A role for viral infection in the aetiology of coeliac disease?

"In this longitudinal study, we found that a higher frequency of enterovirus infections was associated with increased risk of coeliac disease."

So said the findings reported by Christian Kahrs and colleagues [1] (open-access available here) based on the results of their: "Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016."

Following the screening of some 47,000 infants for the 'genetics of coeliac disease' - HLA genotype DR4-DQ8/DR3-DQ2 - over 900 children were entered on to the study. This group were followed "with repeated blood and faecal samples from the age of 3 months" for quite a few years. Just over 500 participants who quite regularly donated blood samples, were asked if they wanted a screen for coeliac disease. Two hundred and twenty of them (or their parents/guardians) said 'yes please' and the study results were drawn from this group. Twenty seven of the 220 participants with those all-important coeliac risk genes were diagnosed with the condition. Twenty five of those 27 diagnosed with coeliac disease were matched against 50 of the no coeliac disease participants; matching was done "for duration of follow-up, date of birth, and county of residence." It was then just a case of looking at all the biological data that had been accrued from those blood and fecal samples to ascertain things like (a) "the time interval when cases seroconverted for coeliac disease markers" (i.e. when the antibodies diagnostic of coeliac disease began to be present) and (b) if and when enterovirus was detected in some of the samples (stool samples) via PCR (polymerase chain reaction).

Results: as shown in the supplementary material, the mean age at first presence of coeliac disease (CD) antibodies in the CD diagnosed sample (n=25) was around 42 months (when the first positive sample was recorded). Symptoms 'debut' was around an average age of 73 months and CD diagnosis was received on average at 87 months. Enterovirus was reported in both CD (n=25) and non-CD groups (n=49). Some 20% of the stool samples from the CD group were positive for some kind of enterovirus exposure compared with 16% of controls. Slightly more enterovirus positive stool samples were observed in the CD group (median 4 positive samples per child) than the control group (median 3 positive samples per child).

As per the opening quote to this post: "Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls." Further: "The association was restricted to infections after introduction of gluten." In other words, there seemed to be some evidence of a possible temporal connection between enterovirus and the development of CD, suggesting that enterovirus exposure and not gluten was the more important trigger for CD.

Mechanisms? Well, there's some speculation about that in the Kahrs paper and a: "plausible explanation is that enterovirus causes impaired barrier function, which in turn increases the risk of coeliac disease." Enterovirus causing impaired intestinal (gut) barrier function eh? Interesting, does that mean 'leaky gut' might have a viral origin in some cases? Mmm, that could have lots of implications...

Obviously more investigation is required in this area. The Kahrs study has some strengths in terms of the sample collection protocols and frequency and potentially establishing a temporal *link* between CD and enterovirus exposure. But there's still more to do: "unmeasured confounding factors or residual confounding can never be entirely ruled out in non-randomised studies." But don't let that take anything away from the potential importance of these findings.

And on the topic of prospectively following children who might be prone to develop coeliac disease, the study findings published by Lionetti and colleagues [2] are equally interesting. In particular, based on 23 of their 26 children who received a "potential diagnosis of CD" but nonetheless "continued a gluten-containing diet... 19 (83%) became antibodies negative at 1 year from the first biopsy and remained negative up to 10 years of follow-up." Could there be a tie-up with the Kahrs findings perhaps?

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[1] Kahrs CR. et al. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ. 2019 Feb 13;364:l231.

[2] Lionetti E. et al. Long-Term Outcome of Potential Celiac Disease in Genetically at-Risk Children: The Prospective CELIPREV Cohort Study. J Clin Med. 2019 Feb 5;8(2). pii: E186.

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"The most common peri-onset events reported by subjects were infection-related episodes (64%)"

The quote titling this post - "The most common peri-onset events reported by subjects were infection-related episodes (64%)" - comes from the (open-access) findings reported by Lily Chu and colleagues [1] continuing something of a research theme from this authorship group examining myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) (see here).

Indeed, it's probably no coincidence that the Chu cohort of "150 subjects fitting Fukuda 1994 CFS criteria" is the same as that used in their other research [2] when discussing another important issue: "post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome."

