"Cognitive behavioral therapy for children with autism spectrum disorder"

I'll admit that I was the one with the furrowed brow when the paper by René Kurz and colleagues [1] cropped up on my research radar. Detailing results from a "prospective observational study", authors set out to examine "the effectiveness of cognitive behavioral therapy (CBT) in children with autism spectrum disorder (ASD)." They concluded that: "CBT is an effective therapy for children with ASD." You'll note that I've underlined the word 'children' in those past sentences...

OK, CBT represents one of the talking therapies that seem so popular these days. The NHS Choices website describes it as being based on "the concept that your thoughts, feelings, physical sensations and actions are interconnected, and that negative thoughts and feelings can trap you in a vicious cycle." Kurz et al applied such principles to autism, and specifically what effect CBT had based on pre- and post-scores on the Aberrant Behavior Checklist (ABC) over 12 months. They observed significant changes to things like irritability, lethargy and hyperactivity, and called for further investigations.

Why my furrowed brow on this topic? Well, several reasons. Methodologically, the Kurz study was pretty weak. A participant group of 9 boys, including pre- and post observations over 12 months, no control group, no blinding, no comparison intervention... not exactly a stand-out study. It's not inconceivable that changes to behavioural presentation might have been due to lots of other reasons aside from the use of CBT (and that's before one considers how N=9 might impact on the statistical methods used by the authors).

Then there's the use of CBT. I know that CBT is finding some favour when it comes to 'managing' certain conditions/symptoms over-represented in relation to autism such as anxiety (see here for example). The purpose however of the Kurz study was slightly more specific: "To evaluate prospectively the effectiveness of cognitive behavioral therapy (CBT) in children with autism spectrum disorder (ASD)." It strikes me that in much the same way that CBT is being utilised in relation to another set of conditions (see here), the focus on the 'biopsychosocial' angle in the context of autism harks back to a shady past. And yet again, I'm going to emphasise the word 'children' in the Kurz study group.

I don't want to totally poo-poo things like talking therapy in the context of 'some' autism. I don't doubt that for some on the autism spectrum, there could be some merit in 'breaking down' thoughts and feelings in order to try and help resolve some more problematic features. I don't doubt that just being able to talk to someone about things like feelings and the like is probably going to be useful for some people including young children aged 6 or 7 years old.

But the idea that children (with a mean age of about 6 years old) are somehow going to be responsive to CBT in the context of their autism seems to be based on something a little more 'old-fashioned' in the authors' thinking. Y'know, going back to those days when sweeping (and illogical) psychological theories had a stranglehold on the way that autism was viewed. I'm also minded to mention that CBT and related therapies are not somehow 'side-effect' free, even if science needs to do more to report on possible adverse effects (see here).

The evidence for using something like CBT in the general context of autism is not great (see here). Part of this is because methodologically vigorous trials are still few and far between [2] and with regards to using children as participants, even more few and far between. I know psychology and psychological theory upon which CBT is based, still wants to play a part when it comes to autism - one need only look at the continuing fixation on Theory of Mind (ToM) to see that. But there must come a time when one steps back and asks whether a talking therapy will significantly impact on the core features of a developmentally-defined condition with strong evidence for an organic basis? Would we for example, ever entertain the use of CBT 'for' a condition like phenylketonuria (PKU) for example, where autism can and does occur alongside? No, we wouldn't.

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[1] Kurz R. et al. Cognitive behavioral therapy for children with autism spectrum disorder: A prospective observational study. Eur J Paediatr Neurol. 2018 May 30. pii: S1090-3798(17)31856-1.

[2] Weston L. et al. Effectiveness of cognitive behavioural therapy with people who have autistic spectrum disorders: A systematic review and meta-analysis. Clin Psychol Rev. 2016 Nov;49:41-54.

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"weak evidence that EIBI may be an effective behavioral treatment for some children with ASD"

Today I bring to your attention the 'Cochrane does...' findings reported by Brian Reichow and colleagues [1] which concluded that: "There is weak evidence that EIBI [early intensive behavioral intervention] may be an effective behavioral treatment for some children with ASD [autism spectrum disorder]."

