Preventing some Polygenic Autism by Immunizing the Mother with Mycobacterium vacca bacteria - or just have Pets at Home and visit Farms.

In today’s post we look at maternal stress induced autism and how to prevent it using a bacteria from cows.  It may sound crazy, but it seems to work.

The first described strain of M. vaccae was isolated from cow dung

In the next post we will look at p-cresol autism and reversing it by a microbiota transplant. P-cresol is a chemical derived from phenol that is produced by the bacteria living in your gut. P-cresol is elevated in some young children with autism and it may explain some of those who appear to grow out of their autism.  As the level of P-cresol falls from about 7 years of age, autism symptoms fade away.

In both posts the conclusion is similar.  You are dependent on the bacteria in your environment and what the bacteria in your gut makes of you.

I did write a long time ago in this blog about the Holobiont, which is a neat idea that I think does partially explain the rise of autoimmune diseases and what is nowadays called the “autism epidemic”.

The other driver of the “autism epidemic” is the continuously evolving epigenome, where we accumulate inherited tags on our DNA, that alter expression of our genes, even though the genetic information in our DNA may be otherwise perfect.  Our genes evolve over thousands of years, but our epigenome can incorporate significant changes from each generation. An “epigenetic epidemic” is at least plausible, whereas a “genetic epidemic” is not.

Secretome,Microbiome/Hologenome, Proteome, Epigenome, Exome and Genome

In my “how to prevent future autism” advice, I do include having pets at home during pregnancy and visits to handle farmyard animals.

The reason is that over millions of years humans have evolved to depend on their environment and that includes bacteria.  The immune system is calibrated very early in life based on exposure the mother has to bacteria from numerous sources, including domesticated animals and pets.  Take away exposure to this expected-bacteria and your immune system forever lacks the knowledge it needs to protect you.  It seems to invariably over-react and we are left with people liable to allergy, dermatitis, arthritis, irritable bowel syndrome and people with polygenic disorders with an auto-immune element like autism.

In today’s post the research takes a protective bacteria from a domesticated animal and uses it to successfully immunize mothers to resist autism in their offspring. It works.

I did mention a while back that pregnant human mothers, with doggy “dust” at home, produce children who are much less prone to have asthma; doggy dust is actually doggy poo.  This may be the doggy equivalent of cows’ mycobacterium vaccae.  The Mum just breathes in the bacteria or gets it on her hands and ingests it, like Mums have been unknowingly doing for thousands of years.  Nowadays we are obsessed with buying products that kill 99.9% of germs, rather than living with them. 

Giving good bacteria to stressed mothers prevents autism-like disorder in offspring

Giving beneficial bacteria to stressed mothers during the equivalent of the third trimester of pregnancy prevents an autism-like disorder in their offspring, according to a new animal study by University of Colorado Boulder researchers.

The study, published in the journal Brain, Behavior, and Immunity, marks the latest in a series of studies in animals and humans suggesting that exposure to certain immune-modulating microbes can dampen inflammation, positively impacting the brain and central nervous system.

It's among the first studies to suggest that such exposures during pregnancy influence neurodevelopment of a fetus and, while far more research is necessary, could open the door to new prenatal interventions.

For the study, the researchers exposed rats to mild stressors and gave them terbutaline during what would be the equivalent of the third trimester of pregnancy in humans.

Half were also given a series of injections of a heat-killed preparation of a friendly bacterium known as Mycobacterium vaccae (M. vaccae), shown in previous studies to have lasting anti-inflammatory effects on the brain. A third control group of rats got no treatments.

At two and four months, the pups were given a series of tests assessing, among other things, their degree of social interaction and whether they exhibited repetitive behaviors.

As in the previous study, those whose mothers had been stressed and given terbutaline showed autism-like behaviors. But those who had been immunized with M. vaccae did not.

"Immunization with M. vaccae appears to provide some protection against the negative effects of environmental stressors during development, specifically against Autism Spectrum Disorder (ASD)-like behavior," said Smith.

