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Showing posts with label self-injury. Show all posts
Showing posts with label self-injury. Show all posts

Wednesday, 13 September 2017

Verapamil still working after 3+ years, for SIB in Autism


There are numerous ideas about how to treat self injurious behavior (SIB) associated with autism. ARI (the former home of Defeat Autism Now) have just had their take on the subject published.
In this blog we have seen that Tyler has developed a BCAA (branch chained amino acid) therapy, based on the idea of Acute Tryptophan Depletion, to control his son’s type of self injury.
The silver bullet for my son’s summer time raging and self-injury continues to be the L-type calcium channel blocker Verapamil.
I think many people will be skeptical of both BCAAs and Verapamil, which is entirely understandable. Unlike other aspects of autism, which are hard to measure, self-injury is really easy to measure and so you know when you have cracked the problem; what other people think tends not to matter.  
Now that Monty, aged 14 with ASD, has moved to secondary/high school the routine has changed a little and his assistant forgets to give him his midday dose of verapamil.
On the days she forgets, between 4.00pm and 4.30pm Monty starts to punch himself. On all other days and during the entire summer there has been no sign of self injury.
So when asked is it really necessary Monty keeps taking his pills, my answer remains yes.  In the case of verapamil I now have further evidence that after more than three years of use, his pollen allergy driven self injury continues to be entirely controllable using this therapy.
I do not know what ARI have put forward in their book. If your child has SIB that does not respond to whatever therapies you have tried, it might well be a helpful read. 

Other readers have noted GI and behavioral improvement from Verapamil and our doctor reader Agnieszka did try and collect case reports, but it seems parents are more interested in reading reports than writing them.
           







Friday, 11 March 2016

Treating Adults with Autism?





 
 




Almost the entire focus of treating autism is targeted at young children; only rarely do you hear about clinical trials involving adults, yet we are often reminded that autism is a lifelong condition.

For those of you that read the proposed guidelines to drug companies developing autism therapies, this issue raised its head again.  Will therapies effective in children be effective in adults (and vice versa)?

There are many issues here.  On the one hand there is great caution about giving drugs to very young children, but there is the realization that many therapies may only be effective if given at an extremely young age.

I only started treating the biological dysfunctions in Monty, now aged 12, when he was 9 years old.  By good fortune the first therapy (bumetanide) I tried was highly effective, otherwise this blog would not exist.

Had that Bumetanide clinical trial been published 5 years earlier, would I have given my then 4 year old son that same drug?  Probably not.

With what I now know, I would be happy to give Bumetanide as soon after birth that autism was even suspected.  (To the trained eye, this is but a few months old)


The effect of no treatment

For three years I have been developing a personalized autism treatment, Monty’s Polypill, and I think it works well, but a few weeks ago we decided to see what happens with no treatment at all.

This did provide some useful insights into treating young adults, as opposed to young children.

The first thing is that all the new skills that have been acquired, at close to neurotypical speed, in the last three years, did not just fade away. 

The old obvious repetitive behaviors/stimming/stereotypy did not return, but more subtle new ones did.  (no NAC)

He could still play his piano nicely with his teacher, but his interest in playing out of lessons faded away as did his skill level out of lessons.

He showed an occasional aversion to doing anything new, for example when his assistant came in the afternoon, I told him to go outside and meet her.  He could happily open the front door (his normal routine) but was not able to walk though it and meet her by the gate.  (no statin)

When I offered to go with him, he had a brief tantrum. 

He started asking permission to do things he knew how to do, which some people saw as a positive.  When lying in bed at 9pm he called out “Mum can I read a book”, rather than just picking one from the shelf by his bed and when at a small birthday party he had to bend down to light the candles, he turned round and said “can I squat?”  Most people thought that was good use of vocabulary, I was thinking “just do it”.  (statin effect)

I received comments like “how patient he is”, or at school  words like “peace” and “peaceful”.  I was thinking how passive he was. (no bumetanide/low dose clonazepam)

While there was no glaring loss of cognitive function and spelling tests and maths test at school were not showing any deficit, I noticed a loss of ability to develop new skills. 

We use an excellent online program called Math Whizz and one thing we were learning was to how to use the calendar.

Typical questions would be:-

“What date is the second Friday in May?”
“What date if the first Monday in December?”
“What day (of the week) is the last day in June?”

You first have to click on “May” to get the calendar to turn to the correct month and then you can figure out the answer.

To my surprise, while still on the Polypill, Monty was getting pretty good at this exercise, on his first attempt.

However, a few days later, when we tried with no Polypill, he was struggling and as the days passed he got worse and worse.  (chloride levels gradually rising?)