The Cochrane in the term 'Cochrane does...' refers to the Cochrane Database of Systematic Reviews, an important resource that provides systematic reviews on various aspects of healthcare that help inform practice and policy. I've talked about them a few times previously on this blog (see here and see here). EIBI - "a treatment based on the principles of applied behavior analysis" - is something that has been part and parcel of the autism research scene for many years. It aims to 'target' the early presentation of autism in both severity and "functional behaviors and skills" among other things; in the context to 'modify' the presentation of autism and "lessen the impact of symptoms on children's functioning."

The Reichow review found five studies that examined EIBI in the context of autism or autism spectrum disorder (ASD) and included over 200 children. They concluded that: (a) "No adverse effects were reported across studies" following the important tenet: first, do no harm, (b) there was "weak evidence that children receiving the EIBI treatment performed better than children in the comparison groups after about two years of treatment on scales of adaptive behavior, intelligence tests, expressive language (spoken language), and receptive language (the ability to understand what is said)", and (c) "Differences were not found for the severity of autism symptoms or a child's problem behavior."

Although the overall key message from authors was one that: "The evidence supports the use of EIBI for some children with ASD", the authors caution that the evidence base in this area remains weak. They mention that: "only a small number of children were involved in the studies, and only one study had an optimum design in which children were randomly assigned to treatment groups." There is a requirement for more [longitudinal] investigation following more 'rigourous' methodological designs.

I've always been in two minds about the usefulness of EIBI and autism, and indeed, early behavioural intervention in general. Yes, infants and young children are always going to be reactive to the behaviour of those around them, but the inference that the course of autism can be universally and significantly 'affected' by [various] structured programs of this type, has always been a challenge to me (see here). I've been particularly worried about headlines reporting that something like 'super-parenting' could potentially affect the presentation of autism (yes, someone did actually say that) and the connotations stemming from them. I also have concerns coming from a perspective that the behavioural presentation of autism probably comes about for various reasons in various people; some of them are likely linked to biology, as per the examples of various inborn errors of metabolism manifesting autism (see here) and autism presentation following viral or bacterial infection (see here and see here). In such cases, it strikes me that one perhaps needs to look at the biology first rather than the presented (secondary) symptoms in a sort of 'catch-up' manner. I know that last sentence is likely not to sit well with some people who follow the sweeping generalisation that autism is innate and immutable, but there are some good examples in the peer-reviewed research literature on well-controlled intervention studies of this type (see here and see here). And yes, there needs to be more longitudinal follow-up in these areas too...

I'm not totally poo-pooing the idea of EIBI in the context of autism, but rather, would wish to see greater long-term, controlled evidence before grand sweeping generalisations and big headlines are made. A better focus on 'sub-groups' might also be quite useful when it comes to possible best- and non-responders [2] to the various interventions put forward with autism in mind...

To close, a crow with a Yorkshire accent. This is what the internet was made for.

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[1] Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2018 May 9;5:CD009260.

[2] Paynter J. et al. Differential outcome subgroups in children with autism spectrum disorder attending early intervention. J Intellect Disabil Res. 2018 May 23.

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Baby teeth, metals and autism part 2

Consider this post on the findings reported by Paul Curtin and colleagues [1] which concluded that "altered zinc-copper rhythmicity precedes the emergence of ASD [autism spectrum disorder]" an extension of other previous discussions on this blog (see here). The research starting material was, once again, baby teeth, including teeth derived from an interesting initiative called "the Autism Tooth Fairy Project" based in Texas, USA.

On the last blogging occasion, the paper by Manish Arora and colleagues [2] was central to my discussions, and the use of some really interesting analytical technology to look at levels of various metals in tooth layers: Laser ablation-inductively coupled plasma mass spectrometry. Fast forward a year or so, and authors (including Arora) moved on to bigger and better things, this time focusing specifically on the metals zinc and copper "from the second trimester to approximately 1 year postnatally." Such a feat was achieved because baby teeth, much like the rings of a tree, provide a sort of 'album' of levels of such metals over a child's earliest years. Both these metals and their ratio also have some previous research 'form' when it comes to autism (see here).

