Chemo-Brain and Apparently Cyto-Brain in some Autism and even ADHD

Some readers of this blog have developed quite advanced personalized medication for their child with autism.  As you might expect, given the wide variety of autism sub-types, the medical therapies found to be effective vary widely.  It is interesting that many people see fluctuations in cognitive function and some develop strategies to counter them.

I came across another form of variable cognitive dysfunction, “Chemo-brain”, that occurs in people after cancer treatment.  Chemo brain can also be called chemo fog, chemotherapy-related cognitive impairment or just cognitive dysfunction.

It is interesting for readers of this blog because chemo brain is thought to be caused by changes in inflammatory cytokine expression within the brain, over a few years the symptoms usually fade away.  Some people’s autism just fades away, although tell-tale signs usually remain.

Cytokine expression appears to be both a cause of autism and a consequence of it.  One clever researcher in this field is Paul Ashwood, who recently published another paper, this time regarding their causal effect.

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation

A confusing term that also appears is dyscognition; this is not a real word, but is either used to describe another condition sometimes called “fibro fog”, or it just means cognitive dysfunction.   Fibro fog is the name given to cognitive dysfunction in fibromyalgia, which occurs alongside fatigue and muscle pain.

Many doctors believe that fibromyalgia is often a made up condition.  I think, in some people, fibromyalgia is one step short, in a multiple hit process, of a progression to autism.  If you look at biological links between neuropathic pain and autism, like purinergic signaling (P2Y2 etc) there are connections between pain and autism.  As we know, people with autism can be both hypo and hyper sensitive to pain.  

This post is really just look to see are there any clever thoughts regarding chemo brain that can be translated to treating cognitive dysfunction in autism, be it the baseline autism or those flare ups.

Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy

Further, the cytokine hypothesis suggests a range of potential therapeutic targets. One potential approach would be to prevent the acute change in cytokines related to cancer treatment from occurring. Agents that inhibit cytokine activity, such as monoclonal antibodies and small molecular inhibitors, may confer benefit either alone or as an adjuvant treatment to chemotherapy-induced cognitive decline in cancer patients. TNF-α antagonists (etanercept and infliximab) have been shown to inhibit fatigue and improve depressive symptoms in patients with advanced cancer. P2×7 antagonist that inhibits IL-1b release has been shown to reduce depressive-like profiles and neuropathic pain in animal models. Specific p38 MAPK and NF-κB inhibitors that block inflammatory signaling transduction have generated great interest from their use in the treatment of cytokine-induced depressive behavior and antidepressant-like effects in animal models. Anti-inflammatory cytokines, IL-10, IL-4 and minocycline may also have the potential therapeutic effects on chemotherapy-induced cognitive decline by inhibition of pro-inflammatory cytokine release through modulation of the caspase pathways. Even acupuncture may have therapeutic potential considering its effects on suppressing proinflammatory cytokines, TNF-α, IL-1β, IL-6, and IL-10. Acupuncture has been often used to alleviate the side effects of cancer treatment, including pain, nausea, hot flashes, fatigue, anxiety/mood disorders, and sleep disturbance. A series of interesting studies suggest a therapeutic role in dyscognition, for example, acupuncture improved cognitive function of patients with mild cognitive impairment (MCI) and various dementia, with clinical improvement correlating with alterations in functional connectivity and resting state activity of particular brain regions. Such approaches to the prevention of cancer-therapy dyscognition are reasonable, currently feasible, and scientifically testable.

