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Tuesday, 13 January 2015

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism




A recent post looked again at inflammation in autism and some possible therapies to try.  Over Christmas and New Year, Monty, aged 11 with ASD, had occasional outbursts, more typical of his summertime raging, which was later solved using allergy /mast cell therapies.

At least it did let me establish whether Verapamil was a universal “cure” for SIB.  It is not.  It works great for allergy-driven aggressive behaviors, but had no effect on these ones.

Christmas is often a stressful period for many people with, or without, autism; but Monty likes presents and he loves food.

Having pulled out a wobbly tooth on Boxing Day and noticed an apparent behavior change, I thought that perhaps the loss of milk teeth and development of permanent teeth might cause an effect similar to that of his mild pollen allergy.  Monty, in common with many people with autism, has a high pain threshold.  While teething causes well known problems in babies, most children have minimal problems when their milk teeth are replaced by their permanent ones.

I just wondered if perhaps the underlying biological mechanism might provide an inflammatory insult to the highly inflammation-sensitive autistic brain.

Just as histamine provokes a release of inflammatory cytokines like IL-6, perhaps losing your milk teeth does something similar.


Ibuprofen experiment

I decided that I would buy some Ibuprofen, the least problematic NSAID.   A day or two later, Monty declared that another tooth was wobbly and needed to be pulled out.  This tooth was, and remains, well and truly attached.

So I decided that in advance of another, potentially stressful, Christmas event, I would give 10 ml of Ibuprofen.  I did not give it in response to any comment about pain.

It did indeed seem to work.


Skiing

A few days later we were in the Alps for skiing.

Monty can ski, but we always give him a 1:1 instructor.  On the first day, without Ibuprofen, he got agitated during the queuing at the bottom of the beginners’ ski lift.  The instructor thought it was the loud booming music.  It was clear that by the end of the lesson, it was no fun at all.

The following days, I gave 10 ml of Ibuprofen, 20 minutes before the lesson started.  He had a great time, going up by cable car to the top of the mountain and skiing along the blue/red slopes and coming down in a neighboring resort a couple of hours later.  Even a change of instructor on one day, passed without issue.

It might not be scientific proof of the effectiveness of Ibuprofen, but it was enough for me.


The Science

Since this is a scientific blog, arriving home I did some checking on the biology of what happens when you lose your milk teeth.

There is more written about “teething” when you first get your milk teeth, but there is information about “root resorption” of milk teeth and “eruption” of the permanent teeth.  The process is indeed modulated by inflammatory cytokines and transcription factors.

These cytokines will then circulate around the body and cross the blood brain barrier.





Abstract

PURPOSE:
The aim of this study was to investigate whether there are increased levels of the inflammatory cytokines IL-1beta, IL-8, and TNF alpha in the gingival crevicular fluid (GCF) of erupting primary teeth. This increase could explain such clinical manifestations as fever, diarrhea, increased crying, and sleeping and eating disturbances that occur at this time.

METHODS:

Sixteen healthy children aged 5 to 14 months (mean=9.8 months) were examined twice a week over 5 months. Gingival crevicular fluid samples were taken from erupting teeth. As a control, GCF was collected from the same teeth 1 month later. Cytokine production was measured by ELISA. Signs and clinical symptoms were listed. Pearson correlation coefficients were used in the comparisons described below. A paired t test was used to analyze the same variable at different times.

RESULTS:

Fifty teeth of the 16 children were studied. GCF samples were collected from 21 of these teeth. Statistically significant differences (P<.05) were found with regard to the occurrence of fever, behavioral problems, and coughing during the teething period and the control period. During the control period, 72% of the children did not exhibit any clinical manifestations, whereas during the teething period only 22% of the children did not exhibit any clinical manifestations. The study revealed high levels of inflammatory cytokines during the teething period, with a statistically significant difference in TNF alpha levels (P<.05) between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1beta and TNF alpha were correlated with fever and sleep disturbances; IL-beta and IL-8 were correlated with gastrointestinal disturbances; IL-1beta was correlated with appetite disturbances.

CONCLUSIONS:

Cytokines appear in the GCF of erupting primary teeth. The cytokine levels are correlated to some symptoms of teething.



Mechanism of Human Tooth Eruption: Review Article Including a New Theory for Future Studies on the Eruption Process



Physiologic root resorption in primary teeth: molecular and histological events


Root resorption is a physiologic event for the primary teeth. It is still unclear whether odontoclasts, the cells which resorb the dental hard tissue, are different from the osteoclasts, the cells that resorb bone. Root resorption seems to be initiated and regulated by the stellate reticulum and the dental follicle of the underlying permanent tooth via the secretion of stimulatory molecules, i.e. cytokines and transcription factors. The primary root resorption process is regulated in a manner similar to bone remodeling, involving the same receptor ligand system known as RANK/RANKL (receptor activator of nuclear factor-kappa B/ RANK Ligand). Primary teeth without a permanent successor eventually exfoliate as well, but our current understanding on the underlying mechanism is slim. The literature is also vague on how resorption of the pulp and periodontal ligament of the primary teeth occurs. Knowledge on the mechanisms involved in the physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases that the permanent successor teeth are not present and thus preservation of the primary teeth is desirable. (J. Oral Sci. 49, 1-12, 2007)


Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, work by inhibiting the enzyme COX which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins ,which are mediators of pain, inflammation, and fever.


Prostaglandin E synthase


Prostaglandin E2 (PGE2) is generated from the action of prostaglandin E synthases on prostaglandin H2 (PGH2).

PGE2 has various known effects, but one known effect is to increase the pro-inflammatory cytokine IL-6.  The same one that is increased by histamine released from mast cells during allergic reactions.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.


Abstract

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine


Indomethacin is another NSAID, like Ibuprofen.



