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Wednesday, 18 January 2017

The Clever Ketogenic Diet for some Autism


I have covered the Ketogenic Diet (KD) in earlier posts. 

There are more and more studies being published that apply the KD to mouse models of autism.

Calling the KD a diet does rather under sell it.  The classic therapeutic ketogenic diet was developed for treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective epilepsy drugs.

There are various exclusion diets put forward to treat different medical conditions; some are medically accepted but most are not, but that does not mean they do not benefit at least some people.

When it comes to the ketogenic diet (KD) the situation is completely different, this diet is supposed to be started in hospital and maintained under occasional medical guidance. The KD was developed as a medical therapy to treat pediatric epilepsy.  It is very restrictive which is why it is used mainly in children, since they usually will (eventually) eat what is put in front of them.

The KD was pioneered as a medical therapy by researchers at Johns Hopkins in the 1920s, over the years they have shown that most of the benefit of the KD can be achieved by the much less restrictive Modified Atkins Diet (MAD).  The first autism mouse study below suggests something similar “Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior”.


What about the KD in Autism?

Most people with autism, but without epilepsy, will struggle to get medical help to initiate the KD.  Much research in animal models points to the potential benefit of the KD.




·        Drug treatments are poorly effective against core symptoms of autism.


·        Ketogenic diets were tested in EL mice, a model of comorbid autism and epilepsy.


·        Sociability was improved and repetitive behaviors were reduced in female mice.


·        In males behavioral improvements were more limited.


·        Metabolic therapy may be especially beneficial in comorbid autism and epilepsy.


The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.






·        The BTBR mouse has lower movement thresholds and larger motor maps relative to control mice.


·        The high-fat low-carbohydrate ketogenic diet raised movement thresholds and reduced motor map size in BTBR mice.


·        The ketogenic diet normalizes movement thresholds and motor map size to control levels.


Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T + Itprtf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.





Background

Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBRT + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile.

Findings

Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals.

Conclusions

Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.





·        We evaluated, throughout a systematic review, the studies with a relationship between autism and ketogenic diet.


·        Studies points to effects of KD on behavioral symptoms in ASD through the improve score in Childhood Autism Rating Scale (CARS).


·        Reviewed studies suggest effects of KD especially in moderate and mild cases of autism.


·        KD in prenatal VPA exposed rodents, as well in BTBR and Mecp2 mice strains, caused attenuation of some autistic-like features.



Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.



Conclusion

Since very many parents do not want to use drugs to treat autism, it is surprising more people do not try the ketogenic diet (KD) or at least the KD-lite, which is the Modified Atkins Diet (MAD).
I think you have to be pretty rigid about the MAD, if you go MAD-lite you will likely achieve little; rather like thinking you have a Mediterranean diet because you buy the occasional bottle of olive oil.
Many children with epilepsy who started out on the KD continue in adulthood with the Modified Atkins Diet (MAD).
There is anecdotal evidence that people with mitochondrial disease benefit from the KD.
All in all, it is hard to argue that the KD/MAD should not be the first choice for those choosing to treat autism by diet. It really does have science and clinical study to support it.

In some people with autism it appears that when you eat is as important as what you eat.  There can be strange behaviors just after eating, presumably caused by a spike in blood sugar, or for others before breakfast. 

In regressive autism (AMD) Dr Kelley, from Johns Hopkins, wrote that:- 


Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.  In some children, early morning symptoms can be a consequence of compromised mitochondrial function, whereas, in others, a normal rise in epinephrine consequent to a falling blood glucose level in the early morning hours can elicit agitation, ataxia, tremors, or difficulty waking.  In children who normally sleep more than 10 hours at night, significant mitochondrial destabilization can occur by the morning and be evident in biochemical tests, although this is less common in AMD than in other mitochondrial disorders.  When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period.  Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours.



I still find it rather odd that none of Dr Kelley's work on treating regressive autism has been published in any scientific or medical journal.  After all, he was a leading staff member at one of the world's leading hospitals.  He is no quack.  It is extremely wasteful of knowledge and clinical insights that could help improve the lives of something greater than 0.2% of the world's young children.  That is a lot of people.












61 comments:

  1. Hello Peter,

    I am not sure whether this is all quack science or pseudoscience, but are individuals with blood group A more likely to get an autism diagnosis than others. Actually my son is A+, so am I and so is sis/mom. A blood type is relatively rarer amongst Indians and I just scanned through certain writeups which propose that secretin intusion might help some if these kids. Now I know secretin treatment has been dismissed by the scientific community but this blood group thing seems intersting..there was a small survey on 'wrong planet' and there seemed to be a higher incidence of autism/asperger in the A types.

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    1. I am unaware of any research linking blood type to autism. If there was a connection, then I would assume by now it would be found because there are large troves of research data publicly available on autism that could easily link a patient's blood type to various factors of their ASD diagnosis.

      This is just my assumption here. It is possible nobody has yet done a study on the matter, perhaps because it sounds too quacky to even follow up on (one of the worst biases in science that unfortunately has the side effect of both ignoring unpopular yet trie viewpoints as well as not ruling out quacky stuff you find on the internet because nobody wants to waste their time and reputation on doing a "negative finding" study.

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    2. Hi Tyler,

      Yes, it seems to be duck talk but we Indians have great affinity for this kind of stuff and seem to transition seamlessly from science to pseudoscience to quack science to superstition when it comes to stuff capturing our imagination. Actually even in ayurveda, blood groups have been linked to personality type and diet prescriptions. A predominantly vegetarian diet and low amounts of animal protein which incidentslly our family follows. Then hypersensitivity to environmental conditions and exaggerated reaction to supplements/drugs/diet which I have observed for both myself and my son (linked to A blood type in popular articles, not the peer reviewed ones obviously), made me a little curious.

      Thanks for even replying to that dumb query.

      Regards

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    3. Chinese herbal medicine and Ayurveda methods to me are kind of like a 1000 year old trial and error method for guessing what works and what does not. Since human beings have been walking the planet, people have been testing various plants and animal parts for properties other than "mmmmmmmm this tastes good". Sometimes they make you sick, and sometimes people notice that some sickness someone has is improved by something they just recently ingested.

      Western medicine is full of biases as well and is only recently maybe a 200 year old tradition that tries to find truth using objective methods, but as long as human beings are the ones trying to find truth in trying to be objective, you are going to have our humanity throwing its biases in all the time.

      On top of that, the way many drugs in western medicine are found is essentially an accelerated version of eastern practices where you take a giant swath of different plants and substances, put them all in a centrifuge and then have automatic machinery screen them all for having the best of some various property. Most people here in the west have this naive idea that drugs are created by scientists literally building drug molecules block by block without some other natural substance to first build upon, when that couldn't be farther from the truth. A lot of times, drug companies get lucky on screening massive numbers of chemicals and then when they find something, they patent it and then give some weird name to it with a common suffix of "ide, ib, a, etc.".

