Caesarean section births and autism risk?

It was a familiar story. Big media headlines such as: Caesarean sections 'may increase risk of autism' appearing all over, but when it came to finding the study behind the headlines, the publishing journal seemed to be trailing a little way behind. We've been in a similar situation before.

"As the flames rose to her Roman nose"

Anyhow, the paper by Eileen Curran and colleagues [1] (open-access) has finally made it to the research table and hence is fodder for today's ramblings with the suggestion that the way we make our grand entrance into the world might correlate with some heightened risk for autism spectrum disorder (ASD).

I have to say that I was initially quite interested in the Curran findings for quite a few reasons. Primary among them is some curiosity I have about the gut microbiota in relation to quite a few states and diagnoses (see here) and how our mode of entry into the world can seemingly impact on our first exposure to the bacterial passengers which eventually call us home. It is perhaps one of the lesser known observations, that the voyage down our dear mothers birth canal is also a great meet-and-greet opportunity for baby and bacteria. For those who don't get to experience such wonders, there is a suggestion that different types of bacteria might make friends which are then 'programmed' to be accepted by our developing immune systems [2] with onwards possible significance for future health and wellbeing. That being said, there is still a way to go to understanding such a relationship more thoroughly despite some intriguing results specifically with autism and the gut microbiome in mind (see here). I might also add that some of the authors on the Curran paper seemingly have some interest in the whole gut bacteria - behaviour relationship as per another recent paper [3].

The Curran paper is a systematic review of the literature which looked at: "mode of delivery on autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD)". They concluded that: "Thirteen studies reported an adjusted estimate for CS-ASD [Caesarean section-ASD], producing a pooled odds ratio (OR) of 1.23 (95% CI: 1.07, 1.40)". Said studies were analysed up to February 2014. The population attributable fraction calculated by authors implied that: "5.36% of cases of ASD may be attributable to delivery by CS assuming the observed association is causal".

The lead author is rightly cautious about their findings, as per some other comment in the media: “Parents should be reassured that the overall risk of a child developing ASD (Autism Spectrum Disorder) is very small and that Caesarean section is largely a very safe procedure and when medically indicated, it can be lifesaving,”. I wouldn't disagree with those sentiments allowing for the fact that (a) a fair proportion of deliveries these days are by C-section, and (b) not every child diagnosed with autism is delivered via C-section.

That being said, there does seem to be more to do in this area of science. Subsequent studies published after the cut-off point set by Curran have reported C-sections as a 'risk factor' for autism. The paper by Salhia and colleagues [4] for example, looking at the epidemiology of autism in [some] Arab Gulf countries found as much, alongside some other quite frequently reported variables potentially influencing autism risk (e.g. advanced maternal and paternal age).

I'm going to drop in a few additional papers and then I'm done. Chien and colleagues [5] also talked about C-sections as a risk factor for autism but with the added twist that the use of a general anaesthetic during said procedure might be implicated in any relationship. You might scoff at the suggestion that anaesthetic has anything to do with autism but before you do, perhaps have a read through the paper by DiMaggio and colleagues [6] first and slightly more speculatively, the paper by Johnson and colleagues [7]. The study by Chudal and colleagues [8] - mentioned by Curren et al - looking at various perinatal factors in the context of bipolar disorder is also worthwhile introducing bearing in mind that interest in such comorbidity is increasing in the context of some autism (see here). As with many other variables 'correlated' to autism risk, to shut the door on any association with comorbidity outside of just the diagnosis of autism is foolhardy.

Irrespective of your opinion about whether C-sections might be linked to autism risk and the other possible reasoning behind said suggestion [9], the Curran paper joins a growing list of variables potentially associated with autism. Systematic reviews and meta-analyses are consolidating quite a bit of this data, although as always the heterogeneity covered under the label of autism and the important issue of comorbidity need to be kept in mind. As with the growing idea that many small genetic issues might cumulatively be linked to [some] autism further compounded by more recent data [10] (see here for some media), so one might assume that multiple small contributions from the 'environment' might likewise also influence offspring risk of autism too. Determining how and when these genetic and environmental variables come together seems to be to be the next logical step...

Music to close: The Specials and Ghost Town. Have a spooky day!

----------

[1] Curran EA. et al. Research Review: Birth by Caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Journal of Child Psychology and Psychiatry. 2014. October 27.

[2] Weng M. & Walker WA. The role of gut microbiota in programming the immune phenotype. J Dev Orig Health Dis. 2013 Jun;4(3):203-14.

[3] Stilling RM. et al. Friends with social benefits: host-microbe interactions as a driver of brain evolution and development? Front. Cell. Infect. Microbiol. 2014. October 29.

[4] Salhia HO. et al. Systemic review of the epidemiology of autism in Arab Gulf countries. Neurosciences (Riyadh). 2014 Oct;19(4):291-6.

[5] Chien LN. et al. Risk of Autism Associated With General Anesthesia During Cesarean Delivery: A Population-Based Birth-Cohort Analysis. J Autism Dev Disord. 2014 Sep 26.

[6] DiMaggio C. et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51.

[7] Johnson B. et al. Fibromyalgia, autism, and opioid addiction as natural and induced disorders of the endogenous opioid hormonal system. Discov Med. 2014 Oct;18(99):209-20.

[8] Chudal R. et al. Perinatal factors and the risk of bipolar disorder in Finland. J Affect Disord. 2014 Feb;155:75-80.

[9] Gialloreti LE. et al. Are caesarean sections, induced labor and oxytocin regulation linked to Autism Spectrum Disorders? Med Hypotheses. 2014 Jun;82(6):713-8.

[10] Iossifov I. et al. The contribution of de novo coding mutations to autism spectrum disorder Nature. 2014. October 29.

----------

Curran EA, O'Neill SM, Cryan JF, Kenny LC, Dinan TG, Khashan AS, & Kearney PM (2014). Research Review: Birth by caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Journal of child psychology and psychiatry, and allied disciplines PMID: 25348074

Pain and adolescent Chronic Fatigue Syndrome

"We found a higher prevalence of severe pain among adolescents with CFS [Chronic Fatigue Syndrome] and lowered pain thresholds compared with HCs [healthy controls]".

