Carnitine supplementation and autism: "side-effects and behavioral outcomes"

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

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[1] Goin-Kochel RP. et al. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Global Pediatric Health. 2019; 6: 1-8.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011 Jun;17(6):PI15-23.

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Psychiatric and seizure medicines for autism: what 'works' best

The paper by Devon Coleman and colleagues [1] represents pretty good scientific value for money by my reckoning. Describing the results of a 'survey' called the "National Survey on Treatment Effectiveness for Autism" created by the researchers, the aim was to provide "separated... scales for overall benefits and overall AEs [adverse effects]" for a wide range of interventions used in the context of autism.

The focus this time around was on "Psychiatric and Seizure medications data" but it looks like there may be quite a bit more to see from this group in future with regards to data on "supplements, diets, therapies, and educational interventions" also collected during this initiative. Before continuing on with this paper I have to hat-tip the authors for mentioning a great and much under-valued resource in autism circles: "the Parent Ratings of Behavioral Effects of Biomedical Interventions Survey,... conducted by the Autism Research Institute (ARI) and published in 2008." Indeed, in other posts talking about the medicines cabinet and autism (see here) I've expressed my positive views of the ARI resource albeit with caveats.

Anyhow: "we report ratings of 26 psychiatric and seizure medications by 505 participants." Researchers actually noted that nearly 900 people completed their survey; most of whom were described as the "Primary caregiver of an individual with autism." Some people might um-and-ah about the lack of 'authentic autistic representation' in this study, but one needs to bear in mind that most participants - about three-quarters - were under 18 years of age, most diagnosed with autism and not autism spectrum disorder (described as "less severe than a diagnosis of autism") and most were currently described as having mild, moderate or severe autism. I know this won't be enough for some people, but there you have it.

Then to the medicines that were 'graded', which fell into "five general categories: stimulants (four medications), SSRIs [selective serotonin reuptake inhibitors] (five medications), antipsychotics (four medications), seizure (nine medications), and other (four medications)." There's a lot of data included in the Coleman paper which really is too much for a blog post. I'll direct you to Figure 8 of the Coleman paper which provides a handy 'net benefit score' taking into account an 'overall benefit score' and an 'overall adverse score' for each medicine. When it came to SSRI medicines - typically indicated for treating depression - sertraline came top. When it came to antiepileptic medicines - primarily used to manage epilepsy and/or seizures - lamotrigine came top. When it came to antipsychotic medicines, aripiprazole came top. I was also interested to see that buspirone, a medicine typically indicated for anxiety, also did pretty well according to the Coleman results, which kinda ties in with some continuing research interest in this medicine with autism in mind (see here). Researchers also provide a handy 'medications for symptoms' overview as a consequence of their results (see Table 7) covering various symptoms from aggression/agitation to tics/abnormal movements. I can see this being particularly useful when it comes to physicians having to make big medication decisions (which should never be entered into lightly).

There's a couple of other details that are also mentioned in the Coleman paper outside of those 'how was medicine rated?' sentiments. Some details are not likely to make many friends in some quarters. So, around 2% of participants were described as follows: "No current diagnosis, but he/she was on the autism spectrum previously." Yes folks, such data once again harks back to the idea that for some people at least, autism is not a lifelong diagnosis (see here and see here). And also: "Thirty-four percent of participants had early onset of symptoms, but 56% had normal development followed by a plateau or regression." Regression accompanying autism is not the 'dirty' concept that it used to be (see here). Indeed, in the few years that I've been blogging about autism research, I've seen it become a lot more commonplace to talk about regression and autism (see here) even to the point that some now talk about it being 'the rule rather than the exception' (see here). Interesting.

And then there's something even more controversial in the Coleman paper: "The perceptions of possible causes of the regression are listed in Table 2." So we have things like high fever, illness, seizure and then... vaccination. I know this takes us into some uncomfortable territory, but the authors report that 51% of respondents to their survey who cited regression as part of the clinical picture mentioned vaccination as the 'perceived cause' whether singly or in conjunction with other factors. Of course I'm going to provide a link to what the population-based science says on this matter (see here) with the caveat that such 'perceived cause' data perhaps needs objective and dispassionate follow-up (see here and see here).

The Coleman results are not without their limitations as per author comments such as: "The survey is retrospective and based on respondent memory which reduces the accuracy" and "The results are subject to “placebo effect” since it represents clinical data without a placebo control, so the real benefit is likely less than the perceived benefit." But let's not take too much away from the findings and how they may, as well as informing clinical practice, also hopefully lead to further inquiry to make medicines safer and more reliable for those on the autism spectrum who access them.

