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Showing posts with label ASD. Show all posts
Showing posts with label ASD. Show all posts

Monday 7 March 2016

Guideline on the clinical development of medicinal products for the treatment of Autism Spectrum Disorder





Most readers of this blog are in North America and I think this will be by far the largest market for any new drugs approved for autism.

An even bigger market by population (508 million vs 354 million) is the European Union, where the drug regulator is now developing guidance for those developing new treatments for autism.  They are asking for comments.

The only people really qualified to give comments are those with some experience of treating autism, very few of whom live in Europe.

Regardless of where you live, I would suggest that the doctors and researchers who read this blog take a look at the short guideline document and pass on any comments they may have to the European Medicines Agency.  

For everyone else, I do not suppose they expect to get comments from lay people, but why not go ahead and surprise them?

The obvious comment would be to hurry up, but there are many more constructive comments that can be made. 



The Press Release:




The Draft Guidance Document:- 








Tuesday 29 July 2014

Steroids for Regressive Autism

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


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




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

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


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

Here are some key points from the paper:-

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

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


  
'Wicked'

Slightly off-topic but, the following is relevant.  

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

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

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

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

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


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

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

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



Conclusion

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

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

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

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




Saturday 28 June 2014

Traumatic Brain Injury and Autism, linked again, but not in a good way


It came as no surprise to me that many people involved in high profile mass shootings suffer from mild autism (Asperger’s).  What did surprise me was that so many people with TBI (Traumatic Brain Injury) also commit such crimes.  Indeed in a recent study (see later) of 239 killers, 28% appear to have autism and 21% suffered from TBI.

Indeed the name used by the Austrian, Hans Asperger, in 1943 for his newly identified condition was “Autistic Psychopathy”, it was only many decades later when his work was discovered for the English-speaking world by Lorna Wing in 1981, that the condition became known as Asperger’s.  Wing did not like the term “Autistic Psychopathy” that Asperger had chosen, because she thought it would apply sociopathic (violent) behaviour to the lay public.

Wing recently passed away and the New York Times wrote a nice article about her.



Her paper, that first established Asperger’s syndrome, is here:-



Since this paper was published only in 1981, it is hardly surprising that so few older adults have been diagnosed with Asperger’s.  Indeed it was a full ten years later, in 1991, that an authoritative English translation of Asperger's work was made by Uta Frith; before that Asperger’s Syndrome (AS) remained virtually unknown.

As we have noted before, Psychiatrists and Psychologists like to take their time; no Space Race or Manhattan Project in their little world.  Still, half a century is pretty slow.

People suggesting an autism “epidemic” might take note that only 25 years ago, absolutely nobody bothered to diagnose mild cases of autism, they did not even have a word for it.  Those of you still wondering why your doctor still knows so little about autism, might also take note.

Now I understand why there were no Aspies in my school, when I was a child.  They had not been invented.  I had assumed that Asperger’s syndrome was of the same era as the man himself, but Hans Asperger died in 1980.

I had no idea it took Psychiatrists, Psychologists, and yes, Doctors, half a century to absorb, accept, and begin to act on a new idea;  all because Asperger spoke/wrote in that “extremely rare” German language.  Incidentally, 50 million Americans claim German ancestry, not to mention that the British royal family is actually German; the House of Windsor is really the House of Saxe-Coburg-Gotha, before some image building took place in 1917 during WW1.

So don’t raise your expectations of these people too high, for the next half century.  Hopefully they have figured out Google Translate.

Here is the Pediatrician, Professor Hans Asperger at work in Austria; nice drawing on the black board:-




  





  

Asperger’s (Autistic  Psychopathy) and  TBI among Mass Murderers

In the recent study of 239 mass murderers almost 50% had either ASD or head injury /TBI, the other half suffered from “psychological stresses”.












At least the author has clearly read about Hans Asperger, he suggests a new diagnosis, Criminal Autistic Psychopathy, as a subcategory of Asperger's syndrome.

I will not dwell on the murder angle, other than to say that perhaps if people with Asperger’s were actively included at school, they would ultimately lead happier and more successful lives.  The percentage that currently go on to have very violent thoughts, might not then do so, and the tiny percentage of those might not act on those very thoughts.

I should point out that I do not find it odd at all that the boy with Asperger’s in my elder son’s class keeps telling him “I will kill you and your parents”, to which Ted, now 14,  says “but I won’t let you” and the response is “but I will wait until you are not there”.  I am not seriously worried that he will do this, but if I was his parent, I would be very concerned that he says/thinks such things.

Fortunately there are no serial killers with Classic Autism, so no need to lock up Ted’s brother.


ASD, TBI & PTSD

We have come across TBI several times in this blog, and I note that many people coming to this blog are TBI sufferers.

