Is Reductive Stress a common feature of Atypical Autism?

Lay summary:

·        Oxidative injury can be caused by both oxidative stress and the opposite, reductive stress. 

·        Both extremes of redox balance are known to cause cardiac injury

·        Both extremes of redox balance disrupt mitochondria

·        It appears that either extreme of redox balance may occur in autism.

Reductive stress is the opposite of oxidative stress and I am calling it “Atypical Autism” because all the research shows that the great majority of autism and indeed schizophrenia is associated with oxidative stress.

NAC and stereotypy/stimming

Most young children with classic autism exhibit stereotypy/stimming; this kind of obsessive, repetitive behavior can really get in the way of daily life.  You can use the principles of ABA to limit or redirect this behavior, but it turns out that there is a biological cause for it.

Taking NAC (N-acetylcysteine) increases the body’s production of GSH, its main antioxidant.  Once the intake in NAC is high enough to shift the balance between oxidants and antioxidants the stereotypy/stimming stops all by itself.  This does not mean that the child will still not enjoy repetition.

In some children it takes quite a lot of NAC before any effect is visible, one parent mentioned no effect until 1,800 mg a day.  In other people, the effect starts with the first 600mg and just keeps growing before plateauing around 3,000 mg a day.

This variation makes sense; it all depends just how out of balance the oxidants/antioxidants were at the outset.

If you have access to lab testing you would look at the ratio between GSH and GSSG. This would give you a good indication of your Redox balance.

NAC and Nrf-2 Activators making things worse

In a small number of cases NAC and Sulforaphane/broccoli (a Nrf-2 activator) actually makes things worse.  This does not mean more stereotypy/stimming; I think it quite likely that in those people, stereotypy/stimming are not a feature of their "autism",

Worsening autism can be an increase in anxiety.

Anxiety is often a feature of Asperger’s.

Anxiety is not an issue at all in many cases of classic autism.

NAC is itself an anti-oxidant as well as increasing GSH.  

Sulforaphane/broccoli activates Nrf-2 which in turn affects the genes that control the antioxidant response.  If this make things worse, it seems likely that there was no oxidative stress; either redox was in balance or they are already at the other extreme, reductive stress.

Some Science

The summary below is from the following paper

Oxidative Stress in Diabetes Mellitus and the Role Of

Vitamins with Antioxidant Actions

“Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption.

This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells.

Therefore, ROS formation is a physiological response to stress.

The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal. Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA. Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism.”

But reductive stress also leads to ROS formation

Reductive Stress and Oxidants

Reductive stress can be just as bad as oxidative stress and, very surprisingly, can have exactly the same negative effect on mitochondria (see below)

Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity

Abstract

To investigate the effects of the predominant nonprotein thiol, glutathione (GSH), on redox homeostasis, we employed complementary pharmacological and genetic strategies to determine the consequences of both loss- and gain-of-function GSH content in vitro. We monitored the redox events in the cytosol and mitochondria using reduction-oxidation sensitive green fluorescent protein (roGFP) probes and the level of reduced/oxidized thioredoxins (Trxs). Either H₂O₂ or the Trx reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), in embryonic rat heart (H9c2) cells, evoked 8 or 50 mV more oxidizing glutathione redox potential, E_hc (GSSG/2GSH), respectively. In contrast, N-acetyl-l-cysteine (NAC) treatment in H9c2 cells, or overexpression of either the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) or GCL modifier subunit (GCLM) in human embryonic kidney 293 T (HEK293T) cells, led to 3- to 4-fold increase of GSH and caused 7 or 12 mV more reducing E_hc, respectively. This condition paradoxically increased the level of mitochondrial oxidation, as demonstrated by redox shifts in mitochondrial roGFP and Trx2. Lastly, either NAC treatment (EC₅₀ 4 mM) or either GCLC or GCLM overexpression exhibited increased cytotoxicity and the susceptibility to the more reducing milieu was achieved at decreased levels of ROS. Taken together, our findings reveal a novel mechanism by which GSH-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.—Zhang, H., Limphong, P., Pieper, J., Liu, Q., Rodesch, C. K., Christians, E., Benjamin, I. J. Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.

Reductive Stress in Disease

Reductive Stress Increases Reactive Oxygen Species Production in Cardiac Mitochondria: A Key Role of Thioredoxin Reductase

Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production.