Exposure to 'good bacteria' during pregnancy buffers risk of autism-like syndrome

Study in rats suggests prenatal microbial exposures influence neurodevelopment

Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy

Highlights

·        Immunoregulatory bacterium M. vaccae, prevents the expression of ASD-like behavior in a rat model.

·        Immunization with M. vaccae, had no significant effect on epilepsy in stress-terbutaline rats.

·        ASD-like behavior in this model does not appear to be driven by epileptiform excitability.

·        M. vaccae prevents stress-terbutaline induced microglial expression.

Abstract

Autism spectrum disorders (ASDs) and epilepsy are often comorbid. The basis for this co-occurrence remains unknown; however, inflammatory stressors during development are a shared risk factor. To explore this association, we tested the effect of repeated immunizations using a heat-killed preparation of the stress-protective immunoregulatory microbe Mycobacterium vaccae NCTC 11,659 (M. vaccae) on the behavioral and epileptogenic consequences of the combined stress-terbutaline (ST) rat model of ASD-like behavior/epilepsy. Repeated immunization of the dam with M. vaccae during pregnancy, followed by immunization of the pups after terbutaline injections, prevented the expression of ASD-like behavior but did not appear to protect against, and may have even enhanced, the spontaneous epileptogenic effects of ST. Maternal M. vaccae injections transferred an anti-inflammatory immunophenotype to offspring, and repeated injections across development prevented ST-induced increases in microglial density at early developmental time points in a region-specific manner. Despite epidemiological comorbidity between ASD/epileptic conditions and shared environmental risk factors, our results suggest that the expression of ASD-like behaviors, but perhaps not epileptogenesis, is sensitive to early anti-inflammatory intervention. These data provide support for the exploration of immunoregulatory strategies to prevent the negative neurodevelopmental behavioral effects of stressors during early critical periods.

Hopefully this new evidence will convince at least some people to take some simple steps to reduce the future prevalence for autism and other auto-immune conditions.  

Conclusion

If you buy into the holobiont/evolution theory of auto immune disease, you are left with two choices.

1.     Adjust lifestyles to be more like the old days of your great grandparents. Keep pets indoors at home and visit farmyards when planning a family.

2.     Identify the bacteria missing in modern lives and package them up like drugs

The best solution would be number (1), but I think you could make number (2) work.

Clearly avoiding stress during pregnancy is another good piece of advice; maybe easier said than done in many cases.  Having a pet should reduce stress and expose you to helpful bacteria. 

Most autism is “idiopathic”; it is polygenic meaning numerous genes are disturbed rather than in most syndromic autism (TSC, Rett etc) when a single gene is the root cause, which then causes a cascade of other genes to be miss-expressed. The origin of idiopathic autism is multifactorial, it is where you combine otherwise trivial genetic variances with environment triggers like immune over-reactions, and epigenetic tags from an ancestor who worked in a mine or even smoked cannabis.  The effects of the environment change gene expression. You have two types on genetic change, one directly from your DNA, so hard to avoid, and a second type of genetic change that was entirely preventable. Best not to pollute your epigenome until after producing children.

Cow poo is not going to reduce single gene-type autism. Cow poo might well improve auto-immune health and take away one contributing factor to the perceived epidemic of auto-immune conditions, including autism.

In reality you could add back hundreds/thousands of different missing bacteria to mimic the environment of when autism was a rare diagnosis.  Cow poo is just an example.

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.

“It’s Prohibited … He’s in Critical Condition”. Can Reading Fiction Help Genuine Autism Disorders? Perhaps so.

Today’s post is about reading books, which is not one of my favourite pastimes, but it does indeed seem to have significant benefits, particularly if you have autism.

Monty is now aged 16, but I still recall the amazement his teachers at school expressed when his 1:1 Assistant taught him to read (using ABA and endless enthusiasm). Teaching someone who could hardly speak, to read, is no small achievement. 

We have also done endless exercises at home to learn to read, to write, to do maths and of course to speak.