Implications

If, as seems likely, many incidents of anxiety, aggression, explosive behavior, or "meltdowns" are made possible by elevated levels of the pro-inflammatory cytokine IL-6, then the occasional use of drugs known to inhibit IL-6 makes a lot of sense.

Ibuprofen is an NSAID and it is known that some people respond much better to certain NSAIDs and suffer side effects from others.   NSAID drugs work by affecting both COX-1 and COX-2.  It appears that desired effect of NSAIDs comes from their effect on COX-2, while the side effects come from changes made to COX-1.  So it is logical that some NSAIDs are better tolerated than others and for some people a different NSAID may be more appropriate.

Other common drugs also lower IL-6;  leukotriene receptor antagonists like Montelukast (Singulair)  being an example.  This drug is used in autism, but a known side-effect in typical people is to worsen behavior, sometimes severely.  There are plenty of reports of Singulair in autism, some good and some bad.  Since almost all drugs have multiple effects, this is not surprising.

Interestingly, one of the drugs in my Polypill, NAC, is also known to reduce IL-6; but it also reduces the “good” anti-inflammatory cytokines like IL-10.  Perhaps this is why NAC is not beneficial to some people with autism?

Occasional use of Ibuprofen at times anticipated to be stressful makes a lot of sense. 


Conclusion

While it is well known that Ibuprofen relieves pain from teething, low level pain is often completely ignored by people with ASD.  The cytokine release associated with the resorption of the milk teeth and the eruption of the permanent tooth appears to be much more problematic.

Ibuprofen, available OTC, limits the production of pain mediators, called prostaglandins, which in turn stimulate production of the inflammatory cytokine IL-6.

Ibuprofen will reduce both pain and the level of cytokines like IL-6.

In earlier extensive posts on mast cell degranulation in autism, I concluded that the resulting elevated levels of IL-6 likely produced behaviors ranging from anxiety, through aggression, all the way to self-injury.




71 comments:

  1. HI I am new to your blog and have found it very useful! Thank you very much. My son had an autoimmune second hit (rheumatic fever/sydenham's chorea in Africa was the hit AGAIN for a mild on the spectrum kid) which has been disastrous. You mention ibuprofen but we have been using Alleve because it is longer acting nsaid (naproxen?) -- and recommended by the doctor. Can you point me on your blog where ibuprofen is better? IVIG has been very good for his condition. I think mito. is becoming more apparent.

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    1. Ibuprofen seems to have the least side effects and that was the reason for my choice. Naproxen is much longer lasting and so should work better. NSAID drugs can cause side effects and in children the GI ones seem the most likely. Ibuprofen is claimed to cause the fewest GI side effects.

      You can test for mitochondrial dysfunction at a major hospital laboratory. If you live in the US, Kennedy Krieger / Johns Hopkins seem to be the experts in autism combined with mitochondrial disease. They have their own mito-treatments, that do seem to work.

      Delete
  2. I don't know if it works due to pain relief or for the inflammation or both, but I agree with you that it works.
    When my son gets too moody (lets say low frustration threshold), it makes a huge difference.
    Now... why doctors think someone with chronic brain inflammation has no need of anti-inflammatory drugs or painkillers, is beyond me.
    Unfortunatelly long term use is not recomended, and the alternatives need prescription.

    J.

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    1. Yes, you are right about side effects from NSAID type drugs. But the drugs needing prescriptions also have side effects and generally worse ones.

      Using OTC drugs like Ibuprofen, from time to time, seems like a low risk strategy.

      The arthritis drugs that target inflammation are all potentially interesting. There are also many age-old remedies (OTC) that have been used for arthritis. Some new prescription only drugs for arthritis do reduce IL-6, but they can be hugely expensive.

      One interesting OTC therapy for arthritis/inflammation is Boswellia Serrata.

      http://en.wikipedia.org/wiki/Boswellia_serrata

      An OTC version called 5-loxin has shown some promise in arthritis research and some people have found it helpful in autism. Others did not find it helped. I guess it all depends on "which" autism you have.

      http://www.arthritisresearchuk.org/arthritis-information/complementary-and-alternative-medicines/cam-report/complementary-medicines-for-osteoarthritis/indian-frankincense/trials-for-oa.aspx

      Several producers sell 5-Loxin. So it might be worth a try.

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    2. Interesting options, I'll look into it, but keeping my Ibuprofen at hand to ease things up now and then. :-)

      J.

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  3. Hi Peter. I hope you had a good holiday.

    You have mentioned throughout your blog that there are biomarkers and tests that could be done that could reveal a lot about the underlying conditions that show up as autism in our kids. Moreover, some of these conditions, if found, have simple and very effective therapies (Biotin for example). This approach should give physicians and parents a strategy for treating autism in their child.

    As you know, there seem to be very little doctors or psychiatrists interested in this approach, the parent must become the expert if they want to treat their ASD child.

    Could you provide a list of tests that could be done along with the possible therapy? There are probably several black and white ones, like Biotin for example. More abstract ones could be included as well. For example, would testing for calcium in the blood be strong evidence for the possibility of excess calcium signaling in the brain, therefore, giving credence to verapamil as a possible therapy?

    Ideally, this would be a great tab to add at the top of your page. Sort of like your polypill chart that displays tests that could be done and their possible therapy.

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    1. It is a good idea and when I finally figure everything out I do plan something like this.

      In the case of Verapamil, I think it is most likely to be effective in people with any kind of GI problem, Rhinitis or other allergy related condition, even a very mild one, and perhaps even Asthma. Measuring calcium levels in the blood will not help. It would be possible to check for genetic errors associated with the Cav1.2 gene, this may be the underlying cause, but would be very expensive.

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    2. Peter, did you consider QT interval on ECG as an indirect indication of genetic errors of the Cav1.2 gene and verapamil efficacy? Several years ago I asked one doctor if there are any more medical exams, that should be done in my son after ASD diagnosis and got surprised by the answer: “ECG as many of such kids have longer QT, so it’s good to know before any treatment with QT prolonging drugs ”.

