Nom de guerre, Mon frère - Manchopathy

Today’s post had better be a quick one.  The desk research in the background is getting complicated and I have just ordered a 900 page book on Human Physiology, so as not to spout complete nonsense.  Worse still, a couple of days ago, I received in the mail, a big brown envelope from Tokyo with a juicy report on the use of Ceredist, a TRH analog.  It is 20 pages long, and the bad news is that 18 pages are in Japanese.  The good news is that I had expected all 20 pages to be in Japanese.

To business.   You are slowly being introduced to the cast members of this blog.

The star of course is “Monty”, aged 9.

His supposedly “typical” big brother, aged 12, is going to be called “Ted”.

Head of Applied Research, part-time biker and Speech Therapist will be called Dule (“Doolay”)

Last week I decided that it was time for some good old fashioned primary research, to test a hypothesis that I had formulated.  This is what we presented to the in-house ethics committee, for approval:-

1.    Many children with autism exhibit what appears as sensory overload.  On hearing a moderately loud sound, they will cover their ears, almost as if in pain.  Bright lights, darkness, certain smells, even touch can trigger similarly strong reactions.  Entire books have been written documenting these odd behaviours, but I never read an explanation for them.

2.    In my trawl through the literature, I noted that a disorder with surprisingly similar symptoms has been documented -   Hypokalemic sensory overstimulation

This disorder manifests itself as an overwhelming feeling of sensory stimulation.  But then disappears 20 minutes after a dose of oral potassium.  A related, but much more severe, disorder that causes temporary paralysis also exists -  Hypokalemic periodic paralysis

3.    The recommended daily amount of potassium for adults is 3,500mg.  A typical banana contains 400 mg of potassium. A dissolvable tablet of Potassium Citrate contains 500mg of potassium.  So 500mg is a safe dose to experiment with.

4.    A laboratory experiment is proposed using an MP3 file of a baby crying. Dule will first establish a baseline volume (VB) at which Monty will cover his ears. Monty will be sitting in a fixed position in the lab. This test will be repeated over a few days to see if VB varies.

 

5.    Then the subject will receive 500mg of oral potassium and wait for 20 minutes. The MP3 file will be played again while he is sitting in the identical test position. Dule will crank up the volume and note the new threshold volume (VT).

 

6.    The same test will be repeated with Ted and Dule as subjects.

 

Prior to providing Dule with the oral potassium solution, Peter suggested to Dule that he would perhaps prefer if the test did not show up anything worthy of further investigation.  Since that would again drive Peter crazy, that no serious scientist had noticed this, done something about it and published their work.

Here is the raw data from the test:-

 

Volume * at which sound becomes disturbing
	7-Mar-13	8-Mar-13		11-Mar-13		11-Mar-13
						after K+
Monty	9	9		9		16
Ted				23		26
Dule				21		23
* sound level on digital display of Philips mini HiFi
room is about 20 m2, subjects were 2.5 m from HiFi unit

 

Discussion

As you see, Monty is far more sensitive to sound than both Ted and Dule.  Monty experiences a sharp increase in his capacity to cope with sound stimulation after drinking the potassium.  Ted and Dule show a small increase in capacity, that may be just down to measurement tolerance/error. (Dule was testing himself, after all)

Mon Dieu!  It looks like we have to do a serious follow on study with more subjects and some flashy equipment.  Worse still, now I have to be able to explain scientifically why this is happening !

 

The cause is related to something called VDCC (voltage dependent calcium channels) these are like little valves that open to let  Ca²⁺ ions in or out; they are misbehaving.   Recall that Bumetanide works in a similar way by triggering NKCC1 and NKCC2 (Sodium, Potassium, Chloride Cotransporters) to let in/out  Cl^- ions.  The subject of misbehaving ion channels has already been given a fancy name by scientists, its Channelopathy.  Now I was wondering how I was going to explain my use of French in this post.  It's all about the English Channel or should I say la Manche, and so we'll call it Manchopathy.

