Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?

Today’s post allows me to cross off several topics from my to-blog list, since I can link them all together.

N = 1 or N > 1

If you are the parent of one of more children with autism, you will have a very specific view of autism, since your kind is the only kind that affects you.  This is natural and so for most readers it is case of N = 1.

When it comes to everyone else, and what they (should) teach medical students, it is the big picture that matters.  So large clusters of people behaving in a certain way is more significant that any outliers.  If you are the outlier, this is not much consolation.

In the world of autism, rather strangely, it is the very rare types that have an established medical therapy.  This ranges from the types caused by rare metabolic disorders to the more common PANDAS/PANS.

The large cluster that is classic autism remains untreated.

Polypill N = 3

To date I am aware of only a handful of people who have implemented the majority of my suggested Polypill for classic autism.  Three parents found major improvements and one found no impact; but the no impact case was not classic autism, it was very late regressive autism, later diagnosed as mitochondrial disease.

Many parents have implemented 1-2 elements of the Polypill with good results; these usually are elements that are the non-prescription drugs.

Three is not many, but it is more significant than one; and three out of four is a pretty good success rate.

As it stands, the Polypill will be a therapy for some children whose parents happen to be doctors, or own a pharmacy.

What does this have to do with antibiotics?

The other day I wrote a post about a recent 6 month clinical trial of Minocycline, an antibiotic.  The hope was that drug would reduce microglial inflammation and improve autism; but it did not.

Then I received a comment from Seth, a regular reader of this blog, to say that in his son tetracycline antibiotics really do improve autism.

I just read about John, another Dad, who found his child’s autism improved greatly while on antibiotics.  He has started his own charity N of One (N = 1) to raise funds for autism research and published an account of what he noticed.

An n=1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean

There are many other accounts of certain antibiotics improving certain people’s autism.

In the case of PANDAS/PANS antibiotics are just the initial part of the therapy, but unless you live in the US you are unlikely to get diagnosed with PANDAS/PANS, let alone treated for it.

I will not be able to solve this puzzle today, but I will make my observations, for what they are worth.

First of all, Seth is talking about tetracycline-class antibiotics, one of which is Minocycline, the subject of that six month autism trial.  Now as we saw in a recent post, that trial was deemed a failure, but that was a trial of 10 children with regressive autism.  

Note that what people mean by "regressive autism" varies widely; most autism has some degree of regression.  In classic autism, the person is born different and then gradually becomes more evidently "autistic" during early childhood. Regressive autism, as defined by Chez, is when things are normal for at least the first 12 months.  Language can be normal or abnormal and then lost.  

I should also highlight that are other reports of Minocycline being beneficial in Schizophrenia and other neurological disorders.

Minocycline: therapeutic potential in psychiatry.

Abstract

Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialed in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.

Minocycline is not just an antibiotic; it has several other known modes of action.

Minocycline is the most lipid-soluble of the tetracycline-class antibiotics, giving it the greatest penetration into the prostate and brain, but also the greatest amount of central nervous system (CNS)-related side effects, such as vertigo.

In various models of neurodegenerative disease, minocycline has demonstrated neurorestorative as well as neuroprotective properties

Minocycline is also known to indirectly inhibit inducible nitric oxide synthase (NOS).

As an anti-inflammatory, minocycline inhibits apoptosis (cell death) via attenuation of TNF-alpha, downregulating pro-inflammatory cytokine output.

Early research has found a tentative benefit from minocycline in schizophrenia

Amoxicillin

The antibiotic that John (from N=1) found to have magical properties was Amoxicillin, a very common type of penicillin.  Amoxicillin is a standard therapy for a strep throat.

Streptococcal infections are the initial trigger for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

Amoxicillin seems to be have just one mode of action, that of an antibiotic.  This means it is a type of antimicrobial used specifically against bacteria, and usually used in medical treatment of bacterial infections. Antibiotics may either kill or inhibit the growth of bacteria.

          From the US National Institute of mental Health  (NIMH):-

Can penicillin be used to treat PANDAS or prevent future PANDAS symptom exacerbations?