BDNF and its receptor tropomyosin-related kinase receptor type B (TRKB) play a potential role in the pathogenesis of neurological and neuropsychological disorders . Epigenetic or pharmacological enhancement of BDNF–trkB signaling restores was reported to reverse the aging-related cognitive decline. BDNF polymorphisms are associated with impaired memory and cognition, along with reduced hippocampal activation as measured by fMRI. Age-related BDNF declines have been reported to be associated with declines in hippocampal volume and spatial memory in the elderly. Low BDNF is associated with cognitive impairment in patients with schizophrenia and Alzheimer’s disease. Significantly decreased blood serum BDNF levels have been detected in patients with cognitive impairment due to obstructive sleep apnoea/hypopnoea syndrome. Given its potent effects on neuronal function and survival in various cell systems in the CNS, BDNF has been evaluated in patients with various neurology cal disorders, including amyotrophic lateral sclerosis (ALS), peripheral neuropathy, Parkinson’s disease and Alzheimer’s disease. However, delivery of BDNF remains a substantial challenge for clinical trials because it is a moderately sized and charged protein and only minimal amount of BDNF administrated peripherally crosses the BBB to reach neurons in the brain. Acupuncture has been reported to increase neurotrophic factors  and the levels of nerve growth factors in the brain by altering the permeability of the BBB. In rats, electric acupuncture enhanced motor recovery after cerebral infarction that was associated with increased expression of BDNF in the brain.

With cytokines acting as a trigger to upstream changes, anti-cytokine therapies may have little therapeutic effect once upstream mechanisms responsible for dyscognition have been established, given that the most clinically available anti-cytokine antibodies are not readily to penetrate the blood–brain barrier. Antibody concentrations in the brain are typically about a thousand times lower than in the blood. Therefore, to better prevent development of cognitive dysfunction, anti-cytokine therapies would be best used by blocking cytokine production or inhibiting cytokine release in the peripheral prior to triggering the consequent events in the CNS. However, epigenetic changes are dynamic and the pathological changes caused by epigenetic modifications can be reversed prior to the development of permanent symptoms by targeting enzymes or other factors that control or maintain the epigenetic status. Treatments that seek to reverse casual epigenetic modifications have the potential to be effective. Such treatments are still in their infancy. S-adenosyl methionine (SAM) is an important methyl group donor required for proper DNA methylation and has been used to treat memory and cognitive symptoms in depressed patients. Betaine, another methyl donor, has been shown to improve memory in mice memory impairment induced by lipopolysaccharide. Histone deacetylases (HDACs) inhibitors can also alter epigenetic modifications, which have been studied in memory and cognition . In a mouse model, administration of crebinostat, a HDAC inhibitor, improves memory. Sirtuins, a class III HDAC inhibitors found in red grape skin and wine resveratrol have been found to improve cognitive function in mice and are currently under phase II clinical trial (ADAS-Cog, ClinicalTrials.gov; NCT01504854, 2013).

In summary, cognitive dysfunction remains a common and debilitating effect of cancer treatment, with no effective prevention and treatment, although a variety of pharmacologic and non-pharmacological strategies have been investigated. We present a speculative but testable hypothesis of how cognitive dysfunction may occur following chemotherapy. Unlike other dyscognitive illnesses, it is both scientifically and ethically feasible to study the onset of “chemobrain” by administering a major physiologic stress and observing the biological ramifications. It should be possible to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identifying methods to both prevent and treat cancer-treatment dyscognition and potentially other dyscognitive disorders.

ADHD

Rather by coincidence a very recent study on ADHD was just published and highlighted on the Questioning Answers Blog, it shows something rather similar.  In people with ADHD and allergy, when you treat their allergy with antihistamines and/or steroids their ADHD symptoms improve.  In other words the inflammatory signaling from allergies exacerbates their underlying neurological problems.

Attention-deficit/hyperactivity disorder-related symptoms improved with allergic rhinitis treatment in children.

BACKGROUND:
Increased prevalence of attention-deficit/hyperactivity disorder (ADHD) in children with allergic rhinitis (AR) has been reported. Our previous study showed that children with untreated AR had higher ADHD scores than did the controls.

OBJECTIVE:

This prospective follow-up study aimed to investigate whether elevated ADHD scores in children with AR could be decreased by AR treatment.

METHODS:

Sixty-eight children with AR (age range, 6-14 years) and who were drug naive were enrolled and evaluated by AR symptom score, ADHD symptom scores, and computerized continuous performance test, before and after AR therapy, which included nonpharmacologic intervention, oral antihistamines, and topical steroids. Thirty-one age-matched controls and 13 children with pure ADHD were also enrolled for comparison. The relationship between the AR and ADHD score change was analyzed by a partial correlation test, and univariate and multivariate linear regression models were applied to investigate possible predictors for the improvement of ADHD scores by AR treatment.