The issue later at junior school was to what extent Monty understood what he read.  There can be a lot of wishful thinking on the part of the parent.

Fast forward to 2020 and Monty spends about an hour a day reading a “grown-up” novel.  This was a plan I instigated and again the question arose, how much does Monty understand and frankly, is there any point in the exercise.

I have no doubt that a decade ago when Monty was reading aloud, it was like a mechanical process, with little comprehension going on.

Today, Monty is far more fluent when writing than speaking, which is a pity, because we all tend to judge people by what that say.

Having read a growing number of novels in the past months, Monty’s vocabulary is changing.  These are not new words and phrases picked up from cartoons or songs.

I recently had to get Monty to use a medical mouthwash, which you are not supposed to swallow.  I was explaining to him, “Don’t swallow it, just swish it around your mouth for one minute. Don’t swallow.” He looked at me and said “It’s prohibited”.  Where did that come from?

While going for a walk down the hill where we live, he was repeating his current favourite story about what happens if scoot down the hill really fast, you will crash into the fence at the bottom, and cry like a baby.  This then gets extended with an ambulance coming, going to hospital and of course being made better.  This time the story became even longer and ended up with the boy being “in critical condition”, which was a totally new embellishment to the story.

So, I no longer have to explain why I now get Monty to read his book every evening; I do not give him a comprehension test afterwards.  I think the results speak for themselves.

My original idea was to add a calm activity that does not involve a TV, phone or computer.  He takes it very seriously and sends everyone away so he can read in peace.  He does actually read aloud, and when gets stuck on a word we can hear him say “try again” and then he goes back and repeats the sentence.

Fortunately, we have a lot of books at home; Monty is now reading from his big brother’s collection.

Why try to teach people with severe autism?

A recurring question that does come up is “Why bother to teach people with severe autism?”.  The answer some people give is “you have to try”, but for how long?

The hope of course is that some of this learning will “stick” and the person can move on to the next level up.  This indeed has been the case with Monty and eventually you end up with knowledge not so different to a typical person.

More often than not, in untreated severe autism, the learning does not stick and development plateaus at a very low level.  If that happens, then focusing on functional, living skills is the way to go, forget about going to algebra classes.

Does Monty need to know about the Periodic Table in chemistry?  Do any of his NT classmates need to know about it?  Probably not, but it is just like mental aerobics, stretching your brain.

You have to be “teachable” to gain any benefit from sitting in a regular classroom.  I do think inclusion with an IEP is generally a waste of everyone’s time.  If you cannot follow the class teacher, you probably should not be in the class.

Where we live there actually is a publicly funded day care service for disabled school-age children, it does not pretend to be a school.

The best option is to make unteachable children more teachable.  I think Lovaas would have claimed that this is what his ABA does, and perhaps it does for a small proportion of children.  I think ABA is a valuable teaching method, but it cannot overcome biological limitations, if they are present.  The other option is to use biology to increase cognitive function and skill acquisition; this has worked for Monty and others.

The Research?  Reading and Autism

Someone actually got paid to do a PhD at Liverpool University in this very subject.  She is a late diagnosed adult with autism, so she is likely researching herself; her autism is far away from severe childhood autism diagnosed in a toddler.

We once had a 1:1 classroom assistant who was clever but pretty clearly “on the spectrum”, it became clear that having an NT assistant is the only way to go.  People with very mild autism think they understand severe autism but, in reality, they are the least likely to have a clue.  The best assistants are themselves the complete opposite of autistic.

Can reading fiction help autism disorders? 

This new research will explore whether improvements in ToM (Theory of Mind) and self-reflection, in association with the contemplation of fiction, can translate to ASD. It aims to develop a reading intervention that can improve 'metarepresentational' capacity, which means the ability to contemplate and think about mental states.

The funding will help in the development of a pilot study to determine the type of material that is best to use – poetry or different genres of literary fiction – and to identify any problems encountered such as visualisation so that they can be counteracted.