Penicillin and other antibiotics kill streptococcus and other types of bacteria. The antibiotics treat the sore throat or pharyngitis caused by the strep by getting rid of the bacteria. However, in PANDAS, it appears that antibodies produced by the body in response to the strep infection are the cause of the problem, not the bacteria themselves. Therefore one could not expect antibiotics such as penicillin to treat the symptoms of PANDAS. Researchers at the NIMH have been investigating the use of antibiotics as a form of prophylaxis or prevention of future problems. At this time, however, there isn't enough evidence to recommend the long-term use of antibiotics.

However, a quick “google” will show more n=1 cases, of people claiming their child’s autism/PANDAS improving on Penicillin and then regressing again afterwards.

  

Vancomycin

The other antibiotic that has been researched in autism is Vancomycin.  This drug is not absorbed from the intestine, so for systemic therapy it has to be taken by injection.  

When given orally it is used for things like treating bacterial infections of the intestines that cause colitis.  Orally administered vancomycin is recommended as a treatment for intestinal infection with Clostridium difficile, a common side effect of treatment with broad-spectrum antibiotics.

Vancomycin was first isolated in 1953 at Eli Lilly, from a soil sample collected from the interior jungles of Borneo by a missionary.

.

Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism

Abstract

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism

What is going on?

The truth is that nobody knows for sure what is going on.  That also applies to PANDAS & PANS, which is why most of the world does not recognize them as genuine diagnosable conditions.

It would seem to me that various different processes are likely involved.  It would not be so hard to do some detective work, on a case by case basis.

For example, both Seth and John were using broad spectrum antibiotics.  If they gave Vancomycin a quick trial, they would find out if the problem was in the intestines, since that is the only place oral Vancomycin can have an effect.

John has written in his paper all about possible changes to the gut microbiome and how repeated antibiotic use early in life could set the stage for the development of autism in some children.  It is very easy to test this hypothesis, just try some Vancomycin.

We know that ulcerative colitis is comorbid with autism.  We know that this will lead to a permeable gut and the flow of unwanted substances to other parts of the body.  We see that Vancomycin is used for treating bacterial infections of the intestines that cause colitis.

So it is no surprise that in some people with autism, Vancomycin will improve behaviors.  You just need to identify which people.

Once apparent that Vancomycin is indeed effective, at least you know where the problem is.  Then it is a question of finding long term solutions to manage the problem.

We already know much about the so-called “leaky-gut” and the many GI problems in autism.  This is very well covered on the SFARI site and blog, so here are some highlights from there.

'Friendly' bacteria treat autism-like symptoms in mice

The new study is the first to show that maternal infection alters the microbiome in the offspring. The finding is significant for autism, as many children with the disorder are plagued by gastrointestinal problems, including diarrhea, vomiting and stomach discomfort. 

Leaky gut is also reported in children with autism and is associated with several other disorders, such as inflammatory bowel disease and Crohn’s disease, and perhaps with Alzheimer’s and Parkinson’s diseases, says Sarkis Mazmanian, professor of biology at the California Institute of Technology.To diagnose leaky gut in the mouse pups, the researchers fed them a carbohydrate molecule attached to a fluorescent molecule. The molecule later turned up in their blood, showing it had escaped through the gut wall. The mice also showed elevated gut levels of an immune molecule called interleukin-6 (IL-6) — a prime suspect in mediating the effects of maternal infection

The researchers then treated the mice with B. fragilis. This strain of bacteria isn’t commercially available, but exists naturally in about 20 percent of the human population. 

Mice treated with B. fragilis at 3 weeks of age don’t have a leaky gut five weeks later, their levels of blood 4EPS and gut IL-6 plummet, and the assortment of bacterial species in the gut reverts to something closer to that of control mice. And the mice do better behaviorally: They stop obsessively burying marbles in their cages, become as vocal as controls and are less anxious.

Probiotic curbs autism features in mouse model

• Guest blog: The case for using 'prebiotics'

• A probiotic therapy for autism

Sarkis K. Mazmanian, Ph.D.California Institute of Technology

Most research into autism spectrum disorders has focused on genetic, behavioral and neurological aspects of the illness, but people with autism also show striking alterations in immune status.