On this most recent publishing occasion, Chu et al set out to: "Describe ME/CFS onset and course in one United States-based cohort." They did this via the use of "a detailed survey" that asked various questions about the first stages of participants' illness and what this eventually led to. The results obtained weren't exactly unexpected, but yet again stress how lots of things 'assumed' about ME/CFS really need to be properly verbalised in the peer-reviewed science literature (see here and see here for other examples). Of particular note in the Chu findings pertinent to inquiry on the 'course' of ME/CFS is this important snippet of information: "Based on available data, the median age of illness onset was 36.6 ± 12.3 years and median duration of illness was 12.5 ± 10.1 years." That's 'median duration of illness was 12.5± 10.1 years'.

Results: "The most common peri-onset events reported by subjects were infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%)." Infection or rather 'infection-related episodes' came out top of the pops with regards to possible onset events. I've said 'possible onset events' in that last sentence not to be belittle the first-hand reports obtained, but rather to emphasise how we're still in a bit of a 'not knowing' state when it comes to definite causative infective agents and ME/CFS onset. Yes, there is some quite strong evidence that infections caused as a result of Epstein–Barr virus (EBV) seem to be involved in some cases of ME/CFS (see here) but more often that not, people aren't screened for every possible viral or bacterial agent. At this point, I'd also hark back to the viral 'hit-and-run' hypothesis that has been talked about in some ME/CFS circles recently (see here and see here) and what this also means.

Onward: "For the overwhelming majority of patients (96%, n = 141), their illness did not improve with time although different patterns of illness were seen." That last sentence really speaks for itself in terms of what ME/CFS means in the long-term. That's not to say that symptoms did not 'fluctuate' - "59%, fluctuating (symptoms could change in severity but were always present)" - but participants on the whole did not 'shake off' their disability. And when it came to some details about how symptoms ebbed and flowed over the course of time, Chu et al have some data on that too: "Over time, flu-like symptoms, fatigue, unrefreshing sleep, and exertion-related items decreased the most, by between 12 and 25%... Cognitive symptoms present at the beginning of the illness tended to persist, declining by only 4–10%." Further focus on 'cognitive symptoms' is perhaps important [3].

Further: "Ninety-seven percent suffered from at least one other illness: anxiety (48%), depression (43%), fibromyalgia (39%), irritable bowel syndrome (38%), and migraine headaches (37%) were the most diagnosed conditions." The authors phrase this in the context that "patients with co-morbid medical or psychiatric conditions are the rule rather than the exception" when it comes to ME/CFS. But just before anyone starts making noises that anxiety and depression are so significantly present in this cohort and probably beyond, such findings does not open the door to any psychobabble 'biopsychosocial' (BPS) explanations about the cause/perpetuation of ME/CFS. I think many patients (and researchers) have had quite enough of all that (see here).

The Chu paper is a comprehensive one and adds to our knowledge about ME/CFS. It has its limitations - "reliance on subject self-report, recall bias, and relative superficiality of some survey items" - but no more or less than lots of other ME/CFS research. It hopefully will open the door to a lot more similar study; perhaps also including the odd biological measure also.

And just before you go, I'll draw your attention to the findings reported by Katherine Rowe [4] who also asked a cohort of participants with ME/CFS about their illness experiences. There's a few important matching details included in the paper - "Eighty percent reported a defined onset following an infection" - but also some other noteworthy information. One such observation was that: "Many indicated the need to be sensitive about when psychological assistance is offered... They were sensitive as to whether this was implying that psychological issues were the “cause.”." It's not difficult to see why patients with ME/CFS would think such [BPS] things.

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[1] Chu L. et al. Onset patterns and course of myalgic encephalomyelitis/ chronic fatigue syndrome. Front. Pediatr. 2019. Jan 16.

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

[3] Robinson LJ. et al. Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction. PLoS One. 2019 Feb 5;14(2):e0210394.

[4] Rowe KS. Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service. Front Pediatr. 2019 Feb 21;7:21.

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Regression and autism: "The regression group was significantly more functionally impaired..."

The quote forming part of the title of today's post - "The regression group was significantly more functionally impaired..." - comes from the findings reported by Lucy Thompson and colleagues [1] (open-access available here). It continues something of an important theme in autism research circles whereby regression, as in a regression of previously acquired skills, is being seen as important not just for a few but for many (see here).