 

 

 

Beware of Men in White Coats - plus some interesting research

I am not quite ready yet to start presenting my own research findings.  They will start appearing in a few days.  In the meantime there are a couple of very readable papers from two different sources that are well worth looking at.

The first paper is a review of drug therapy in autism.  It was written in 20102 and includes more drugs than appear in comparable literature written in the US.  As a matter of interest, it was written by Indian scientists, but published by the Polish Academy of Science.  It is open access, so you can download it in full.

It is highly readable and even includes Bumetanide, my original epiphany drug.

Well done Baldeep Kumar et al from Chandigarh.  If it was up to me, all parents of kids with autism would get a copy of your paper Drug therapy in autism: a present and future perspective.  At least they would then have a sound factual understanding of what is available and what is on the horizon.

 

The second paper sounds even better:- Novel and emerging treatments for autism spectrum disorders: A systematic review.  It is also free to acces the complete paper.

It is published by the American Academy of Clinical Psychiatrists.  I have no idea who they are, but the name sounds very impressive.  The paper is certainly worth your time to read and undoubtedly took a great deal of desk research.

However, as I pointed out in my earlier post, about primary and secondary research you have to be very careful who is analysing the data.  It is best to do it yourself, whenever possible, or failing that contact Baldeep in Chandigarh.  Always read the label, even if you are one of those people that cut them off.  The paper is written by an author who is so prolific even my desk has got 5 of his papers lurking on it.  He is a big believer in the merits of hyperbaric oxygen therapy. The problem is I also have 2 papers on my desk that are highly critical of how he interprets his research data.  I think he may be suffering from Autistic Stress Syndrome (ASS) that I introduced in an earlier rather harsh post.

In her paper, Doreen Granpeesheh really lays into his powers of analysis and data interpretation.  Look at the bottom of page 272 if you are interested.

The other paper I have, really trashes the author.  Enough said.

Beware of Men in White Coats.

 

The risk of doing nothing

Everything you do entails some level of risk.  What is important is to understand the risk and takes steps, where necessary, to mitigate it.  We do this every day, even if we do not realise it.

 In the field of autism there are many risks to consider in daily life.  Many of them are the same risks that apply to very young typical children;  running out into the road without paying attention to the traffic, falling into an unattended swimming pool, even touching a hot iron, or hot pan on the cooker.  These are risks you can mitigate by good parenting.

When it comes to chemical/pharmacological interventions extreme care should be taken by the parents.  This puts them in an awkward question.  They undoubtedly want a miracle cure and thanks to the internet there is no difficulty in accessing them.  When such therapies are put forward by actual medical doctors, mainly from North America, you can hardly blame the parent for turning off their built-in risk assessor.  The doctor must know best.

I am not going to give you a list of the various chemicals/supplements/drugs that some parents are even injecting into their kids.

I think you need to do your own risk assessment of whatever intervention(s) you are going to use, be it behavioural, chemical, musical, swimming with dolphins etc.  If you are not able to assess the risk, then best not to take it.

If there is no downside, it is not going to be the end of the world if there turns out to be no benefit.  It may just lighten your wallet a little.

For me, the biggest issue has always been the risk of doing nothing.

 

My own experience with risk

I have taken some seemingly big risks in my time, but because I usually took mitigating action, I never came to regret them.  I travelled once from Delhi, up through floods in Nepal, across the Himalayas to Tibet, across to Hong Kong, then back to Beijing and across what was then Soviet Russia, to Moscow, then East Berlin over to the English Channel and home.  This was all done over land with public transport.  I came back without even a scratch, although several kilos lighter.

When you stop thinking about the risks, is when trouble will find you. A year after graduating from Imperial College, I heard that my favourite professor, Neil Watson, a world renowned expert on turbochargers (page 2 of link), had fallen off a ladder at home and killed himself.  Many years later, I nearly killed myself, on my own building site, falling backwards into an empty swimming pool.  

