Summertime Raging in Autism – H1 Anti-histamine Effect on Histamine Levels and IL-6

Last summer, I wrote a lot about autism getting much worse in that time of the year and how I found that common “24 hour” anti-histamine drugs seemed to have a magical effect; but one that lasted only 2-3 hours. There were only visible signs of a mild allergy, which could indeed easily be overlooked.

I did later receive a message from a reader who noticed his child’s ASD behaviours were greatly improved by Zrtec and his doctor agreed to prescribe this H1 antihistamine all year round.

Recently, I stumbled upon a blog, rich with many comments of parents of kids with severer types of autism.  Here I noted some parents referring to “summertime raging”, and I thought to myself, I know what they mean.  Fortunately, I found out how to make it go away.

Ant-histamine drugs

The two most common antihistamine drugs are Claritin (Loratadine), its active derivative Aerius (Desloratadine) and Zrtec (Ceterizine) and its active derivative Xyzal (levocetirizine).

The main action of an antihistamine is not actually to reduce the amount of histamine in your blood, rather it is to block the effect of histamine on the H1 receptors.

An H2 antihistamine blocks H2 receptors that are mainly in your intestines, and is used to reduce the amount of acid in the stomach.

This led me on a quest for substances that actually stop the increase in histamine, rather than just blocking some effects.  The only thing that does this is something that can stop so-called mast cells from degranulating and spilling their load of histamine, serotonin, nerve growth factor and cytokines, including IL-6, into the blood; from where, all except serotonin, are free to travel to the brain, across the blood brain barrier (BBB).  Serotonin cannot cross the BBB.

According to the mast cell specialist Theoharides, conventional drugs are not genuine mast cell stabilizers.  There are some partial ones, like Ketotifen, Cromalin, Rupatadine and Azelastine, but Theoharides thinks naturally occurring flavonoids like Luteolin and Quercetin work best.

Last summer in this blog I looked at newly discovered histamine receptors types H3 and H4 which are known to be present in the brain.

So how is it that Claritin and Zrtec can reduce autistic behaviours ?

I did note that both the above drugs did reduce summertime raging and also the Theoharides' research that showed they probably should not, since they are not mast cell stabilizers. 

Since my blog reader also found Zrtec helpful, so much so he gives it to his kid year round and it now seems summertime raging is not an unusual phenomenon in autism, I did some more checking.

In spite of what Theoharides tells us, it turns out that both Claritin and Zrtec do indeed reduce the amount of histamine in the blood.

Also, it turns out that not only is the pro-inflammatory cytokine IL-6 released from mast cells but it is also released from another type of cell, called the endothelial cell.

The endothelium is the thin layer of cells that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. The cells that form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.

And what prompts endothelial cells to release IL-6? Histamine does.

Indeed we have studies showing how Claritin (loratadine) and  Zrtec (Ceterizine) reduce histamine and IL-6; it is the IL-6 from the endothelial cells.

Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of endothelial cells.

"CONCLUSION:

These results demonstrate that both L and DCL are active to reduce the histamine-induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion."

The above study would suggest that Aerius (DCL) should be more effective than Claritin (L) its predecessor.

Human Mast Cells(HMC-1 5C6) Enhance Interleukin-6 Production by Quiescent and Lipopolysaccharide-Stimulated Human Coronary Artery Endothelial Cells

"Histamine is a major constituent of the mast cell. The effect of histamine on endothelial cells is primarily mediated through H1R

Collectively, our results suggest that mast cell-derived histamine and proteases play an important role in vascular inflammation and calcification in addition to their well-recognized participation in allergic diseases."

This study, and others like it, show how mast cell degranulation contributes to heart disease.  This would suggest that mast cell stabilizers have a much wider role in human health than is realized.  Another example of how a red apple a day (with the skin) may indeed help keep the doctor away and a glass of red wine will do the same.  Both are rich sources of the mast stabilizer Quercetin.  The alcohol increases the bio-availability.

Cetirizinea histamine H1 receptor antagonist improves viral myocarditis

"Conclusion

These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice."

