitter GABA, I say this because Monty’s behaviour somehow resembles life without Bumetanide.  

Bumetanide’s role in autism is to lower brain Cl- concentration and to switch GABA to be inhibitory.  A recent comment on one of my Bumetanide posts was from somebody highlighting a paper that questioned whether enough Bumetanide crosses into the brain to switch GABA to be inhibitory.  

Note that a recently published comprehensive review on the use of bumetanide in the treatment of neonatal seizures indicates that theres is no evidence to support the use of this drug in the treatment of central nervous system disorders via the NKCC1-dependent mechanism described above, as at the very low doses that are given to infants and children bumetanide does not reach sufficient levels in the brain.

direct link to the original review:
http://onlinelibrary.wiley.com/doi/10.1111/epi.12620/pdf

It is conceivable that allergies affect the blood brain barrier (BBB), although you might expect allergies to weaken the BBB, rather than strengthen it; but the body does plenty of strange things.  So a second daily dose of Bumetanide just might help.  In France, the autism researchers working with Bumetanide do give it twice a day.

The simplest method to reduce the “brain allergy effect” would be to just avoid the allergen(s).  In the case of Monty, this would be to go and live in a low pollen environment, and perhaps even avoid cats.

Since 30+% of people with autism apparently suffer from asthma, then 30% of people with autism might also find behavioral relief by avoiding pollen.  Those suffering from aggression and SIB would very likely benefit dramatically from Verapamil.

This might also suggest that residential facilities for people with severe autism should be in low pollen areas.

Incidentally, our local special needs school used to be surrounded by a rampant overgrowth of ragweed/ambrosia.  This is one of the most notorious plants for causing allergies in humans.  The current number 1 in the ATP world tennis rankings then gave them some money to tidy up the grounds.  Coincidentally, like many of the “inmates”, he also favors a gluten free diet.






Tuesday 29 July 2014

Steroids for Regressive Autism

As we have seen at various points in this blog, there is mounting evidence to support the use of steroids in autism, particularly in regressive autism.


Since long-term steroid use has side effects, there have been no large long-term trials.  There is plenty of anecdotal evidence, particularly from the US.  We saw a paper on Immunomodulatory Therapy, by Michael Chez, which discussed the benefits of Prednisone, a very cheap oral steroid.




In the days before inhalers for asthma, it was low dose oral prednisone that kept many sufferers from an early death.  It did result in reduced height, but this is probably a price worth paying to stay alive.

A paper was recently published by specialists at Harvard Medical School on the subject of steroids and regressive autism.


It pretty much concludes the same as Chez and others have been saying for many years; corticosteroids can have a profound effect on some types of autism.  It remains unlikely that there will ever be large scale trials, due to the scaremongering about side effects.  Much is known about how to minimize the side effects of steroids, for example tapering and pulse dosing.

Here are some key points from the paper:-

·        Up to a third of children with Autism Spectrum Disorder (ASD) manifest regressive autism (R-ASD).They show normal early development followed by loss of language and social skills. Absent evidence-based therapies, anecdotal evidence suggests improvement following use of corticosteroids
·        Twenty steroid-treated R-ASD (STAR) and 24 not-treated ASD patients (NSA), aged 3 - 5 years, were retrospectively identified from a large database.
·        Star group subjects’ language ratings were significantly improved and more STAR than NSA group subjects showed significant language improvement. Most STAR group children showed significant behavioral improvement after treatment. STAR group language and behavior improvement was retained one year after treatment. Groups did not differ in terms of minor EEG abnormalities. Steroid treatment produced no lasting morbidity
·        Steroid treatment was associated with a significantly increased FMAER response magnitude, reduction of FMAER response distortion, and improvement in language and behavior scores. This was not observed in the non-treated group. These pilot findings warrant a prospective randomized validation trial of steroid treatment for R-ASD utilizing FMAER, EEG, and standardized ASD, language and behavior measures, and a longer follow-up period.
·        Referring physicians often enquire about the utility of adrenal corticosteroids or glucocorticoids to treat patients with R-ASD

Prednisone is already a treatment used in PANS, PANDAS and Landau-kleffner syndrome, which all have autism-like symptoms.


  
'Wicked'

Slightly off-topic but, the following is relevant.  

There was a recent documentary by the BBC about US-style DAN autism therapies now being sold to parents in the United Kingdom.  The UK has a government funded institute (NICE) that publishes lengthy advice to doctors as to what drugs to prescribe for almost all conditions, including autism. UK doctors will get into trouble if they do not follow NICE guidelines.