E Learning or is it E(asy) Learning !

This blog is mainly about finding science-based therapies for autism and the focus is actually on the pill-popping variety.  If you ended up on this blog looking for general tips to help for your recently diagnosed child with ASD, this is a post just for you.

Before getting to the easy part, let’s keep in mind the foundations on which it should be built.

 
Applied Behavioural Analysis (ABA)

If you know nothing factual about ABA (and there are lots of bizarre stories on the web and spread by followers of other faiths), you will be interested in a great new free resource on YouTube.  A company called Butterfly Effects published a superb series of free training videos.  I wish they had been around 5 years ago.  Here is one halfway through the course when the child is already partially verbal.

 

There are currently 66 videos in their channel, scroll down a bit to get to the nitty gritty.  They also do on-line training courses.

The other link is a web-based retailer in the US that ships worldwide all the books and accessories you could possible need for your home-based ABA programme.  They used to do a starter pack with what you need to get going.

Those two links should be enough to get a motivated parent into action.  If it does not, then ABA probably will not work wonders for you.  With ABA, you have to put in a great deal to get a little back, then slowly, investing a great deal starts to give you a lot back.

Now for the E(asy) Part

E  Learning

Going back to the not so distant past, when there was no internet and you did not have a computer at home, let alone in your jacket pocket, I learned some new acronyms:-  CAD (computer aided design) and CAM (computer aided manufacturing).  Nowadays most of us have a pretty good idea of what this is all about.  At the time I thought CAD-CAM was pretty cool.  That makes me an early adopter.  So no surprise then that I looked to see how computers could help with learning in autism.  Five years ago, there were no Ipads, but you could easily buy a touch screen monitor for your home PC. There are now lots of Apps written for kids with ASD and the good news is they are cheap.

I spent a small fortune on computer-based training (CBT) and its techy cousin Web-based training (WBT).  It was money well spent.  In reality the adult generally needs to sit by the PC, so it is better described as computer assisted learning (CAL).  Whatever you call it, it is great.

Toddlers learning to communicate

From about age 2 and up I would strongly recommend Laureate Learning

They have a special website for families, as opposed to schools and therapists, with lower pricing, but it is still seriously expensive.  The software logs the child's performance and only when one area is mastered can he move forward.  There are specific programmes for each topic, for example nouns, verbs, prepositions etc.

I spent many hours using the entry level programs with my son, before he was verbal.  They were really helpful and allowed him to show that he really did have a wide receptive vocabulary and understanding, even though he could not talk.  At that point (under 4 years old) we used a touch screen, rather than a mouse and it worked a treat.  He could very happily spend 20- 30 minutes per session.

If your budget cannot stretch to Laureate Learning, there is much cheaper alternative to see if your child is going to like computers. It is called LDA software, from Sherston.   It is not as sophisticated, but I still spent many hours prompting my son to use it.  LDA make a wide range of flash cards that form the initial basis of a home ABA programme, Sherston just made a computer programme out of the cards.

The software is a bit old (2005)  but still works.  Buy direct from the publisher because some places sell it for a much higher price.

 

Verbal child learning to read

Once your child is verbal, you will start to wonder how he is ever going to learn to read.  Here again science can help you.

There is a truly wonderful programme that used to be called HeadSprout and is now called MimioSprout.  The developer got taken over and the new owner changed the name.  It is a product for the mass market, but under the cover lurks a great deal of ABA.  It has great sound and graphics.  I found it fun.  My son loved it.
 

The programme allows you to repeat lessons.  Typical kids rarely need to do this and will speed to the end of the course.  Kids with ASD need lots of repetition and I was repeating lessons on average about 5 times.

A computer probably cannot teach an autistic child to read, but it can certainly help a great deal.

Numeracy

Having learned to talk and then read, the next big hurdle is to learn some maths.  For a typical kid you do not even have to think about this. Maybe you get called in to help with long division, but not with 1 + 1.