"Our participants were recruited from four different studies being undertaken in three countries." Yep, so alongside teeth from the RATSS study initiative (aptly named the 'roots' of autism/ADHD study) forming a discovery dataset, authors also examined teeth gathered as part of other research initiatives including a favourite here in Blighty: the Avon Longitudinal Study of Parents and Children (ALSPAC). These non-RATSS teeth formed a replication set (to try and replicate the data found in the discovery set). Add in some nifty statistical analysis and set lasers to stun or should that be ablate...

Results: authors reported finding "strong evidence for abnormalities in zinc-copper cycles in ASD characterized by shorter duration, lower complexity, and less determinism." A quick translation: well, I'll be honest and tell you that I'm not exactly sure what that actually meant. I think it had something to do with the way the data were analysed, being "analogous to a spectrogram." Suffice to say that levels of copper and zinc were seemingly different in those diagnosed with autism compared with not-autism controls at different tooth time periods. When all this metal data was analysed using some statistics designed to try and 'classify' those with autism from those not-autistic, authors also noted zinc-copper cycles in teeth "allowed for a robust classification of ASD cases and controls." So: "Using optimal threshold criteria, this model was 90% accurate in predicting ASD cases, with 100% sensitivity for ASD diagnosis and 85% specificity to controls." Those stats aren't bad when one considers the importance of sensitivity and specificity to any classifying 'test'.

Although interesting, one has to bear in mind that this research was based on the use of baby teeth and their possible 'retrospective' association with autism. Nobody is advocating pulling out baby teeth as some sort of autism test! The focus on metals however, and specifically "measures of metal rhythmicity" provides some welcome information about how such 'rhythms' *might* show differences in relation to autism. This could reflect things like differing 'exposure' patterns or, more likely, some innate differences in the biological 'processing' of such metals. On that last point, this work potentially fits in with what is emerging in other independent data: metal (various metals) metabolism in the context of some autism seems to be 'unusual' (see here).

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[1] Curtin P. et al. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Science Advances. 2018. 30 May.

[2] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.

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Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

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[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

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More welcome research on post-exertional malaise (PEM) in ME/CFS

The findings reported by Lily Chu and colleagues [1] provide the blogging fodder today, and some further welcome research into the concept of post-extertional malaise (PEM) in the context of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).

PEM represents a cardinal feature of CFS/ME, where physical exertion - whether covering exercise or even just daily activities - brings about a period of (even more) exhaustion, weakness and fatigue. As per my previous discussion of the paper by McManimen and colleagues [2], there's still some ambiguity when it comes to clinically defining PEM (and indeed, whether the word 'malaise' covers the range of symptoms that the term includes). What is clear however is that PEM is real and can be absolutely disabling.

The Chu study, including the name Jose Montoya on the authorship list, set out to "describe symptoms associated with and the time course of PEM." Authors designed an online survey "asking subjects about the history and course of their ME/CFS" that asked a few questions about PEM. This included: "1) What symptoms, if any, are triggered or worsened by physical or mental activity?; 2) What symptoms are triggered or worsened by emotional distress?; 3) How soon usually after starting mental or physical exertion does your illness begin to worsen?; and 4) If you feel worse after activities, how long does this worsening usually last?" They also describe how they were careful not to actually use the word 'PEM' during the course of their research in order to "try to decrease the chances that subjects already diagnosed with ME/CFS would automatically answer our question based on their knowledge of or preconceived notions about PEM." Smart move.

Results: some 150 people as part of something called the MGEISD (Genetic Expression and Immune System Dynamics) study responded to the survey. While some of the participants were formally diagnosed with ME/CFS, the cohort also included those "waiting to be seen at the clinic, members of online ME/CFS forums, and participants of local ME/CFS support groups." Although all were telephone screened to see "if they fitted Fukuda 1994 CFS criteria" one does need to be a little careful with describing such a process as providing anything approaching a 'homogeneous' group.