There was even a return of the sensory overload that causes many problems for some people with autism and also Asperger’s.  Even the sound of a crow became disturbing.  Both Acetazolamide and Bumetanide are used to treat Hypokalemic Periodic Paralysis, which is a more severe form of Hypokalemic Sensory Overload and at least some types of Autistic Sensory Overload are a subset of this.

After two weeks of Bumetanide and Potassium the sound over-sensitivity has gone again.  It did not go away immediately.


Pleiotropic effect of Verapamil

While I initially identified the calcium channel blocker, Verapamil, as an effective inhibitor of aggression and SIB triggered by allergy/mast cell degranulation, I was once asked if I thought Verapamil might have pleiotropic effects in Monty.  Having stopped using Verapamil and then restarted it, all outside of the problematic allergy season, I have all the proof I need in my n=1 case.  Life is better with a little Verapamil; his calcium channel dysfunction goes beyond those in mast cells.

Verapamil was the last element of the Polypill that I re-started; I was rather hoping it would show no effect outside the allergy season.  Only after adding it back did things really return to what has become our "normal".

There is after all a vast amount of evidence linking calcium ion channel dysfunction and autism.



My Verdict

I think many people would be very happy to have a passive child, who can sit for two hours in restaurant.

Most people do not notice the fading of good behavior, because their overriding concern is the lack of any “bad” behavior.  So a bad behavior is followed by a “is this better?”, rather than a “Wow, do you know Monty did today …”.

I prefer a child who can learn, even if that means he may get fed up from time to time, and show it.

I was pleased to come home earlier this week and find Monty sitting alone playing his piano beautifully (no prompting, no reinforcement needed), with his music book laid out in front of him, playing one melody, turning the page and playing the next one, while his big brother had gone upstairs to play his computer games, because little brother does not need him. 

  

Intervention in Adults

Other than halting self injurious behavior (SIB), I am far from convinced that most people would even notice the difference if you took an adult with classic autism and started to treat him.

At that age, passive and patient is what most caregivers want.

So I see little prospect that “corrective biological therapy” will ever be initiated in many adults with more serious autism;  they will continue to be “tranquilized”.

Many adults with Asperger’s and high IQ do their own research and self-treat; some even read this blog. For them, even a small biological "improvement" can have a welcome effect on well-being. Good for them.



Intervention in Young Children

The best way forward is to intervene immediately after diagnosis.  In the US/Canada that might be two years old, but more like four years old in Europe.


If I was a Roche or Novartis, this would be my target:- non-verbal, non toilet-trained toddlers who make no eye contact, possibly cry a lot and tend to be kept at home.





Thursday, 1 May 2014

Channelopathies in Autism - treating Cav1.2 with Verapamil





 
In December 2013 I wrote about a leading Italian researcher and clinician called Professor Antonio Persico and gave a link to an excellent presentation he gave in the US, about his views on the underlying biological process behind autism.




  
He had a nice graphic in which he depicted the puzzle that is autism.



  
One of his findings was that in the autistic brain there is an excess of both physical calcium and calcium signaling (via ion channels). He did not draw any therapeutic conclusions, which as I said was a pity.

In fact, Persico is far from the first scientist to point the finger at calcium channelopathies.

A few months before this, I had decided I would apply myself to see if there were any safe, practical therapies that could be applied, based on all the scientific research about calcium ion channels; incomplete as it might be.

After a few hours, or so, of reading about the biology of calcium channels, the available drugs and the existing research in their use in conditions other than autism, I came to the conclusion that Verapamil looked a very likely candidate.

Verapamil is a so-called L-type calcium channel blocker (L representing long-lasting length of activation); it particularly affects a type of voltage-gated calcium channel called Cav1.2.  For various reasons, I had deduced that these Cav1.2 channels were possible open more often than they should be in the brain of Monty, aged 10 with ASD.  I proposed that over activation of these channels resulted in extreme agitation that leads to aggression and self-injurious behavior in autism.

Back in September 2013, Monty was still having behavioral problems, apparently brought about by summertime pollen allergies.  I did write extensively about this and how I had narrowed the problem down to mast cell degranulation and histamine.  Treating the allergy did a lot of good, but was never a complete solution, since the standard allergy drugs worked for only a couple of hours, rather than the 24 hours they claimed.

So I had Monty in a state of near explosion by mid-afternoon most days, with a red face and letting us all know he was not feeling good.  He would say things including “be nice”, “I want to be nice”, “to hit your head” or even, on a good day, “to hit your head and see birdies”.  By then, he was also having Rupatadine, a mast cell stabilizer, which did seem to help.  The eruptions were far less often and less severe than in July, but it was clear that more could be done.

One afternoon, I decided to give a very small dose (20mg) of Verapamil, and before my eyes, the anger and agitation began to fade and was replaced by calm.  It was the most amazing experiment that I have witnessed and within 20 minutes there was complete calm.

