Biogaia Trial for Inflammatory Autism Subtypes

UPDATE: A significant minority of parents report negative reaction to Bio Gaia, this seems to relate to histamine; but more than 50% report very positive effects without any side effects; so best to try a very small dose initially to see if it is not well tolerated. 

Histamine Reaction to Bio Gaia gastrus

Alli, our reader from Switzerland, has established that a large daily dose (5 tablets a day, cycled 3 weeks on and 3 weeks off) of the Biogaia Gastrus probiotic has a positive effect on the inflammatory sub-type of her son’s autism and also in other people she has shared her therapy with.  There is plenty of science to support its use.

In earlier posts I looked at a different probiotic bacteria (Clostridium butyricum Miyairi 588) that is widely used in animals to improve auto-immune health.  That bacteria is used in humans, but as is the case with BioGaia Gastrus, the focus is on stomach health not auto immunity.  Nobody has proposed an effective dose of Miyairi 588 in human autism; I have only used it in small doses.

It turns out that there is vast wealth of research into the effects of specific probiotic bacteria.  The research is really very interesting for anyone with any kind of allergy.  I expect that, as Alli found, the potential therapeutic benefit goes far wider, to many kinds of inflammatory disease outside the gut, particularly the very hard to treat ones, perhaps even MS (multiple sclerosis).

Biogaia and Lactobacillus Reuteri 

Lactobacillus reuteri is a species of bacteria that belongs to one of the major lactic-acid producing genera of bacteria. It can be found in the human intestinal tract, though not always and often in relatively low numbers. Lactobacillus reuteri is also found in the gut of other mammals and birds.

Initially, Lactobacillus reuteri was used to treat necrotizing colitis, a gastrointestinal disease characterized by infection and inflammation that is particularly dangerous for infants, particularly those born prematurely. Lactobacillus reuteri was used due to its anti-inflammatory effects.

The research on Lactobacillus reuteri and necrotizing colitis used the Lactobacillus reuteri strains ATCC 55730 and its daughter strain DSM 17938, both of which can survive oral supplementation.

Interest in Lactobacillus reuteri grew after research confirmed that changing aspects of the digestive system can influence the immune system. A strain of Lactobacillus reuteri called ATCC PTA 6475 has been found to improve levels of testosterone and oxytocin, as well as skin quality in animal studies. Research on animals has also found potential benefits for hair quality, bone mass and preventing weight gain from obesity-causing diets.

One of the ways Lactobacillus reuteri may work involves a kind of T cell called a Treg cell (a T cell that down-regulates the immune system in part by producing a cytokine called IL-10). Lactobacillus reuteri increases the amount of Treg cells in the body, which suppresses the actions of another kind of T cell called a Th17 cell (which secretes IL-17). Preserving or reversing this process (either by increasing IL-10 or by blocking IL-17) appears to provide therapeutic benefits.

Lactobacillus reuteri increases the number of Treg cells in the intestines, which can then be absorbed back into the blood to benefit the rest of the body.

BioGaia Gastrus is a combination of the well-researched probiotic strain Lactobacillus reuteri17938 (Lactobacillus reuteri Protectis) and the anti-inflammatory strain Lactobacillus reuteri ATCC PTA 6475. It contains 200 million CFU of live bacteria.

The original Biogaia product is called BioGaia Protectis; it only contains Lactobacillus reuteri 17938 (Lactobacillus reuteri Protectis).  It contains 100 million CFU of live bacteria.

Since some readers are already trialing Alli’s therapy, I thought it would be useful to have a single place on this blog where people could leave feedback.  Here is her explanation:-

Dear all,

Lactobacillus Reuteri ATCC 55730 was initially discovered and sourced from women from Peru who carried this strain in their breast milk. 

"The first strain of Lactobacillus reuteri for human use was isolated in 1990 from the breast milk of a Peruvian mother living in the Andes. This strain was deposited at the American Type Culture Collection (ATCC) as Lactobacillus reuteri SD 2112 (SD = safety deposit), and was later given the number ATCC 55730.

In 2007 Lactobacillus reuteri ATCC 55730 was replaced by the “daughter strain” Lactobacillus reuteri DSM 17938. The only difference between the strains is the loss of two plasmids of ATCC 55730 that carried resistance to tetracycline and lincomycin, respectively."http://www.biogaia.com/history-lactobacillus-reuteri

Through my personal review of immunology literature and ASD/immunity related literature and documenting crossroads between immune pathways and Mtor pathways, I came to the conclusion more than one year ago that this was a very interesting strain to try on my son with ASD and a TH1 profile. Biogaia Gastrus was only available in Korea and Italy at the time so I ordered it from an Italian pharmacy online.
It has helped my son significantly in combination with other interventions.