Both ASD and TBI are associated various degrees of mood disorder.  These feelings are driven by neurological changes that are usually ignored, or treated rather crudely with drugs that rarely seem to work entirely as intended. 

I think the world of autism could learn much from the mood disorders that follow TBI.

Epilepsy occurs very frequently in both ASD and TBI.

The third condition that we might usefully consider is Post Traumatic Stress Disorder (PTSD).  This condition is also associated with severely affected mood.  Army veterans returning from recent conflicts can be greatly affected by PTSD.  We came across the military type of PTSD in the post about the hormone TRH.  One of the many roles of TRH in the body seems to be linked to mood, and very specifically suicide.  The US military is funding development of a TRH nasal spray to reduce the incidence of suicide.  They cannot give antidepressants, like Prozac, because a well-known side effect is suicidal thought.  TRH is included in my autism PolyPill.

People with Asperger’s do have an elevated risk of suicide, another reason to sniff some TRH, perhaps?


The Link between ASD, TBI and PTSD

The above conditions are very different, but they share some similar symptoms relating to mood disorders.  By understanding the neurological underpinnings of the mood disorder in one condition, we might well learn something useful for the others.

The research into TBI seems to focus on better surviving the first few hours.  We saw in earlier posts that by giving intravenously either statins, or the female hormone progesterone, in the Emergency Room, there was a marked increase in survivability.  Progesterone and statins are both highly neuroprotective.

When Michael Schumacher had his TBI in a recent skiing accident, I was saying to myself “give him progesterone”, I very much doubt the French neurologists did.  They probably do not read American/English research.

In the case of autism, very recent research has shown an excess of male hormones in the amniotic fluid of mothers who give birth to a baby that will later be diagnosed with autism.  We also have seen how some people with mild autism treat themselves with progesterone to feel better.

Many years ago pregnant women were often prescribed progesterone and/or estrogen, now it seems to be limited to some women undergoing infertility treatment.  Perhaps giving progesterone might reduce the incidence of autism?

Statins are a known treatment for cytokine storms and are included in my autism PolyPill.

Once back home, people recovering from TBI and PTSD do seem to face similar treatment to adults with autism; they get ignored.

Due to all the recent conflicts in Iraq and Afghanistan, we do hear quite frequently about the consequences of untreated PTSD.  There are also very many cases of TBI, resulting from motor vehicle accidents (cars, bikes, quad bikes etc), sports accidents (skiing) and shootings (particularly in the US).  It seems that in many cases there can outwardly be a physical recovery, but personality has altered.  As we have seen in this blog, all the various hormones and neurotransmitters are interrelated and so any neurological damage will have multiple knock-on effects.  This will consequently transform, for better or worse, someone’s personality.  I used to know a person once, who was about to marry for the third time.  The second wife had been hit by a bus while crossing the street, and I remember how odd it sounded what he said next, “when she got better, she was a different person and I had to divorce her”.  The change in personality makes perfect sense, we are all the result of the particular homeostasis our brains settled at.  So some people are gregarious, others are loners, and a very small number become psychopaths.

If we more fully understood how the brain works, most types of mood disorder would likely be treatable.  Since people with TBI and mild autism are now easily identifiable, there is yet another reason to accelerate this research.  A frequent justification for the low expenditure on autism research is that “you don’t die from autism”.  Well, the above research shows that plenty of people do die from autism, just not the ones you expected.

Just to give the full picture, sadly people with severer types of autism have substantially elevated risk of mortality in their early years, due to seizures, drowning and other accidents.  There is research showing this, but it also shows up any time you see cause of death on the samples from brain tissue banks, used in autism studies.  This is why it is very important to teach people with severer autism to be confident swimmers, however hard it might seem.






Wednesday 25 June 2014

NAC and Rotten Eggs – Where to draw the line?


One effective intervention in autism, particularly to reduce stereotypy, is N-acetylcysteine (NAC).  Here NAC is being used as an anti-oxidant in its own right and as a precursor to the body’s own main anti-oxidant, called GSH.  Classic autism is associated with oxidative stress and so NAC should be beneficial.

In much of Europe, NAC is seen primarily as a pharmaceutical, in North America, and much of the rest of the world, NAC is primarily just another supplement.

As a drug, it is mainly used as a so-called mucolytic agent, and as such is used as a cough medicine, because it breaks down mucus and liquefies it, making it easier to cough up.  It is frequently prescribed by doctors for children, but only in some parts of the world.

The problem with NAC, and all supplements, is quality control.  There is pressure to drive down prices and so quality will vary.  NAC is not particularly stable (it is labile) and so it tends to break down and release some foul smelling compounds.

