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Thursday, 9 June 2016

Longitude, Latitude & Epilepsy in Autism




It is not always easy to decide which subjects to study, never mind if you have autism.

For Monty, aged 12 with autism, it has been me choosing what he studies.  At the beginning it was rather overwhelming for his 1:1 assistant, because there was so much to learn and never enough time.  It takes years to learn very simple things that typical kids just pick up naturally.

One big change after three and half years of Polypill use, is that Monty follows the standard academic curriculum, albeit for kids two years his junior.

An excellent but not very user friendly curriculum/skill list is in a book called ABLLS (assessment of basic language and learning skills).  It is both a curriculum and an assessment tool.  It covers all the very basic skills that kids need as a foundation for future learning.

We were working from this list of simple skills for four years, until the age of eight.  These are skills most kids effortlessly pick up in the first three or four years of life.

After you have mastered those simple skills what do you teach next to someone with classic autism?

I did my research and concluded the generally accepted answer is “not much”.

One phrase I still recall was a mother writing “our kids don’t need to learn longitude and latitude”, because this is going to go way over their heads.

It seems that for kids entirely non-verbal at three, about 10% have some maturational dysfunction that self-corrects by six, leaving just minor tics or perhaps mild "quirky" autism. Most of the remaining 90% end up "graduating" high school with an academic level of a four to seven year old.  A small number do better.  

A few years after ABLLS and Monty has mastered X,Y coordinates, even using negative numbers and identifying objects using Northwest, Southeast etc.

Regular readers will be aware that Monty’s recent academic development did not happen spontaneously, nor through ABA, it came from pharmacotherapy (drugs) and is reversible (hopefully not entirely).


Burden of proof

In spite of all this change it would be hard to prove what has caused it. Fortunately I do not need to.

Monty is still autistic, just less so and is now educable. That is a really big deal to me, but not to others. 

If you could convert 100% of kids with autism into outgoing, talkative, social, intelligent, typical kids then people would take note.  No therapy will ever deliver this. Just to confuse the issue, 10% will indeed "recover" without any intervention at all, which then is used to justify all kinds of interventions that those people used.

Have I measured Monty’s IQ?  No I have not.  A lady from California asked me why not, because over there they have excellent autism services, even assisted employment and sheltered housing but it is rationed based on things including IQ. 

One doctor reader of this blog suggested that some of the drug interventions in this blog will also reduce the development of seizures and therefore reduce the rate of premature death in autism; “surely we should tell people about this”.  I had a sense of déjà vu.

It is clear that in treating the excitatory/inhibitory imbalance that underlies much autism and also treating other channelopathies, you should also be avoiding some of the neuronal hyper-excitability that is epilepsy.

So treating autism should reduce death from seizures that reduce life expectancy in severe autism to just 40 years old.

This is all true and a year or so back I did suggest this to the Bumetanide researchers.  There was little interest and some skepticism. 

In fact there is a great deal of epilepsy research and some does indeed overlap with autism research.  One key area is Cation Chloride Cotransporters (CCCs), where the same type of immature neurons found in autism are found in epilepsy. Another is elevated BDNF (brain-derived neurotropic factor); in epilepsy, seizures trigger an increase in BDNF which then reduces expression of KCC2 which then shifts neurons further towards immature (high intra-cellular chloride) worsening the excitatory/inhibitory imbalance and making the next seizure more likely.  A clever idea we can borrow from the under-utilized epilepsy research is to consider blocking BDNF, or trkB, as a means of increasing KCC2 expression.  This could be a useful adjunct therapy to bumetanide, which blocks NKCC1. We want less NKCC1 but more KCC2, to give lower levels of chloride inside the cells and then neurons can fire when they are supposed to.


It takes decades for research findings, like those in the above paragraph, to be translated across into therapies.

If you, or particularly a researcher, make a statement that is controversial and not backed by a big stack of evidence (based on human trials, not mouse trials) nobody is going to believe you.  Worse still, the next time you make a claim, they will be even less likely to believe you.

So better under-promise but over deliver.  Start finally treating some autism and then watch in the next thirty years that epilepsy incidence falls and along with it SUDEP (Sudden Unexpected Death in Epilepsy).  Then you can say “I told you so, it was those Cation Chloride Cotransporter after all ”.

