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Monday, 28 November 2016

Leukemia, IL-6 IL-10 and an Autism Flare-up


   
Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.
 

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 



Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.





If only some more of the clever people studied autism.






28 comments:

  1. Thank you Peter for anotehr great reminder why it is so important to control inflammatory processes in our kids. In addition to mito dysfunction being a casue of regressive autism, immune dysregulation seems to be also - many triggers could be involved - early antibiotics, microbiome, chronic low gradde viral infections, automimmunity in pregnancy, maybe autoimmunity to the brain, glial cell involvement - keeping immune system in balance is key.

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  2. I really hate it when people use the term "our kids" when talking about autism.

    I have some of the same medical problems as you mention here,as well as others,like celiac/coeliac,IBD,inflammatory neuopathy,chronic urinary tract infections,and more.I also had frequent acute infections,mostly pneumonia,and CNS infections,that always led to severe regressions

    I also have both MTHFR deficiency,folate receptor autoantibodies,and resulting cerebral folate deficiency.As well as severe mutations of what can be a cancer gene.There are so many cancer genes implicated in autism.I really wish more studies could be done about the clinical presentation of these cases.

    Treating the folate problems with leucovorin.and B12,not only reversed my autism,but also has allowed me to go seven years without an acute infection.I still have all my chronic medical problems,including seizures.As you know,the medical literature is filled with documentation of autoimmune causes of epilepsy and seizures.C(o)elic can even be one such cause.

    Leucovorin,as you know,was originally a cancer drug,used to combat the negative effects of chemotherapy.Dr. Frye now is saying there are benefits of taking leucovorin in all types of autism.Not just those with CFD/FRAs.

    http://www.nofone.org/dr-frye-q-and-a-folinic

    As an adult it took me longer to see the benefits Dr.Frye speaks of here,but they were just as profound.

    Leucovorin also increases the production of Interleukin-1,which plays a big role in regulting immune and inflammatory reactions.

    http://onlinelibrary.wiley.com/doi/10.1002/art.1780331121/pdf

    https://en.wikipedia.org/wiki/Interleukin-1_family

    The interleukin connection may explain why leukemia is a comorbidity with autism.

    Peter,have you considered getting your son tested for FRAs?I know from our Facebook group,there are families in the UK,who have sent blood to the hospital in Belgium,where Dr Ramaekers is to be tested for FRAs.There are also families in our group,where the children do not have mitochondrial disorders,but do have immune disordes,like PANDAS or PANS,pediatric lupus,or Common Variable Immune Deficiency.

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    1. Roger,

      I too find it funny when someone does this 'our kids' thing. The last time I checked my son was my and my husbands kid. But hate is too strong an emotion, don't you think, to feel for a normal human tendency to find affinities and form tiny communities especially when threatened by marginalization.

      On a more relevant note, is there any possibility that a physically healthy child with no apparent motor deficits and robust growth might still have cerebral folate deficiency. Are there any indirect indicators to look for in a healthy child?

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    2. Roger, I did contact Dr Ramaekers who put me in contact with Iliad who have the test. I was surprised that in the US they suggest the test and then prescribe calcium folinate regardless of the result. It turns out that calcium folinate has other effects on some types of oxidative stress, which is interesting. In this case you might as well just do a trial of calcium folinate, which is available as a generic drug. It also appears that more people cannot tolerate the drug than Dr Frye suggests, another reason to see if you tolerate it before having the test.

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    3. I've found 2 studies (humans) showing that granulocytes and lymphocytes from autistic kids are slower and less effective then control due to reduced mitochondrial activity.

      Study on lymphocytes
      https://www.ncbi.nlm.nih.gov/pubmed/21119085

      Study on granulocytes
      http://pediatrics.aappublications.org/content/133/5/e1405#ref-1
      http://www.ucdmc.ucdavis.edu/publish/news/newsroom/8932

      I can see a scenario where less effective cells means the body produces more cells to compensate, but then there is oxidative stress so this cells also have increased mitochondrial DNA copy numbers and there goes epigenetics and a cascade to several levels of immune disregulation and/or even leukemia, which may or not be related to autism but should anyway be taken seriously.