That was the headline generated by the study from Anette Winger and colleagues [1] (open-access) looking to describe several parameters tied into experience of pain in the context of CFS. Further: "The total sum of bodily symptoms represented a heavy burden with great functional consequences".

Your hokey pokey dragon is out helpin' Santa Claus pull his sled!

The Winger paper is open-access, and pretty self-explanatory in terms of the hows and whys of the study (including strengths and limitations) so no need for me to further complicate things. As part of the NorCAPITAL project (The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial) (ClinicalTrial.gov entry here) which has already reported on the use of clonidine for CFS [2], the latest publication is an important add-on.

There are a few details included in the results which do however merit some additional highlighting. So:

• "In the present study, almost three-quarters of the adolescents with CFS suffered from weekly pain, and pain on a daily basis was a problem for half of the patients". This was "highly significant" when compared with reports from controls, particularly where two-thirds of CFS participants reported weekly headaches. 
• Muscle and joint pain were also recorded by adolescents with CFS alongside almost half reporting abdominal pain. Indeed, joint pain showed the most disparity between the groups with reports of such pain tipping 70% in the CFS group compared with only 10% of controls reporting this more frequently than once a month.
• When looking at result examining the pressure pain threshold (PPT) - "the minimum intensity of a stimulus that is perceived as painful" - and examining scores based on completion of the Brief Pain Inventory (BPI), authors concluded that: "At all measure points, PPTs were significantly lower (all p<0.001) among patients with CFS than HCs".
• "In our study, the adolescents reported that pain interfered with school, general activity and mood; however, we cannot conclude from this study that pain has a causal effect, because it could be the other way around". 

What's more to say about this research? Well, the very important message that the presentation of CFS might go well beyond just 'chronic fatigue' is paramount. This is not new news to science and practice as per the various reviews on the topic of pain exemplified by Nijs and colleagues [3]. I dare say that some public perceptions of CFS/ME would also change if more people understood that pain is a seemingly important manifestation of the condition. Oh and that CFS and pain sensation might not just be all in the mind...

I'm also inclined to introduce the condition fibromyalgia (FM) into proceedings, given the many and varied reports talking about key symptoms overlapping [4]. I'm not altogether sure of the hows and whys of FM and CFS connecting, but certainly the primary FM symptom of widespread pain and extreme sensitivity strikes me as being potentially important. With no medical advice given or intended and perhaps somewhat counter-intuitive to analgesia, the increasing body of work looking at the use of something like low-dose naltrexone (see here for some of my interest in this area) for pain in FM [5] may also very well be something in need of a little more study with pain in CFS in mind, alongside other possible pain relief options.

So then, The White Stripes with Ball and Biscuit.

----------

[1] Winger A. et al. Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. BMJ Open. 2014; 4(10): e005920.

[2] Fagermoen E. et al. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Research Notes 2012, 5:418

[3] Nijs J. et al. Pain in patients with chronic fatigue syndrome: time for specific pain treatment? Pain Physician. 2012 Sep-Oct;15(5):E677-86.

[4] Aaron LA. et al. Overlapping Conditions Among Patients With Chronic Fatigue Syndrome, Fibromyalgia, and Temporomandibular Disorder. Arch Intern Med. 2000;160(2):221-227.

[5] Younger J. et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38.

----------

Winger, A., Kvarstein, G., Wyller, V., Sulheim, D., Fagermoen, E., Smastuen, M., & Helseth, S. (2014). Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study BMJ Open, 4 (10) DOI: 10.1136/bmjopen-2014-005920

The stability of an Asperger syndrome diagnosis

"Asperger Syndrome, when considered as an ASD/PDD [autism spectrum disorder/pervasive developmental disorder] diagnosis, was fairly stable into adulthood, but there was a significant increase over time in cases no longer meeting criteria for an ASD diagnosis according to the DSM-IV, or AS according to the Gillberg criteria".

The night is darkest just before the dawn.

That was one of the primary conclusions made in the paper by Adam Helles and colleagues [1] who prospectively followed a group of males diagnosed with Asperger syndrome (AS) in childhood into adulthood covering a period of some 20 years. I believe the starting point of this study has been seen before in the peer-reviewed literature in the paper by Cederlund & Gillberg [2] (open-access here) (a paper which takes me back to my own PhD days with it's important influence to some of my work). Other follow-ups have also been reported [3].

Looking at the diagnostic stability of AS, Helles et al noted that compared with baseline where all participants fulfilled diagnostic criteria, at follow-up (two follow-ups actually) there was a "significant decrease in the rate of cases fulfilling any PDD diagnosis according to the DSM-IV, from 91% at T1 [time 1] to 76% at T2 [time 2] in the 47 cases followed up twice". The decline in cases according to the Gillberg criteria was even more stark (82% at T1 and 44% at T2).

Researchers also noted a few other potentially important points in their findings such that: "Severity of autism spectrum symptoms at T1 was the main predictor of diagnostic stability at T2" and a fifth of those who met criteria for DSM-IV criteria for a PDD diagnosis "did not meet DSM-5 ASD criteria although they had marked difficulties in everyday life". This last point has been mentioned by other authors (see here).

There are a few ways one could take the Helles findings. One could see it as further evidence of the fluidity of presented symptoms when it comes to the autism spectrum as per other discussions in this area (see here). You might even view it as an extension of all that chatter on something like differing developmental trajectories along the autism spectrum (see here) or 'optimal outcome' and autism (see here) albeit without the focus on early intervention as potentially being involved (see here) as far as we know. Indeed, one has to wonder whether for those not meeting the diagnostic criteria as they age and mature, this may in part be because of the various strategies learned over a lifetime to overcome some of the barriers posed by the diagnosis?

