The over-activated immune system, Kv1.3, ASD-IE, Acacetin and sloppy science

One of the people I have met during my investigation into autism, recently pointed out to me that much scientific research cannot be trusted.  He forwarded a study to me showing just how many researchers admit is omitting data that did not suit what they were trying to prove.  I replied that I made a point of checking the credentials of the lead author.  He then replied that it is not the lead researcher who collects the data, he has a little army of PhD students doing this and nobody is checking them.

The study showed it was the younger researchers, eager to prove themselves that were the most likely to “fiddle” the results.  The problem is that by the time you become an “older researcher” you are not the one collecting the data.

Doubts about Sprouts 

One of the people who I keep forgetting to add to my Dean’s list is John Gargus; he is a professor at University of California at Irvine and Director of the Center for Autism Research and Treatment at UCI.  He is also a specialist in the complex field of ion channels and channelopathies.

He was asked to comment about the Johns Hopkins broccoli/Sulforaphane autism trial.

Trial sprouts doubts about broccoli extract for autism

Cruciferous caution: 

Some independent researchers have similar reservations, noting that the control group showed an unusually small placebo response.“You always see a 20 to 25 percent improvement in placebo,” says John Jay Gargus, director of the Center for Autism Research and Translation at the University of California, Irvine. For example, the placebo effect plagued trials of the gut hormone secretin and antidepressants for autism.
“It’s stunning that they’ve managed to have found a placebo that doesn’t give the placebo effect that we see in every other neuropsychiatric drug trial,” Gargus says.

Now as regular readers will know, at least in Monty, aged 11 with ASD, broccoli sprout powder and we assume the Sulforaphane produced by it, does have a near immediate effect.

But as Gargus says, you will always have some people with the placebo appearing to improve.  In an old post I looked at the placebo effect in autism.  It seems that the more involved the trial and hence the more 1:1 attention the child gets, the more the placebo appears to make things better.  In fact it was not the placebo, it was the 1:1 attention that improved the autism.

So, just as we have to be cautious of the placebo effect, we have to be cautious of sloppy science/scientists.  When financial interests are involved you need to be even more cautious.

The other thing I have learnt to be cautious of, is scientists who have spent many years in one very narrow field, often trying to prove their initial hypothesis to be correct.  Their eyes are then closed to everything else.

Autism Flare-ups, Summertime raging and GI issues

We have investigated in depth the fact that in some people with autism their immune system appears to be over-activated, as the result of an allergic response.  What then happens is that their autism “flares-up” and therapies that previously worked, seem to stop doing so.

The conclusion was that the allergy had caused mast cell activation and this triggered the release of pro-inflammatory chemicals (IL-6, histamine etc).  The solution was:-

·        Avoid the allergen (a type of food, or even airborne pollen)
·        Use mast cell stabilizers to minimize degranulation; even common H1 anti-histamines are partially effective
·        Inhibit the potassium ion channel Kv1.3, which seems to mediate the resulting “over-activation” of the immune response.

The good news is that it really does work and not just in Monty.  The bad news is that the optimal therapy uses a prescription drug (Verapamil).

While trawling through the research on novel anti-oxidants, I stumbled upon something that may help those people who cannot access Verapamil.

There is a flavonoid called Acacetin, which is found in asplenioid ferns.  This flavonoid has long been has used for its anti-inflammatory and immunomodulatory effects.  Now it has been shown to block Kv1.3 channels and inhibits human T cell activation.  This is one of the effects of Verapamil (there are others).  Acacetin has also been shown to have anti-cancer properties in prostate cancer cells.

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin (5,7-dihydroxy-4'-methoxyflavone)exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signaling in prostate cancer cells

Remember the odd therapy used to block Kv1.3, those TSO parasites, I mentioned in previous posts.  My favorite is this one:-

Immunomodulatory Therapy in Autism - Potassium ChannelKv1.3, Parasitic Worms, and their ShK–related peptides

Acacetin is available as a supplement.  So if you think blocking Kv1.3 might help and cannot access Verapamil or TSO, there are other options.

Indeed, for completeness, there at least two other Kv1.3 blockers that are available.  One is progesterone, the hormone and the other is Curcumin.

  

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes.  Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activities.

  

You may recall that Progesterone was found to be highly neuro-protective and for this reason was trialed for use in the ER, immediately after a traumatic brain injury.  It was shown to save lives.  In autism, we previously found that some people, at the high functioning end, find they feel better when they apply progesterone cream, i.e. transdermal route.

Curcumin has been used for centuries as a drug.

I have not tried them, but I will continue to use Verapamil.  Acacetin, Progesterone and Curcumin share some, but not all of each other’s effects.

Progesterone, in common with Verapamil, affects both potassium and calcium channels.

There are many different potassium and calcium channels and you would hope to find a selective channel blocker and hence affect only the ones you need to.

ASD-IS  (Inflammatory Subtype)

I came across a promising study on Paul Whiteley’s blog.  It is a study of a sub-type of autism characterized by fluctuating behavioral symptoms following immune insults.  In the trial group the children all had GI problems, some had enterocolitis or esophagitis.  The entire group had been noticed by teachers/therapists to lose cognitive skills following immune insults.

Cytokine profilesby peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

Regular readers of this blog will see lots of familiar points.  This appears to be exactly the same thing as my “over-activated immune response”.

Now this study comprised children who had Non-IgE mediated allergies.  This does matter because classic allergies are called IgE-mediated and they result in little cells called mast cells getting activated and then releasing IL-6 and histamine in the blood supply.

