Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

 

There are two closely related hormones, vasopressin and oxytocin, that have been extensively researched in autism. 

With oxytocin you can modify social-bonding behavior. You can increase oxytocin in the brain either via a nasal spray containing oxytocin, or you can add a specific bacterium to your gut that triggers a signal to the brain to produce more of its own oxytocin.  The latter is my preferred method, because you can produce a mild long-lasting effect throughout the day.

Oxytocin has a very short life and it does not cross the blood brain barrier.

There is even a new study in the works that will compare these two methods of treating autism.

 

Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication. Oxytocin (OXT), as a neuropeptide, plays a role in emotional and social behaviors. Lactobacillus reuteri (L. reuteri) supplementation led to an OXT-dependent behavioral improvement in ASD mouse models. Despite some promising results from animal studies, little is known about the efficacy of supplementation with L. reuteri, alone or with exogenous OXT therapy, on social-behavioral functions in ASD patients. This paper presents a protocol for a pilot randomized controlled trial to evaluate the feasibility of conducting a full trial comparing oral supplementation of L. reuteri probiotics and intranasal OXT spray to placebo on the effect of social and behavioral functions in ASD patients. The study will also capture preliminary estimates of the efficacy of the proposed interventions in ASD patients.

Methods

This pilot trial is a two-staged, randomized, double-blind, placebo-controlled, parallel-group study. Throughout the study (0–24 weeks), 60 patients with ASD will be randomly assigned to receive either oral L. reuteri probiotics or placebo. In the second study stage (13–24 weeks), all participants will receive intranasal OXT spray. As primary outcomes, serum OXT levels will be assayed and social behaviors will be assessed via the Autism Behavior Checklist and the Social Responsiveness Scale which are validated questionnaires, an objective emotional facial matching test, and a new video-based eye-tracking test. Secondary outcomes include the GI-severity-index and Bristol Stool Chart to assess GI function and gut microbiome/short-chain fatty acids. All the outcomes will be assessed at baseline and weeks 12 and 24.

Discussion

This pilot study will provide important information on the feasibility of recruitment, blinding and concealment, treatment administration, tolerability and adherence, specimen collection, outcome assessment, potential adverse effects, and the preliminary efficacy on both primary and secondary outcomes. If successful, this pilot study will inform a larger randomized controlled trial fully powered to examine the efficacies of oral L. reuteri probiotics and/or intranasal OXT spray on social-behavioral improvement in ASD patients. 

My conclusion was to add two drops of L.Reuteri DSM 17938 (Biogaia Protectis) into the liquid part of my son's Polypill therapy. That way there are no extra pills to swallow and in theory the bottle should last 50 days, so I am not forever looking to buy more.  If you want a bigger effect, just add more drops.  The producer suggests a daily dose of 5 drops for babies, to promote GI health - the original intended purpose.

When it comes to Vasopressin it looks like you cannot avoid a nasal inhaler, unless you want to try transcutaneous electrical acupoint stimulation (TEAS).  There is a debate as to whether Vasopressin and its analogs (man-made modified versions) can cross the blood brain barrier and to what extent. 

There are 4 previous posts that looked at Vasopressin. 

https://epiphanyasd.blogspot.com/search/label/Vasopressin 

The Vasopressin showing good results in the trials at Stanford is the injectable pharmaceutical version of the hormone made into a nasal spray.  This kind of spray could be made easily at a compounding pharmacy.

It turns out that a synthetic analog of vasopressin, called desmopressin, has been widely used for over 40 years to treat nocturnal enuresis (night-time bed-wetting) among other more serious conditions.

 

Desmopressin in Autism 

“Nocturnal enuresis is common in individuals with but to our knowledge, there are no reports that desmopressin enhances social functioning in ASD (or in any other clinical population). This may be because desmopressin is typically administered at bedtime (so prosocial effects would be less evident) and orally (oral desmopressin does not cross the blood-brain barrier). The most likely explanation, however, is that desmopressin acts selectively on AVPR2, rather than on AVPR1A”

 

From:

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism

 

Desmopressin N=1 example 

I was recently contacted by the father of a young boy with autism who has been prescribed Desmopressin nasal spray by his neurologist.