What’s more, a significant subset of children with autism spectrum disorders show chronic intestinal abnormalities, such as loose stool and altered bacterial microbiota (the collection of beneficial bacteria within the intestine). Antibacterial treatments are reported to provide behavioral improvements in some cases.

In addition, many children with autism have been diagnosed with food allergies and are on special diets. Societal advances (including 'Western' diets and antibacterial products) may have paradoxically compromised human health by reducing our exposure to health-promoting gut bacteria.

The connection between gut bacteria, intestinal disease and autism is a promising area of investigation. Sarkis Mazmanian and his team at the California Institute of Technology used mouse models that show autism-like features to evaluate the efficacy of probiotics.

They found that specific probiotic bacteria ameliorate autism-like behaviors in both environmental models of ‘induced’ disease (by mimicking viral infection of the mother during gestation), as well is in two genetic models of autism spectrum disorder.

These studies are an important step in furthering research that addresses the connection between the gut microbiome and altered behaviors, a link suggested by studies in humans. Finally, Mazmanian’s findings may help validate the use of probiotics as a safe and effective treatment for autism when it is accompanied by gastrointestinal abnormalities.

   

What it means?

It certainly appears that some people with ASD and GI problems have a something similar going on to my case of “N=1” (ASD + pollen allergy).  An allergic reaction has caused mast cells to degranualate releasing histamine and  IL-6.  That histamine causes further release of IL-6 elsewhere.  IL-6 is a pro-inflammatory cytokine and “public enemy number one” in the case of autism flare-ups.

It does appear that some people with autism + GI problems improve somewhat with supplemental digestive enzymes, like Creon/Kreon.  This does appear to be the basis of CM-AT, the long awaited therapy from Curemark.

However, based on feedback from this blog, it appears that blocking the calcium channel Cav1.2 with Verapamil may be even better.  It will certainly be much cheaper.

The standard treatment for this type of allergy related GI problem, is Cromolyn Sodium, a mast cell stabilizer.  Verapamil is also a mast cell stabilizer, among other properties.

Interestingly, some people “do grow out” of some allergies.  I myself, as a child, was prescribed Intal (Cromolyn Sodium) for GI problems of unknown origin.

You will find countless reports on the internet of children with “autism” who, on various diets, “recovered”.  You will hear plenty of people saying that young children will “grow out of” their autism.  It is generally accepted that most people’s autism does moderate as they become adults, just like many people’s asthma.

There is some sense in all of this.  Allergies can seriously aggravate autism.  So if you have someone with very mild autism, but a severe allergy, when you control the allergy you will see dramatic behavioral improvement.

Some readers of this blog have found that common allergy treatments like Zyrtec (cetirizine), have a profound behavioral improvement on their child, who was supposedly allergy-free.

In “my” subgroup of classic autism one underlying problem appears to be a channelopathy (Cav1.2); this might be genetic, or it might be an “epigenopathy”.  In either case, you could detect it, with existing technology, if you really wanted to.

Conclusion

The clever people at the NIMH think that PANDAS/PANS is a kind of Rheumatic Disease, where an autoimmune disorder (triggered by strep throat infections) causes the body to produce antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. However in a rheumatic disease, the antibodies mistakenly recognize and may attack the heart valves, joints, and certain parts of the brain.  When they attack the joints it is called Rheumatic Arthritis, when they attack the brain it is now called PANDAS.

The NIMH thinks that PANDAS/PANS is distinct from autism.

If you regularly read the research in this blog, you may disagree with the NIMH and see that PANDAS/PANS is just another autism variant.  Likely many things, other than strep infections, can also trigger this over-active immune system.

Many strange things occur in autism, one being that adults apparently cannot have PANDAS.  Of course they can; it just would have to be called ANDAS.

If an adult with autism wants to check for some rare for metabolic disorders leading to “autism” he/she may need to get referred to a children’s hospital, like Arkansas Children’s Hospital.  All the while, some of their diagnoses/treatments continue to be regarded as quackery by many other clinicians.

Some people with Schizophrenia, who improved on Minocycline, should try Vancomycin.  If the benefit is lost (as I suspect, it will be), then we would know that the effect was elsewhere than in the intestines.