      My son does seem to have a sluggish immune system. His cousin did had leukemia (diagnosed by age 3 years, about the same age my son regressed into autism). I always wondered on this coincidence.

      Jane.

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  3. Hi Roger, how do you know in terms of behaviour if the child has PANS?, how severe should be the symptoms? I know that PANS is related to bacterial infection and parasites, not strep like PANDAS.
    Valentina

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  4. Speaking of calcium, there was a study released today that links calcium entry into T Cells as a master switch in immune function that governs whether the various molecules that permeate the body are "foreign" or else molecules produced by the body. Obviously, the question of how immunity is related to autism (even though it is strongly linked) is still an open question in many ways, but there are probably about a dozen areas of interest off the top of my head that are relevant to autism and intersect with this research (allergies, autoimmunity disorders like FRA, cancer, diseases of the gut, etc.).

    This research group (from the press release) previously discovered that once calcium enters the cell nucleus, it also acts as a master switch for many brain functions (which types of brain cells are not elaborated but figuring this out should not be hard with a cursory lookup of his research on Google Scholar).

    Maybe this calcium signaling balance may have a lot to do with the reports of Verapamil helping with some autisms, while in other people it does nothing or even makes things worse. Maybe this dysfunctional calcium signaling can yield autism like symptoms if there is too much calcium influx or else if there is too little and then the question becomes how do you achieve the perfect balance (or at least good enough) for cells in the body, brain, and immune system to get the proper calcium signaling.

    Press release:

    http://medicalxpress.com/news/2016-11-immune-reaction.html

    Paper:

    http://jcb.rupress.org/content/215/2/231

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    1. Thanks Tyler, have you seen this http://www.autismcalciumchannelopathy.com/

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  5. Another amazing study I read today deals directly with the recent discussion about the gut microbiome and especially with respect to Lactobacilli bacteria and how specific genes (yes DNA) can influence which species of bacteria and of what abundance they are allowed in the host (this study was done on mice, but it is likely it applies to humans as well). The other big finding was that early life exposure to microbes seems critical in establishing a functional healthy microbiome for life (these are not new theories obviously but this research also shows another multigenerational effect for the mother have a dysfunctional gut microbiome, and alludes to what the consequences might be from caesarian section or early doses of antibiotics in the newly born (in other words, before the microbiome is able to program the immune system of its host).

    And though you could say this might be confirmation bias on my part, this research seems to suggest some of the interventions mentioned on this blog might be a very big deal for children who were born via caesarean (all 4 of my kids) or else children who had a strong regimen of antibiotics in the first days of life.

    Press Release:

    http://www.news-medical.net/news/20161129/Early-life-history-and-genetics-may-play-crucial-role-in-shaping-gut-microbiome.aspx

    Paper (took a while to find since the title was not mentioned in any press release I could find):

    http://www.nature.com/articles/nmicrobiol2016221

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  6. I have now (-:

    That is a lot of reading material about calcium. Will take a look see soon enough.

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  7. Peter, I discovered tiazinidine for my son by chance, my husband gave 2mg to him at bed time instead of melatonin and the results where incredible. The quality and duration of the sleep improved a lot. He got up very relaxed and awake at the same time and no stimming. But the efect doesn't last much. The question is if tiazinidine is similar to baclofen, I believe that is similar to clonidine also,could I use tiazinidine for him during the day? which dose would you recommend me?
    Valentina

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    1. Tiazinidine like Clonidine is an A2 adrenoreceptor agonist and I am guessing your issues were similar to the ones I had when using Agmatine Sulfate which is also an A2A agonist, as well as a mild NMDA antagonist, and also increases NO production thereby boosting blood flow to the brain. In theory, it should be amazing for some types of autism but quite often when dealing with drugs/substances that modulate neurotransmitter activity, what is great short term is not so great long term as the body habituates to the substance.