RESULTS:

AR symptom scores in children with AR decreased significantly after treatment (p < 0.001), and their ADHD scores also decreased significantly (p < 0.001). An improved AR symptom score was positively correlated with improved detectability (rp = 0.617, p = 0.001) and commission error (rp = 0.511, p = 0.011). Significant predictors for the improvement of ADHD scores included age, AR drugs, AR subtypes, and multiple atopic diseases (ps < 0.05).

CONCLUSION:

Higher ADHD scores in children with AR compared with healthy controls decreased significantly with AR treatment. For children with AR and borderline ADHD symptoms, who do not meet full ADHD diagnostic criteria, we recommend initially treating their AR and monitoring improvement of ADHD symptoms.

I have documented in this blog how allergy can make autism worse and numerous people have left comments that allergic rhinitis treatment in children reduces their autism.

This would seem to me to suggest that controlling inflammatory cytokines may ameliorate the issues faced by people with conditions ranging from ADHD and autism to chemotherapy-related cognitive impairment and quite possibly some types of dementia and MCI (mild cognitive impairment) not to mention TBI (traumatic brain injury).

There are numerous possible ways to influence pro and anti-inflammatory cytokines, very likely different people will respond to different therapies.  What helps people with chemobrain may well be worth investigating for people with what I am calling cytobrain.

In the world of autism, as the door appears to be closing on the development of TSO parasites as immuno-modulators another one is opening for probiotic bacteria.  This was discussed in the comments section of the last post.  

Immunomodulatory probiotics for chemobrain perhaps?  Probably worth a try.

Butyric Acid– my choice of short-chained fatty acid (SCFA), as a potential anti-inflammatory autism therapy

Stockholm in spring

Hot on the heels of the last post that showed that regulatory T cells (Tregs) may indeed be a useful target to treat inflammation in autism, today’s post is about the particular short chained fatty acid (SCFA) that I have chosen to treat it.

There are seven SCFAs:- Formic acid, Acetic acid, Propionic acid, Butyric acid, Isobutyric acid, Valeric acid, Isovaleric acid.

Based on my homework, I have chosen Butyric Acid.

Some of my posts do not lead to therapeutic interventions, but the posts on Treg and SCFA are going to lead to some good options, particularly for those with GI problems.

As usual with effective interventions, there are multiple possible modes of action. 

Since I have introduced epigenetics to this blog, I will also highlight a paper showing the epigenetic effects of Butyric Acid.  My real objective is to increase Tregs, as a means of shifting the balance between the proinflammatory IL-6 and the anti-inflammatory IL-10.

Monty, aged 11 with ASD, does not have GI problems and has a very mixed and healthy diet, so I have not really looked at the myriad of possible GI therapies.  However, in this blog we have seen that the integrity of the Blood Brain Barrier (BBB) is critical in autism and that, in fact, it has variable permeability (it can self-repair).  I suggest that increased permeability might lead to worsening behaviour and observed flare-ups/regressions.

We have also seen that the mechanisms controlling the BBB overlap with those governing the Intestinal Epithelial Barrier (the gut-blood barrier).

The SCFAs that appear to be able to repair the Intestinal Epithelial Barrier have been shown to be able to circulate throughout the body, reach, and then cross the Blood Brain Barrier.  As a result it is certainly plausible that increasing SCFAs and Tregs will benefit those both with, and without, GI problems.  What is clear from the research and anecdotal evidence is that those with ulcerative colitis (UC) do very much benefit.  People with UC will have a compromised Intestinal Epithelial Barrier.  Some people with autism may have both a slightly permeable Blood Brain Barrier and a compromised Intestinal Epithelial Barrier (leaky gut).

I have also established from the research that a moderate increase in Butyric Acid has many measurable good effects and for this reason it is already widely used as an additive in animal feed.  It results in more healthy chickens, with less inflammatory disease and measurably lower levels of e-coli and salmonella.  I expect there is also more meat and less fat.

First, Why Bother?

