HBOT and autism systematically reviewed again (and the same results?)

"To date, there is no evidence that hyperbaric oxygen therapy improves core symptoms and associated symptoms of ASD [autism spectrum disorder]."

So said the results of the review by Xiong and colleagues [1] (open-access available here) completed under the auspices of the Cochrane Collaboration, leaders in the science and publication of systematic reviews (see here for another example).

Looking at the collected peer-reviewed science on the topic of hyperbaric oxygen therapy (HBOT) for autism - where "the patient breathes near 100% oxygen intermittently while inside a hyperbaric chamber pressurized to greater than sea level pressure", authors looked to determine several factors. Whether "treatment with hyperbaric oxygen: 1. improves core symptoms of ASD, including social communication problems and stereotypical and repetitive behaviors; 2. improves noncore symptoms of ASD, such as challenging behaviors; 3. improves comorbid states, such as depression and anxiety; and 4. causes adverse effects."

The results kinda mirrored what has already been previously described in the existing research review literature (see here), that based on one trial only [2] reaching their inclusion criteria, there is little evidence at the moment to say that HBOT is blanket indicated for autism.

Obviously one has to be a little careful that 'absence of science' is not construed as 'absence of evidence'. Indeed, I'm a little annoyed that the authors start suggesting that HBOT "may not be appropriate" for further study with autism in mind in light of the lack of studies in this area based on "the absence of a persuasive theory of change from experimental and clinical studies, the unknown long-term safety of the treatment, and the financial and opportunity costs of not participating in other proven therapies." No, I'm not defending HBOT as an intervention for autism but I am defending the idea that research reviews based on one study should really be trying to clarify the science rather than block future research efforts. Indeed, I'm inclined to direct you to the paper by Rossignol and colleagues [3] potentially answering questions such as mode of action and how one might want to look at potential best-responders to this type of intervention (autisms people, autisms). That and what the Sampanthavivat study included in the Xiong review actually said about 'safety' during their trial: "interventions were safe and well tolerated with minimal side effect from middle ear barotraumas."

To close, and in keeping with the date, a spooky song (and a rather spooky singer it has to be said...)

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[1] Xiong T. et al. Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2016 Oct 13;10:CD010922.

[2] Sampanthavivat M. et al. Hyperbaric oxygen in the treatment of childhood autism: a randomised controlled trial. Diving Hyperb Med. 2012 Sep;42(3):128-33.

[3] Rossignol DA et al. Hyperbaric oxygen treatment in autism spectrum disorders. Medical Gas Research. 2012; 2: 16.

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Xiong T, Chen H, Luo R, & Mu D (2016). Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 10 PMID: 27737490

Living with severe autism: families share their experiences

Appreciating that the autism spectrum is truly a wide and heterogeneous one (or even several?), I'd like to direct your attention today to the findings reported by Jocelyn Bessette Gorlin and colleagues [1] on the topic of "the experiences of families living with a child with severe autism."

In particular, I'd like to highlight the six areas that emerged from the "29 interviews with 22 participants from 11 families" related to family experiences and how, minus any sweeping generalisations, moves to tackle some of the issues raised in these areas might do quite a bit for the quality of life of everyone concerned.

So, the six areas:

(1) "families experienced autism as mysterious and complex because it is an invisible and unpredictable condition with diagnostic challenges." 'Mysterious' and 'complex' are words that have always followed the label of autism and as things stand at the moment, are unlikely to change in the coming years. Sure we know a little more about autism than we did a few years ago (i.e. the 'autisms', lots of comorbidity is potentially over-represented, etc) but in terms of longitudinal course and those important discussions (and actions!) about how to maximise quality of life 'for individuals' (the stress being on 'individuals'), concrete strategies are still few and far between. Diagnostic challenges? Well, certainly there are challenges to 'getting a diagnosis' in quite a few quarters still (see here for example) which is probably just as much down to money and resources as anything else. And just before you suggest that parents might not be sensitive to early issues potentially linked to autism, you're probably wrong (see here).

(2) "families described severe autism behaviors that often caused self-injury, harm to others and damaged homes." This is the side of autism that people generally don't talk about as much as they should. Acknowledging that extremes like self-injurious behaviour (SIB) aren't exactly great dinner table conversation, such patterns of behaviour are often the ones that cause the most distress both to the person themselves and their family/loved ones around them. I don't think I can stress enough how vital it is that SIB is further (a) understood (in terms of potential meaning) and (b) acted upon, particularly where a person is at high risk of hurting themselves or others (see here for example). I might also add that important issues such as wandering (elopement) in relation to autism should also be given due consideration given its potential inclusion under the category of 'challenging behaviour'.

(3) "profound communication deficits resulted in isolation between the family and child." I think this area is pretty self-explanatory. We can talk about the emerging role for assistive technologies as part of a package of interventions to aid this issue, but a lot more needs to be done in this area and indeed, is being done. And yes, this probably includes discussions around a re-framing of the communicative relationship between child/adult and family.

(4) "families discussed the unrelenting stress from lack of sleep, managing the child's developmental delays, coordinating and financing services, and concern for the child's future." I'm a big fan of caring for the carer(s) when it comes to the quality of life for families touched by autism (see here for example). To mention words like 'parenting stress' when it comes to autism shouldn't be a taboo subject (see here) the same as it shouldn't be when talking about parenting in general. There may be many ways that professionals can intervene in this respect (see here). Insofar as parents/families looking to the future of their children/loved one and tackling the sentiments of 'why I can never die' (see here), well, this is where society also needs to step up both in terms of future planning and delivery of services appropriate, welcoming and responsive to the needs of individuals. And some parents do have to do it all themselves...

(5) "families described consequences of isolation from friends, school, the public, and health providers." Although not everyone's experience, another uncomfortable issue associated with parenting a child with severe autism can be how isolating it is. It's little surprise that in the age of social media, this medium is being used to enable families to be/feel that little less isolated from the outside world. Aside from making more support agencies 'available' to families, there are a few other suggestions that might make things a little less isolating (see here).