      So what you had to say is certainly not a dumb query, at least from my perspective.

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  2. Hi Petra,

    So after a trial with biogaia gastrus, I have concluded that even at half a tablet, its eliciting a little bit of momentary aggression..and I might be giving a very simplistic explaination but I think rather than anything very profound, digestive discomfort seems to be the driving force here. No great benefit..I do have biogaia protectis with me so will make a switch as I am certain it will suit my son.

    Petra, I just happened to read some of your o observations about Nac in relation to your sons response..mixed response. This is exactly how my son responded to NAC..to gastrus also. Cognitive enhancement but some irritability, probably anxiety in your case. I feel there is a mental response which is positive but a physical response which is nehative which in turn impacts the mental response a little as well. Its all so complex. Is it drug reaction? Is it allergy? Is it indigestion? NO, its AUTISM!

    Well..I am getting really impatient here which I should not be. I have the carnosine and piracetam which I will try soon as right now I have put my son on liver life and cytoflora.

    And Petra, some psychsdelics have long term impacts following single dosing..or so it seems. Lot of information on net. So if thing get really upsetting you could look at that option as well probably with the help of a medical expert. I just take each day at a time ..keeping future or thoughts about it at arms length. Slowing down life's pace, keeping it simple and hopeful???. Gently tread through life lest you wake the ghosts of reality.

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    1. Hi Kritika,

      I also wanted to raise the subject of blood type A+ in Asperger's a while back but of course I can't possibly know if there is scientific basis or if this could lead to interventions.
      My son has A+ blood type. I have to check for my nephew or other family members.

      I followed your advice on lowering Biogaia dose but unfortunatelly didn't see any improvement; I've missed some.
      I currently use, on a regular basis, 1 tablet and sometimes add a second one when I suspect digestive problems.

      I have some reasons to believe that Nac is a great antioxidant but I cannot account for some adverse responses.

      Thank you for reminding me that I should do some work with psychsedelics, especially if things get really upsetting, as you say. In my opinion the least harmful would be medical cannabis which is being trialled for inflammation, pain perception, PTSD, arthritis, cancer and lots of other devastating diseases.

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    2. Petra,

      I do not know either if blood groups can be linked to autism incidence but the practical takeaway from what I read and which I think holds true for my son and probably yours too is to supplement and medicate gently as their metabolism/digestion is way off. They might thrive best in settings in tune with nature which I do not know how to provide. If Hitler had been alive, he could have deported all Jews to our delhi. I am also A+ and I a m telling you if I get a single whiff of diesel fumes I feel nauseated for two days..so sensitive am I. I am sure Greece is better.

      As for psychedelics, ultimately everything is atoms and molecules. If i could find somerhing which at a very low dosing frequency gives descent benefits and if my son was even ten or twelve I would go for it provided there are safety measures in place..no adverse effects and no possibility of addiction. Is that possible?
      I am sure the way medical research is going, we will have that option in a few years time.

      My wishes always

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    3. Petra,

      Another gem from the realms of

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    4. Petra,

      Another gem from the realms of quackery..A blood group types are more sensitive to sulfur and methionine supplementation. NAC in case of my son??? Will lowering dose therefore be helpful? It seems too naive perhaps.

      That is all..do not want to mess with the high science.

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    5. Hi Petra,

      Sorry for hounding you but I would like to have your advice on probiotic choice for my son. I am currently giving him bioray liverlife and cytoflora, a bacterial lysate and observing some expected side effects but more verbalisations. I was also giving him half a tab of biogaia gastrus as cytoflora acts more like a prebiotic and a suitable probiotic is recommended as an accompaniment. Now, in my son every positive change is first visible in.his motor skills..with homeopathy, bumetanide, with gastrus. Another change I have noticed in the past few days is to put back his things even when I disappear after giving him an instruction..earlier I had to keep on repeating and be around for him to finish task like putting all the blocks back into the box. But gastrus is making him a little aggressive..h does not dare with me but with my dog and husband..just going and hitting or kicking with clenched teeth. Its not a long drama or meltdown but had he been neurotypical we would have called it braty behaviour. My problem is school opens on Monday and bdcause it is a mainstream school, even a hint of aggression makes the situation bad. What to do..should I stop biogaia gastrus and start biogaia protectis. I do not understand..nac and gastrus are making him respond in an identical manner. Same amplified responses, awareness but mean behaviour. I wonder if instead of oxytocin gastrus is increasing his testosterone levels. Or bringing out the hidden meanness which is my sweet sons true and intrinsic nature.

      Please give your opinion.

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    6. Sorry Petra, Peter

      This is really important but for the past few days, he is having those uncomfortable erections again..he is holding onto his erection and crying and yesterday when we were going for walk he suddenly stopped and held his pants crying. This is happening again after a truce lasting almost seven months.


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    7. Kritika,
      Biogaia Gastrus boosts testosterone and this could be a problem. There was a post here, about aromatase and making autistics a little less male.
      There is a probiotic that my sister used sometime ago and told me that it worked well for my nephew. It's from Frezy Derm with the brand name Prodilac in Greece. It has 100,000,000 Lactobacillus rhamnosus and Bifidobacterium longum.
      I'll check it myself, soon.

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    8. Kritika, do you think he might be constipated? I would think in a young child constipation could be causing the erections. Certain probiotic strains for some people can initially constipate - it was the case for my son. Also NAC can be very hard on the gut. My son could not handle sulfury things when he was little. Molybdenum is supposed to help with this but i have no "scientifc proof" for that. I would take him to the pediatrician and ask for a KUB (stomach xray) to see if there is poop backed up - this way it can confirm that when you see these behaviors, it is constipation, and you can focus on getting things to move and giving him foods that are easy on the belly, maybe focus on soups for a couple of days, extra magnesium to get things to move, soothing teas .... I would put probiotics on the back burner for now. and the NAC. Hope he feels better soon. I know there is always so much stress on us moms to make things better especially when they are in a "mainstream" school.

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    9. Hi Petra,

      Thank you so much for that information..you are great! I will read up biogaia gastrus related research articles again and I remember the 'making males less so' post. Will go through it again. Was thinking of trialling EPO for the estrogen effect..and the efa.

      Will look up the probiotic you mentioned also.

      Thanks Petra

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    10. Hi Tanya,

      I too had read that incomplete evacuation of bladder and constipation can cause erections. My son has regular bowel movements, usually twice a day and even a slight irregularity elicits sensory behaviour so I am very particular about that aspect. However, digestive issues do not cause erections in my son. And in fact, though NAC was hard on his gut and caused a bloat, his erectile discomfort started getting better from then on till now.

      I trialled NAC for only a month or so and have long stopped it. This erectile problem exhisted before any intervention and basically its not a problem of frequent erections but extra sensitivity to erections..on waking up in the morning, after afternoon nap or as he is falling asleep or some random occasions. He has again started finding them too uncomfortable after a period of respite when he could ignore them.

