Time to update the Autism Polypill?

It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.

However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.

I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.

The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.

Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.

A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.

The broccoli sprout powder already in the Polypill is a rich source of kaempferol.

Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   

KBr

The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.

In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.

It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.

In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K⁺ and the Br^-.

Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br^- in your body.  Only then can you judge whether you are a responder or not. 

What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.

Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.

Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.

I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.

L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.

Enhancing the effect of Bumetanide in Autism

Many readers of this blog, and some of those who leave comments, are using the Bumetanide therapy proposed by Ben-Ari and Lemonnier.

At some point it should become an approved autism drug and Ben Ari has already patented it for use in Down Syndrome, so I guess that will come later on.

I have been developing my own add-on therapies that might help people for whom a high level of intracellular chloride is part of their autism, or indeed Down Sydrome.  If Bumetanide has a profound impact on your autism, this is almost certainly you.

Monty, aged 13 with ASD

After 4 years of Bumetanide, it continues to be effective and if Monty stops taking it there is a gradual cognitive decline over a few days, presumably as chloride concentration gradually increases.

In spite of an odd temporary Tourette’s type verbal tic that developed after an infection before Christmas, I have been getting plenty of feedback that Monty has got cleverer in 2017.  So it looks like some bumetanide add-on does indeed work.

The Colosseum

Monty’s big brother continues to be a fan of Lego and indeed Nanoblocks from Japan.  Nanoblocks is like extremely small Lego.

Having completed the Colossuem, his latest Nanoblocks model, he asked Monty “where is it?”.

Back came the answer, unprompted, “Italy”.

This was a big surprise.

That was not the answer big brother expected, he expected no answer or a silly answer like “over there”.

Add-ons

The first is potassium bromide (KBr) which was the original epilepsy therapy 150 years ago.  One of its effects is that the bromide (Br^-) part competes with chloride (Cl-) to enter neurons and bromide is known to be faster.  As a result some of the chloride inside cells is replaced by bromide.  Bromide is extremely similar to chloride, but is not reactive; this is why it can be used with any anti-epileptic drug (AED) without fear of negative interactions.

KBr has an extremely long half-life, meaning that if you take it every day it will take 4-6 weeks to reach its stable level in your body.

KBr is used for pediatric epilepsy in Germany and Austria and for epilepsy in pet dogs all over the world.  

A dose of 8mg/kg is far below the dose used for epilepsy, but does have a bumetanide enhancing effect in one 50kg boy.

The even more recent add-on is based on the experience of our reader Petra’s son with Asperger’s, who found that taking his bumetanide with Greek coffee seemed to make it more effective.

It turns out that dopamine is known to increase the effect of diuretics on the chloride cotransport NKCC2 in your kidneys.  There is a myth that coffee is a diuretic, but it is clear where this myth has come from.  Coffee will increase diuresis and so does caffeine.

In the brain it is the chloride cotransporter NKCC1 that is also blocked by bumetanide.  So it would be plausible that dopamine/coffee/caffeine it might have the same effect on NKCC1 as it does on the very similar NKCC2.

The cheap and widely available 50mg caffeine tablets do seem to serve as a proxy for a steaming cup of Greek coffee.  Indeed 50mg of caffeine is more like a weak cup of instant coffee.

I did much earlier propose the use of Diamox/ Acetazolamide to reduce chloride.  It seems that in some neurons 2/3 of the chloride enters via NKCC1 and 1/3 via the exchanger AE3.  Diamox/ Acetazolamide works via AE3.

Diamox has some other ion channel effects, making it useful in some epilepsy.

Some readers of this blog use Diamox, but in Monty it seems to cause reflux.

Caffeine is a very simple add-on to try.

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.