There were a few aims to the Thompson study such as establishing "the relative prevalence of regression in autism" and "possible predictors, mediators and moderators of regression in autism, including pre- and perinatal factors." The data for the study were derived from "two community-based cohorts" in Sweden totalling just over 300 participants (children) diagnosed with an autism spectrum disorder (ASD) who were observed over two different time points (T1 and T2 2 years later). Another important detail is mentioned by Thompson et al: "Given the lack of previous systematic representative studies in the field, our study sets out to be descriptive rather than hypothesis-driven." Figures and details on regression in the cohort(s) were obtained via specific questioning on this topic "defined as loss of expressive language skills (loss of 5 or more words that had been used communicatively) in connection with the onset of autism." This data was also combined with other medical records information to determine 'consistency'.

Results: "Just over 20% (62/303) of the combined sample of children had regressive autism." That's 1 in 5 children with autism experiencing some kind of regression in relation to language skills. When looking at those who regressed (n=62) compared with those with no regression (n=241), a few details emerged: "Those with regressive autism had a younger age when they first walked... had a more severe language impairment at T1... and more often intellectual disability... [and] lower mean VAB [Vineland Adaptive Behaviour Scales-II] scores." Also: "Severity of autism was higher in the regressive group, with a higher proportion of children with autism... (as opposed to autistic-like condition)."

This is important data. It kinda tallies with other studies of regression accompanying autism suggesting that those who regress tend to have a more 'severe' form of autism with accompanying learning (intellectual) disability. The diagnostic issues - as in more likely to be diagnosed with Kanner's autism rather than other diagnoses - similarly ties in with other findings.

Caveats? Well, a few: "We have chosen to focus on language regression specifically (rather than social, play or motor regression) as communication is by far the most common skill to be lost or diminished in regressive autism." That being said, regression accompanying autism seems to take many, many forms and does not always just mean a loss or partial loss of vocal communication (see here).

Also: "There was also a similar level of maternal disease in pregnancy in the regressive and non-regressive groups, suggesting that prenatal exposure via maternal disease does not seem to be a key feature in the development of regressive autism." I have to question why the authors stuck to looking at just pre- and perinatal factors as possibly being *linked* to regression when regression is likely to occur quite some time after such a developmental window. Surely it would have made more sense to ask a few further questions about the timing of regression - "The average age at regression was 20.13 months... with 54 children (88.5%) showing regression by the age of 24 months" - and whether one or more event might have proceeded such regression in a similar time frame. Y'know whether infection might be a feature (see here and see here for examples) or whether other events might require further investigation (see here). I know this might take such research down some uncomfortable paths, but temporality is surely an important factor for some regression in some cases of autism? Or am I being too unreasonable?

I might also advance the idea that the time to start asking questions about the biology of regression accompanying autism is fast approaching. We've already had some clues in the recent (at the time of writing) peer-reviewed research literature (see here) but lots more needs to be done in this area. Are there important genetic and/or epigenetic variables to consider? Do mitochondrial issues play a role in some regressive autism (see here)? We just don't know enough yet. And yes, this does mean also asking about whether regression in behaviour or cognitive skills was also accompanied by any changes to somatic variables too (see here).

And then there is another question to ask/answer: does regression mean that certain 'therapeutic' options might be particularly useful? I'm thinking back to some research a few years back talking about corticosterioid therapy *potentially* being indicated for some cases of regressive autism (see here). No, I'm not making any medical or clinical claims or giving any advice on such an issue. Merely mentioning that regressive autism needs to be more of a research priority than it currently is. To quote Thompson and colleagues again: "Children with a regressive developmental trajectory, with or without autism, always need a careful neuropediatric work-up to investigate possible neurological disorders that may lead to developmental regression, taking into account possible treatable conditions." Who would argue with that?

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[1] Thompson L. et al. Autism With and Without Regression: A Two-Year Prospective Longitudinal Study in Two Population-Derived Swedish Cohorts. J Autism Dev Disord. 2019 Feb 4.

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"Has Daniel always been autistic?"

"Has Daniel always been autistic?"

That was the question that led to Twitter uproar and newspaper headlines calling a TV presenter an 'idiot' and "embarrassing" and "ignorant" these past few days. Some have even called for veteran daytime TV presenter Richard Madeley to be sacked, as one of the premier national autism charities here in Blighty authoritatively announced "autism is a lifelong condition, people are born autistic, it’s not something a child grows out of" following the reporting of an interview between Madeley and Daniel Wakeford, one of the stars of the not particularly well titled TV series called The Undateables. Personally, I would have liked to have seen said charity comment on how the term 'undateable' really shouldn't be used in this day and age with any diagnosis/label in mind...

