Bullying and autism: not always originating from where you might expect...

There is something rather uncomfortable about the findings reported by Imar Toseeb and colleagues [1] but, at the same time, they do raise an important issue that needs to be openly discussed. Specifically their findings on: "sibling bullying, and the associated psychopathological adversities, in children with and without ASD [autism spectrum disorder]" deserve some airtime.

Bullying and autism is quite a regular talking point in the peer-reviewed research literature (see here) and beyond. Although a diagnosis of autism is by no means protective of someone becoming a bully or being involved in what could be considered bullying behaviour, it is far more typical that those with autism are going to be a victim of bullying rather than perpetrator (see here). Indeed, I reluctantly use the word 'vulnerable' yet again on this occasion but...

When one thinks about bullying in any context including that with autism in mind I would imagine that the school bully who name calls or becomes physical aggressive towards someone - usually smaller and quieter than them - probably first springs to mind. Siblings by contrast, conjure up an image of being caring, supportive and again, with autism in mind, often very protective of their brother(s) and/or sister(s) given their important role, present and probably future. And indeed, many, many siblings are just that (see here).

But real life is rarely so clear-cut or 'homogeneous' as many parents, whether with children diagnosed with autism or not, will attest. Siblings argue, fight and probably because of how well they 'know each other', often know all the right buttons to press to get their required reaction. And yes, behaviour sometimes can spill over to what would be considered bullying under any other circumstance...

Toseeb et al started with the hypothesis that: "children with ASD (child has ASD but their sibling does not) would experience higher levels of sibling bullying compared to those without ASD (child and sibling do not have ASD)." They arrived at this hypothesis on the basis of various factors such as a role for the social-communicative issues that follow autism, the possible effect of the 'broader autism phenotype' (BAP) on siblings, and issues such as a greater frequency of aggression - "reactive aggression" - accompanying particularly boys with autism.

They relied on data from the Millennium Cohort Study (MCS) (a resource that has been mentioned before on this blog) and eventually included data from nearly 500 children with autism alongside over 13,000 not-autism controls. The question(s) on sibling bullying were asked at 11 years of age and went: "he/she was asked to respond to two questions on a six-point scale (never, less often, every few months, approximately once a month, approximately once a week, most days): “how often do your brothers or sisters hurt you or pick on you on purpose?” (victimization) and “how often do you hurt or pick on your brothers or sisters on purpose?” (perpetration)." Responses were coded according to who did what and how often. Various other measures were also examined as part of the MCS and used in the Toseeb paper: socio-demographic data (single parent status, birth order, number of siblings, household incomes), parenting style, psychopathology and cognition.

Results: children diagnosed with autism or ASD were more likely to be bullied by their non-autistic sibling compared with those who did not have autism. This finding held "even after controlling for socio-demographic and family level variables" and "was associated with adverse psychopathologies." Further: "having ASD, being a girl, of White ethnicity, having more siblings, and experiencing harsher parenting were all associated with increased odds of being bullied by a sibling." Whilst we're on the topic of 'adverse psychopathologies, it's perhaps pertinent to mention the findings reported by Dantchev and colleagues [2] observing a possible connection between sibling bullying receipt and psychotic disorder. Yes, it is quite an extreme example, but nonetheless demonstrates the effects bullying can have long-term. I might also refer you back to some discussion arising from the ICF core sets development with autism in mind too (see here).

I digress. I note also that authors discuss sibling bullying as a two-way street: "Our findings indicate that children with ASD are specifically at increased risk of sibling victimization as a bully-victim."

As I said at the beginning of this post, this all makes for uncomfortable reading. If it's not bad enough that a child may be being bullied at school to also then potentially learn that there is little respite from such behaviour at home, makes for an uncomfortable (intolerable?) situation all-round. The question then arises minus any sweeping generalisations: what can be done about sibling bullying for the good of all concerned? And please, don't just solely suggest 'coping strategies' for the bullying victim either.

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[1] Toseeb U. et al. The Prevalence and Psychopathological Correlates of Sibling Bullying in Children with and without Autism Spectrum Disorder. J Autism Dev Disord. 2018 Feb 8.

[2] Dantchev S. et al. Sibling bullying in middle childhood and psychotic disorder at 18 years: a prospective cohort study. Psychological Medicine. 2018. Feb 12.

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Regression in autism: the rule rather than the exception?

"Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD [autism spectrum disorder] and may be more the rule than the exception."

So said the findings reported by Sally Ozonoff and colleagues [1] who reported results based on a study of developmental / behavioural regression in autism, and specifically: "how rates of regression differed by measurement method."