      It took me 3 years to get my son to cardiologist for ECG: already on verapamil and bumetanide, his QTc is in “upper normal range”, I was told. I wonder if there could be any association. That might be useful, as ECG is painless and can be done in a “low stress manner” by a skilled doctor as ours did.

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    3. This is a good idea. Also, since Verapamil and Bumetanide are usually drugs for heart conditions, cardiac health should be monitored. Maja, the other reader (and doctor), using Verapamil in her child commented how her child's heart beat is no longer racing. Given the role of Cav1.2 in the heart and the known effect of the extreme mutation (Timothy Syndrome) anything unusual in the ECG might very well be a good indicator for the potential of Verapamil.

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    4. I am thinking of another biomarker for Verapamil treatment in autism. Mast cell activation in general is one of them, as I understand this. I have just received the opinion of one of the clinicians from the US, involved in defining the criteria for mast cell activation syndrome, confirming that the urinary N-methylhistamine increase seen in my son is indicative of mast cell activation. This was something that doctors argued about here, as my son was the first person who had this test done in my city, it’s not well described in papers and the results were not sky-high: 112 ug/l baseline and 200 ug/l during symptoms. The symptoms were: headache and the behavioral things, mainly irritability. A year ago we would notice only irritability in such situations as he was unable to communicate the pain. Urinary biomarkers measurement is stress free for a child. Testing N-methylhistamine can be tricky, but having had such a result a year ago would have saved my son a few months of behavioral programs to reduce his aggression (bad idea for behavior induced by pain left without relief) and Risperidon prescription. Tha last one had one advantage though: leaving me so disappointed that I decided to help my son on my own and found this blog. For that I am grateful every day.
      There are more lab tests to prove mast cell activation, however I am not sure if they would be relevant for other kids with ASD. But for someone in similar situation to ours it could be helpful. For Verapamil perhaps the best idea is to try it for few days anyway.

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    5. There is another thing which I think may be likely to help your son, given his elevated histamine. I will shortly write a post about it, but if you look at how histamine is "de-activated" in the brain, you will find that SAMe is required. SAMe is known to be low in people with ASD. If you are low with SAMe and have elevated histamine then there will likely be problems. There is a solution to this, you gave give the precursor to SAMe with is L-methionine. This is cheap and already used at Johns Hopkins for autism where they seem to use it for "cognitive improvement". In another post about IL-10 and IL-35 I will write about how these anti-inflammatory cytokines are modulated in part by SAMe. So if you are low with SAMe, many things wills be affected. As usual you can also find people on the web saying L-methionine, or the more expensive SAMe itself did not help.

      It is clear that it does help some people with ASD and I even found one NT person with severe allergies raving about the benefit of SAMe.

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    6. Thank you for thinking about help for my son, I appreciate it very much.

      I remember you’ve already mentioned SAMe with regard to IL-10. I didn’t know about IL-10 and SAMe association and also can't find much on this. I’ll be waiting for your post about it with IL-10 still on my mind having just seen another episode of “afebrile fever effect” in my son..

      I understand that SAMe might enhance histamine metabolism in the brain via HNMT and possibly reduce the prolonged symptoms related to histamine released from abnormally activated mast cells? It seems that histamine metabolites may also play some role in all that, another thing for me to learn about. I read that another histamine metabolising enzyme, DAO, may be inhibited by certain drugs with verapamil and acetylcysteine listed among many others. That’s confusing.

      Why SAMe is low in people with autism? Does it make sense to measure blood level of it? Methionine blood concentration is normal in my son, but his homocysteine is low and B12 always too high. So there’s clearly something wrong about it.

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    7. This paper is very well known:-

      http://ajcn.nutrition.org/content/80/6/1611.full.pdf+html

      DAO is elevated in schizophrenia (nobody measured in autism) and SAMe is low. Perhaps, via feedback loops, the body compensates for low SAMe by raising DAO and this then causes further behavioral issues.

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    8. I read this paper a while ago and my conclusion was: "reduce oxidative stress". I didn't make a connection with histamine metabolism. It seems that DAO activity and SAM/SAH can be tested at a reliable laboratory here, ironically it’s the same place, where they advise parents to lower their expectations about ASD kids and don’t believe in mast cells. Your new post is really outstanding in linking several mechanisms which may be involved in autism symptoms.

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    9. I do not know if brain DAO levels will be reflected in blood levels. The research into schizophrenia will likely show this. If brain DAO is elevated the suggestion in schizophrenia is to raise D-Serine and use DAO inhibitors. Many people with schizophrenia already use D-Serine and write about it on the web. Many also use NAC.

      If you are measuring various things, biotin is worth checking and so are triglycerides. It turns out that high triglycerides is known to affect mood and behavior. One thing that biotin has been shown to do is lower triglycerides. So even in people who are not biotin deficient, additional biotin may result in improved behavior/mood. I am currently testing various things and the one that actually appears to do something is, surprisingly, biotin.

      The other thing is that oxytocin may help further reduce Cl- levels. So people who respond to bumetanide, might further benefit from oxytocin and vice versa.

      http://www.valas.fr/IMG/pdf/oxytocin.pdf

      Syntocinon is available as a POM and one reader finds it very effective in his young son.

      In effect Ben Ari is saying that Oxytocin and Bumetanide have the same mode of action.

      The dose suggested in autism is small (one spray per nostril) and perhaps the effect uses a slightly different mechanism.

      I have not used it, because it is not available here. But it is widely used elsewhere.

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    10. You are right, all papers are rather about DAO brain levels or genetic findings. I also found none mentioning histamine involvement and I think your idea of increasing DAO activity via feedback loop because of HNMT dysfunction is very interesting. Influencing NMDA receptors with D-serine and DAO inhibitors would be useful then. But there are also ASD kids who benefit much from memantine, so this gets complicated for me as it’s NMDAR antagonist. Are there any clues that may indicate hypo- or hyperfunction of this receptor? Or is it too simple way to think about that? Perhaps the answer is already somewhere in your blog, as was the answer for my latest idea - I googled “etanercept + autism”...