But I can also see how for some people such research might be less well-received particularly when added to the 'disappearance' of the term Asperger syndrome from the latest revision of DSM (DSM-V). The paper by Spillers and colleagues [4] described concerns about "identity, community, the cure movement, and services" following the DSM-5 changes when talking to people on the autism spectrum. I wonder how the Helles findings on 'falling out of the spectrum' diagnostically speaking for some, might have similar tones if and when discussed.

Accepting that the Helles findings were eventually based on quite a small participant group and their insinuation that not reaching the diagnostic thresholds for something like Asperger syndrome does not imply a life free of some of the more 'disabling' aspects on and around the diagnosis (yes, including various comorbidity), I do think there is more to see in this area. The realisation that we know so little about the autism spectrum in the long-term [5] and how behaviours ebb and flow, that our systems of diagnosis might not necessarily be as robust as we want them to be (see here) and the continued alliance between diagnosis and service receipt excluding many at the diagnostic periphery all come into play. With all the research data collected down the years, one suspects that with a little bit of organisation and willingness to plough some financial and other resources into this issue, further insight into exactly how stable an autism diagnosis might be and for who should be fairly readily available...

Music to close, and having enjoyed the impressive tones of Sheryl Crow last evening, a song most parents will have a heard a few times: Real Gone.

----------

[1] Helles A. et al. Asperger syndrome in males over two decades: stability and predictors of diagnosis. Journal of Child Psychology and Psychiatry. 2014. 3 October.

[2] Cederlund M. & Gillberg C. One hundred males with Asperger syndrome: a clinical study of background and associated factors. Dev Med Child Neurol. 2004 Oct;46(10):652-60.

[3] Cederlund M. et al. Asperger syndrome and autism: a comparative longitudinal follow-up study more than 5 years after original diagnosis. J Autism Dev Disord. 2008 Jan;38(1):72-85.

[4] Spillers JL. et al. Concerns about identity and services among people with autism and Asperger's regarding DSM-5 changes. J Soc Work Disabil Rehabil. 2014;13(3):247-60.

[5] Howlin P. et al. Cognitive and language skills in adults with autism: a 40-year follow-up. J Child Psychol Psychiatry. 2014 Jan;55(1):49-58.

----------

Adam Helles, Carina I. Gillberg, Christopher Gillberg, & Eva Billstedt (2014). sperger syndrome in males over two decades: stability and predictors of diagnosis Journal of Child Psychology and Psychiatry : doi: 10.1111/jcpp.12334

Zinc and depression

"Low dietary zinc intake is associated with a greater incidence of depression in both men and women, as shown in two prospective cohorts".

At the risk of overdoing the whole 'you are what you eat' sentiment, today I'm addressing a portion of the peer-reviewed research literature linking issues with zinc availability to depression. That opening quote by the way, comes from the paper by Khanrin Phungamla Vashum and colleagues [1] who looked at self-reported dietary intake of zinc based on data derived from "the Australian Longitudinal Study on Women׳s Health (women aged 50-61 years) and Hunter Community Study (men and women aged 55-85 years)". I'll come back to that shortly...

Absinthe is the aphrodisiac of the self

As I've mentioned once or twice before on this blog, the description of 'depression' covers quite a lot of diagnostic ground, with all-manner of correlations put forward to try and account for why depression is seemingly so prevalent in modern society. What does seem to be apparent from the voluminous literature is that various factors, at various times and under various situations seem to contribute to depression as a clinical condition with comorbidity also seemingly playing an important hand. In short, it's very, very complicated and very, very individual.

I've tended to talk more about the physiological correlates linked to various types of depression on this blog as per discussions as diverse as gut bacteria (see here) and autoimmune conditions (see here) and upcoming conversations on something like depression and inflammation. This on top of my borderline obsession with all-things vitamin D (see here). It's not that I'm not interested in the psychological or sociological side of things (as per some chatter about overlapping syndromes) but quantifying such factors is rather more difficult than for example, taking a blood sample and looking at the performance of compound X or gene Y. I'd also drop in the fact that quite a bit of the 'causative' research in the area of psychological and/or sociological factors seems to overlook important factors such as resilience too.

Anyhow, aside from the focus on 'self-report' noted in the Vashum study, which is notoriously problematic when it comes to recording eating habits and patterns, there is actually quite a bit of research already published on the topic of zinc and depression.

• The splendidly named Walter Swardfager and colleagues [2] published a very comprehensive review and meta-analysis on the topic of zinc and depression a little while back (covering the peer-reviewed text up to June 2012). Based on data looking at blood zinc levels in over 1500 people with depression compared against 800 asymptomatic controls, they concluded that: "Depression is associated with a lower concentration of zinc in peripheral blood". Indeed, zinc levels were: "approximately -1.85 µmol/L lower in depressed subjects than control subjects".
• Other studies have complemented the Swardfager findings albeit with zinc deficiency present in a more general context in psychiatry. The findings from Grønli and colleagues [3] (open-access) are a good example, whereby researchers reported: "a significant difference in zinc deficiency prevalence between the control group (14.4%) and the patient group (41.0%)" where the patient group consisted of "psychogeriatric patients" who were "compared with the elderly controls". The findings from Maserejian and colleagues [4] (open-access) also suggested some gender effect mediating the zinc-depression link; specifically: "inadequate dietary zinc intake contributes to depressive symptoms in women".
• Insofar as the reasons for zinc deficiency appearing in cases of depression, science is yet to settle on a definitive answer. The paper by Marcin Siwek and colleagues [5] (open-access) suggested three possible reasons: (i) nutritional deficiencies as per the Vashum findings, (ii) "hyperstimulation of the hypothalamic-pituatary-adrenal (HPA) axis, and the associated hypercortisolism" and/or (iii) the result of an inflammatory response "associated with oxidative stress". That last variable on inflammation and oxidative stress might also tie into other data on zinc supplementation "decreasing oxidative stress and generation of inflammatory cytokines such as TNF-alpha and IL-1beta" in certain patient groups [6]. I might also refer you to an excellent post by Dr Emily Deans titled: 'Zinc! An Antidepressant?' with a more detailed analysis of some of the possible hows and whys.
• The supplementation of zinc in cases of depression has also been covered in the research literature. As an adjunctive therapy, Ranjbar and colleagues [7] (open-access) reported that: "zinc supplementation together with SSRIs antidepressant drug improves major depressive disorders more effectively in patients with placebo plus antidepressants (SSRIs)". A review of some of the controlled trials prior to the Ranjbar results by Lai and colleagues [8] concluded similar things with regards to zinc as an 'add-on' treatment but that: "There is less clear evidence on the effectiveness of zinc supplementation alone on depressive symptoms of non-depressed healthy subjects". 
• Animal studies have complemented this collected literature as for example, reported by Tassabehji and colleagues [9] looking at rats; the authors suggested that: "zinc deficiency leads to the development of depression-like behaviors that may be refractory to antidepressant treatment".