Having established that Minocycline had no benefit in children with regressive autism, perhaps Johns Hopkins and NIMH should trial it in early-onset autism (classic autism).  It is Johns Hopkins after all, who believe that regressive autism is primarily mitochondrial disease.  The research indicates that mitochondrial disease is but one feature of classic autism.

Vancomycin is a useful diagnostic tool, rather than a long term therapy, but if Vancomycin improves behaviour, then you have plenty of choices:-

·        Cromolyn Sodium

·        Verapamil

·        Digestive enzymes like Creon/Kreon and, eventually, CM-AT

·        Probiotics & Prebiotics  (one day even Bacteroides Fragilis)

·        Exclusion diets

So if your child improves after taking antibiotics, or anything else, my suggestion is to investigate it yourself, rather than found yet another autism charity.

There is actually plenty of existing research and clever people, like those at the Simons Foundation, are funding further work on a prolific basis.

Other than readers of the SFARI blog and the Questioning Answers blog, is anyone actually reading (nearly) all this research? (let alone applying it)   Evidently not.

The academic researchers just read narrowly around their very focused area of interest.  The majority of clinicians read almost none of the research.

If you want to solve a complex problem, collect all the available data, look for connections and then think about it.

You should not have to do this for yourself, but with autism you do.

Tics, Ticks, Autism - Wnt signaling & PAK1

I was interested to receive a comment from a reader of this blog who finds that the anti-parasite drug Ivermectin has a major impact on her child’s  autism, debilitating tics and OCD (Obsessive Compulsive Disorder).

Regular readers may recall that when looking at so-called PAK1 inhibitors, which look like the Holy Grail for both common cancers and autism, it turned out that two already exist.  One is an old anti-parasitic drug called Ivermectin and the other is a substance found in certain types of bee propolis from Brazil and New Zealand.

It then turned out that a handful of “alternative” practitioners in the US are already using Ivermectin for autism, but for entirely different reasons.  They believe that various parasites exist inside the children and cause/exacerbate autism.

I thought this was intriguing and quite likely another case of “the right therapy, for the wrong reason”.

Tics and Ticks

Tics are those sudden, repetitive involuntary actions that can vary from annoying to debilitating.

Ticks are tiny parasites that like to attach themselves to your skin, they can fall from trees/bushes or attach themselves to skin as you pass through long grass. Some ticks carry Lyme Disease.

Tics are common in autism, PANDAS, PANS and many forms of OCD (Obsessive Compulsive Disorder).

It seems that some “alternative” practitioners in the US are treating PANDAS and PANS on the assumption that it is caused by Lyme Disease.  Others are recommending “de-worming” for autism, on the assumption that intestinal parasites are to blame.

Here is a link to somebody writing about these alternative practitioners, for those who are curious.

My take

This all sound highly odd to me, partly because it seems that you have to keep taking the de-worming tablets for the long term.  With regular mild parasites found in developed countries, drugs therapy can eliminate the parasites.  In some tropical climates more aggressive parasites exist that are almost impossible to eradicate 100%.

So regular de-worming of humans in the United States, in 2014, sounds bizarre.

On the other hand, you cannot dispute when somebody finds their child’s tics and OCD have disappeared with the de-worming therapy and that they return when the therapy stops.

Is it, as I suggested in the early posts, that the PAK1 inhibiting properties of Ivermectin are behind its effect?  Hopefully yes, but I am not sure.  So I will take a look at Ivermectin and see if it has any other properties that could impact autism, tics and OCD.

Ivermectin - not just for your dog

Most people would only come across Ivermectin at the vet, but there is much more to it.

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Discovered in the late-1970s, originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil, Ivermectin has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found.

The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The disease causes visual damage for some 1–2 million people, around half of who will become blind.

Lymphatic Filariasis, also known as Elephantiasis, is another devastating, highly debilitating disease that threatens over 1 billion people in more than 80 countries. Over 120 million people are infected, 40 million of whom are seriously incapacitated and disfigured. The disease results from infection with filarial worms

Modes of Action

Let us look at the various modes of action proposed for Ivermectin.