Again, a great mass-market web-based programme is here to help.  It is called Whizz.  It has lots of fun graphics and goes from the very basics up to the end of primary school.  It includes the full curriculum, so things like weights and measures, telling the time, interpreting graphs and charts are all included.  It is much more than just numeracy.  As with Headsprout, the key is to repeat the excercises before moving on.

If your typical child used Whizz, I think they would hardly need to go to maths class at school. In the US Whizz seems to be used a lot for home schooling. I first came across Whizz on a US home schooling website.

Again, this continues to be money very well spent.

 

 

Rats in the Basement - lab update #1

This may be only the 4^th post on this blog, but in the background research is actually quite far advanced.  A few hundred learned papers on, have there been any further epiphanies?

Well at the risk of sounding smug, I have to say yes, or least maybe.

 

When I started out in late January 2013, I knew that rats in the basement was not going to be an option; either my elder son would use them for target practice, or my wife would object.

My original plan was to rely on my powers of observation to guide my research and just draw on the pool of existing scientific research as needed to develop a plausible hypothesis, that could then be tested and quite likely rejected.  This is more like primary research, the fun type. I used to do a lot of this.  Primary research is used extensively in the business world and sometimes verges on espionage.

In primary research I now have two projects:

 

·         TRH and more specifically TRH analogs.  This looks very promising, but gets pretty complicated and there will be lots of citations.

·         Hypokalemic Sensory Overstimulation.  This may prove to be just a curiosity.

Secondary research is what most people do.  It is all about reading other people’s research and then either dutifully regurgitating it, or putting a new spin on it and taking it forward.  I used to this a lot and it can also be fun.  The interesting thing I learned is that two different people, or “expert” teams, could look at the same data and come to diametrically opposing conclusions.  This has great relevance to Applied Neurological Analysis, which as from post #1 is now officially known as ANA.
 

Researching TRH took me into the depths of research concerning a wide range of psychiatric disorders, addictions, epilepsy and even HIV-AIDS.  It also led me to read some much lighter weight studies that actually did have the word autism in them.  Then one evening, on Google Scholar, I was jumping between Hyperbaric treatment for autism and vitamin B12 injections and had about 20 windows open on my laptop.

 

Just as lithium-ion batteries can overheat and start smoking on Boeing 787s, it is also possible with your laptop.  Not wanting my research to be grounded, I picked up the pace.

 

I was reading a paper that was in effect junking the use of Methylcobolamin (Methyl-B12) injections in autism.  Then I saw that it mentioned a subgroup for which it appeared the therapy had indeed produced a measurable  positive effect.  The author hypothesized that in these children the B12 was somehow raising the level of Glutathione (GSH). A-Ha and what exactly is that?  All will be revealed in a later post.

 
This led to 2 developments:-
 

·         Open up an investigation into GSH

·         Note that sub-groups can exist in autism and so there just may be more to a “failed” clinical trial than meets the eye.

 
Having allowed the laptop to cool down, I did a trawl through the research on Omega 3 fish oil.  I am not a follower of Complementary and Alternative Medicine (CAM), but it turns out that its followers are big buyers of fish oil.

I used to take omega 3 capsules because I read they are good for your heart.  A friend recently asked us to pick up some special ones in London that are supposed to make your kid get higher marks at school.  It turns out that even my Mum used to be given cod liver oil and malt during World War 2.  I would have written “during the war”, but in many parts of the world, where you read this blog, it then raises the question “which one?”.

Having learned from my friend Colin, that you can actually be allergic to specific kinds of fish, I had discovered a few months back that I too have intolerance to farmed salmon and trout.  When I looked into what they feed the fish, I soon came to believe that this was a plausible cause of my symptoms.  So this means no more salmon and much less “natural” omega 3.  It turns out that some people are even allergic to the fish oil supplements as well, but thankfully not me.

I concluded that I have a ready use for a large batch of unwanted, long expiry dated fish oil, should I need one.  So I decided to add an Omega 3 to my secondary research and potentially add it to the primary research pile.  I do admit to starting with a sceptical bias.