So how do Claritin and Zrtec reduce summertime/year round raging in autism?  Well it could be histamine or it could be IL-6, we cannot know for sure.  The science tells us that the brain has many H3 and H4 receptors, so they are possibly to be implicated.  Or, it may just be IL-6;  histamine’s involvement could be just provoking the endothelial cells to release more IL-6.

Conclusion

Claritin/Zrtec/Xyzal are relatively cheap, in theory they are long lasting drugs.  In Monty, aged 10 with ASD, they all work for summertime time raging, but not for long.  Adults should take one per 24 hours.  Monty would need one every 3 hours.

The, supposedly better, mast cell stabilizers like Ketotifen and Rupatadine take a few days before they have any effect at all.  Azelastin is available as a nasal spray and is supposed to be effective quickly as an allergy treatment.

My preferred mast cell stabilizing, IL-6 inhibiting, strategy is to combine PEA (palmitoylethanolamide) which is already naturally in your body, with the flavonoid quercetin, which is found in the skin of red apples and red grapes.  In theory, according to the research, this is both a potent combination and should be free of harmful side effects.

Very frequent doses of Claritin/Zrtec/Xyzal are not going to be good.

Links

Blog with 1000s of parent comments, some are very insightful

  

Theoharides on mast cells

On this blog:-

http://epiphanyasd.blogspot.com/2014/02/is-subtype-of-autism-allergy-of-brain.html

http://epiphanyasd.blogspot.com/2014/03/palmitoylethanolamide-pea-vs-flavonoids.html

http://epiphanyasd.blogspot.com/2013/07/histamine-allergies-and-reducing.html

http://epiphanyasd.blogspot.com/2013/11/seasonal-autistic-mastocytosis.html

Seasonal Autistic Mastocytosis

 

 The degranulation process in a Mast cell. 1 = antigen; 2 = IgE; 3 = FcεRI; 4 = preformed mediators (histamine, proteases, chemokines, heparin); 5 = granules; 6 - Mast cell; 7 - newly formed mediators  leukotrienes, platelet-activating factor)

Source: Wikipedia 

Some of the most popular posts on my blog refer to my investigation into the role of histamine in autism.  The investigation was productive and lead to a highly effective treatment for the wild summertime flare-ups in autistic behaviour exhibited by Monty, aged 10 with ASD. 

Since I have found a therapy it is only reasonable to give the condition a name. 

Seasonal Autistic Mastocytosis (SAM)

Seasonal Autistic Mastocytosis (SAM), sometimes known as Airborne Autistic Mastocytosis, occurs when airborne allergens like pollen, cause mast cells in the eyes, nose, mouth and lungs to degranulate.  These mast cells contain many granules, themselves containing histamine, serotonin and heparin, a naturally occurring anticoagulant.  This mast cell activation also releases inflammatory cytokines, leukotrienes and platelet activating factor (PAF).  Some of these pro-inflammatory agents enter the brain and stoke up the ever-present neuro-inflammation, starting a downward spiral with further localized cytokine release.  In behavioural terms, the result is that all the earlier bad behaviours will return, but in a magnified form.  The observer may notice swings to aggression and self-injurious behaviour (SIB).  If the subject is verbal, he may complain of unpleasant itching on arms and legs, typical of mastocytosis.  The autistic subject, not understanding the reason for the itching, is likely to react with some form of tantrum, aggression or hitting that part of his body.

SAM should be considered even when only very minor symptoms of an allergy are visible, like red eyes or runny nose.  

The most effective therapy is to use mast cell stabilizers, but even a standard OTC H1 antihistamine will provide some relief within 20 minutes.  The dosage required to have an effect, may be much higher than the recommended dose for allergic rhinitis (hay fever), but should still be within safe limits.

 

An alternative therapy is simply to move to somewhere that is pollen free, even just for a weekend and observe the effect.

Depending on where you live, SAM may be possible for about 5 months of the year.

Mast cells are particularly present in the digestive tract, the lungs, skin, eyes, mouth and nose.  They undoubtedly also play a major role is asthma.