There is quite a compelling scientific case for far greater research inspection of zinc in relation to depression and for example, further working out what it seems to be doing. Important too is the issue of who might be the best-responders to something like zinc supplementation in relation to depression/depressive symptoms.

That being said, I wouldn't want anyone to assume that I'm advocating zinc supplementation as some sort of cure-all for depression or anything else. To repeat myself: depression is a very complex set of conditions combining both biology and psychology. Science is still feeling its way around this area, despite the importance of nutrition to depression being increasingly recognised (see here).

So... Cosmic Girl by Jamiroquai.

----------

[1] Vashum KP. et al. Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts. J Affect Disord. 2014 Sep;166:249-57.

[2] Swardfager W. et al. Zinc in depression: a meta-analysis. Biol Psychiatry. 2013 Dec 15;74(12):872-8.

[3] Grønli O. et al. Zinc deficiency is common in several psychiatric disorders. PLoS One. 2013 Dec 19;8(12):e82793.

[4] Maserejian NN. et al. Low dietary or supplemental zinc is associated with depression symptoms among women, but not men, in a population-based epidemiological survey. J Affect Disord. 2012 Feb;136(3):781-8.

[5] Siwek M. et al. Zinc as a marker of affective disorders. Pharmacol Rep. 2013;65(6):1512-8.

[6] Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):646-52.

[7] Ranjbar E. et al. Effects of zinc supplementation in patients with major depression: a randomized clinical trial. Iran J Psychiatry. 2013 Jun;8(2):73-9.

[8] Lai J. et al. The efficacy of zinc supplementation in depression: systematic review of randomised controlled trials. J Affect Disord. 2012 Jan;136(1-2):e31-9.

[9] Tassabehji NM. et al. Zinc deficiency induces depression-like symptoms in adult rats. Physiology & Behavior. 2008; 95: 365–369

----------

Vashum KP, McEvoy M, Milton AH, McElduff P, Hure A, Byles J, & Attia J (2014). Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts. Journal of affective disorders, 166, 249-57 PMID: 25012438

Diagnosing autism late: after psychosis

The case report from Marly Simoncini and colleagues [1] (open-access) is the topic of today's post. Describing the case of Mr. A, a young man who attempted suicide during a psychotic episode, the paper tracks the developmental history and diagnostic evaluation of this person culminating in a diagnosis of autism spectrum disorder (ASD) "that had been completely overlooked".

The best thing we can do is go on with our daily routine

The paper is open-access and I would encourage readers to take some time to look through the narrative. Not only are some of the more commonly cited features of autism in childhood described in the paper as per his toy preferences and his wish to "play alone for hours with a few toys" but also other potentially important points: "He continued with selecting his food (white and squared foods only) and drinking milk only from his infant feeding bottle, until he was an adolescent". The outcome of various psychometric assessments specific to autism are also discussed, including his scores on the ADOS and ADI (see here) eventually placing him on the autism spectrum.

The important story of how this case report illustrates how much further we need to go in terms of awareness of autism across the lifespan is also complemented by the discussions on how the autism spectrum seems (in some cases) to merge with other spectrums. The authors note: "signs and symptoms of both a psychotic disorder and an ASD might run isolated or in clusters during the entire lifespan, often not reaching the threshold for a categorical diagnosis until adulthood". I might add that the 'autism overlooked' part of this study is probably not something common to modern-day autism (see here).

Treading quite carefully, I have, on a few occasions on this blog, talked about how there may overlapping presentation of autism and psychosis in some cases (see here and more recently here). Indeed not so long ago, I read a very personal account of a mother caring for a child on the autism spectrum and her experiences of a meltdown: "... apparently it used to be called ‘childhood schizophrenia’ and as I watched Ethan totally lost to me at that moment, in what looked like a possessed fit, I could see how it could have been labelled as schizophrenia". I should point out that schizophrenia is not the same as a 'possessed fit' (see here) but can, and does, present as a range of psychological symptoms as part of the psychosis spectrum (see here).

Of course, one should not forget that a diagnosis of autism is seemingly protective of nothing in terms of other somatic or psychiatric conditions to be present. It might also be nothing more than coincidence that autism and psychosis ran parallel in the case of Mr. A. That being said and on the back of other texts such as the go-to paper by Tom Berney [2], I do wonder if greater thought needs to be put into looking at autism across the lifespan. How, in amongst the sometimes fluidic changes in presentation according to factors such as maturation [3], further screening for issues such as psychosis should be more regularly implemented in order to mitigate any negative effects they may have both for the person concerned and their loved ones?

----------

[1] Simoncini M. et al. Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide. Case Reports in Psychiatry. 2014: 459524.

[2] Berney TP. Asperger syndrome from childhood into adulthood. Adv Psychiatr Treat. 2004; 10: 341-351.

[3] Helles A. et al. Asperger syndrome in males over two decades: stability and predictors of diagnosis. Journal of Child Psychology and Psychiatry. 2014. 3 October.