      Tanya, just now I read that cytoflora can cause some genital
      discomfort and can be tackled by applying a topical antifungal, anti inflammatory so will try that option too.

      Thanks for the advice on magnesium. I absolutely have to start giving it to my son as a squekingly clean GI tract equals happy baby and mumma.

      And social defeat is an issue as relevant for nt as those who are atypical. Have to fight tooth and nail to not let that affect our kids.

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    11. Hi Petra,

      Prodilac which you mentioned has Lactobacillus salivarius strain...I will also look for a probiotic with L.rhamnosus and Bifido.longum. I think using a suitable prbiotic is not as ctitical as not using an unsuitable one. Probably will stop gastrus for a few days and watch if the minor aggression abates. I am wondering how all you such knowledgeable parents have managed it..assessing and reassessing positives, negatives, incorporation, elimination with multiple interventions and in variable combinations. Something better work good and fast or else I will....grin and bear and try some more.

      Best of luck to all of us

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    12. Hi Tanya,

      Could you be kind enough to educate me on the dose and Mo compund you used to build up tolerance to sulfur based supplements in your son..if there is such a thing as building up tolerance to sulfur. I wanted to trial ALA but hesitating because of the sensitivity to NAC. I was also wondering if the probkem.might e that we are hurtling straight down to very high dose of these supplements..expecting my son to tolerate 1800 mg of nac when i could not keep up with a 600 mg tablet is blatant tyranny. I think keeping my childs comstitution in mind, keeping it low makes more sense.

      Tanya, have yoy ever tried carnosine. In another forum, I think in an old thread on carnosine, I saw that name. Any advice will be appreciated. You seem to have quite a bit of theoretical as well as practical knowledge about interventions. Its my great fortune to be able to get suggestions and advice from such brilliant people.

      Regards

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    13. Hi Kritika, sorry I wasn't clear - at the time, I didn't use molybdenum for the sulfur tolerance - was just mentioning I have read that it is supposed to help . When my son was that young and reacting we just avoided sulfur compounds and worked on other things, esp. gut issues and inflammation. I have not tried carnosine in earnest. What are your son's biggest issues health wise? Allergies? Gut? you mentioned the cytoflora side effects: maybe he is sensitive to the sugar alcohols in the product? I have read molybdenum helps with detoxing effects from alcohol toxins - along with pantethine. You are kind and gracious Kritika ! I wish I was brilliant with all of this stuff. All I have is trial and error and learning from why things go wrong . :) I agree with not getting too carried away and throwing too much too soon. Had to learn that the hard way.
      Here is some info from Linus Pauling site about molybdenum as co factor functioning:

      Molybdenum is known to function as a cofactor for four enzymes

      Sulfite oxidase catalyzes the transformation of sulfite to sulfate, a reaction that is necessary for the metabolism of sulfur-containing amino acids (methionine and cysteine).
      Xanthine oxidase catalyzes the breakdown of nucleotides (precursors to DNA and RNA) to form uric acid, which contributes to the plasma antioxidant capacity of the blood.
      Aldehyde oxidase and xanthine oxidase catalyze hydroxylation reactions that involve a number of different molecules with similar chemical structures. Xanthine oxidase and aldehyde oxidase also play a role in the metabolism of drugs and toxins.
      Mitochondrial amidoxime reducing component (mARC) was described only recently (4), and its precise function is under investigation. Initial studies showed that mARC forms a three-component enzyme system with cytochrome b5 and NADH cytochrome b5 reductase that catalyzes the detoxification of mutagenic N-hydroxylated bases.

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  3. Hi AJ,

    Its been a week on bioray liver life and few days on cytoflora. Nothing dramatic as yet but even at a few drops, liverlife totally clogged me up and now I know what is this thing called constipation. It was like I had no large intestine. My son tolerated it alright and if effective I should see some noticeable impact in another weeks time.

    I wanted to trial luteolin and apigenin combination but not able to find luteolin without the quercitin or rutin. Also some possible impacts on endocrine system made me a little apprehensive. Phytoestrogens..probably a good thing for my son??? What doses of astaxanthin and apigenin are you giving to your daughter and if I may ask what issues you are trying to address on a priority basis? In my son its language issues..and of course the socialization part. Otherwise he is improving, slowly though.

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  4. Hi Kritika,

    Hope all is well with you!

    Kritika, I use a quarter of the adult dose of the items I am giving my daughter, so about a quarter of an apigenin capsule. I haven't received Astaxanthin yet, but again, will give about a quarter of an adult dose. She's about 1/4 of an adult's weight, so I'm using her weight as a proxy for her dosage.

    In terms of Apigenin, I'm looking to keep IDO in check. IDO is the natural chemical that results in Quinolinic acid, too much of which can act as a neurotoxin.

    First, check out one of the papers on autism that I go back to often:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121959/

    It shows that Quinolinic acid is generally high in ASD kids.

    Now check out:

    https://www.ncbi.nlm.nih.gov/pubmed/26497015
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680090/

    So basically, assuming too much Quinolinic Acid (QA) is neurotoxic, and that ASD kids in general have too much QA (based on the Italian Study), then QA is a legitimate target.

    Out of interest to all - aged garlic and QA:


    https://www.ncbi.nlm.nih.gov/pubmed/26343296
    https://www.ncbi.nlm.nih.gov/pubmed/15380627

    As far as Astaxanthin, it looks like it has multiple benefits (noted in my earlier post), one of which is it may target NKCC1, which many are only targeting with Bumetanide (which I will try to get)

    Hope this is helpful Kritika!

    AJ

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    1. Speaking of neuroinflammation, an interesting paper came out today that confirmed what many of us already suspected or intuitively know about gut problems and neuroinflammation:

      Press Release:

      https://www.sciencedaily.com/releases/2017/01/170118145937.htm

      Paper:

      http://molecularautism.biomedcentral.com/articles/10.1186/s13229-016-0110-z

      Now, in terms of specific interventions in light of this information, I think much has been covered so far here, but one intervention I don't think has been talked about much which is super simple is supplementing soluble fiber into the diet of your child in a smoothie, in a peanut butter sandwich, or whatever you need to do to give your kid plenty of soluble fiber. Insoluble fiber from plant cells with intact cellular walls (i.e. not overly processed) also seems to be very important helping to prevent excess inflammation in the first place via a complex regulation of bacterial species, but supplementing soluble fiber is the easiest and one of the cheapest, and in my opinion one of the most reducing one of the core causes of inflammation so that all the other subsequent interventions have a chance at working.