As you can see, often you need both primary and secondary research for the same job, but for the moment at least, there are no rats in the basement.

 

 

P.S.

If a further dose of humour is required at this time of day, ponder the reaction of the Japanese airline executive from ANA (All Nipon Airways) who is googling to see how much PR he is getting due the Lithim-Ion batteries in his parked fleet of Boeing 787 Dreamliners. Colin will be famous in Japan, as he deserves to be, and the sales of fish oil will rise.

 

 

See you in Hell then.

Does religion have something to do with treating autism?  It should not have, but actually it does.

 

Depending on where you live in the world, you may come across a lot of religious intolerance.  In Iraq, Muslim Sunnis don’t seem to care for Muslim Shias, in the Indian subcontinent Hindus for Muslims, in Northern Ireland some Protestants for Catholics, the list goes on.  To an outsider, the differences between the competing teachings may seem marginal, but to an insider it can even be a reason to go to war.  It has often been the case that some of those going to these extremes, do not even really understand the competing teachings of their own religion.

 

What you might ask does this have to do with Autism and the subject of my blog?

 

If you have a child with autism, or you work full-time as a carer or therapist, you will likely have experienced emotional stresses that would destabilize all but the calmest of souls.  If you are new to the subject of autism you will probably skip over this part, if not, it will surely resonate deeply.

 

As will become apparent in forthcoming posts, this syndrome is very relevant when sifting through the research papers.  Acronyms are very popular in the literature of Applied Behavioural Analysis, neuroscience and psychiatry. Being a mixture of engineer/strategy consultant/PR consultant and aspiring entrepreneur I often struggle with spelling, let alone remembering what all the acronyms mean.  In this case, I will make an exception.  I will term it Autistic Stress Syndrome (ASS) and define it as when a sufferer loses all, or part of, their rational objectivity and becomes obsessive, close minded and  perhaps judgemental themselves.  A professional suffering from the syndrome will be lovingly termed “a smart ass”.  There are of course very many well intentioned smart asses and indeed some of the most useful people you can know will be smart asses.

 

This blog is all about science.  To be a good scientist you have to rational and objective.  To be a great scientist you also need to challenge accepted wisdom, realize that you do not (yet) know everything and sometimes you might just have got it wrong.

 

In the field of managing/teaching children with autism there are several schools of thought, some of which overlap.  Here is a short list:-

 

1.    Applied Behavioural Analysis (ABA) / Lovaas / Verbal Behaviour (VB)

2.    Floor time / Greenspan

3.    Hannen

4.    Occupational Therapy (OT)

5.    Picture Exchange Communication System (PECS)

6.    Speech  & language Therapy (SLT)

7.    Structure, Positive, Empathy, Low arousal, Links (SPELL)

8.    TEACCH

 

It is striking is that in many cases a professional specialized in one of these areas will not even want to discuss there being any merit whatsoever in the others.  As with religion, if you advocate a mix and match approach, rather than accept a one size fits all approach you will be consigned to purgatory or even hell.

 

When it comes to the field of Complementary and Alternative Medicine (CAM) the religious fervour grows even stronger and science goes completely out of the window.

 

 From my own biased experience of behavioural intereventions, here is what matters:-

 

·         Earliest possible start of intervention

·         Consistency 24/7 among care givers / therapists

·        Superhuman effort to provide near constant, stimulating, one-to-one contact during waking   hours for as a many years as it takes

 

I looked into all methods and found that the choice of ABA/ VB was a no brainer.  VB is just an approach within ABA that prioritizes speech.  PECS is a communication system for non-verbal kids, that is based on the principals of ABA.   Before the child is verbal, Hannen and Floor time are very useful approaches to encourage interaction. SPELL and TEACCH have lots of good methods highlighting the need to have structure, employ visual cues etc.  If the speech therapist (SLT) can teach you and your non-verbal child PECS that would be great.  Motor skills and play skills are a key part of an ABA/VB programme; they are also part of Occupational Therapy.  The OT therapist is probably using ABA without even knowing it.