----------

Simoncini, M., Miniati, M., Vanelli, F., Callari, A., Vannucchi, G., Mauri, M., & Dell’Osso, L. (2014). Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide Case Reports in Psychiatry, 2014, 1-4 DOI: 10.1155/2014/459524

Autism and intolerance of uncertainty

Good morning, gentlemen,
the temperature is 110 degrees

'Change' is often mentioned as something potentially problematic for many on the autism spectrum, and how unexpected change can sometimes have profound effects in terms of those so-called 'challenging behaviours' or when it comes to the presentation of important comorbidity such as anxiety. Like many others from the outside looking in, I was always taught that change as a more general concept was the important issue in autism, but recently the word 'uncertainty' has been creeping into various discussions that I've seen and in particular, the concept of an 'intolerance of uncertainty' noted in cases of autism.

As far as I can ascertain, intolerance of uncertainty with autism in mind was first described in the peer-reviewed literature by Christina Boulter and colleagues [1] and subsequently by Sarah Wigham and colleagues [2]; both papers originating from the University of Newcastle, here in the bracing North East of England. The Boulter paper initially looked at how intolerance of uncertainty (IU) tied into the expression of anxiety in paediatric autism noting results "consistent with a causal model". The Wigham paper extended these findings, drawing on how the IU-anxiety relationship may also stretch to the presentation (interplay) of sensory issues among other things.

Focusing specifically on the Boulter paper, a few details might be in order (unfortunately the paper is not open-access)

• IU - defined as "a broad dispositional risk factor for the development and maintenance of clinically significant anxiety" - was assessed as part of a larger research platform looking at anxiety and autism.
• Derived from various sources (including the Daslne initiative), participants (N=224) including children/young adults diagnosed with an autism spectrum disorder (ASD) (n=114) and asymptomatic controls (n=110) were assessed for IU via the Intolerance of Uncertainty Scales (child and parent report versions). "The scale assesses IU by asking respondents to rate the extent to which statements relating to emotional, cognitive and behavioural responses to uncertainty are like them, or... like their child". Various other measures including the SRS and the Spence Children's Anxiety Scales (SCAS) were also delivered to participants.
• Results: well as if we needed telling "children with ASD showed higher levels of anxiety than TD [typically developing] children". As per previous discussion on quality of life and autism, the question of who reports anxiety (first person vs. second person reports) featured in the Boulter findings, although "disagreement appears to have been more pronounced in the TD group than in the ASD group". 
• Children with ASD were also reported to have "significantly higher levels of IU" and such elevations in IU "accounted for the increased levels of anxiety in the children with autism" hence the previous chatter about causal models et al. Perhaps also importantly, the relationship between IU and anxiety "was the same in both children with ASD and those without" so "similar processes may be at work within both populations".

There are some obvious caveats to these results. The authors point out that their focus on ability "within the normal range" as a function of their questioning is a limitation, and the 'caution' that goes with "generalising conclusions to all children with ASD". I might add that the introduction of a non-ASD anxiety-only control group would probably not have gone amiss either. Drawing on the more general literature on IU, the findings from Yook and colleagues [3] might also suggest that additional measures of worry and rumination (another important concept [4]) might have been useful to investigate too. This may be particularly important given the reports of overlap in depressive-type symptoms/syndromes occurring alongside cases of autism. Me being me, I would also have liked to seen some physiological measure(s) included too...

Still, I am rather intrigued by these initial findings on IU and how they may potentially fit into the often very disabling anxiety which can accompany a diagnosis of autism. If anything else, they may present a further target for intervention - bearing in mind the need for further research on the use of something like CBT for anxiety in autism - with the aim of improving quality of life.

Music to close, and continuing a recent theme on this blog: The Smiths and Ask (yes, I have been listening to their greatest hits, and yes, they probably were one of the best bands ever).

----------

[1] Boulter C. et al. Intolerance of uncertainty as a framework for understanding anxiety in children and adolescents with autism spectrum disorders. J Autism Dev Disord. 2014 Jun;44(6):1391-402.

[2] Wigham S. et al. The Interplay Between Sensory Processing Abnormalities, Intolerance of Uncertainty, Anxiety and Restricted and Repetitive Behaviours in Autism Spectrum Disorder. J Autism Dev Disord. 2014 Sep 27.

[3] Yook K. et al. Intolerance of uncertainty, worry, and rumination in major depressive disorder and generalized anxiety disorder. J Anxiety Disord. 2010 Aug;24(6):623-8.

[4] Hare DJ. et al. Anxiety in Asperger's syndrome: Assessment in real time. Autism. 2014 May 8.

----------

Boulter C, Freeston M, South M, & Rodgers J (2014). Intolerance of uncertainty as a framework for understanding anxiety in children and adolescents with autism spectrum disorders. Journal of autism and developmental disorders, 44 (6), 1391-402 PMID: 24272526

Autism, siblings and DSM-5 Social Communication Disorder

A quick post to bring to your attention the paper by Meghan Miller and colleagues [1] who concluded that: "Pragmatic language problems are present in some siblings of children with ASD [autism spectrum disorder] as early as 36 months of age". Further: "As the new DSM-5 diagnosis of Social (Pragmatic) Communication Disorder (SCD) is thought to occur more frequently in family members of individuals with ASD, it is possible that some of these siblings will meet criteria for SCD as they get older".

Isn't this a school day?

The DSM-5, as many in the autism community will already know, has been the source of quite a bit of discussion/argument as to how it has started to re-define what we label as autism or autism spectrum disorder. The initial signs have been that use of the DSM-5 criteria does indeed impact on the numbers of cases of autism (see here) and in particular, that the category termed 'Social Communication Disorder' (SCD) is filling up with those who might present with social communication issues without the repetitive or restricted behaviours required to fulfil the ASD label. Whether this implies the same levels of services and resources will be available to those with SCD as it is supposed to for those with ASD remains to be seen.

I did wonder whether the Miller findings were an important indication (although not the first [2]) that science might also be putting a bit more flesh on to the bones of the concept of a broader autism phenotype (BAP). Describing the subtle speech and language and social interactive issues described on the diagnostic borderlands of autism [3], it strikes me that there is more than a smidgen of overlap between SCD and the BAP (at least with more strength of data than the suggestion of a link between the BAP and postnatal depression). With cautions down the years about assuming "all children with pragmatic difficulties have autism" [4], does the advent of the SCD diagnostic category offer a viable alternative?