The mechanism at stake is probably the following:

- downregulation of TH1 through upregulation of IL-10 and downregulation of IL-17
This prevents autoimmune phenomena and cytokine flares which affect cognition in certain subtypes of ASD. However, the downside is that long term intake also impairs one's immune system's capacity to fight off infections... 

We use Biogaia on and off for 3 week periods- at a dosage of 5 tablets a day (less is useless in terms of potency).

Use must be stopped if a child shoes any sign of infection.

I have shared this over the past year with several parents around me who have children with similar subtypes and they report similar results.

Effect of Lactobacillus reuteri 17938 on Monty

My son Monty, aged 12 with autism, pollen allergy and occasional asthma, was again my willing test subject.  This is the worst time of the year when his allergy triggers asthma and autism flare-ups.

Where we live, only the older version of Biogaia is sold.  So he has been taking Lactobacillus reuteri 17938, 400 million CFU a day.

In Alli’s dosage there is 500 million CFU of reuteri 17938 and 500 million of reuteri ATCC PTA 6475.

There was an effect almost immediately on his allergy; his nose changed colour.  His pollen allergy gets gradually worse in the summer and the sides of his nose becomes bright red.  Short term use of topical steroids reverses this, but the pollen season is four months long.

Along with his red nose, his behavior gets worse leading to aggression,SIB and cognitive decline.  This lasts from mid June to October.  The aggression and SIB responds very well to treatment with Verapamil, but this does not reverse the cognitive decline.  

My behavioural observations might be wishful thinking, but I cannot be imagining bright red fading to a mild pink.

Clearly even at my reduced dosage and lack of the second anti-inflammatory bacteria (L. reuteri ATCC PTA 6475) something very helpful is happening.

As is my habit, I did a quick review of the literature and found plenty of supporting evidence for the potential benefit of specific bacteria on allergy.

As Alli has found, the potential benefit goes far beyond allergy.

  

Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice

RESULTS:

Oral treatment with live Lactobacillus reuteri but not Lactobacillus salivarius significantly attenuated the influx of eosinophils to the airway lumen and parenchyma and reduced the levels of tumor necrosis factor, monocyte chemoattractant protein-1, IL-5, and IL-13 in bronchoalveolar lavage fluid of antigen-challenged animals, but there was no change in eotaxin or IL-10. L. reuteri but not L. salivarius also decreased allergen-induced airway hyperresponsiveness. These responses were dependent on Toll-like receptor 9 and were associated with increased activity of indoleamine 2,3-dioxygenase. Killed organisms did not mimic the ability of the live L. reuteri to attenuate inflammation or airway hyperresponsiveness.

CONCLUSION:

Oral treatment with live L. reuteri can attenuate major characteristics of an asthmatic response in a mouse model of allergic airway inflammation. These results suggest that oral treatment with specific live probiotic strains may have therapeutic potential in the treatment of allergic airway disease.

Probiotic Therapy as a Novel Approach for Allergic Disease

Various effects of different probiotic strains in allergic disorders: an update from laboratory and clinical data

The various effects of different probiotic strains in allergic diseases are shown from laboratory and clinical studies referred to in the text.

↑: Increase in symptoms or negative effect; ↓: decrease in symptoms or positive effect; ↔: no change in symptoms or no effect

