Potassium Bromide for Intractable Epilepsy and perhaps some Autism

Potassium Bromide has been on my to do list ever since I read a case study about Ida, a girl with epilepsy and non-verbal autism being treated at London’s Great Ormond Street Hospital 150 years ago.  Of course, the doctor not did not use the term autism, but it was obviously present.  

What I took away was not the resolution of her seizures but her behavioral change and most importantly the initiation of age-appropriate play.

Later I read a Brazilian paper called “Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures”.

My first toe in the water in treating my son’s autism was to use Bumetanide.  That trial was successful and ever since I have looked at ways of increasing this bumetanide effect.

Bumetanide partially blocks the flow of chloride (Cl-) into neurons and over time lowers the concentration towards where it should be, in typical mature neurons.  This allows the neurotransmitter GABA to function as it should and brings back neurons into a less excitatory state and hence gives better cognitive function.

Other ideas to further lower the level of chloride included using the AE3 ion exchanger and so I proposed the possible use of Diamox.

It might also be possible to increase the expression of KCC2, the transporter that takes chloride out of neurons; this might be achieved using intranasal insulin or indeed IGF-1.

Yet another theoretical method might be to introduce bromide and allow it to compete with chloride.  We know that Br^– ions cross cellular membranes more quickly than Cl^–. So by adding bromide we should automatically reduce chloride concentration within neurons.

Medical use of Potassium Bromide

It is surprising how medicine varies so much by country.  One example is the continued use of potassium bromide (KBr) to treat childhood epilepsy in Germany, Austria and Japan.

It is currently used to treat severe forms of generalized tonic-clonic seizures, early-childhood-related Grand-Mal-seizures, and also severe myoclonic seizures during childhood.

KBr was the world’s first epilepsy drug and its use was pioneered by Sir Charles Locock in 1857.  It is still the first-line treatment for treating epilepsy in dogs, but no longer in humans.

Due to a very long half-life, it takes a month of use to reach a stable level, so in the earlier years it is likely that un-necessarily high doses (up to 6g per day) were used.  This led to side effects.  The modern dosage is 50 to 70 mg/kg in infants and toddlers, 30 to 50 mg/kg in school children and 20 to 30 mg/kg in adults.  Tolerability of bromide treatment is much improved.

It is possible to start therapy with a loading dosage to overcome the problem of the long half life, but I expect this just increases the chance of side effects.

My thought was that at a lower concentration than prevents seizures, bromide might still be effective in some autism that responds to bumetanide.  At such a dosage the side effects that occur in German epilepsy therapy might become trivial.

The main side effects are usually drowsiness (19%) and acneiform skin eruption (13%) at the 50mg/kg dosage.  I was thinking that at a quarter of this dose you might get the good without the bad.

If you have one of the many kids with autism and intractable epilepsy then you might as well follow the standard dosage and just accept the risk of some spots.  After all, the standard anti-epileptic drugs (AEDs) all have side effects and we are not just taking about spots.

Interestingly, while KBr does not interact directly with other AEDs, it is found in Germany that previously ineffective AEDs can become effective when the person is given KBr.  There are various theories to explain this.  As a result KBr look doubly useful for intractable epilepsy.  

Dravet Syndrome

KBr seems to be particularly effective in people with SCN1A-mutations suffering from Dravet syndrome.  You may recall that Professor Catterall trialed his low dose clonazepam therapy in the mouse model of Dravet syndrome.  German and Austrian clinicians have shown that KBr is highly effective in treating seizures in the human form of Dravet, while a Japanese retrospective analysis of 99 patients which found complete prevention of status epilepticus in 41.7% of patients receiving bromide.

Mode of Action

Nobody knows exactly why KBr is effective in epilepsy, but that also applies to many other AEDs.