Social understanding

Melissa Chapple, said: "We are seeing more research suggesting that improved theory of mind and empathy due to fiction literature can improve well-being in numerous cognitive conditions.

"Over the past year I have been using popular fiction as a self-intervention to temporarily improve social and emotional understanding of those with an ASD, as I didn't agree with the typical view that people on the spectrum can't compute fiction very well.

"My only issue with the intervention was that I couldn't visualise characters and places, so to counteract that I started assigning actors' faces and images of real places and found the intervention really helped.

"That made me want to explore the potential for fiction as a therapeutic intervention in Autism and Asperger's and to debunk the idea that fiction isn't compatible with those of us on the spectrum."

Cognitive ability

It is widely acknowledged that ASDs are associated with impaired social cognitive abilities, such as ToM and empathy deficits, which can result in patients struggling with social identification and in making friends.

Currently available ASD interventions attempt to reduce the impact of traits that may compromise wellbeing while enhancing beneficial individual characteristics. These interventions aim to arm patients with a set of 'tools' for combating traits that they find problematic.

Applied behaviour analysis (ABA), which uses learning principles such as reinforcement to increase favourable behaviour, and TEACCH, a multi-dimensional therapy including cognitive behavioural therapy and skill enhancement, have been found to improve social communication and cognition in ASD.

The strength of these formal interventions is that they are believed to be generalisable, in that parents, carers or the individual themselves can implement the interventions in everyday life for continued benefits.

Potential

As part of the study a number of one-on-one reading aloud sessions will be conducted using people with an ASD diagnosis. They will then be interviewed to assess the benefits.

Melissa added: "If effective, an informal and voluntary literary reading activity would possess the same generalisable benefit of ABA and TEACCH, by encouraging literary reading in everyday life and by having the potential for training relatives, friends and/or carers to facilitate the reading intervention."

I could not find her actual thesis, maybe she did not finish; but I don’t think we are missing much.  Here is an extract from a paper she wrote that was actually published.

Framework Analysis: Reading and Autism

This small-scale pilot study involved five participants, four attending a focus group and the fifth taking part in a single one-to-one interview. All participants were over 18 years of age, fluent in English, and were current or past students at the University of Liverpool in order to reduce ethical issues around intellectual vulnerability. The sample included three participants formally diagnosed with autism, and two who had been referred for professional assessment. All were current or previous higher education students, four of the five participants identified as female.

In her “autism sample”, 40% did not even have an autism diagnosis.  They are/were all university students; they do not have any intellectual disability, but seem to struggle with the concept of gender. In science, you are biologically either male or female, it is very simple and you do not get to choose.

It is now remarkably common that people are referred to as having autism, when they have no such medical diagnosis, or they have had multiple previous diagnoses, like schizophrenia and schizoaffective disorder, but they decide now it is fashionable to say they have autism.  US official autism statistics even include "school-diagnosed" autism, that is behavior not troubling enough to warrant asking for a medical assessment.  It all looks painfully amateur to me.

I would imagine people with high IQ and mild autism are often avid readers.  In the case of some males, probably reading science fiction and comics, when not assembling Lego Star Wars. It only becomes a problem if you read odd things that are far from what they sell at your local bookstore, now possible thanks to the internet.

Many people are probably unaware that a person with autism, as opposed to Asperger’s, may be able to read aloud pages from a book and yet comprehend absolutely nothing.  For them reading does not have much purpose, cognition needs to be improved.

Common sense benefits from reading

I think we can revert to common sense; extensive reading likely improves vocabulary.  Monty’s big brother attributes his wide vocabulary to having been a prolific reader when he was a young boy.

Extensive Reading: A Stimulant to Improve Vocabulary Knowledge

The results showed that EG (Extensive Reading) at both levels indicated improvement in their vocabulary learning after the experiment.

Does extensive reading improve spelling?  It very likely does help, but Monty was good at spelling anyway.  Is the converse true? Quite possibly; I did not read for fun and I cannot spell.

