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.

PANDAS, PANS, Penguins and Autism

Anyone with a serious interest in autism should also be aware of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome).  These are two syndromes which have acute onset of symptoms very similar to some of those found in autism.  It is claimed to affect 1 in every 200 children in the US.

The good news is that a very thorough and dedicated doctor called Susan Swedo has worked logically through from starting to identify the syndrome, all the way through to treating it.  Good job Susan.

Though she insists that PANDAS and PANS are distinct from autism, one can only wonder how many other distinct, but yet to be identified, syndromes exist that also present with autism-like symptoms.

Thanks to the efforts of Dr Swedo and the US NIMH (National Institute of Mental Health), these two conditions have been remarkably well investigated, in a very short period of time.  It shows what medical science can achieve when the right people are in charge.  It is odd that such effective clinical attention has not been focused on autism itself.

Here is a very recent presentation given by Dr Swedo, which really covers all the important aspects of both PANS and PANDAS.  For those with a serious interest, have a look though this post and then watch the presentation, to get the most from it.

Dr Susan Swedo (click for IPad users)

Penguins and PANDAS

One of the reasons I was so impressed by how PANDAS has been addressed, as opposed to the much more common autism, is the before and after data.  For example, many people talk about regressive autism, but nobody quantifies from what, to what.  Some children went from a spoken vocabulary of 10 words to 2 words, while others went from 500 words to zero; there is a profound (and relevant) difference.

In the case of PANS and PANDAS we have the before and after artwork from the affected kids. As usual, a picture is worth a thousand words.

I have no great panda pictures, but Monty aged 10 with ASD, brought back his artwork from school last week and pride of place goes to his picture of two penguins.  We were all more than a little taken aback to see it.  Did he really draw this? Unassisted?  It looks much more like the work of his big brother.  Even his assistant was surprised and confirmed that this was the result of his work in the art room for a double lesson.  I never expected to be displaying Monty’s artwork to the world.

Later in this post you will see the before and after PANDAS artwork.

PANDAS and PANS

When I first came across a condition known as PANDAS or PANS, I did not take that much notice; with such a name I assumed it was nonsense.   Researchers should give a serious syndrome a serious name/acronym.

I imagine that with the ever widening of the diagnosis of autism, some people with PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) /PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) have been misdiagnosed as autistic and vice versa.

When you look at the symptoms and apparent cause of PANDAS/PANS you may wonder how many other similar conditions exist within the myriad of conditions leading to autism.

The shocking regression in cognitive function (illustrated by children’s drawings further down the page) produced by this condition and the fact that it can be reversed, should really be carefully evaluated in comparison to regressive autism.

It would be appear that all of this is caused by an immune system gone “haywire”.  I wonder how many other immune dysfunctions leading to regression and odd behaviours will be identified in future decades.

The treatment for all these current, and future, conditions are likely to revolve around immunomodulatory therapy, ranging from very cheap steroids (prednisone) to the very expensive, like IVIG (Intravenous immunoglobulin)

If you have a case of regressive autism and the expert says it does not fit the definition of PANDAS/PANS, he might think the case is closed.  Perhaps it should not be.

I suggest that immune over-activation is involved in both groups of autism:-

Early onset autism

In these cases the immune activation is secondary; when it occurs the existing autism just gets much worse.  In some cases these flare-ups are evidently caused by food allergies/intolerance or pollen allergies.

Regressive Autism

I think that in mild cases, some autism may be solely an over-activation of the immune system, without any of the channelopathies and other dysfunctions common in classic autism.  I would put PANS/PANDAS is this category.  I suggest that many other cases of regressive autism could be traced back to allergies and food intolerance, which triggered an immune over-response.

It does seem that many regressions followed a viral infection, and of course, many people believe their regression was triggered by vaccines.  I expect in most cases the vaccine is just a scapegoat, but I very much doubt it is in every case.   

I do not expect there will be any research in this area, because the results would inevitably be misinterpreted by the public.  What a pity.

If we better understood what events could radically disrupt brain function, we might be able to better understand how to treat the resulting neuropsychiatric phenomena, known as regressive autism, PANDAS, PANS and other, yet to be invented, acronyms.

A serious condition with some serious followers

Many people’s knowledge of autism seems to come from sound bites from scientific luminaries like Oprah, Jenny McCarthy and even Donald Trump.  Somewhat remarkably, the PANS doctors are actually a very serious bunch, under the umbrella of the International OCD Foundation (and the NIMH).  This foundation is a serious organisation with a scientific advisory board loaded with people from top US Medical Schools.

Not only have they concisely explained the symptoms, but they have also found therapies; albeit, they do not really know why they work.

The US National Institute of Mental Health has great information.

There is also a very serious parent run organisation called PANDAS Network.

About PANDAS and PANS

In the early 1990s, 50 years after Kanner noticed autism, researchers in the US noticed what they thought was an odd acute-onset type of Obsessive Compulsive Disorder (OCD).  At first it was thought that only streptococcal infections and Scarlet fever triggered this abrupt regression in the child’s behaviour and cognitive performance.  The first name they came up with was PANDAS, (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections); when reports came in that many other infections caused acute regression the name got changed to PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). 