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[1] Coleman DM. et al. Rating of the Effectiveness of 26 Psychiatric and Seizure Medications for Autism Spectrum Disorder: Results of a National Survey. J Child Adolesc Psychopharmacol. 2019 Feb 6.

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"a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP)" for autism?

The study findings reported by Megan Sanctuary and colleagues [1] caught my eye recently, and their aim to "assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI [gastrointestinal], microbiome and immune factors in children with ASD [autism spectrum disorder] and GI co-morbidities."

I appreciate that such a study is probably not going to be everyone's cup of tea given, for example, the rather *interesting* history of colostrum and autism (including the words 'transfer factor' [2]). The Sanctuary study however, should be taken on its own merit regarding "concurrent supplementation with both the probiotic B. infantis and bovine colostrum product (BCP) as a source of immune factors and prebiotic glycans could alter the microbiota to a more beneficial composition in order to improve gut health in children with ASD and GI symptoms." The rationale behind such work is that (a) what goes on the in the deepest, darkest recesses of the GI tract in a microbial sense could impact on the functional gut symptoms, and (b) said functional gut symptoms seem to be 'over-represented' in relation to autism (see here) and *could* in some cases, be linked to behavioural presentation (see here). Ergo, try and impact on functional gut symptoms and one *might* be able to impact on behaviour...

Sanctuary et al report preliminary findings designed to "assess tolerability" and "to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities." This work represented a first step towards a bigger research trial to ascertain whether such a supplemental combination *might* be useful for some people on the autism spectrum in a 'clinically relevant' sense. Despite being a pilot study, researchers did conduct what is considered a gold-standard study insofar as it being a "double-blind, crossover, randomized clinical trial (RCT)." The study protocol was also research registered (see here), so quite a few methodological boxes were ticked.

Given that this study was carried out at the MIND Institute, an institution that has quite a lot of experience in all-manner of different autism research areas (see here and see here), researchers were pretty precise when it came to diagnosing autism/ASD and ascertaining the presence or not of GI symptoms in their small cohort (N=11). The authors also provide quite a bit of information about the supplements used including "the bovine colostrum product (Imucon)" and details of its safety: "The product was tested and found to be negative for Escherichia coli, Salmonella, Listeria, coagulase positive Staphylococcus and antibiotic residue." Insofar as dosages, we are told that: "The colostrum powder dose administered in this study was 0.15 g/lb body weight per day" and "The probiotic dose administered in this study was 20 billion CFU [colony forming units] per day." A couple of supplemental combinations were examined during the study including BCP on its own and BCP+probiotic.

Results: there were quite a few different types of results reported on for 8 of the original 11 participants. Importantly: "Bovine colostrum product appears to be well-tolerated in these children [diagnosed with autism] as its own treatment as well as when combined with the probiotic B. infantis." 'Well-tolerated' means that there were "no participants needing to withdraw due to adverse events" despite a small number of reports of things like gassiness. A couple of kids were also reported to find the taste of the products not too great.

Also: "Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors." Being really careful here because of the small participant number included for study for example, researchers reported that "87.5% (7/8) of participants exhibited some improvement in GI symptoms while on the BCP only arm and 100% (8/8) of participants exhibited some improvement in GI symptoms while on the combination treatment arm." The sorts of GI effects mentioned included reductions in "pain with stooling, frequency of diarrhea, and consistency." Researchers also reported that appetite seemed to be improved for some kids too, particularly the consumption of fruit and meat.

A few other changes were noted in the study, but on the basis of the small participant size and the aims of the study I'm gonna leave them for now. As the authors mention: "the lack of a clear control group receiving a placebo" means that this was a "cross-over study where each participant was his own control" and therefore one needs to be cautious for now. What is needed next is a larger trial and more focus on the behavioural presentation side of autism...

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[1] Sanctuary MR. et al. (2019) Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS ONE 14(1): e0210064.

[2] Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7.

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Pioglitazone for autism?

Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass index] did not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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Cannabis treatment and autism

"This preliminary study supports [the] feasibility of CBD [cannabidiol]-based cannabis trials in children with ASD [autism spectrum disorder]."

That was the research bottom-line suggested by Adi Aran and colleagues [1] following their retrospective study of some "60 children with ASD and severe behavioral problems" who were given cannabidiol (CBD)-rich cannabis. They report that nearly two-thirds of parents/caregivers of those children in receipt of CBD-rich cannabis observed "much improved or very much improved" behaviour on the Caregiver Global Impression of Change scale, "a 7-point, caregiver rated scale, designed to assess how much the child's symptoms have improved (‘No change’, ‘Slightly improved’, ‘Much improved’, or ‘Very much improved’), or worsened (‘Slightly worse’, ‘Much worse’, or ‘Very much worse’) relative to the baseline state."