In spite of all the “evidence” that some autism is treatable, cognitive dysfunction is reversible, the world has not taken any notice.  Where is the undisputed concrete proof?  I just have to think “longitude and latitude”, that’s my proof.

So in reality while avoiding epilepsy should be a big deal for the parents, it is not for anyone else.  The current wisdom is keep your fingers crossed and hope that you are not in the one third that will develop epilepsy around puberty.  In some people this triggers an epigenetic change, opening the way to many future seizures.  For those who are interested:-

          Epigenetics and Epilepsy

If you follow 100 kids with autism on bumetanide for 10 years and found 5 developed seizures that would not be regarded as proof.

Based on my reading of the literature, you would expect 30+% of people with classic autism to develop epilepsy.  So if they had just 5 cases, I would see that as vindication, but it would not be seen as conclusive proof by others, just another paper to file and forget.

So the idea of prophylactic drug treatment to avoid the onset of epilepsy in autism is unlikely to catch on and is easy to rubbish.

Just like prophylactic use of drugs to avoid dementia, avoid type 2 diabetes or avoid the nasty side effects of type 1 diabetes, they will not enter the mainstream.


Conclusion

Setting low standards and targets will guarantee poor outcomes.  Aim to learn longitude and latitude, but it might be easier with a daily dose of bumetanide.

Some epilepsy is avoidable, some may not be, but if treating autism can also reduce the chance of epilepsy and SUDEP do you really need to wait for absolute evidence?

It is currently a matter of geography and google competence who is going to access effective pharmacotherapy.  For a change it is the poorer countries who have the advantage, since they have less rigid control over access to prescription medication.

I was just reading that the excellent New England Center for Children (NECC) charges up to $300,000 a year to educate kids with autism.  It is a great school and we employed a former teacher from there a few years ago, to help with our home program.  With something like 0.3% of all kids having serious autism, there needs to be a less expensive solution available to all.  

Spending $300,000 at NECC will almost definitely have a positive impact on one severely autistic child for one year.  Alternatively, for the same money, you could treat 480 kids with strict definition autism with my Polypill for one year.  It looks like around a half would respond very well.  Ideally you would spend $300,620 and have both the NECC and the Polypill; this is pretty much what was my target, but without leaving home.

 






25 comments:

  1. Well having your kid be educable is a big deal and it is a big deal to me and my children.

    I have three children with autism diagnoses, with the oldest the most severe. He started out at a special school for autistic children at age 2 and was the worst of the worst of any kid there in terms of behavior and autism symptoms. Now he has some speech and slowly he is becoming less rigid (i.e. more intelligent and cognitively flexible) and is able to do more and more things on his own without my guidance (which can be annoying when he thinks it is OK to drink all the milk just because he has the motor control now to poor a full gallon of milk into a glass without spilling it at only the age of 7). He is now playing with his brother and sisters without me having to worry he will bite them and he can give me simple commands as to what he wants me to do plus a lot more. I employ some of the interventions mentioned on this blog, plus a good deal of my own, plus another one I have discussed vaguely here (it is not a drug or anything that goes into the body) which hopefully I will be able to release to the general public in the next year or so once patents are filed and I am able to make enough time to embed the technology into software (I used to write software before this whole autism journey, but being a parent in this situation is a full-time join in and of itself).

    Two of his siblings, both twins (boy and girl) are now both in a mainstream classroom and this first year of kindergarten was very challenging with behavior from the beginning, but they managed to finish the year off strong and score well on the silly standardized tests they give (way above average in math and reading for my daughter and 75th percentile for most subjects for my son). The biggest win I feel was that my daughter had her first play date with a girl at her school a few days ago, something I never thought would of been possible a year ago and her biggest deficit now is expressive speech which she is rapidly improving on now. A couple years ago she showed no interest in playing with other children and now she loves to play with anyone she has the opportunity to play with. The university where she was diagnosed said that she would probably never have higher than a 70 IQ. Nevertheless, her pediatrician cannot believe her transformation and two years ago she even remarked that she is a "brand new girl".