      In my experience it was amazing for a few days as my son had a huge cognitive boost that was very noticeable and then the effects would wear off and he would have pretty bad anxiety. There are too many possibilities for why this happened, so I just shelved it after a couple tries. I might give it one more try again, but the experience was one of those feelings where you have something that you think is solving a lot of problems and then you learn again the hard way that the body and brain are pretty stubborn about maintaining homeostasis with respect to blood pressure and stuff like that and will fight back whatever you throw at it, so I don't really know how you get around the habituation issues at this time though perhaps finding the perfect low dose is key.

      Or it could of been something else thrown into the mix when I was giving it to him that caused the anxiety so I will probably try it again at very low doses when he is off school to see what happens this time around because it really seemed to give him a big cognitive boost if only for a short while.

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    2. Valentina, Tiazinidine has similar uses as Baclofen, but does not have the same mode of action. It can cause low blood pressure so you should ask your doctor about whether to use it.

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    3. Thanks Tyler,to think that we have succeeded and then fall again, is what makes this a real fight every day. Try again if you had once an amazing result. To use tiazinidine, do you think that a low dose could be 1mg in the morning, 1 mg in the afternoon and 2 mg at bedtime? or is too much, could you suggest me a good dosage to avoid the effects wear off?
      Valentina

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  8. Peter, if he responded well to tiazinidine,does it mean that I can expect a similar effect on my son with baclofen or even better? I can't get it now here, I don't know why.
    It seems that is safer than tiazinidine.
    Valentina

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    1. Valentina, it looks like people with Aspergers respond to baclofen whereas people with more severe autism either do not respond or need a much higher dose, ideally from R-baclofen. So it is worth trying baclofen regardless of the tiazinidine response.

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    2. Peter, if I could get baclofen, would give him 15mg a day, but now he is taking 2 mg tiazinidine at bedtime, should I start weanning off? I know that you can't take both at the same time.
      Valentina

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  9. Here is some very interesting Parkinson's disease research that intersects with a whole lot of topics on this blog and autism in general:

    Press Release:

    https://www.sciencedaily.com/releases/2016/12/161201122159.htm

    Paper:

    http://www.cell.com/cell/abstract/S0092-8674(16)31590-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867416315902%3Fshowall%3Dtrue

    What I find interesting are too numerous in this paper to discuss all at once, such as the link the researchers made between diseased microglia and their reactivity to short-chain fatty acid signaling. Also, IL-6 signaling effects are discussed in this paper as well and even though this paper discusses a Parkinson's disease mouse model, it almost reads like that of an autism mouse model research paper in terms of the strong similarities in symptoms.

    But the biggest surprise or at least topic to think about with respect to this paper is that of SCFA's worsening motor symptoms via microglial activation when we normally think of SCFA's as good products for the intestine as not having enough SCFA production can cause a leaky gut due to the cells of the intestinal lining using SCFA's as their primary metabolic fuel source so that they have the energy to do everything they need to do to maintain gut lining integrity.

    The researchers in the paper were clear to say that massive dosages of antibiotics (a permanent regimen so to speak) are not a practical therapy for Parkinson's disease, though finding the microbial species responsible for excess SCFA production or at least the mechanism for SCFA's causing excessive microglial activation would be a good place to start in finding a therapy that addresses the findings in this research.

    The one thing they didn't address in this paper is which SCFA's cause microglial activation the most (I guess there is other research out there that probably answers these questions, but I didn't see them discuss it).

    Nevertheless, though this is a Parkinson's disease paper, there is so much here that is right up the autism alley that may give us some hints about everything discussed with probiotics, prebiotics, and maybe another route of exploration for why some probiotics might help autism symptoms and why some might hurt autism symptoms. Also I thought that supplementing a bunch of sodium butryate might give an acute response if there is something similar going on in autism as what seems to be happening in this paper (which I must stress is for Parkinson's disease and is in mice, but nonetheless likely relevant to humans as well or at least that is my hunch).

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    1. Tyler, Thanks for your post. In this case could sodium butryate could cause harm since it is a SCFA? Perhaps I have that wrong? How do you know if there is microglial activation specifically. It is becoming all too clear for my 4 kids that having a messed up gut opened up lots of bad things to happen.