      I also have seen a zillion probiotic products for autism, and many of them seem underpowered and are also likely mostly useless without sufficient prebiotic (i.e. fiber) supplementation as well to support the core ecosystem and to provide adequate SCFA's to the intestinal lumen. Biogaia seems to do a good job, but I dispense with it in an unorthodox manner both to save money and to increase its yield before ingestion, nevertheless I think soluble fiber is as important or more important than Biogaia.

      For reducing neuroinflammation, well the best I have come up with is the BCAA/Hydrolyzed Collagen/Apigenin/Nicotanimide Riboside. I have no idea if it is actually reducing neuroinflammation, but it definitely seems to reduce the symptoms of neuroinflammation (anxiety aggression issues from an inflamed amygdala and memory and learning problems from an inflamed hippocampus). Of course, eliminating whatever is causing the neuroinflammation in the first place is the ideal goal here, but there is yet to be conclusive research yet on how exactly this process comes about.

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    2. Hello Tyler,

      It would be really kind of you if you could give your opinion on wide applicability of the specific dietary/supplementary combination you have used with your son with good results.

      My son is going to be five in a few days and does not have much mood/anxiety or behavioural issues as yet (or probably with a dog and husband with some, my standards are set pretty low). Anything which could enhance cognition is what I am getting desperate for.

      Bumetanide, which I trialled, though enhancing focus and cognition affected him weirdly, which I feel was not solely related to falling potassium levels/dehydration. Within fifteen minutes of taking the drug he would start giving strange side glances (the only other time he does this is when his intestines are not absolutely clear). Also, he developed a strange act of running from switch board to switch board gazing deeply at the holes. And probably the most disturbing of all, he almost stopped speaking and the sounds were unclear. It took almost three/four months following disuse of bumetanide for him to get back his footing. Possibly the bunetanide dose (1mg/day) was too high for him.

      Is the bcaa/soluble fiber/apigenin/nic.rib combination worth a trial for my son too? I have already checked for availability. I would really be grateful if you could give your invaluable advice.

      Regards

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    3. Well, my son is on the moderate to severe end of the spectrum to the point we have been kicked out of speech therapy (and had to find a new provider) because he would have outbursts of violence. Most of that seems to be gone now but that is kind of the level he has been at. He also has limited speech which is getting slowly better. He can request things and has even started expressing simple emotional words, but I have never had a real back and forth conversation with him ever.

      So what kind of interventions you should employ with your child really depends on whatever objective scientific information you can gather (does your child have syndromic autism or idiopathic autism), as well as other hints like where does your child's head size rank relative to other children his age (my son was in the 99% head size circumference at birth if I remember correctly). Then after that you can make guesses with behaviors and the available research on what might produce them.

      As for Bumetanide, the fact he responds so acutely and negatively to it is actually probably a good thing because this is very specific information that can help you understand what type of interventions will actually work for him. Based upon everything I have learned my gut reaction would be that the running from switch board to switch board is due to basal ganglia dysfunction. In MRI studies looking at morphological abnormalities in autism, the most consistent findings seem to be an enlarged amygdala with reduced neuron cell number, and an enlarged caudate nucleus with reduced neuron cell number. Of course this sounds strange in how could the size of the amygdala or caudate nucleus be larger, but yet have less neurons. Well, people forget there are many other brain cell types including glial cells which outnumber neurons 4 to 1. So it is likely there are just too many support cells around, perhaps because of inflammatory issues in the brain or developmental insults during pregnancy.

      So the running back and forth is maybe a problem of action selection and switching (or rather selecting) the appropriate action and inhibiting the others which is what the caudate nucleus is supposed to do with regards to cognition and emotional affect while its sister nuclei the putamen is more diverse in areas of the brain it helps modulate even though it classically was always thought to be involved mostly in motor control. There have also been studies showing an enlarged putamen in autism as well, but the caudate enlargement is more consistent.

      The basal ganglia (which consists of both the caudate, putamen, and several other nearby brain nuclei) are 95% GABAergic which makes it unique in that way as only 15-20% of the neurons in the brain are inhibitory. These circuits are very complex and nobody really knows exactly how they work. The neurons in much of the basal ganglia also express dopamine receptors so broad acting drugs like bumetanide that affect GABA signaling are going to have an effect on the basal ganglia, though what kind of effect in an abnormally functioning basal ganglia is going to really hard to predict (you just have to test for it). Also, dopaminergic drugs or just supplemental dopamine via L-DOPA will have an effect on the functioning of the basal ganglia as well.

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    4. There is also a part of the basal ganglia called the subthalamic nucleus which has glutamatergic projections to the main output nucleus of the basal ganglia, and if signaling is not working properly, then the inhibition of inappropriate actions and the stoppage of already selected actions won't work very well (this is the part of the brain where Deep Brain Stimulation devices are implanted in Parkinson's disease). So if either the subthalamic nucleus is behaving abnormally or if its target glutamate receptors in the medial global pallidus are not working properly, you can have problems as well.

      Or there could be some specific alternative explanation for bumetanide not working as bumetanide does more than just block NKCC1.

      So things you can try:

      (1) Reduce dopamine (BCAA therapy or drugs along those lines). If things get worse, you might even want to try increasing dopamine with L-DOPA or Mucuna Pruriens just to rule things out, but first try reducing dopamine (I wish there were better options but that is the best and safest method I know of).

      (2) Consider some of Peter's suggestions for correcting dysfunctional GABAergic subunits such as low-dose clonazepam.

      (3) You might also want to consider that he might have an excess amount of inhibitory cells like the case happens to be in Down Syndrome. In this case, increasing inhibition via bumetanide could make things worse depending on whether the interneurons are in a pathologically depoplarized state or not. For enhancing cognition the general idea of course would be to take the breaks off of the brain a little bit, but things are really not that simple because inhibitory interneurons are generally "driven" by the firing of excitatory pyramidal cells (this is where brain rhythms come from, especially gamma wave activity). So in this situation you might want to try and enhance glutamatergic (excitatory) signaling and GABAergic (inhibitory signaling) at the same time so that the normalize their firing patterns with respect to each other.

      These are just the ideas off the top of my head. Recent research on intelligence suggests that having your sensory cortices behave rigidly while your association cortices behaving very flexibly is correlated with improved cognition, so the more push and pull you have going on in the brain, in theory the better your cognition is going to be. Scientists have been trying to figure out how to raise IQ for well over a hundred years now and have had little success though you can find plenty of websites with "brain training games based on science" peddling nonsense that suggests you can increase your IQ (fluid intelligence) with a subscription to their services.

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    5. One other idea with respect to your bumetanide issue is that you could have excessive NMDA receptor activity. GABAergic neurons in the hippocampus typically are much more sensitive to NMDA receptor activity (like 10 times as much) as excitatory pyramidal cells. This is why NMDA antagonists can sometimes cause excitation rather than inhibition as you would typically think from blocking a particular type of glutamate receptor.