1.     GABA

Initially, researchers believed that Ivermectin blocked neurotransmitters, acting on GABA-gated Cl⁻ channels, exhibiting potent disruption at GABA receptors in invertebrates and mammals.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal cord. But mammals have a so-called blood-brain barrier (BBB) that prevents microscopic objects and large molecules to get into the brain. Ivermectin, while paralyzing body-wall and pharyngeal muscle in nematodes has no such impact in mammals.  Consequently Ivermectin is much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock, pets and humans.

2.     Glutamate

Subsequently, researchers discovered that it was in fact glutamate-gated Cl⁻ channels (GUCl⁻) that were the target of Ivermectin and related drugs.

3.     Reversing Immunosuppression

The growing body of evidence supports the theory that the rapid parasite clearance following Ivermectin treatment results not from the direct impact of the drug but via suppression of the ability of the parasite to secrete proteins that enable it to evade the host’s natural immune defence mechanism.

Researchers discover how key drug kills worms in tropical diseases

In a major breakthrough that comes after decades of research and nearly half a billion treatments in humans, scientists have finally unlocked how a key anti-parasitic drug kills the worms brought on by the filarial diseases river blindness and elephantitis

Regular readers will recall that a beneficial parasite therapy in inflammatory diseases is the TSO worm.  This worm also modulates the host’s immune system so as not to be ejected.  This calming of the over activated immune system appears to be beneficial in several conditions and possibly autism.

4.     Inhibitor of Wnt-TCF Pathway

Recent cancer research has shown the Ivermectin has a highly unexpected property; it can block a pathway called Wnt-TCF on which many cancers are dependent.

The river blindness drug Ivermectin and related macrocyclic lactones inhibit pathway WNT-TCF responses in human cancer

Wnt signaling is also a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS), in other words oxidative stress, known to cause DNA and cellular damage.

Perhaps aberrant Wnt signaling is involved in the mechanism of autism?

Well it appears to be the case.

Role of a novel Wnt pathway in autism spectrum disorders

The canonical Wnt signaling pathway in autism.

 Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism.

5.     Inhibitor of PAK1

We already know from earlier in this blog, that Ivermectin is a PAK1 inhibitor.  Blocking PAK1 should prevent several common cancers, according to researchers at MIT, who also suggest that autism cannot occur without PAK1.\

Not entirely surprisingly, if you look into the cancer research you will see that PAK and WNT are interrelated.

p21-Activated kinase (PAK) interactswith Wnt signaling to regulate tissue polarity and gene expression

Wnt signaling is mediated by three classes of receptors, Frizzled, Ryk, and Ror. In Caenorhabditis elegans, Wnt signaling regulates the anterior/posterior polarity of the P7.p vulval lineage, and mutations in lin-17/Frizzled cause loss or reversal of P7.p lineage polarity. We found that pak-1/Pak (p21-activated kinase), along with putative activators of Pak, nck-1/Nck, and ced-10/Rac, regulates P7.p polarity. Mutations in these genes suppress the polarity defect of lin-17 mutants. Furthermore, mutations in pak-1, nck-1, and ced-10 cause constitutive dauer formation at 27 °C, a phenotype also observed in egl-20/Wnt and cam-1/Ror mutants. In HEK293T cells, Pak1 can antagonize canonical Wnt signaling. Moreover, overexpression of Ror2 leads to phosphorylation of Pak1. Together, these results indicate that Pak interacts with Wnt signaling to regulate tissue polarity and gene expression.

So there at least five possible effects that Ivermectin can have.

Too much Ivermectin is not good

According to the literature in the developing world, there are 200 million people (http://onlinelibrary.wiley.com/doi/10.15252/emmm.201404084/abstract) currently taking Ivermectin, which is provided free for river blindness; some of those have been using the drug for over 20 years - so much is known about it.

It is suggested that at excessive doses, Ivermectin starts to cross the BBB and then affects the neurotransmitter GABA.  Ivermectin stimulates the release of the GABA in the presynaptic neurons and enhances its postsynaptic binding to its receptors. This increases the flow of chloride ions in the neurons, which causes hyperpolarization of the cell membranes. This on its turn disturbs normal nervous functions and causes a general blockage of the stimulus mechanisms in the CNS. The resulting cerebral and cortical deficits include mainly:

• Ataxia (uncoordinated movements)
• Hypermetria (excessive or disproportionate movements)
• Disorientation
• Hyperesthesia (excessive reaction to tactile stimuli)
• Tremor (uncoordinated trembling or shaking movements)
• Mydriasis (dilatation of the pupils); in cattle and cats also myosis (contraction of the pupils)
• Recumbency (inability to rise)
• Depression
• Blindness
• Coma

So, too much Ivermectin is not a good idea.

