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Showing posts with label PANDAS. Show all posts
Showing posts with label PANDAS. Show all posts

Friday 27 November 2015

Inflammatory Response to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)



Michele Zappella was Head of the Department of Child Neuropsychiatry
 at Siena Hospital from 1973 to 2006


Today’s post is the one I mentioned some time ago about odd behavioral reactions to Group A Streptococcus.  It does veer off to Italy and Tourette’s Syndrome and the interesting sounding Dysmaturational Syndrome, which probably accounts for many of those autism “recovery” stories that are used to support some pretty odd therapies.

Several readers of this blog have noticed that exposure to Group A Streptococcus causes their child’s autism to worsen.  Quotes range from facial grimacing, to raving like a lunatic.

Much has been written about the conditions PANDAS and PANS.  The proposed mechanism behind PANDAS/PANS is highly disputed, with some strong evidence showing it not to be valid.

What is clear is that in some people, following a strep infection, they change overnight from completely normal to something quite different.  This is the PANDAS/PANS phenomenon.

In people with autism, it is possible that a different mechanism is in play, rather similar to the allergy induced behavioral change that has been discussed in depth in this blog and that is triggered by mast cell degranulation.

Parents naturally assume that if their child has autism and strep infections make it worse, that they must have PANDAS/PANS.  Maybe they do, but there is another completely different explanation.


TICS, OCD and Stereotypy

There are only a limited number of behavioral responses a human can make, whereas there seem to be an endless list of possible biological or genetic dysfunctions.  The end result is that entirely different dysfunctions can lead to apparently similar behaviours and a lot of confusion and misdiagnoses.

In autism, Obsessive Compulsive Disorder (OCD) and Tourette’s Syndrome common features are repetitive behaviors, physical tics and stereotypy. These three disorders are diagnosed solely based on observation, rather than any biological testing.

The underlying biological causes for these behaviors are not understood and there are likely many different causes, some overlapping, between the three observational diagnoses.

We can also work backwards from a therapeutic perspective and see what therapies work in each condition.  One well documented compulsive behavior is trichotillomania, which is when people compulsively pull out their own hair.

Many people with this type of OCD find near complete relief from the same therapy that benefits people with autism and stereotypy.  Both groups respond to the antioxidant NAC and their compulsive behaviors abate.

I recently noted that some people with trichotillomania find Inositol also makes these compulsive behaviors abate.  A very small trial showed that Inositol did not help autism.

I think it is fair to say that there is some overlap between what is causing stereotypy and what is causing some OCD.

When it comes to tics, there seems to be an endless list of causes.  Numerous conditions are known to cause foot flapping and restless leg syndrome.

Breath holding is a common problem in Rett Syndrome, it occurs in classic autism, but it is also seen as a tic disorder.

Most people with OCD, Tourette’s and tic disorders do not have autism.  However, some very young children with Tourette’s and apparent autism, actually may have something termed “Dysmaturational Syndrome”.

Dysmaturational syndrome was identified and documented by Michele Zappella, an Italian doctor interested in autism and Tourette’s syndrome.

He identified a sizable subgroup of autism in very young children that was comorbid with the Tourette’s Syndrome tic disorder.  The unusual thing is that by the age of six, these children had “grown out” of their autism entirely.

Zappella’s study in 2010 suggests that his Dysmaturational syndrome applies to about 6% of early childhood autism.  In effect, he is saying that 6% of the children diagnosed before 5 years old with autism, fit this Dysmaturational syndrome and “recover” to have normal IQ, no seizures, and no signs of autism.  The tics though do not go away.


Early-onset Tourette syndrome with reversible autistic behaviour: A dysmaturational syndrome. European Child and Adolescent Psychiatry



ABSTRACT
Early-onset Tourette syndrome comorbid with reversible autistic behaviour is described in twelve young males. After a normal gestation, delivery and first-year development, regression set in between the age of one and two with loss of various abilities and the emergence of autistic behaviour. At this time, or slightly later, they showed multiple motor and vocal tics, simple and complex: the latter could also be traced to most of their parents. Following an intervention based on intense cuddling, motor activation and paedagogic guidance, these children's abilities rapidly improved, reaching at follow-up a normal or borderline intellectual functioning and with the disappearance of their initial autistic behaviour. At follow-up tics were present in all, usually with the features of a full-blown Tourette syndrome, often comorbid with ADHD, and in some cases with OCD.


Autistic regression with and without EEG abnormalities followed by favourable outcome.


Abstract


OBJECTIVES:

To explore the relationship between autistic regression (AR) with and without EEG abnormalities and favourable outcome.

METHODS:

Follow up data on children with favourable outcome in a series of 534 cases aged below 5 years and diagnosed as ASD.