References	Probiotic strain	Type of allergic disease	Outcome
		Atopic dermatitis (eczema)
Sistek et al.[31]	Lctbs rhamnosus + Bfdbm lactis	Food-sensitized atopic children	↓
Kalliomäki et al.[45]	Lactobacillus GG	Atopic dermatitis	↓
Kopp et al.[46]	Lactobacillus GG	Atopic dermatitis	↔, ↑
Wickens et al.[47]	Lctbs rhamnosus	IgE-associated eczema	↓
Viljanen et al.[41,48]	LGG	Atopic eczema/dermatitis syndrome	↓
Rosenfeldt et al.[49]	Lctbs rhamnosus + Lctbs reuteri	Atopic dermatitis	↓
Kuitunen et al.[50]	Lctbs + Bfdbm + propionibacteria	IgE-associated allergy	↓
Boyle et al.[54]	Various	Eczema	↔
Lee et al.[55]	Various	Atopic dermatitis	↔
Soh et al.[63]	Bfdbm longum + Lctbcs rhamnosus	Eczema and atopic sensitization	↔
		Food allergy and anaphylaxis
Kim et al.[27]	Lctbs acidophilus + Bfdbm lactis	OVA-induced allergic symptoms	↓
Isolauri et al.[56]	Bfdbm or Lctbs	Food allergy	↓
Majamaa et al.[57]	LGG	Food-sensitized eczema	↓
Shida et al.[60]	VSL#3 + Lctbs casei strain Shirota	Anaphylaxis with food allergy	↓
Hol et al.[61]	Lctbs casei + Bfdbm Bb-12	Cow's milk allergy	↔
Taylor et al.[62]	LGG or Lctbs acidophilus	Cow's milk allergy	↔, ↑
		Allergic rhinitis
Di Felice et al.[59]	VSL#3	Allergic rhinitis	↓
Giovannini et al.[67]	Lctbs casei	Allergic rhinitis	↓
Morita et al.[69]	LGG + Lctbs gasseri	Allergic rhinitis	↓
Xiao et al.[71]	Bfdbm longum	Allergic rhinitis; JCP	↓
Tamura et al.[72]	Lctbs casei strain Shirota	Allergic rhinitis; JCP	↔
		Asthma
Kruisselbrink et al.[33]	Lctbs plantarum	Dermatophagoides (Der p1) sensitization	↓
Feleszko et al.[43]	Bfdbm-12	Airway reactivity	↓
Blümer et al.[73]	LGG	Allergic asthma	↓
Repa et al.[74]	Lactococcus lactis + Lctbs plantarum	Birch pollen allergen (Bet v1) sensitization	↓
Karimi et al.[75]	Lctbs reuteri	Allergic airway inflammation	↓
Helin et al.[78]	LGG	Pollen allergy	↔

Reader Trials

It would be helpful if readers would share feedback on their use of high dose Biogaia probiotics.

There are many other types of probiotic, but it would be helpful to first focus on the one that has been shown by Alli to be effective.

It seems to me that within a week you are going to know if you have a responder.  As usual you need to see how the effect varies over time.  Numerous interventions seem to be effective and then fade away and some even go from positive to negative.  I will certainly be continuing to see the longer term effect and hopefully finally adding something new to my PolyPill.

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.

Autism – Getting Lost in the Translation

I think most lay people would be surprised to know that literally tens of thousands of scientific papers have been published on autism and yet not a single drug has been approved to treat core autism.

Surely there must be some value in all this research, that can be extracted today?

A reader recently sent me a link to an excellent lecture about propionic acid in autism.  The first part of the lecture was much more general and concisely summarizes what we know about autism.  We know a vast amount; it just has not been translated (applied).  Click below for the video.

Source:- American College of Nutrition

Translation

Alli from Switzerland, a medical reader of this blog did raise this issue a while back.  Why has the vast knowledge about autism not been translated across into medical therapies?

Her conclusion was the same as mine; don’t wait, do the translation yourself.  This is of course easier said than done, because there are wide variations in what causes autism.  Not surprisingly, her effective therapy is very different to mine.  In fact almost nothing that helps my son helps hers; but that is of course the point, there isn’t one autism.  There are thousands of variations, within which fortunately there are some clusters.

These are the elements of that therapy:-

·        PAK1/WNT inhibitor

·        Longvida Curcumin / J147  as cognitive enhancer via mtor inhibition

·        Ibudilast, a Pde4 inhibitor, as a modulator of microglia

·        Sodium Butyrate 500mg

·        Propranolol 30mg as PI3K/Akt/enos/vegf inhibitor

·        Garlic, to moderate Cytokine related autism flare ups

·        L-Theanine to regulates hyperactive behavior

·        Syntocinon (oxytocin) to improve social awareness

·        Biogaia gastrus probiotic (which down regulates TH1 and upregulates IL-10)

As in my case, there are flare-ups in symptoms and they are accompanied by loss in cognitive function.

Alli points out that dosage is key (paradoxical effects can occur at lower or higher dosages) and that some components of the treatment should be taken alternatively.

We also have the UK paediatrician who stumbled upon the fact that moderate dosage of baclofen is a remarkably effective therapy for the majority of people with Asperger's and shared that on this blog.  This does not appear anywhere in the literature and that doctor did not want to publish a trial, so it will remain hidden, except to readers of this blog. The more potent R-baclofen is being studied for more severe autism, but it is a research drug.