So why is Ivermectin good for Tics, OCD and Autism?

At low doses Ivermectin does not cross the BBB (blood brain barrier), but in autism it appears that the BBB can be more permeable than it should be.  So possibly Ivermectin produces an increase in GABA, like that caused by Valproic Acid.  Some people with autism find Valproic Acid very beneficial.

Perhaps those glutamate-gated Cl⁻ channels (GUCl⁻) play a, yet unidentified, role in autism.

Or, perhaps we got it right and PAK inhibiting property is what matters. 

Perhaps being an PAK1 inhibitor will also make it a Wnt inhibitor, or maybe not, worth checking though?

Perhaps the MIT guys got it wrong and it is Wnt rather than PAK that we should be focused on? 

I hope the blog reader that prompted this post does indeed give the bee propolis a go and see if it has the same effect as Ivermectin.

Cancer

Having said in an earlier post that I will not try and out-smart the cancer researchers, I will just say that the extremely cheap drug Ivermectin does seem to have some potent anti-cancer properties.  

I know that cancer drugs are supposed to be hugely expensive.

An earlier post mentioned Ivermectin’s positive effect on Leukemia, but it seems that the WNT-TCF Pathway is involved in very many cancers.  This is not to mention that just being a PAK1 inhibitor should be enough to prompt further interest.

Conclusion

Well it looks like Dr Wu and Dr Klinghardt have indeed got the therapy right, but I believe for entirely the wrong reasons. By promoting themselves via organisations like Autism One, they are almost guaranteed to be ignored by mainstream doctors and researchers. The therapy will therefore remain on the fringe, with the quacks and cranks.

From my perspective, what really matters is whether a therapy works.  We can always later on figure out why it works.  So thank you Dr Wu and Dr Klinghardt.

Double-tap Autism – perhaps an important variant

In spite of the recent drive to improve autism awareness, mainly in North America, very much more could be done to understand the condition itself.  

Rather than just giving it different names (now ASC rather than ASD, for example) and broadening the “catchment area” of the autism diagnosis, would it not be wise to better study the “disease” itself?

In most countries, people with autism are not treated by any doctor, so a huge pool of possible information is lost forever.  We just have anecdotal evidence, and much of that can be emotionally distorted by care givers.

Whether I want to or not, I just can’t keep noticing things in the media that make me take note.  I do get lots of people writing to me, sending me links to articles and I do admit to looking at some other people’s blogs.

The clever researchers studying autism, and the handful of clinicians writing about it, do not seem to notice the same things as me.  So I will go a little further and define a new type of autism that I would have thought must have been noticed many times before.

Double-tap Autism

I am here referring to the more severe types of autism, not high functioning autism (HFA) and definitely not Asperger’s.  Double-tap autism is a variant of what I call “disabling autism”.

The younger generation of gamers, will all know where I got the name from.  So in my case, Ted, aged 14 and very neurotypical, is the inspiration.

There does seem to be a substantial group of children who are diagnosed with autism (very) early, i.e. younger than 36 months and sometimes younger than 24 months.  They then start their intensive ABA program, since they are either North American, affluent, or both.  All goes well and little Charlie, or Billy, is responding well to his therapy and the parents are even beginning to think that autism is not as bad as they had feared.  Then along comes a viral, perhaps flu-like, infection and all of a sudden things go into reverse and Charlie is no longer the little ABA star he once was and he regresses further. Progress thereafter remains painfully slow.

I do keep noticing very similar descriptions in blogs and newspaper reports.  I just read another example in the UK’s Daily Telegraph, with a father describing his son’s double-tap and descent thereafter. Hence this post.

Rapha boss Simon Mottram: my life with autism

Understanding the Underlying Science

While your family doctor likely knows absolutely nothing about autism, there is actually a great deal of scientific knowledge out there in the literature.