Cannabidol (CBD) is a component of cannabis. Distinct from tetrahydrocannabinol (THC) in terms of chemical arrangement, CBD is still thought to have some psychoactive properties, although perhaps not as 'detrimental' as THC [2]. Cannabis and CBD have been fairly big news lately as a consequence of the legalisation of such compounds for specific medicinal uses here in Blighty (see here).

Aran et al report findings suggesting that further controlled research is required in this area. They observed that among their 60 children (50 boys and 10 girls with an average age of 12 and 10 years respectively) taking on average between 4-5 "drugs for behavioral problems", quite a high proportion were still being treated with cannabis "≥ 6 months from treatment onset." Perhaps also importantly, a third of children received less medications or lower dosage of medication following their "cannabis treatment."

I will however add in a word or two of caution following the Aran observations. First, although there is a lot of discussion and hype around the use of medicinal cannabis and various diagnoses / conditions / labels, one still has to remember that this is a drug, and a drug of abuse at that. This mirrors the chatter about another substance of abuse being potentially indicated in the context of autism (see here). Aran et al also talked about some adverse effects noted in their cohort ("sleep disturbances (14%) irritability (9%) and loss of appetite (9%)") including: "One girl who used higher tetrahydrocannabinol [THC] had a transient serious psychotic event which required treatment with an antipsychotic." Others have also independently warned about medical cannabis use [3] citing ASD as one example. What this information imply is that alongside any potential studies of cannabis or specific compounds derived from cannabis with autism in mind, one needs to also keep a focus on the potential downsides to its use as well as any positives...

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[1] Aran A. et al. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2018 Oct 31.

[2] Pierre JM. et al. Cannabis-induced psychosis associated with high potency "wax dabs". Schizophr Res. 2016 Apr;172(1-3):211-2.

[3] Bou Khalil R. Why Is It Important to Protect Children with Mental Disorders from Medical Cannabis? J Dev Behav Pediatr. 2015 Nov-Dec;36(9):766.

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Project TENDR and chemical exposures part 2: organophosphate pesticides aren't great for child health

So, without striking too many chords on the old 'we've been here before' piano, consider this post an extension of some other discussions a while back suggesting that exposure to some classes of 'chemicals' might not be particularly great for child health (see here).

The findings reported by Irva Hertz-Picciotto and colleagues [1] continue the Project TENDR theme with their assertion that there is "compelling evidence" that prenatal exposure to organophosphate (OP) pesticides "is putting children at risk for cognitive and behavioral deficits and for neurodevelopmental disorders." Their observations have also been picked up by the lay media with some striking headlines like 'Ban entire pesticide class to protect children's health, experts say' complete with the required stock photo of crops being sprayed from the air.

Organophosphate (OP) compounds such as OP pesticides have a very mixed history. As well as being the insecticide of choice in many countries as a result of their excellent pest control profile, the organophosphate chemistry has also been utilised for less desirable purposes as per its classification as a component of nerve agents. Remember all the quite recent chatter about a nerve agent called Novichok? Well, the chemistry behind Novichok apparently has a very distinctive OP "structural backbone" [2]. That's not to say that every OP pesticide is Novichok. But rather that the activity of OPs specifically targeting the action of acetylcholinesterase (AChE) enzymes, important enzymes that are required for proper nerve function, is also an important biological action of various nerve agents. This in itself would suggest caution in the use of OPs.

The Hertz-Picciotto paper (policy forum) is pretty data heavy in terms of how much OP pesticides are used across the globe, the slew of mostly observational research studies that have looked at pesticide exposure and various neurodevelopmental variables and the concerns voiced at both high and low levels of OP pesticide exposure. They make a few recommendations: better training for health professionals on the potential risks attached to OP pesticide exposure, greater moves to switching to "nontoxic approaches to pest control" and perhaps most controversially: "Governments phase out chlorpyrifos and other OP pesticides."

The caveats? Well I might mention a few, minus any charges of me somehow 'standing up for OPs'. First, I don't think it's unreasonable to suggest that children in particular, do need to be more strongly protected against pesticides that are (chemically-speaking) not a million miles away from nerve agents. As the authors mention, there is quite a bit of evidence in the peer-reviewed literature to suggest a possible *association* between pesticide exposure and diagnoses such as autism (see here and see here) or beyond (see here). The thing is that like many other non-genetic environmental factors (e.g. air pollution) *linked* to a heightened risk of autism or other neurodevelopmental labels, it's more about environment + genetics when it comes to risk (see here) rather than environment just working on its own. We need for example, to know more about the ways and means that OPs are metabolised in the body and whether there could be some interesting biochemistry potentially linked to labels like autism (see here).