      What effects of biotin can you see? I tried biotin several months ago (with biotin blood level borderline and elevated 3-OH-IVA in my son), but did not see improvement. However, this was before we started Cromoglicate, Verapamil and Bumetanide and I think that many subtle, but significant effects may have passed unnoticed among behaviors typical for my son then (which hopefully are gone).

      Syntocinon is not available here. Is it available anywhere in EU?

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    11. Etanercept is interesting but hugely expensive. I think all arthritis drugs need to be considered - they have now again trialed vagus nerve stimulation for arthritis. There are even some natural substances like Boswellia/5-loxin that seem to help some people.

      Some people with schizophrenia take D-serine. They also take NAC.

      I am looking into NMDA receptors and schizophrenia at the moment. NMDA receptors have a Redox binding site. I expect this is another reason NAC helps.

      There have been several trials of Memantine in schizophrenia and more planned. I think that schizophrenia will have many different causes, just like autism. What works in autism may be the opposite of what works in schizophrenia, or being entirely uncorrelated.

      I think Syntocinon spray is available in the EU. One reader from Portugal has been using it for two years. It is made by Novartis. In some countries it is only available in ampules. I think you could make your own spray using saline + oxytocin from an ampule. The ampules exist in UK and France. It cannot just be Portugal.

      The biotin seems to have a mild effect just making things calm and "normal", it may just be a coincidence. It is nothing radical. I think it is the same effect that some people get from their high dose omega-3 fish oil. It is reducing triglycerides. There are numerous omega 3 trials in schizophrenia, depression, bipolar and indeed autism. They are mostly inconclusive. They should have measured triglycerides before and after. Elevated triglycerides is linked to worsening depression/schizophrenia etc.

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    12. Syntocinon is available in Austria:-
      http://www.apotheke-st-anna.at/produktdetail/syntocinon-spray.html?detail=55188
      so it probably is in Germany.

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    13. Last time I looked, it was available in the Netherlands and I think it is also available in Germany.

      I wouldn't not make it with the common ampules. Its concentration is 8 times lower than the nasal spray and it would be necessary to do 8 nasal sprays for nostril instead of one. It would be discomfortable and a serious challenge to use it over long periods of time.

      Last year it went out of market (for unknown reason, but it appears to be associated with a change of ownership of the producer in Portugal) for a few months here in Portugal and I looked in to the ampules possibility. Luckily I hoarded an 8 month supply and after 5 months it returned to market.

      João Santos (Portugal)

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    14. “Calm” and “normal” - it’s so reassuring to see such words when autism is discussed…

      I couldn’t find Syntocinon spray in German resources I know, but parents here get this drug sent from two pharmacies: the Swiss and Italian one. Maybe they can send it to your country as well. I don’t know how it is transported, but according to portuguese SmPC this drug can be stored at room temperature for one month after opening, so it seems that low temperature during transportation is not necessary for short term use. I’ll get it and try.

      Was thinking about Etanercept as my son is just off prednisone taper. It was decided to give him short course of steroids without autism in mind, but as recommended for MCAS flares because this problem got really difficult few weeks ago. But what happened then to his speech and cognition for one week is a whole another story. The side effects are nasty and I’ve read what you wrote about safety of autism treatments, however the effect was as shocking as Verapamil for GI issues half a year ago and something to explore further. Obviously, for the time being my son is in the need for the safe antiinflammatory for daily, long-term use, I am not sure what would be the best choice.

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    15. I think oral steroids, like prednisone, are very interesting. They clearly are highly effective in some people. The more you learn about autism(s), the less surprising this is. If you consider it for long term, I would suggest contacting mainstream doctors in the US who use it for autism, like Dr Chez in Sacramento or the Boston Children's Hospital. They do prefer replying if you are a doctor and some can be extremely helpful.

      Before inhaled steroids were available, oral steroids were the only choice for people with severe asthma. So the side effects can be managed and that is also Dr Chez's point.

      You may find other things that work, but it will be a case of trial and error. Quercetin works, but at some point may actually switch to pro-inflammatory. This is also shown in the literature.

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    16. I wrote (18 January in this post) about my son experience with acute oral corticosteroid experience (liquid solution) in the aftermath of croup infection (hospital treatment).

      Although I was overwhelmed with him being hyperactive as a side effectn (resolved with l-theanine), occupational therapist immediately reported a remarkable change in motor planning (without knowing that he had taken the drug), stating that he looked like a different kid.

      This change is still "active" so I'm wondering if it had gene expression impact.

      Best regards,
      João Santos (Portugal)

      Delete
    17. It is very interesting João. How many days did he take the steroid?

      I think a short course of such corticosteroids is well worth a try, particularly in children who do not develop speech, or who lose it. The risk is minimal, and in a certain percentage there will be a response.

      Nobody will ever do a clinical trial, because of the side effects of long term use. But as you found, short term use can also have benefits is some people.

      Delete
    18. Just one dose to prevent respiratory issues. Doctor said it would have a 5 day effect.

      It immediately had noticeable effects: it made him hyperactive for several days (gone although he still his a little restless compared to previously) and moved him to another whole new level on motor skills (ever since).

      João Santos (Portugal)

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    19. João, was it prednisone? Can you share the dose given to your son then? I’ve read your previous comment, you wrote that your son has regressive autism. Have you ever tried carnitine despite no mitochondrial dysfunction diagnosed?

      It may be coincidence, but yesterday I received a comment about improvement of motor planning in my son. I don't know if this can be associated with permanent prednisone effect as I modified his mast cell targeted treatment along with steroid withdrawal. Also with the use of Quercetin - thank you Peter for advice on this.