(6) "families portrayed their need for compassionate support and formed 'hybrid families' (nuclear, extended families and friends) to gain support." See point 5. I'd also argue that the formation of those 'hybrid families' perhaps overlap with those 'kingdoms of autism' talked about a few years back. Indeed, I get the impression that talk about families and kingdoms intersecting with how wide and heterogeneous the autism spectrum is, might be one reason why there are so many varied opinions about autism from all sorts of angles...

These are all important points. Yes, I know that their relevance is going to be variably applicable to those (a) on the autism spectrum or (b) falling into that 'severe autism' bracket, but I don't doubt the lessons that could be learned would benefit quite a few people beyond the intended audience. As the authors note, their study results "could influence health care policies to improve the care for families caring for children with severe autism."

Great words indeed, but how to put words into 'life-changing' practice? Well, for a start understand that the autism spectrum is indeed a wide and heterogeneous one...

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[1] Bessette Gorlin J. et al. Severe Childhood Autism: The Family Lived Experience. J Pediatr Nurs. 2016 Oct 6. pii: S0882-5963(16)30279-2.

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Bessette Gorlin J, McAlpine CP, Garwick A, & Wieling E (2016). Severe Childhood Autism: The Family Lived Experience. Journal of pediatric nursing PMID: 27720503

Lower autism rate under DSM-5 (yet again)

So: "Results indicate that individuals diagnosed with PDD [pervasive developmental disorder] by DSM-IV-TR criteria may not be diagnosed using DSM-5 criteria."

That was the conclusion reached by Ferhat Yaylaci & Suha Miral [1] following their study of 150 children (3-15 years old) diagnosed with PDD "by DSM-IV-TR" whose symptoms/presentation were "reviewed through psychiatric assessment based on DSM-IV-TR and DSM-5 criteria." The percentage figure they arrived at (19.3%) indicated that about a fifth of participants might not reach diagnostic thresholds based on the DSM-5 criteria for autism spectrum disorder (ASD). PDD in DSM-IV by the way, refers to the autism spectrum.

As per the title of this post, I'm not surprised by this data as previous independent studies have similarly shown a drop in numbers of those 'fitting' the revised diagnostic thresholds included in the latest version of the DSM (see here and see here and see here). Combined with data indicating that the new diagnostic category termed 'social (pragmatic) communication disorder (SCD)' in DSM-5 is likely to fill up rather quickly (see here) to accommodate those not reaching the ASD diagnostic thresholds, the question on everyone's lips is: what will it mean to be diagnosed with SCD in terms of function of the diagnosis, services offered and public perception?

The short answer: we don't yet know.

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[1] Yaylaci F. & Miral S. A Comparison of DSM-IV-TR and DSM-5 Diagnostic Classifications in the Clinical Diagnosis of Autistic Spectrum Disorder. J Autism Dev Disorders. 2016. Oct 17.

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Yaylaci, F., & Miral, S. (2016). A Comparison of DSM-IV-TR and DSM-5 Diagnostic Classifications in the Clinical Diagnosis of Autistic Spectrum Disorder Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2937-8

Autism and inborn errors of metabolism

I'd like to think that the review article by Annik Simons and colleagues [1] (open-access) highlights some pretty strong evidence to suggest there being at least some connection between some autism and some of the collected inborn errors of metabolism. Indeed, when people generally talk about 'not knowing what causes autism' if we perhaps consider a more plural view of 'the autisms', there is a case to be made to say we might know what causes 'some' autism and some of it might lie in this area...

Inborn errors of metabolism (IEM) cover a whole host of different conditions "in which there is an accumulation of toxic and/or complex compounds or energy problems within the cells due to enzymatic defects or other protein dysfunction." The absolutely magnificent work of people like Robert Guthrie who's name is synonymous with the neonatal heel prick test offered to newborns to screen for various IEMs and a jobbing physician called Ivar Asbjørn Følling who lent his name to a condition that was eventually called phenylketonuria (PKU), have proved to be some of the real successes of modern medicine.

For quite a few years, peer-reviewed science has suggested some potentially important 'associations' between various behavioural and psychiatric labels manifesting in both treated and untreated IEMs (see here and see here for examples). Simons and colleagues decided to look through the collected research on this topic to provide "child and adolescent psychiatrists with an overview of metabolic disorders associated with child psychiatric symptoms, their main characteristics and recommendations for further investigations."

So after boiling down the available peer-reviewed literature to some 71 articles (and in so doing making an important distinction between an inborn error of metabolism and the 'metabolic syndrome'!) authors summarise some of the key IEM associated with labels such as autism, attention deficit hyperactivity disorder (ADHD), learning disability, psychosis and eating disorders. Given that (a) the paper is open-access and (b) this blog tends to favour autism research, I'm gonna focus in on some of the details pertinent to the autism spectrum. I do however recognise that when it comes to the term 'over-represented comorbidity' in autism some of the other diagnostic labels covered by Simons et al might also come into the frame.

Long quote coming up: "Known metabolic disorders in autism are phenylketonuria, disorders in purine metabolism (such as adenosine deaminase deficiency, adenylosuccinate lyase deficiency, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies), organic acidurias (such as propionic academia, 3-methylcrotonyl-CoA carboxylase deficiency and pyridoxine dependency), disorders of branched-chain amino acids creatine deficiency, biotinidase deficiency, cerebral folate deficiency, succinic semialdehyde dehydrogenase deficiency, Smith–Lemli–Opitz syndrome (SLOS), late infantile ceroid lipofuscinosis, histidinemia, Sanfilippo disease, glucose 6-phosphate dehydrogenase deficiency, urea cycle disorders, X-linked ichthyosis, and mitochondrial disorders." I've popped in a few links to other occasions where a specific IEM has been associated with autism and covered on this blog.

Simons and colleagues also cover some of the important research findings where specific amino acids have been analysed and found in unusual levels in cases of autism as potentially being important too. This is relevant because disordered amino acid levels as noted in the case of phenylketonuria (PKU) and the aromatic amino acids phenylalanine (and tyrosine) can be an important finding in relation to some IEM. That they specifically focus on some of the research looking at homocysteine levels and autism is rather interesting (see here) and something that I am going to be discussing in future posts.