For various reasons mainstream clinicians do not publish their autism therapies, this was also the case with autism secondary to mitochondrial disease (AMD) where the detailed knowledge from Johns Hopkins does not appear in any medical journal.

In my post on the history of autism we saw that way back in 1877 there was an effective autism therapy (then being used as an epilepsy therapy) by a Dr Dickinson at London's Great Ormond Street Hospital.  He used potassium bromide which modifies the effect of GABA in a broadly similar way to Ben-Ari's use of Bumetanide today, that I promote on this blog. 

Likely other discoveries have also been lost.

Cancer Research

Cancer research is being translated into clinical use and so numerous new drugs are being developed.  As I have pointed out before, many of the affected pathways in some autism are shown to be affected in some cancer.  This means some new drugs can potentially be used to treat both conditions.

The idea of sub-types in cancer is now widely accepted.  Therapies can only be effective if used in the specific sub-type of the cancer.  The same applies to autism. The same applies to epilepsy.

The overlap between cancer genes and autism genes is very clearly shown in a recent graphic on Spectrum News (Simons Foundation). More food for thought.

Note WNT. mTOR, AKT, P53 etc.

  

Dozens of autism genes have cancer connections

Conclusion

It would be very helpful to gather together the combination therapies of other parents who have followed the science and applied it to an unrestricted palette of drugs/supplements that exist today.  There must be other people who have successfully done this.

Some OTC therapies are indeed very helpful, but full access to pharmacotherapy is needed to effectively translate science into therapy.  

There are of course DAN/MAPS type doctors in North America.  Some of them have some clever therapies, but there is also a great deal of nonsense and the priority appears to be making money rather than translating science.

I do get people writing to me with various theories and it is always important to keep an open mind. It looks like all truly effective therapies are reversible, they are not curative or disease changing.  If you stop the therapy you gradually lose the benefit. 

Only radical therapies, like the one below, are likely to be curative and only partially so in autism.  I do not see anyone giving high doses of chemotherapy drugs to two and three year olds any time soon.

MS breakthrough: Replacing diseased immune system halts progression, allows repair

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?

In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy

In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 

The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.

Current view on the functional regulation of the neuronal K⁺-Cl⁻ cotransporter KCC2

The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.

Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.

The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome

Discovery of a new drug target could lead to novel treatment for severe autism

The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.

"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."

More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats

Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.

More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).

Insulin-Like Growth Factor 1 and a Cytosolic Tyrosine Kinase Activate Chloride Outward Transport during Maturation of Hippocampal Neurons

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABA_A receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABA_A receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.

Development and regulation of chloride homeostasis in the central nervous system

Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO₄) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.

Longitude, Latitude & Epilepsy in Autism

It is not always easy to decide which subjects to study, never mind if you have autism.

For Monty, aged 12 with autism, it has been me choosing what he studies.  At the beginning it was rather overwhelming for his 1:1 assistant, because there was so much to learn and never enough time.  It takes years to learn very simple things that typical kids just pick up naturally.

One big change after three and half years of Polypill use, is that Monty follows the standard academic curriculum, albeit for kids two years his junior.

An excellent but not very user friendly curriculum/skill list is in a book called ABLLS (assessment of basic language and learning skills).  It is both a curriculum and an assessment tool.  It covers all the very basic skills that kids need as a foundation for future learning.

We were working from this list of simple skills for four years, until the age of eight.  These are skills most kids effortlessly pick up in the first three or four years of life.

After you have mastered those simple skills what do you teach next to someone with classic autism?

I did my research and concluded the generally accepted answer is “not much”.

One phrase I still recall was a mother writing “our kids don’t need to learn longitude and latitude”, because this is going to go way over their heads.

It seems that for kids entirely non-verbal at three, about 10% have some maturational dysfunction that self-corrects by six, leaving just minor tics or perhaps mild "quirky" autism. Most of the remaining 90% end up "graduating" high school with an academic level of a four to seven year old.  A small number do better.  

A few years after ABLLS and Monty has mastered X,Y coordinates, even using negative numbers and identifying objects using Northwest, Southeast etc.

Regular readers will be aware that Monty’s recent academic development did not happen spontaneously, nor through ABA, it came from pharmacotherapy (drugs) and is reversible (hopefully not entirely).

Burden of proof

In spite of all this change it would be hard to prove what has caused it. Fortunately I do not need to.

Monty is still autistic, just less so and is now educable. That is a really big deal to me, but not to others. 

If you could convert 100% of kids with autism into outgoing, talkative, social, intelligent, typical kids then people would take note.  No therapy will ever deliver this. Just to confuse the issue, 10% will indeed "recover" without any intervention at all, which then is used to justify all kinds of interventions that those people used.