Music to close, and the sheer brilliance of Morrissey (live). And for those who might want to know a little more about the man behind the music: The Importance Of Being Morrissey.

----------

[1] Miller M. et al. Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder? J Child Psychol Psychiatry. 2014 Oct 15.

[2] Botting N. & Conti-Ramsden G. Pragmatic Language Impairment without Autism. Autism. 1999; 3: 371-396

[3] Dawson G. et al. Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives. Dev Psychopathol. 2002 Summer;14(3):581-611.

[4] Bishop DV. & Norbury C. Exploring the borderlands of autistic disorder and specific language impairment: a study using standardised diagnostic instruments.  Journal of Child Psychology and Psychiatry. 2002; 43: 917–929. doi: 10.1111/1469-7610.00114

----------

Miller M, Young GS, Hutman T, Johnson S, Schwichtenberg AJ, & Ozonoff S (2014). Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder? Journal of child psychology and psychiatry, and allied disciplines PMID: 25315782

Postpartum depression and the broader autism phenotype?

"The findings suggest that pregnant women with BAP [broader autism phenotype] have an elevated risk for PPD [postpartum depression]".

That was the conclusion reached by Ryosuke Asano and colleagues [1] based on their analysis of data derived from the Hamamatsu Birth Cohort (HBC) Study [2]. The idea being that the more subtle presentation of issues linked to a diagnosis of autism spectrum disorder (the BAP) might predispose to a great likelihood of other behavioural or psychiatric symptoms [3] to be present. We'll see about that.

What're you lookin' at, ya hockey puck?

The Asano paper is open-access but just in case...

• As part of the HBC study looking at pregnant women to ascertain "an early diagnostic algorithm for [offspring] ASD" [2] researchers garnered various snippets of information from over 800 pregnant women in mainland Japan.
• Covering mid-pregnancy to approximately 3 months after childbirth, women were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) (a tool fairly routinely used here in the UK) to "measure their depressive symptoms after childbirth". The EPDS was completed 3 times after childbirth (between 2-4 weeks, 5-7 weeks and 8-12 weeks).
• The BAP was assessed using the Broader Phenotype Autism Symptoms Scale (BPASS) [4] and administered via interview "mainly during the 2nd trimester of the pregnancy". Authors also did some additional work to "check whether our use of the BPASS is reliable and valid". Potential confounders such as a history of depression or anxiety and the level of emotional support provided by partners during pregnancy were also examined in participants; indeed, some 11% of the research cohort "had a history of depression and/or anxiety disorders".
• Results: "The overall cumulative incidence of PPD was 15.2%". This figure is not a million miles away from other estimates of PPD [4] based on the use of the EPDS (albeit with a slightly different cut-off point). Indeed, the HBC study had already hinted at something around this figure previously [5].
• Scores on the BAP were "weakly but positively associated with depressive symptoms after childbirth at all measurement periods". I have to say that despite these various correlations being significant, I was not particularly impressed with the correlation (r) values reported (ranging from 0.14 to 0.16 assuming 0 is no correlation and 1 is a perfect correlation). Indeed, when looking at the mean (average) composite score of the BPASS (see Table 1) between the PPD and non-PPD groups you can see there is very little difference in measured BAP (13.77 vs. 13.14).
• Again, based on the data provided in Table 1, of more interest is the effect of a history of depression/anxiety on PPD status, where 30/128 (23%) and 65/713 (9%) of the PPD and non-PPD groups respectively reported. The authors note that a: "history of depression and/or anxiety disorders was associated with a more than 3-fold increase in the risk of PPD".

With all due respect to the authors, I have to say that I'm not convinced that scoring high on the BAP is truly a major risk factor for postpartum depression. I'm not totally ruling out any relationship as per the Ingersoll findings on the BAP and depressed mood [3] or based on the increasing body of work looking at autism and subsequent mood disorders (see here for example). It's just that there are far more likely predictors/predisposers to PPD than subclinical autistic traits. Indeed, yet another paper from the HBC study [6] further hinted at some of those other factors based on that history of depression/anxiety among other things.

Music then... You've got the love (Florence + The Machine version).

----------

[1] Asano R. et al. Broader autism phenotype as a risk factor for postpartum depression: Hamamatsu Birth Cohort (HBC) Study. Research in Autism Spectrum Disorders. 2014; 8: 1672–1678.

[2] Tsuchiya KJ. et al. Searching for very early precursors of autism spectrum disorders: the Hamamatsu Birth Cohort for Mothers and Children (HBC). Journal of Developmental Origins of Health and Disease. 2010; 1: 158-173.

[3] Ingersoll B. et al. Increased rates of depressed mood in mothers of children with ASD associated with the presence of the broader autism phenotype. Autism Res. 2011 Apr;4(2):143-8.

[4] Verreault N. et al. Rates and risk factors associated with depressive symptoms during pregnancy and with postpartum onset. J Psychosom Obstet Gynaecol. 2014 Sep;35(3):84-91.

[5] Matsumoto K. et al. Age-specific 3-month cumulative incidence of postpartum depression: the Hamamatsu Birth Cohort (HBC) Study. J Affect Disord. 2011 Oct;133(3):607-10.

[6] Mori T. et al. Psychosocial risk factors for postpartum depression and their relation to timing of onset: the Hamamatsu Birth Cohort (HBC) Study. J Affect Disord. 2011 Dec;135(1-3):341-6.

----------

Asano, R., Tsuchiya, K., Takei, N., Harada, T., Kugizaki, Y., Nakahara, R., Nakayasu, C., Okumura, A., Suzuki, Y., Takagai, S., & Mori, N. (2014). Broader autism phenotype as a risk factor for postpartum depression: Hamamatsu Birth Cohort (HBC) Study Research in Autism Spectrum Disorders, 8 (12), 1672-1678 DOI: 10.1016/j.rasd.2014.08.010

Autism, parental concerns and socioeconomic status

I'd like to think that there are some rather important messages to be taken from the paper by Xiang Sun and colleagues [1] on level of parental concern, socioeconomic status (SES) and risk of autism. Not only did the authors conclude that: "a higher SES was not associated with the risk of having ASC [autism spectrum conditions]" they also found that: "No child met ASC criteria where parents expressed no concerns".