What's more to say? Well, I think it is also important to highlight how Simons and colleagues talk about 'other signs and symptoms of the metabolic disease' [IEM] alongside the presentation of autism. This is important in the context that science is starting to more fully understand how a diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here) and quite a lot of different types of comorbidity seem to be 'over-represented'. I'd be inclined to suggest that this detail provides even stronger evidence for how IEM and at least some autism represent an important partnership.

Finally, I refer back to one of the statements made by the authors on "recommendations for further investigations." They suggest that those presenting with: "A positive family history of metabolic disease... Symptoms or signs are triggered by food intake (esp high protein content foods), fever, fasting, surgery (catabolism)... Feeding difficulties, food refusal, failure to thrive, eating disorders combined with symptoms of myopathy or fatigue... Mental retardation and/or regression... Epilepsy, episodes of lethargy or confusion... Dysmorphic feature" should be considered for further investigations. Yes, some of the language is not what I would use and yes, that covers quite a bit of clinical ground but screening is the first part to ruling out such a potential organic correlate of some autism and may in some cases, yield potentially important insights (see here)...

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[1] Simons A. et al. Can psychiatric childhood disorders be due to inborn errors of metabolism? European Child & Adolescent Psychiatry. 2016. Sept 30.

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Simons A, Eyskens F, Glazemakers I, & van West D (2016). Can psychiatric childhood disorders be due to inborn errors of metabolism? European child & adolescent psychiatry PMID: 27695954

'Super-parenting' improves children's autism: headline fail as PACT re-emerges...

The title of this post is partially taken from the BBC take on the findings reported by Andrew Pickles and colleagues [1] detailing a long-term follow up (and slight adjustment to the calculation of behavioural scores) of the Preschool Autism Communication Trial (PACT). PACT by the way, is a strategy based on the important tenet of shared attention where: "The approach aims to help parents adapt their communication style to their child’s impairments and respond to their child with enhanced sensitivity and responsiveness."

OK, just before I get started, use of the term 'super-parenting' in that headline is a bit of a fail by my reckoning and I don't doubt that this will probably change/have changed quite soon. Appreciating that there is as much variability in parenting a child with autism as there is parenting a child who does not have the label, the implication that parents of autistic children are somehow 'not doing it right' made by such a headline is frankly, a little rude. Many parents with children with autism are already 'super-parenting' well beyond what you might imagine to be humanly possible.

The study... well, greeted with quite a fanfare as words like 'breakthrough' are used (see here for example) the findings are basically a longer-term follow-up of the original PACT trial [2] which unfortunately reported at the time: "On the basis of our findings, we cannot recommend the addition of the PACT intervention to treatment as usual for the reduction of autism symptoms." Indeed, allied to some of other quite high-profile unspectacular scientific results based on the analysis of short-term parent-mediated intervention discussed on this blog (see here), there is quite a U-turn seemingly being adopted in this area (see here too). I might also add that even an analysis of the cost of PACT vs treatment as usual (TAU) did "not support the cost-effectiveness of PACT + TAU compared to TAU alone" [3]!

That all being said, the recent results from Pickles and colleagues are not bad at all. Tracking down some 120 participants of the original 150-ish cohort, researchers assessed them [blinded in some cases] "with the ADOS Comparative Severity Score (CSS)" among other things to see whether there were any behavioural presentation differences between those who were in receipt of PACT vs. those assigned to TAU. Differences were noted: "the severity of autism symptoms was significantly lower for children in the intervention group than for children in the treatment-as-usual group." And with that the authors pronounce: "We now show that a 12 month parent-mediated preschool intervention can produce sustained improvement in child autism symptoms and social communication with parents, which remained at nearly 6 years after the end of treatment. These findings support the potential long-term effects and value of early parent-mediated interventions for autism." I might also add: "these results are encouraging and provide evidence that sustained changes in autism symptoms can be possible after early intervention, something that has previously been regarded as difficult to achieve."

Caveats? Well, there are a few, not least the observation: "we cannot be sure how our results would generalise to young children with less severe symptoms." The authors also stress that the word 'cure' is not part and parcel of their results, and when it came to important comorbidities such as anxiety: "our related hypothesis that levels of child anxiety, which are often linked to levels of restricted and repetitive behaviours in autism,would also show a treatment effect at follow-up was refuted." Autism rarely exists in a diagnostic vacuum. Given also the quite long time between original and follow-up, it's not outside of the realms of possibility that other 'interventions' may also have 'chipped in' when it came to contributing to the behavioural outcomes noted or there being some element of natural waxing and waning of symptoms at work for some.

For the scientific sticklers out there (good on yer!), there are also a few details included in the study appendix pertinent to protocol and analysis amendments that were included in the study as it is presented, including dropping the Autism Diagnostic Interview-Revised (ADI-R) from the assessment battery and reported results. Does this mark the beginning of the end for the ADI-R I wonder?

So there you have it. After a slightly shaky start potentially illustrative of only modest short-term effects, early intervention of this type might actually have some more positive longer term effects. Of course, I'd like to see some further independent replication of this study and such behavioural intervention does not disqualify other approaches as also potentially being useful for some on the autism spectrum (see here for example). It's all about getting the right support and strategies in place for each individual person and perhaps getting the timing right too (see here).

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[1] Pickles A. et al. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial. Lancet. 2016. Oct 26.

[2] Green J. et al. Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet. 2010 Jun 19;375(9732):2152-60.

[3] Byford S. et al. Cost-effectiveness analysis of a communication-focused therapy for pre-school children with autism: results from a randomised controlled trial. BMC Psychiatry. 2015 Dec 21;15:316.