From Research Subgroup to Clinical Syndrome: Modifyingthe PANDAS Criteria to Describe PANS (Pediatric Acute-onset NeuropsychiatricSyndrome)

Symptoms of PANS

It is pretty clear to me that some people diagnosed with regressive autism actually have PANS.  I have from two sources a list of symptoms:-

International OCD Foundation

• Acute sudden onset of OCD
• Challenges with eating, and at the extreme end, anorexia
• Sensory issues such as sensitivity to clothes, sound, and light
• Handwriting noticeably deteriorates
• Urinary frequency or bedwetting
• Small motor skills deteriorate - a craft project from yesterday is now impossible to complete (see images below)
• Tics
• Inattentive, distractible, unable to focus and has difficulties with memory
• Overnight onset of anxiety or panic attacks over things that were no big deal a few days ago, such as thunderstorms or bugs
• Suddenly unable to separate from their caregiver, or to sleep alone
• Screaming for hours on end
• Fear of germs and other more traditional-looking OCD symptoms

US National Institute of Mental Health

• Severe separation anxiety (e.g., child can't leave parent's side or needs to sleep on floor next to parent's bed, etc.)
• Generalized anxiety. which may progress to episodes of panic and a "terror-stricken look"
• Motoric hyperactivity, abnormal movements, and a sense of restlessness
• Sensory abnormalities, including hyper-sensitivity to light or sounds, distortions of visual perceptions, and occasionally, visual or auditory hallucinations
• Concentration difficulties, and loss of academic abilities, particularly in math and visual-spatial areas
• Increased urinary frequency and a new onset of bed-wetting
• Irritability (sometimes with aggression) and emotional liability. Abrupt onset of depression can also occur, with thoughts about suicide.
• Developmental regression, including temper tantrums, "baby talk" and handwriting deterioration (also related to motor symptoms)

In case you want to see what they mean by regression, look at these pictures drawn by a child with PANDAS before and after treatment.  Panel A is before and Panel B is after.   Source International OCD Foundation

  

Treatment

Compared to Autism, a very refreshing approach is taken to treating PANS.

The treatments include:-

·        Treatment with antibiotics to eradicate the infection, if it is still present.

·        Immune-based therapies such as

o   Plasmapheresis

o   intravenous immunoglobulin (IVIG)

o   corticosteroids (such as prednisone).

The good news about the immune therapies is that the treatment gains were maintained long-term, which is exactly what you would want to see. 

Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood

Implications for Autism

In spite of what your doctor might tell you, if your child has regressive autism, you would be well advised to check and re-check that he/she does not have PANS or a (yet to be identified) variant thereof. 

The immune-based therapies that ultimately are proved to be successful in PANS are highly likely to be helpful in treating the kind of autism in which the immune system remains in a state of over-activation.  Also the immune-therapies being trialled for autism, if successful, might very likely be helpful alternative therapies for PANS; the therapy I have in mind is TSO.

Classic early-onset autism, as researched in post-mortem studies at the Courchesne lab and elsewhere, is associated with physical brain abnormalities, that should be irreversible.  It would seem that PANS is something entirely different and should be treatable and potentially fully recoverable.

For those of you unaware of Courchesne, here is a short video; he is quoted by many of the leading autism researchers, so I hope he has got things right.

Eric Couchesne &Karen Pierce from University of California at San Diego

Where does regressive autism fit in?  I really doubt that all those people with regressive autism have the physical brain abnormalities of classic autism.  Research has shown that regressive autism has even higher bio-markers of neuroinflammation than classic autism.  Perhaps regressive autism is neuroinflammation, without physical brain abnormalities?

Just as PANS is a mini-spectrum of conditions, pathologically distinct from early onset autism, I suspect that regressive autism is equally pathologically distinct from early onset autism.

Why does it matter?  Well if you want to treat something, it helps to know what you are dealing with.

PANS looks like it has some clever people working on it.  Regressive autism, which may indeed be the most prevalent type, is in need of some similarly clever people.

Conclusion

If regressive autism is your area of interest, I would suggest you look very carefully at PANS/PANDAS and the therapies that have been shown to be effective.

If you have PANS/PANDAS, taking a look at the experimental immunomodulatory therapy used in autism might be very worthwhile, for example the TSO therapy from Coronado Bioscience.

We know that PANS/PANDAS is caused by an ongoing inappropriate immune response, but we do not know how this is mediated into the odd behaviours.  One possible mechanism would be via a weakening of the blood brain barrier (BBB).  

It has been shown that the similar mechanism controls the BBB and the gut immune barrier.   Clever research into Celiac Disease has resulted in the discovery of Zonulin, which is now known to be the only physiological modulator of both these barriers.  Using a type of laboratory test called ELISA, it is now possible to measure Zonulin levels.  If people diagnosed with PANS/PANDAS were shown to have low Zonulin levels, we could assume that the BBB was compromised; this would certainly advance understanding of the condition. It would of course point the way to new therapies.