The father noted major positive behavioral changes from the first dose.

This is of course great news.

Desmopressin is a widely available drug, seen as safe, and that is why it is prescribed to children.

In the US the nasal spray version is no longer widely used for children and they use the oral version.

In some countries it is used for people with MS (Multiple Sclerosis) with nocturnal enuresis.

 

Desmopressin Shortage

Before readers get too excited, Ferring Pharmaceuticals, the big producer of Desmopressin nasal sprays did voluntarily withdraw its brands (Minirin, DDAVP Nasal Spray, Desmopressin Acetate Nasal Spray) from the market in August 2020 due to a quality problem. 

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ferring-us-issues-voluntary-nationwide-recall-ddavpr-nasal-spray-10-mcg01ml-desmopressin-acetate

  

There is now a shortage and so what was an easy to obtain drug, may be more difficult to get.  There is a Pfizer version called Presinex.  

From the above paper on vasopressin for autism:-

Vasopressin benefits 

“In conclusion, the present pilot study determined that 4-week intranasal AVP treatment compared to placebo enhanced social communication abilities, diminished anxiety symptoms, and reduced repetitive behaviors in children with ASD. On nearly all behavioral measures, participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP treatment, suggesting that pre-treatment blood AVP concentrations may be useful for setting dosing guidelines for this medication. Last, intranasal AVP treatment was well tolerated with minimal side effects in this pediatric study population. These preliminary findings suggest that intranasal AVP treatment has potential to enhance social abilities in an ASD patient population characterized by currently intractable social impairments” 

Transcutaneous electrical acupoint stimulation (TEAS) to raise vasopressin 

“there is evidence that nonpharmacological interventions may facilitate endogenous AVP release, for example, electroacupuncture stimulation increases brain AVP concentrations in rats. Transcutaneous electrical acupoint stimulation (TEAS) therapy improves social functioning and anxiety symptoms in children with ASD, particularly in those with the largest post-treatment increase in blood AVP concentrations. The authors of this prior report theorized that increased AVP signaling may be the mechanism by which the prosocial and anxiolytic benefits of TEAS treatment were achieved” 

 

Vasopressin with Bumetanide  - take great care

A while back, one reader did ask me about taking intranasal Vasopressin with Bumetanide.  His doctor in California thought this might not be wise since the two drugs have opposing effects.

·        Bumetanide (a diuretic) makes you pee more.

·        Vasopressin (the anti-diuretic hormone) makes you pee less.

The real problem is the risk of low sodium, hyponatremia.  This is always a risk with vasopressin and the risk might well increase if you took Bumetanide.  The risk is going to be dose dependent.

If you take Vasopressin and then drink large amounts of water this will disturb the volume of fluids in your body and in particular it will lower the level of sodium.  This may lead to seizures and ultimately worse.

Bumetanide does disturb the level of electrolytes, but nearly all the change usually occurs in Potassium, this is why you need to add back potassium via diet and add a supplement.  Sodium is not normally a problem, but always check all electrolytes when taking a blood draw.

If someone adds vasopressin to their existing bumetanide therapy, the doctor should definitely monitor the level of sodium.

In most people’s diet, sodium is one thing you are likely to have too much of and it is very easy to add a bit more sodium if the blood test suggests it is necessary.  In extreme cases of low sodium you need to use a special re-hydration drink, or an intravenous saline solution.  Monty has a relative who keeps going to hospital for the latter.

The diuretic action of Bumetanide is a side effect of the "autism effect" and so if you can reduce the diuresis of bumetanide that would be good thing.  Researchers are trying to find a better-bumetanide and their goal is to have no diuresis.