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Pickles, A., Le Couteur, A., Leadbitter, K., Salomone, E., Cole-Fletcher, R., Tobin, H., Gammer, I., Lowry, J., Vamvakas, G., Byford, S., Aldred, C., Slonims, V., McConachie, H., Howlin, P., Parr, J., Charman, T., & Green, J. (2016). Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial The Lancet DOI: 10.1016/S0140-6736(16)31229-6

"Increased risk for substance use-related problems in autism"

"We aimed to investigate the risk of substance use-related problems in ASD [autism spectrum disorder]."

Findings: "The risk of substance use-related problems was the highest among individuals with ASD and ADHD [attention-deficit hyperactivity disorder]."

So said the findings reported by Agnieszka Butwicka and colleagues [1] (open-access) looking again at an important but slightly uncomfortable topic: substance use-related problems or substance use disorder (SUD) with autism in mind. Covering various issues including those related to alcohol, drugs, tobacco, crime, somatic disease and death, authors "identified 26,986 probands with an autism spectrum disorders (ASD) among all individuals born in Sweden between January 1, 1973 and December 31, 2009" (yes, yet again it was one of those Scandinavian population registries that provided the data). Data from those diagnosed with autism or ASD were cross-referenced with information on substance-use related problems and compared with "unaffected (without an ASD diagnosis) full siblings (N = 30,456), half-siblings (N = 15,946), and parents (N = 50,155) of probands with ASD." Researchers also took into account issues such as comorbidity - "stratified on probands’ psychiatric comorbidity with ADHD" - and disposable family income and parental education. The examination of ADHD + autism continues an important research direction in recent times (see here).

Results: "Probands had a substantially increased risk of any substance-related problem..., such as substance use disorder..., somatic disease linked to alcohol misuse..., substance-related crime... and death." The sorts of statistics being produced with regards to 'risk' were not unimportant and indeed, were quite contrary to the 'stereotyped' view that "ASD patients are somehow protected from substance use-related problems" (authors words not mine). Further: "Within the substance use disorder category, the highest risk was found for drug use disorder..., followed by tobacco... and alcohol use disorder." The risk figures remained similar even when parental age, region of birth, education and family income were taken into account.

Insofar as one of the opening sentences of this post suggesting that autism + ADHD might be a particularly 'sensitive' combination when it comes to substance-use related problems, the data is pretty stark: "comorbid ADHD or ADHD with ID [intellectual disability] entailed a substantially higher risk, especially for substance use disorder." Autism + ID (without ADHD) however "was not associated with an increased risk of any substance use-related problems..., when all outcomes where regarded as one group."

I don't really want to go too far into the 'hows and whys' of the Butwicka data because this important area of investigation is still in it's infancy. I do appreciate the authors' discussions on how "substance use-related problems in individuals with ASD were indeed less common in the past, but that some factor(s) caused an increase over time" as being potentially important. They for example, talk about how "prior more narrow diagnostic practice may have [previously] excluded ASD patients with substance use-related issues or assigned other diagnoses to them." In other words, taking also into account how autism +ID did not seem to substantially increase the risk of substance use-related issues, the widening of the autism spectrum to potentially include more people might have had some effect on the relationship examined [2]. Obviously, if true, this might have some important implications particularly when it comes to screening and also questioning what role substance use serves for this group in terms of reason(s) for starting and maintaining such behaviour(s).

The important autism + ADHD relationship also picked out by the authors is noteworthy. On several occasions on this blog I've discussed the cold, hard science that suggests that long-term outcome following a diagnosis of ADHD is not exactly brilliant when it comes to various individual and social variables (see here and see here for example). Without trying to generalise/stigmatise nor shift 'blame' from label to label, it's not outside the realms of possibility that comorbid ADHD diagnosis or even features of ADHD, might exert a significant influence on substance use behaviours [3] and the related problems stemming from their use. The implication is therefore, that efforts to minimise such adverse effects linked to a label of ADHD perhaps need to be stepped up.

It's always going to be difficult to talk about substance use disorder and the problems stemming from such behaviours with any specific diagnostic label in mind. There is a particular stigma attached to substance-use behaviours and certainly with autism in mind, more adverse sweeping generalisations are not required (see here for example). But this should not mean that discussions are buried and reality somehow airbrushed for the sake of political correctness or positive public relations. The reality as demonstrated by the Butwicka and other peer-reviewed data [4] is that substance use is / can be a destructive behaviour not least for the person and the people around them. Certainly in the context of autism and the quite large health and social disparities that seem to continually surround the diagnosis (see here for example), a failure to screen for and tackle substance use behaviours further adds to the adverse risks/inequalities that can potentially accompany a diagnosis.

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[1] Butwicka A. et al. Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study. J Autism Dev Disorder. 2016. Oct 12.

[2] Clarke T. et al. Substance use disorder in Asperger syndrome: An investigation into the development and maintenance of substance use disorder by individuals with a diagnosis of Asperger syndrome. Int J Drug Policy. 2016 Jan;27:154-63.

[3] Connolly RD. et al. Probabilities of ADD/ADHD and Related Substance Use Among Canadian Adults. J Atten Disord. 2016 May 14. pii: 1087054716647474.

[4] Arnevik EA. & Helverschou SB. Autism Spectrum Disorder and Co-occurring Substance Use Disorder - A Systematic Review. Subst Abuse. 2016 Aug 17;10:69-75.

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Butwicka, A., Långström, N., Larsson, H., Lundström, S., Serlachius, E., Almqvist, C., Frisén, L., & Lichtenstein, P. (2016). Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2914-2

Vitamin D toxicity and autism: a case report

"Alternative medicine treatment put four-year-old boy in A&E [accident & emergency / emergency room]" went the recent BBC headline talking about the case report published by Drs Catriona Boyd and Abdul Moodambail [2].

Describing the experiences of a 4-year old boy who attended A&E (the emergency room) following an extended period of "vomiting, loss of appetite, constipation, polyuria, polydipsia and loss of 3kg in weight" in previous weeks, the authors report how after an unremarkable series of test results, parents disclosed that "for a number of months he had been taking 12 different holistic supplements recommended to the family by a naturopath to help with his autism."