Emotions ran high following the interview, as many parents of children with autism and autistic people voiced their opinions about their own personal experiences of autism. These are all valid opinions. The problem however, is that within the wide - very wide - heterogeneity that is autism, some of the peer-reviewed science on the topic of autism actually supports the line of questioning from Madeley. Some of the peer-reviewed science highlights the sweeping error in saying that autism is (a) lifelong for everyone and (b) that everyone, past, present and future is 'born autistic'.

OK, first things first, autism is a label ripe for sweeping generalisations. We've seen it numerous times as psychological theories for example, have swept through proclaiming that everyone with autism is lacking a theory of mind or empathy or some other related construct. Likewise, I've seen people quite vehemently opine that autism is the product of this or that 'environmental factor' insinuating that simple changes to drink, food or medicines use for example, will 'stop autism'. The reality however is that autism is a label used to describe vast heterogeneity. It's also a label that says nothing about how a person came to be autistic and nothing about the prognosis of their presentation or their life in general.

So what is the cold, objective peer-reviewed scientific evidence to say that autism is not present from birth for everyone? Well, it's multi-fold. It comes from a number of studies that have followed children from early infancy into later childhood to see whether autism *always* manifest from the very earliest days. Take the recent findings from Sally Ozonoff and colleagues [1] (see here for my take) that concluded among late diagnosed children in their cohort: "Seven showed very little evidence of ASD [autism spectrum disorder] in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology." Add it to other independent data [2] that "validate parents' reports that ASD may appear after a period of nonautistic development" (also that "such reports should not be attributed to recall bias") and then throw in the idea that 'regression', as in a regression of previously acquired skills, is perhaps no stranger to many instances of autism (see here). Then to top it all add in other data highlighting specific cases of 'acquired autism' following exposure to particular post-natal infections for example (see here), and the old 'autistic from birth' mantra does not universally hold for everyone diagnosed as being on the autism spectrum. The evidence against the sweeping 'autism is a lifelong condition' statement made following the interview? I'll direct you to some of the numerous occasions that I've talked about such an idea on this blog (see here and see here and see here) based again on the available peer-reviewed science. Cold. Objective. Science.

Minus making any sweeping generalisations of my own, there is scientific evidence out there that 'born autistic' is not something that can be universally applied to everyone on the autism spectrum no matter how many people would like it to be so. In that respect, the question from Richard Madeley was not ignorant nor disrespectful but rather quite sensible and easily discernible from the available science. The fact also that Daniel's mother Carol talked about a 'loss of his language abilities' in her reply to the question (something I'm sure must have been mentioned before the interview took place and was aired) kinda adds to the sound reasoning for Madeley to ask. It also implies that science should keep studying such an important phenomenon.

It seems that when Carol Wakeford responded with the words 'yes, well there's controversy about that' as the first part of her answer to Madeley's question about Daniel, she certainly wasn't wrong...

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[1] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):849-857.e2.

[2] Landa RJ. et al. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007 Jul;64(7):853-64.

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On autism symptom trajectories and diagnosing autism late...

It's another one of my mash-up posts today, as two paper are brought to the blogging table. The first paper is from So Hyun Kim and colleagues [1] and looked at the rather interesting topic of differing symptom trajectories in the context of diagnosing autism. The second paper by Sally Ozonoff and colleagues [2] follows in a similar vein in terms of their analysis of children "who had undergone multiple comprehensive assessments in preschool and were determined to be ASD [autism spectrum disorder]-negative, only to meet criteria for ASD when tested in middle childhood."

Both these paper originate from well-respected autism research groups and appear in the same respected journal (Journal of the American Academy of Child & Adolescent Psychiatry). The common theme between them is that within the significant heterogeneity seen under the label of 'autism', there are various different developmental and presented symptoms trajectories, some of which (a) are not as stable as one might imagine, and (b) do not seemingly follow the oft-used assertion that 'autism is present and manifests from birth'. Indeed, on that last point, the implications are that autism is sometimes very much associated with regression (see here) and onward, that genetic and/or non-genetic post-natal factors may very well influence some children reaching clinical cut-off thresholds for a diagnosis of autism (see here for example).