If combining vasopressin with Bumetanide is accompanied by both reduced diuresis and a matching reduction in fluid intake, this might actually work well.  Clearly, extra care needs to be taken and what might be perfectly safe in one person may not be safe in another person.

  

Conclusion

I do have to give a big thank-you to our reader who shared his experience with Desmopressin and to the neurologist for suggesting it.

Desmopressin looks like one of those autism therapies that needs only a very short trial to determine whether it is beneficial.  This is a big advantage.

You would hope the Stanford vasopressin researchers make a short trial of Desmopressin, just to compare the effect.  They probably will not.

All you have to decide is whether it is going to be the left nostril, or the right nostril.  With intranasal insulin there was a problem with irritation inside the nose, so alternating left and right sides might be best.  You hold your breath and then squirt the spray; the objective is not to breath the spray into your lungs.  An easy mistake to make.

Note that I am referring to the 10 mcg/0.1mL Desmopressin nasal spray.  The one used to treat kids that wet their bed at night.

There is also a much more potent 1.5 mg/mL version, called Stimate in the US.  This is used to treat von Willebrand’s Disease (Type I) and hemophilia/haemophilia.  You do not want that version.  This version is 15 times more potent than the anti bed-wetting variant. 

I have been suggesting to Aspies living in the US that they give Vasopressin a trial to counter the social deficits that some find troubling.  I think they are able to obtain this via a compounding pharmacy, with a helpful doctor’s prescription.

I think outside the US your doctor will think you are mad if you ask for a specially compounded vasopressin nasal spray, or indeed a compounded  oxytocin spray.

For people unable to get the intranasal vasopressin prescribed/compounded, Desmopressin is on option to discuss with your doctor. Maybe time to develop a bed wetting problem?

The Aspies in the Netherlands have the legal option of a tiny non-hallucinogenic dose of Psilocybin once a month, which seems an effective way to target Serotonin 5-HT_2A receptor-mediated pathways and so improve social behavior. What caught my attention was that the effect of this tiny dose lasts a month and it can also be used to treat severe, otherwise untreatable, cluster headaches.

Psilocybin is the fancy name for magic mushrooms.

Psilocybin is also legal in Brazil and not surprisingly in Jamaica.  It looks like the US is moving in the same direction - medicinal magic mushrooms!

FDA grants Breakthrough Therapy Designation to Usona Institute's psilocybin program for major depressive disorder

The “medical” dose of Psilocybin is a tiny fraction of the “recreational” dose and is only taken when the effect of previous dose fades to zero.  It is not a crazy idea at all, just not currently a legal therapy in most countries.  More than half a century ago Lovaas was researching something very similar at UCLA, but using LSD.

All told, there are several potential ways to fine-tune social behavior in autism. Sulforaphane is yet another option.

 

Calcium Folinate (Leucovorin) to Prevent as well as Treat Autism?

 

Belgium is famous for many things from chocolate and beer to comic books like Tintin.

  Even the Smurfs are from Belgium.

 

If you want to investigate autism you might need the skills of the most famous fictional Belgian, Hercule Poirot.

Today’s post is about the detective work of Dr Ramaekers from Liège.

Liège is a city in the French-speaking part of Belgium. The northern half of Belgium speak Dutch and southern half speak French. The capital Brussels is officially a bilingual city, but if you do not want to upset an unknown local, the safest language to use is actually English.

Liège used to be a major European centre for steel making.  My elder son tells me that Liège is still famous for making guns.

In 2020 Liège is the European home of Folate receptor antibodies research and more importantly, its treatment.

Outside of Brussels the touristy parts of Belgium include Bruges, Gent and Antwerp, where your French from school is less useful. If you like medieval towns, excellent food and mayonnaise on fries/chips these places are well worth a visit, on a sunny day.   I used to go there on business.

The point of today’s post goes beyond the fact that Dr Ramaekers and Dr Frye have demonstrated that a large sub-group of autism benefit from supplementation with calcium Folinate (Leucovorin).

