Leukemia, IL-6 IL-10 and an Autism Flare-up

   

Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.

 

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 

“Serum levels of Interleukin-6 can be used as prognostic serum markers at diagnosis of adults acute myeloid leukemia and it could be used as follow up parameters for early detection of relapse stage”

Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.

Link between Down syndrome, leukemia uncovered

If only some more of the clever people studied autism.

Autism, Allergies and Summertime Raging in 2016

  

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

A single species of gut bacteria can reverse autism-related social behavior in mice

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

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.

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

A recent post looked again at inflammation in autism and some possible therapies to try.  Over Christmas and New Year, Monty, aged 11 with ASD, had occasional outbursts, more typical of his summertime raging, which was later solved using allergy /mast cell therapies.

At least it did let me establish whether Verapamil was a universal “cure” for SIB.  It is not.  It works great for allergy-driven aggressive behaviors, but had no effect on these ones.

Christmas is often a stressful period for many people with, or without, autism; but Monty likes presents and he loves food.

Having pulled out a wobbly tooth on Boxing Day and noticed an apparent behavior change, I thought that perhaps the loss of milk teeth and development of permanent teeth might cause an effect similar to that of his mild pollen allergy.  Monty, in common with many people with autism, has a high pain threshold.  While teething causes well known problems in babies, most children have minimal problems when their milk teeth are replaced by their permanent ones.

I just wondered if perhaps the underlying biological mechanism might provide an inflammatory insult to the highly inflammation-sensitive autistic brain.

Just as histamine provokes a release of inflammatory cytokines like IL-6, perhaps losing your milk teeth does something similar.

Ibuprofen experiment

I decided that I would buy some Ibuprofen, the least problematic NSAID.   A day or two later, Monty declared that another tooth was wobbly and needed to be pulled out.  This tooth was, and remains, well and truly attached.

So I decided that in advance of another, potentially stressful, Christmas event, I would give 10 ml of Ibuprofen.  I did not give it in response to any comment about pain.

It did indeed seem to work.

Skiing

A few days later we were in the Alps for skiing.

Monty can ski, but we always give him a 1:1 instructor.  On the first day, without Ibuprofen, he got agitated during the queuing at the bottom of the beginners’ ski lift.  The instructor thought it was the loud booming music.  It was clear that by the end of the lesson, it was no fun at all.

The following days, I gave 10 ml of Ibuprofen, 20 minutes before the lesson started.  He had a great time, going up by cable car to the top of the mountain and skiing along the blue/red slopes and coming down in a neighboring resort a couple of hours later.  Even a change of instructor on one day, passed without issue.

It might not be scientific proof of the effectiveness of Ibuprofen, but it was enough for me.

The Science

Since this is a scientific blog, arriving home I did some checking on the biology of what happens when you lose your milk teeth.

There is more written about “teething” when you first get your milk teeth, but there is information about “root resorption” of milk teeth and “eruption” of the permanent teeth.  The process is indeed modulated by inflammatory cytokines and transcription factors.

These cytokines will then circulate around the body and cross the blood brain barrier.

Cytokine levels in gingival crevicular fluid of erupting primary teeth correlated with systemic disturbances accompanying teething.

Abstract

PURPOSE:

The aim of this study was to investigate whether there are increased levels of the inflammatory cytokines IL-1beta, IL-8, and TNF alpha in the gingival crevicular fluid (GCF) of erupting primary teeth. This increase could explain such clinical manifestations as fever, diarrhea, increased crying, and sleeping and eating disturbances that occur at this time.

METHODS:

Sixteen healthy children aged 5 to 14 months (mean=9.8 months) were examined twice a week over 5 months. Gingival crevicular fluid samples were taken from erupting teeth. As a control, GCF was collected from the same teeth 1 month later. Cytokine production was measured by ELISA. Signs and clinical symptoms were listed. Pearson correlation coefficients were used in the comparisons described below. A paired t test was used to analyze the same variable at different times.