Second, some thought needs to go into the possible replacements if OP pesticides were to be banned outright. Thinking back to a post not-so-long-ago talking about DDT exposure and offspring autism (see here) I was struck by how short some memories are in terms of why such products were developed in the first place. I don't think anyone would seriously contemplate that the development of OP pesticides was anything more than to stop pests attacking crops and to maintain yields that can feed the population. These compounds were developed with good intentions. Obviously, as the research literature has grown, we have come to realise that such products are not side-effect free and more stringent controls have been put into place regarding safety. But to ban them outright is not something that can be done overnight. What do we replace them with? Do we just accept that crop yields will be lower and less food will be produced? Do we instead start thinking about other ways to make crops more resistant to the pests that blight them? That last question has already had its own 'issues'.

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[1] Hertz-Picciotto I. et al. Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms. PLoS Med 15(10): e1002671.

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On Cochrane and 'facts' and 'politics' in evidence-based medicine

The controversy surrounding the reported expulsion of Peter Gøtzsche from the Cochrane Collaboration (or should that just be Cochrane?) is something that I've been following for a few days now (see here). Cochrane, under the heading "Trusted evidence. Informed decisions. Better health", represents one of the premier go-to sources for evidence-based healthcare advice on a range of topics. Some of those topics have been previous fodder for this blog too (see here and see here for examples).

I don't profess to have any unique insight into the various goings-on leading to the reported expulsion of Gøtzsche and resignations of fellow members beyond that which has been discussed in various sections of the science media (see here and see here and see here). From what I gather, things look like they've been 'brewing' for a while with regards to Cochrane and the views and opinions expressed by some of those who are seemingly departing. Such a public spat however, is unlikely to be good for science or evidence-based medicine, and indeed may have some wider implications for some fundamentals of science and science communication...

One of the possible [late] precipitating events mentioned around the Gøtzsche saga was the publication of a quite scathing article by Lars Jørgensen and colleagues [1] (including Gøtzsche as an author) questioning the published results of a recent Cochrane review [2] titled: "Prophylactic vaccination against human papillomaviruses [HPV] to prevent cervical cancer and its precursors". The original review by Marc Arbyn et al garnered media headlines when published (see here) as per conclusions such as: "There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26." A comforting finding by all accounts. Accompanying such efficacy data were other statements made by the authors on the basis of the evidence reviewed that: "The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination."

Jørgensen and colleagues however put forward their [peer-reviewed] view that the Arbyn paper fell short of the expected standards from Cochrane: "We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias [3] and biased trial designs." They highlighted several 'issues' with the original review stretching from trial selection for the review, to the assessment of "serious and systemic adverse events" to potential "conflicts of interest." Similar sentiments had been voiced about other Cochrane reviews too that were subsequently pulled from the scientific literature. Feathers were inevitably ruffled (see here) by the Jørgensen paper, even as far as prompting a response from the journal that published the paper [4] about the peer-review process leading to publication of the critique. Things are getting serious when a journal has to defend its publication of a paper.

Without wishing to reduce this saga to any one event, I don't think it would be unreasonable to assume that the Jørgensen paper might have influenced matters quite considerably; perhaps even bringing them to a head. As per involvement on the Boesen paper [5] Gøtzsche is no stranger to calling out Cochrane reviews that seemingly don't make the grade, alongside also voicing opinions on various other matters down the years. To quote: "... in another book, [he] likened the pharmaceutical industry to "organized crime""; such forthright statements stretching back some years are unlikely to have made too many friends in certain circles.

As per the title of this post mentioning the words 'facts' and 'politics', one particular write-up of this saga I think hits the nail on the head. The opinion piece from Trish Greenhalgh [6] presents the two sides to this 'dispute': on the one hand is that the “crisis” is "philosophical (relating to the nature of facts)" and on the other, "political (relating to organisational governance)." The philosophical side of things is pretty evident as per the publication of the Jørgensen paper as a counter to the Arbyn paper. Greenhalgh mentions about how "Gøtzsche might be classified as an evidence-based medicine purist" given his views and sizeable contribution to various "statements on how to undertake and publish research." In this respect, his published views on the original Arbyn paper (and similarly in other reviews) seem to detail scientific standards not being met, or at least not being met to his and his co-authors standards. And certainly on points such as access to trial results and data, he's seemingly not alone in his concern (see here).