For those who remember chemistry from school, the chemical formula is C5H9NO3S and the following chemical structure:





The smell of rotten eggs is associated with H2S, hydrogen sulphide/sulfide.  The ‘S’ in NAC is sulphur/sulfur and so when it breaks down or oxidizes you get a nasty smell.

The question is how much of a smell is normal and how much means your cheap NAC capsule has spoiled to the point of being worthless?

There is plenty of online discussion on this subject among regular users of NAC.  As usual, much is nonsense; some people are even saying that NAC has to stink and that it is a sign that it is good.

When it is freshly produced, there should be very little smell.  When you open the pharmaceutical NAC from its blister pack there is no smell whatsoever.


Cheap NAC

Since you need large amounts of NAC for treating autism, I found a brand of the cheap NAC capsules, but I always open the individual capsules and mix them in juice.  I never had any stinky bad egg smell until recently.  Now as soon as I open the jar, let alone the capsule, there is a potent smell.  Try a jar from a different batch, same smell.  More to the point, I have noticed small signs of stereotypy when Monty, aged 10 with ASD, goes for a swim.  He is swimming in the water and then starts wiggling his fingers and looking at them.

So I have decided to switch to the pharmaceutical NAC, which where we live is called Fluimucil and is made in Switzerland.  You buy it in the pharmacy over the counter, but without a prescription.  The cheap NAC does not say where it is made, or even have a use by date.  I suspect that different batches are made by totally different producers, whichever offers the lowest price.

The well-known expensive brand of NAC sold in the US is actually produced in Europe, if it turns out to be Swiss, we can probably guess who is making it for them.

It is clear that when the cheap NAC is very fresh, it works fine, but I want a product that functions as it should, 100% of the time.

I will see if the small re-emerging signs of stereotypy disappear with the Swiss NAC.





Friday 16 May 2014

Spiderman, and the Amazing Ted and Monty


Age-appropriate behaviour is not something you can really teach a child with autism.  In the toddler years, so many other children are behaving "badly", that nobody is really bothered by other toddlers with their autistic behaviours.  As children get older, the limits of acceptable behaviour change and it is then that many kids with special needs gradually get left behind. 

Monty, aged 10 with ASD, has a classmate from Angola called José.  Monty’s big brother, Ted aged 13, goes to the same high school as José’s big brother Eduardo.
Yesterday was José’s birthday party and so I decided to ask Ted if he would go to the party and look out for his brother.  Prior to this Monty always has had a parent close by, in full view, in case of need.
It turned out that the plan was to go to see a movie, Spiderman 2.  Ted had already seen it and said that it is really long; nearly two and half hours, and he thought that no way was his brother going to sit through that.  Also, it is not a baby cartoon film, it is PG13.
So we turned up at the mall as agreed at 5.30 pm, but it turned out that the film started at 7pm and before that the kids were to roam around a toy store before food at McDonalds.  That meant that they would finish at 9.30pm.  How was Monty going to survive 4 hours of big boy’s birthday party, with no Dad?
Ted is a typical teenage boy and so hanging out, in public, with an autistic brother is not something he wants to do.  In fact, he complains if I ever bring Monty to collect him from school.  I keep telling him that there is no need to feel embarrassed; the other kids just say “hey look, there’s Ted’s brother” and then some of the girls usually come and hug him.  There are no silly comments.
So for the first time ever, Ted would be alone with Monty, and for FOUR hours.
Ted did have a mobile phone and I was always in the building, getter further away, as the time past.

The result
Monty roamed the toy store with the gang of kids, had his Happy Meal at McDonalds, then the all-important birthday cake.  Ted made sure Monty visited the toilet and then all 15 of them went to the multiplex.  Ted bought his brother popcorn and they went inside.  At 9.30pm they all emerged with smiling faces.  Monty was happy, Ted was happy and nobody was embarrassed.

This is quite a step up from seeing the matinee performance of Rio 2 with Dad the weekend before; I think you could call it age-appropriate behaviour.
Without the Polypill, this would not have been possible, and we would have been home by 7pm, or even worse, we would have said “far too late to have a party, on a school day”.    

So it was a case of the Amazing Ted and Monty, rather than the Amazing Spiderman.








Thursday 8 May 2014

Oxidative Stress, Central Hypothyroidism, Autism and You




   Warsaw University of Life Sciences, Source: Wikipedia


Regular readers of this blog will have noticed there are some strange things going on related to endocrinology in the autistic brain; in effect there are low levels of certain critical hormones.

We saw in research from the Harvard Medical School that it seemed that oxidative stress in the brain affected the level of a key enzyme D2 (iodothyronine deiodinase type 2).  D2 has an important role; it converts the passive thyroid pro-hormone T4,  into the active thyroid hormone T3.  Without enough T3, you are said to be hypothyroid.  When the brain is affected, it is called central hypothyroidism.