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    2. There are three main SCFA's namely butyrate, propionate, and acetate. The paper seesm to suggest an elevated yet normal distribution of all of them causes microglial activation in their Parkinson's disease model. What I was trying to say is that if someone had autism and this kind of mechanism was at play, giving a person some sodium butyrate might have a very acute negative reaction that might give you the information you need to know about possibly restricting fiber and carbs so as to restrict excess SCFA's being produced. Another thing I know is that where SCFA's are produced seems related to obesity and general health. If they are produced in the colon, this seems to be a good thing, but if they get produced via fermentation in upper levels of the digestive tract, then the SCFA's get drained via the portal vein and into the liver and get converted to longer chain fatty acids which then need to be stored which raises triglyceride levels which of course is associated with metabolic syndrome. This all suggests you might have the wrong kind of bacteria colonizing the wrong part of the gut. In fact, many researchers believe now that one of the main mechanisms of action for gastric bypass surgery is the change in the gut microbiota, especially in the upper digestive tract (as much of that has been bypassed obviously via the operation).

      Now obviously I think having all your kids get gastric bypass surgery would be a terrible idea, but hypothetically if your child had weight problems and neurological problems from a high carb diet (as excess carbs and especially fructose in some people with a certain type of gut microbiota get fermented into SCFA's), this might be one of the many mechanisms why. So hypothetically if your child was supplemented a high, yet safe dose of sodium butyrate, and lots of bad things happen neurologically after half a dozen trials, then that might tell you that restricting carbs (certainly not eliminating them) might be beneficial.

      I also must stress, these are just my own ideas here based upon this research only released yesterday, not some that actually has been proven with respect to autism itself (just that I found the parallels striking).

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    3. That is very interesting Tyler, thanks for sharing. Butyrate didn't seem to suit my son. We pulled it after a relatively short trial as he seemed to be more foggy and spaced out on the 'on' days. I don't know if your hypothetical scenario could play out so fast, ie within days and with a relatively small dose, but who knows. Our son also never did very well with any oil supplements if given longer term - things like cod liver oil or EPA fish oils would seem to suit him for a few weeks only, then slight negatives would start appearing slowly. He always seemed to perk up cognitively and mood-wise after stopping. With MCT oil those negatives appeared in a matter of days, not weeks.

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  10. Hello Peter,

    I was wondering if there really is difference in bioavailability of magnesium from different supplemental compounds. Despite lot of hype surrounding mag threonate as a potential nootropic which crosses the blood brain barrier, even anecdotal evidence regarding its effects are scant or practically nil. The only thing great about it or even the glycinate seems to be its cost. Though reports suggest that chelated forms are better. I wanted to try out Mg, b6 and taurine and probably some micronutrients though not really expecting too much from this.

    Have ordered cytoflora..although how sustained a response it gives if any I do not know. All this non pharmaceutical stuff especially the ones which are discussed most on fora as being effective, probiotics, herbal extracts, digestive enzymes..they are exorbitant. And all through life, my parents told me that money matters least.

    Does giving methyl folate 400 mcg make any sense in terms of reducing oxidative stress/inflammation. You had mentioned or I think I had read research paper where apocyanin, taurine and high dose folinate combination significantly reduced oxidative stress.

    Finally, I would really appreciate if you could give an opinion on use of psilocybin for cognitive enhancement. It seems to enhance brain's organizational capacity and connectivity apart from anxiety alleviation. What I found interesting was that at John Hopkins they found that the positive effects of a single administration of psilocybin were sustained at six months. Six months is a lot of time.

    Right now son is on nothing so its systems reboot. And months beginning so pocket is warm.



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  11. Hello Kritika,
    I'd like to make a comment on taurine and the possibility of adverse effect.
    I trialled 500mg taurine and felt really horrible. The effect on me lasted for more than 3 days and felt like a hangover.
    I was looking for an antidode on the internet but I could only find articles with the benefits of taurine.
    I suppose not all people react like that but I thought I should warn you and maybe try it yourself first.

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    1. Thanks Petra.