      So another thing you can trial for cognition is agmatine sulfate which does many different things, but caused bouts of really improved lucidity in my son. I stopped using it because getting the dosage right was hit or miss and long-term blockage of receptors tends to have counteracting effects (which means any use of it probably means it needs cycled).

      Agmatine sulfate is a weak antagonist of the NMDA receptor via multiple modulatory mechanisms and is neuroprotective in that regard. It is most typically used by people in the gym trying to get a good pump due to its effects on Nitric Oxide (which increases blood flow). It could have horrible effects, or it could really give your son a boost or both, but if your son does not have much in the way of behavioral issues, you can try it out with very low dosages and then go from there.

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    6. Hello Tyler,

      Its so generous of you to respond with such a detailed explaination..will have to go through it a few more times to really absorb all that information.

      My son was born with an apgar score of 9 through an NVD and met all milestones in time including those initial few words..ma, milk, some imitation, empathy, fear of unpleasant visuals on tv or books and was the happy affectionate child everybody loved..but socially things were way off. It was as if he inhabited a parallel world gracing us with his presence occasionally and everbody could see that he is..well..different. After his first year or so his autism started catching up, progressing and at two it was visible in a slight regression in motor skills. It was not a regression but progression of his autism if you understand what I mean. At 2.8 he was given a formal diagnosis of mild autism with huge deficits in area of communication.

      He keeps on progressing, has a good memory and at 3.5 years of age could play a game on the computer where you burst letter balloons as they appear on the screen by typing on the keyboard and this he was able to do without looking down.at the keyboard...he had memorised the placement of letters on the keyboard. So intellect is something I really do not understand..its assessment and relevance. Functionality, the business of daily living is critical.

      Tyler, bumetanide did not impact my child only in a negative way..his handwriting and focus became much better. He became a little smarter cognitively but I think some other mechanism impacted him negatively.

      Because my son is not cognitively stagnant, improving a nd learning spontaneously too, one major challenge for me is objectivity in assessing effects of intervention. There is a placebo effect and then there is what is called a Pygmalion effect where greater expectation from an individual leads to more investment and hence a better outcome.

      Thank you once again for sharing your insights. You are a brilliant mind and a perfect parent. So hang on there.

      Regards and best wishes for your super son who can pour out his own milk from that huge can independently. He will do well.


      And I checked..my sons weight height and head circumferenve were in the fiftieth percentile during his first year. He gained lot of weight and height in the last year but again slowed down so it sort of balances. And he has a marginally low lymphocyte count if that is of any relevance.

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    7. Hi AJ,

      Wanted to inform you that bioray cytoflora and liverlife, supposed to be immunomodulatory and detoxifying, respectively, with some other beneficial properties a s well, has made a difference, basically in his attempts at verbalization. He looks happier, more present but some sensitivities and minor agression seem to have developed. For instance, he will grind his teeth hard clutching our dogs fur, increased mouthing or jump from end to end of room very hard..the earth trembles beneath his feet! But it is only for a few seconds and as it is he is not a very unregulated child so it is all manageable. This behaviour indicates a requirement for lowering the dose...or it could be consequence of biogaia gastrus, half a tablet of which I am giving to my son.

      In conclusion, cytoflora seems gentle and helpful, liverlife is stronger, so you might give it a shot but go low as per the recommendation..not like me who have a psycho logical block in following instructions.

      Please share your clonazepam experience..I am fiddling with that idea for months now.

      Delete
  5. Tyler, I left a comment in the post Enhancing the effect of bumetanide, about the immune related triptophan breakdown and bacterial infection, perhaps my son shouldn´t take it, but it would be a problem if he takes BCAA. Peter, what do you think?
    Valentina

    ReplyDelete
    Replies
    1. Tryptophan is an essential amino acid (your body can't synthesize it and it is required for life). The original reason for the BCAA's for my son was to reduce kynurenine levels in the brain as peripheral kynurenine making its way through the BBB is the primary source of kynurenine in the brain. Kynurenine's entry through the BBB is regulated by the same amino acid transporter that the aromatic amino acids use (tryptophan, tyrosine, phenylalanine) as well as the BCAA's (leucine, valine, isoleucine) and glutamine to a limited extent. So competitively blocking kynurenine with BCAA's will also competitively block the aromatic amino acids. This causes a problem with respect to tryptophan as it is needed in the brain to produce serotonin as well as NAD+ via quinolinic acid. So to address that problem I incorporated 5-HTP and green tea extract (helps to inhibit an enzyme that produces serotonin in the periphery so more of the 5-HTP gets into the brain) as well as Nicotanimide Riboside which through an evolutionarily conserved hack, will raise NAD+ levels throughout the entire body and brain. If you could upregulate the NAD salvage pathway via an enzyme called NAMPT, then just adding cheap niacin (vitamin B3) would be as effective (and much cheaper) than Nicotanimide Riboside. I don't know of any great way to do that even though resveratrol seems to be able to upregulate NAMPT. Nevertheless NR is superior in doing the job.

      Also if the body and brain are under stress, they can easily use up all the available NAD+ faster than it can be synthesized which leads to cellular decay and eventually death (or at least the body starts making compromises to keep its cells alive).

      Now in studies on tryptophan, excess amounts of it tend to get converted to kynurenine. This is not necessarily a bad thing as if you don't have any problem metabolizing it, you just pee it out. However, if there is an issue of quinolinic acid being produced faster than it can be used for producing NAD+, you are going to have various problems relating to quinolinic acid. Also, I added in apigenin for IDO inhibition as a further stopgap for limiting kynurenine access to the brain.

      So this is the whole motivation for the BCAA therapy originally and had nothing to do with regulating dopamine in the brain, just that since phenylalanine and tyrosine (tyrosine is produced from phenylalanine) are the precursors to L-DOPA which is the precursor to dopamine, it seemed obvious BCAA's could help acutely lower dopamine levels in the brain and it turns out I am not the only one with this idea (by the research I posted a few pages back). But back then Nicotanimide Riboside was not even around.

      My son's improvement from BCAA's which I still do today could of possibly been from reduced dopamine levels in the brain as well as I know a lot more about dopamine now than when I started doing this therapy several years ago. All I know is it seems to help a lot in various areas of mood and cognition. I have not done it without the NR, because I don't want to risk pellagra like symptoms and unless his inflammation issues are resolved first. I will admit I think Biogaia has potentially helped a lot in dealing with the upstream mechanisms, so we will probably do formal testing to see where we are now considering his improvements, so for a young child with no medical problems, taking NR is a waste of money, whereas for people with NAD+ producing or excess NAD+ consuming problems or else older people (NAD+ levels in cells start declining in your early 20's). That being said NR has been used successfully to treat mitochondrial myopathy which is comorbid in many cases of autism, so on its own I feel it may make a big difference in many cases of autism, rather than just being used in my case to address the potential pellagra side effects of long-term BCAA therapy.