    My second son (also with a diagnosis) nobody would diagnose him with autism at this point anymore as he simply shows no symptoms. He plays with kids and always wants to be the alpha which of course is not typical of those with autism who usually show no interest in social hierarchy at all. He had some socialization/behavior problems at the beginning of the year, but other than him doing some very annoying things from time to time (he is a kid after all), he is doing great and this is without any of the dopamine boosting drugs that are so readily prescribed here in the states these days for children with even minor behavior and attention issues. His teacher was very proud of him and pretty much finished off the last third of the year without any problems, so I am optimistic about first grade for both of them now.

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  2. So again I reiterate that this is all a big deal to me as well, a very big deal in fact, but I feel yah in the frustration with how autism is treated and approached by the people with the credentials. Of course, there are many researchers who agree with your frustrations but the way science works these days, it is hyperconservative in the sense that you can't rock the boat with stuff seen as "far out there" or else you will find yourself doing science out of your garage, rather than in a university funded lab. You also can't focus on anything super complex for very long as the whole "publish or perish" mentality forces scientists, especially those who are postdocs, to rack up citations by only picking the lowest hanging fruit. Most Nobels these days are not given out to researchers working on a very hard problem for 20 years, rather they are given out for accidental discoveries found in the hustle and bustle of exploring something else.


    Furthermore, mainstream scientists cannot share their true feelings via email with someone like you or me for fear you might make them look like a looney for associating with us if there name and info was posted online. Suffice to say it is all a lot of red tape and extremely frustrating for everyone.

    In my case it is very frustrating that with the technology I have, I need an fMRI lab and the skilled staff to manipulate the data (they only cost 10 million dollars) to move my work along a lot faster, plus research candidates so the route I have decided to gois to basically just patent the stuff and put it out there as it has a lot of use way beyond autism as that is the only way you can get credibility if you don't have the right pedigree. In your case, you would be better off just trying to get an investor for your polypill, generate income, then fund the research you need. In my particular case, that happens to be the only way forward for all the reasons you cited above. At least in the United States, if you patent something a lot of people believe you have something of value even if it could be a totally useless patent. They will at least listen to you, whereas if I were to just walk into my local university and tell them what I have (which invalidates any patents as you have in effect put the stuff in the public domain), they would probably call the local board of mental health because they could not possibly believe someone without a PhD could accomplish anything in this arena, let alone what I have managed to stumble upon and continually improve over the last several years of reading many thousands of neuroscience papers and almost as many hours coding and testing the technology. I have a second degree relative who is an actual neuroscientist at a prestigious institution and even he won't go out on a limb and take what I have seriously because I don't have a suffix to my name (he also lives several states away which makes demoing the technology difficult).

    My oldest son can't do longitude and latitude yet (he is a little younger than yours), but someday I hope to be in your shoes as a father and am very hopeful that I will.

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  3. Asperger's in my family strikes quick and hard.

    My 10 year old nephew has severely regressed for the last few weeks. Inhibition system is broken and he is left in an autistic chaos. This is the way asperger's manifests itself for both my son and nephew.
    I beg my sister to give Verapamil but he wouldn't cooperate. He only drinks from bottles he opens, otherwise he spills everything down.
    I don't know which part of the brain/gut controls inhibition filters. There must be an inflammation, though. My nephew's regression happened much earlier than my son's. I can only suppose that Ponstan might have upregulated my son, or other, gene mutations are "getting crazy" as being evolved in my family.
    Both my son and nephew were born with G6PD deficiency (my son doesn't look to have this anymore) and despite not having striking malformations, there is a slight lower part ear rotation in my son and something like that in my nephew's ear.
    Peter, such pathological perseveration in our male offsprings is devastating.

    I am so glad Monty is doing fine with longitude and latitude. I just hope Bumetanide may have a positive effect on others as well.

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    1. Petra, you can crush pills and hide in food. With G6PD deficiency, I see that oxidative stress is a big issue as is lack of nitric oxide. So in addition to NAC you might want to try 150ml of beetroot juice a day, this raises nitric oxide and you can measure it by checking blood pressure, which will be reduced as blood flows more freely. It is all on Wikipedia.

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    2. Peter, I can't use beetroot juice to raise nitric oxide but I can use pomgranate juice, some dark chocolate and also order citrulline supplements. So if it's nirtic oxide issue it will show.
      I 'll also trial lecithin to optimize cholinergic and liver function.
      Next step is clonazepam. My son is 90+ kilos (1.92cm tall)what would be the safe low dose, not reaching levels of irritability. I think there is also a liquid form. It's red line prescription drug.