Mastocytic enterocolitis is a related condition.  This condition is acknowledged in the medical community.  I am not a gastroenterologist, but I think Messrs Wakefield and Krigsman may have really stumbled upon cases of Mastocytic enterocolitis, when they came up with their diagnosis of Autistic enterocolitis.  Incidentally, Krigsman recently published an interesting paper on genes and colitis in ASD.

Some of the frequently reported cases of GI problems in autism may also be caused by mast cell degranulation.  Some of the DAN doctors treat GI problems with mast cell stabilizers and allergists routinely prescribe them.

Note on Serotonin

Approximately 30% of people with autism have high blood serotonin; perhaps a contributing factor is serotonin released by the degranulation of mast cells.  We have already seen that there often appears to be central hypo-function of serotonin in autism (i.e. low brain serotonin).  The endocrine system functions using feedback loops, so high blood serotonin sends a signal to lower serotonin; thus you could get low brain serotonin but high blood serotonin.  Remember that serotonin does not cross the blood brain barrier.

Controlling Anger in Autism - Part 2

I wrote extensive earlier posts about using H1 anti-histamine drugs to control autism flare-ups.  Summertime allergies can result in anger, loss of control and ultimately, self-injury.

Controlling Anger In Autism with H1 antagonist, Claritin

Histamine, allergies and reducing challenging “autistic-like” behaviours

More on anti-histamines in Autism and introducing H4

 
Although this blog is about pharmacological interventions that can help in autism, I am firmly in the ABA behavioural intervention camp.  The drugs can indeed help, but are always going to be secondary to a very labour intensive intervention.

 

Anger in autism

Depending on how lucky you are, parents experience widely differing levels of anger from kids with ASD.  For those who have not experienced the extremes, here is my summary:-

Level 1           Bad temper

Level 2           Tantrum with screaming, maybe rolling around on the floor but no  violence

Level 3           Self-injury, like hitting head with fist, but no external “objects”

Level 4           Violent self-injury like banging head into a wall

Level 5           Violence towards care givers (punching, kicking, biting etc.)

There seems to be little correlation between anger and intellect.  Some highly verbal kids with ASD exhibit self-injurious behaviours.

 

Drugs

This post is about alternatives to antipsychotic drugs such as risperidone and haloperidol, which I personally do not believe should be given to children.

 

ABA (Applied Behavioural Analysis)

The underlying principle of ABA is to reward good behaviours and, in effect, ignore the bad behaviours.  You are taught to understand behaviours with the “ABC” of antecedent, behaviour and then consequence.

If you take your 4 year old to the Mall and he rolls around screaming on the floor, the typical embarrassed parent would make a swift exit to the car and back home.  So the kid has won and gets to avoid a boring visit to the Mall.  The same behaviour will repeat the following weekend.  Kids quickly learn which adults this behaviour works with and who the hard cases are.  Consistency among the adults is a key part of successful ABA. 

When children are still very small, a violent tantrum can be extinguished by the care giver physically restraining the child.  In some countries, in special schools this is still being done with quite big kids.   Monty’s former therapist, Dule, used to work in the local special school and as one of the few male staff members was regularly the one called upon to do the “restraining”. 

Generally, ABA is more useful for understanding the reason for tantrums and violence, so that it can be avoided in future.  The child can be redirected towards some other activity and thus calm is restored.

 

Alternative Strategies

Faced with a child who has lost control and the tantrum has become self-reinforcing, you are faced with the choice of letting it runs its course, or doing something about it.  This does rather depend on how big the child is, how big you are and where you are at the time.

My son Monty is only 10 years old and so my policy of zero tolerance to violence is still easy to enforce.  It is clear that once bad behaviours (violence) are learned (or self-taught) they can only very gradually fade away and be forgotten.  If violence is allowed to persist, the child will turn to it more readily and as he grows up, big problems will surely lie ahead.

Hit the reset button

I learned a long time ago that if you do something totally unexpected to a child (with or without ASD) it is like pressing the “reset button”.  It clearly depends how old the child is, but what still works for me is picking up my son and holding him upside down, or when he was very small, getting down on all fours and get right in front of him and bark like a dog.  It may sound crazy, it is crazy, but it works.