The Brazilian view is:-

“bromide may exert antiepileptic activity not only because of its reinforcement of the Cl^– hyperpolarizing Nernst potential, but also because of its low affinity for the NKCC enzyme in comparison with Cl^– . In summary, bromide's antiepileptic effect may be divided into three parts: (1) compensation of Cl^– accumulation by means of its hyperpolarizing effect on chloride channels; (2) antagonism of chloride flow through the channels because of its competition with chloride; (3) low affinity for the NKCC enzyme”

That paper is:-

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

The German view is:-

“While the exact mode of action of bromide is still unknown, the most acceptable hypothesis besides an inhibition of carbonic anhydrase is stabilization of excitable membranes through hyperpolarization of neurons. Bromide crosses cellular membranes more quickly than chloride, enhancing

GABA-activated inhibitory postsynaptic potentials and leading to hyperpolarization. Not only GABA-activated chloride channels are more permeable to bromide, but also voltage dependent channels. Studies using combined rat hippocampus-entorhinal cortex slices showed that bromide reduced or even blocked low calcium and low magnesium induced recurrent discharges, including the low magnesium induced late recurrent discharges which do not respond to most clinically used anticonvulsants. This mechanism might explain why our patients who previously did not

improve with various other antiepileptic drugs responded to treatment with bromide.

The above is from one of many good German papers on KBr :-

Bromidein Patients with SCN1A-Mutations Manifesting as Dravet Syndrome

Intractable Epilepsy

About one-third of people with epilepsy will eventually develop intractable epilepsy. This means that standard anti-epileptic drugs (AEDs) do not work well, or at all, to control the seizures.

Intractable epilepsy can have a big effect on life. People with intractable epilepsy may have trouble at work or school. They may worry a lot about when their next seizure will come. They may also have injuries that result from their seizures.

In the case of the 30+% of people with strictly define autism (SDA) and epilepsy things can get particularly difficult and depend a great deal on where you live.

In the US some children with severe autism and recurring seizures can still be collected from home by the school bus and dropped back at the end of the day.  Not only do they have qualified nurses at school to deal with any seizures but even the bus has a nurse.

I was just reading about a teenage girl in the UK who no longer attends school at all because she may have a seizure.  The irony here is that the girl has been to the county’s top children’s hospital, Great Ormond Street.  Had she been there one hundred and fifty years ago she would have been prescribed KBr.  Had she attended a hospital in Innsbruck or Salzburg, Austria this year she would very likely also have been prescribed KBr.

The literature supporting the use of KBr is published in the English language and so there is no excuse for epilepsy experts not to be aware of it. Both the US and the UK have provisions in place where clinicians can apply to treat patients with non locally approved drugs.  So there is nothing to stop a neurologist or epileptologist in the US or UK from using KBr if he really wants to.  He just has some extra paperwork.  The simpler solution if you have intractable epilepsy might be to pay a visit to Germany, Austria or indeed Japan. Or you go see the vet.

Conclusion

This blog does not have many German/Austrian readers, in fact for a condition “invented” by Austrians (Kanner and Asperger) there is very little coming out of that part of the world nowadays.

German/Austrian parents would be the ones best placed to see the effect of KBr on intractable epilepsy and perhaps some autism.

Any readers that do try potassium bromide are very welcome to share their experiences.

Quantifying the Benefits of Stimulation over Neglect in Early Childhood

Today’s post is about the Bucharest Early Intervention Project (BEIP), which really deserves a mention somewhere in any autism blog.  It has been going for many years but they recently added some very tangible MRI data.

BEIP is a long term study lead by Charles Nelson, a professor of neuroscience and psychiatry at Harvard Medical School.  It compares the effect of neglect versus stimulation in early childhood.

You may be wondering the relevance of this to autism, in particular since Kanner’s old theory about refrigerator mothers was debunked long ago.

The study shows how physical development of the brain can be altered by the living environment of a young child.  It reinforces the fact that institutionalized of young children, with or without developmental disorders, is precisely the wrong strategy.

Bucharest Early Intervention Project (BEIP)

The Bucharest Early Intervention Project was a randomized controlled trial of foster care as an intervention for children abandoned at or around the time of birth and placed in one of six institutions for young children in Bucharest, Romania.

The BEIP began in 2000 with a comprehensive baseline assessment of 136 children and their caregiving environments. Following this assessment, half the children were randomly assigned to high-quality foster care (designed specifically for this study) and the other half to remain in institutional care. The average age at entry into foster care was 22 months (range=6-31 months). All children were seen for follow-up assessments at 30, 42 and 54 months, 8 years, and 12 years, and the development of children in foster care was compared to the development of children randomized to remain in institutional care and to a group of never institutionalized children (community controls). 