So, to the Kim paper first: authors looked at over 900 "observations of the Autism Diagnostic Observation Schedule (ADOS)" from nearly 150 young children. They were specifically looking at symptoms trajectories based on those ADOS scores and whether or not 'clusters' of similar symptom trajectories were evident. The answer: yes, yes there were some different clusters of symptom trajectories noted. Not six developmental trajectories as per other research (see here) but four clusters: "Nonspectrum ∼25%; Worsening ∼27%; Moderately-Improving ∼25%; Severe-Persistent ∼23%)." Authors also report how: "Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, the level of baseline and final verbal/nonverbal abilities, and symptom severity."

Then to the Ozonoff paper: "Fourteen children met inclusion criteria for the Late Diagnosed group and were compared to a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at age 3." Authors focused in on these 14 children and concluded that: "Seven showed very little evidence of ASD in preschool, while seven demonstrated subtle, subthreshold symptomatology." They also suggest that their results identifying a small but important group of children who seemingly first present with 'typical' behaviour but then 'grow into' the presentation of autism "shed light on reasons why the mean age of ASD diagnosis remains over 4 years." Indeed (see here).

I don't really need to say much more than I have already on these studies. Aside that is, from reiterating that the autism spectrum is truly wide and heterogeneous in both symptom presentation and also it seems, with regards to symptom onset and stability too. Alongside other research (see here) talking about how the presentation of autistic signs and symptoms wax and wane for some, I'm wondering when autism research is going to start looking beyond just presented behaviour, at whether for example, genetic and biological 'changes' might accompany such fluidity in behaviour and 'cluster' differences. Y'know, the same way that another group seemingly heading in the opposite direction - those who 'lose their diagnosis' (see here and see here) - also need to be closely investigated from a biological point of view too. It's only when we have such biological data that we can then start meaningfully probing the possible hows-and-whys...

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[1] Kim SH. et al. Variability in Autism Symptom Trajectories Using Repeated Observations from 14 to 36 Months of Age. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 5.

[2] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 3.

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Healthcare use before, during and after a diagnosis of CFS/ME

"Adults and children with CFS/ME [chronic fatigue syndrome / myalgic encephalomyelitis] have greater health care needs than the rest of the population for at least ten years before their diagnosis, and these higher levels of health care resource use continue for at least ten years after diagnosis."

So concluded the study published by Simon Collin and colleagues [1] (open-access available here) who once again (see here) relied on data derived from the "Clinical Practice Research Datalink (CPRD) GP practices in the UK" to further explore aspects of the debilitating condition(s) headed under the banner of CFS/ME.

Using a case-control design, researchers set out to "investigate long-term patterns in health care resource use before and after a diagnosis of CFS/ME." They had a hypothesis in mind before any study results were produced in that "health care resource use would increase from around the time of patient-reported onset of illness... until diagnosis" but "did not have a prior hypothesis about post-diagnosis health care resource use, although this might be expected to fall if diagnosis led to referral and effective treatment."

Their results based on "916 child (age <18 years) and 6710 adult patients" suggested a few things: (i) "a steep drop in resource use immediately after diagnosis was followed by sustained higher levels of health care resource use for at least ten years after diagnosis", (ii) adults and children with CFS/ME tended to have greater healthcare resource use "for at least ten years before the diagnosis", and (iii) allied to that last point: "there were steep increases in use of health care resources 2–4 years before diagnosis in adults and 1–2 years before diagnosis in children." Healthcare resource use, by the way, was defined as including several things including: "GP [general practitioner] consultations, tests, prescriptions, and referrals" (with certain caveats).

Although carrying an important message that elevated healthcare resource use is associated with a diagnosis of CFS/ME (bearing in mind the limitations of the CPRD when it comes to CFS/ME), one has to be quite careful with how facets of the Collin data are handled. I say this specifically on the basis that healthcare use 'at least ten years before diagnosis' was found to be elevated for those with CFS/ME and how authors talk about this conflicting with "patients reporting that they were fit and well prior to the onset of their illness." You can perhaps see how this data *could* be used by some to 'challenge' patients with reference to their reliability in reporting their illness onset for example and/or the idea that "behaviour traits such as disease conviction and somatic concern could not be discounted as aetiological factors." This in the context that the biopsychosocial model of CFS/ME is still prevalent in some quarters (see here) particularly those linked to healthcare interactions.