      Peter, what surprised me was not the prednisone effect itself, but the dose enough to see it: 0,5 mg/kg for about 2 weeks. It's much lower than used by dr Chez or doctors from Boston: 2 mg/kg. Maybe higher doses are needed for long-term effect, but I wonder what would doctors from the US see if their patients have already been treated with Verapamil, Bumetanide, antioxidants etc.

      The pediatric immunologist here when told about the prednisone effect concluded that… my son needs to be screened for neuroinflammatory disease instead of being diagnosed with autism… So I mailed her all negative autoantibodies checked before and relevant recent papers highlighted in your blog. Now this doctor offers help and encourages us to continue with such kind of treatments also as she says, to learn something for other kids. I would really need an honest, off-label advice from the US doctors you mentioned, however this would be the first time that any professional answers my mail ;-)

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    20. The US doctors and other researchers are more likely to respond to an academic, medical or hospital-sounding email address. Maybe the immunologist has such an email address. If you send enough emails, you will get a response..

      There are lots of different strategies with prednisone. We have it in reserve for asthma.

      "Although seven to 10 days is the usual treatment duration for oral corticosteroids, three days of therapy (1 mg per kg of prednisone) has been shown to be as effective as five days for the complete resolution of symptoms within one week in children two to 15 years of age."

      An extremely expensive alternative would be Everolimus, which is in two trials for the TSC variant of autism. It does seem to work.

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    21. Hi,
      It was Dexamethasone and not Prednisone. Don't know dosage.
      João Santos (Portugal)

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    22. Thank you all for answers. I also saw some hyperactivity in my son over several weeks after steroid withdrawal, so it might be a common phenomenon (or not). As there are no clinical studies done, we won‘t probably have the chance to learn more about such issues and also about all those modern treatments mentioned above, which are somewhat difficult to try at home. Anyway, yesterday I gave my son 2,5ml Supersprouts for the first time. After school two of his teachers came to tell me how he surprised them with speech, that’s rather unusual. What I saw later was clearly increased interest in appropriate play with toys, also quite rarely seen in my son. Actually he was happy to play at 3 AM this night as well... Whether all this is just a coincidence or not I will see in next weeks...

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    23. I think the Supersprouts does also affect sleep, at least at the beginning. It is best to give at the start of the day. I later added a half dose in the afternoon; too late and it certainly will affect sleep.

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    24. Recently my son suffered from the same type of mast cell reaction with headaches the next day after we started Supersprouts, but at the same time he developed respiratory infection together with new teeth emerging - enough triggers to get confused. According to blood test results: SAM is slightly higher and SAH is lower than normal range in my son. I don’t' know how to read this as I expected rather opposite values. Can this reflect oxidative stress related treatments, anything else or, as you recently wrote, "human body functions in quite irrational ways"?

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  4. I started my 7 year old son on ibuprofen(300 mg in the morning and 300 mg at night) about a week ago. I didn't tell anyone but immediately his school aide, occupational therapist, and teacher started telling me that he had made big improvements and his aggression at home and school dropped significantly. I am worried about the side effects but the results have been very encouraging.

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    1. I am using 200mg in my 11 year old. You may get the same benefits with a lower dose and the potential for side effects is less. You could also see whether the night dose is needed, the morning dose may be enough.

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    2. Thank you - I will try that.

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  5. After reading your posts for the last two hours I see I am going to have to try to talk my doctor into trying Bumetanide or Clonazepam. I tried NAC a few years ago after reading about the clinical trial but I wonder now if I was too conservative in the dosing. Just ordered some more Pharma Nac to try again. Thank you for blogging! My older son has had metastatic stage IV Ewing's Sarcoma for six years now, and the reason that he is alive and thriving is the online sarcoma community suggesting out of the box options. Thankfully my doctors have been open to trying new things. I am a firm believer that the online autism community can also be of great value but unfortunately there is a lot of misinformation to sift through first. I am appreciative to have found this site and all of the good information on it.

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    1. I would suggest Bumetanide. It is now in the process of being approved in Europe as an autism drug. It is known to be safe, the side effects are known and can be managed easily (measure K+ levels in blood and add potassium supplement if needed; drink more water to replace lost fluids). If you use 1mg twice a day and give it a trial for a month, you will know if you are in the "responder" group. You may notice changes much earlier.

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    3. Is there any on-line information about Bumetanide for autism approval process in Europe? I talked to some doctors involved in ASD, literally all were familiar with paradoxical benzodiazepines effects in ASD patients. No one knew Lemonnier studies, however all were interested to read it (but not necessarily use it in practice). I discussed it more deeply with one psychiatrist here and it turned out that we think the same way about autism treatment, but have different “risk tolerance”. I hope that maybe such information could change this a little.

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    4. Normally you can look on the US clinical trials website, which usually has the trials in other countries as well

      https://clinicaltrials.gov/ct2/results?term=Bumetanide&Search=Search

      I think when you have autism at home, rather than just occasionally seeing at work, you look at it in a different light. Autism is not degenerative and so doing nothing is considered "risk free", but with autism the risk of doing nothing can be the biggest risk of all. This only becomes apparent/credible when you see behavioral changes in front of your own eyes.

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    5. I totally agree with you about the risk of doing nothing. Autism may be considered not degenerative, but one thing I can’t understand is how many times I’ve read or heard about the increased risk of epilepsy in people with autism during their life and how rarely this has been accompanied by any comment about prevention.

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    6. The epilepsy point is very valid. A while back when I was trying to persuade doctors to treat autism, I raised this with the European Medicines Agency. I said that I thought treatment with my "Polypill" would reduce the risk of both epilepsy and heart disease later in life. So not only could you treat the autism, but you could avoid some of the likely comorbidities. I think this was a bit too advanced for them, since the idea of treating autism still is seen as fanciful.