I thought reading in someone with more severe autism might affect mood, reduce anxiety and improve patience.  We saw a long time ago in this blog that music, both listening to it and playing it, is beneficial to most people. A trial even measured the stress hormone cortisol in saliva, after choir practice.

I do think forcing kids to read certain types of books at school is totally counter-productive.  They should find genres they actually want to read. 

Conclusion

Even if you are not entirely sure how much is actually comprehended, reading fiction does seem a good addition to the activity list for a teenager with autism.

I do actually hate feeling the need nowadays to add “severe” in front of the word autism. In what I consider severe autism, you would not even be reading simple fairy tales, let alone two hundred-page novels.

In 2020 most people now think autism refers to high IQ people, who are just a bit “odd”; like the researcher from Liverpool University and characters in many recent TV programs.  We have the not-so-clever US psychiatrists behind DSM5 to thank for the loss of Asperger’s, as a much more precise and useful observational diagnosis.  

There actually is the tag #ActuallyAutistic on Twitter, which, for our literary readers, must be an oxymoron.  How can a genuinely autistic person possibly use Twitter? Much better to use #ActuallyalittlebitAutistic, or better #ActuallyAspie.  The defining end of the ASD spectrum is "Autistic Disorder" and they do not tweet.

The people using the #ActuallyAutistic tag often do have many issues, like being bullied, eating disorders, anxiety, loneliness, gender dysphoria/confusion and even suicide. Very likely many of these issues are treatable.

Bumetanide for TSC-type Autism, Verapamil now for sinusitis, Lower dose Folinic Acid looks interesting for Autism in France, Roche cuts Balovaptan and Basmisanil; Stanford continue repurposing Vasopressin for Autism

 Repurposing what already exists – cheap, safe, effective and sometimes colourful

Today’s post is nice and simple.

Yet another sub-type of autism is shown in a clinical trial to respond to the cheap drug bumetanide, this time it is children diagnosed with TSC (tuberous sclerosis complex); TSC is a leading genetic cause of autism often used in research.

In France researchers repurposed Folinoral, a lower dose equivalent of Dr Frye’s, and our reader Roger’s, Leucovorin to treat autism with a positive result.  Folinoral is Calcium Folinate, but the dose was just 5mg twice a day, much less than the dose used in the US research.

The potential off-label uses for Verapamil, the old calcium channel blocker helpful in some autism, continue to grow.

Original purpose:  

Lower blood pressure by blocking L-type calcium channels

Alternative uses:

·        Treating bipolar disorder

·        Treating cluster headaches and some migraine

·        Halting the loss of insulin production in people with diabetes

·        Treating diarrhea-predominant irritable bowel syndrome (IBS-D)

·        Treating aggression/anxiety in some autism

We can now add, as our reader Lisa discovered by chance,

·        Treating chronic sinusitis

Patients with severe chronic rhinosinusitis show improvement with Verapamil treatment

"Recently, we became aware that some of the inflammation in chronic rhinosinusitis (CRS) with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines," said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. "Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores."

Roche ditching experimental autism drugs

Basmisanil which targets the alpha 5 sub-unit of GABA_A receptors was originally being developed to improve cognition in Down Syndrome; those clinical trials failed. Now Roche have pulled the plug on the trials to improve cognition in Schizophrenia.

Balovaptan was Roche’s expensive bet on Vasopressin to treat autism, covered in earlier posts; it blocks the activity of the V1a vasopressin receptor.  The Balovaptan phase 3 clinical trials have also been cancelled.

Roche culls key phase 3 drug trials, including a cancer med and an autism 'breakthrough'therapy

Stanford still pursuing Vasopressin for autism

Stanford’s bet on Vasopressin for autism is still ongoing.  They had the much simpler idea of just putting some pharmaceutical-grade vasopressin in a nasal spray and trialling that.

Intranasal delivery of drugs to target the brain appeals to me, as do eye drops.  Your eyes are part of the central nervous system, in the case of your nose it appears that drugs are transported directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. 