Commenting for the BBC, on the DAN-type treatments, Francesca Happe, a professor of cognitive neuroscience at King's College London and apparently one of the world's leading researchers into autism, said practitioners who "peddled" treatments without proof were "wicked".

But how much proof do you need?  And who is to say which published researcher is serious and which is a charlatan.  The lay autism parent might (falsely) assume that if a researcher is publishing papers, they must be serious and the conclusions reliable.  The reality is that some of the papers are indeed flawed and the conclusions are nonsense.  That is why I keep a list of the researchers who I believe in.

At the extreme are bodies like the UK’s NICE, who conclude that absolutely none of the hundreds/thousands of drugs/supplements proposed for treating core-autism should be used.

The short version of the NICE clinical guidelines is below.  The much longer version reviews in detail many of the papers I have reviewed in this blog, but comes to a very different conclusion.


I read the same papers as NICE and concluded something entirely different.  I found several drugs that do indeed work.  The difference is that my standard of proof is lower than that of NICE and professor of cognitive neuroscience at King's College London.

The DAN/TACA/MAPS/ARI doctors from the US are also hopefully read all these papers, but they come up with ideas of the sort that do fall into the “wicked “category mentioned above.  

Autism parents are not surprising bewildered.  It is the parent that ends up deciding where to draw the line between what treatment is genuine and what is fantasy, perhaps like this one.



Conclusion

Yet again, we have a therapy based on solid science that is in use by a very small number of serious mainstream doctors.  It has not crossed into general use due to a lack of large scale trials.

As a result, medical science continues to tell families that there are no drug therapies for core autism, except some anti-psychotics, anti-depressants and anticonvulsants most of which have serious side-effects and/or cause dependence.

In the case of prednisone, this is a cheap generic drug that does have side effect with prolonged use.  Severe regressive autism can also have side-effects, like complete loss of speech and cognitive impairment.

The answer might be parents signing a waiver to get open access to drugs that have been used successfully in experimental use for autism, without the doctor worrying about losing his license, or being blamed for any side effects.




Friday 25 July 2014

Carnosine for Autism – an Alternative to N-Acetylcysteine (NAC)? or is it Complementary?


Several people have mentioned to me a supplement called L-Carnosine, so I thought it was worthy of its own post.

The first thing to note is lots of supplements have very similar names and indeed two entirely different substances are abbreviated to NAC.

·        Carnosine
·        Carnitine
·        L-Carnosine
·        L-Carnitine
·        N-Acetylcysteine    (abbreviated to “NAC”)
·        N-Acetylcarnosine  (also abbreviated to “NAC”)

In this blog, and in most literature on autism, NAC refers to N-Acetylcysteine.

This post is about Carnosine and L-Carnosine, but there is also research on the use of Carnitine and L-Carnitine regarding autism and Retts syndrome.  So double check what is on the label, if you do indeed order some.


Vladimir Gulevich, Carnosine (and Carnitine)






Vladimir Gulevich  received the degree of doctor of medicine in 1896 from the department of medicine of Moscow State University. From 1900, he rejoined the Moscow State University where he was rector for a brief period of time in 1919. He was a full member of the USSR Academy of Sciences since 1929.

Gulevich discovered both Carnosine and Carnitine in his work in Moscow.  Even today his university is a centre of research for both these substances.

Carnitine and carnosine are composed of the root word carn, meaning flesh, alluding to its prevalence in animal protein. A vegetarian (especially vegan) diet is deficient in adequate carnosine, compared to levels found in a standard diet.

Researchers in Britain, South Korea, Russia and other countries have shown that carnosine has a number of antioxidant properties that may be beneficial.

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress.

Carnosine can chelate divalent metal ions.  DAN Doctors probably do not know what divalent means, but in Hg2+ the “2” means divalent and Hg means mercury.

Carnosine was found to inhibit diabetic nephropathy.

Carnosine-containing products are also used in topical preparations to reduce wrinkles on the skin.

Some studies have detected beneficial effects of N-acetylcarnosine in preventing and treating cataracts of the eyes.


Carnosine and Autism

Small studies, including this one by Michael Chez, have shown the benefit of L-carnosine in autism.  By the way, Chez seems to be one of the handful of genuinely knowledgeable autism clinicians anywhere on the planet.


Abstract

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.


As Dr Chez points out, nobody is 100% certain why it is of benefit.  It could just be the anti-oxidant properties of carnosine or it could be something related to the interaction between carnosine and GABA in the brain.  GABA is an important neurotransmitter in the brain.

Other GABA related drugs show a positive effect in types of autism.  These include Baclofen, Arbaclofen, Bumetanide, Clonazepam and even Valproic acid (VPA).  The underlying mechanisms do differ, but all relate, in one way or the other, to GABA.