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  6. I don't know that this question is relevant to this particular blog, but my 7 year old (almost 8) just had the mthfr blood test done and he has the c677t mutation. His doctor prescribed Deplin. I have been working to get his "temper" under control for quite some time, and the only thing that has fixed it has been curcumin, which makes me think he would be a responder to verapamil. The mutation is heterozygous, but the research seems to be writing off this mutation as a potential cause of autism. His Deplin should arrive soon, and we'll see what effect it has. I've been surprised with the methylation issues associated with this mutation that NAC wasn't more effective. Same issue with the broccoli sprouts. We'll be talking about Bumetanide after he has been on the Deplin for a couple of months.

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    1. If there are GI or allergy issues, Verapamil is worth a try.

      If nothing seems to work, then check for mitochondrial dysfunction. There are widely accepted lab tests for this.

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  7. Hi Peter- thank you so much for all the information you so generously share. I am very interested in your comment about Bumetanide. You may remember I've been looking into it before but I haven't been able to source it yet. Do you know what the timeline is for the license for autism? Reading how Bumetanide helps our kids by making them more present sounds exactly what my son needs so I am really keen:-) Thanks again
    Monica

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    1. It will be 3-4 years, the process is very slow and expensive. They gave up with the US approval because of the cost, so it is just Europe.

      People in the US either find a doctor who is happy to prescribe off-label, or buying from Mexico or Canada.

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  8. Hi Peter,

    A question on Clonazepam.

    Firstly as discussed previously, we're giving 1800mg NAC and 2.5ml Broccoli. These have been moderately effective - mostly with increased sociability and reduced agitation. The effect is noticeable. He also has the MTHFR mutation as above.

    We tried a 0.2mg dose of Clonazepam for a specific social event and the results were significant. His chronic fear and restlessness no longer affected him. He was everything he is at home - social, engaging, conversant and calm but he was not a zombie but very much alert.

    Is it the I/E ratio that the Clonazepam/NAC are working on and should this be an area of focus? Are there viable alternatives to Clonazepam?

    Thanks Peter.

    Regards,
    D&G

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    1. Clonazepam affects the GABAa receptor. In the usual (high) doses it does make GABA more inhibitory and that is why it has a calming effect; it is stimulating the receptor. In tiny doses Clonazepam was found (by Prof Catterall) to tune/ modulate the GABAa receptor, so that when stimulated by something else the effect is magnified. So tiny doses and the regular doses have a different mechanism.

      Large doses are habit forming even after a few weeks of daily use.

      The half-life is long and so if used daily, only after 3 days do you achieve a stable dose in circulation. It is not clear which effect you noticed. If he took 0.2mg every day it would be one effect, if you gave an even lower dose like 0.05mg every day it would be the other.

      Many of the genetic differences in autism are associated with GABA. There are two types of receptor a and b. In some people drugs affecting GABAb are helpful, Baclofen being one. Many of these drugs are habit forming.

      Most typical people would feel better after a single "regular" dose of clonazepam.

      NAC is unlikely to affect GABA. Oxytocin does affect GABA.

      The best way to find out if the I/E balance is the problem, would be to try Bumetanide for 2-4 weeks. If there is no effect then you are 99% sure that I/E is OK.

      Occasional use of clonazepam, would be must less likely to be habit forming. Clorazepate is a very similar drug that is known to be less habit forming.

      I would suggest you try the very low dose of 0.05mg Clonazepam for a few days and see if it does anything. The tiny dose is not considered to be habit forming.

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    2. Thanks for your response Peter.

      In all likelihood, we will trial low dose Clonazepam as you suggest. The fact that it is not habit forming is our overriding concern.

      The research material on the effects of benzodiazepines on GabaA receptor/subunits and frequency control of chloride channels and concentrations and everything else entailed is fascinating and appears a real 'hot-spot' for further trials/research.

      In your research - and I suspect it's been more extensive than ours - have you come across material relating to low levels of bicarbonate and its implications? Our childs' level just came in at 21 mmol/L for an accepted range of 24 to 31.

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    3. I am not sure what low levels of bicarbonate imply.

      Since you are in Australia, you might want to read my recent posts about low doses of other anti-epileptic drugs, including Clonazepam. An Australian Psychiatrist is using similar drugs to the same effect. He is near Brisbane. http://www.gosforthclinic.com.au/. I think it may be easier to find the effective tiny dose using a different drug, Valproate. This will be outlined in my next post. Dr Bird is using low-dose phenytoin and low dose-Valproate rather than low dose-Clonazepam. The effects may be very similar.

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  9. My son had a beginning of Croup (laryngotracheobronchitis with swelling inside the throat) last thursday and, as a measure of precaution, hospital MD gave him corticosteroids (orally).
    Although the next day he was noticeably more active and appeared to be bit more responsive, he has since been clearly more hyperactive and a lot less attentive.
    He has regressive autism although typical mitochondrial diagnoses state no problem.
    Best regards,
    João Santos (Portugal)

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  10. I think you would need to try the steroid when he is healthy to really know the effect. My son had oral prednisone as a single dose for asthma and there was no autism effect. A longer course might have a different result. In the US some of the serious doctors believe it can help and others think it does not. Long term use is not a good idea.

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  11. I've already tried to do ECG to my daughter, but she won`t stay still. I will try again, with, and without Verapamil (even the dose is so small, 2x20mg). She often had arrhythmias - in the form of short period of tachycardia as the result of stress (even physical effort). It is usually ok in healthy children.
    Didn't know that the long QT is usual in ASD (except the Timothy sy). More reasons to worry about...
    I was suspicious (checked it several times) - but, rinitis withdraws with Verapamil.
    My colleges are surprised with my choice, but there solution is more aggressive than this small dose of Verapamil (Singulair,...etc.). Also, digestive problems are forgotten - I am exploring this connection...
    ALA in the dose of 3x100mg seems to be exellent choise - she has cognitive jump with it. And, unexpectedly, she is much calmer with ALA. I don`t belive in Cuttler`s protocol and in all that story about redistribution of heavy metals - all the studies seems to me like pure speculations. Well, who am I to judge... It is just my belief.
    Started with Broccoli spruit today... I shell let you know the result.
    Are you still pleased with "broccoli effect", Peter?