Mechanism of intranasal drug delivery directly to the brain

One feature of this blog is a belief that central hormonal dysfunction is a core feature of much autism.  The big problem is that you cannot easily measure hormone levels in the central nervous system (CNS) and you may get quite contradictory results measuring hormone levels in blood samples.

Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid.

I was encouraged to see that the Stanford vasopressin researchers measured vasopressin in samples from spinal fluid.  They found that children who went on to be diagnosed with autism has very low levels of vasopressin in their brains early in life. Making it a potential biomarker.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the “social” neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at −70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

  

Easy to read version: -

Potential autism biomarker found in babies

Cerebrospinal fluid levels of a hormone called vasopressin were lower in babies who went on to develop autism than in those who did not, a study found. 

Cerebrospinal Fluid Vasopressin and Symptom Severity in Children with Autism

 

Cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration differs between children with and without autism (AUT), predicts AUT diagnosis, and predicts symptom severity. (A) CSF AVP concentration is lower in children with AUT (n = 36) compared to control children (n = 36), whereas (B) CSF oxytocin (OXT) concentration does not differ between groups. 

(C) The effect of CSF AVP concentration on predicted (line) and observed (symbols) group is plotted, corrected for the other variables in the analysis. Children with AUT plotted above, and control children plotted beneath, the dashed line (which represents 50% probability) are correctly classified. Specifically, across the range of observed CSF AVP concentrations, the likelihood of AUT increased over 1,000-fold, corresponding to nearly a 500-fold increase in risk with each 10-fold decrease in CSF AVP concentration (range odds ratio = 1,080, unit odds ratio = 494, β1 ± SE = −6.202 ± 1.898). (D) CSF AVP concentration predicts Autism Diagnostic Observation Schedule (ADOS)–Calibrated Severity Score (CSS) in male but not in female children with AUT.

I think many hormones are likely disturbed in autism and that modifying them is one potential method of treating autism.

At Stanford they have already had success by squirting vasopressin up kids’ noses:-

Hormone reduces social impairment in kids with autism

In a Stanford study of 30 children with autism, intranasal vasopressin improved social skills more than a placebo, suggesting that the hormone may treat core features of the disorder.

A RANDOMIZED CONTROLLED TRIAL OF INTRANASAL VASOPRESSIN TREATMENT FOR SOCIAL DEFICITS IN CHILDREN WITH AUTISM

Stanford University, Department of Comparative Medicine, Stanford Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and restricted, repetitive behaviors. Despite ASD’s prevalence, there are currently no medications that effectively treat its core features. Accumulating preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in mammalian social functioning, may be a possible treatment for ASD. Objective: The goal of this investigation is to examine the safety and efficacy of AVP in the treatment of social deficits in children with ASD. Material and Methods: Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-week intranasal AVP treatment in a sample of N=30 children with ASD aged 6-12 years. Results: AVP compared to Placebo treatment significantly enhanced social abilities in children with ASD as measured by change from baseline in the trial’s primary outcome measure, the Social Responsiveness Scale (a parent-report measure). AVP-related social improvements were likewise evident on clinician impression and child performance-based measures. AVP treatment also diminished anxiety symptoms and some restricted/repetitive behaviors. An endogenous blood AVP concentration by treatment group interaction was also observed, such that participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP (but not Placebo) treatment. AVP was well tolerated with minimal side-effects. No AVP-treated participant dropped out of the trial, and there were no differences in adverse event rates reported between the AVP and Placebo groups. Finally, no significant changes from baseline were observed in electrocardiogram, vital signs, height and weight, or clinical chemistry measurements after 4-week AVP treatment. Conclusions: These findings suggest that intranasally administered AVP is a well-tolerated and promising medication for the treatment of social impairments in children with ASD.

Using a double-blind, randomized, placebo-controlled, parallel clinical trial design, we found that the 4-week intranasal AVP treatment enhanced social abilities in children with ASD as assessed by the trial’s primary outcome measure, the SRS-2 T score. The robustness of this parent-reported social improvement score was corroborated by convergent evidence from clinician evaluation of the social communication abilities of trial participants and by performance of trial participants on laboratory tests of social cognition. These preliminary findings suggest that intranasally administered AVP may be a promising medication for treatment of core social impairments in children with ASD.

