Showing posts with label IVIG. Show all posts
Showing posts with label IVIG. Show all posts

Friday, 10 July 2015

Clinical Investigation vs Off-Label Treatment for Autism

Antonio Hardan, the psychiatrist at the Stanford School of Medicine, has published another paper.  Hardan is interesting, he is a clinician rather than a rocket scientist, but he gets involved in a very wide variety of clinical trials, usually of existing drugs that might be effective in autism.

In his latest paper, this time about Glutamatergic Dysfunction in Autism, he highlights the problems with clinical trials:-

·        Heterogeneity of autism

·        Subjective rating scales rather than biological measures.

In other words there is no single autism and there is no good way to reliably measure the efficacy of any drug tested on it.  Consider what that really means.

Hardan really should know about this, just look at the clinical trials he has been involved in:-

So why bother with Clinical Trials?

This may sound like a very unscientific question, but perhaps it is not.  A couple of years ago Roche pulled the plug on Arbaclofen, because it “failed” in its autism clinical trial.  Many parents thought it worked.  Now the Simons Foundation has acquired the rights to the drug and is restarting trials.  How many other trial drugs were prematurely brushed aside?

Many years ago the hormone secretin was put forward as a therapy for autism, particularly for people with GI problems.  Several expensive clinical trials later, it was determined to be ineffective.  But some people continued to rave about it.  Where they all deluded?

The very expensive IVIG therapy has also been put forward as a wonder therapy for autism.  The critics highlight that in studies 90% of people do not benefit and therefore the therapy has little value.  But what if you are in 10% that do respond very well?

Intravenous immunoglobulin treatment of children with autism.


Since autism has been associated with immunologic abnormalities suggesting an autoimmune cause of autistic symptoms in a subset of patients, this study was undertaken to investigate whether intravenous immunoglobulin (i.v.Ig) would improve autistic symptoms. Ten autistic children with immunologic abnormalities, demonstrated on blood tests, were enrolled in this study. Their ages ranged from 4 to 17 years, with two girls and eight boys. Eight children (1 female and 7 male) historically had undergone autistic regression. Intravenous immunoglobulin, 200 to 400 mg/kg, was administered every 6 weeks for an intended treatment program of four infusions. In five children, there was no detectable change in behavior during the treatment program. In four children, there was a mild improvement noted in attention span and hyperactivity. In none of these children did the parents feel that the improvement was sufficient to warrant further continuation of the infusions beyond the termination of the program. Only in one child was there a very significant improvement, with almost total amelioration of autistic symptoms over the time period of the four infusions. Once the treatment program was completed, this child gradually deteriorated over a 5-month time period and fully reverted to his previous autistic state. In this treatment program, five children had no response to intravenous immunoglobulin. In the four children who showed mild improvements, those improvements may simply have been due to nonspecific effects of physician intervention and parental expectation (ie, placebo effect). However, in one child there was a very significant amelioration of autistic symptoms. There were no distinguishing historic or laboratory features in this child who improved. Given a positive response rate of only 10% in this study, along with the high economic costs of the immunologic evaluations and the intravenous immunoglobulin treatments, the use of intravenous immunoglobulin to treat autistic children should be undertaken only with great caution, and only under formal research protocols.

Just in this blog, which is amateur and not intended as a rigorous scientific review, we have seen numerous “rare” conditions that lead to “autism” that are actually treatable.

If you add up all these “rare” conditions you get a sizeable proportion of all the autism, diagnosed in those under four years old (i.e. more severe autism).

Clinical Investigations

If you accept that the initial autism diagnosis really tells very little, then you are left, like Hardan, testing all sorts of clever ideas on a trial group of kids who may have one to several, of thousands of discrete dysfunctions (CNVs etc.).

Then if you get a 10% response rate, you are doing great.

If you target something like oxidative stress, that is caused by hundreds of those thousands of discrete dysfunctions (CNVs etc.), then your odds of success shoot up.  This was the case in Hardan’s trial of N-acetyl cysteine.

Hardan is now going to trial oxytocin on kids with autism, but this idea has already been well and truly “trashed” by highly respected mainstream doctors.  They do this because they think autism is something easy to define and measure like high blood pressure.  If it is therapeutic in 10% of cases, that is great.

Quacks, Off-label and Clinical Investigations

I think it is great that Hardan can try all these drugs at Stanford and nobody even thinks of calling him a quack.  The same applies to a small number of inquisitive doctors at Johns Hopkins and Boston Children’s Hospital.

It would be interesting to know how Hardan treats his patients with ASD, who are not enrolled in a clinical trial.  Does he prescribe off-label? 

It is clear that most doctors in developed countries will run a mile/kilometer at the idea of treating somebody off label.  They fear being struck off/sued/ridiculed.

We had the UK pediatrician commenting on this blog that Baclofen was effective in 70+% of her/his patients with anxiety plus Asperger’s, but did not feel happy to continue prescribing it without some supporting evidence from elsewhere.  The fact that it was safe and effective was not enough.

Many of the tiny number of off-label doctors really do look like quacks to me, so I can understand the concern of mainstream doctors not to want to be associated with them.

What is the, scientifically well-briefed, parent supposed to do? (if self-treating is not an option)

I think there should be a way where you can enroll your child in a “clinical investigation”, where you accept that all the treatments are experimental and therefore have a higher level of risk than normal.  You waive your right to sue the doctor, or the hospital.  You can opt out of up to 10% of the therapies, based on valid concern.  For example, you might think IVIG is not safe.

You then enter a program in which all your child’s data can be used for research purposes.  So you agree to have to have EEGs, scans, genetic testing, spinal tap/lumbar puncture, blood tests, urine tests, hair tests etc.

The child is completely profiled and material is stored for possible further analysis later.

All known tests are then carried out, even obscure things like biotin deficiency, creatine deficiency and those amino acids we saw that triggered rare autism.

Then you go through all of the therapies known to be effective in some people.  So it includes memantine, IVIG,  donepezil, bumetanide, oxytocin, propranolol, baclofen, arbaclofen, even Zyrtec, NAC, D-Cycloserine, carnosine, carnitine, pancreatic enzymes, probiotic bacteria  etc.

The whole process would take a year.  If you treated 1,000 children you would then have a wealth of data.

You might have individually rare disorders totaling 15% of cases and then several clusters where the same drugs were effective in sizeable groups of children.  Then you would be able to look back in the data for the biomarkers of each cluster.

Then you would write a smartphone app for doctors to treat autism.  They would input the various biomarkers requested and out would come the suggested drug therapy recommendation(s).  So it would be a “guided off-label” approach where the doctor knows that the recommendations are “scientifically supported” but may not be perfect.

We just need the Simons Foundation to sponsor it! 

If you think it might be too expensive, just remember that at the recent international autism conference in Utah, there were 2,000 scientists and researchers in attendance. What exactly have they achieved, in practical terms, in the last 10 years and are likely to achieve in the next 10 years?

It does seem that some view success as diagnosing ever more people with "autism", so that they can receive "services", when they really should be diagnosing specific biological dysfunctions.

It is not an easy task, but you do not need 2,000 researchers.  You just need 20 pragmatic people to review the data and make a decision tree showing how to choose the 5 drugs most likely to help a particular person, based on their specific biomarkers.  

I guess that would leave 1,980 people with not much to do. 

Saturday, 21 June 2014

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.


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.


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). 

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


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   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.

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.


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.