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    1. Yes, the broccoli effect continues. I give 2.5ml once a day mixed in water.

      The digestive issues improve because the same Cav1.2 channels are widely expressed in the pancreas, where various enzymes are produced including for digestion. The replacement enzymes, Creon/Kreon, used to treat cystic fibrosis, would also likely help your daughter, but Verapamil is a better and much cheaper solution.

      Are you giving ALA in addition to NAC/fluimucil, or as an alternative? What NAC/fluimucil dose are you giving ? I think the heavy metal / chelation issue is nonsense. All the chelators are anti-oxidants and they show an improvement because they are reducing oxidative stress.

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  12. Thank you for the tip about connection between Verapamil and digestive symptoms, Peter, you've explored it really thoroughly. I am taking care of possibility to "over treat" my daughter. Why shell I give her two, or even tree drugs, when I have the same result with one? Singulair is interesting, but I was too afraid about some psychological nus effect that I`ve read about.
    And thank you for the honest opinion about chelating.
    I gave to my daughter ALA as an alternative for NAC tor several reasons:
    - found out that echolalias are her own way of developing a language skill. She is changing and adapting them - they are more and more appropriate to the real situation.
    - she has regressive autism (lost her speech skills and withdraw clearly almost in one day after stomach flu in 18th month - I am still in shock, after 8 years, waiting for my perfect baby to come back...). According to the Richard Kelly`s research (found out about it thanks to you), ALA is the one in the scheme for complex I deficiency.
    - she doesn't has SIB like behavior
    - and again, as in the beginning: don't want to over treat .
    Found out that some parents are using them together (3x100 mg ALA and 3x300mg NAC)
    I shell do exactly the same when the time comes to go to the HBOT, it is our 5-th cycle of 20 dives (I know about your opinion about HBOT, but it is free in Serbia - not only for Serbs but for all kids in the word. It is the only free therapy I`ve got in my country and I think that it made my child more friendly and open).
    I am not worried about yeast and similar things - reports about "dying yeast" that is releasing toxins is in domain of science fiction to me. Also, all diets end therapies that are about to show first effect in the time longer then the month, doesn`t make sense.
    Peter, the main thing about ALA is that cognitive and calming effect in my child. It developed almost instantly, from the beginning.
    I am using ALA 100mg from NOW, it can be found in every good drugstore.
    Maja

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    1. There are many thousands of ASD variants due to all the possible combinations of genetic dysfunctions (there are 200+ genes just for epilepsy), so no two kids will be the same. However, there do seem to be clusters of people where similar therapies do seem to help. If your daughter only had mitochondrial disease (like Richard Kelley) then she would not have Cav1.2 dysfunction and Verapamil would be ineffective. One reader was diagnosed personally by Kelley and prior to that not one of my Polypill ingredients had helped, not even NAC.

      Girls are better protected from neurological insult, for many possible reasons, one being that Progesterone is highly neuroprotective. It is even sometimes given I/V in the ER after a traumatic brain injury.

      I would suggest that perhaps your daughter may have had underlying issues that had not been noticed, only when the stomach flu came at 18 months did things regress.

      I had another reader recently tell me how it was rheumatic fever that caused a massive regression in his already mildly autistic son.

      In Serbia nobody is diagnosing autism in 18 month old children.

      All this leads me to suggest that you might give Bumetanide/Yurinex a try. It is used in neonatal babies and so trying it for a couple of weeks should not be a big risk.

      When I first gave bumetanide I did worry about these risks, but later on I thought about just how big is the "risk of doing nothing".

      You should be wary of overmedicating any patient, whether or not she is your child. But if the cognitive impairment is partially reversible, with a well tested 40 year old drug, is it would indeed be tragic not to trial it.

      Bumetanide is on the way to being approved for autism, hundreds of kids in France are taking it.

      It may not help, but if she is a responder, you will see lots of cognitive improvements.

      The dose used in France is 1mg twice a day. Lower doses can be totally ineffective and higher doses have no extra benefit. You should monitor K+ levels and it is a good idea to supplement with K+.

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  13. I`ve red your answer several times.
    Not afraid of bumetanide, I`am more worried of taking the blood sample for monitoring K level. She used to pass out as the result to stress.
    I understood everything you wrote...
    Thank you so much for sharing your time, knowledge and thoughts with me,
    Maja

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    1. I was advised to wait 2-3 weeks before checking K+ levels, you will very likely have found out by week 2 whether your daughter responds to Bumetanide. If she does not, you will never need to take any blood.

      Taking blood is a big issue, for the child and the parent. If only a small sample is needed it can be taken from a finger, which is what we did the first time. Just like having a haircut or visiting a dentist can be a huge problem, eventually it will be overcome.

      If you add extra K+, either a banana extra a day, or a K+ supplement with each bumetanide dose, the K+ level will very likely be totally normal. This was our case and so frequent monitoring is not needed. I have only done it 3 times and it was high normal on each occasion. I give 200mg of K+ with each 1mg of bumetanide.

      Your big advantage is that you can access bumetanide, 90+% of readers of this blog cannot and many would dearly love to be able to try it, but their GP will not prescribe it.

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  14. Hi Peter,
    My son is 9, he has been treated since he was 2, he has no seizures but yes electrical activity, we realized about his problem only because he became very overstimulated and anxious when watching colourful cartoons when he was 2, now, the problem remains and is worse,moving his body, hands,shoulders including facial grimacing, like tics, this is his main problem that we couldnt solve, that happens in other situations like school acts, shoppings, cinema. I think this can be part of his sensory disorder, in spite he cant stand noises, the visual sense seems to be the more affected. Y read your blog about potassium, do you think that could be something to try?or his problem has more to do with his electrical activity? He is on sodium divalproate,minerals and antioxidants.Thankyou for your time.