Coinciding with the detected presence of hypercalcaemia - high calcium levels in the blood - and a circulating vitamin D level that was pretty much off the scale ("Vitamin D level was checked and was 2130 nmol/L (normal range: 50-150 nmol/L)") authors set about correcting such issues and eventually reported that he "has had no further problems since stopping the supplements." His symptoms by the way, matched other reports of vitamin D toxicity present in the peer-reviewed literature [2]. Insofar as any long-term side-effects associated with this case, well, we just don't know yet.

Whilst this is an unfortunate incident, there are a number of important wider points potentially raised from such a case report worth mentioning. So, treading very carefully:

1. Quite a lot of the media chatter about the Boyd/Moodambail report has focused on the more general role of complementary and alternative medicine (CAM) particularly when applied to autism (see here). The authors, in that BBC news report, stress as much with comments like: "When some complementary and alternative therapies are suggesting they can cure these situations, these parents get a hope - which is probably a false hope." Bearing in mind what was actually being reported on in their paper - hypercalcaemia and vitamin D toxicity - primarily due to either/combined excessive calcium intake and vitamin D supplementation and as far as I can see, no mention of the word 'cure' in the case report when it comes to the reasoning behind their use, one has to be a little cautious about turning such reports into something more than they are. Vitamin D - the sunshine vitamin/hormone - is an important nutrient as science and (UK) Government health policy is starting to realise (see here) and this includes that research potentially relevant to [some] autism (see here). Indeed, a response to the Boyd/Moodambail paper highlights this fact. This case report highlights how we should be treating our nutritional supplements as what they are - medicines - and how professional medical advice should always be sought when it comes to their use including that related to dosage and importantly, any contraindications. I might also suggest that this case highlights the value of screening before and during supplementation [3] - "obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended". The further question of 'whether vitamin D actually comes under the auspice of CAM' also surfaces. I'm sure many people will have different opinions about this but like other important vitamins (e.g. folic acid) where specific government advice is available, I'd be inclined to say not anymore.

2. There were some rather extreme reactions to this paper/story when it broke. Despite the fact that "The safeguarding team became involved as well as the police to investigate the naturopath who had advised the therapies" some people were calling the parent's actions as being tantamount to 'child abuse'. I however go with the authors on this one where the parents were naive at worst and perhaps far too trusting. Such a response does however intersect with various other thoughts and opinions in relation to autism and its' 'treatment' and calls by some for more regulation when it comes to the vast number of interventions being put forward 'for autism'. There are no easy answers to this because as well as balancing parental responsibility with the health and wellbeing of the child, blanket calls to 'ban all nutritional supplements for children/adults with autism' for example, are neither practical nor enforceable. Indeed, it could be viewed as discriminatory given our population habits when it comes to such pharmaceutics. I might also add that if one assumes that 'autism' should be replaced by the more plural 'autisms', peer-reviewed science has actually suggested that the presentation of some of the 'autisms' may be potentially amenable to certain dietary or nutritional intervention as function of their underlying genetics/biology (see here for example). The bottom line is that as long as autism remains a 'singular mysterious condition' where very little information about aetiology and life course exists, so these sorts of scenarios will unfortunately continue to occur.

3. Finally, very little discussion has centred on the individual supplements 'recommended' in this case outside of those containing calcium and vitamin D. Cod liver oil is mentioned "(containing 1000IU vitamin D") alongside camel milk, zinc, Epsom salts baths and something called AFP peptizyde. I'm sure some people might see these kinds of interventions as pure 'woo' when it comes to autism but it's perhaps important to realise that there is some preliminary peer-reviewed science behind some elements of them (see here and see here for example). Focusing specifically on cod liver oil and the idea that as well as containing vitamin A (be careful with that one) and vitamin D it contains some of those essential fatty acids that everyone keeps going on about these days, the suggestion that certain facets of cognition could be 'affected' by their inclusion as a supplement for some continues to gain scientific ground (see here). Obviously quite a lot more investigation needs to be put into the 'hows and whys' of their possible actions and mechanisms of effect with a specific focus on autism, onwards to the identification of criteria for potential best or non-responder to such approaches.

The Boyd/Moodambail report represents an important example of how supplements that can be easily purchased in-store or on-line are not just benign tablets or pills but can have very real physical effects if used inappropriately or without the right medical consultation. I certainly don't want to downplay the 'suffering' that the child in their report went through which ultimately led him to be hospitalised with some pretty serious health issues. I do however object to the 'throwing the baby out with the bathwater' sentiments that potentially stem from the translation of reports such as these, where important research on something like vitamin D and autism (which continues on at a pace [4] I might add) could easily become 'vilified' as a result of the actions of one or two parties at fault.

And perhaps it is timely to report that at least in the United States, dietary supplement use remains pretty high among the adult population albeit with a changing pattern of consumption not so dissimilar to that highlighted in the Boyd/Moodambail paper...

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[1] Boyd C. & Moodambail A. Severe hypercalcaemia in a child secondary to use of alternative therapies. BMJ Case Reports. 2016; Oct 6.

[2] Kaur P. et al. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf). 2015 Sep;83(3):327-31.

[3] Vogiatzi MG. et al. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014 Apr;99(4):1132-41.

[3] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

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Boyd, C., & Moodambail, A. (2016). Severe hypercalcaemia in a child secondary to use of alternative therapies BMJ Case Reports DOI: 10.1136/bcr-2016-215849

Bipolar disorder and the autism spectrum continued

In a previous post on this blog I talked about an important paper by Vannucchi and colleagues [1] summarising the state of the peer-reviewed research (up to 2014) on bipolar disorder and Asperger syndrome (AS). Today, I'm adding to the conversation on this important topic by introducing two papers to the discussions: the first by Xenia Borue and colleagues [2] and the second by Ahmad Abu-Akel and colleagues [3] covering the longitudinal course of bipolar disorder (BD) in relation to autism and the appearance of autistic and other traits in relation to cases of BD respectively.