Thankfully the authors offer a couple of other potentially important reasons to account for their results based on (a) "people may simply have had CFS/ME for a very long time" and/or (b) "it is possible that people who develop CFS/ME have pre-existing risk factors which lead to higher rates of health care resource use." Indeed, on that second point, one might even argue that specific pre-existing medical complaints could/would/might predispose someone to developing CFS/ME (see here) particularly with all the talk about immune function potentially being a facet of some CFS/ME for example (see here). In this context, we perhaps need to know a little more about the genetics potentially important to CFS/ME, bearing in mind the emerging theme that condition-specific genes are not just genes specific to any one condition (see here for example).

Accepting also that authors were "unable to determine from our data whether the type of health care resource use by patients changes following diagnosis" the finding that healthcare use continues to be fairly high after diagnosis is a worrying sign. It suggests that modern medicine might not be particularly good at treating/managing those with CFS/ME (and their associated conditions) in the longer term based on current best practice. I could be a little bit cynical on this point in relation to how current 'best practice' for managing/treating CFS/ME involves some rather controversial techniques which could be construed as 'failing' in the context of these results. Indeed, I will refer you to a quote by Jonathan Edwards [2] talking about the on-going controversy in CFS/ME circles in relation to how current best practice might not be as successful as many might think: "If they are still ill, presumably these approaches have failed and the priority is to find something more effective." Indeed.

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[1] Collin SM. et al. Health care resource use by patients before and after a diagnosis of chronic fatigue syndrome (CFS/ME): a clinical practice research datalink study. BMC Fam Pract. 2017 May 5;18(1):60.

[2] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

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Collin, S., Bakken, I., Nazareth, I., Crawley, E., & White, P. (2017). Health care resource use by patients before and after a diagnosis of chronic fatigue syndrome (CFS/ME): a clinical practice research datalink study BMC Family Practice, 18 (1) DOI: 10.1186/s12875-017-0635-z

"Predisposition" to autoimmunity and inflammatory activation linked to autistic regression?

The paper by Ori Scott and colleagues [1] provides some very welcome interest in the concept of regression in relation to autism. As I've indicated quite a few times on this blog, regression accompanying cases of autism has [finally] been accepted by the research community at large (see here for example) but there is still some way to go with regards to the hows-and-whys of regression. There are some clues (see here) but more data is required. What the evidence available so far suggests is that sweeping generalisations about autism exclusively occurring/appearing during very early infancy or even before, are probably not as accurate as many people might realise (see here)...

So, starting from the idea that autistic regression might have an important 'immune-related' component to it, the authors set about reviewing the medical charts/records of some 240 children diagnosed with an autism spectrum disorder (ASD). A small but significant proportion of the cohort presented with an "autistic regression variant". Researchers looked at various potentially important facets of those medical charts in relation to things like "febrile illness preceding initial parental concern" (in relation to autistic features) and "possible non-immune precipitants such as pregnancy and postnatal complications." Another important feature of the study was to look-see whether various autoimmune disease/conditions were a feature of the immediate family in regressing and non-regressing cases.

Results: well, febrile illness did seem to be quite a lot more apparent in those children who experienced autistic regression. Indeed the figures went something like 30% in those with autistic regression and 0% in those without. Wow. Researchers also reported that rates of autoimmune disease in the immediate family were quite a bit higher in the regression group compared with non-regressing participants (33% vs. 12%). Further: "Type 1 diabetes and autoimmune thyroiditis were both more common in families with children with autistic regression." The authors conclude: "Our findings suggest that predisposition to autoimmunity, and immune/inflammatory activation, may be associated with autistic regression."

Accepting that this was research based on chart reviews (and indeed chart reviews in 2014) and the relatively small group numbers presenting with autistic regression, these are potentially important findings. Familial autoimmune conditions/disease *correlating* with autism is by no means a new thing (see here). Type 1 diabetes - the one where the pancreas don't produce any insulin as a result of the body failing to recognise self as self - has some history in relation to offspring autism risk (see here). Autoimmune thyroiditis, or at least some of the biological markers of this disease, also has some research history (see here). Interestingly, autoimmune thyroid disease also might have some connection to cases of depression too (see here) which could pose some intriguing questions in relation to the body of research talking about antidepressant use being potentially important to offspring autism too (see here). It would be a brave person to say there is no possibility of a connection between these and other familial autoimmune conditions and offspring autism...