Do you prefer "fashion victim" or "ensembly challenged"?

SES - including variables such as family income, parental educational attainment(s) and parental occupation(s) - has been something of a talking point in autism research down the years and the rather mixed messages which have come out of the research literature on SES and offspring autism risk (see here). The growing appreciation that children of those positioned in a higher SES bracket don't seem to be at any significantly greater risk of autism is something rather important as per other evidence, for example, noted by Fujiwara [2]. Whether this means previous contrary findings were in error or that there has been some shift in the factors linked to the onset of contemporary autism is unknown at this time.

Some of my first thoughts on the Sun SES findings were in relation to all the discussions about offspring autism potentially being associated with certain types of parental occupational choices [3]. Indeed, considering that the Sun study was both carried out in and originated from Cambridge (UK) and included Prof. Simon Baron-Cohen on the authorship team, it is coincidental that the findings could be construed as counter to such occupational links with autism (assuming that Physicists, Engineers and Mathematicians would be described as higher SES jobs).

Of course I'm not saying the research on any relationship between offspring autism and parental occupation choice is all bunk; the paper from Windham and colleagues [4] and other evidence is too strong to negate (including that of occupational exposures potentially being involved). Merely that there may be much more to see than just a spectrum of 'talent' genes overlapping with autism risk genes [5] when it comes to receipt of a diagnosis on the very wide autism spectrum. Oh, and assuming you believe talent is all in the genes...

The other finding from Sun et al discussing parental concern and potential diagnosis of autism in offspring also carries quite a bit of potential importance. Regular readers of this blog might already have picked up my respect for parents and carers as active agents both in terms of picking up the signs and symptoms of autism in their loved ones (see here) and also detecting and reporting other important comorbidity (see here). I see the Sun findings - "No child met ASC criteria where parents expressed no concerns" - as corroborating parents and caregivers as doing what they do best: knowing their own child. I might also suggest that the discussions on increasing autism rates solely being down to better awareness and greater diagnostic vigilance are not seemingly backed up by the Sun findings if we assume parental concerns represent the starting point of the diagnostic journey into autism.

Some music to close. Gershon Kingsley and Popcorn.

----------

[1] Sun X. et al. Parental concerns, socioeconomic status, and the risk of autism spectrum conditions in a population-based study. Res Dev Disabil. 2014 Sep 25;35(12):3678-3688.

[2] Fujiwara T. Socioeconomic status and the risk of suspected autism spectrum disorders among 18-month-old toddlers in Japan: a population-based study. J Autism Dev Disord. 2014 Jun;44(6):1323-31.

[3] Baron-Cohen S. Does Autism Occur More Often in Families of Physicists, Engineers, and Mathematicians? Autism. 1998; 2: 296-301.

[4] Windham GC. et al. Autism spectrum disorders in relation to parental occupation in technical fields. Autism Res. 2009 Aug;2(4):183-91.

[5] Baron-Cohen S. Autism and the technical mind: children of scientists and engineers may inherit genes that not only confer intellectual talents but also predispose them to autism. Sci Am. 2012 Nov;307(5):72-5.

----------

Sun, X., Allison, C., Auyeung, B., Baron-Cohen, S., & Brayne, C. (2014). Parental concerns, socioeconomic status, and the risk of autism spectrum conditions in a population-based study Research in Developmental Disabilities, 35 (12), 3678-3688 DOI: 10.1016/j.ridd.2014.07.037

Antibiotics and childhood obesity: a weighty correlation

It's been a few weeks since the publication of the paper by L. Charles Bailey and colleagues [1] correlating early multiple exposure to broad spectrum antibiotics with obesity in infancy. On purpose I've left it a while before talking about this research so as to let the scientific dust settle a little and get a flavour for some of the discussions about this research (see here and see here).

You're a true vulgarian, aren't you?

A few details about the Bailey study first:

• Looking at the electronic records for a large cohort of children (~65,000), researchers picked out "Treatment episodes for prescribed antibiotics" based on prescription data before the age of 2 years.
• Anthropometric (growth) data was also determined from visits to healthcare providers between the ages of 2 and 5 years and compared with body mass index (BMI) norms derived from a large US-based survey, NHANES.
• Results: "Sixty-nine percent of children were exposed to antibiotics before age 24 months" with a rough average of 2 antibiotic prescriptions per child. For those who received 4 or more courses of antibiotics, the risk of obesity during early childhood was slightly elevated (11%) compared with those receiving fewer courses.
• The authors specifically focused on broad spectrum antibiotics as being correlated with infant weight issues; antimicrobials acting against a broad range of bacteria rather than more targeted pharmaceutics.
• They concluded: "Repeated exposure to broad-spectrum antibiotics at ages 0 to 23 months is associated with early childhood obesity". That being said, they also noted that various other factors seemed to correlate with infant obesity including: "Steroid use, male sex, urban practice, public insurance, Hispanic ethnicity, and diagnosed asthma or wheezing".
• I'm also minded to pull in a few other findings which did not get so many media headlines such as the reporting that at 4 years of age, 15% of the cohort were found to be obese and 33% overweight (source here).

The Bailey results are interesting insofar as the association being made between early antibiotic use and obesity but, as always, a little caution needs to be applied before reading too much into the findings. I note the BBC coverage of this article mentions limitations: "they were not able to look at the children's weight or exercise regimes" so correlation not necessarily being the same as causation comes into play. I might also add that whilst antibiotic stewardship is still a developing area, many/most antibiotic prescriptions are not just given willy-nilly as any parent with a young child suffering from an ear infection for example, will probably be able to attest.

