Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism

Today’s post is another one to fill in some of the gaps in this blog.

Psychiatrists have long been using electric shocks, of one kind or the other, to treat their patients. There is even a special school in the US (the Judge Rotenberg Center) where they used electric shocks as aversive therapy, until very recently.  

FDA Proposes Ban On Electric Shock Devices Used On Autistic Children 

Cannabis, in the form of Cannabidiol (CBD), is currently the subject of an autism trial in Israel, home to some very innovative people.

Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment, is a psychiatric treatment in which seizures are electrically induced in patients to provide relief from mental disorders. The ECT procedure was first conducted in 1938 is often used as a last line of intervention for major depressive disorder, mania, and catatonia.

As of 2001, it was estimated that about one million people received ECT annually.

Several hundred people with autism have been treated with ECT in the US. 

Transcranial Magnetic Stimulation (TMS)

Do not confuse ECT with Transcranial Magnetic Stimulation (TMS).

Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. This is rather similar to the way the base station of a rechargeable electric toothbrush works.

A big fan of TMS is Manuel Casanova, a neurologist and Autism blogger. 

A while back I watched a BBC documentary following an autistic girl adopted from a Serbian orphanage by a US family. All was going well until she later developed a serious problem with aggression and self-injury that was being treated by monthly visits to the hospital for electroconvulsive therapy.  The shocks did indeed seem to do the trick and suppress her aggressive tendencies. She is an example of what I call double tap autism, where an autistic person later suffers a profound setback for some reason. 

Video:- 

My Child, ECT (electric shock) and Me (click the picture below)

Long article from Spectrum News:- 

How ‘shock therapy’ is saving some children with autism 

What I found interesting was that you could see that when you took away the SIB, the girl was pretty high functioning. She could read, write and do math.

This made me recall a previous idea of mine that you might grade people’s autism in terms of both their good days and their bad days.  So on a scale of 100, this girl might have been 30/100.  On a bad day she was a major danger to herself and those around her and so she scored 100, but on a good day she was able to be part of the family and be educated.  She clearly had autism but not such a severe kind, so she might score a 30.

The point missed by the BBC was that in this example, electric shock therapy was not an autism therapy, it was an SIB therapy and it appears to have been a pretty effective one.

Many people with autism do not have flare-ups, they do not have SIB; they are pretty constant in their behavior, so they might be a constant 30/30.  

Cannabis 

Much is written on the internet about the use of cannabis for all kinds of conditions, the ones relevant to this blog are autism and epilepsy.  There is a study currently underway in Israel where they are using CBD oil, the non psychoactive part of cannabis, as an autism therapy.

As you might expect they had no difficulty recruiting people to participate in the study, which is still ongoing. 

Israeli Doctors to Use Cannabis to Treat Autism in First-of-its-kind Study

 In pioneering study, Israeli researchers target autism with cannabis 

Israeli Study Shows Medical Cannabis Can Treat Autism In Children

Dr. Aran is the Director of the Neuro-pediatric unit in Shaare Zedek Medical Center and his latest research involves treating the symptoms of autism using medical marijuana. “So far,” Aran tells NoCamels, “our impression is that it’s working.”

The clinical study began in January 2017 in Jerusalem at the Shaare Zedek Medical Center. There are 120 participants, including children and young adults, diagnosed with various degrees of ASD ranging from mild to severe. Dr. Aran hopes to have final results by December 2017.

According to Dr. Aran, “there are theories” for why medical cannabis can alleviate symptoms of autism, “but we don’t know exactly how. There are theories and models but we don’t know. It can’t be explained.”

This is worrisome given that cannabis is being given to children with little knowledge of why or how it may help. Of course, “We are worried with children because of the long-term impact. But it is considered mostly safe and we have already tested it with epilepsy.” Other studies, like the one published in Seizure: European Journal of Epilepsy 2016, conducted in Israel, successfully demonstrated that cannabis reduced the number of seizures of children with epilepsy. Nonetheless, Aran admits that “There are always worries that something will happen that we don’t know about.”

It is key to note that the participants are receiving cannabidiol (CBD), a non-psychoactive compound, as opposed to the more commonly known tetrahyrdrocannabinol (THC), which creates the “high” feeling. Therefore, the benefits they seem gain from the treatment “help the children cooperate more,” reduce behavioral problems, and “improve their functioning.”