As T3 is essential for cellular metabolism, growth and differentiation, and thus critical for brain development, thyroid deficiency during embryonic or early postnatal periods would likely lead to developmental abnormalities, including autism.

Now we have some follow up research from Harvard and Warsaw University.  The paper is more readable than many scientific papers, so click on the full version below.



“While the mechanism responsible for the decrease in brain T3 levels in ASD is unclear, the relationship between T3 and Hg (mercury) should not be that easily dismissed.

Our recent animal study of perinatal mercury exposure in rats supports the possibility that the environmental toxicants can affect brain deiodinases and thus affect brain TH (thyroid hormone) status even in absence of systemic hormonal deregulation

Total Hg levels were determined in human postmortem cerebellar and brain stem samples derived from both male and female ASD cases. The results of this analysis, presented in Fig. 4 as the male and female combined data, indicate no significant difference in Hg levels between control and ASD cases in either the brainstem or the cerebellar samples.

Thus, changes in oxidative stress levels reported here could also modulate D2 activity. It is of interest that TH regulates GSH levels in the developing brain and treatment of astrocyte cultures with TH results in increased GSH levels and improved antioxidant defense, suggesting that TH plays a positive role in maintaining GSH homeostasis and protecting the brain from oxidative stress. Thus lower T3 levels in ASD brain may exacerbate the oxidative stress.

The results presented here suggest that putamen is the brain region that exhibits not only an increase in oxidative stress and a decrease in T3 levels, but also most prominent changes in gene expression in ASD. Interestingly, the putamen's main function is to regulate movements and influence reinforcement and implicit learning, processes that rely on interaction with the environment; abnormal sensory reactions are part of autistic pathology. Thus, present study further implicates this brain region in autistic pathology.

Decreased brain TH levels and changes in gene expression in ASD brains, suggested by the present study, are likely to impact the developing brain and have clinical implications. It has been previously observed that deficiency of T3 during early postnatal periods impacts basic stages of development i.e. neurogenesis, cell migration of, and synaptogenesis that could contribute to downstream functional and structural damages observed in ASD brains. At this point, because the instability of D2 in the postmortem tissue and lack of detectable D3 activity we can only speculate on the molecular mechanisms involved in decreased TH in ASD brains. However, present data suggest that the role of TH in ASD pathology should not be dismissed prematurely and certainly requires further study, especially since correction of TH deficiency may offer new therapies.

Our results showed, for the first time, brain region-specific decrease in TH levels in the cortical regions of ASD male cases. Data reported here, although derived from a limited sample size, suggest the possibility of brain region-specific disruption of TH homeostasis in autistic brain. Furthermore, brain region-specific changes in TH-dependent gene expression reported here suggest disruption of gene expression that could possibly impact the developing brain and contribute to the autistic pathology. While the postmortem instability of brain deiodinases precluded further molecular studies, the role of TH in ASD pathology and TH-based new therapies warrant future studies.

The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism. “


Conclusion

We know that T3 is reduced in the autistic brain.  This may be because oxidative stress has reduced the level of the enzyme D2, but we cannot be sure, because the brain samples are old and D2 will decay with time.

The authors clearly hope that thyroid hormone-based therapies for autism will emerge.  Autistic people are likely to be euthyroid, so in their blood the thyroid levels are just fine; it is just in the brain the level of T3 is low. A successful therapy would raise the level of T3 in the brain, without affecting the level of T3 in the blood.

Reducing oxidative stress (if present) can only do good.  This is easily done with N-acetylcysteine (NAC).  If giving NAC reduces stimming/stereotypy, then the odds are that you have oxidative stress.  Oxidative stress appears to be chronic, it never goes away; you can treat it, but you cannot cure it.  We also saw this is the asthma research, where smokers were resistant to asthma drugs.  Even decades after ceasing to smoke, oxidative stress lingered and reduced the effectiveness of drugs.  In asthma the treatment for oxidative stress is NAC.

If you want a diagnostic test to establish central hypothyroidism (without any injections), this is easy.  Just give a small dose of T3 for a few days.  Before the thyroid has time to reduce its natural thyroid output, there will be a temporary increase in brain T3 levels.  If behavior improves notably for a day or two and then reverts, you have established a case of central hypothyroidism and seen how it affects behavior.

The scientific method of determining central hypothyroidism uses a test called the TRH stimulation test; but you do not get to see how behavior changes when T3 increases in the brain.

Also, note again that while mercury is definitely very bad for you, the study showed that the brains of people with autism had no more mercury than the control group.

We also see that while oxidative stress may cause a reduction in brain T3 levels, low T3 levels promote further oxidative stress.  So it is a self-perpetuating process.  This brings us back again to my venn diagram, where everything is inter-related.