The Benefit of Defining Severity in Autism

We have seen in this blog that many hundreds of different dysfunctions can lead to symptoms broadly diagnosed as autism.  At the same time, the boundary at which people seek to medicalize behavioral problems continues to shift (more ADHD, more autism etc.), making it now hard to know what people mean by “autism”.

Rather than grading autism severity 1, 2 or 3, which is the new clinical practice under the American psychiatrists’ DSM5, my scheme might be more useful, since it would also show the variability of the symptoms.

I would rate “autism” on a scale of 1 to 100, but would state typical and peak values.  This could be established via an intelligent questionnaire given to parents and teachers.  It certainly would remain subjective and be far from perfect.

0 to 100 scale, with typical to peak

Some examples:-

Asperger’s plus Sensory

Somebody with what used to be called Asperger’s, who attends mainstream school, but has now developed sensory issues that the parents and child find troubling might be 5/15.

This would mean that most of the time the child is at 5, but when the problems arise from sensory issues he moves up to a 15.  The increase of 10 is a shock to the parents and would be noticed in mainstream school, but to someone at the other end of the scale, it would be like a hiccup.

Boy on the Bus

The nonverbal teenager with “autism” in the US, who the school bus driver forgot on the bus and was found dead a few hours later, still on the bus, parked back at the depot, might be 85/90.  This person needed assistance to wash, toilet and dress himself.  Clearly his issues were quite different from the 5/15 child.

85/90 should mean never be left alone and do not hand over to the “care” of the unknown relief bus driver.

Classic Autism at Special School

In most countries children with Classic Autism are in special schools.  What is interesting is that in this group there are often big variations over time.  These variations, just like all those comorbidities, are big signposts as to what the underlying neurological dysfunctions are.

A child might be 40/70; meaning that much of the time (i.e. at 40) things are nicely under control, but sometimes things get much worse.  Some parents describe this as “my child raves like a lunatic”, for others it might be aggression towards others and in some it might be self injury.

By far the most read posts on this blog come from people searching on google “autism + histamine”, so it looks likely that very many people find that summertime allergies cause big spikes in autism, as odd as that may sound.

There appear to be many other reasons for this temporary change 40/70 or 70/90 or even 10/30.  These big changes can be caused by all kinds of things.

In a future post I will look at the inflammatory response to GAS (Group A Streptococcus) and aberrant immunological reactions to GAS antigens.  The first of these might well cause the “raving loony” effect, while the second might the produce the facial grimacing and tics, observed by some readers of this blog.  If there was an effective rating scale, you could easily distinguish between the two.  Is the change 40/45 or 40/70 for example?

Double tap autism

In an earlier post I gave the term “double tap” autism to those people who started out with regular classic autism, say 40, who then suffer a sharp (permanent, if not treated) regression taking them to say 70 or even higher.

The internet is full of untreated examples of just this phenomenon.

Knowing that this person is 40/70, might then prompt the clinician to look for what had happened to cause this step change in autism symptoms.  If you managed to get to 4 years old before the regression to 70 occurred, there should be a good chance of finding out what happened, treating it and getting back to at least 40.

      

Autism Secondary to Mitochondrial Disease (AMD)

This young child might appear as 0/50, showing that before the onset of mitochondrial disease he was a typical child, but he regressed over a few weeks/months to something similar to classic autism.  It is the big change from 0 to 50 that should sound alarm bells.

The sooner it is treated, the better the final result. 

Primary and Secondary Causes of Autism

This all fits nicely with the segmentation I suggested in a previous post, regarding Primary and Secondary causes of autism.

If someone is 40/70, the 40 represents the primary cause(s) of their autism and the increase by 30 to 70 is the effect of the secondary dysfunctions when they are active.

Note that many people have commented that their therapy for Primary autism ceases to be effective when the secondary dysfunction(s) become active.  Hence “NAC has stopped working”, “Bumetanide has stopped working” etc.