Ramaekers is looking at Folate Receptor Autoimmunity in the parents, to understand why/how the child developed autism in the first place and then taking the very logical step to prevent future autism.

My elder son is very keen that I master the art/science of preventing future autism, so as to ensure his own children will be neurotypical.

Attempting to prevent future autism will very likely also give some protection against all those "autism-lite conditions", like selective eating, AD(H)D, dyslexia, dyspraxia etc.

At the 2020 Synchrony autism conference, Dr Ramaekers spoke about how several healthy babies have now been born to parents treated with Leucovorin for their Folate Receptor Autoimmunity.  I assume the parents already have at least one child with autism and do not want more.  I thought that was a bold move by Dr Ramaekers. Dr Ramaekers has been publishing research on Folate Receptor Autoimmunity for many years and so I suppose he has the freedom to do this.  In some countries I think you would not be able to do this, or at least talk about it.  Anyway, “dix points Dr Ramaekers”  (ten out of ten).

As with the potential use by mothers of the antioxidant NAC during pregnancy, the mode of action is epigenetic and preventing differentially expressed genes (DEGs), or just call them miss-expressed genes.

In Dr Ramaeker's case he does have a biomarker to identify parents likely to benefit from his autism prevention strategy.  He uses the FRα autoantibody test and so could you.

I have been having an interesting public discussion with Dr Ramaeker's on the online app used for the Synchrony 2020 autism conference. The key point arising is that you can avoid the side effects of using Leucovorin (Calcium Folinate) by slowing increasing the dosage over several weeks.  Here is the relevant part:-

You had one naughty remark concerning the Use of folinic acid causing agression. My response is that folinic acid will increase the production of BH4 which will suddenly increase the synaptic levels of dopamine AND serotonin AND cause temporarily overstimulation of downregulated dopamine AND serotonin receptors. After about 6 weeks will settle down as a new equilibrium will be installeer. So I begin with low dosage folinic acid AND slowly increase at interval of 4 weeks.It was a wonderfull overview about your sons history.

For anyone interested to watch my Bumetanide presentation, that Dr Ramaekers, AJ and Lisa  seem to have enjoyed, here is a link.

https://drive.google.com/file/d/15s_1x01VR2v-iMNpgbsFtt12Ug4xbGTh/view

The paper by Dr Ramaekers below is open access and many people will find it interesting to read the entire paper.  Just skip over any parts that get too complicated.

 

Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

Background. In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FRα) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FRα) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits. 

Methods. All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements. Serum FRα autoantibodies were assessed in patients, their parents, and healthy controls. A self-controlled therapeutic trial treated nutritional derangements with addition of high-dose folinic acid if FRα autoantibodies tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline and following 2 years of treatment was compared to the CARS of untreated autistic children serving as a reference. 

Results. In this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years; male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 % of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in healthy controls. Compared to untreated patients with autism (n=84) whose CARS score remained unchanged, a 2-year treatment decreased the initial CARS score from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD: 34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82 children (20.7 %). Prognosis became less favorable with the finding of higher FRα autoantibody titers, positive maternal FRα autoantibodies, or FRα antibodies in both parents. 

Conclusions. Correction of nutritional deficiencies combined with high-dose folinic acid improved outcome for autism, although the trend of a poor prognosis due to maternal FRα antibodies or FRα antibodies in both parents may warrant folinic acid intervention before conception and during pregnancy.

 

 

The treatment protocol for the self-controlled treatment trial based upon abnormal biochemical findings and FRα autoantibodies.