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    2. Ok Tyler,thanks, I will add triptophan and niacin or niacinamide in small doses, and also propolis for its content of apigenin, and bacilor.

      Delete
  6. Hi AJ,

    Hope things are great on your side too.

    Thanks for sharing such valuable information. I went through the links you so kindly provided..I had read the first paper earlier also but this time it made a little more sense to me. It put together so many issues ..CDR, gut dysbiosis, b6 deficiency and aberration in tryptophan and purine metabolism. So you are trying to inhibit the acitivity of IDO through apigenin.

    Astaxanthin looks good. I was thinking of trialling luteolin too (neuroprotective, antiinflammatory, antioxidant and with neurogenetic properties) but the products that I am getting (lutimax, neuroprotek) have quercitin or rutin. Now I read somewhere that quercitn has been linked to reduction in
    seizure threshold and someone on this blog informed that it might aggravate anaemia (my son is mildly anaemic). However as I search, I am getting contradictory information. Brain gain, which has only luteolin is not shppied to India so I might try lutimax in near future. (After carnosine and piracetam..hopefully get better speech).

    All the best and keep us informed. And thanks for being so helpful.

    ReplyDelete
  7. Peter, perhaps supplementing pantethine, higher than what is in average multi vitamin blend, could make a difference?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880308/

    ReplyDelete
    Replies
    1. Tanya, I think that would be a good one for someone already on the KD/MAD like RG's daughter to try.

      Delete
  8. Hi Em,

    Just a quick note to say thank you for suggesting Clonazepam in another thread. I have to admit, I wasn't aware of the potential of low dose Clonazepam, so kept your message in mind, and have been so busy with work lately that I just looked into it and ... wow! I had no idea. I thought when people were suggesting Clonazepam, it was in relation to Anxiety, which my daughter doesn't suffer from (she's actually a real daredevil).

    Now that I've looked into it this week, I am so intrigued, and just wanted to say a big thank you for suggesting it. I will definitely give this a shot.

    Do you (or anyone) have any good methods for getting relatively equal doses of 1/20th of a pill? I assume using a pill splitter a few times, or grinding it and eyeballing it into equal portions?

    Again, a big thanks Em, I had no idea about the potential of super low dose Clonazepam to actually improve symptoms. If this actually works for my daughter, I will be thrilled.

    AJ

    ReplyDelete
    Replies
    1. I hope it helps, if there is a difference (any difference, make sure all other baselines are static in terms of interventions & environment), then it makes much more sense to add other, less simple interventions that would make GABA inhibitory, namely bumetanide, diamox and potassium bromide.

      Thereafter you can go the route of trying to augment GABA production if the underlying problem was actually that it was misfiring, if not then some other part of the excitatory/inhibtatory mechanism (or another part of the cycle) may be off..

      What I do is crush extremely fine, then use a 10ml syringe to rinse and transfer to a 100ml dropper bottle that I pop in the fridge.

      500mg tablet into 100ml = 5mg/ml after shaking it well (I assume 4-4.5mg/ml due to settling)

      I typically dispose of the solution at 10ml or so and make a new bottle.

      A better solution would be to get it compounded or maybe use a different vector such as the liquid in ibuprofen or antihistamines (shaking really throoughly) if also supplementing that.

      Good luck.

      Delete
  9. Peter, Do you think intranasal insulin might help with fear conditioning?
    I've read some papers connecting fear conditioning with IGF2 pathways in the brain.
    It's easy to find insulin and some kind of a dispenser to spray.

    ReplyDelete
    Replies
    1. Petra, I do not know if it will help with fear conditioning. I think intranasal insulin is interesting and we know from existing studies that it is safe. It does not affect circulating blood sugar levels in the rest of your body. I tried it on myself and did notice an effect after a few minutes, just very mild. I would be interested to know how it affects your son.

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    2. Hi Peter,
      I have completed 24 days of Bumetenide.My son is severely autistic functioning at a 2 year old level.He says single words.No 2 words sentences.Cognitively impaired.There has not been any change cognitively.What would be the best medicine for cognitive improvement.
      I tried gfcf for 1 year by going to a DAN doctor.Tried MB12 shots for 6 month.My son is deficient in iron.They did a urine test and found that he has low cretenine.
      Please advice
      Regards
      SB

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    3. SB, depending on what dosage of bumetanide you are using and your son's size, it might be worth continuing a bit longer with bumetanide.

      Another similar GABA dysfunction that may be present, and will impair IQ if present, can be treated with very low doses of clonazepam. This is based on the work of Professor Catterall.

      The dose most people find effective is about 25mg a day, but it will take three days to reach a stable level in the body, so 3 days to show effect. It is very dose dependent, slightly too high a dose will give anxiety/agitation. If the dose is too low there will be no effect. This dose if far lower than the usual dose used in medicine.

      A 0.5mg tablet can be dissolved in a 100 ml medicine bottle and then you mix very well and using a syringe to measure 5ml. That equated to 25mg.

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    4. Peter,

      There is some confusion with the final dose..is it suppossed to be 0.025 mg or 25 micro gram.

      Em, in an earlier comment clearly indicates towards 25 mg dose while you I think mean a much smaller dose. I am keen yo try the ld clonazepam for hopefullly giving me a possible direction, if not for the actual remediation. I have 0.25 mg tablets..should a ten times dilution be a good place to start..or even a greater dilution.

      Delete
    5. Kritika, yes I missed out the "c", I am using 25 micro grams, so 25 mcg which equals 0.025 milligrams (mg). So your 0.25mg tablet would be enough for 10 days at my dosage. I am surprised you could buy such a small tablet.

      Delete
    6. Peter,

      In India it is...seek and you shall find.

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    7. SB, Peter,

      Can inflammatory/allergic comorbidities decrease bumetanide effect? According to the French studies, high-functioning children were the best responders and I wonder why. Peter, I think I recall one of your blog posts about the need to increase bumetanide dose during pollen season. I can't find it now, do I remember it right?

      I think (but I cannot prove it) that if my son with severe autism wasn't on verapamil and other mast cell stabilizers earlier, then I might not see good cognitive and social effects of bumetanide among all his mast cell driven behaviors he used to have before.

      So maybe in severe autism and little or no improvement on bumetanide, it would be worth checking if there are any treatable chronic inflammatory or allergic issues? Considering that they may present atypically and some trial and error way of treatment could be needed?

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    8. Agnieszka, it appears that inflammation affects the expression of KCC2 and NKCC1. This is documented in studies, but I also found this paper:-

      Modulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons

      https://molecularpain.biomedcentral.com/articles/10.1186/1744-8069-4-32

      “Conclusion
      Our findings indicate that inflammatory mediators impact on Cl- homeostasis in DRG neurons. Inflammatory mediators raise intracellular Cl- levels”

      I found that bumetanide, but also NAC, appeared to "stop working" in the allergy season. Others also found this. Even a second daily dose of bumetanide in summer does not fully reverse this loss. I hope that the additional effect of KBr will help.