We also sought to investigate whether pretreatment neuropeptide concentrations in blood could predict AVP treatment response. We found that participants with the highest pretreatment AVP concentrations in blood benefitted the most from intranasal AVP treatment. This finding may seem counterintuitive, particularly in light of our recent studies showing that low AVP concentrations in CSF could be used to differentiate ASD cases from non-ASD control individuals (13, 14). One might therefore expect that it would be those children with the lowest endogenous AVP concentrations that stood to benefit the most from intranasal AVP treatment. However, being mindful of safety in this pediatric population, our pilot study used a conservative dose escalation regimen in which children were treated with fairly low doses of AVP throughout much of the trial. Assuming that blood AVP concentrations are related, in some manner, to brain AVP activity—a notion about which there is debate (14, 22–25)—it is possible that participants with lower endogenous AVP concentrations at the trial’s outset were “underdosed” in terms of drug amount or duration of treatment and, therefore, would not benefit as fully from AVP administration as those with higher endogenous AVP concentrations. This interpretation is consistent with our finding that AVP treatment enhanced simple social perceptual abilities independent of pretreatment AVP concentrations in blood, whereas it was only those AVP-treated individuals with higher pretreatment blood AVP concentrations who showed gains in complex social behaviors and a reduction in repetitive behaviors.

Pharmacological intervention

Commercially available injectable sterile AVP was used in this study. It was initially purchased from JHP Pharmaceuticals (Rochester, MI), which was subsequently acquired by Par Sterile Products (Chestnut Ridge, NY) in 2014. The placebo solution was prepared by Koshland Pharm (San Francisco, CA) and consisted of ingredients used in the active solution except for the AVP compound. A pharmacist transferred 25 ml of AVP (20 International Units (IU)/ml) or placebo solutions into standard sterile amber glass bottles with metered (0.1 ml per puff) nasal spray applicators to ensure that the AVP and placebo applicators were visually indistinguishable to the research team. These applicators were coded and given to the Stanford Health Care’s Investigational Drug Service for refrigerated storage (2°C to 8°C) and subsequent dispensing. After the first AVP dose (see below), the dose-escalation regimen at home for all participants involved administration of 4 IU twice daily (or BID) of AVP during week 1 and 8 IU BID of AVP during week 2. Participants aged 6 to 9.5 years then received 12 IU BID of AVP during weeks 3 and 4, whereas participants aged 9.6 to 12.9 years received 16 IU BID of AVP during weeks 3 and 4. A range of possible AVP doses was identified by review of the published literature; the final study doses were then determined in close consultation with the FDA.

A few years ago I did write about the hormone TRH as a potential means of improving autism.  TRH can also be squirted up your nose, although I favoured an oral TRH super-agonist called Taltirelin/Ceredist.

I also suggested that DHED, an orally active, centrally selective prodrug of estradiol, could well be a therapeutic in autism. DHED should give all the benefits of the female hormone estradiol, without any side-effects outside the CNS.  Many of the benefits are via ROR alpha.

Without having samples of spinal fluid, identifying, let alone treating, central hormonal dysfunction is rather a matter of guesswork.

Hormones are very much interrelated and perform different functions in different parts of the body, so it would be easy to get unwanted effects, as with estradiol, if taken orally.

  

Bumetanide for TSC (Tuberous Sclerosis Complex)

A small trial in children with TSC (Tuberous sclerosis complex) has shown that bumetanide improved their features of autism (social behavior, irritability and hyperactivity) but did not reduce seizures.

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study

Conclusion

This pilot study indicates the potential efficacy of bumetanide on behavioral problems in young patients with TSC. Bumetanide improved irritable, explosive, and social behavior in the majority of patients in this sample and treatment was well tolerated.