Primary Dysfunctions in Autism	Secondary (some transient) Dysfunctions
Excitatory/Inhibitory GABA imbalance	Food allergy (e.g. gluten)
Oxidative stress	Pollen allergy
Neuroinflammation	Mast cell activation disorder
Activated microglia (over-activated immune system) inviting secondary dysfunctions	Mastocytosis
Vitamin B7 (biotin) related dysfunctions	Reaction to GAS and/or GAS antigens
Vitamin B9 (folate) related dysfunctions	Reaction to candida
Vitamin B12 related dysfunctions	Mitochondrial dysfunction
Central hormonal dysfunction (T3, TRH, Serotonin, IGF-1, BDNF etc)	Inflammatory events raising IL6 (e.g. slowly losing milk teeth)
Ion channel dysfunctions	Disturbed gut microbiota
Mitochondrial disease	Leaky Blood Brain Barrier (BBB) & leaky gut
etc …	etc…

The thing to remember is that while the some of the above may be relevant to most people exhibiting “autism”, many will be irrelevant to any one person.  So in many people candida, gluten and disturbed gut microbiota are not an issue at all, but in a small number one may be.

I think that some mild cases nowadays defined as autism are likely caused by just one of the secondary dysfunctions that may, on occasion, fade by themselves, or by dietary modification.

Resource Allocation

Since there will never be enough resources to go around, authorities have to prioritize where money is spent.  Do you start with the worse affected and then work down?  Do you invest the limited resources where the impact is greatest?

One thing we know for sure is that there will never be enough money and often those who complain the most, get the most resources.  Those without lawyers and parents who can write long letters get what is left.

If there was a severity scale, it could be used to better allocate resources and also to differentiate between those affected.

For example, you could say people rated > 30 should receive some ongoing financial support, or people < 10 do not need publicly funded services, or people > 50 need constant supervision, or people >70 cannot travel on the school bus without an assistant.  It is not rocket science.

Employment

You regularly hear about some big software company or another wanting to hire people with autism.  This further adds to the confusion of what autism is.  What they really mean is that they want people with a high IQ and autism 5/7.  So they have Asperger’s and have the occasional off-day, but nothing severe.  They are not going to throw the coffee jug at someone, or pee in the elevator.

The car wash where they hire people with “autism” is talking about the 30/40 type where everyone is glad that person is getting out of the house to work and in a loosely supervised environment, the odd behavioral “event” is acceptable.

Travel on Planes

You do hear horror stories about people with autism having tantrums on planes.  You could have a rule saying that people with autism peaking at 50 should have to notify the airline in advance, and then the pilot and crew are forewarned.  The airline can then make, and publish, its own policy of whether to accept such passengers.

Small children going berserk on a plane can be dealt with, but fully grown “children” may not be so easily controlled by their, then older, parents.

Conclusion

The better you can define a problem, the closer you are to a solution.  If other people use the same definition the easier it is to identify shared solutions.

Given the complex nature of autism and the huge numbers of people affected, it should be possible to do much better, so that similar clusters can be identified and people can then be more accurately treated.  As it stands today what might help 5% of people is tried on 100% and then, after a few failures, people give up.  We need to know more about those 5%; that applies to all the therapies that do seem to help some people. 

No fancy genetic testing is required to grade severity of autism and it is the most obvious place to start.

Change in severity of autism can really tell you a lot.

As usual, I should add, I do not expect any of this to happen.

Primary and Secondary Dysfunctions in Autism - plus Candesartan

Sometimes the secondary event can completely overshadow the primary event.  
The above relates to dust explosions (in large silos containing grain, sugar etc.) rather than autism.

As we continue to investigate the science behind autism and associated possible therapies, it is becoming necessary to introduce some further segmentation.

I have referred to autism “flare-ups” many times, but even that term means very different things to different people.

We now have many examples of autism treatments (NAC, Bumetanide etc), once effective, suddenly stopping working in certain people.  This needs explaining.

We know from the research that in most cases, autism is caused by multiple “hits”, only when taken together do they lead to autism.

We also see the “double tap” variety of autism, when relatively mild autism later develops into something more serious, following some event, or trigger.  

Thanks to the internet, we know have numerous n=1 examples of certain drugs showing a positive effect in some people.  You do have to discount all those people trying to sell you something, or support the cause of others trying to sell you something.  We also have full access to all those people who have patented their clever ideas, although 99% never develop them.

Within all this information there are some very useful insights, which can help further our understanding of autism

Candesartan

A case in point is Candesartan, which one reader of this blog brought to my attention, in the comment below.  This drug is used to treat high blood pressure and is often combined with a diuretic.