The Carnosine dosage used by Dr Chez was 800mg per day.

The body deploys a range of enzymes, called carnosinases, to break down carnosine.  In order to maximize the effect, and out-smart the  carnosinases, it might be wise to split the dose into two per day.

In a perfect world it might be simpler to inhibit the carnosinases and just rely on the carnosine from meat in the diet.

You cannot patent naturally occurring substances, so nobody can patent carnosine and no drug firm will therefore research it.  A carnosinase inhibitor could be patented and therefore could be made into a drug.


Carnosine and GABA

It looks like Moscow State University is still the centre of knowledge for Carnosine and Alexander A. Boldyrev recently published a book called:-


Book Description:

The main aim of this new book is to summarize the knowledge on the metabolic transformation of carnosine in excitable tissues of animals and human beings and to analyze the nature of its biological activity. At the beginning of monograph, the short history of the problem is stated. Distribution of carnosine in tissues, its appearance in ontogeny of vertebrates and correlation between carnosine content and functional activity of tissues are discussed. Chemical properties of carnosine and its natural derivatives and their ability to bind heavy metals and protons in water solution are documented. Special attention is paid to free radical quenching ability and to anti-glycating action. Biological activity of carnosine and carnosine containing compounds was tested using biological models of several levels of complexity, starting from individual enzymes and acellular mixtures and finishing to living cells and survival animals. Effects of carnosine on the whole animals under ischemic, hypoxic and other extreme conditions are described. In conclusion, the ability of carnosine to protect brain and muscular tissues from oxidative injury during exhausting exercise, extreme loading or neurodegenerative diseases is demonstrated. Based on these properties, carnosine is postulated to be a potent protector of human beings from oxidative stress.

You can preview much of the book on Google Books

We know from many autism researchers that oxidative stress is a feature of many people’s autism.  Anything that reduces this stress should have a positive effect on behaviour.

Common antioxidants used in autism include:-

·        N-Acetlycysteine (NAC)
·        Alpha Lipoic Acid (ALA)
·        All the many “chelating” substances used by DAN Doctors

Carnosine may be just an alternative anti-oxidant.

However, when you look through Boldyrev’s book, it does look possible that the chemical relationship between GABA and Carnosine many also play a role.


Conclusion

People currently taking Carnosine for Autism might well want to try N-Acetlycysteine (NAC) and see if they notice an additional benefit.  Conversely, the current NAC converts, like my son Monty, aged 11 with ASD, may well want to give Carnosine a try and see what happens.

One blog reader with Asperger’s finds Baclofen highly beneficial; he might as well give Carnosine a try, based on the GABA relationship.

Current research indicates 2,400 mg of NAC and 800 mg of Carnosine. 

It would be nice if one day somebody would do a controlled trial of NAC vs Carnosine vs Carnosine+NAC;  but don’t hold your breath.

Some people with diabetes are already taking ALA (Alpha lipoic acid) or Thioctacid for neuropathy, but find it also increases insulin sensitivity; this means they need less insulin.  They might well find both NAC and Carnosine will further increase insulin sensitivity.  Generally speaking it seems that low insulin sensitivity is bad and high insulin sensitivity is good; but I am no expert on diabetes.

In some counties Carnosine is not available, but you simply can buy it online on Amazon, ebay or many other sites. 






Wednesday 16 July 2014

Verapamil for a Broader sub-group of Autism and even Diabetes?



This blog is about science rather than medicine, and believe me there is a much bigger difference than you might hope for.
Many aspects of the research literature indicate the potential of certain calcium channel blockers, like Verapamil, to be useful in treating autism.  As we have seen, there are many different causes of autism and what treatment works in one type may be totally ineffective in another type.

For almost a year Monty, now age 11 with ASD, has taken Verapamil to control the behavioural effects of allergy that are driven by so called “mast cell degranulation”.  His pollen allergy makes his summertime behaviour dramatically worse; a reaction that is almost entirely reversed by Verapamil.

In my page in this blog on Allergies and Autism I raised the question as to whether Verapamil would be effective in treating the many people with autism who have food allergies leading to gastrointestinal (GI) problems.  Many people with autism have symptoms like Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) and these are widely associated with worsening autistic behaviours.  Monty has no GI issues or food intolerance.  I was very interested to receive some lengthy comments from a mother with a son who does have autism plus GI problems.  She found Verapamil highly effective in treating both his GI problems and the autism.  This is rather significant, since while I do receive the odd comment that H1 antihistamines have an unexpected beneficial effect on autism, which supports some of my own findings and theories, the issue of GI problems is very common in autism.  Could a pill called Verapamil be the little wonder for them as well?  The science does indeed support this, even if current medicine does not.