Bipolar disorder (BD) previously known as manic depression is a condition affecting mood and specifically how it can 'swing' between extremes of depression and mania. There are a couple of different 'types' of BD reflective of how such mood swings can sometimes centre more on one aspect of BD over the other. As per the Vannucchi findings, the experience of BD may not be uncommon to the autism spectrum - "BD prevalence in adults with AS ranges from 6% to 21.4% of the cases" - but importantly: "is often characterized by atypical presentation, making its correct identification particularly difficult." Keep that in mind for now.

The papers by Borue and Abu-Akel put a little more scientific flesh on to the discussions about autism and BD. Specifically, how in these days of increasing recognition that autism rarely appears in some sort of diagnostic vacuum (see here), comorbidity might have some pretty important effects on clinical presentation.

To discuss the Borue findings first... well, based on a cohort of some 360 youths diagnosed with various types of BD who were followed for around 9 years, authors "compared youth with and without ASD [autism spectrum disorder] on clinical presentation, percentage of time with mood symptomatology, and psychosocial functioning." Approximately 8% of their cohort "met DSM-IV criteria for Asperger disorder or pervasive developmental disorder-NOS (referred to here as ASD)" which is an important detail. Further: "Compared to youth with BD, the clinical presentation of youth with BD+ASD more frequently involved distractibility, racing thoughts, depressed mood, social withdrawal, and low reactivity of negative mood states." The 'distractibility' side of things tallies with the observation that comorbid "attention-deficit/hyperactivity" (akin to ADHD) was more frequent in this group too and might be important [4]. Insofar as longitudinal course (at least over about 9 years), authors note: "Significant amelioration of clinical symptoms occurred over time, suggesting that early recognition and treatment of mood disorders in youth with ASD may improve clinical outcomes."

The Abu-Akel group set out to "determine the expression of autistic and positive schizotypal traits in a large sample of adults with bipolar I disorder (BD-I), and the effect of co-occurring autistic and positive schizotypal traits on global functioning in BD-I." BD-I focuses more on the manic side of clinical presentation. Bearing in mind autistic and schizotypal traits were self-assessed, authors reported that nearly 50% of their BD cohort (~800 people recruited via the Bipolar Disorder Research Network) "showed clinically significant levels of autistic traits." Around a quarter of their group also showed potentially important schizotypal traits too. Interestingly: "In the worst episode of mania, the high autistic, high positive schizotypal group had better global functioning compared to the other groups" with the requirement for quite a bit more study in this area.

What could these collective results mean?

Well, first and foremost all the chatter about traits and behaviours 'overlapping' shines through in these results. ESSENCE may indeed extend quite a bit further than just in childhood (see here) and this has some important implications for preferential screening services when an autism diagnosis is suspected or given. Second, I'm struck by how important traits outside of the autism spectrum might be to the presentation of something like BD in those reaching clinical thresholds for autism. I'm yet more convinced that the increasingly important association being made between autism and ADHD for example (see here) is really, really important. Third, the idea that autistic and certain schizotypal traits might actually be useful when it comes to 'global functioning' in cases of BD-I is an eye-opener. This needs further investigation. Finally, treatment for BD exists and with no medical or clinical advice given or intended, should not be withheld on the basis of a comorbid autism diagnosis.

Timely and accurate diagnosis of BD when co-occurring alongside autism (or the presence of autistic traits) continues to be a priority. Not least because of the potentially far-reaching and sometimes extreme effects that BD can have (see here for example) potentially overlapping with some distressing figures noted alongside autism (see here). Yes, the presentation of BD might be slightly different when autism/autistic traits are included in the diagnostic mix, but clinicians and other health professionals need to be sensitive to such subtleties. Once again, screening is the first step of the process...

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[1] Vannucchi G. et al. Bipolar disorder in adults with Asperger׳s Syndrome: a systematic review. J Affect Disord. 2014 Oct;168:151-60.

[2] Borue X. et al. Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2016. Oct 4.

[3] Abu-Akel A. et al. Autistic and Schizotypal Traits and Global Functioning in Bipolar I Disorder. Journal of Affective Disorders. 2016. Oct 3.

[4] Wang HR. et al. Prevalence and correlates of bipolar spectrum disorder comorbid with ADHD features in nonclinical young adults. J Affect Disord. 2016 Sep 28;207:175-180.

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Borue, X., Mazefsky, C., Rooks, B., Strober, M., Keller, M., Hower, H., Yen, S., Gill, M., Diler, R., Axelson, D., Goldstein, B., Goldstein, T., Ryan, N., Liao, F., Hunt, J., Dickstein, D., & Birmaher, B. (2016). Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder Journal of the American Academy of Child & Adolescent Psychiatry DOI: 10.1016/j.jaac.2016.08.011



Abu-Akel, A., Clark, J., Perry, A., Wood, S., Forty, L., Craddock, N., Jones, I., Gordon-Smith, K., & Jones, L. (2016). Autistic and Schizotypal Traits and Global Functioning in Bipolar I Disorder Journal of Affective Disorders DOI: 10.1016/j.jad.2016.09.059

Language and motor skills: preschool predictors of academic achievement in autism

A fairly quick post for your reading delight today as I bring the paper by Miller and colleagues [1] to your attention suggesting that: "Early intervention targeting language and motor skills may improve later achievement in this population."

'This population' referred to a small cohort (N=26) of children diagnosed with an autism spectrum disorder (ASD) who were examined "at the approximate ages of two, four, and ten" years with regards to their academic achievement and the variables that might be important to 'successful' achievements.

Including some familiar names when it comes to the concept of 'outcome' in relation to autism ('optimal outcome' that is), researchers determined a few potentially important relationships from their collected data: "Preschool verbal abilities significantly predicted school-age reading comprehension" and "early motor functioning predicted later math skills."

I'm not entirely surprised that infancy verbal (talking) abilities might play a role in later reading comprehension but I was rather more intrigued by the observation potentially linking motor skills to later maths abilities. Yes, I get that children learn to count on their fingers (and toes) and no doubt this and other scenarios might influence the connection between the two, but it strikes me that this connection requires quite a bit more study [2]. Indeed, welcoming the idea that motor skills are an important issue with regards to autism (see here) and that maths ability is 'as varied as the label of autism is itself' (see here) the idea that the archetypal all-rounder that is the occupational therapist (OT) might have a key role here is rather interesting (see here).