However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADP/NADPH and GSH/GSSG. Here we have further explored, using isolated intact and permeabilized cardiac mitochondria and purified NADP-dependent enzymes, how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems.

We show that one of the latter components, thioredoxin reductase 2, is converted into a potent NADPH oxidase during reductive stress, due to limited availability of its natural electron acceptor, oxidized thioredoxin. This finding may explain in part how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury.

Reductive stress: A new concept in Alzheimer’s disease

Reactive oxygen species play a physiological role in cell signaling and also a pathological role in diseases, when antioxidant defenses are overwhelmed causing oxidative stress. However, in this review we will focus on reductive stress that may be defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. This may occur in hypoxia and also in several diseases in which a small but persistent generation of oxidants results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments. This is the case of Alzheimer’s disease. Individuals at high risk of Alzheimer’s (because they carry the ApoE4 allele) suffer reductive stress long before the onset of the disease and even before the occurrence of mild cognitive impairment. Reductive stress can also be found in animal models of Alzheimer’s disease (APP/PS1 transgenic mice), when their redox state is determined at a young age, i.e. before the onset of the disease. Later in their lives they develop oxidative stress. The importance of understanding the occurrence of reductive stress before any signs or symptoms of Alzheimer’s has theoretical and also practical importance as it may be a very early marker of the disease.

 Oxidative Shielding

I was surprised that one of the very few papers to mention Reductive Stress is by Robert Naviaux, a well-known autism researcher.  He is the one behind Antipurinergic Therapy and Suramin as a therapy.  I just promoted him to my Dean’s List.

Oxidative Shielding or Oxidative Stress?

Abstract

In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed “oxidative shielding” response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health

In his paper Naviaux is quite right, it is much better to treat the cause of the oxidative/reductive stress; right now I do not know how to do this.

Oxidants as a therapy?

Most people with autism should avoid oxidants.

They should avoid paracetamol/ acetaminophen/Tylenol, because it depletes the body’s main antioxidant, GSH.  This is the mechanism behind why, at very high doses, it can kill you.  If they put NAC inside Tylenol, people could not use it to kill themselves.

One surprising oxidant that some people use to “treat” autism is MMS a, toxic solution of 28% sodium chlorite.  Is this the reason why there is such a cult therapy for drinking “bleach” to “cure” autism?

The only reason I mention this is that one reader whose child responded negatively to NAC and Sulforaphane had responded very positively to three doses of MMS some years ago.

For people with autism, and apparent reductive stress, I certainly do not suggest drinking bleach, but a few days of paracetamol / acetaminophen, as if you had the flu, might tell you a lot.

For most people with autism, Ibuprofen is a much better choice of painkiller;  it does not deplete GSH.

OPN-300 Oxytocin and Autism

This post is about nasal spray drugs and Oxytocin.

Monty, aged 12 with ASD, uses a conventional anti-histamine nasal spray and I do sometimes wonder just how much of the drug reaches its target.  

With inhalers for asthma this is a well known problem and often even adults do not use them correctly; they are proven to work much better when they are fitted with a spacer chamber, that way the drug ends up in your lungs and not stuck to the inside of your mouth.

Many adults with asthma and COPD nowadays use spacers.

So my interest was drawn to a company called Optinose that is developing drugs for nasal delivery using a novel dispenser.  I was particularly surprised that in its small drug pipeline is an oxytocin spray for autism.

If you look on the US National Institute of Health website listing clinical trials of oxytocin and autism, you will find that thirty, yes three zero, studies are listed.

According to their website, Optinose intend to be the first to bring a product to the market approved for autism.

On the clinical trials website you may notice that other trials use an existing drug called Syntocinon that is a synthetic form of Oxytocin already approved for other purposes.

I did mention in an earlier post that the US rights to Syntocinon were sold to a company hoping to develop a therapy for Schizophrenia and Autism.

Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)

In Europe Syntocinon is available in most countries as a prescription drug.


The Optinose idea is that their dispenser can much more reliably dispense the correct amount of drug and have it reach the membrane deep inside the nose.  None gets in the mouth and less should get stuck at the entrance to the nose.

Previous trials of Oxytocin have yielded very mixed results.  Perhaps part of this is due to the nature of the spray pump being used?  It is certainly plausible.