On the political side of things, well, at the time of writing we just don't know enough to reasonably comment. Greenhalgh mentions that: "The political explanation for Cochrane’s crisis relates to the tension between governing an organisation and respecting individual members’ academic freedom to express dissent." The fact that such dissent has over the years covered various important public health topics - "cast doubts about the safety of a vaccine against human papillomavirus (HPV), a cause of cervical cancer, and says psychiatry has “gone astray” by coercing patients into taking medication, such as antidepressants, they don’t want to use and that cause “brain damage” over the long run" - is likely to have really stretched those organisational relationships with Gøtzsche. Not least because immunisation and antidepressant use reflect important pillars of modern public healthcare and, historically, uptake of such medicines is very, very susceptible to differences in scientific views, opinions and beyond.

As to the idea mentioned by Greenhalgh that: "We should cut it [Cochrane] some slack while it gets its house in order", I'm not exactly sure how it's going to approach this 'house in order' requirement and what this means for the future credibility of Cochrane. Based solely on the 'facts' side of this saga, it strikes me that organisations like Cochrane actually need people like Peter Gøtzsche and their "evidence-based medicine purist" beliefs. They need them in order to critically (really critically) boil down the ever-growing research literature into scientifically sound statements for public and policy consumption without fear or favour. Minus such voices, it's more likely that evidence-based messages originating from such initiatives are perhaps going to be weakened, which in turn means that population healthcare is potentially going to suffer. Moreover, I assume also that just because Gøtzsche is reportedly not part of Cochrane any more does not mean that he won't be heard from again in the peer-reviewed domain...

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[1] Jørgensen L. et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. July 27.

[2] Arbyn M. et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018 May 9;5:CD009069.

[3] Jørgensen L. et al. Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: a necessary basis to address reporting bias in a systematic review. Syst Rev. 2018 Jan 18;7(1):8.

[4] Heneghan C. & Onakpoya I. Editors’ response to concerns over the publication of the Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. Sept 12.

[5] Boesen K. et al. The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder. Evid Based Med. 2017 Aug;22(4):143-147.

[6] Greenhalgh T. The Cochrane Collaboration—what crisis? BMJ. 2018. Sept 17.

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In-utero exposure to antiepileptic drugs and offspring learning disability

There was something quite familiar about the findings reported by Laura Fuglslang Bech and colleagues [1] investigating any "association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring." Familiar because this class of medicines - antiepileptics - used to primarily treat/manage epilepsy and seizure disorders have been put under the spotlight in recent years as a result of various *associations* with offspring childhood developmental disorders/conditions when used during pregnancy (see here and see here).

Obviously one has to be quite careful when it comes to talking about this class of medicines. Antiepileptics, as I have mentioned before, are not typically dispensed willy-nilly, and on many occasions have proved to be not just a life-enhancer but also a lifesaver to those living with epilepsy. The balancing act comes when they are prescribed to women of child-bearing age and ability, and the possibility of them producing 'adverse' effects' on the developing child.

Bech et al focused on learning disability as a possible offspring outcome following pregnancy exposure to a range of antiepileptic medicines. One of those marvellous Scandinavian population registries provided the research starting point (based in Denmark) and lead to the participation of some 630 cases ("offspring exposed to antiepileptic drugs in utero") and 430+ controls ("unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions").

Results: "Learning disabilities were identified among 7.1% cases compared with 3.7% for controls." Although not at first glance showing a huge difference between the groups, a little statistical analysis revealed that: "During any trimester, the adjusted OR [odds ratio] of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17)." When taking into account different types of antiepileptic medicines and their possible risk profile, yet again one particular medicine stuck out: valproate. As the authors mention: "valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59)" compared with other antiepileptic medicines. This accords with other findings.

As with any observational study of this type, one has to be a little careful with the old 'correlation is not necessarily causation' thing. But set against a tide of research observing similar trends - particularly with respect to the use of valproate - and indeed, a rodent model of autism called the valproate rodent model of autism - it's getting ever harder to say that pregnancy valproate use in particular, is not associated with a variety of adverse offspring outcomes...

If in doubt, please speak to your prescribing physician. Please don't tinker yourself with things that you shouldn't tinker with...

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[1] Bech L. et al. In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring. J Neurol Neurosurg Psychiatry. 2018 Aug 3. pii: jnnp-2018-318386.