RESULTS:

Fifty teeth of the 16 children were studied. GCF samples were collected from 21 of these teeth. Statistically significant differences (P<.05) were found with regard to the occurrence of fever, behavioral problems, and coughing during the teething period and the control period. During the control period, 72% of the children did not exhibit any clinical manifestations, whereas during the teething period only 22% of the children did not exhibit any clinical manifestations. The study revealed high levels of inflammatory cytokines during the teething period, with a statistically significant difference in TNF alpha levels (P<.05) between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1beta and TNF alpha were correlated with fever and sleep disturbances; IL-beta and IL-8 were correlated with gastrointestinal disturbances; IL-1beta was correlated with appetite disturbances.

CONCLUSIONS:

Cytokines appear in the GCF of erupting primary teeth. The cytokine levels are correlated to some symptoms of teething.

Mechanism of Human Tooth Eruption: Review Article Including a New Theory for Future Studies on the Eruption Process

Physiologic root resorption in primary teeth: molecular and histological events

Root resorption is a physiologic event for the primary teeth. It is still unclear whether odontoclasts, the cells which resorb the dental hard tissue, are different from the osteoclasts, the cells that resorb bone. Root resorption seems to be initiated and regulated by the stellate reticulum and the dental follicle of the underlying permanent tooth via the secretion of stimulatory molecules, i.e. cytokines and transcription factors. The primary root resorption process is regulated in a manner similar to bone remodeling, involving the same receptor ligand system known as RANK/RANKL (receptor activator of nuclear factor-kappa B/ RANK Ligand). Primary teeth without a permanent successor eventually exfoliate as well, but our current understanding on the underlying mechanism is slim. The literature is also vague on how resorption of the pulp and periodontal ligament of the primary teeth occurs. Knowledge on the mechanisms involved in the physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases that the permanent successor teeth are not present and thus preservation of the primary teeth is desirable. (J. Oral Sci. 49, 1-12, 2007)

Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, work by inhibiting the enzyme COX which converts arachidonic acid to prostaglandin H₂ (PGH₂). PGH₂, in turn, is converted by other enzymes to several other prostaglandins ,which are mediators of pain, inflammation, and fever.

Prostaglandin E synthase

Prostaglandin E₂ (PGE₂) is generated from the action of prostaglandin E synthases on prostaglandin H₂ (PGH₂).

PGE₂ has various known effects, but one known effect is to increase the pro-inflammatory cytokine IL-6.  The same one that is increased by histamine released from mast cells during allergic reactions.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.

Abstract

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine

Indomethacin is another NSAID, like Ibuprofen.

Implications

If, as seems likely, many incidents of anxiety, aggression, explosive behavior, or "meltdowns" are made possible by elevated levels of the pro-inflammatory cytokine IL-6, then the occasional use of drugs known to inhibit IL-6 makes a lot of sense.

Ibuprofen is an NSAID and it is known that some people respond much better to certain NSAIDs and suffer side effects from others.   NSAID drugs work by affecting both COX-1 and COX-2.  It appears that desired effect of NSAIDs comes from their effect on COX-2, while the side effects come from changes made to COX-1.  So it is logical that some NSAIDs are better tolerated than others and for some people a different NSAID may be more appropriate.

Other common drugs also lower IL-6;  leukotriene receptor antagonists like Montelukast (Singulair)  being an example.  This drug is used in autism, but a known side-effect in typical people is to worsen behavior, sometimes severely.  There are plenty of reports of Singulair in autism, some good and some bad.  Since almost all drugs have multiple effects, this is not surprising.

Interestingly, one of the drugs in my Polypill, NAC, is also known to reduce IL-6; but it also reduces the “good” anti-inflammatory cytokines like IL-10.  Perhaps this is why NAC is not beneficial to some people with autism?

Occasional use of Ibuprofen at times anticipated to be stressful makes a lot of sense. 

Conclusion

While it is well known that Ibuprofen relieves pain from teething, low level pain is often completely ignored by people with ASD.  The cytokine release associated with the resorption of the milk teeth and the eruption of the permanent tooth appears to be much more problematic.

Ibuprofen, available OTC, limits the production of pain mediators, called prostaglandins, which in turn stimulate production of the inflammatory cytokine IL-6.

Ibuprofen will reduce both pain and the level of cytokines like IL-6.

In earlier extensive posts on mast cell degranulation in autism, I concluded that the resulting elevated levels of IL-6 likely produced behaviors ranging from anxiety, through aggression, all the way to self-injury.