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    3. The clonazepam dose is very low. In young children about 0.025 mg a day. Your son is much bigger, so it might be around 0.075 mg. It does depend on what other drugs he is on. The smallest tablet is usually 0.5mg. Due to the long half life, it takes three days to reach a stable level. It is not easy to find the effective dose and it is hard to give such a small dose.

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  4. Dear Peter is it possible to give potassium at night before bed.the polypill can all medications be mixed together.its impossible for the school to give any of these medications.i am just thinking how I can give these in the mornings before school.Thank you

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    1. Before my son could swallow pills, I just crushed them all up and mixed them in a drink.
      I give it before breakfast. Bumetanide causes diuresis so you need to allow for extra toilet visits for the next hour.
      I think morning is the best time because you want the greatest effect to be during the day.

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    2. If you are not afraid of artificial sweeteners (or you can do straight orange juice though real sugar sometimes causes hyperactivity in my son) you can get sucralose, ace-k, or aspartame from bulksupplements.com to mix in a drink with some sort of base your child likes (I have a watermelon BCAA powder I add). That will help with some of the yuckier stuff, especially the NAC which like anything sulphur based is not gonna go down very well without additional sweetening. If your child likes cheese you can also mix the sulphurish stuff in and that can mask the bad taste pretty well.

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  5. Peter, I'm a bit confused... In most cases of learning and memory impairment, don't we want to increase bdnf? Rather then block it ?

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    1. It is confusing. In many types of dementia in older people, there is low BDNF and/or low NGF.

      In most (but not all) autism BDNF is elevated. BDNF is like brain fertilizer, a small amount is a good thing but too much is bad thing, just like putting too much fertilizer on your lawn.

      So in people with autism and a very small head and no epilepsy they may indeed have low BDNF.

      The data tends to be for "average" autism, and in this case it suggests autism has high BDNF, but we know that in a minority of cases the other extreme exist.

      It is much easier to raise BDNF than to lower it (eg exercise).

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  6. How can you target KCC2 in practice?

    There is a recent paper about one of my favourite compounds with the authors’ conclusion: “our findings suggested that melatonin restores KCC2 expression”. It’s about TBI:

    http://www.ncbi.nlm.nih.gov/pubmed/27159133

    Once more very high dose of melatonin (10 mg/kg) proved beneficial.

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    1. I think it will get complicated. Melatonin actually increased both BDNF and KCC2 expression in TBI.

      The epilepsy model may be closer than TBI to autism in this case. Those researchers suggest inhibiting BDNF or trkB, but they have not figured out how to achieve this. I plan to look further at this to see if there any practical steps that can be taken.

      Melatonin does indeed have wide-ranging positive effects and it would be interesting to see some study on humans using 10mg/kg dosage. It might clear up many cases of IBS/IBD, as well as mitochondrial dysfunction and other aspects of autism.

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    2. Hi Agnieszka, did you use melatonin, in the first place, as a sleep aid for your son? Does he have any sleep disorders?

      My son has severe late onset sleep disorder which I think, if treated, might solve other problems, too. Melatonin 10mg doesn't help as sleep aid.

      Some people use clonazepam as a sleep aid, that's why I asked Peter about the dose and if it works in low dose it's certainly better.

      This might sound weird, but sometimes he looks as if he has some kind of atypical narcolepsy with cataplexy. I also saw him experiencing sleep paralysis, with full consciousness, but unable to react. Neurotransmitter hypocretin (orexin) might be implicating in those neurological symptoms.

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    3. Hi Petra,

      At first I gave melatonin for jet-lag long ago and to my surprise I saw both behavioral and sleep improvement. My son never had severe sleep disorder though. In him and other family members (affected much more) melatonin 3-15 mg is helpful for sleep, but it has been reported that high dose of melatonin can interfere with circardian rhythm phase shift. In such case switching to low dose (for sleep) might be beneficial, as described here for example:
      http://www.ncbi.nlm.nih.gov/pubmed/12069043

      I have some more papers on that printed before and will try to find them. From my experience it’s worth trying at least if high dose melatonin stops working for sleep.

      Low dose clonazepam is not sedative and does not make my son fall asleep. I will not be surprised however if you find this treatment improving sleep disorder indirectly.