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Treading carefully: vaccination rates among younger siblings of kids with autism

'Treading carefully' is a requirement for any discussion about a research study that mentions 'vaccination' and 'autism' in the same breath. I say this on the basis that vaccine coverage is an important cornerstone of public health and now appears to be making significant in-roads with regards to public health, at least here in Blighty.

But much like [scientific] discussions covering other areas of the important public health topic of immunisation, one shouldn't be afraid to look, examine and yes, talk about this subject (see here) particularly where there may be a need for further study minus any hype, sweeping generalisations or logical fallacies...

The paper by Gena Glickman and colleagues [1] discussed an important topic in relation to vaccination behaviour - "whether or not and when parents choose to vaccinate a child" - in the context that parents who already have a child with autism may perhaps be slightly more hesitant to vaccinate their other children in light of "the perceived link between vaccines and autism spectrum disorder." This is a topic that has cropped up on this blog previously (see here). Far be it from me to question any parent about their own child, but I will refer you to some of the peer-reviewed science already done on this topic (see here and see here).

Based on a sample of over 200 families, Glickman et al looked at "vaccination behaviors" as a function of having a child with autism or not. From what I surmise from their report, the focus was specifically on "vaccination against measles–mumps–rubella (MMR)." They reported: "no significant difference between rates of vaccination among children with and those without autism" which is rather comforting. Minus too much politics or anything related, this data suggests that anti-vaccination sentiments are not naturally rife among parents/caregivers of children with autism, at least before a diagnosis of autism is given. Indeed with vaccination rates of 100% among children with autism vs. 98% in the slightly larger control group, one might argue that parents of children with autism are/were extremely vaccine compliant when it came to their first born child.

But then also: "Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children." Authors observed that: "the rate of vaccination among full biologic infant siblings of children with autism spectrum disorder was 83.1%, as compared with 97.0% among low-risk infants."

One can speculate (and speculate) about the reason(s) why younger siblings of children with autism were seemingly less likely to be vaccinated but I'm sure the answers are going to be complex. The authors suggest that: "parents who had an older child with autism spectrum disorder retrospectively reported a higher rate of adverse reactions to vaccination among the older child than did those who did not have an older child with autism" and that this may have impacted on subsequent vaccination behaviour. The rates of adverse reactions reported - 22% in the autism group vs. ~4% in the control group - are not to be sniffed at and indeed, seemingly filtered down to observations of adverse reactions in younger siblings too (6.9% vs. 0.8%). Authors also noted that: "Reported reactions included fever, diarrhea, unusual crying or screaming, and general malaise."

This is a nice piece of research. It doesn't go overboard in it's interpretations of the findings and calmly suggests that "a better understanding of the relationship between perceived adverse reactions to vaccine and autism spectrum disorder is necessary in order to more effectively address concerns about vaccination." It is important to note that the authors don't mention 'onset of autism' or anything like that in their discussion of 'reported reactions' following vaccination, despite the seemingly 'once bitten, twice shy' sentiments portrayed in the findings.

Personally, I would have like to have seen more details about the hows-and-whys of this study insofar as what "available data on vaccination behaviors" were used and whether important information on the timescale(s) of adverse reactions were also available keeping in mind certain issues [2]. Some idea of the rate of autism recurrence among younger siblings might also have been useful too (something that at least one of the authors on the Glickman paper seems to be interested in [3]). Given also the quite apparent differences noted in the rates of reported adverse reactions among those with autism vs. controls, there is also a requirement for further careful investigation in this area. Specifically, whether aspects of the biology (or genetics [4]) of at least 'some' autism (or it's possible comorbidity [5]) might be something to consider when it comes to studies of adverse reactions [6] or indeed whether for example, other medications used at the same time of vaccination might have had an effect [7] onward to finding ways and means to minimise such issues.

To close, although some ten years old, the paper by Shona Hilton and colleagues [8] still stands the test of time in this often fractious area...

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[1] Glickman G. et al. Vaccination Rates among Younger Siblings of Children with Autism. N Engl J Med. 2017 Sep 14;377(11):1099-1101.

[2] Ozonoff S. et al. Reliability of parent recall of symptom onset and timing in autism spectrum disorder. Autism. 2017. Sept 13.

[3] Ozonoff S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95.

[4] Verbeek NE. et al. Effect of vaccinations on seizure risk and disease course in Dravet syndrome. Neurology. 2015 Aug 18;85(7):596-603.

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

[6] McClenathan BM. et al. Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics. Vaccine. 2017 Mar 1;35(9):1238-1245.

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

[8] Hilton S. et al. MMR: marginalised, misrepresented and rejected? Autism: a focus group study. Archives of Disease in Childhood. 2007;92(4):322-327.