Findings through the assessment at 12 years of age suggest that early institutionalization leads to profound deficits in many domains examined to date, including cognitive (i.e., IQ) and socio-emotional behaviors (i.e., attachment), brain activity and structure, alterations in reward sensitivity and processing, and a greatly elevated incidence of psychiatric disorders and impairment. 

  

The foster care intervention was broadly effective in enhancing children’s development, and for specific domains, including brain activity (EEG), attachment, language, and cognition, there appear to be sensitive periods regulating their recovery. That is, the earlier a child was placed in foster care, the better their recovery. Although the sensitive periods for recovery vary by domain, our results suggest that placement before the age of 2 years is key.

  

There are a few areas, such as executive functioning (i.e., memory and cognitive monitoring), in which placement into foster care does not significantly impact development/performance. 

In 2015 another paper was published.

BEIP initially enrolled 136 children in research. Only 69 were involved in the MRI study, of these, 23 were drawn from the group randomly assigned to foster care, 26 from a group assigned to remain in orphanages, and 20 from the local community, as controls. Lead author Johanna Bick, a clinical psychologist at the Boston Children’s Hospital, and colleagues in the BEIP group used an MRI technique called diffusion tensor imaging to look at the microstructure of 48 white matter tracts in each child, comparing results at 2 years and 8 years of age.

The analysis found that the children who stayed in orphanages were consistently worse off—with less mature development in four key sets of white matter. The most affected tracts included nerve circuits involved in general cognitive performance, emotion, maintaining attention and executive function, and sensory processing. Another analysis suggested that the foster care group was more like the community group in brain development, but this finding appears to be less robust.

Other nonrandomized studies have reported broad cognitive deficits or reduced white matter in adults and some children who suffered neglect or maltreatment in the past. They highlighted "the same regions that we find affected by early life neglect. These results and those from BEIP converge," Bick claims.

Four estimates of white matter integrity (Fractional Anisotropy, and Mean, Radial, and Axial Diffusivity) for 48 white matter tracts throughout the brain were obtained through Diffusion Tensor Imaging.

Significant associations emerged between early life neglect and microstructural integrity of the body of the corpus callosum and tracts involved in limbic circuitry (fornix crus, cingulum), fronto-striatal circuitry (anterior and superior corona radiata, external capsule) and sensory processing (medial lemniscus, retrolenticular internal capsule). Follow up analyses revealed that early intervention promoted more normative white matter development among previously neglected children who entered foster care.

Results suggest that removal from conditions of severe early life neglect and entry into a high quality family environment can support more normative trajectories of white matter growth. Findings have implications for public health and policy efforts designed to promote normative brain development among vulnerable children.

The BEIP study started ten years after the fall of communism in Romania, when the outside world became aware of life inside their orphanages.  As childless couples from the West started to adopt Romanian orphans it became clear that there was a very high prevalence of autism and other disorders.

Romania had been a country under extreme communism with a dictator, Nicolae Ceaușescu, but his official tittle he was General Secretary of the Romanian Communist Party, from 1965 to 1989.  He had some very particular ideas.  He wanted to encourage large families so both abortion and contraception were banned.  He did not like the idea of foreign debt and in his later years decided to pay down the nation’s debt as a matter of urgency.   In 1982, to be rid of foreign debt, Ceaușescu ordered the export of much of the country’s agricultural and industrial production. What followed was extreme poverty and people did not have enough food.  Excess children were deposited at the orphanage because there was no food to feed them at home.  So Romania developed a totally oversized orphanage system, that was itself extremely poorly funded.  Children were often totally neglected, left unclothed, some chained to their beds and given no stimulation.  Older children beat younger children.  All kinds of children ended up in orphanages and most had living parents.  Even after the Revolution of December 1989 which ended with Ceaușescu  and his wife being executed by firing squad, things did not improve very much, due to the dire state of the economy.  Foreigners later started to adopt children from Romania’s orphanages.

Nelson did not go to Bucharest to study autism, he went to study the consequences of neglect and to see if those consequences could be reversed.

The studies do show how a warm stimulating environment can reverse some physical brain malformations, but most effectively intervening before the age of two.

There are clear parallels with autism where some children effectively exclude themselves and when great efforts are made to engage with them using any one of a variety of therapies from Floortime, to Son Rise to ABA, great progress can sometimes be made.