Abnormal biomarker Daily oral supplement dosage Zinc deficiency 0.15-0.25 mg/kg zinc-sulfate Selenium deficiency 3-5 µg/kg sodium-selenite Manganese deficiency 5-10 mg/kg Vitamin C, 20 IU/kg Vitamine E, with 1 coffespoon Soya oil at night. Manganese excess idem Heavy metal excess (Cu, Al, Hg, Pb) idem Raised copper/zinc ratio idem Bèta-carotene excess idem; limit foods rich in bèta-carotene Vitamin A deficiency 600-1500 µg Vitamin D (25-hydroxy-D) 10 µg or 400 IU Vitamin C deficiency 5-10 mg/kg Vitamine C (maximal 500mg) Ubiquinon-10 deficiency 2 mg/kg co-enzyme Q10 Vitamin E deficiency 20 IU/kg Gamma-Tocopherole deficiency 1 coffeespoon soya, corn or sesame oil Bèta-carotene deficiency Consume tomato or carot juices Serum folate deficiency 0.5 mg/kg folinic acid RBC folate deficiency 0.5 mg/kg folinic acid Apolipoproteine B deficiency Supplement vitamins A D E, and vitamine K in case of secondary coagulation disorder FR-alpha antibodies Start with 0.5-1 mg/kg folinic acid daily;   Increase to 2 mg/kg daily without a clinical response after six months. Maximum daily dose 50 mg.

 

 

In the study they used the CARS rating scale to measure the severity of autism.

A score 30 and above 30 means autism.  37 and above means severe autism.

The results do look good.  This was not a study with a placebo group for comparison.

Blue is before therapy and orange is after therapy.

 

 

The upper figure (a) shows the plotted CARS with age for 84 untreated patients. The middle figure (b) shows the effect of treatment among 82 treated patients (blue bars represent CARS at baseline and orange bars the CARS after two years treatment). Figure (c) represents the treatment results among different groups with FR autoantibodies in the child (K), mother (M), or father (P).

 

 

Our self-controlled treatment trial showed that the presence of maternal FRα autoantibodies or FRα antibodies in both parents tended to be associated with a higher initial baseline CARS score among affected children with autism. Thus, this may explain that the final result and change in CARS score following 2-year treatment was less pronounced as compared to all other groups, although the small number of patients within each group did not allow a profound statistical analysis. These issues will be clarified when more patients will be included into similar treatment trials. Our findings in a minority of 7 out of 68 families (10%) identified no FRα autoantibodies in the children whereas FRα antibodies could only be detected in the mother (N=5), father (N=1), or both parents (N=1). Although feeding and nutrient problems for each child have to be taken into account, this finding suggests that parental FRα antibodies may impair folate transport into oocytes and spermatozoides and also block sufficient folate transport across the placental barrier to the embryo and fetus. Because an adequate folate pool is essential for purine and pyrimidine synthesis, and for mediating epigenetic mechanisms involving DNA methylation and histone modification, the initial embryonic development and subsequent stages of neurodevelopment will rely heavily on availability of adequate folate. Therefore, the risk of autism with its poor prognosis in the offspring associated with parental FRα antibodies warrants FRα testing among future parents followed by folinic acid intervention before conception and during pregnancy.

The common feeding disturbances associated with autism may provoke oxidative stress due to altered nutritional states where elevated metals (copper, manganese) or beta-carotene act as prooxidants through induction of Fenton chemistry. Nutritional deficiencies of radical scavenging vitamins (vitamins A, C, E, and gamma-tocopherol) as well as metals and trace elements (copper, zinc, manganese, and selenium), being cofactors of antioxidative enzymes, predispose to failing antioxidant defences. Moderate apolipoprotein B deficiency has been encountered in a significant number of autistic subjects and leads to deficient liposoluble vitamins A, D, E, and K. Deficiency of a number of vitamins and coenzyme Q10 necessary for mitochondrial metabolism, will result in mitochondrial dysfunction. Thus, oxidative stress in the brain due to mitochondrial dysfunction, elevated prooxidants, or deficient antioxidants on the one hand and FRα autoimmunity on the other hand, represent two independent variables at the basis of autism where correction of each variable showed a clinical response with a decline in the CARS score. Therefore, in addition to treatment for FRα autoimmunity [9, 10, 29], specific supplements are required to correct nutritional deficiencies in order to ameliorate intermediary metabolism and to neutralize abundant reactive oxygen species (ROS) deranging brain metabolism and function. As stated above, it appears from our findings in this study that the group of patients, where FRα antibodies tested negative in the child and its parents, benefitted only through correction of nutritional derangements as their CARS score dropped significantly.