In the following weeks, I would still hear Monty say “be nice”, but this was no longer followed by any aggressive behaviour.  The trigger was still there to energize these channels, but they had blocked by Verapamil.  It was like firing a gun, but with no ammunition; there was a “click”, but no “bang”.

This is the reason that Verapamil is in the PolyPill, in case anyone has wondered.

Before you start googling, there is absolutely no published research to support the use of Verapamil in autism.  This is part of the reason I did not to write about it at the time.

Verapamil is also a blocker of certain voltage-gated potassium channels and has the effect of raising potassium levels in the blood.  We have seen in earlier posts that potassium channel dysfunction is also present in autism and that raising potassium levels helps reduce sensory overload.  One effect of bumetanide is that it lowers levels of potassium, so bumetanide and verapamil are in that way very complementary.

Subsequently, I have read that mutation of the CACNA1C gene is associated with schizophrenia, which is like adult-onset autism.  The calcium channel produced from the CACNA1C gene is Cav1.2.  So this might be a case of what helps in autism might help in schizophrenia.


 If you are interested in why I decided to test Verapamil, read on.

 
Observations


Anger & SIB

Anger, leading to violence against others and to yourself are behaviours that arise in many people with autism.  There are undoubtedly many causes, and many are behavioral.  If a non-verbal person cannot express what he wants, or a partially verbal child has some pain (e.g. toothache) and does not understand it, things are likely to get out of control.

But there are other times, when for no apparent reason, nasty behaviour can occur, so I presumed that there might be a biological explanation.  If there was one, then I would think about a biological intervention.

My wife always asked Monty if his head was hurting when these kinds of behaviors popped up.  He would usually say “yes”, but it could well have been to avoid any other questions.  But why not consider it as possible that there is a pain prior to SIB.


Fever Effect

Then we have the recurring observation about autistic behaviours changing when the person has a high temperature; the fever effect.  This has now been studied by literally warming people up in hot water and then carrying out behavioural test.


As usual in autism, this effect applies much more to some people than to others.  Monty is moderately affected, but some people are dramatically improved.


Headaches

Headaches are very common, but some people do seem to get far more than their fair share.  Migraines are particular nasty and so is another type, the cluster headache.

Cluster headaches are severe headaches that are clustered together.

Cluster headaches are occasionally referred to as "alarm clock headaches" because of the regularity of their timing and they may awaken individuals from sleep. Both individual attacks and the cluster grouping can have a metronomic regularity; attacks striking at a precise time of day each morning or night is typical. This has prompted researchers to speculate involvement, or dysfunction of the brain's hypothalamus, which controls the body's "biological clock" and circadian rhythm.

Now I have noted that in some literature it is claimed that parents of children with autism often have a history of headaches (and I do not mean caused by dealing with their child’s autism).  

Note that most younger people with autism have a “faulty” biological clock, so they have trouble sleeping through the night.
 

Febrile seizures

Seizures and autism are closely related.  Febrile seizures occur in some children when they have a temperature greater than 38 °C (100.4 °F).  They are twice as common in Japanese children than they are in Western children, occurring in up to 9% of children and mainly in boys.

It is not agreed exactly what causes febrile seizures, Japanese research points to voltage-gated sodium channels, which does not really support my theory.  However, rather than delete this part of the post, I did a little more digging and found a paper in the Journal of Neuroscience that does neatly fit by theory.



Comorbidities

It is well documented that poor cardiac health is associated with autism.  I have commented before that it is not entirely by coincidence that some drugs that help autism were actually developed as drugs for heart problems.  By treating the autism, a side benefit is that you may also be treating (and perhaps avoiding) the heart disease that would otherwise likely to develop at quite a young age.

So, while giving statins and calcium channel blockers to a healthy young person would be irresponsible, the same may not true for people with autism.  In the same way that people with type 1 diabetes have been recognized as being at high risk of heart disease and are put on preventative drugs at a much younger age than the wider public. Patients with type 1 diabetes are 10 times more at risk from heart disease than other healthy patients.  They are recommended statins, aspirin therapy and an ACE inhibitor.  An ACE inhibitor reduces blood pressure in a different way to how Verapamil also lowers blood pressure.

Due to the severity of neurological/behavioral problems of autism, medical practitioners are not really worrying about cardiac health.


Too Much Calcium

There are opposing views about the role of vitamin D in autism; in other words, too much or too little.  There have been some interesting thoughts about milk and autism, and not about whether or not it is fortified with extra vitamin D; the point was the role played by calcium.

Then there is the mother who found that supplementing her autistic child with calcium had some frightening consequences, producing profound regression.



Basic Biology

If you want to read about the basic biology of calcium channels, here are links to Wikipedia;-





Connections with the biology

One of the things that drew my attention was the fact that the behaviour of some calcium channels is temperature dependent.  There are other ion channels that are also temperature dependent.  The Cav1.2 channels are known to behave differently according to their temperature.