"Most subjects (N = 129, 90%) experienced PEM with both physical/ cognitive exertion and emotional distress." There didn't seem to be any specific 'rules' in terms of the connection between the 'stressor' and onset of PEM, although around 40% of participants reported experiencing PEM within 24 hours. This was however subject to quite some variation. Symptoms reported in relation to the PEM questionnaire items were also variable. Fatigue is up there as one would expect, but also things like sleeping issues and headache were noted. Around 40% of participants also reported on a constellation of PEM symptoms: fatigue, sleep disturbance, pain and "at least one immune-related symptom."

What is becoming a little clearer from this and other research is that (a) PEM or whatever you want to call it is a real issue for many people diagnosed with CFS/ME and (b) the symptoms of PEM are not necessarily uniform in either character or timescale (onset, duration, etc.) What's still missing? Well, biology is still missing from quite a lot of the PEM literature; biology in terms of what PEM looks like on a physiological level and whether there may be something that can be done to alleviate it at a biological level aside from resting up (often for days at a time). I've talked about this before on this blog, in terms of biologically characterising PEM and how, for example, it might look in terms of defining recovery from ME/CFS (see here). To that end, lots more investigation in this area is implied...

And while on the topic of ME/CFS, I'll draw your attention to the paper by Karfakis [3] talking about the "biopolitics of CFS/ME." Yes, there has been and continues to be lots of that, including the phrase: "CFS/ME is an illness trapped between medicine and psychology". Discuss in 500 words.

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[1] Chu L. et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811.

[2] McManimen SL. et al. Deconstructing post-exertional malaise: An exploratory factor analysis. Journal of health psychology. August 2016:1359105316664139.

[3] Karfakis N. The biopolitics of CFS/ME. Stud Hist Philos Biol Biomed Sci. 2018 Jun 8. pii: S1369-8486(17)30070-5.

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Constipation in kids with autism: financial as well as health implications

I've always be a little perplexed about the response to gastrointestinal (GI) issues appearing alongside autism. Time after time after time, the peer-reviewed science domain serves up evidence that both functional and more pathological bowel issues are over-represented in autism (see here and see here for examples) and cause considerable suffering. Yet some parts of the lay and research community seemingly 'gloss over' such findings. It's almost as if the acceptance that 'some' autism seems to be 'bowel-related' would shatter some people's view of autism. Perhaps it's also because there would have to be some [partial] acceptance of other related uncomfortable findings too (see here)...

The findings reported by Brandon Sparks and colleagues [1] continue the theme that functional bowel issues such as constipation are part and parcel of some autism. And not only do they have often severe health implications for the person concerned, but there may also be wider economic implications too. So, researchers concluded that: "ED [emergency department] visits by children with ASD [autism spectrum disorder] were more likely to be constipation-related compared with visits by children with other chronic conditions or children with no chronic conditions." Further: "Hospital charges were higher in children with ASD than in those without chronic conditions."

Based on data derived from the Nationwide Emergency Department Sample (NEDS), a US initiative that records diagnostic trends in ER (also known as Accident & Emergency here in Blighty) visits, authors looked for those with and without a diagnosis of autism (ASD). They observed that constipation was an important variable in those ER visits when it came to autism and continued to be important when ER visits turned into hospital admissions. They conclude by saying that there may be a need for "developing more effective outpatient therapies for constipation in children with ASD."

Constipation might not sound like a condition that requires an ER visit. But if and when it does, I guess you could probably say that it's something quite serious. Just as reports in relation to those with a learning disability have highlighted how constipation is (a) over-represented, and (b) has actually been cited as a cause of death (see here), so perhaps you can see why there should be a lot more urgency in this area of the autism research and practice landscape.

I added in the 'financial as well as health implications' bit to the title of this post to stress how, even if someone chooses to ignore the pain and physiological effects that constipation can cause, such symptoms are also placing quite a burden on resources and finances. I personally don't much like the idea of talking too much about 'how much autism costs' but if that's the only way to make people listen and actually do something about bowel issues in relation to autism, then I'm quite willing to continue to talk money and strains (no pun intended) on resources...

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[1] Sparks B. et al. Constipation in Children with Autism Spectrum Disorder Associated with Increased Emergency Department Visits and Inpatient Admissions. The Journal of Pediatrics. 2018. June 1.

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