The febrile illness stats produced by Scott and colleagues in relation to the regression group are really very interesting. Febrile illness denoting fever and corresponding symptoms in relation to autism onset is an area crying out for further research. Yes, febrile illness can affect onset of things like seizures and/or epilepsy and it would be rather intriguing to see whether this might play a role in the onset of some autism bearing in mind the epilepsy connection posed so far (see here). But more than that are the numerous voices talking about fever being a facet of symptoms onset under quite a few circumstances [2]. The words 'post-encephalitic' spring to mind and with it, quite a bit more scientific inquiry being indicated. And there is also another area that might benefit from some additional scrutiny in relation to developmental regression 'plus' other factors accompanying cases of autism [3]...

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[1] Scott O. et al. Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression. Dev Med Child Neurol. 2017 Apr 6.

[2] Mankoski RE. et al. Etiologies of autism in a case-series from Tanzania. J Autism Dev Disord. 2006 Nov;36(8):1039-51.

[3] 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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Scott O, Shi D, Andriashek D, Clark B, & Goez HR (2017). Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression. Developmental medicine and child neurology PMID: 28383115

Comorbidities surrounding paediatric chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME)

"This large nationwide registry linkage study confirms that the clinical picture in CFS/ME [chronic fatigue syndrome / myalgic encephalomyelitis] is complex."

That sentence, taken from the paper by Inger Bakken and colleagues [1] (open-access available here), is perhaps the under-statement of the year as authors sought to "describe comorbidities diagnosed in primary care in children diagnosed with CFS/ME in specialist health care" and "describe the timing of the diagnoses from primary care in relation to the timing of the CFS/ME diagnosis."

I grow tired of saying this but yet again, one of those very useful Scandinavian population registries was the starting point for the study - this time based in Norway - as some 1600 children diagnosed with CFS/ME were identified. Their data were compared against nearly 5000 children diagnosed with type 1 diabetes (T1DM) and a little over 1.3 million control - general child population - children. You could say that this was an adequately powered study.

A couple of important points were identified from the analysis of patient records. First: "Among children with CFS/ME, the most frequently observed primary care diagnosis was “weakness / general tiredness”." This is probably not unexpected given the nature of CFS/ME. Despite such weakness/general tiredness being initially identified in the vast majority of those with CFS/ME, sleep disturbances were also found more commonly among this group compared to other participants. Rather interestingly, asthma was also reported to be more common in the CFS/ME group than either of the control groups potentially reinforcing a role for atopy in the course/onset of at least some CFS/ME [2].

Next: "we found higher frequencies of depression and anxiety in the CFS/ME group." This is an important point that one has to be slightly careful with in terms of the introduction of psychological/psychiatric elements to a diagnosis of CFS/ME. I'll come back to this shortly.

Next: "Elevated frequencies of all diagnoses related to infection were observed in the CFS/ME group. In particular, infectious mononucleosis was far more frequent in this group (17.2 %) than in the control groups (T1DM: 3.7 %, general child population: 2.9 %). Influenza, acute tonsillitis, “strep throat”, and pneumonia were also more frequent in the CFS/ME group." Minus any sweeping generalisations, the suggestion that an infection illness might be part and parcel of at least some cases of CFS/ME is potentially borne out by this data. Infectious mononucleosis a.k.a glandular fever as a 'trigger' for CFS/ME is not unknown to the research [3] and other literature for example.

Finally: "The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %." Whilst everyone would love to see a timely diagnosis of CFS/ME made, particularly when it comes to children, this data kinda suggest that diagnosis in Norway can still a long and drawn out process. Yes, I understand that many of the numerous diagnostic criteria used to diagnose CFS/ME rely on symptoms being present for an extended period of time but this does little to aid the child and their family and the important effects of such symptoms on things like schooling and other important facets of childhood.

The Bakken findings provide an important research snapshot of CFS/ME in children. The themes of (i) infection being potentially important to quite a few cases and (ii) the quite long time lag between primary care (i.e. General Practitioner, GP) diagnosis of weakness / general tiredness and specialist diagnosis of CFS/ME are important ones that research and practice can/should perhaps learn some lessons from.