I have kinda talked around this area of antibiotics and weight before on this blog (see here) and the implication that antibiotics, broad spectrum, by their very nature have a pretty profound effect on the trillions of bacterial beasties which inhabit places like the gastrointestinal (GI) tract. Carl Zimmer's post on swallowing a grenade (not literally) is a good starting point. The idea being that as well as helping digest our food, said bacteria (whether individual strains or through a more collective action) might also be able to influence a variety of issues like energy homoeostasis, weight management and even our risk of disease (see here and see here). If I take you back to some work looking at a particular bacterium called Akkermansia muciniphila you might get a flavour for this possible connection with weight in mind (at least in rodents).

I'm going to finish with another quote included with the BBC report on the Bailey findings. It comes from an independent commentary of the paper and sums up some important issues arising from reading this work:

"It would be a concern if parents took from this that they ought to be reluctant to allow antibiotic use in their children. The key risk factors for childhood obesity are over-consumption of high energy, nutrient-poor foods and lack of exercise."

Whilst I would perhaps suggest that 'energy in - energy out' is too simplistic an explanation of weight management issues (see here) I would agree that under the right circumstances, antibiotics still make a valuable contribution to the medicines cabinet, and obesity is, very much, a multi-faceted condition.

Music... Stevie Wonder and Superstition.

----------

[1] Bailey LC. et al. Association of Antibiotics in Infancy With Early Childhood Obesity. JAMA Pediatr. 2014. 29 Sept.

----------

Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, & DeRusso PA (2014). Association of Antibiotics in Infancy With Early Childhood Obesity. JAMA pediatrics PMID: 25265089

Reasons for visiting ER by those with autism

ER - Emergency Room - or as we call it here in Blighty Accident & Emergency (A & E), is never a particularly desirable place to visit given the emphasis on illness or injury of yourself or loved one. That being said, staff there do a sterling job sometimes under very stressful circumstances, responding to all-manner of complaints, some of which are life-threatening.

The paper by Dorothea Iannuzzi and colleagues [1] sought to identify some of the medical reasons why ER visits were made by people on the autism spectrum. They concluded that, depending on age, epilepsy or seizure-type disorders and "psychiatric conditions" were well represented in cases of autism based on data derived from the US 2010 National Emergency Department database.

Realising that epilepsy / seizure-type disorders seem to have more than a passing connection to quite a few cases of autism (see here) and can, in some cases, lead to that most extreme of outcomes (see here), I'm not going to focus any further on this part of the Iannuzzi findings. Rather the finding that: "Psychiatric conditions were primary among ASD individuals aged 12-15 years, accounting for more than 11 % of all visits" merits some further analysis.

The findings reported by Kalb and colleagues [2] documenting that: "Thirteen percent of visits among children with ASD [autism spectrum disorder] were due to a psychiatric problem, as compared with 2% of all visits by youths without ASD" provides further evidence for the extent of the Iannuzzi finding. Whilst treading carefully in this area of autism research, one detail stuck out from the Kalb report, whereby ER visits due to psychotic disorders seemed to be increased in likelihood compared to visits by asymptomatic children/youths. This seemed to tie in well with my recent discussions on the observations of Maibing and colleagues [3] and the risk/onset of schizophrenia spectrum disorders following a previous child or adolescent psychiatric diagnosis.

Unfortunately, my discussions on the research literature on ER visits and autism do not get any happier as I turn to the body of work looking at suicide attempts and autism, and as per the conclusion from Kato and colleagues [4], "ASDs should always be a consideration when dealing with suicide attempts in adults at the emergency room". Again, I've covered the very sensitive topic of suicide (ideation and attempts) and autism previously on this blog (see here and see here) and as we speak further research has emerged pertinent to this topic [5]. Though sometimes quite uncomfortable to discuss, this collected work emphasises how we all really need to be talking a lot more about this issue and what can be done to divert people away from this most extreme type of behaviour. Admission to the ER - which will often be the first point of contact after such behaviour - could be a good place to start having those discussions.

In amongst the literature talking about the ER and autism, there are other details which provide a rather more positive discussion about this topic. Take for example, the paper by Giarelli and colleagues [5] looking at the ways and means ER might be made more comfortable to [some of] those on the autism spectrum. Similarly, the guidance supplied by McGonigle and colleagues [6] talking about ways of managing agitation in the ER for those on the autism spectrum might also be better referenced in this clinical setting. Oh, and a bit more knowledge about medical comorbidities potentially affecting people with autism would probably not go amiss more generally.

I should conclude that whilst I've focused on some of the more frequently reported reasons why people with autism might present to the ER, one shouldn't forget that all the other reasons why the general population go to the ER are similarly as pertinent to those on the spectrum. That being said, I very much doubt that "help with removing false nails" would feature on most people's reasons to attend hospital...

----------

[1] Iannuzzi DA. et al. Brief Report: Emergency Department Utilization by Individuals with Autism. J Autism Dev Disord. 2014 Sep 27.

[2] Kalb LG. et al. Psychiatric-related emergency department visits among children with an autism spectrum disorder. Pediatr Emerg Care. 2012 Dec;28(12):1269-76.

[3] Maibing CF. et al. Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophr Bull. 2014 Sep 5. pii: sbu119.

[4] Kato K. et al. Clinical features of suicide attempts in adults with autism spectrum disorders. Gen Hosp Psychiatry. 2013 Jan-Feb;35(1):50-3.

[5] Takar K. & Kondo T. Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case–control study. Annals of General Psychiatry 2014, 13:33.

[6] Giarelli E. et al. Sensory stimuli as obstacles to emergency care for children with autism spectrum disorder. Adv Emerg Nurs J. 2014 Apr-Jun;36(2):145-63.

[7] McGonigle JJ. et al. Management of agitation in individuals with autism spectrum disorders in the emergency department. Child Adolesc Psychiatr Clin N Am. 2014 Jan;23(1):83-95.

----------

Iannuzzi DA, Cheng ER, Broder-Fingert S, & Bauman ML (2014). Brief Report: Emergency Department Utilization by Individuals with Autism. Journal of autism and developmental disorders PMID: 25261249