RESULTS:

Cases with regression were 167 (31.8%), usually with persistent ASD, intellectual disabilities and EEG abnormalities. Thirty nine children (7.3%) went off autism and recovered entirely their intellectual and social abilities. Few of them included examples of pharmacologically treated Landau and Kleffner syndrome and other similar complex cases with abnormal EEG. The majority was represented by 36 (6.7%) children, mostly males, with a dysmaturational syndrome: their development was initially normal up to 18 months when an autistic regression occurred accompanied by the appearance of motor and vocal tics. Relational therapies were followed by rapid improvement. By 6 years all children had lost features of ASD and their I.Q. was in most cases between 90 and 110. Convulsions were absent and EEG was normal in all cases except one. In a few of them recovery was spontaneous. Seventeen children were followed after 5 years 6 months: 12 (70%) had ADHD, 10 (56%) persistent tics. Tics were often present in parents and relatives, ASD absent, suggesting a genetic background different from cases with persistent ASD. With one exception all "off autism" children had a previous autistic regression.


Back to Group A Strep

For those of you not familiar with PANDAS/PANS.  The term ‘PANDAS’ is short for ‘Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus’.  A child can be diagnosed with PANDAS when Obsessive Compulsive Disorder (OCD) or tic symptoms suddenly appear for the first time, or the symptoms suddenly get much worse, and the symptoms occur during or after a strep infection in the child.








Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis.



Even though Dr Swedo, the leading researcher in the field, says that PANDAS/PANS is not autism, many parents of children with autism think they do have PANDAS/PANS.  This is likely because they have noticed that a strep infection makes their kind of autism worse.

All I can say is that there are very good reasons why strep infections can make autism worse and this has nothing to do with the autoantibodies that are the disputed cause of PANDAS/PANS.



Response to Group A Strep

Your immune system has two levels of defense:-

·        The innate immune system

·        The adaptive immune system


When you have a strep infection both systems respond.  Both of these responses could cause problems for people with autism.  The response from the innate immune system should continue only as long as the bacteria is present, while the response from the adaptive immune system may in some cases continue long after the bacteria is gone.


Innate Immune Response

It is well known that GAS is followed by a robust inflammatory response.

As you can see from the figure below, the inflammatory response results in a wave of pro-inflammatory cytokines including the “arch enemy” of autism, IL-6.

This surge in IL-6 will likely cause a sub-set of those with autism and an over activated immune system (activated microglia and so the “immunostat” is set to high) to go crazy.  This is the same IL-6 surge triggered by mast cell degranulation and the Il-6 surge used to signal milk teeth roots to dissolve.




Infections caused by group A Streptococcus (GAS) are characterized by robust inflammatory responses and can rapidly lead to life-threatening disease manifestations. However, host mechanisms that respond to GAS, which may influence disease pathology, are understudied.










Figure 1. Cellular receptors and signalling pathways involved in GAS recognition and inflammatory mediator release.

Inflammatory mediators are released from multiple leukocyte types during GAS infection; including PMNs, monocytes, macrophages, and dendritic cells . GAS and GAS-derived LTA, SLO, and soluble M1 protein (sM1), activate cellular responses to infection . Receptors involved in recognition of GAS include TLRs, TREM-1, complement receptors (CR), immunoglobulin receptors (FcR), Mac-1, and NLRP3 . Ligand binding to these receptors leads to downstream signalling via MyD88, HIF-1α, STING, IFR3, IRF5, and TBK1 . Recognition of GAS triggers release of interleukins, TNF-α, IFN-β, HBP, resistin, and LL-37 .




The Adaptive Immune Response:

Streptococcal Infection Causing Rheumatic Fever


Acute rheumatic fever (ARF) may occur following an infection of the throat by the bacteria Streptococcus pyogenes. If it is untreated ARF occurs in up to three percent of people.

Acute rheumatic fever (ARF) is not caused by the strep bacteria, but to aberrant immunological reactions to Group A streptococcal antigens.  The underlying mechanism is believed to involve the production of antibodies against a person's own tissues.

ARF, is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a throat infection. Signs and symptoms include fever, multiple painful joints, and involuntary muscle movements.
It would appear that in some children, following a strep infection, they develop tics.  These involuntary muscle movements are a symptom of acute rheumatic fever (ARF).  So rather than calling it by a new name PANDAS, perhaps better just to use the old name?



Strep infections PANDAS, OCD and Tourette’s

There is quite a lot of research on this subject, but much is contradictory. The idea put forward by researchers like Swedo is that elevated streptococcal antibodies causes PANDAS, but other researchers appear to have disproved this.