While the study offers much hope for the children and families affected by ASD, Aran warns that “It won’t cure the symptoms, that’s for sure. It will never cure autism. But it certainly can help the quality of life of the families.” 

The lead researcher recently made some revealing comments, he suggested that the results so far are very positive and that it seems that the quality of life has been improved but it does not cure the symptoms. That made be draw the connection to the adopted child in the US; the therapy does indeed seem to be helpful because it is treating the “100” in the 30/100. So it may not improve cognition or reduce stereotypy, but it makes life better, just like the girl receiving the electric shocks.  Hopefully when they publish the results Dr Aran will be much more precise as to the effect of his therapy, since perhaps I am inferring too much from his comments. 

Why does any of this matter?

Well if you want to solve a problem, you have to define it and the more precisely you can define it, the more likely you are to find a solution.

If you have a girl who is a stable 30/30 with no SIB and no epilepsy, it might well be shown that neither electric shocks nor CBD oil will help here.

If you have a girl who is 30/100 with SIB and epilepsy it might well be the case that both electric shocks and CBD oil might help here; but it appears that neither will improve her core autism (which is the 30).

Mode of Action

Neither the doctors using electric shocks nor CBD oil claim to fully understand the mode of action. There are of course various plausible theories.

In the case of CBD it is an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been shown to act as a 5-HT_1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic, and neuroprotective effects of cannabidiol. It is an allosteric modulator of the μ- and δ-opioid receptors as well.  Cannabidiol's pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release.

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

  

Do the therapies “work”?

What we have seen in this blog to date is that there are very many things that do seem to help specific people.  It is sometimes hard to figure out for sure the mode of action; but if high doses of biotin, or vitamin B6, or anything else consistently improve someone’s condition over years of use you have to take note.

The electric shocks did indeed seem to successfully control SIB for 3-4 weeks.  Maybe someone clever might figure out the biological cause triggering her SIB and so provide an alternative  drug therapy, but for now it seems she will go once a month for more shocks.

There are people who think long term use of CBD oil will have negative effects and I guess monthly electric shocks may also have some unforeseen consequences.

The Israeli researchers seem pretty keen on pursuing CBD oil and so they may well end up with a large enough clinical trial to make people take notice.

I do not see hundreds of parents signing up to a clinical trial of electric shock therapy, so it looks likely to be a niche therapy used by one or two clinicians.

CBD oil is the sort of therapy that will appeal to many parents and it is being trialed on so many different people we will soon know if there are harmful long term effects.

  

My Take

It looks to me that electroconvulsive therapy is rather crude and while it does evidently help some people, it might not be without serious risk. If the person has uncontrollable SIB, it looks a risk worth taking.

Short term use of CBD oil looks a safer bet, but if the effect required is just calming/sedating there may be other ways to achieve this.  Many parents are already using CBD oil as a home autism therapy.

There are hundreds of clinical trials completed, or in progress, using CBD to treat everything from ulcerative colitis to anxiety. It is being trialed in schizophrenia and even Dravet Syndrome and other kinds of epilepsy.  There is even a trial of a CBD chewing gum to treat Irritable Bowel Syndrome. CBD actually now has designated orphan drug status with the FDA for Dravet Syndrome.

I have no plans to use either therapy; I seem to have addressed the variable nature of my case of autism.  I am more interested in treating the core autism symptoms, the “30” in the 30/100; it is clear that much more remains possible.  

Tackling the “30”

An interesting recent finding came from a study on Oxytocin at Stanford. This time researchers had the good sense to actually measure the level of the oxytocin hormone in the blood of the trial participants before and after they started having oxytocin squirted up their noses. 

Oxytocin improves social abilities in some kids with autism, Stanford study finds 

Not surprisingly it was people with low natural levels of oxytocin who were the favorable responders and interestingly those in the placebo group who also responded actually increased their natural level of oxytocin production.

As we know there are other ways to increase you level of oxytocin, one of which is via certain L. reuteri probiotic bacteria.

Oxytocin would fit in the tackling the “30” category, for those with naturally lower levels of this hormone.

The Stanford researcher is again Dr Hardan, from that interesting phase 2 trial of the antioxidant NAC.  He is now planning a larger oxytocin trial. Has he forgotten about making a phase 3 trial of NAC?   