Folinic Acid for Autism, but at a lower dose than Dr Frye

I did recently complete my trial of generic Calcium Folinate at something like Dr Frye’s Leucovorin dose.

I found that it did indeed have a positive effect on the use of expressive language.  It prompted the use of more complex sentences.

The downside was that it did also cause aggressive/violent outbursts, so I put it in my “rejected” pile of therapies.  

I was interested to see that in France a trial has been carried out using a lower dose than that proposed by Dr Frye.  Is it possible to get benefits without the side effects? 

Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial  

Highlights 

Folinic acid treatment is well tolerated in children with Autism spectrum disorders.

Folinic acid treatment shows improvement in Autism Diagnostic Observation Schedule score.

Effect of 10 mg/d folinic acid should be confirmed by a larger a multi-center trial.

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily.

Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety.

The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (−2.78 vs. −0.4 points) and (−1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed.

This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.

  

Covid-19

There was concern that people with severe autism might be at increased risk during the current pandemic and indeed the death rate among people with intellectual disability/learning disability/mental retardation did double from 240 a month to 480 a month in the UK.  The real scandal though was deaths in care homes for the elderly, in countries with advanced healthcare systems, where tens of thousands of extra deaths have occurred.

In “advanced” healthcare systems like the UK, early in the epidemic, elderly people caught Covid-19 in hospital and when they returned to their care home, they infected others.  Care workers who are allowed/forced to work in multiple care homes then caught the virus in one home and transmitted it to the others.  Nobody was tested until care homes had already become breeding grounds for the virus.

In Hong Kong they report zero covid-19 deaths in care homes.  Elderly people could not return to their care home from hospital without testing negative for the virus, and procedures were in place to release elderly patients from hospital first to repurposed hotels, where they stayed until negative for the virus. Due to their grim experience with the 2003 SARS epidemic, Hong Kong already had very strict measures in place to limit infections and they even had regular rehearsals in care homes of the procedures to implement in future pandemics.

Where we live there was an outbreak in a care home and the authorities’ reaction was to arrest the boss of the care home.  I suppose that is one way to get other care homes to take matters seriously. We even had soldiers posted outside care homes to stop people entering.  In New York, Cuomo’s threat to care homes was that you might eventually lose your license to operate if you flout the rules. If most care homes are flouting the rules, they cannot all lose their licenses.

Some rich Western countries apparently implemented their much-vaunted flu pandemic procedures.  It looks like they have much to learn from other places, from Hong Kong to Greece, who did very much better.  Greece implemented a draconian lock down, very early, and has had a tiny number of cases and just 166 deaths. When Greece re-opens in July to tourists from high risk countries (UK, France, Italy, Spain etc) we will see what happens.

I do wonder why so many people are living in care homes. In Sweden, I saw on TV, one lady complaining that her fit and healthy father, capable of walking a few miles/km had caught covid-19 in his care home, was refused transfer to hospital and later died.  Why was he sent to live a care home in the first place?

Milan has an old care home called Pio Albergio Trivulzia ("Baggina"), it had over a thousand residents and media reports 200+ covid deaths.

There are horrific cases in the UK of young adults being sent to live in small mental hospitals by their parents; they subsequently deteriorate and some have even died.  Why did the parents hand their children over in the first place?  They thought they could not cope at home, but clearly some dedicated institutions have even less capacity to care. 

Conclusion

Re-purposing existing cheap drugs to treat a different medical condition makes a lot of sense, but it is not going to make the inventor or the drug firm much money.  It is not popular with drug producers.

Developing new drugs to treat any neurological condition looks great in the early stages of research and then they all seem to fade way, wasting many tens of millions of dollars.  Don’t raise your hopes.

Is intranasal vasopressin the smartest hormone to choose to modify?  It is possible today, using existing products and appears to be safe, which are the most important issues. I think there is more potential beyond this single hormone.

Treat autism and intellectual disability/mental retardation medically, so those people can live more normally, be more fulfilled and do not later need such expensive care home provision. It is a win-win strategy.