Chewing Gum

I noticed a long time ago that giving Monty a toy pipe to play with, intended for blowing bubbles, had a strange calming influence.  When I look at people smoking, I think that many of them have no need to inhale at all.  The mere ritual of lighting up, puffing and stubbing might be enough.

Then a few weeks ago Ted, Monty’s older brother, told me that a friend of his had told him something very funny.  She told him that she always has to be chewing something or have something in her mouth, otherwise she gets very stressed.  This fitted with what her Mother had being telling us adults; she declared that she (the Mother) is like Monk in the crime series on TV, where the character Monk has obsessive behaviour and many traits of Asperger’s.  Not surprising, the mother is a smoker, as will be the daughter in due course.

This brings me to our latest experiment, chewing gum.  Not as a reward, but as a therapy.

You may have seen from earlier posts that summertime allergies affect Monty’s behaviour.  With plenty of antihistamine we have the allergy under control, but the associated behaviours are not fully controlled.  It is much better than at the start of the pollen season, but not perfect.  I still do not have the optimal H1 antihistamines.

We just had a visit from our American ABA consultant, who flew in to see us and fine tune Monty’s programme at school and then his home programme.  This spurred me to think further how to give Monty the ability to fully control his behaviour by himself.  He is now able to tell us when he is about to “lose it”, so we have the three minute warning.  We need to give him the ability to himself subdue whatever is going on inside his head.

With an active and stimulating day at school, the problem now only arises at home, and hopefully ,with no pollen in a couple of months, the problem will disappear until next June.  But for now, the new secret weapon is “unlimited” chewing gum.  I say “unlimited” because it is not supposed to be a reinforcer (reward), if it was, the result would likely be the opposite of what I want.  The “calm down son here’s a gummy bear” method would be a disaster  and just prompt future tantrums to “earn” gummy bears.

Calming a tantrum

Giving gum to calm a self-injurious tantrum seems to work .  No restraint is required, just “here’s your gum”.  One minute later all is calm and Monty is joking, “Monty was hitting his head”.

 

Avoiding/anticipating a tantrum

 
The warning signs Monty gives are all verbal; “I want to be nice”; “I want to be happy”; “to hit your head”.  I just need to promptly offer the chewing gum.  Monty starts chewing and indeed calm is gradually restored.

I have since learned that Michael Jordan started a huge trend for basketball players to chew gum, it supposedly helps them be calm and concentrate.  There are actually studies showing health benefits of chewing gum, and not just for your teeth.

Here are some chewing gum facts.

 

Conclusion

I was already a regular buyer of gummy bears, now I am loading up with kid’s chewing gum as well.  If it works, I am happy to continue doing so.  The only side effects are clean teeth and sticky fingers.

 

 

Autism Flare-ups - News on Allergy Drugs

I wrote earlier posts about the role of histamine in summertime autism flare-ups.  I ended up using a combination of a regular antihistamine like Claritin with Ketotifen, which though also an antihistamine, is a partial mast cell stabilizer.
 

I recently found a very useful table which shows different regimens that can be used for just this problem:-

 

The table is from a paper, again by Dr Theoharides, called:
 Autism: an emerging ‘neuroimmune disorder’ in search of therapy

Rupatadine is a safe and cheap antihistamine mainly sold in Europe.  The science appears to show that it is more effective at stabilizing the mast cells involved in allergies than Ketotifen.

The problem I found with Ketotifen is that it has very little immediate effect, unlike Claritin, so I ended up using both.  By the looks of things, Rupatadine may indeed do the job of both.

The table also mentions Periactin, which is an old first generation antihistamine.  It has a secondary antiserotonergic properties.  It was trialed in Iran for autism, apparently with some success.

Cyproheptadine in the treatment of autistic disorder: a double-blindplacebo-controlled trial.

 

Conclusion

Not all antihistamines are the same and some have very interesting secondary effects.  It looks like science has given up on investigating this further, which is a pity; but you don't have to.

 

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?

 Prevention of asthma by ketotifen in infants with atopic dermatitis

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.