Self Injurious Behavior (SIB)

You do wonder why some clinician does not compile a list of all the known causes and therapies for self-injurious behavior (SIB) in autism.  There is even a study planned at Emory University to test the efficacy of NAC to treat SIB, but with only 14 participants, I do not really see the point.

We do know that a small number of people with SIB respond well to NAC. If just 10% are responders, you would need a really large trial prove anything at all. With 14 participants you should have just one, but as luck might have it, it could be none.

With a more scientific/engineering approach you might identify five sometimes effective SIB therapies, and then go systematically through testing each therapy on each person with SIB. Then you would have some useful data.    

As I mentioned in a recent comment, the late Bernie Rimland from ARI, was a big believer in high dose vitamin B6 to treat SIB.  For some people it is a nicotine patch, for my son in summer it is an L-type calcium channel blocker.

The reality is that numerous complex dysfunctions can lead to SIB, but so do some simple things like untreated pain and inflammation, which could be from IBS/IBD or even tooth eruption/shedding or just tooth decay.

Refining Antioxidant (ROS & RNS) Therapy in Autism - Selenium and Molybdenum

Today’s post is about further refining antioxidant therapy.

As we saw in a recent post, oxidative and nitrosative stress is a very common feature of autism and is treatable with OTC products.

The cheapest antioxidant, N-acetylcysteine (NAC), looks to be the best one, but there are numerous others with exotic names and equally exotic prices.

Today we just look at selenium and molybdenum.  Selenium was on my to-do list for a long time because it affects some key enzymes call GP_X (glutathione peroxodases).

Molybdenum was enthusiastically recommended in a recent comment and this blog has previously touched on Molybdenum Cofactor Sulfurase (MOCOS).

Rather surprisingly, there is a commercial product that contains NAC, Selenium and Molybdenum. 

Selenium and GP_X (glutathione peroxodases)

There are eight different glutathione peroxodases, but GPx1, GPx2, GPx3, and GPx4 are all made from selenium.

GP_X speeds up the antioxidant reactions that involve glutathione (GSH).

In autism we know that both GSH and GP_X are lacking.

We know how to make more GSH, just take some NAC.  But what about the catalyst GP_X? 

There may be an equally easy way to increase that. 

Selenium and Thyroid  Enzymes

Selenium is also part of the three deiodinase enzymes D1, D2 and D3.

The active thyroid hormone is called T3, but most of what is circulating in your body is the inactive pro-hormone form called T4.

Deiodinase 1 (D1)  both activates T₄ to produce T₃ and inactivates T₄. Besides its increased function in producing extrathyroid T₃, its function is less well understood than D2 or D3.

Deiodinase 2 (D2), located in the ER membrane, converts T₄ into T₃ and is a major source of the cytoplasmic T₃ pool.  It looks like some people with autism may lack D2 in their brain.

Deiodinase 3 (D3) prevents T₄ activation and inactivates T₃. It looks like some people with autism have too much D3 in their brain.

D2 and D3 are important in homeostatic regulation in maintaining T₃ levels at the plasma and cellular levels.

·        In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T₃

·        in hypothyroidism D2 is upregulated and D3 is downregulated to increase cytoplasmic T₃ levels

Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis since T3 and T4 levels may vary by organ.  

It appears that some people with autism may have central hyperthyroidism, meaning in their brain.

Regular readers may recall this post:-

Central Hypothyroidism or Low Brain D2 Levels in Autism

The major source of the biologically active hormone T3 in the brain is the local intra-brain conversion of T4 to T3, while a small fraction comes from circulating T3. 

As evidence derived from in vitro studies suggests, in response to oxidative stress D3 increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010).  As we know in the autistic brain we have a lot of oxidative stress.

Furthermore, in ASD, the lower intra-brain T3 levels occur in the

Absence of a systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity of D3.

So in some autistic brains we have too much D3 which is inactivating T3 and preventing T4 being converted to T3.

Reduced D2 is reducing the conversion of T4 to T3. 

We would therefore want to increase D2 in some autism.

This can be achieved by:-

·        Reducing oxidative stress, which we are already sold on. 