When my own son was diagnosed aged 3.5 years, the developmental pediatrician told me that there was no way to predict his outcome, because up to the age of 5 years old the brain can develop remarkably.  She sees very many such children.

In the parts of the US autism diagnoses is possible before the age of 2 years old.  It would be useful if clinicians routinely carried out MRI scans of such children and the tracked their development keeping a note of what therapy the parents implemented.  Then we might see whether there were indeed defects in the microstructural integrity of the body of the corpus callosum and tracts involved in limbic circuitry and in which children these defects reduced in later years.

Monty’s new assistant was just telling me how she went to a Floortime seminar, but there was nothing much new in it and she will instead continue with he plans to study ABA.  There are so many of these therapies, the most ridiculed one is Son Rise.  My conclusion a long time ago was that it does not matter which of these “hands on” interventions you follow, you just need to be animated, energetic and engage with the child in an intensive fashion all day and every day.

A child with severe autism is trying to do the opposite, preferring to sit in a swing or watch videos all day.  This is hardly more stimulating than the Romanian “orphan” neglected in his dormitory with twenty other boys.

Just as Nelson has shown that normal babies can be made to develop brain abnormalities by their living environment and that these abnormalities can be reversed by changing their living environment, we need to know to what extent similar brain abnormalities exist in some autism and whether they are reversible, in some cases, by intense Mary Poppins-like intervention.  I suspect this is indeed the case.  If people with autism were routinely monitored this would be easy to prove one way or the other.

If the parents of the two year old, just diagnosed with autism, were told the child was in the 20% group that has some structural brain anomalies that are known to be partially reversible by some extreme Mary Poppins-like intervention, they probably would do something about it.

In fact all kids would benefit from a Mary Poppins, but perhaps some much more so than others.

Monty had his own Poppins, his full time assistant, for several years and she achieved what had seemed impossible.  I really do not believe many parents can achieve this themselves, unaided.  All day long, providing a stimulating, educative, one on one environment is a huge task. Doing it for one hour a day is not enough.

   

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.

Performances

Nearly all parents like to see their children performing on stage.  

This week I attended two very different performances.

The first was a play organized by my son Monty’s piano teacher; we came along to show support.  She organizes numerous events for children with special needs, she includes people with Asperger’s and all kinds of autism; some have an assistant on stage to support them and some do not.  One was in a wheelchair. She also includes some typical kids in the more demanding roles.  

As expected there were big smiles all around, happy performers and happy friends and family in the audience.  They have several repeat performances.

A couple of days later was another performance, this time Monty’s big brother was performing at the school poetry night.  Here again, the students were performing in front of the assembled parents.  As usual it was poems in a wide variety of languages, from Russian to Indonesian to Swedish.  Some students were showing off by reciting in their third or fourth language.

On the one hand the two performances were very different, because of the different level of ability, but in other ways it shows how everyone enjoys the chance to perform with their friends.

I don’t see Monty enjoying reciting poetry up on the stage, but he would happily play his piano.

Big brother clearly enjoyed reciting his poem in German and next year he will probably choose Russian. While little brother will likely always struggle with spoken language, big brother now speaks five languages.  But he probably would not enjoy having to play the piano up there on stage.

Each to his own and as the student presenter of the poetry night commented, “it beats sitting at home”.

Agenesis of the Corpus Callosum

Today’s post is about another supposedly rare cause of autism called Agenesis of the Corpus Callosum (ACC).

As regular readers of this blog will have noted, extremely rare causes of autism, taken as a group are not so rare after all.  In fact it seems that autism is just a very large collection of somewhat rare biological conditions. 

Of the very few "Autism Dads" I have had a face to face conversation with, one has a child with ACC and another has a son with the even rarer Sotos syndrome. Sotos syndrome is characterized by gigantism, mild ID/MR and often autism. Mutations in the NSD1 gene cause Sotos syndrome

ACC is physical malformation of the brain that shows up clearly on MRI scans and potentially shows up on the mother’s regular ultrasound scans. 

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.

Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.

ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.

Symptoms of ACC  vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.

It is suggested by many that a diagnosis of ACC is not compatible with a diagnosis of autism; this just shows a lack of understanding.

Autism is just a description of behaviors, ACC is a biological diagnosis, like Fragile X syndrome or Down Syndrome.  So if a person has autistic behaviors caused by ACC, it is still autism, it is just autism with an explanation of its origin.