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ADHD and law enforcement contact: not a straight-forward relationship

Several times on this blog I've talked about how a diagnosis of attention-deficit hyperactivity disorder (ADHD) seems to place the recipient at quite a bit of excess risk for various unfavourable outcomes (see here). I've tried hard not to make too many sweeping generalisations on this issue; mindful that behind every statistic in every peer-reviewed bit of science there are real people and real lives. But the data is becoming quite compelling on this matter...

The paper by Mark van der Maas and colleagues [1] makes an important contribution to the idea that the relationship between a diagnosis of ADHD and contact with law enforcement 'systems' is perhaps not as straight-forward as many might believe. Concluding that: "The observed connection between ADHD and criminality may be better understood through their shared relationships with indicators of poor social bonds", researchers suggest that social factors may very well come into play.

OK, based on a sample of over 5300 adults "representative of the general population of Ontario, Canada" researchers asked participants about their "self-reported arrest on criminal charges" history alongside examining ADHD-linked symptoms via the Adult Self Report Scale (ASRS-v1.1). They also interviewed/questioned about various social bonds - household size, education level, drug and substance abuse, etc.

They observed that: "screening positive for ADHD was twice as likely... and past use of medications for ADHD three times as likely... to be associated with ever having been arrested." But... when statistical modelling took into account the data on social bonds, things started to get a little more fuzzy. So: "In the best fitting statistical model, ever having been arrested was not associated with ADHD, but it was significantly associated with indicators of strong and weak social bonds." So things like anti-social behaviour, not progressing well in educational terms and substance use (abuse) might have some important influences on contact with law enforcement agencies. A shocker, I know.

I do have to point out a few important things about this research before anyone gets too immersed in the idea that ADHD is completely off the hook. First was the reliance on self-report when it comes to both ADHD signs and symptoms and also arrest record. The ASRS might very well be a nice rough-and-ready measure of ADHD symptoms but it is no substitute for a thorough assessment for a diagnosis of ADHD. Similarly, people may not always be completely truthful when it comes to their arrest record under several circumstances including research conditions...

Second is the concept of cause-and-effect. As easy as it is to say that ADHD was not itself linked to arrest record(s), it is important not to interpret the findings to say that there is 'no connection' between ADHD and 'having been arrested'. Minus sweeping generalisations, facets of ADHD - such as impulsivity and inattention - can and do perhaps account for some of the heightened risk for various types of offending behaviour [2]. It's fine to say that these facets of ADHD might be exacerbated under conditions of substance use/abuse for example, but one could easily then ask whether ADHD might have actually been involved in facilitating such substance use/abuse in the first place. Certainly, there is (peer-reviewed) evidence that a diagnosis of ADHD - if left untreated - may very well impact on educational outcomes for example [3] which could be one of several factors in determining other life choices.

The idea however that ADHD as a sole risk factor for adverse outcomes such as law enforcement contact does not exist in some sort of social vacuum is an important one to come from data such as that presented by van der Maas et al. It is perhaps the issue of 'vulnerability' that comes to the forefront, and how an ADHD diagnosis should perhaps be explored with that tenet in mind...

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[1] van der Maas M. et al. Examining the effect of social bonds on the relationship between ADHD and past arrest in a representative sample of adults. Crim Behav Ment Health. 2017 Jul 5.

[2] Berryessa CM. Attention, reward, and inhibition: symptomatic features of ADHD and issues for offenders in the criminal justice system. Atten Defic Hyperact Disord. 2017 Mar;9(1):5-10.

[3] Lu Y. et al. Association Between Medication Use and Performance on Higher Education Entrance Tests in Individuals With Attention-Deficit/Hyperactivity Disorder. JAMA Psychiatry. 2017 Jun 28.

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"a single intravenous infusion of autologous umbilical cord blood" and autism

'Could stem cells offer hope for autism?' went one media headline referencing the very preliminary "phase I, open-label trial" published by Geraldine Dawson and colleagues [1] (open-access) detailing the experiences of a single intravenous infusion of autologous umbilical cord blood in 25 children with "a confirmed diagnosis of ASD [autism spectrum disorder]."

Well, the results were promising in respect of important issues such as safety in light of the tenet 'first do no harm': "Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated" and some potentially interesting effects were noted when it came to behaviour "across a wide range of outcome measures in this study." But much like another quite innovative study with a similar research design published quite recently (see here) one needs to be a little cautious about the limitations of this current study. Not least that: "As an uncontrolled open-label study, it is not possible to determine whether the observed behavioral changes were due to the treatment or reflect the natural course of development during the preschool period." I might add that any study mentioning the words 'stem cells and autism' in the same sentence is going to be subject to significant scrutiny (see here for example).