·        We can also potentially upregulate the gene that produces D2 using some food-based genetic therapy. Kaempferol (KPF) appears to work and may explain why broccoli sprout powder makes some people go hyper and some others cannot sleep  

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF

·        Perhaps low levels of selenium differentially affect the synthesis of D1, D2 and D3?

  

Where does selenium come from? 

We know from Chauham/James that selenium levels are reduced in autism, but we also know that selenium levels vary widely by geography.  

You get selenium from your diet and the level of selenium in the soil varies widely.  It is widely held that most healthy people should have plenty selenium in their diet. 

In the following paper there is an analysis of Selenium status in Europe and the Middle East.

Since we have plenty of Polish readers I have included the chart with the Polish data (on the left).  It shows that Polish people may be a little deficient in selenium.

You can see the level of selenium in Poland is below that needed to optimise plasma GPx activity.

So if you already have reduced GPx activity, because of autism, and you really need to make the most of your limited glutathione (GSH) because you have oxidative/nitrosative stress, then a little extra selenium could be just what the doctor should have ordered.

  

A Review of Dietary Selenium Intake and Selenium Status in Europe and the Middle East

Se is an essential non-metal trace element [3] that is required for selenocysteine synthesis and is essential for the production of selenoproteins [4]. Selenoproteins are primarily either structural or enzymatic [2], acting as catalysts for the activation of thyroid hormone and as antioxidants, such as glutathione peroxidases (GPxs) [5]. GPx activity is commonly used as a marker for Se sufficiency in the body [6], where serum or plasma Se concentrations are believed to achieve maximum GPx expression at 90–100 μg/L (90.01 μg/L as proposed by Duffield and colleagues [7] and 98.7 μg/L according to Alfthan et al. [8]). However, plasma selenoprotein P (SEPP1) concentration is a more suitable marker than plasma GPx activity [9]. Prospective studies provide some evidence that adequate Se status may reduce the risk of some cancers, while elevated risk of type 2 diabetes and some cancers occurs when the Se concentration exceeds 120 μg/L [10]. Higher Se status has been linked to enhanced immune competence with better outcomes for cancer, viral infections, including HIV progression to AIDS, male infertility, pregnancy, cardiovascular disease, mood disorders [2] and, possibly, bone health [11–14].

  

Selenium and NAC for Rats with TBI

Perhaps not surprisingly, selenium and NAC have been found beneficial for Rats unfortunate enough to have sufferred a traumatic brain injury (TBI).

 N-Acetylcysteine and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats

It has been suggested that oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI). N-acetylcysteine (NAC) and selenium (Se) display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties although there is no report on oxidative stress, antioxidant vitamin, interleukin-1 beta (IL)-1β and IL-4 levels in brain and blood of TBI-induced rats. We investigated effects of NAC and Se administration on physical injury-induced brain toxicity in rats. Thirty-six male Sprague–Dawley rats were equally divided into four groups. First and second groups were used as control and TBI groups, respectively. NAC and Se were administrated to rats constituting third and forth groups at 1, 24, 48 and 72 h after TBI induction, respectively. At the end of 72 h, plasma, erythrocytes and brain cortex samples were taken. TBI resulted in significant increase in brain cortex, erythrocytes and plasma lipid peroxidation, total oxidant status (TOS) in brain cortex, and plasma IL-1β values although brain cortex vitamin A, β-carotene, vitamin C, vitamin E, reduced glutathione (GSH) and total antioxidant status (TAS) values, and plasma vitamin E concentrations, plasma IL-4 level and brain cortex and erythrocyte glutathione peroxidase (GSH-Px) activities decreased by TBI. The lipid peroxidation and IL-1β values were decreased by NAC and Se treatments. Plasma IL-4, brain cortex GSH, TAS, vitamin C and vitamin E values were increased by NAC and Se treatments although the brain cortex vitamin A and erythrocyte GSH-Px values were increased through NAC only. In conclusion, NAC and Se caused protective effects on the TBI-induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.

  

Dietary selenium stabilizes glutathione peroxidasemRNA in rat liver

  

And now to Molybdenum 

Molybdenum (Mo) is a trace dietary element necessary for human survival.

Low soil concentration of molybdenum in a geographical band from northern China to Iran results in a general dietary molybdenum deficiency, and is associated with increased rates of esophageal cancer.  Compared to the United States, which has a greater supply of molybdenum in the soil, people living in those areas have about 16 times greater risk for esophageal cancer.
So you would not want to have molybdenum deficiency.