In our study we also detected deficiencies of serum and red blood cell folate in 18.3 % of all patients. In vitro studies have supported the concept of an existing link between oxidative stress and deranged folate homeostasis. In a previous study we found that the generation of superoxide anions in vitro catabolizes 5-methyl-tetrahydrofolate by 75% within one hour, which can be prevented through preincubation with the radical scavenger ascorbic acid [26]. This study also found that KB-cells in culture exposed to superoxide anions and hydrogen peroxide reduces cellular folate incorporation mediated by FRα or RFC1 transport mechanisms. Thus transmembrane folate passage mediated by these transporters at the placenta and choroid plexus is expected to be impaired in the presence of ROS and predisposes to intrauterine folate deficiency and cerebral folate deficiency.

The consequences of folate deficiency affecting brain development may be more prominent in autistic children from mothers with folate deficiency or the presence of maternal FRα autoantibodies during pregnancy. Our finding of a higher initial baseline CARS score and less favorable outcome in these children confirms this hypothesis. In summary, the treatment response will be influenced in a negative fashion by the presence of maternal FRα autoantibodies, by late-onset treatment associated with a higher initial CARS score and in the event of elevated antibody titers. Paternal FRα antibodies may also influence the outcome and need to be further investigated, because we only identified one family.

 

5. Conclusion

In the pathogenesis of low-functioning autism, feeding disturbances predisposing to oxidative stress and acquisition of folate receptor autoantibodies during the pre- or postnatal period appear to play an important role by affecting intermediary metabolism and potentially deranging epigenetic control mechanisms. Early detection and appropriate therapeutic intervention is postulated to reverse core features and improve outcome.

 

 

Conclusion

Today’s paper showed several interesting things:- 

·        Correcting the effects of very poor diet can have a dramatic benefit on autism, regardless of folate status.

·        Folate receptor problems are very common in autism.  FRα autoantibodies were found in three quarters of children with autism and a third of their mothers and fathers, versus just 3 % in healthy controls.

·        A trial of Calcium Folinate (Leucovorin) for anyone with autism looks like a “no-brainer” but, as Dr Ramaekers cautions, mega dose folate might be unwise in the 25% of autism who do not have FRα autoantibodies.  

Note that in the study, prognosis became less favorable with the finding of higher FRα autoantibody levels, maternal FRα autoantibodies, or FRα antibodies in both parents.

·        Couples/parents who want (more) children, but want to avoid autism, should consider first taking the FRα autoantibody test

http://iliadneuro.com/

if you get a positive result, you might contact our man in Liège.

·       Generic Calcium Folinate (Leucovorin) is cheap in most of the world.  As usual, the exception is the United States. 

     I will have to write a post on prenatal bumetanide to prevent autism. Dr Ben Ari did mention again at the Synchrony event the potential for this therapy.  It seems that the oxytocin released by the mother during delivery not only helps to trigger the developmental GABA switch that forces neurons to transition from immature to mature over the first couple of weeks after birth, but it also causes a one time shock reduction in chloride during delivery (this shock may indeeed be the GABA switch trigger).  It seems that the fragile brain is given protection during delivery, with GABA switching from the fetal excitatory state to one of extreme inhibition, just for birthing.  This protective sudden drop in chloride levels does not occur in autism models and likely not in human autism either. The logic would be to give the mother bumetanide for 2 weeks before her delivery date.  This would protect the baby's brain during birth and hopefully help ensure the GABA switch occurs and the child develops normally.

 

I

 

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.

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

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, 

https://epiphanyasd.blogspot.com/search/label/pioglitazone

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.