Have I measured Monty’s IQ?  No I have not.  A lady from California asked me why not, because over there they have excellent autism services, even assisted employment and sheltered housing but it is rationed based on things including IQ. 

One doctor reader of this blog suggested that some of the drug interventions in this blog will also reduce the development of seizures and therefore reduce the rate of premature death in autism; “surely we should tell people about this”.  I had a sense of déjà vu.

It is clear that in treating the excitatory/inhibitory imbalance that underlies much autism and also treating other channelopathies, you should also be avoiding some of the neuronal hyper-excitability that is epilepsy.

So treating autism should reduce death from seizures that reduce life expectancy in severe autism to just 40 years old.

This is all true and a year or so back I did suggest this to the Bumetanide researchers.  There was little interest and some skepticism. 

In fact there is a great deal of epilepsy research and some does indeed overlap with autism research.  One key area is Cation Chloride Cotransporters (CCCs), where the same type of immature neurons found in autism are found in epilepsy. Another is elevated BDNF (brain-derived neurotropic factor); in epilepsy, seizures trigger an increase in BDNF which then reduces expression of KCC2 which then shifts neurons further towards immature (high intra-cellular chloride) worsening the excitatory/inhibitory imbalance and making the next seizure more likely.  A clever idea we can borrow from the under-utilized epilepsy research is to consider blocking BDNF, or trkB, as a means of increasing KCC2 expression.  This could be a useful adjunct therapy to bumetanide, which blocks NKCC1. We want less NKCC1 but more KCC2, to give lower levels of chloride inside the cells and then neurons can fire when they are supposed to.

It takes decades for research findings, like those in the above paragraph, to be translated across into therapies.

If you, or particularly a researcher, make a statement that is controversial and not backed by a big stack of evidence (based on human trials, not mouse trials) nobody is going to believe you.  Worse still, the next time you make a claim, they will be even less likely to believe you.

So better under-promise but over deliver.  Start finally treating some autism and then watch in the next thirty years that epilepsy incidence falls and along with it SUDEP (Sudden Unexpected Death in Epilepsy).  Then you can say “I told you so, it was those Cation Chloride Cotransporter after all ”.

In spite of all the “evidence” that some autism is treatable, cognitive dysfunction is reversible, the world has not taken any notice.  Where is the undisputed concrete proof?  I just have to think “longitude and latitude”, that’s my proof.

So in reality while avoiding epilepsy should be a big deal for the parents, it is not for anyone else.  The current wisdom is keep your fingers crossed and hope that you are not in the one third that will develop epilepsy around puberty.  In some people this triggers an epigenetic change, opening the way to many future seizures.  For those who are interested:-

          Epigenetics and Epilepsy

If you follow 100 kids with autism on bumetanide for 10 years and found 5 developed seizures that would not be regarded as proof.

Based on my reading of the literature, you would expect 30+% of people with classic autism to develop epilepsy.  So if they had just 5 cases, I would see that as vindication, but it would not be seen as conclusive proof by others, just another paper to file and forget.

So the idea of prophylactic drug treatment to avoid the onset of epilepsy in autism is unlikely to catch on and is easy to rubbish.

Just like prophylactic use of drugs to avoid dementia, avoid type 2 diabetes or avoid the nasty side effects of type 1 diabetes, they will not enter the mainstream.

Conclusion

Setting low standards and targets will guarantee poor outcomes.  Aim to learn longitude and latitude, but it might be easier with a daily dose of bumetanide.

Some epilepsy is avoidable, some may not be, but if treating autism can also reduce the chance of epilepsy and SUDEP do you really need to wait for absolute evidence?

It is currently a matter of geography and google competence who is going to access effective pharmacotherapy.  For a change it is the poorer countries who have the advantage, since they have less rigid control over access to prescription medication.

I was just reading that the excellent New England Center for Children (NECC) charges up to $300,000 a year to educate kids with autism.  It is a great school and we employed a former teacher from there a few years ago, to help with our home program.  With something like 0.3% of all kids having serious autism, there needs to be a less expensive solution available to all.  

Spending $300,000 at NECC will almost definitely have a positive impact on one severely autistic child for one year.  Alternatively, for the same money, you could treat 480 kids with strict definition autism with my Polypill for one year.  It looks like around a half would respond very well.  Ideally you would spend $300,620 and have both the NECC and the Polypill; this is pretty much what was my target, but without leaving home.