Regression in relation to autism is a topic I've covered a few times on this blog (see here and see here for examples). I've followed the [peer-reviewed] story from where behavioural and/or developmental regression was initially thought to be a figment of the [parental] imagination, right up to these days where regression is pretty much accepted as being part and parcel of quite a few cases of autism. The road has not been a smooth one; but the question of whether autism is universally something inborn and hereditary for everyone is slowly starting to be answered: no, it is probably not. The reason(s) for regression still remain fertile grounds for discussion / debate / argument, but there are some important clues in the science literature (see here and see here for examples) with the caveats that autism is a very heterogeneous condition and onset patterns are likely to be influenced by all-manner of different variables. Think different phenotypes in the context of autism (see here) for example; and that's outside of the label previously known as Heller's syndrome.

Anyhow, Ozonoff et al report results for infants "with (n = 147) and without a family history of ASD (n = 83)" who were "seen prospectively for up to 7 visits in the first three years of life." Various different ways and means of assessing reports of symptom onset were collected, "that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective)."

Depending on who said what and how they said it, patterns of regression in skills were noted in quite a large proportion of the Ozonoff cohort. So: "A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings." The authors suggest that their observations highlight how quite a few more resources (and cautions) need to go into looking at symptom onset patterns in relation to autism.

For quite a few people, the findings reported by Ozonoff et al are 'catch-up' rather than something novel. I can think of quite a few instances where parents / guardians have had their important observations - very important observations - described as being 'talked down' when it came to reporting a regression in previously acquired skills in the context of autism. This should no longer be the case; particularly when also set in the context of the increasing pluralisation of the label of autism (see here) and perhaps even, the changing face of autism (see here) compared with yesteryear.

Then to the next important questions: how and why? I've already alluded to a role for infection in relation to the onset of regressive autism for some, but much more data is required on the specific details and mechanisms. There is also the issue of what *might* potentially be done to minimise factors linked to regression in autism too. Minus any sweeping generalisations, I'd also direct your attention to other mentions of regressive autism in the peer-reviewed science literature [2] and where, minus any hype, there could be some important clues for some. The important point once again, is that the diagnosis of autism should be the start of further investigations, not the finishing line.

To close, don't ask me how or why but one of my brood has started watching and enjoying an old staple part of the weekend TV quiz scene in 1980s Blighty... BFH by the way, is most classically referred to as your 'bus fare home'.

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[1] Ozonoff S. et al. Onset patterns in autism: Variation across informants, methods, and timing. Autism Res. 2018 Mar 10.

[2] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

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"A pilot study of high-dose intravenous immunoglobulin 5% for autism"

Intravenous immunoglobulin (IVIG), the treatment of choice for "patients with antibody deficiencies" [1] has some research history when it comes to autism (see here).

Quite a few years back, I remember some chatter about the use of IVIG for at least a subset of children/adults diagnosed with autism [2]. Interest in IVIG subsequently waxed and waned, partly as a result of some politics 'accompanying' research but also because of things like the cost of such an intervention.

Judging by the recent results published by Isaac Melamed and colleagues [3] however, it looks however, like IVIG *might* be coming back into research fashion...

So: "we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD [autism spectrum disorder]." The words "immune dysregulation" and "neuroinflammation" are mentioned a few times in the Melamed paper so you can probably work out the reason(s) why IVIG was examined. I might add that this study appears to have been registered with ClinicalTrials.gov too (see here).

This was a pilot study so, of course, one always needs to be a little bit cautious when it comes to the study and any findings. But, from what I can see, the authors put in place quite a few 'primary' and 'secondary' endpoints covering various aspects of behaviour - "Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]" - and also some 'experimental' biomarkers of immune function in this study. That's quite a comprehensive battery all-in-all.

Based on the use of a "high-dose intravenous immunoglobulin" (1g/kg dose of Gammaplex 5%) for ten 21-day treatment cycles with some 14 research participants diagnosed with autism, researchers reported some signs of 'effect'. Behaviourally speaking, they talk about significant improvements in core areas such as reciprocal social interaction, communication and repetitive and/or stereotyped behaviours being observed. This, alongside significant reductions in "numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation." In short, IVIG seemed to show effects and, importantly: "no subjects withdrew due to an adverse event" providing some well needed 'first, do no harm' data.

One study - an open label study at that - does not an evidence base make. Not even close, and that's despite other open label studies also being published [3] in this area. One also needs to bear in mind that IVIG is a blood product typically derived from more than one donor which, although screened for various infectious diseases, might still leave some people a little nervous about its use.