So you can make what you will of the research.

What is undisputed is that a strep throat can lead to acute rheumatic fever, which can affect the brain and cause involuntary muscle movements (tics) amongst other things.



Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A β-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and α-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.




ABSTRACT

Background: An autoimmune-mediated mechanism has been proposed for both pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and Tourette syndrome (TS). Confirmatory evidence has, in part, been based on controversial findings of autoantibodies in the sera of children with these disorders.

Objective: To compare antineuronal antibody profiles in subjects with TS and PANDAS to age-matched controls.

Methods: Sera were obtained from 48 children with PANDAS, 46 with TS, and 43 age-matched controls. Serum autoantibodies were measured by use of ELISA and Western immunoblotting against a variety of epitopes, including human postmortem caudate, putamen, and prefrontal cortex (Brodmann area 10). Immunoreactivity was also measured against commercially available α- and γ-enolase, aldolase C, and pyruvate kinase M1. Several assays were repeated after preabsorption of sera with M6 strain streptococci.

Results: Median ELISA optical density readings were similar among the groups. Western blot analyses showed complex staining patterns with no differences in any tissue region based on the number of bands, reactivity peaks at molecular weights 98, 60, 45, and 40 kDa, or total area under ScanPack (Biometra, Gottingen, Germany)–derived peaks. Immunoreactivity against four putative pathologic antigens did not differentiate the clinical groups. Repeat immunoblotting after serum preabsorption with streptococci showed no loss of reactivity. ELISA values exceeding a specified cutoff did not predict changes in binding to either brain epitopes or commercial antigens.

Conclusions: Results do not support the hypothesis that PANDAS and Tourette syndrome are secondary to antineuronal antibodies. Longitudinal studies are required to determine whether autoantibodies correlate with fluctuations in clinical activity







CONCLUSIONS. The failure of immune markers to correlate with clinical exacerbations in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections raises serious concerns about the viability of autoimmunity as a pathophysiological mechanism in this disorder.




Conclusions: The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations.






Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.





Background: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder.
Methods: Twenty-one patients, ages 4–17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology.
Results: During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=−1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=−0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use.
Conclusions: These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders.






Objective: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a subtype of obsessive compulsive disorder (OCD) marked by an abrupt onset or exacerbation of neuropsychiatric symptoms. We aim to characterize the phenotypic presentation of youth with PANS.
Methods: Forty-three youth (ages 4–14 years) meeting criteria for PANS were assessed using self-report and clinician-administered measures, medical record reviews, comprehensive clinical evaluation, and laboratory measures.
Results: Youth with PANS presented with an early age of OCD onset (mean=7.84 years) and exhibited moderate to severe obsessive compulsive symptoms upon evaluation. All had comorbid anxiety and emotional lability, and scored well below normative means on all quality of life subscales. Youth with elevated streptococcal antibody titers trended toward having higher OCD severity, and presented more frequently with dilated pupils relative to youth without elevated titers. A cluster analysis of core PANS symptoms revealed three distinct symptom clusters that included core characteristic PANS symptoms, streptococcal-related symptoms, and cytokine-driven/physiological symptoms. Youth with PANS who had comorbid tics were more likely to exhibit a decline in school performance, visuomotor impairment, food restriction symptoms, and handwriting deterioration, and they reported lower quality of life relative to youth without tics.
Conclusions: The sudden, acute onset of neuropsychiatric symptoms, high frequency of comorbidities (i.e., anxiety, behavioral regression, depression, and suicidality), and poor quality of life capture the PANS subgroup as suddenly and severely impaired youth. Identifying clinical characteristics of youth with PANS will allow clinicians to diagnose and treat this subtype of OCD with a more strategized and effective approach.


Conclusion

If exposure to strep causes your child to “go crazy” I think this is a case of IL-6 triggering an autism flare-up.  Once the strep is treated, IL-6 levels will fall and the crazy behavior and raging will subside.  This should be a short term problem.  This is unrelated to PANDAS/PANS.  IL-6 autism flare-ups caused by an inflammatory response, as opposed to an allergic response, do respond remarkably well to a small dose of ibuprofen. Ibuprofen can even be used to prevent this type of flare-up.  If the IL-6 surge was triggered by mast cell degranulation, ibuprofen will not help.

If exposure to strep causes facial grimacing and other tics then the short term increase in IL-6 and TNF-α is exacerbating a, likely already existing, tic disorder.  If the tics do not go away after the strep has been treated, then it may be that strep autoantibodies are indeed the problem and you may have a variant of rheumatic fever, in which case you could look at the suggested PANDAS/PANS therapies.










Friday 27 March 2015

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.



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
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.
.


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.
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.