Four Molybdenum-dependent enzymes are known, all of them include molybdenum cofactor (Moco) in their active site: sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and mitochondrial amidoxime reductase.

Moco cannot be taken up as a nutrient, and thus it requires to made in your body from molybdenum.

If your body cannot make enough Moco you may develop what is called molybdenum cofactor deficiency, which would ultimately kill you. It is ultra rare.

Symptoms include early seizures, low blood levels of uric acid, and high levels of sulphite, xanthine, and uric acid in urine.


When caused by a mutation in the MOCS1 gene it is called the type A variant.

Molybdenum cofactor deficiency may indeed be extremely rare, but MOCS1 is a known autism gene.  Perhaps there exists partial molybdenum cofactor deficiency, which is not rare at all?

Source:-  Identification of candidate intergenic risk loci in autism spectrum disorder

MOCOS (Molybdenum cofactor sulfurase)


Molybdenum cofactor sulfurase is an enzyme that in humans is encoded by the MOCOS gene.

MOCOS sulfurates the molybdenum cofactor of xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1), which is required for their enzymatic activities.

MOCOS is downregulated in autism and is suggested to induce increased oxidative-stress sensitivity, which would not be good.

So it looks like we need a clever way to upregulate MOCOS.

You need adequate molybdenum cofactor (Moco), for which you do need adequate molybdenum.

You need the genes MOCS1 and MOCOS to be correctly expressed.

SIRT1 activation, which is a future therapy for Alzheimer’s, is suggested to increase MOCOS, as may NRF2.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are molecules able to prevent aging related diseases like Alzheimer's, diabetes, and obesity.  There is quite a long list that includes ranges from polyphenols such as resveratrol, the flavonols fisetin, and quercetin also butein, piceatannol, isoliquiritigenin,

Fisetin is found in strawberries, cucumbers and supplements.  In normal animals, fisetin can improve memory; it also can have an effect on animals prone to Alzheimer's.

Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice

Here is the excellent French paper on MOCOS:-

Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.  

Lately, a diminished seric expression of glutathione, glutathione peroxidase, methionine and cysteine has been highlighted in a meta-analysis from 29 studies on ASD subjects.⁴⁵ Along this line, purines and purine-associated enzymes are recognized markers of oxidative stress. ROS are generated during the production of uric acid, catalyzed by xanthine oxidase and XDH.⁴⁶ Conversely, uric acid is nowadays recognized as a protective factor acting as a ROS scavenger.^{47, 48} Interestingly, allopurinol, a xanthine oxidase inhibitor, was found efficient in reducing symptoms, especially epileptic seizures, in ASD patients displaying high levels of uric acid.⁴⁹ However, in our cohort, only 3 out of 10 patients exhibited an abnormal uric acid secretion. It can therefore be postulated that still unknown other MOCOS-associated mechanisms may have a role in the unbalanced stress response observed in ASD OSCs.

Identifying and manipulating downstream effectors of MOCOS will be the next critical step to better understand its mechanisms of action. In parallel, we plan to ascertain some of its upstream regulators. For example, bioinformatic analyses revealed that the promoter region of MOCOS includes conserved binding sites for transcription factors such as GATA3 and NRF2. In addition, other putative interactors, such as the NAD-dependent deacetylase sirtuin-1 (SIRT1), may have a regulatory role on MOCOS expression. Interestingly, these three genes have been associated with ASD, fragile X syndrome, epilepsy and/or oxidative stress.^{54, 55, 56, 57} In conclusion, our study opens an unexplored new avenue for the study of MOCOS in ASD, and could set bases for the development of new diagnostic tools as well as the search of new therapeutics.

Conclusion

It looks like a little extra selenium may be in order to increase those GPx enzymes that are need to speed up aspects of the antioxidant activity of GSH.

When it comes to molybdenum, things get much more complex. You certainly do not want to be deficient in molybdenum and you do not want Molybdenum cofactor deficiency; you also do not want molybdenum cofactor Sulfurase (MOCOS) mis-expression.

It is fair to say that quite likely there is a problem related to molybdenum that affects oxidative stress in autism; but it is not yet clear what to do about it.  I rather doubt the solution is as simple as just a little extra molybdenum, but it is easy to try.