      If my son has trialed bumetanide in summer, I would have rejected it as an intervention.

      Delete
    9. Hi Agneiszka,

      Greetings!

      I just read one of your comments which I feel is significant with regards to my sons odd bumetanide experience.

      Looking back, my husband and I feel that bumetanide as well as nac, had given a smart edge to my son. His body movements had become more neurotypical...which could not have been a placebo affect. His gait, posture apart from the focus and learning. Agneiszkaa, following every effective intervention, improvement is first most perceptib le in his movements which sort of leaves lesser room for subjectivity. For instance, biogaia gastrus has given him a jump in coordination and imitation..this was visible within twenty four hours of the first dose which is half a tablet..he started imitating dance movements on tv and is getting better everyday. He displayed minor, momentary mean behaviour which I feel is also getting better. Bumetanide had led to improved academic performance too but the most disturbing side effect (there were others too) which I could not dismiss was his slow but steady loss of speech..it was as if his oral motor skills had declined due to fatigue. Also, he was hyperfocussing on something going on inside his body within 15 min of taking the drug, probably the physical discomfort of diuresis in a sensitive child. Potassium supplementation did not help..rather made things worse by causing stomach discomfort.

      Now, I think you mentioned somewhere that before your son turned 7, he could not tolerate 1mg of bumetanide and you were giving him 0.5 mg twice a day. It would be really helpful if you could recall what behaviours, symptoms made you decide that the dose is too high for him.

      I was keen to retrial bumetanide and wondering if halving the dose would be helpful. Your observation and balanced views regarding tolerance issues with bumetanide dose will really be valuable in helping me decide. You can understand..my son is behaviorally not really problematic and is becoming compliant and receptive. He is not even too hyperactive anymore now. So I do not want to do anything to jeopardize whatever natural progress he is showing.

      Best wishes

      Delete
    10. Hi Kritika,

      When my son was younger bumetanide > 0.5 mg twice was associated with lots of urination, immediate fatigue and dark circles under his eyes, so I considered it all symptoms of dehydration. Or low blood pressure, shame on me, when my kids destroyed pediatric blood pressure meter at home I didn't buy new one. All was not severe and resolved quickly.

      So this was something different than you described.

      I would think that hyperfocusing on internal sensations could be manageable for example with explaining the situation (urination) in advance with pictures etc - at least in some children. Actually I think that everyone to be put on bumetanide should have it explained by means of communication best suitable for particular child.

      Speech loss is worrying. Can you describe more how it looked? Was it gradual or acute? Did it fully resolve? I am asking as my son has been experiencing speech disfluency for a year. The only medication that was new when it appeared was acetazolamide/Diamox, but all deteriorated rapidly after febrile infection together with stressful event at school afterwards. Unfortunately I am not able to explain it and help him.

      Diamox and bumetanide share some mechanisms. I haven't heard about speech issues as bumetanide side effect from the French doctor I asked. Also I asked some neurologists here about Diamox, none saw such problems.

      On the other hand there are case reports of reversible speech regression on memantine (NMDAR blocker) in ASD kids. Bumetanide was found to act as NMDAR antagonist as well:
      https://www.ncbi.nlm.nih.gov/pubmed/1371581

      I don't know if this is relevant and would appreciate if someone here can help to explain your or my son's speech issues.

      This is not related to epileptiform discharges, his EEG is best ever now and clear from sleep spikes.

      Perhaps I would try lower dose with caution and withdraw immediately if you see any speech deterioration, provided it resolved fully before.

      Wish you good luck if you retry.





      Delete
    11. Peter, this is very interesting.

      In a child with mast cell activation inflammatory mediators may be abnormally released year-round in reaction to several triggers.

      "These data demonstrate that the inflammatory mediators induce the phosphorylation of NKCC1 in DRG neurons and suggest that this phosphorylation causes the early (< 3 hr) phase of enhanced Cl- accumulation" - do you think that this can be targeted in some way?

      Delete
    12. Thank you Agneiszka. You have done me a big favour by putting things in perspective which I think I was losing. I feel I should keep a record of things..how drug responses turn out over time because I tend to lose critical data and end up with a looose description which might not be as helpful.

      Before bumetanide, my son had started developing lot of clarity in his sounds...ma..n, ba..t, ba..d. Slowly he started losing the clarity and then he started muttering as if too bored or tired to speak. What concerns me, after you raised the point, is that even now he has not regained back that clarity and strength of sound I feel...on some days he is better. I do not understand. On one hand his writing strokes had become so good, even his therapist had commented on his better learning and more importantly, interest in learning.

      Could this be something else...if I remember right Christine's son and another persons daughter had issues with speech dysfluency coinciding with bumetanide use. In the light of this knowledge, its best to postpone another trial.

      I feel right now its best to focus on GI issues, inflammations and/allergies. Brain function is so fragile it becomes real daredevilry to try and rectify the problem..like a layperson trying to defuse a bomb following a manual written in a foriegn language and to add to the woes, this is a bomb different from.the one this manual describes.


      Agneiszka, thanks for that very objective assessment of things. You probably just saved us from more trouble.


      Delete
    13. Agneiszka,

      I read the abstract which you so kindly forwarded about certain chloride transport blockers action as non competitive nmdar antagonist. More importantly this seemed to be dose dependant..
      This makes bumetanide a drug with wider neurological impacts. I do not have any idea if my son wil do better with an nmdar agonist or antagonist. I have read of severe reactions of certain kids to memantine and know of a kid who was danaged irreversibly following a drug/gfcf protocol designed by a respectable doctor.

      But without going into a panicky mode, I think a short, extremely well monitored retrial of bumetanide should not be too risky an endeavour. I feel pu

      Delete
    14. Sorry..my son just pressed the publish button on my phone. I just wanted to ask you if ensuring adequate levels of magnesium, calcium, sugar apart from potassium and lowering the dose be a good retesting strategy. I am trying to be objective here but as Peter had mentioned I feel slowly some of the good developments with bumetanide...specifically perseverance and interst which is so much linked to good learning ability has faded over time after stopping the bumetanide. The handwriting has also showed a deterioration..unfortunately we sometimes notice subtle gains only after we miss them following suspension of a therapy.

      OR do you think a clonazepam trial would be safer? In your sons case, do you have any earlier experience with a nmdar antagonist or agonist? Or could your son have reacted to the a antibiotic and diuretic combination? Diuretics can in combination with certain antibiotics cause ototoxicity and speech problems..I think I had read that somewhere when I was trying to ascertain the loss of sound clarity in my son.

