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.
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.
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
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):-
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.
.
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.
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.
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.
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.