A very recent study relating to neurodegenerative disease and Parkinson's especially:

http://www.sciencedaily.com/releases/2015/05/150512150022.htm

discusses the use of a new drug as well as another blood pressure drug sometimes used in conjunction with Bumetanide called Candesartan. Their goal in this study was to explore how to attenuate chronic microglial activation (a hallmark of autism) by targeting toll-like receptors TLR1 and TLR2 via these two drugs.

Candesartan also modulates NKCC2 activity:

http://www.ncbi.nlm.nih.gov/pubmed/18305093

which is interesting considering the original cited research above deals with attenuating microglial activation, rather than modulating the chloride levels within GABA inhibitory neurons as Bumetanide does.

Note that Bumetanide affects both NKCC1 and NKCC2 transporters.  NKCC1 is present in the brain at birth, but should not be present in the adult brain.  However, it appears to remain in a large sub-group of those with autism, causing GABA to remain excitatory.  NKCC2 is found specifically in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood

This drug is, along with Minocycline, is one of the few that is known to have an effect on microglial activation.

In a clinical trial, Minocycline was shown to have no effect on autism.

I do feel this kind of assessment is too simplistic; so I was interested to see the actual effect of Candesartan in autism, albeit with n=1.

Conveniently somebody has filed a patent for the use of Candesartan in autism.  Within the document is the n=1 case report of its effect.

Example of treatment with Candersartan in autism

[00047] A 16 year old boy with autism was evaluated for behavioral management. He was frequently aggressive, primarily directed to himself but to others as well. These episodes were usually unprovoked but would also occur when his parents attempted to re direct him. The child was essentially non verbal except for echolalia. His comprehension to verbal re direction was limited, making non pharmacological interventions to his aggression limited.

[00048] His neurological exam was otherwise normal.

[00049] An MRI, EEG were normal. Routine studies, including examination for fragile x and other metabolic disorders were negative.

[00050] Prior medication trials included anti convulsants which were without benefit and atypical neuroleptics, which resulted in weight gain and unsatisfactory effects on behavior.

[00051] After obtaining consent from his parents, Candesartan was started. An initial dose of 8 mg resulted in significant attenuation of aggressive behavior. Blood pressure remained stable. After 2 weeks, the dose was raised to 16 mg. Further improvement in aggression was noted with no adverse lowering of blood pressure.

[00052] The patient has remained on Candesartan with beneficial anti aggression effects being maintained over one year.

[00053] A preferred dose found by the inventor to treat autism is approximately O.lmg/kg. In children, a liquid form may be used.

So we can conclude from this that in a non-verbal 16 year old boy with autism, with significant aggressive tendencies, this drug successfully reduced aggression.  Since he was on the drug for a year, there were no other major changes, such as language or cognitive function, otherwise they would surely be mentioned to support the patent.

I can of course look further into why Candesartan might have been effective.

Our blog reader suggested this research:-

Unraveling mystery of a-synuclein inneurodegenerative disease and reversing its course

"The real job of microglia is to keep the brain healthy by getting rid of pathogens as well as cellular debris," says Maguire-Zeiss, "However, in a diseased state microglia can become chronically activated, leading to a continuous onslaught of inflammation which is damaging to the brain."

In this study, the Maguire-Zeiss lab found that only a certain size structures of misfolded α-synuclein can activate microglial cells -- normal protein and even smaller forms of misfolded α-synuclein cannot. Then the researchers sought to discover precisely how microglia responded to misfolded α-synuclein; that is, which of its many "pattern recognition receptors" reacted to the toxic protein.

Microglia use many different pattern recognition proteins, called toll-like receptors (TLR), to recognize potential threats. The investigators found that misfolded α-synuclein caused TLR1 and TLR2 to come together into one complex (receptor), creating TLR1/2. They traced the entire molecular pathway from the protein's engagement of TLR1/2 at the cell surface to the production of inflammatory molecules.

Then Maguire-Zeiss and her team tested a drug, developed by researchers at the University of Colorado, which specifically targets TLR1/2. They also tested the hypertension drug candesartan, which can target TLR2. Both agents significantly reduced inflammation.