      Regards

      Delete
    15. Hi Agnieszka,

      I have something interesting to report here. Over the last month, with all that was going on, my daughter's dosing of sytrinol and verapamil had become irregular. I thought it wouldn't matter too much since we were stuck in deep winter. This last week, she started having slight reddening of her eyes and bouts of irritability and a little bit of SIB. I put her back on the regular dose of sytrinol and verapamil, but things hadn't stabilized after a couple of days. At that point, I looked at the bottle of clonazepam and realized that the compounding pharmacy had made a mistake and that it had expired in December. I think it was effective for a month longer and then went dead. I am only going to have the replacement tomorrow. In the middle of all this, the neurologist admitted her urgently three days ago for a 24 hour EEG and we will be discharged tomorrow. Since the EEG was completely normal after the first night, they stopped the Diamox to see if they could catch abnormal activity. Also, with all the diarrhea and lack of appetite etc, she had fallen out of ketosis. Two days ago, as far as I could tell things were deteriorating rapidly. Then, something interesting happened. My daughter's Bumetanide prescription is written for 1mg twice a day, though we have only been on 1mg once a day. The hospital adhered to the prescription and she got an additional 1mg in the evening. The poor behaviors stopped completely. Her calmness came back, with more speech. She began thanking the nurses appropriately, talking a bit to the doctors, and told the EEG technician that she was going to 'throw the EEG leads in the bin and go home on Friday'. We were doing reading classes and she has been doing very well.

      Her writing is not as good as it was, and today, strangely, after writing a couple of lines, suddenly she could not write an m. She kept saying and trying, but couldn't. She just kept scratching up and down with the pencil. It was as if her brain froze. It was unnerving, and I though it might be a seizure, but it wasn't. I have never seen this before. I wonder if the clonazepam and Diamox will override this if I keep the extra bumetanide dose. I will report back on this after a week of trialling.

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    16. Peter, Agnieszka,

      Not having the clonazepam, has very clear and direct effects. Last week, during singing lessons her voice began sinking, and except for the songs that she was proficient at, her voice wouldn't rise up, and there was no initiative from her to keep up with the accompanying piano. Before we started the clonazepam, she used to be almost completely inaudible in class, and nothing could make her raise her voice. Last year, the singing group she belongs to had two performances, one on May 1st, and the second on June 4th. Both were in front of huge audiences. At the May program, she was nearly silent, couldn't even be heard by people next to her, and became very anxious on stage and had a meltdown and we had to usher her off quickly. Sometime in May we started the clonazepam, and at the June 4th program, she stunned us all by leading the group and singing to great applause. Confident on stage, without any anxiety or fear. Nowadays, we have the opposite problem, with her getting into rows with the other kids because she refuses to give them their turn at leading and insists on singing over everybody else.

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    17. A snapshot of the effect of all the medicines and supplements she takes was at the Mayo clinic at the beginning of the month. The first week that we were there, we had to spend almost entire days at the clinic as they would set us up with several appointments with the doctors, each lasting over an hour, and also many lab visits, imaging etc. She was completely calm, and managed brilliantly, including having her blood drawn several times. The most impressive was the MRI with contrast dye that was 45 minutes long and which she did perfectly without sedation.

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    18. Kritika,

      Just to make it clear: my son used bumetanide for 1,5 year without any speech issues. So it is possible that there is something different going on in your son and mine.

      I didn't use memantine or similar drugs. There was memantine trial where I live few years ago. It was a part of a big, international study, which finally failed. Anyway I was told that all parents in my city decided to continue memantine after the trial ended.

      Here is a paper on memantine induced speech issues:
      https://www.ncbi.nlm.nih.gov/pubmed/23819879
      In both kids it was reversible and in one of them "the speech difficulty
      was completely relieved despite continuation of memantine."

      It is not about anitbiotic in my son as he did not use antibiotic then. It was viral, flu-like illness.

      Low dose clonazepam is a good idea. It is one of few treatments that clearly improved expressive speech in my son. Unfortunately whenever I use acetazolamide it seems like it increases clonazepam blood level and it works only in narrow therapeutic window in my son.

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    19. Hi Agneiszka,

      Thank you so much for that information. Last time I had trial led NAC, bumetanide and l.reuteri in quick succession probably with some overlap too so attributing effects to specific interventions became a little complex. If and when I retry I will be more careful.

      Regards

      Delete
  10. Peter, for some of the RORa -- would good old Vit A help. Or a certain form of Vit A? Thanks, MH

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  11. Agnieszka,Peter,

    How do I find if my son has inflammation?Which medicines would work for inflammation?

    Thanks
    SB

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    Replies
    1. SB,

      In my son mast cell disorder was suggested by a clever immunologist although his symptoms were far from typical (crying spells every full moon). So I used mast cell stabilizers (cromoglicate and antihistamines) and then tried verapamil according to Peter's blog, which effect was profound.

      But it is just one example and I think there can be many reasons for inflammation in a child with autism.

      Some people use anti-inflammatory drugs eg. ibuprofen and others were found helpful in some studies:
      https://www.ncbi.nlm.nih.gov/pubmed/22782459
      My son does not tolerate ibuprofen.

      In Peter's PolyPill atorvastatin has anti-inflammatory properties.

      Delete
  12. Kritika,
    I just saw your post and yes, my son did have increased dysfluency while trialing Bumetanide. It is difficult to say if that was the cause because he has had this issue at various times in his life, but it absolutely increased during the trial. I took some time off after Bumetanide and a trial of Monteleukast as well as Zoloft (not at the same time). After he was cleared out of all drugs/supplements for a couple of weeks, I decided to try the supplement Inositol. Anxiety is a big problem for him and I had read about the relief some people get while taking it. It is helping a lot. I am happy to share with anyone who is interested. The OCD was still a big problem so I went back to the pharmaNAC (I had about 6 or 7 tabs left). Things got even better with NAC. Much less dysfluency and less repeating and scripting. Two days ago I ran out of NAC and quickly ordered more. Since he was only taking Inositol I decided to add in the Enduracell broccoli sprouts. Day 1 -- FANTASTIC -- school said he was able to work for 1/2 hour straight without a break! Day 2 (TODAY)-- Bad dysfluency and very panicky. So, I can say this: NAC helps my son with dysfluency and repetitiveness.
    Christine

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    Replies
    1. Christine,

      What a relief it must be to find something which helps your son. I had read about inositol..such a simple intervention. About the dysfluency aspect, in fact even I am.not sure if sppech problems increased with bumetanide..its only that he was suddenly pronouncing words with such clarity around thst period that the loss became more accentuated. I wish we could put in a microchip inside our kids bodies which would record all biochemical fluctuations..this seems to be the only way we can ever say with decent certainty what is causing what.

      What you found out about the nac is interesting. In fact, I felt that in my son, keeping the discommfort caused by the high dose aside, nac even brought about improvement in cognition. I think low dosing of drugs/supplements especially the ones which can cause uncomfortable physical experience is what will work best for my son. I absolutely have to try nac again but follow my own gut instincts when it comes to my sonds gut health.

      Warm wishes

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