From Wikipedia we have a summary:-

Conditions caused by food allergies are classified into 3 groups according to the mechanism of the allergic response:

1.     IgE-mediated (classic) – the most common type, occurs shortly after eating and may involve anaphalaxis.

2.     Non-IgE mediated – characterized by an immune response not involving immunoglobulin E; may occur some hours after eating, complicating diagnosis.

3.     IgE and/or non-IgE-mediated – a hybrid of the above two types.

Treating allergy is a “fuzzy” area and, depending on which country you live in, some aspects are seen as science and others pseudo-science. 

Perhaps we should see it as an important, but emerging field of science.

I am not an allergist/immunologist, so I have to look things up.

Since in the trial the children had Non-IgE mediated allergies, we can then look to see whether mast cell activation is relevant.

NON-IgE MEDIATED FOOD ALLERGY 

Mast cell and eosinophil activation is an important component of the non-IgE-mediated response

The authors of the autism study believe that the research subjects with allergy did not have mast cell activation, because they had NON-IgE mediated allergies.

Since I am not an allergist, all I can say is the author of the above paper from the Royal Free & University College School of Medicine in London thinks that mast cell activation is an important component of the non-IgE-mediated response.

Anyway, make your own mind up and continue to see what the study found.

The study looked at children with autism and allergy, whose autism flares up and affects (impairs) their cognitive function.  This group is ASD-IS (Inflammatory Subtype)

ASD-IS children: ASD-IS children are defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection). Symptoms must have been documented by individuals other than parents, such as teachers/therapists, a minimum of three times. In addition, a history of persistent GI symptoms, often diagnosed as non-IgE mediated food allergy (NFA - see next section for diagnostic criteria), is required. Among the ASD-IS subjects, 14/24 subjects were diagnosed with food protein induced enterocolitis syndrome (FPIES), a severe form of NFA, prior to enrollment in this study, and two ASD-IS subjects were diagnosed with eosinophilic esophagitis (EoE) on the basis of biopsy results. These ASD-IS subjects reported to have had loss of once-acquired cognitive skills based on the reports of teachers, therapists and/or previous records of developmental assessment.

We defined ‘flares’ as worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults). Most of the immune insults in this study were clinically judged to be microbial infection (mainly viral syndrome). In ASD-IS children, we obtained samples at least once in the ‘flare’ and ‘non-flare’ states. Changes in behavioral symptoms by parental reports were confirmed by reports from

teachers and other caregivers.

The authors have an entirely different hypothesis to mine.

But I find their data remarkably similar to what I see being caused by a pollen allergy in my son - summertime autism flare-up and regression.  This is why there were so many posts about the inflammatory cytokine IL-6 and how to minimize it.

Have the authors stumbled upon exactly the same phenomenon as I did?  I very much think so.

I have shared my therapy with the authors, but they think that Non-IgE mediated allergies have nothing to do with mast cell activation.   That sounds odd to me.

Cognitive Function Restored, with Bumetanide

Regular readers will know that every summer Monty, aged 11 with ASD, has a “flare-up” in his autism.  Behaviour gets very much worse and now we notice that also cognitive function is impaired.

In my last post I repeated how the aggression and SIB (self-injurious behaviour) was very effectively suppressed by Verapamil and I was pondering how to solve the, now visible, cognitive decline.

I suppose some readers may be thinking all this sounds fanciful.  Once a child with autism is verbal and has got as far as basic maths, it is very easy to measure cognitive function.  For years I have asked Monty what he had for lunch at school that day, to check how “switched-on” he was.  Now, I just need to ask him something like “what is five times five”.

Ted, Monty’s older brother, has also noticed these changes and has recently delighted in showing how his brother does not know six times six, or even twelve plus five.  He would ask him questions when we are all in the car, and then I would have to start making excuses for his brother.  Well with Verapamil, at least Ted is not going to get punched by Monty, as they sit in the back of the car.

We know that for most of the year Monty knows the right answer to all these questions, but from July to early October he may get them wrong, or does not answer.  This was all traced back to the effect of a mild pollen allergy.

Rather than look for something new, I decided that as a first step I would just increase the dose of one of his existing Polypill ingredients and “hey presto” the problem was solved.  A nice surprise, indeed.

I increased the Bumetanide dose from 1mg once a day, to 1mg twice a day.

Every time since that I ask Monty five times five, or six times four he gets the right answer, even if he is in the middle of doing something else, like jumping into the swimming pool.  That is proof enough for me.  Even Ted has noticed.

In previous posts I did complain about the effectiveness of autism rating scales and suggested that measuring academic performance (in older kids) might be more reliable.   In the case of Bumetanide this really is the case.

As to the relationship between bumetanide and allergy, there are various possibilities.  I did yesterday highlight this impact to the French researchers currently working to get Bumetanide approved officially as drug for autism, since it could be useful for them to know.

Conclusion

So, the current summertime allergy solution is:-

Aggression and SIB – Verapamil three times a day

Cognitive impairment – Bumetanide one extra daily dose of 1mg

All that is left of the “autism flare-up” is a very occasional rapid mood swing from happy to sad.

Compared to last summer, the difference is profound and now the difference between behaviour in summer and winter is very small.

  

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.

Is a Subtype of Autism an Allergy of the Brain?

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.

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.

Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers

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. 
 

Effect of pioglitazone treatment on behavioral symptoms in autistic children

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 PD_20FEVHi 416%). There was still significant protection (Δ PD_20FEV1Hi>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.