I found some other possible explanations:-

Angiotensin II AT1Receptor Blockade Ameliorates Brain Inflammation

Brain inflammation has a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post-traumatic stress disorder, Parkinson's and Alzheimer's disease, and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting angiotensin II AT₁ receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus, and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells, and cerebral microvascular endothelial cells. ARBs are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.

However the underlying mechanism may indeed be (yet again) activating PPAR γ.

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP modelof Parkinson's disease


This paper suggests that the effect of Candesartan on microglia is :-


"Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions."

Primary Autism Dysfunctions

I define Primary Autism Dysfunctions as those core dysfunctions that are always present.

So in the case of Monty, aged 11 with ASD, the primary dysfunctions include:-

·        GABA_A dysfunction, due to over expression of NKCC1,  leading to excitatory imbalance

·        Oxidative stress

In some other people the primary dysfunctions are quite different:-

·        Mitochondrial disease

·        etc...

I think that most aggressive behavior resulting from these dysfunctions can be traced back to communication problems and frustration.  So if the person is non-verbal and cannot get what he/she wants, aggression may follow; or if the person has pain and cannot understand it or seek help he may lash out at his care giver.

Secondary Autism Dysfunctions

I define Secondary Autism Dysfunctions as additional dysfunctions that can appear and disappear over time, these are my "flare-ups".

These dysfunctions can be more disabling that the Primary Autism Dysfunctions and it appears these are the dysfunctions that may trigger un-prompted self-injury and other random aggression.

These secondary dysfunctions can be so strong that they completely outweigh the primary dysfunction, giving the effect that the treatment for the primary dysfunction has “stopped working”.

It appears that many  Secondary Autism Dysfunctions are linked to an “over activated immune system”.  It does appear that from the research that activated microglia is an expression of this immune state and we saw one researcher calling the microglia the brain's “immunostat”. 

So in the case of Monty, aged 11 with ASD, the secondary dysfunctions are:-

·        over activated immune system / activated microglia

·        mast cell degranulation as a trigger

·        Il-6 from dissolving milk teeth as a trigger

·        Emotional distress (aged 8, when his long-time assistant left) as trigger (Emotional distress is known to cause oxidative stress)

In other people the secondary dysfunctions may be similar or quite different, for example:-

·        over activated immune system / activated microglia

·        leaky gut with GI problems as a trigger

·        food intolerance as a trigger

·        bacterial infection, with remission while on antibiotics, as a trigger

·        etc …

So I think the trial of Minocycline may have failed because the subjects were only affected by Primary Autism Dysfunctions.

I think the 16 year old aggressive boy in the Candersartan patent most likely had big Secondary Autism Dysfunctions.  The drug reduced microglial activation and so damped the effect of whatever his particular triggers were.

So probably Minocycline should be trialed again, but only in people with autism and regular SIB and aggression.  Success would be measured as a reduction in violent events.

Drugs targeting Primary Autism Dysfunctions should show things like:-

·        Cognitive improvement

·        Increased speech

·        Improved social interactions

·        Reduction in stereotypy

·        Reduction in anxiety (in higher functioning cases)

So I could classify my own interventions as

Primary

·        Bumetanide

·        Low dose Clonazepam

·        NAC

·        Sulforaphane (broccoli)

·        Atorvastatin

·        Potassium

Secondary

·        Verapamil

·        Sytrinol/Tangeretin PPAR-γ agonist for microglia

·        Occasional use of Ibuprofen (anti IL-6 therapy)

·        Quercetin/Azelastine/ Fluticasone Propionate for mast cells

The over activated immune system/activated microglia needs a trigger

Just like a modern plastic explosive is completely harmless to touch and needs the combination of extreme heat and shock wave from a detonator, it appears that the activated microglia, commonly found in autism, is in itself harmless, like Play-Doh, without a trigger.

But with a trigger, you probably know what can happen next.

What about all those failed clinical trials? False Negatives?

So now you not only need to match the trial therapy with the correct sub-type of autism, but you also cannot reliably trial a drug for a Primary Dysfunction, if there is an "active" Secondary Dysfunction.

This is indeed the reason why I do not try new therapies during the summer pollen season.

Perhaps this partly explains why clinical trials in autism always seem to fail.