On the plus side, we see that if you have autism, epilepsy and high uric acid you are likely to benefit from allopurinol, which also seems to help in COPD.

There is nothing new about allopurinol possibly be effective in some autism, as from this 25 year old book, Diagnosis and Treatment of Autism.

Again we see that activating NRF2 looks a good idea, that applies to both autism and COPD.

One thing to note is that NRF2 activators are good for cancer prevention, but if you have a cancer you want NRF2 inhibitors.

NRF2 activators include sulforaphane (SFN), R-alphalipoic acid (ALA), resveratrol and curcumin.  SFN is by far the most potent.  Resveratrol and curcumin have a problem with bioavailability.

Preventing Auto-Immune Disease and some Autism

Today’s post is another one filling in some gaps in this blog.

I think it is common sense to say that preventing a problem from developing is much wiser than trying to solve it later on.  This is a recurring issue in both life and medicine.

In the research we now see preventative measures developed to reduce the risk of cancer, we also see how some interventions are only effective when started very early.

In the case of autism we have seen than often it is caused by a myriad of factors that by themselves might have been harmless but when taken together are the multiples hits that caused the brain to develop differently.

Much research looks individually at these factors that increase the risk of autism.  In the wider media much disdain is directed to these findings as if each factor is THE cause of autism and how can so many things cause autism.  But by understanding these factors you can then set about countering them.

I did create my simplified schematic to explain classic autism a while back.  It is not perfect but it does illustrate much of what is going on.

I do get occasional questions about reducing the risk of autism.  For example, Monty now aged 13 with ASD, has a big brother and he wants to know.  Our reader, Kritika from India, has also raised this issue.  If you have autism in your family you may well decide you would like to minimize the risk of more cases.

In practical terms, you cannot change your genes or those inherited epigenetic markers.  Maybe this will change in future.  But there are things you can do.

We know that oxidative stress is a driver of much disease including autism.  This can be minimized by lifestyle changes and indeed with a little pharmacological help.

I was interested to see a study that used NAC to treat mothers who suffer unexplained pregnancy loss, the antioxidant showed a “significant increase in the take-home baby rate”.  I was really just looking for safety information.

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss 

Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.

This then made be recall a US fertility clinic, that our reader Roger once mentioned in a comment.

http://www.preventmiscarriage.com/

http://www.preventautism.com/

“At Braverman Reproductive Immunology, we believe Autism Spectrum Disorder (ASD) and various pregnancy and infertility complications (listed below) appear to have the same cause. In fact, we have found that a large number of patients who present to our center with the below complications already have a child with ASD.

This discovery started us on the journey to see if ASD itself could be prevented while treating other associated conditions. We believe treatment for these common issues will not only prevent the pregnancy complications listed below, but may also prevent ASD in the group of patients that have already had a child with ASD.”

Dr Braverman does not mention oxidative stress, but perhaps he should.

So step one would be to reduce oxidative stress during pregnancy, via lifestyle changes and taking antioxidants.

Step two would be to avoid inflammation, Dr Braverman refers to the link to auto-immune disease and miscarriage/autism.

We know that maternal inflammation is one of the easiest ways to cause autism in mouse models (the MIA model - Maternal Immune Activation).

  

We have some research to show that the risk of auto-immune disease can indeed be reduced and indeed that the risk of progression from minor to more major auto-immune disease can also be minimized.

We even have a tiny study showing that immuno-modulatory therapy using a probiotic during pregnancy can reduce incidence of ADHD and autism. For me ADHD is just a case of autism-lite.

A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial

Background:

Recent experimental evidence suggests that gut microbiota may alter function within the nervous system providing new insight on the mechanism of neuropsychiatric disorders.

Methods:

Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.

Results:

At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.

Conclusion:

Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.

The issue, as with NAC during pregnancy, is whether immuno-modulatory therapy is safe.

The study on ADHD and autism was actually a study looking at whether a certain probiotic if given during pregnancy could reduce eczema later on in the child.

  

We also have the studied effect of having a pet dog at home.

House dust exposure mediates gut microbiome Lactobacillus enrichmentand airway immune defense against allergens and virus infection

 

Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response.

One of my views is that by early treatment of autism you may indeed reduce the risk of epilepsy.  The key here is “reduce the risk”, it does not mean there is no risk.  There are likely hundreds of causes of epilepsy, but if you can reduce the incidence by 30+% that would look like a big success to me.