Although the Dawson paper is open-access, here are a few choice details:

• "All participants had to have an available autologous umbilical cord blood unit banked at a family or public cord blood bank."  This was a study using the participants own stored cord blood - blood 'left over' from the umbilical cord and/or placenta at birth - which was initially screened to make sure it was both viable and safe: "negative maternal infectious disease markers tested on the maternal donor or cord blood product (minimally including hepatitis B, hepatitis C, human immunodeficiency virus [HIV], human T-lymphotrophic virus [HTLV], and syphilis)." Cord blood contains stem cells; cells that have significant [mighty] morphing capabilities in terms of turning into different cell types. In amongst the various peer-reviewed research (and research hype) surrounding stem cells, their use with autism in mind has been slowly creeping into the public consciousness (see here for example) with appropriate caveats.
• Participants were given one infusion of their cord blood samples. They were fairly closely monitored over the study duration to ensure that any adverse effects (AEs) were catalogued. Researchers reported: "A total of 92 AEs were reported in 23 participants... with a median of three events per participant. All events were graded as Mild (71 events) or Moderate (21 events)." Further: "Twelve events (13%) were considered related to the infusion, with the most common being allergic reaction, manifested by urticartia and or/cough occurring on the day of infusion (5 events in 4 participants; all Mild; 2 requiring an additional dose of IV Benadryl). The most common unrelated AEs were agitation, skin changes, and typical childhood infections, reported between 2 days and 1 year post-infusion."
• Alongside looking for AEs, authors also reported some changes to the various behavioural schedules included for study. Looking at scores at baseline (pre-infusion) and then at 6 and 12 months, a pattern started to emerge based on group results. So: "Most of the observed behavioral changes occurred during the first 6 months and were sustained between 6 and 12 months post-infusion." The direction of the behavioural change were all positive (i.e. behavioural measures indicated improvement) and were spread out across both parent-reported and clinician-reported schedules. Interestingly too, eye gaze measurements for some 21 participants who were scanned also showed changes: "a 20% increase in odds of gazing at the actress’ eyes over time." Researchers also noted that: "children's nonverbal IQ was correlated with change for the majority of outcomes measures, with higher nonverbal IQ being associated with greater improvements in behavior." Such a finding might also tie into some other research looking at a group termed 'optimal outcome' (see here).

There is a scheme of research required to follow this preliminary study, of that there is no doubt. We don't for example, know exactly how any behavioural changes were tied into the infusion (or not) because among other things, no other physiological measurements were made over the course of the Dawson study pointing to possible mechanisms. This is not entirely unexpected given the preliminary nature of the study. I will also stress again that these results were based on participants' own stored cord blood samples not other donor samples just in case any incorrect generalisation of results is made. As an aside, I was quite interested to see the use of IV (intravenous) Benadryl in relation to some of those AEs. Benadryl is an antihistamine used to manage allergy symptoms. I've talked before on this blog about how treating allergy issues in relation to some individual cases of autism might have some interesting effects on the presentation of autistic symptoms too (see here). I wonder...

I am assuming that there will be more to talk about in this area of autism research as a consequence of a concluding sentence made by the authors: "we have also included the clinician-rated CGI and additional measures as secondary endpoints in our next study, a phase II, double-blind randomized clinical trial designed to formally evaluate the efficacy of umbilical cord blood infusion in improving core symptoms of ASD." Accepting that there is still some PR to be done with regards to the issue of cord blood and stem cell use in relation to autism [2] (that also includes work related to modelling conditions like autism too [3]), I'll be interested to see whether the current Dawson results survive more rigorous scientific study...

To close, skin problems in Hollywood villains. No really, someone has actually studied this... 

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[1] Dawson G. et al. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine. 2017. April 5.

[2] Sharpe K. et al. In the Know and in the News: How Science and the Media Communicate About Stem Cells, Autism and Cerebral Palsy. Stem Cell Rev. 2016 Feb;12(1):1-7.

[3] Wen Z. Modeling neurodevelopmental and psychiatric diseases with human iPSCs. J Neurosci Res. 2017 May;95(5):1097-1109.

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Geraldine Dawson, Jessica M. Sun, Katherine S. Davlantis, Michael Murias,, Lauren Franz, Jesse Troy, Ryan Simmons, Maura Sabatos-DeVito, Rebecca Durham, & Joanne Kurtzberg (2017). Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine : 10.1002/sctm.16-0474