The Optinose Spray

The Optinose spray is inserted in one nostril and your mouth.  You blow out through mouth, sealing the nasal cavity in the process, and the spray is forced out into your nose.  This should ensure it goes deep inside to the nasal membrane, where the oxytocin can cross directly into the blood stream.

Click on the link below and then click to play the short video.

http://www.optinose.com/optinose-platform/technical-overview

As the video points out, this kind of drug delivery can “enable new and improved brain treatments”

They are talking about direct nose-to-brain drug delivery, bypassing the blood brain barrier (BBB).  This is not fantasy and is already quite well studied.

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.

Coming back to Oxytocin ...

Not only is Oxytocin a well-known hormone affecting social behavior, but it also plays a role in switching the neurotransmitter GABA between excitatory and inhibitory.

Oxytocin and GABA_A

Oxytocin has a role at birth in the GABA “switch”, but it also has an ongoing role via binding to a particular subunit of GABA_A receptors.

Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring

We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Further evidence as to the precise effect of Oxytocin on GABA receptors was found by chance.  It was found that having dosed rats with Oxytocin, they did not get drunk when fed alcohol.

Oxytocin prevents ethanol actions at δsubunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats

Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats.

Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA_ARs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA_ARs

The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.

Is Oxytocin a useful Autism Therapy?

Given the large number of trials and the number of people already taking Oxytocin, some people clearly believe in the therapeutic potential of Oxytocin.

What is clear is that there a numerous modes of action for Oxytocin, some of which relate to GABA_A receptors.

So why is it taking so very long for these trials to come to any usable conclusion? Well just looking at the long list of researchers, it includes some of those who have spent twenty years "researching" autism and producing absolutely nothing tangible, just papers concluding more research is needed or even producing, supposedly therapeutic, cartoons (Cambridge University).

We have the usual problem that numerous different dysfunctions lie at the root of “autism” and so only a moderate proportion, at best, would be expected to benefit from any therapy.

In the case of nasal sprays we have the question of how much actually gets delivered to the right place deep inside the nose where there is a very thin membrane that allows the Oxytocin to cross over into the blood.

OPN-300 Clinical Trials

The Phase 1 trial for OPN-300 was actually on healthy adults, and looked at things like dosing.  Low doses were more effective than high doses.  Next follows the trial on people with autism.  

Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Importantly, the current findings are the first to suggest that a low dose of OT is more effective than a higher dose in modulating social cognition

Converging biological and behavioral evidence suggests that lower OT doses may be more efficacious than higher doses. For instance, compared with higher doses, lower doses increased peripheral levels of OT in saliva,⁶⁵ attenuated cortisol stress responses⁶⁶ and increased eye gaze in patients with Fragile X syndrome.⁶⁷ In animals, a low dose of OT administered shortly after birth increased partner preference later in life, whereas higher doses did not.⁶⁸ Similarly, lower doses have been associated with stronger increases in social recognition compared with higher doses.^{69, 70} The dose–response data reported here provide useful preliminary evidence concerning the optimal dose for social cognition modulation; however, extrapolation from healthy individuals to patients must be with caution. Patients with social-cognitive deficits may respond differently than healthy volunteers, so future studies should explore effects in patient populations to determine the generalizability of these findings to target illnesses. Future work should also further investigate the role of different delivery devices, administration routes, dosages and social cognition tasks on the efficacy of intranasal OT, ideally using larger sample sizes given the limitation of a relatively small sample size in the present study.

In addition, this study provides preliminary evidence that a lower dose (8 IU) may offer greater efficacy than a higher dose (24 IU) when administered with the Breath Powered device.

There are a number of interpretations regarding why no effect was observed at the 24 IU OPN-OT dose, in contrast to the 8 IU dose. For example, a higher OT dose is more likely to influence the balance of AVP/OT, as evidenced by the decrease in AVP concentration after 24 IU OPN-OT (but not 8 IU OPN-OT) observed in the present study, which can modulate social behavior.

OptiNose reports positive results from Phase 1 trial of intranasal oxytocin for autism

Jul 15 2015

OptiNose has announced that a study comparing OPN-300 intranasal oxytocin to intravenous oxytocin for the treatment of autism showed the achievement of similar blood levels but significantly greater social-cognitive effects after intranasal administration. The results were published online July 14, 2015 in Translational Psychiatry.