I recall another study that looked at treating people with eczema to see if you could reduce the chance of progression to asthma.  Using Ketotifen the trial showed that it was indeed possible.

Prevention of asthma by ketotifen in infants with atopic dermatitis. 

To evaluate the prophylactic effect of ketotifen against the onset of asthma we selected 121 infants with atopic dermatitis, without any history suggestive of asthma (cough and/or wheezing). Sixty-one children received ketotifen twice daily. Those who weighed less than 14 kg received 0.8 mg; 14 kg or more, 1.2 mg. Sixty children, a placebo syrup indistinguishable from the active syrup. Both groups were followed for 1 year, with bimonthly evaluations. The criteria for onset of asthma were two different episodes of wheezing treated with bronchodilator drugs. Both groups were comparable regarding age, sex, weight, onset, and duration of atopic dermatitis and age at the onset of asthma. During the 1 year study, asthma was observed in eight children of the ketotifen group (13.1%) and in 25 children of the placebo group (41.6%) (P less than .001). Side effects were negligible and routine laboratory tests disclosed no significant alterations. Ketotifen is a very useful drug for prevention of asthma in children with atopic dermatitis and total IgE more than 50 IU/mL.

Somali Autism Clusters

This then takes me back to that issue I looked at long ago, which was the reason for the Somali immigrants to Sweden and US having so many children with autism.  This even got termed the Swedish Disease by the migrants, they claimed to have never seen autism back home in Somalia.

Then we have the hygiene hypothesis which in effect says that, within limits, a little dirt is good for you.

Hormonal Dysfunction

We know that gestational diabetes increases the risk of autism and we also known that the mother being hypothyroid increases the risk.  In some cases the hormone dysfunction is a consequence of the auto-immune dysfunction.

We also know the female hormone progesterone is extremely neuro-protective.  The level of this hormone is supposed to rise during pregnancy.

  

In past times hormones were given to some pregnant mothers, but this went out of fashion.  Perhaps this should be revisited?

Then we have the surge of the hormone oxytocin that the baby is supposed to receive at birth.  This surge may be relevant to the GABA switch when shortly after birth this neurotransmitter is supposed to switch from excitatory to inhibitory as the neurons mature. If the baby is born by Caesarian there will be no oxytocin surge for the baby.   

Preventing Regressive Autism Secondary to Mitochondrial Disease (AMD)

It is on open secret that doctors at Johns Hopkins have identified a variant of regressive autism called Autism secondary to Mitochondrial Disease (AMD).

It remains unclear how rare this is and absolutely nobody serious is going to research this, if they ever want to receive a research grant in the future.

We saw that in people with a genetic predisposition to mitochondrial dysfunction, an immune over-reaction to an insult like multiple vaccinations can trigger mitochondrial disease.  This will present itself as autism and quite possibly severe autism in a previously unaffected child.

Those doctors treating AMD use mild immuno-suppressing drugs before any future vaccinations.

How do you minimize the chance of AMD? 

The first thing is to never use paracetamol/acetaminophen in a baby or child, particularly just after vaccination.  This drug may kill the pain but it depletes GSH the body’s main antioxidant, just when it needs it most.   Use something like Ibuprofen.

Vaccines are given in multiples so as to save time and money and I suppose improve compliance. You might expect giving them one-by-one would actually make them more effective as well minimizing any collateral damage to a small percentage of kids.

Conclusion

As I keep reminding readers, I am not a doctor, but it would be nice if a few more doctors other than Braverman took preventing autism seriously.

I would like to know if progesterone is an effective therapy in the MIA model of autism.  In this model they trigger the mother’s immune system during pregnancy which leads to offspring with autism.  What would be the effect of giving progesterone?  Would it protect the pups?

Are progesterone levels reduced in mice that will become autistic?

So I suppose I would trial NAC and progesterone in the mother mouse.

For everyone else it is case of choosing whether or not to make lifestyle changes to reduce oxidative stress.  Improving gut bacteria can be done via probiotics, eating more (slightly dirty) fruit and vegetables, having a pet dog, spending some time in the nature.  

As for vaccine risk, however small it might indeed be, there will never be a serious investigation of this, for understandable reasons.