About 20% into my current autism investigation, one of Monty’s grandmothers suggested that I had now done enough and should stop.   Clearly I did not.  She also told me “just make sure he does not get violent, when he is older”.  As a retired doctor, she is aware of what the end result would be.

At the time I thought “easier said than done”.

A year or so later, I am able to control my son’s mood, anxiety and indeed occasional aggression.  It is not perfect, but it is about 80% perfect.

This makes a huge difference to daily life. 

We just returned from a week in Stockholm, Sweden.  We were on buses, trains, trams, boats, taxis and planes.  We were in museums, shops, cafes and restaurants.  Behaviour was “almost” perfect and with some “fine tuning”, it was actually big brother who was the troublesome one.

Grandma number two has just been reading the well-known book, "The Reason I Jump".

“Written by Naoki Higashida when he was only thirteen, this remarkable book explains the often baffling behaviour of autistic children and shows the way they think and feel - such as about the people around them, time and beauty, noise, and themselves. Naoki abundantly proves that autistic people do possess imagination, humour and empathy, but also makes clear, with great poignancy, how badly they need our compassion, patience and understanding.”

Yesterday, she told me all about why some people with autism self-injure.  It is just something they have to do and you just leave them to it; just make sure they do not do any serious damage.

As you might imagine, I will not be waiting in line to read such a book.

As I explained to Grandma, people with autism self-injure for mostly biological reasons and you can figure out many of them.  Then they will not self-injure.  They will then be happier and higher functioning. 

It also means that when they are full grown adults they will not pose a threat to their carers and develop such “complex needs” that they have to be institutionalized, at great emotional and financial cost.  I suppose Grandma number one had this in mind.

So why bother? because I can.

The epigenetic effects of butyrate

The following paper looks at the positive therapeutic effects of butyrate in terms of epigenetics.  In the paper on Tregs in the last post, the Harvard researchers were attributing some of these effects to the increase in Tregs.  I do not mind who is right, and quite possibly both groups are right.

The epigenetic effects of butyrate: potential therapeutic implications for clinical practice

Butyrate is a short chain fatty acid derived from the microbial fermentation of dietary fibers in the colon. In the last decade, multiple beneficial effects of butyrate at intestinal and extraintestinal level have been demonstrated. The mechanisms of action of butyrate are different and many of these involve an epigenetic regulation of gene expression through the inhibition of histone deacetylase. There is a growing interest in butyrate because its impact on epigenetic mechanisms will lead to more specific and efficacious therapeutic strategies for the prevention and treatment of different diseases ranging from genetic/metabolic conditions to neurological degenerative disorders. This review is focused on recent data regarding the epigenetic effects of butyrate with potential clinical implications in human medicine.

In later posts I will give more of the research evidence in favour of butyrate and you will see how chickens currently get better intestinal care than humans.

As suggested in the original post on Tregs and SCFAs, there will be different methods to raise Butyrate levels.  It can be achieved directly via supplementation, with sodium butyrate, and indirectly by adding a butyrate-producing bacteria, such as Clostridium Butyricum.  This is widely used in Asia as a probiotic, but is available elsewhere.

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

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

N = 1 or N > 1

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

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

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

The large cluster that is classic autism remains untreated.

Polypill N = 3

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

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

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

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

What does this have to do with antibiotics?

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

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

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

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

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

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

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

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

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

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

Minocycline: therapeutic potential in psychiatry.

Abstract

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

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

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

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

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

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

Early research has found a tentative benefit from minocycline in schizophrenia

Amoxicillin

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

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

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

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

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

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

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

  

Vancomycin

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

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

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

.

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

Abstract

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

What is going on?

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

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

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

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

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

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

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

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

'Friendly' bacteria treat autism-like symptoms in mice

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

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

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

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

Probiotic curbs autism features in mouse model

• Guest blog: The case for using 'prebiotics'

• A probiotic therapy for autism

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

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

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

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

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

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

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

   

What it means?

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

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

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

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

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

·        Cromolyn Sodium

·        Verapamil

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

·        Probiotics & Prebiotics  (one day even Bacteroides Fragilis)

·        Exclusion diets

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

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

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

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

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

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