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Sunday 14 June 2020

Summertime Autism Raging and Dumber in the Summer


By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 



Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.



Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.
Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.
Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.
Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.
Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 


Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.


Conclusion

When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 


but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.






15 comments:

  1. This post falls just at the right time. My daughter (almost 10yo, Asperger, not so much with my poly-pill, including some bumetanide) has been having fits of rage/oppositional behavior and regression almost every day for the last few weeks, usually just before noon or in the first part of the afternoon. She is just fine in the morning and towards the end of the day.

    I don't remember her being so consistently like that before. I thought it might be a reaction to her supplements since we use to have a delayed reaction when her antihistamines dosage was too high several years ago. But now I will look more at trying Verapamil again. We tried it a few years ago but it didn't seem to make any difference.

    Chris

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  2. I have, like many parents perhaps, spent the odd moment here and there trying to figure out when all this started and why. One of the things I came upon is - my daughter was born beginning of August which is the prime moment for Ambrosia, a horrible allergen. She received vaccines in the hospital - her immune system was activated - and was then released into an environment rich in Ambrosia pollen. To this day, this is her worst allergy. Looking through her medical files and her photos to see when ‘autism’ appeared - it is mostly connected to springtime, when she was about 7-9 months old. It came on slowly so we really noticed it aged 11-13 months and got her diagnosed in a week aged 14 months. There were many sad, sad things that could have caused her autism - c-section, only 2 months breastfeeding, mthfr mutation, vaccines (of which she received almost none but due to a mistake of my husband she did receive a hep b on her 2 months doctor visit, and hep b vaccine is really causing issues as visible in some chinese studies)...but to me it looks like allergies are what tipped her. nowadays she is on aerius tavegyl and neuroprotek. I will look into this nasal spray you’re mentioning.

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  3. Yes, as I have said, we've been feeling the pollen since early March. I finally realized that I was dosing too much antihistamine for my son producing ADHD like symptoms, anxiety, and lack of energy. Histamine is still a necessary neurotransmitter but with it in food/drink/candy, along with pollen/airborne, trying to find a balance in your child's unique brain chemistry becomes a roller coaster ride. Was giving 1/2 clemastine in the AM, 5mg claritin, LDN, Mg along with lots of quercetin. Backed those two antihistamines down to just Allegra once daily with Montelukast, LDN, Mg, and Clemastine at bedtime. Claritin works better than Allegra at calming the allergies/histamine but after a few days starts to cause anxiety for myself and both sons, I think it's a sign of too much histamine being taken down causing a pendulum like reaction. Clemastine I dose 1mg, just at night now. Magnesium is the only calcium channel blocker I can get my hands on, so I keep him titred on 30mg three times a day and it helps a lot. Haven't tried histidine yet but it may prove to be a good add in, at the right dose/right time. Currently giving 4mg montelukast, which has been good. Very calming, esp. with naltrexone. Have to give before going outside especially or he gets very irritable. Each day is different. If the "histamine load" of food is high and he's going outside for a while, I give him all the big guns: claritin, montelukast, Mg, and quercetin, LDN. If it's a quiet day with low histamine load, we do Allegra, Montelukast, less Mg. It's very time consuming and a lot of work to constantly be dosing, but if it works, it's worth it. I didn't have any plans for the summer anyway ;)
    MKate

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    Replies
    1. MKate, in some people certain antihistamines do cause anxiety after a period of use. Some people get round this by rotating through 2 or 3 different antihistamine drugs. Fortunately there is a wide choice of antihistamines.

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  4. Hi Peter, I've been giving my 7 year old son 1 mg ketotifen every night for 5 weeks and there has been a huge improvement in his allergies, sleep and mood generally. I'm going to start bumetanide this week and wondered if the ketotifen interacts with it or any potassium I might have to give.

    If there are any problems, would you be able to suggest how I might mitigate them? I am unable to get hold of verapimil or atorvastatin. Thank you.
    RKS

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    Replies
    1. RKS, I looked up interactions on www.drugbank.ca and there are none listed for bumetanide and ketotifen.

      Most people need to add about 200mg of potassium supplement per 1mg of bumetanide. It is advisable to increase potassium in diet and measure potassium in blood.

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    2. Quick thought: I started adding a small amount of magnesium in with the bumetanide and potassium dose, as Ling and others had mentioned in comments. My son would get a bit hyper and start stimming after drinking bumetanide/potassium, as it throws electrolytes off for him quickly. For us, about 30-50mg Mg with 300mg K takes care of the imbalance. mkate

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  5. Thanks Peter and MKate. I was thinking about adding in some magnesium.
    RKS

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  6. Like it sometimes happens, I came across three articles mentioning the striatum and autism/pandas today, and I immediately thought of this blog and searched it for mentions of striatum via google, but instead I got this link: https://teamtlr.com/tlr-oa-optimized-agents/72-tao-oa-thyroid-axis-optimizer.html where your blog is mentioned which I, as someone who always thinks it to be a niche interest of people like me, found somehow surprising.

    The three articles on the striatum:
    https://www.sciencedaily.com/releases/2017/05/170518104045.htm?fbclid=IwAR3aFPZetiS1tKr4xi4770D2NAQaH4O9GnYL9ogiROi_JmXlJPWqPkSvygE

    https://www.spectrumnews.org/news/striatum-the-brains-reward-hub-may-drive-core-autism-traits/?fbclid=IwAR3z1sFH17eRBSViz-sLg1FX2dp_ASPjUZ5vaPmjGY1RtDcNWKmLJE0NCHM

    https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2020.19070698?fbclid=IwAR1hNoc75EKOc5s482G44JewkJaJ21-y2JfOTMXo-MQkC4XbVfQKqG3akmM

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    Replies
    1. Thanks tpes!
      That second (or rather third) link mentions FOXP1, which probably causes language impairments in some autism.
      /Ling

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  7. Peter,

    I just stumbled across your blog recently; thanks so much for the amount of information that you have compiled. I have an autistic son with whom we would like to trial Bumetanide. However, locating a physician in the US willing to prescribe has been difficult to say the least. Are you aware of any physicians in the US that are actively prescribing Bumetanide? Or do the majority of those who trial Bumetanide procure from either Mexico or Canada?

    Michael

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    Replies
    1. Michael, there are doctors in the US prescribing bumetanide for autism.

      There is a group called MAPS.

      https://www.medmaps.org/clinician-directory/

      Within this group I know that Dr Frye and Dr Rossignol prescribe it.

      Some non-MAPS doctors in the US also prescribe it.

      I think most people were buying it online from Mexico, but it appears that they have stopped making it there.

      Good luck

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    2. Hello Peter, Miccil is back in pharmacies.

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    3. Lisa, that is good news for Mexico and all those Americans and others trying to buy Bumetanide (Miccil in Mexico) on-line.

      Having experienced Bumetanide shortages/disruptions where we live over the last 8 years, I keep a large reserve supply. I guess Miccil is cheap in Mexico, so not a bad idea to buy a 12 month supply, just in case they run out again.

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    4. Lisa, plz recommend to me one legit web to buy bumetanid from mexico.

      Delete

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