The randomized, placebo-controlled, double-blind, double-dummy, 4-arm cross-over study involved 16 healthy volunteers who received either intravenous oxytocin or two doses of OPN-300 delivered using OptiNose’s bi-directional breath powered intranasal delivery device. Social-cognitive effects were measured by emotional rating of facial images.

Researcher Ole A. Andreassen of the University of Oslo said, “The OptiNose technology significantly changes the way drug is delivered high up in the nose, and may be the drug delivery solution we’ve been looking for. If we can improve social cognition in healthy people with OPN-300 low-dose oxytocin, then we may be able to address a core symptom suffered by millions of patients worldwide with autism.”

OptiNose Chief Scientific Officer Per Djupesland commented, “Although animal data has been encouraging, many would argue that medication transport from the nasal cavity directly to the brain has not been previously proven in humans. Today’s results are quite promising and bolster our belief that we can enable and enhance the treatment of common brain disorders with OptiNose delivery technology.”

The company says that it is initiating a Phase 2 trial of OPN-300 in autism patients in Norway. OptiNose is also developing intranasal fluticasone for chronic sinusitis and recently reported positive results from a Phase 3 trial of that product.

Read the OptiNose press release.

Read the Translational Psychiatry article.

Conclusion

Some parents already use the Syntocinon version of oxytocin for autism; some tried it in one of the earlier clinical trials and found it did not help.  There is nothing surprising in that. 

The people at OptiNose seem to be a bit more motivated than some of the other oxytocin researchers, in relaxed leafy universities, to actually get to the finishing line.  They are initiating Phase 2 trials of OPN-300 in autism patients in Norway.  Some of the other studies have been going on for several years and are still not finished.

Hopefully we will soon have some data on what percentage of people with “autism” respond to OPN-300 and then we could compare that to the response to Syntocinon.

As we have seen several times before, it seems that smaller doses of oxytocin are more effective than larger doses.  Larger doses seem to change (reduce) vasopressin levels, which will also affect social behavior.

One you start changing the level of one hormone, like oxytocin, you are very likely to affect others.  There are many interrelations and feedback loops.  

Oxytocin may well be part of the solution for some people with autism, but I expect in others it may make them worse.  Hopefully in the later trial(s) they will try and indentify biomarkers for the responder group.

A New School Year – Still keeping up

Before I return to the science-heavy posts, this is another post to encourage people not just to read about autism, but to treat it.  No pseudoscience or great expense is required.

After close to three years of using biology, rather than just behavioral therapy, where have we got to?

Acquiring new skills is effortless for clever typical kids; we have also got one of those.  For kids with classic autism, even the most basic skills need to be taught and taught again, until eventually, they might sink in.  I do not think this has anything to do with permanent MR/ID (mental retardation/intellectual disability), although I can see why it often gets diagnosed as such; it turns out to be treatable.

In the race to keep up with the typical kids, or at least keep them in sight, we started with ABA and about 1,800 hours a year of 1:1 time with an assistant.  After a few years the typical kids had pulled far ahead.

At age 9, I started to correct the underlying dysfunctions, first with Bumetanide, using very recent findings in the scientific literature.  This coincided with the decision to change his (neurotypical) peer group at school to those 2-3 years his junior.  Time was reset.

We still had the 1,800 hours a year of 1:1 time with an assistant, half at school and half at home.

At age 12, the original peer group is now far out of sight, but after three years we are still keeping up academically with the new “friends at school”.

Monty, now aged 12 with ASD, is in the same small mainstream international school he has attended for eight years.  Three years ago I held him back two years, since he was becoming completely “un-includable”.  So we went Year 1, Year 2, Year 3 then back to Year 2, then Year 3, Year 4 and now Year 5. 

Since most readers are American, where school starts one year later, to convert UK school year to US grade, just subtract one.  UK Year 5 = US 4^th grade.  In the US you finish in 12^th Grade whereas in the UK system you finish in Year 13, both typically in your 18^th year. (so in the US system, he went K, 1^st, 2^nd, then 1^st, 2^nd 3^rd and now 4^th)

Many kids with autism are now “included” in mainstream education, but in reality some are just having a private 1:1 lesson with their assistant at the back of the class. This is not a good idea; for the last three years Monty has been able to follow the teacher.  If you cannot follow the teacher, you really should not be in that class.