 

How can medicine be so disconnected from science?  It does seem to happen far more often than it should.

I did wonder if I was missing something about Verapamil.  It is an L-type calcium channel blocker and in autism there is a known genetic dysfunction (CACNA1C) that affects the calcium channel (Cav1.2) blocked by Verapamil.  It also turns out that Verapamil has been shown to be a highly effective mast cell stabilizer.  I did a little more digging and found something very surprising, the effect of Verapamil on the pancreas.  The pancreas makes all kinds of enzymes as well as insulin.  In some people with an auto-immune dysfunction the body destroys its own insulin producing cells and diabetes results.  In some people with autism (also an auto-immune condition) the pancreas seems not produce some of the other enzymes and there are various DAN-type treatments for this; and the new CUREMARK drug CM-AT seems to target this dysfunction.

Science has remarkably shown that Verapamil had the potential to reverse diabetes, if intervention is early.  Given that type 1 and type 2 diabetes are becoming increasingly common and account for a substantial part of national healthcare costs, it seem odd that medicine has not taken full note.



It appears that older people on Verapamil for hypertension, strangely do not develop type 2 diabetes, which supports the claim for Verapamil.

There is no mystery as to why this is happening.  Calcium channels are widely expressed in pancreas, just as they are in the heart and the brain.  The effect of aberrant calcium channel signalling does no good for the brain in autism and in some other people, with a tendency to auto-immune problems, it would appear to be the pancreas that suffers.

You will recall that autism is amongst, other things, an auto-immune condition.  If you look at the extended family you will likely notice other auto-immune conditions like diabetes, thyroid problems, and arthritis.  (I would myself add fibromyalgia and even some types of chronic headaches to this list)

Recall that several drugs that help autism have a beneficial effect in diabetes and that the key type 2 drug for diabetes seems to have a positive effect on autism.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes


In the above post we saw that PPAR gamma (PPARγ) is a nuclear hormone receptor which modulates insulin sensitivity.  The following autism study looked at the effect of a common diabetes drug, pioglitazone (Actos), an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. 
 

Pioglitazone is currently in Phase 2 trials for autism.

Another comorbidity of autism that is an auto-immune condition is asthma.  Here again, Verapamil was shown many years ago to hold promise.

Verapamil in the prophylaxis of bronchial asthma

A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi>100%) in the responders 5 h after the oral dose.

I also noted in earlier posts that anti-oxidants seem to reduce the insulin required by diabetics and also improves one of the big problems that occurs along with diabetes that is peripheral neuropathy.  These antioxidants, like ALA, NAC, Thioctacid etc are also chelators of heavy metals.  While the planned study of chelators in autism in the US was effectively “banned”, a large study was carried out on heart patients.  Chelation was shown to be remarkably beneficial, but chelation is really just a shock dose of antioxidants.

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial


My take on this is that in many medical conditions, oxidative stress is present and therefore any antioxidant will be beneficial, but some more so than others.  In the well-researched world of asthma they concluded that the most potent, safe antioxidant was NAC (N-acetylcysteine).  NAC is my choice for autism.


Conclusion

If you have autism and suffer from chronic GI problems, Verapamil might well offer significant relief.

If you have unexplained autism flare-ups, like aggression, in summer this may well be driven by a pollen allergy, Verapamil is likely to help.

If your older relative has hypertension already and looks likely to be heading towards type 2 diabetes, maybe suggest they talk to their doctor about Verapamil;  it may well treat both.

Incidentally, if you have a child with autism and suffer yourself from chronic headaches or fibromyalgia, you might want to try some Verapamil yourself.

Verapamil is a very cheap generic drug; one tablet cost a couple of cents/pence. 


Opinion

I continue to be surprised how far medicine is behind science.

In the case of autism there is now a great deal of “actionable” research that is available for anyone to read.  This blog is about autism, but it seems that in many other areas of medicine the same is true, for example diabetes and types of cancer.   

The idea is that you should wait for clinical trials.  But who do you think is going to do them? There is no financial incentive for drug firms to do trials on old generic drugs for new uses.  Prepare for a long wait.

The medical practitioners involved with autism, mainly psychiatrists if anyone, show little interest in any novel treatment that has not yet been approved.  With such little interest from clinicians, novel treatments will remain well kept secrets for decades to come.

The “alternative” practitioners dealing with autism, like DAN doctors, are mainly in the US; but they are not fully grounded in science and seem overly interested in unorthodox expensive lab tests and costly supplements.

So you really do have to figure out autism for yourself, if you want to control it.