I'm also minded to suggest that a certain sport/discipline that I'm particularly fond of on this blog (the martial arts) might have some rather far-reaching 'mathematical' effects if one considers it's application to autism and motor functioning...

To close, Marvel are going full-strength with their next Wolverine film instalment titled 'Logan'...

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[1] Miller LE. et al. Preschool predictors of school-age academic achievement in autism spectrum disorder. Clin Neuropsychol. 2016 Oct 5:1-22.

[2] Pitchford NJ. et al. Fine Motor Skills Predict Maths Ability Better than They Predict Reading Ability in the Early Primary School Years. Front Psychol. 2016 May 30;7:783.

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Miller LE, Burke JD, Troyb E, Knoch K, Herlihy LE, & Fein DA (2016). Preschool predictors of school-age academic achievement in autism spectrum disorder. The Clinical neuropsychologist, 1-22 PMID: 27705180

One more time: asthma and autism

I'm actually getting a little bored of talking about the various peer-reviewed research looking at a possible connection between asthma and autism on this blog. It's not that it isn't an interesting topic but rather that the data is coming in thick and fast suggesting that behaviour and physiology are not completely separate anymore.

I did however want to direct you to the paper by Alessandro Tonacci and colleagues [1] who, following a systematic review "according to the PRISMA guidelines" suggested that "Autism Spectrum Disorder and asthma could be associated conditions, as evidenced by the higher prevalence of asthma in autistic children with respect to typically developed controls." I might add that this is not the first time that this authorship group have examined the coincidence of allergic disease with autism (see here).

The idea that asthma and autism might be connected is an important finding because not so long ago I talked about another paper [2] - a meta-analysis - that came up with a slightly different conclusion to that listed by Tonacci (see here). OK, a systematic review and a meta-analysis whilst related are not necessarily one and the same and so one has to be a little careful. That being said, I did raise a few 'issues' with that previous meta-analysis by Zheng and colleagues [2] around what they did and did not seemingly include in their paper. A meta-analysis or systematic review is only as good as the number and quality of the studies it includes.

The strength of the Tonacci review is that it followed those PRISMA guidance - the Preferred Reporting Items for Systematic reviews and Meta-Analyses - and also that "Methods for study selection and inclusion criteria were specified in advance and documented in PROSPERO protocol #CRD42014012851." In other words, much like when study protocols for clinical trials are pre-registered to avoid any 'massaging' of results or changing/switching outcomes, so their aims and objectives were on record for all to see.

Where next for the suggestion of a possible link between asthma and autism? Well, how about taking into account a role for comorbidity as per the increasingly strong evidence coming out about how asthma and attention-deficit hyperactivity disorder (ADHD) may be linked (see here) and what that means for the over-representation of ADHD in autism or vice-versa (see here). I might once again suggest that immune function (i.e. inflammation or inflammatory processes) could be a common variable requiring further study too (see here for example). Such research may wish to take into account overlapping genetics/epigenetics as being important as well as the more functional biochemistry of immune system processes.

Given also the specific focus on "allergic asthma" by Tonacci et al I'm also wondering whether the various research on allergy symptoms affecting autism presentation might be important for some (see here). Indeed, with no medical advice given or intended, the idea of treating allergic disease in cases of ADHD for example (see here) is perhaps an area ripe for further investigation when it comes to autistic presentation too...

To close: Guardians of the Galaxy is back (and the soundtrack will be as cool as ever I guess).

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[1] Tonacci A. et al. A systematic review of the association between allergic asthma and autism. Minerva Pediatr. 2016 Oct 5.

[2] Zheng Z. et al. Association between Asthma and Autism Spectrum Disorder: A Meta-Analysis. PLoS One. 2016 Jun 3;11(6):e0156662.

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Tonacci A, Billeci L, Ruta L, Tartarisco G, Pioggia G, & Gangemi S (2016). A systematic review of the association between allergic asthma and autism. Minerva pediatrica PMID: 27706122

"Folinic acid improves communication in childhood autism"

A quote to begin: "... in this small trial of children with non-syndromic ASD [autism spectrum disorder] and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs [folate receptor-α autoantibody]."

Those were the findings reported by Richard Frye and colleagues [1] (open-access) continuing a research theme from this group looking at how folinic acid - a reduced form or vitamer of folate - may "markedly" improve symptoms in some children diagnosed with ASD (see here). Some media reporting about these latest results are available (see here for example) but if you're sticking with my interpretation there are a few important points to note.

So:

• This was a gold-standard "double-blind, randomized placebo-controlled" study meaning that as well as pitting folinic acid against a placebo, both researchers and participants were blind to 'who got what' during the 12 weeks of study. The aim was to compare a "target dose" of folinic acid "(2 mg kg−1 per day)" with said placebo formulation. It also appears that the authors went to some lengths to ensure that folinic acid and placebo capsules were "indistinguishable by sight and feel" as well as odour and taste.
• Participants (~7 years old) (N=48) were allocated to the folinic acid (n=23) or placebo group (n=25). All had a diagnosis of ASD and importantly, "Reconfirmation of the diagnosis using the lifetime version of the Autism Diagnostic Interview-Revised by an independent research reliable rater was requested from all participants." Participants were also required to have "documentation of language impairment" accompanying their autism as well as being free from current antipsychotic medication use alongside various other inclusion/exclusion criteria.
• "Verbal communication was the primary outcome" we are told, offering a rather refreshing prospect insofar as the focus being on symptoms rather than syndromes. That's not to say that various behavioural schemes pertinent to the presentation of autism and other general 'adaptive behaviours' weren't also included, but this was a study looking specifically at what happened to verbal communication.
• Results: well, first and foremost folinic acid seemed to be pretty safe and well tolerated as we are told that "no serious adverse effects" were recorded for the folinic acid group when blinding was broken. First, do no harm and all that. As per the opening sentence of this post, there were some significant group improvements noted for the group taking folinic acid in relation to verbal communication ("an important core ASD symptom") compared with the placebo group.
• Going back to the whole 'positive for FRAAs' there were also some results to be seen. "This study suggests that FRAAs predict response to high-dose folinic acid treatment. This is consistent with the notion that children with ASD and FRAAs may represent a distinct subgroup." Without turning this post into some grand explanation of what FRAAs are (bearing in mind I'm barely getting my head around this myself), this ties into other findings (see here) and how these autoantibodies work to impair folate transport and 'block' or 'bind' to the folate receptor. One explanation is that folinic acid is able to 'bypass the FRα [folate receptor-α] when it is blocked and/or dysfunctional' particularly at higher doses. The use of the term "distinct subgroup" when it comes to autism is music to many ears in these days of the more plural 'autisms' and recognition that certain inborn errors of metabolism seem to be associated with 'some types' of autism [2] (more on this paper to come soon).