By observing clinical changes in the progression of a disease, you really should be able to learn something about it.  But if nobody is making observations, little progress can be made.

Monty, aged 11 with autism, has only ever seen a doctor, with some knowledge of autism, once in his life; indeed his regular paediatrician believes that a child has the “right not to speak” until he is five years old.  For Europe, once in a lifetime would be average and for much of the world, that would be one more than normal.  In parts of North America the situation is very much better, with EEGs, neurologists, genetic testing, diagnosis before 24 months and even free early intensive behavioural intervention on request.

I am certainly not the most qualified to hypothesize as to what is going on in double-tap autism; my son has “single-tap” autism, after all.  Nonetheless I think it would very interesting to understand the mechanism behind the second tap, and then to reverse it.  I do not believe you can necessarily reverse damage caused years ago in utero, but the effects of a viral infection aged 3-4 should be treatable, if you know what to treat.

The term “regressive autism” means very different things to different people, just as the term “autism” has now been devalued by the ever widening of its definition by, not so clever, psychiatrists in the US.   

             

Regressive autism is something different to double-tap autism.  Double-tap autism is like a further regression, after classic autism has already been noticed, diagnosed and become stable.

It is possible that in some cases nobody noticed the first tap and then you would confuse severe regressive autism with double-tap autism.  I think that regressive autism, where initial development was genuinely “normal”, is a different phenomenon to early-onset classic autism. 

I do not believe the brain abnormalities found in post mortem autism studies are necessarily present in regressive autism.  In fact I believe that science has got a distorted view from the post mortem studies, since they are by definition hugely skewed towards severe classic autism, with seizures and indeed MR.  Think where they get the samples from.  

All this does matter; the current scientific belief, based on post-mortem brain samples, is that the autistic brain is damaged prior to birth.  As a result any kind of therapy is based on optimizing the function of a fundamentally damaged brain and hoping to take advantage of the plasticity of the young brain.

If the brain has developed normally to the age of 3 years old, it has already substantially completed its development.  If thereafter things go wrong, it cannot be because of the kind of malformations found in the post-mortem samples.  So there is a much higher chance of being able to reverse those changes.  Just as in PANDAS and PANS, a perfectly developed brain can, in certain circumstances, produce odd autistic-like behaviours.  PANDAS and PANS are treatable and autistic-like behaviours can be reversed.

So serious thought should be given to treating people with double-tap autism.  It should be treatable and it should be possible to revert to the state the child was in, prior to the second tap.

Possible Treatment

I would think that the immunomodulatory therapy that I have been talking about in recent posts would be a good place to start.  Somebody like Dr Swedo, the PANDAS lady, would be needed to do some experiments.  Therapies for PANDAS already include:-

·        Steroids

·        IVIG

·       Plasmapheresis

and, if all that is claimed about it was really true:-

·        Gc-MAF (Gc protein-derived macrophage activating factor)

Another possibility is that the virus is just a trigger for a genetic or epigenetic process.  If it is an inherited genetic anomaly, it was always present, like the gene that often leads to breast cancer, it is like a ticking time bomb; it may or may not explode in your lifetime.  If it is epigenetic then the process is like a bookmark, rather than a genetic defect, that turns on something that should be off, or vice versa.  Regardless of genetic or epigenetic, once you know what gene is affected, you may be able to figure out a way to counter it.  Just like in my PolyPill research, I read that it was already known in autism there may be a defect in the CACNA1C gene. The CACNA1C gene produces the calcium channel Cav1.2.  So I just needed to look at this Cav1.2 channel and figure out how to modify its behavior, just in case it was linked to my son’s particular type of autism.  This only took a few hours to figure out; it took longer to test it and even longer to write about it.

It is quite likely that many of the people with double-tap autism have the same underlying dysfunctions, and so what helps one could help many.  This was also the case with PANDAS/PANS.

I hope somebody, vaguely scientific, eventually does try and help people with this kind of autism.  It should be less difficult than classic autism, which turns out to be treatable after all.  But don’t hold your breath and, as I tell my older son, if a job is worth doing, best do it yourself.  That is unless you have Dr Swedo on your case.