But... results such as the ones from Melamed cannot be easily ignored. Not least set within the context of a growing interest in immune function being *related* to some autism (see here for example) and specifically where 'regression' seems to be part and parcel of symptom onset (see here and see here), further [controlled] investigations are required. And that includes what happens to any behavioural / immunological gains / changes as and when IVIG intervention is stopped too...

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[1] Jolles S. et al. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. 2005;142(1):1-11.

[2] Gupta S. Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999 Mar;14(3):203-5.

[3] Melamed IR. et al. A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation. Autism Res. 2018 Feb 10.

[4] Boris M. et al. Improvement in children with autism treated with intravenous gamma globulin. Journal of Nutritional & Environmental Medicine. 2005; 15.

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The ICF core sets for autism in action

The findings reported by Soheil Mahdi and colleagues [1] (open-access available here) reiterate that 2018 looks like being the year of the ICF core sets for autism.

Having covered this topic yet again only recently (see here), I'm back to talking about the core sets and, once again, get to use the beautiful word 'melange' with reference to the "complex melange of functioning experiences beyond the diagnosis" of autism.

This time around it was about trying to "capture aspects of functioning and contextual factors pertaining to individuals with ASD [autism spectrum disorder] as assessed by the ICF-CY [International Classification of Functioning, Disability and Health (ICF, and Children and Youth version, ICF-CY)] in a clinical practice setting." I must admit to making a cold shudder when seeing the words: "The ICF-CY is grounded on an interactive bio-psycho-social model of functioning" in light of what the biopsychosocial model has 'done' to other conditions (see here). But in this case, I'm willing to give it the benefit of the doubt... at least for now.

So, from a starting participant group of 126 children, adolescents and adults with ASD (even though researchers used the children and youth version of the ICF), this number was slightly whittled down to some 122 who completed the study. It was a worldwide effort, as participants were drawn from 10 countries and, perhaps notably, the United States and United Kingdom were not among the countries taking part on this occasion. I was pleased to read that inclusion criteria for the study was a diagnosis of autism of course, but also did not exclude participants who also presented with "any given common co-morbidity." This, in light of 'autism plus' perhaps being more 'realistic' than autism appearing in some sort of diagnostic vacuum (see here).

Results: "In total, 139 of 161 ICF-CY categories assessed met the cut-off in at least 10% of the participants." The authors observed that this included "64 categories in the activities and participation component, 40 body functions and 35 environmental factors." Although you can look for yourself what issues/factors are included under those headings, I might point out a few of interest including the handling stress and other psychological demands, sensory functions and pain, functions of the digestive, metabolic and endocrine systems and the role of immediate family.

Continuing: "Examples of supportive personal factors included high IQ, acceptance towards own diagnosis and specific interests (e.g., art, sports)." These are also interesting. The role of 'acceptance towards own diagnosis' is something that has cropped up before in the peer-reviewed literature (see here). On that research occasion, the authors leaned towards a role for 'others' (external sources) accepting a person with a diagnosis of autism as being potentially 'positive' when it came to good mental health in the context of autism. I was perhaps more sceptical of the primacy of this 'other' influence - based as it was on rating statements such as "over the past week, I have felt accepted by society as an autistic person/person with autism" on a 5-point scale - insofar as 'personal acceptance' potentially being the more important variable. The Mahdi data seems to agree. The other 'supportive' variable, talking about having specific interests such as art or a sport, also tallies with a lot of other independent research findings (see here for an example, also using a certain WHO tool relevant to the ICF core sets for autism).

Onwards: "Past traumatic life events (e.g., getting bullied at school) were mentioned as a hampering personal factor, as it affected the individual’s self-esteem and self-worth." This, alongside various other routes to stress that "exacerbate ASD symptoms", provides some useful information about what could be done to mitigate such negative influences. I'm not sure that it is possible to completely eradicate issues such as perfectionism, but I daresay that it could be minimised through certain talking interventions for example, thus potentially improving quality of life. Insofar as the role bullying might play, well, probably quite a bit (see here) and any efforts to reduce things like bullying at school should be welcomed.

I do want to pass one final comment on the Mahdi data going back to the issue of comorbidity appearing alongside autism. As I've mentioned, this was a study that did not shy away from comorbidity being central to quite a few people diagnosed on the autism spectrum. The types of comorbidity reported included old friends such as attention-deficit hyperactivity disorder (ADHD), present in about a quarter of participants, and intellectual (learning) disability, present in about 15%. Whilst part of the clinical picture for quite a few, there is always the possibility that some of factors discussed in relation to the ICF core sets for autism *may* be more directly influenced by such comorbidity than by the 'core features' of autism themselves. I guess it doesn't matter if said comorbidity is part of the clinical picture, but if it's not, there may be some assumptions being incorrectly generalised...