Connections within the literature


Timothy syndrome

I have covered Timothy syndrome previously in this blog.

This is a, thankfully, extremely rare condition in which the most people do not survive to childhood; those few that do are likely to have autistic-like symptoms.

The syndrome is caused by severe mutations of the CACNA1C gene.  As a result it is also associated with severe heart problems, since this gene expresses the Cav1.2 channel that is found in the heart and the brain.


In the following article, Dr Ricardo Dolmetsch used an experimental L-type calcium channel blocker, called Roscovitine, to “successfully” treat his model of Timothy Syndrome.


Dolmetsch is now Head of Neuroscience at the Novartis Institute for Biomedical Research.  I did write to him once, when he was still at Stanford, to ask if he was interested in discussing some of my ideas – no answer, I guess he was busy curing autism.

Headaches

It has been known for many years that some L-type calcium channel blockers are effective in treating both migraine headaches and cluster headaches.


Individualizing treatment with verapamil for cluster headache patients

 

CONCLUSIONS:

Providing the dosage for each individual is adequate, preventing CH with verapamil is highly effective, taken three (occasionally with higher doses, four) times a day. In the majority (94%) with episodic CH steady dose increase under supervision, totally suppressed attacks. However in the chronic variety only 55% were completely relieved, 69% men, but only 20% women. In both groups, for those with partial attack suppression, additional prophylactic drugs or acute treatment was necessary.
This study found that some people required 5 times higher dose than others and doses were up to 960mg per day.

Verapamil in prophylactic therapy of migraine

We conducted a double-blind, placebo-controlled crossover study of verapamil HCI in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs


Mice and SIB (Self Injurious Behaviour)

Lots of people do not like the idea of being compared to mice, or even worse rats.  Nonetheless, this following paper is indeed very relevant, it showed that it you active the L type calcium channels in mice they will engage in self injurious behaviour.


The L type calcium channel agonist Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine.

However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

If Monty was a mouse, verapamil would therefore likely not work and I would probably have had to use nimodipine.


Genes

I do not claim to be an expert in Genetics, but I can uses genes to support my case.

In 2013 a paper was published in the Lancet that looked for genetic links between a range of neurological disorders.



In this paper you can find out many things, including:-


  •  Gain-of-function mutations in CACNA1C causes Timothy syndrome
  •  CACNA1C is a susceptibility gene for bipolar disorder, schizophrenia, and major depressive disorder
  • neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, executive function, attention, and memory
  • Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia
  • CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signaling proteins and molecules
Now “my” Calcium channel, also known as Cav1.2, is encoded by the very same CACNA1C gene.

In a similar paper, autism also gets a mention 

“Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders”


So all in all the genetic analysis also point to Cav1.2 as a good candidate for some intervention.


Epilepsy

Verapamil is being investigated to treat various forms of epilepsy and seizure.  This is interesting, since seizures are highly comorbid with autism.

Seizures tend to develop in early puberty in many cases of autism.  It appears possible (maybe not probable) that if you can avoid the onset of epilepsy during this time of hormonal change, you may be free of it for life.  The science has shown that the first seizure makes a biological change occur;  the same is indeed true with asthma.  If you can identify the at risk group (i.e. people with autism for epilepsy and atopic dermatitis for asthma) you may indeed be able to avoid it.

I was not aware of this until after Monty, aged 10 with ASD, had developed asthma, but I am well aware of it now.  I am actively taking steps to avoid epilepsy.

The other useful aspect of this research is that they are all clinical trials of Verapamil in children.  This is important from the safety perspective.








Choice of Channel Blocker

In medicine, calcium channel blockers were developed to treat heart conditions.  A common problem in treating autism is the need for drugs to freely cross the blood barrier (BBB); most do not.

Other issues include the half-life of the drug and most importantly the safety of the drug.

Given these considerations, and the fact that I know precisely which calcium channel I want to block, this led to me to Verapamil.

It is very widely used, and is available very cheaply as a generic in sizes down to 40mg.  Adult and indeed child dosages go all the way up to 400+mg a day.

Since the idea is to subtly affect the brain and not dilate blood vessels in the heart, which increases the supply of blood and oxygen; a small dose was envisaged, 20 mg.

On paper, Nimodipine, also looks a very interesting candidate, but it is rarely used in children.  It would be useful to trial it on adults with autism.  It works better than verapamil in mice with SIB.


Conclusion

I must admit that some of my “evidence” was gathered after I had proved my theory was valid, like the mice with SIB after their L-type channels were activated.

Given all of the “evidence” it does amaze me that it did not occur to anyone to try a drug like Verapamil in children with autism.

Clearly all drugs carry a risk, but so does violence and self-injury.


P.S.  Note that magnesium is also a calcium channel blocker