The most famous person with ACC was Kim Peek who was the inspiration for the character played by Dustin Hoffman in the well-known film Rain Man.

In addition to having the physical ACC malformation it has been suggested that the cause of ACC in his case was likely FG Syndrome.

Most mutations that cause FG syndrome can be found in the MED12 gene. However, mutations have also been found in FMR1, FLNA, UPF3B, CASK, MECP2, and ATRX genes. Mutations on these different genes lead to the different types of FG syndrome, all with similar characteristics.  Congenital heart defects are common and Peek died of a heart attack aged 58, outlived by his father.  

Agenesis of the Corpus Callosum and broader Autism

Undoubtedly there are people diagnosed with autism, who have undiagnosed ACC, since they never had an MRI scan.  Just like there are many people with autism who have an undiagnosed, but treatable, Chiari “brain hernia”.

It also appears that having a smaller corpus callosum, but falling short of what would be diagnosed as ACC by the MRI scan, is a feature of some people’s autism. You could consider it as partial ACC, like we had partial biotin/biotinidase deficiency.

A very recent paper from the 2016 Society for Neuroscience annual meeting suggested one reason why autism is more prevalent in males.  The study looked at infecting pregnant rats with group B streptococcus to activate the mothers immune system.  Inflammation was then triggered in the fetal side of the placenta, but only in male fetuses.

The males go on to develop brain and behavioral features reminiscent of autism.

Female fetuses were somehow protected and developed normally.  Hopefully Barons Cohen will read this and stop looking for undiagnosed females with autism. There are many good reasons why autism is less prevalent in females, and they are not just “better at hiding it”, as the so-called expert claims. 

 Placenta may hold clues to sex bias in autism

What is interesting is that in the male pups with “autism” they had an unusually thin corpus callosum. It turns out that such minor malformations occur in broader human autism. 

Lack of corpus callosum yields insights into autism

Autism May Involve A Lack Of Connections And Coordination In Separate Areas Of The Brain, Researchers Find

The largest of the white matter tracts is known as the corpus callosum, which allows communication between the two hemispheres (halves) of the brain.
"The size of the corpus callosum was smaller in the group with autism, suggesting that inter-regional brain cabling is disrupted in autism," Dr. Just said.

In essence, the extent to which the two key brain areas (prefrontal and parietal) of the autistic participants worked in synchrony was correlated with the size of the corpus callosum. The smaller the corpus callosum, the less likely the two areas were to function in synchrony. In the normal participants, however, the size of the corpus callosum did not appear to be correlated with the ability of the two areas to work in synchrony.

"This finding provides strong evidence that autism is a disorder involving the biological connections and the coordination of processing between brain areas," Dr. Just said.

Atypical development of white matter microstructure of the corpus callosum in males with autism: a longitudinal investigation.

CONCLUSIONS:

These longitudinal results suggest atypical early childhood development of the corpus callosum microstructure in autism that transitions into sustained group differences in adolescence and adulthood. This pattern of results provides longitudinal evidence consistent with a growing number of published studies and hypotheses regarding abnormal brain connectivity across the life span in autism.

Comments on this study

The study suggests that white matter abnormalities manifest early in autism, says Thomas Frazier, director of Center for Autism at the Cleveland Clinic in Ohio. “It also serves as a nice demonstration that brain abnormalities in autism will become clearest and most helpful for pointing to etiology when we look at them developmentally, longitudinally, rather than at a single age," he says.

The findings do not imply that corpus callosum abnormalities cause autism, cautions Ralph-Axel Müller, professor of psychology at San Diego State University, who was not involved with the work. Rather, any irregularities in the corpus callosum may stem from other abnormalities in the brain that have been associated with autism, Müller says.

Still, changes in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others, Travers says. "Is there some aspect of white matter micro-structure occurring early in the developmental pathology that locks in persistent autism across the lifespan? What are the mechanisms? Can they be unlocked?” she says. “These will be important questions for future research.”

  

Conclusion

It is estimated that at one in 4,000 individuals has a disorder of the corpus callosum. I suspect it is more, but you would need to routinely give MRI scans to people diagnosed with autism to find out.

It is clear that milder disorders of the corpus callosum may be a feature of many people’s autism and those changes over time in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others.

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.