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    1. Sodium divalproate is a seizure drug, even though your son does not have them. Many kinds of seizures are linked to ion-channel dysfunctions. The sensory overload that I found linked to potassium is very likely also an ion channel dysfunction. You can test your son by seeing if his symptoms fade when you give him a potassium supplement. If the symptoms improve for an hour or so then you have established something. The particular potassium channel seems to be Kir2.1. In which case you could try a small piece of a nicotine patch, since nicotine is also known to block this channel.

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    2. thankyou for your reply, I have doubts about the amounts, a tablet of potassium is a very tiny amount, if were in powder, a teaspoon of potassium citrate would be ok? about the nicotine patch, 7 mg divided in quarters, one per day? isnt it adictive or toxic? sorry for many questions.

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    3. The amount of potassium supplement varies widely. In the US they are all very mild. I use a 500mg effervescent tablet.

      If you make a trial with your son using a sound he hates (for my son it was the sound of a baby crying) then give him potassium, wait 20 minutes and try again. In my son the difference was indisputable, whereas the effect on his NT brother was zero.

      Potassium has many functions in the body and you cannot safely keep giving supplements or the level will go too high. This is why in the US potassium supplements are so weak.

      Nicotine in large doses is addictive, without doubt, particularly in the form of cigarettes.

      Small doses of nicotine do seem to provide some positive effects in some people. Since there is a big effort to stop people smoking, this is not something that is going to be widely discussed.

      You can make a short trial to see if it helps. If this was the problem, you would see the impact quickly. Then you could always then look for something else which has the same effect.

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    4. having found a relation between his subclinical epilepsy and the sensory overload, ion channel dysfunctions, would be amazing, after many years. The sound of a baby crying is also the worst sound for my son, he becomes crazy and gets me in trouble with the baby´s mother!! I can´t find 500 mg elemental effervescent potassium, where can i get it?or another alternative?About nicotine patchs, nicotinamide could be someting else or is a nonsense?

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    5. You can use any kind of potassium supplement. In the US they are all 100mg or less. In other countries the rules are different. Just don't get carried away and give too much.

      You might also consider increasing potassium in his diet and reduce sodium. Most people have half the recommended daily amount (RDA) of potassium and much too much sodium. In the body, the two are related.

      You could also measure these electrolytes in his blood and see if they are normal. Very high levels of potassium can be very bad for you, this is why the supplements are restricted, the RDA is about 4,000 mg.

      Nicotinamide is something different.

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    6. thankyou Peter, yesterday I read about subclinical photoparoxismal responses to visual stimuli in children with ASD, like TV and the fast cartoons, videogames and of course the environment, when we go in the car, he cant stop moving when he see the sunlight interrupted by roadside structures of tress. That is called photosensitive epilepsy.Practically all visual stimuli, as i told you, affects him.i dont know if something else could work for him. I found potassium citrate,a liquid solution.

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  15. Peter, your blog is fantastic. We have been taking broccomax and think it is effective. However, want to try the Australian product in capsules. I am not sure what the exact product is. Is it this one that you refer to? http://www.supersprout.com.au/broccoli-sprout.html Thanks!

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    1. Yes, that is the correct product.

      It would be good to know whether it works better/worse/same as broccomax.

      The research showed that most broccoli supplements produce no sulforaphane, but you would think the producers would eventually wise up and just copy the products that are effective.

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    2. I just ordered and will let you know how it compares to the broccomax. Thanks again!

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  16. Peter, your blog is fantastic. We have a teen who still has some serious sleep issues (and some autoimmune illnesses -- his doc has him on daily naproxen to keep inflammation down). MRI testing did not reveal anything. I know you have posted on melatonin (which is not our answer)Does Bumen. help with sleep? Benadryl works well for him to sleep. Any guidance? Thank you!

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    1. Thanks for the question.
      I should start by saying that my son sleeps quite well, though he does wake up early. So I do not have first hand experience.
      In a recent post I highlighted a paper on Ferritin, which is involved in storing iron in the body. It seems that a significant minority of people with ASD have a dysfunction with iron storage. Their diet may not be deficient in iron and yet ferritin levels are low. The paper connected low ferritin with sleep disorders in autism.
      If my son had a sleep problem I would definitely go and test ferritin and iron levels. These are the tests for anemia. You can have low ferritin, but not low enough to have signs of anemia. The therapy would be to take iron supplements, but not excessively or else you will create the problem of high iron levels.

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  17. Thank you His sleep is definitely better as his ferritin is in the normal range now (after being low during his illness). So that has helped, but there is still something missing unless we need more time. Unfortunately, most mainstream doctors have encouraged drugs with side effects :( Melatonin makes him pop up at night.

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  18. The normal range is very wide, why not increase iron a little and see if it helps sleep?

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  19. I had a similar experience recently with my son, who is nearly seven and just lost one his front baby teeth and the new one is coming out. He was complaining about the tooth long before it got wobbly and I didn't pay attention to his moaning. At the same time his behaviour got worse at school. I suspect seasonal allergies play a part, as Clarityn did work. Then last night we took my son to his chiropractor for the usual cranio-sacral that he gets every three months. The doctor found his head larger than last time and the bones at the side of his head were a bit "stuck". Basically, during growth spurts, the facial bones are "on the move" and this can cause behavioural issues in a lot of boys, neurotypical or not, but of course our kids are more sensitive, as neuro-inflammation is also an issue, so cranio-sacral manipulation also helps. Ibuprofen is also effective in this case, as you say in your post. My son was born with forceps, which messed up his cranial plates and accounted for a lot of his hyperactivity until we started the cranio-sacral therapy, so this is another piece of the jigsaw for us. Giovanna.

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