We have a new class teacher, an American, he has been teaching for 15 years, but has never had a special needs kid before; that in itself tells you something.  Now he has Monty, aged 12 with “treated” classic autism, something he probably will never see again.

After a couple of weeks, his conclusion is “he can read nicely and do the exercises”.  This makes it sound rather a non-event.  A few short years ago, his school teachers were rather stunned that his 1:1 assistant got him to read very simple words.  Now he can read aloud from “chapter books” to the rest of the class.   

When they had a spelling test (words like graduate, icicles, sausages) he got 18/20 and one of the new girls in class told her mother how clever Monty is.  When told he has “special needs” and an assistant, she replied “special needs … no special needs”.  That was nice, but Monty does still have plenty of special needs, but for three years he has been able to move forward academically at a similar rate to his classmates, albeit that they are all 2 years his junior.  That progression is quite extraordinary, if you know about outcomes in classic autism. 

Having been using ABA for five years prior to starting with the biology/pharmacology, and seen steady but slow progress and so falling ever further behind his peers, I never expected to be here in 2015 with Monty being able to subtract 7,794 from 9,621, or add up 8,756 + 4,326 + 7,832, interpret data from graphs and use x,y coordinates.  Until five years ago he did not even attend numeracy/math classes at school, because we had to focus on basic speech, basic reading and things like standing in line and changing shoes.

I have no idea how far he can go. I was expecting by now to again have to repeat a school year, but it has not been necessary.


Behavioral problems (SIB, anxiety, aggression etc.) were generally rooted in biology and have been more than 90% treatable.

With neither behavioral, nor pharmacological intervention, it would not now be a pretty sight.

It is sad that almost nobody treats Classic Autism pharmacologically; there are so many unnecessary, unhappy, consequences, lives sometimes lost to what can be a treatable condition.

It also appears likely that by treating the dysfunctions in Classic Autism, you may avoid the possible later progression to epilepsy/seizures and all the problems that may cause (even SUDEP, drowning etc).  This was something we had been warned might develop, but now looks much less likely.  For some people, seizures are a bigger issue than their autism. Some data, for those interested:-

Clinical Characteristics of Children with Autism Spectrum Disorder and Co-Occurring Epilepsy

This is among the largest studies to date of children with ASD and co-occurring epilepsy. Our sample includes 5,815 participants with ASD, 289 of whom had co-morbid epilepsy. Using statistical modeling in this well-powered sample of patients we have made several important observations about a contemporary group of individuals with ASD and epilepsy. We identified several correlates of epilepsy in children with ASD including older age, lower cognitive and adaptive functioning, poorer language skills, a history of developmental regression, and more severe ASD symptoms. Through multivariate logistic regression we found that only age and cognitive ability were independent predictors of epilepsy.

The average prevalence of epilepsy among children aged 2 to 17 years in our population-based sample, the NSCH, was 12.5%. This estimate is comparable to a recent report of a 15.5% rate of epilepsy in another population-based sample of children with ASD. While the prevalence was 10% or lower in children under 13 years of age, by adolescence it reached 26.2%. Therefore, the best estimate of the cumulative prevalence of epilepsy in ASD through 17 years of age is 26%. Our study replicates findings from prior studies that have followed children with ASD into adolescence/early adulthood and reported epilepsy prevalence rates from 22% to 38%

Note that Classic Autism accounts for about 30% of ASD; it is not hard to guess where you would find most of the 26% with ASD who later develop epilepsy.  

Odd epileptiform activity (seen on an EEG), falling short of epilepsy, is common in young children with autism and I think might be considered as pre-epilepsy.  Just as someone who has prediabetes has the chance to do something about it, before it progresses to type II diabetes, unusual EEG activity should prompt consideration of a treatable excitatory/inhibitory imbalance. 


Conclusion

At least I have treated the only autism case I am responsible for. I encourage others to do the same; it is never too late, even in adulthood.  We have one reader, Roger, who got his core biological autism dysfunction diagnosed and treated in adulthood.

If you prefer to wait for 100% FDA-guaranteed solutions, you will wait forever.  

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.