      Among other treatments discussed here low dose Mirtazapine has a clear effect on sleep in my son and it seems to be used for narcolepsy as well.

      Does anxiety treatment influence sleep in your son?

      Peter has mentioned circadian rhythm regulatory mechanisms in one of recent posts here as well (CREB):

      http://epiphanyasd.blogspot.com/2016/05/low-bone-density-in-autism-and-brain.html

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    4. Petra, low dose Mirtazapine has potent effects on sleep. The effect on H1 antihistamine remains even after prolonged use, which is not true with many other H1 antihistamines.

      What I noted was that the effect on sleep (waking up later) continues even after stopping the drug. So people with disturbed sleep might benefit from 3 weeks of 5mg at bedtime and then stop the medication. For the first 10 days there is daytime drowsiness.

      It may be that after three weeks of really good sleep, the body resets itself to maintain this mode of sleep.

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    5. Agnieszka, Peter, thank you for your advice.

      I'll keep Mirtazapine in mind and treatment cabinet. Things often build up so rapidly that you need to have solutions in advance.

      I think good sleep is a key word here. Sleep brings more sleep.

      As for melatonin, I lowered the dose for ten days, this prolonged sleep onset, and then raised back the dose and this took him to bed much earlier. So I need to do some tricks because he must have developed tolerance. Lowering the dose also affected his mood.

      Agnieszka, for your information, my son's anxiety and depression isn't treated conventionally other than Verapamil (20-40mg/day) and Baclofen (10-15mg/day)and supplements. This may sound 'heretical' but I know he is treat resistant and his metabolic syndrome gets worse when follow the label protocole.

      Peter, I wanted to ask you about THR agonist. What kind of drug is that? You say it's nootropic, if I am right, I really need something for good mood.

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    6. VSL#3 trial has led me to conclude that it absolutely stops stereotypy and brings normal and stable social manners. Yet, at the same time, it's ehxausting as it's like having the fever effect. If I could find something to outweigh this, it would be perfect.

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    7. Petra, the TRH agonist is an expensive Japanese drug called Ceredist. I suggest looking at things easier to obtain.

      Asperger's does differ from classic autism and you could look at what other people with Asperger's use to improve mood. It seems to be a common problem. There are blogs and forums where Aspies share their discoveries. I think this is better than asking a Psychiatrist, otherwise you may get prescribed some potent drugs that lead to other problems.

      Of my investigations, in some people the broccoli powder has a positive effect on mood that does not fade, in other people it fades away.

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    8. Petra, thank you for your explanation. I asked about anxiety and sleep thinking this might be interlinked. From my personal experience I would add NAC as another safe 'heretical' treatment for mood improvement.

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  7. Agnieszka, I have been using NAC daily for many months. My son seems a responder. In the beginning I used 3grm but during the course I reduced it, which I sense it wasn't proved a good idea. Since I know there are GI issues I now try to give it just before meals to help with oxidative stress during distestion, hopefully.

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  8. Peter, I'd like to ask about the effect of Bumetanide on GABA? My daughter has been found to have high levels of GABA and we try and avoid supplements which would increase this as GABA is inhibitory and adversely affects her speech. Do you think Bumetanide would increase GABA? Thank you.

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    1. Bumetanide does not increase GABA. In many people with autism GABA does not work as it should, in effect it works in reverse, GABA is working as exciitatory. Bumetanide corrects this dysfunction and can make a big difference to cognitive function. For people with severe autism, who respond, it will raise their IQ, as a result many things will become easier.

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  9. How do you get hold of these drugs please? I can't find bumetanide tablets anywhere. My son, 15, has diagnoses of Aspergers, ADHD & he has multiple cafe au lait spots. He has normal - good - intelligence but disastrous working memory & executive function, is oppositional, uninterested in interacting with peers, flails his arms and twists his hands and has full time 1-1 at school. He takes equasym which improves things a little, but we are told there is nothing else that can be done for him and we are desperate. I can't see him having an independent - let alone a good - adult life as he is.

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    1. It all depends in which country you live. Most readers are in the US. In the US a small number of people have an open minded doctor who is willing to prescribe off-label, but most are buying from Mexico, generally on-line. This is all experimental since these drugs are not (yet) approved for autism.

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