      Actually trying to treat my son's autism feels like performing a nonsensical Alice in wonderland kind of act where I am supposed to find a solution for a problem which I do not know.

      I will try taurine myself first. Somewhere i read a glycine and taurine combination works good for focus. But then glycine has been linked with cancer risk.

      Petra, my son has been off everything for the past few days, both of us have been gorging on chocolates and cookies and chips, have not slept well but today my son's behaviour was easily one of his best. Calm, satisfied, receptive, immediate reciprocal smile, cooperative. So what do I make of anything. Strange are the ways of autism.

      By the way, I wanted to ask you if you have tried any psychedelics with your son. I know it's a slippery slope but some high functioning autistics and those with Asperger's have reported miraculous effects, even with a one time administration.

      Not thinking of trialling on my son but just out of curiosity.

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    2. Petra, I like the magnesium taurate. Several people I know also take it with no negative effects. Each tablet is 100mg magnesium chelated to 100mg of taurine. Even at 4 tablets, its a lovely effect, I feel peaceful.

      Magnesium seems to help us tolerate taurine and potassium.

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  12. Hi Kritika,

    It's really nice that your son is happy and cooperative.

    I know little about what is going on, but I can understand that his immune system works in balance this period of time. He doesn't only seem healthy and sound, but this also reflects behaviourally and emotionally.
    I know people, my son for instance, that have at least two kinds of immune imbalances. The one that makes them "go crazy" and the other, which is usually called the "fever effect", during which improve, still in fact being sick. Both of these immune imbalances need treatment accordingly.
    Kritika, what is your son's diagnosis? Why did you take him to the doctor from the first place? You say that there is nothing obvious to treat, if I understood well, but you also say that he shows visual stimming and GI issues. Maybe you could deal with those for a start.
    I've never used psychedelics for my son. What stuff are you referring to? My son has a "non-abusive" profile, he rarely drinks alcohol, never smokes and he is even careful with coffee consumption. He agrees to use things that could promote his well being and have the least side effects.

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    1. Petra,

      My son has been given a diagnosis of ASD, with a CARS score of 29/28 and a clinical impression of having very few autistic traits. But his low score does not translate into less disability as he is severely impaired as far as language (comprehension as well as expression/speech) and social interactions and awareness is concerned. If you look at him, the first thing that you notice about him is his good health. A beautiful healthy boy in whom nature or god obliterated the capacity to communicate through language. He learns well through visual and experiential means but that imposes great limitations on the pace and quanta of learning.

      He does not have GI issues, and on most days has bowel movement twice each day, but a slight deviation from optimum digestion makes him respond behaviourally and sensorially. He eats well and a variety, is assertive and aware of his needs and is able to communicate via non language means, not restricted and not unregulated (although lately displaying newly emerging tantrumming abilities). But he does lack ability to sustain attention for a long time unless it's something thst interests him.

      So Petra, it's mostly comes down to the core autistic traits. No co morbidity as yet treatment of which might ease his autism. This is what makes treating his kind of autism not very uncomplicated. Everywhere i read accounts of autistic kids with allergies or food intolerances, seuzutes, chronic diarrhea or constipation, ear or skin infections, sub optimal physical growth of any other outwardly indication of things going wrong. But none of these bother my son. Probably it's purely a diseased brain, an encephalopathy. Probably behavioural intervention, remedial learning, OT and ST and lots of hands on parenting is the only treatment for him right now.

      As far as psychedelics are concerned, I had read about serious research into compounds like extracts from mushrooms, LSD and marijuana and there seem to be high functioning autistics and aspies who are trying it out with good results. Not suggesting that you try it but just enquiring after reading about long term anxiety alleviation and mood elevation in cancer patients after a single administration of psilocybin, a mushroom extract. But these are all grey areas, probably not worth venturing into unless desperation leaves one with no option.

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  13. We have triple incidences of chronic, late-onset leukemia in my childrens ancestry, and I am a firm believer that this makes up a third of the genetics involved in ASD in our case. I am terribly concerned with the high risk for this type of cancer... I would be greatly thankful for advices on prevention.

    /Ling

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