 

 

 

 

Bumetanide - how a water pill can reduce autistic behaviours

Bumetanide is a loop diuretic that has been used for adults since 1976 and in children since 1986.  It has recently been successfully used to halt seizures in extremely young babies.  The use of Bumetanide for the control of such seizures was proposed in 2005 along with the suggested mechanism. 

 

A summary of that mechanism is that elevated intracellular levels of Cl^-  cause GABA to excite rather than inhibit inside the hippocampus.  But in the spinal cord GABA is already known to be inhibitory.  As a result non-convulsive seizures can occur in very young babies.  Because the GABA in spine is inhibitory there are no violent signs of convulsion, but in the hippocampus there is a seizure going on.

Bumetanide reduces intracellular levels of Cl^- , it inhibits the NKCC1 transporter so renders GABA inhibitory in the hippocampus . This action alone has been shown to make the loop diuretic a much more effective anticonvulsant than phenobarbital, which can actually exacerbate the seizure.

Research shows that during a brief period from just before to just after birth, maternal oxytocin (see note * below) temporarily renders GABA inhibitory, possibly by reducing NKCC1 activity.  

Thereafter, GABA remains excitatory until GABA itself causes a switch from excitation to inhibition of GABA by inducing expression of the mature chloride transporter, KCC2.  KCC2 transports chloride out of the cell, thereby reversing the concentration gradient of chloride.

Most anesthetic and indeed anticonvulsants are GABAergic.  It was found that giving such an anesthetic to a very young rat actually stimulated it, since GABA was still excitatory in the hippocampus.  For the same reason giving the GABAergic anticonvulsant  phenobarbital to a young baby only makes its seizure worse.

Valium is also GABAergic and so when its use in autitstic children demonstrates a stimulating rather than a calming role the question then arose as to the possibility of that elevated intracellular levels of Cl^- are causing GABA to remain excitatory rather than inhibitory in the autistic brain.

The logical question was than would reducing the level of Cl^- trip GABA back to being inhibitory and then this would manifest itself in measurable behavioural changes.

This hypothesis was first tested in a small trial in 2010 and then in full randomized controlled trial in 2012.


Merci beaucoup M.Lemonnier pour votre contribution à la science de l'autisme !
 

Note

*Oxytoxin may sound familiar. It is in Phase II clinical trials as a treatment for autism.

Coincidence ??




 

Epiphany - Applied Neurological Analysis

For 5 years I have been learning and applying ABA (Applied Behavioural Analysis) to treat autism. This is a very time consuming, although highly fruitful process. Continued gradual improvement has been the result.

Then in December 2012 came my epiphany.

I read a very interesting clinical trial - A randomised controlled trial of bumetanide in the treatment of autism inchildren. This turned out to be a transformative moment for my son.

I thoroughly checked the possible side effects, acquired bumetanide, and made my own trial not telling anybody. Almost immediately the positive effects began to show and I kept getting unprompted feedback from school, relatives and even the special piano teacher. "What has happened to Monty ?" they were all asking and then they started telling me all the great things he was doing.

Then I looked into the history of the controlled trial. It all started when Lemmonier asked a colleague why is was that Valium works in reverse in kids with autism. This really shocked me. Is it really true that there are well established blatant biological abnormalities in autism ?  If so, maybe there are more ?

I started looking in the research and there are lots of such abnormalities, several waiting to be thoroughly investigated.

So I termed my new project ANA (Applied Neurological Analysis). I am going through 40 years of research (via Google Scholar) looking for anything that looks odd to me, albeit not a neurobiologist.

I already came up with some great stuff. I am looking for things that have either been proved in a randomised controlled clinical trial, or where just the trial needs to be done.

There is a remarkable amount of relevant research already out there, particularly if you include associated disorders such as epilepsy.