Insofar as the observation of depression and/or anxiety being more frequently present in cases of CFS/ME, the authors make reference to the paper by Winger and colleagues [3] (see this post for more information). Winger et al reported that depressive symptoms in their group did not seemingly link/explain the reduction of health-related quality of life scores they reported for their cohort of adolescents with CFS. Taken together with the Bakken results, the implication is that whilst more commonly reported in CFS/ME, depression (and anxiety) issues are important to cases. They cannot however at this point be described as anything more than comorbid. I say this because, unfortunately, there are still opinions out there that might see depression, anxiety and other psychiatric manifestations as 'causative' of CFS/ME rather than, as I see it, being a symptom stemming from the effects of CFS/ME. If you are bed-bound, not able to go to school, not able to socialise properly and not able to do all the things your peers are doing, it is highly likely that your psychology will eventually be affected to some degree.

"The long time spans observed from the first diagnosis of weakness / general tiredness in primary care to a specialist health care diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal." I also struggle to disagree with that sentence.

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[1] Bakken IJ. et al. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128.

[2] Yang TY. et al. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211.

[3] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13:96.

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Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, & Håberg SE (2016). Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC family practice, 17 (1) PMID: 27590471

The darker side to swimming with dolphins?

Described under the heading of a 'Challenging Case', the paper by Randall Phelps and colleagues [1] titled 'The Curse of the Dolphins: Cognitive Decline and Psychosis' highlights an intriguing case report potentially suggestive of a darker side to the idea of swimming with dolphins.

Yes, you did hear me right - dolphins - those aquatic mammals regarded as one of the earth's most intelligent creatures and the suggestion that swimming with them might somehow 'impact' on aspects of a person's functioning particularly with certain conditions/diagnoses/labels in mind. With autism specifically in mind, swimming with dolphins has been listed as an 'intervention' although the science has not exactly been wholly positive in terms of effects [2] and ethical issues with such 'animal-assisted' intervention still remain.

Phelps et al recount how Isela, "an 11-year-old Mexican-American girl with mild intellectual disability" went swimming with dolphins during a holiday with her parents. Days afterwards she was described as awakening in the night "with laughing spells" and during the day "she was pacing, aggressive, and had a decline in self-care and communication skills." After quite a few examinations and tests (bearing in mind her learning disability diagnosis and subsequent decline was not conducive to significant self-report) she was diagnosed with disorganized schizophrenia with psychosis. The laughter, it was assumed, was in response to hallucinations; the introduction of risperidone was associated with various improvements: "reduced inappropriate laughing spells, reduced pacing, as well as improved eating, sleeping, communication, and self-care." Throughout: "Her parents attributed the symptoms to the dolphins."

Although some might make light of this case report and perhaps even reiterate the old 'correlation is not the same as causation' mantra, I personally find this to be an intriguing description. Appreciating that issues like psychosis are probably over-represented when it comes to learning disability [3] and that there may be several possible 'triggers' for such symptoms [4], the possibility of a darker side to swimming with dolphins is perhaps deserving of further investigation. As to the question of mechanisms, well, I'm sure that there may be psychological explanations that might rank up there as per what is known about the effects of severe stress and anxiety when it comes to [some] psychosis. One must not for example, assume that every child enjoys the company of animals, particularly when combined with an element such as water for example. Other potentially important factors... well, I have to ask whether there could have been some infective agent involved either in the water or on the animal(s) given what we are beginning to understand about infection and mental health (see here for example). Indeed, with news that 'The world’s most successful bug hits dolphins' (that's T. gondii to you and me) there could even be some further work to do in light of other claims in this area (see here).

The messages are don't automatically discard the thoughts and suspicions of parents and perhaps leave our aquatic mammalian friends to get on with their lives...

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[1] Phelps R. et al. The Curse of the Dolphins: Cognitive Decline and Psychosis. J Dev Behav Pediatr. 2016 Apr 18.

[2] Fiksdal BL. et al. Dolphin-Assisted Therapy: Claims versus Evidence. Autism Res Treat. 2012;2012:839792.

[3] Aman H. et al. Prevalence of nonaffective psychosis in intellectually disabled clients: systematic review and meta-analysis. Psychiatr Genet. 2016 Apr 19.

[4] Galdos PM. et al. Puberty and the onset of psychosis. Schizophr Res. 1993 Jun;10(1):7-14.

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Phelps R, Tsai A, Hagen A, Pinter J, Smith R, & Stein MT (2016). The Curse of the Dolphins: Cognitive Decline and Psychosis. Journal of developmental and behavioral pediatrics : JDBP PMID: 27096574