Of course there is more to do in this area as the authors themselves identify the small participant numbers as one limitation and the future requirement to "determine the optimal folinic acid dose". Although no adverse effects were reported during the 12-week period, I'd also suggest that longer-term follow-up is needed to make sure that this effect extends a little longer too. Given the folate connection evident in this line of research, I'd for example, also be interested to see a little more work done on whether everyone's favourite scrabble gene - methylenetetrahydrofolate reductase (MTHFR) - potentially linked to some autism (see here) might also be an important player with regards to folinic acid use and response. Finally, minus any sweeping generalisations, the idea that FRAAs might also extend across labels to schizophrenia (see here) for example, is also potentially worthy of further investigation insofar as the 'links' that still remain when it comes to the autism and schizophrenia spectrums (see here) (remembering too the important work of Mildred Creak).

Having said all that, these are important results as they stand. Not least because under rigorous methodological conditions, folinic acid has seemingly passed yet another scientific hurdle with regards to its potential relevance to at least some autism. We will no doubt see more on this topic in the peer-reviewed literature in times to come...

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[1] Frye RE. et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry. 2016. Oct 18.

[2] Simons A. et al. Can psychiatric childhood disorders be due to inborn errors of metabolism? European Child & Adolescent Psychiatry. 2016. Sept 30.

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Frye, R., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., Jill James, S., Sequeira, J., & Quadros, E. (2016). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial Molecular Psychiatry DOI: 10.1038/mp.2016.168

Paracetamol for fever 'associated' with autism?

"In this study, we again show that acetaminophen use is associated with ASD [autism spectrum disorder]."

That was one of the results reported by Stephen Schultz & Georgianna Gould [1] (open-access available here) as part of their survey of the US "National Database for Autism Research (NDAR) of the National Institute of Mental Health (NIMH)" looking at "whether ASD is associated with acetaminophen use." Acetaminophen by the way, is another name for paracetamol, the over-the-counter pain relief medication that is going through some turbulent times at the moment (see here for example).

Shultz & Gould - one of whom has some research form in this area [2] - eventually relied on information for 118 children diagnosed with an ASD and 79 'non-ASD' children with an average age of about 11 years old. The sorts of data they looked at surrounded the parental choice of medication to treat fevers (I think) including whether paracetamol, ibuprofen or aspirin were used. I have to say that the authors could have made the methodology behind their analysis a little bit clearer in terms of how the questions were posed and to whom rather than just referring to another study with regards to participant selection for example. I had to go fishing for various details which is guaranteed to furrow my brow...

Results: well, I'm slightly puzzled it has to be said. When it came to questions about paracetamol use (I use the term paracetamol 'cos that's what us Limeys are used to) between the ASD and non-ASD groups I didn't see too much difference overall. Take for example the questions about 'only using paracetamol' for fever or 'first choice' use for fever. The percentage figures for the ASD and non-ASD group were 15% and 12% respectively for 'only use this' and 35% and 46% respectively for 'first choice'. Given the participant numbers, I'm not sure that these stats are so wildly different. Yes, I appreciate that when it came to the question about 'rarely or never using' paracetamol to treat fever, 17% of those with ASD reported positive to this question compared with only 3% of controls, but does this really tell us much about very different patterns of paracetamol use?

Further, the authors report results based on "age-adjusted models for levels of fever medication use". They observe that using "acetaminophen as a first choice was 83% less likely in children with ASD... while use of acetaminophen if other medication doesn’t bring down fever was 82% less likely in children with ASD." They interpret this to mean that compared with their previous results [2] findings were reversed in that "older children with ASD compared to control children were significantly less likely to use acetaminophen for fever; whereas, in our 2008 study, younger children with ASD compared to control children were significantly more likely to use acetaminophen at 12-18 months of age and after the MMR vaccination." The mention of immunisation in that last sentence was based on their 2008 paper suggesting that "acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder" but I have to say that I'm left a little wanting in terms of these recent findings by Shultz & Gould.

I do think there is a 'where next?' discussion to be had when it comes to the idea that paracetamol use might be linked to 'some' autism. Given the growing research interest in paracetamol use and a 'hyperactive phenotype' of autism (see here), this stalwart of pain relief is deserving of much further inspection in relation to autism. Shultz & Gould do offer one possible research direction based on some speculation about the how the endocannabinoid system might fit into this (something mentioned by other authors too). I am interested in the hypothetical situation they conclude their paper with implicating the endocannabinoid system and how paracetamol might affect 'endocannabinoid tone' but to what extent is perhaps another question.

Just before I finish on this topic I'm minded to bring to your attention another detail from the Shultz / Gould paper with regards to the sentence: "children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever." I've always thought the observations on behaviour and fever when it comes to [some] autism to be quite important (see here). Speculation that "this increase [in sociability] is due to anandamide activation of the endocannabinoid system in ASD children" is also ripe for further scientific investigation...

It's been a while but here is some music to close: Mrs Robinson.

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[1] Schultz ST. & Gould GG. Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism Open Access. 2016 Apr;6(2). pii: 170.

[2] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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Schultz ST, & Gould GG (2016). Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism-open access, 6 (2) PMID: 27695658