And it appears that autism is not alone in its receipt of the ICF core sets treatment [2]...

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[1] Mahdi S. et al. An International Clinical Study of Ability and Disability in Autism Spectrum Disorder Using the WHO-ICF Framework. J Autism Dev Disord. 2018 Feb 8.

[2] Mahdi S. et al. An international clinical study of ability and disability in ADHD using the WHO-ICF framework. Eur Child Adolesc Psychiatry. 2018 Feb 17.

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Physical conditions accompanying intellectual disabilities

By linking to some media discussing the inquest findings for Richard Handley (see here) I don't want to trivialise his death or use it as some kind of 'I told you so' example. Here was a man who died as a result of "gross failures" in his care as someone with Down's syndrome who also had a history of bowel issues. His death, linked to chronic constipation and "as a result of choking on his own vomit having inhaled gastric contents following complications with surgery", represents failures on many different levels. Not least is a seeming lack of appreciation of how bowel issues can very much be part of the clinical profile of many conditions / labels / diagnoses considered within the spectrum of intellectual or learning disabilities. Said issues require both regular monitoring and appropriate and timely intervention.

It is perhaps notable then that the paper by Deborah Kinnear and colleagues [1] is published these days, highlighting how various physical conditions are over-represented alongside diagnoses characterised by intellectual (learning) disability. The authors reported that: "The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders."

Based on the examination of data for "people with intellectual disabilities living within the geographical area of Greater Glasgow Health Board, Scotland" between 2002 and 2004, researchers reviewed case records and "completed a comprehensive semi-structured health interview and targeted physical examination and followed a phlebotomy protocol, with the person with intellectual disabilities and their carer." This was time consuming affair - the "complete assessment process took about 4 hours per participant" - covering over 1000 people.

Alongside the reporting of those 'top five most prevalent conditions', researchers also observed several other important details. Namely that nearly all of their cohort had a least one co-existing health condition. The average number of comorbid conditions was 11. Yes, that's 11. And some people had over 25 comorbid physical conditions. When also taking into account the presence or not of Down's syndrome, not much changed in relation to the detected physical comorbidity. Similarly, when age and sex/gender were examined, the authors concluded that there only minor differences noted in terms of comorbidity profiles for example.

Relevant to the case of Richard Handley are some discussions in the Kinnear paper about constipation and learning disability. So: "Constipation was the fourth most prevalent physical health condition." Further, they note in another study [2]: "Eight people with chronic constipation had serious side effects (rectal prolapse, diverticula of colon, intestinal obstruction, megacolon and haemorrhoids) and four eventually died of intestinal obstruction... Thus, as well as being painful, constipation may remain undetected for a long time and can cause death due to missed clinical symptoms." Constipation can cause death. It shouldn't in this day and age, but it still does...

In relation to the implications of their findings, the authors make some additional comments. So: "Medical education is also focused on assessment and management of single conditions, yet management of multimorbidity is far more complex." This is important. It implies that outside of the view of one [primary] diagnosis being present per patient, clinicians and others need to have a more plural view, particularly when it comes to something like learning disability. The focus also on 'physical' comorbidities is also important insofar as how various developmental / behavioural / psychiatric conditions can very much manifest other non-developmental / behavioural / psychiatric conditions. This kinda mirrors what has been discussed with autism in mind (see here and see here for examples) and, alongside, the barriers that need to be overcome when it comes to appropriate diagnoses being made in such contexts (see here).

Set within other data indicating that premature mortality is very much over-represented when it comes to learning disability (see here), and that much of that early mortality is due to the presence of physical health conditions, the Kinnear findings should serve as a wake-up call to many sectors of the professional and other communities. Screening, diagnosing and implementing timely and appropriate intervention(s) are key recommendations; with a specific focus on the person as a whole rather than just being the sum of individual somethings like the diagnosis of learning disability. Bear in mind also that guidance on the management of something like constipation in the context of learning disability does exist in the peer-reviewed domain [3].

And finally, just in case you think that today's discussions aren't directly relevant to autism, constipation has also been mentioned in the death of another young person (see here)...

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[1] Kinnear D. et al. Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study. BMJ Open. 2018; 8: e018292.

[2] Evenhuis HM. Medical aspects of ageing in a population with intellectual disability: III. Mobility, internal conditions and cancer. J Intellect Disabil Res. 1997 Feb;41 ( Pt 1):8-18.

[3] Robertson J. et al. Constipation management in people with intellectual disability: A systematic review. J Appl Res Intellect Disabil. 2017 Nov 23.

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"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

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[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

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