Unexpected improvement in core autism symptoms following a probiotic?

The paper by Enzo Grossi and colleagues [1] (open-access) is definitely worthy of a post today and the suggestion that the "appropriate use of probiotics" might be something to consider for at least some diagnosed as being on the autism spectrum.

Accepting that I'm slightly curious as to what would be considered 'inappropriate use of probiotics', the Grossi paper describes the clinical journey of a boy aged 12 diagnosed with an autism spectrum disorder (ASD) accompanied by learning (intellectual) disability who was concurrently diagnosed with coeliac disease (CD). The CD diagnosis was a slightly complicated affair given that whilst he presented with the relevant 'genetics' of CD (HLA genotypes) and "a slight elevation of transglutaminase antibodies" a gluten-free diet seemingly did very little in terms of clinical benefits and when it came to the "blood-specific tests for celiac disease" they were always negative. I'll come back to some of these points shortly but his chronic gastrointestinal (GI) symptoms that were first thought to be CD related were subsequently put down to irritable bowel syndrome (IBS).

In light of the IBS diagnosis and given some pretty important research suggesting that specific probiotic formulations might have treatment-potential for some IBS (see here), a probiotic intervention was prescribed: VSL#3. What happened next is intriguing...

After a few weeks of probiotic treatment, some 'apparent improvements' were noted in the boy's behavioural presentation. This led the authors to start looking more systematically at whether said improvements could be charted and possibly tied into his probiotic use. We are told that the various components of his behavioural plan that had been in place for some 6 years were continued without "any particular change." Use of the gold-standard assessment tool that is the ADOS - Autism Diagnostic Observation Schedule - was employed over a period of about a year-and-a-half to covering the period of probiotic use. Data for two ADOS assessments were available before the probiotic was installed and four assessments were carried out during and post-intervention. The results suggested that scores relevant to social affect (the DSM-5 term describing issues with social and communicative domains) changed over the intervention period in line with some of the observations made of this boy. Further: "This change was surprising since in our assessment records over several years, the patient status had remained steadily unchanged." It should also be noted that the GI symptoms, the initial target of probiotic use, also reduced "as expected."

Yes, I know that this is a case report (and N=1) and given what we (think we) know about autism, such results can by no means be generalised to all autism. There could also be a million and one other variables potentially accounting for the results including something called puberty potentially playing a role (see here) given the age of the boy. One needs to be cautious.

But... these are still potentially important results for quite a few different reasons. Going back to the description of CD being diagnosed and then un-diagnosed, regular readers might know about my interest in something called non-coeliac gluten sensitivity (NCGS) when it comes to something like autism (see here). The suggestion being that although a diagnosis of autism is not protective against a diagnosis of CD, the still emerging peer-reviewed data seems to suggest something slightly more gluten-fuzzy when it comes to at least some autism. That elevated levels of tissue transglutaminase are also not an uncommon finding in relation to [some] autism (see here) adds to the curiosity in this area.

Bowel or GI issues occurring alongside autism? Well, I've said it before and I'll say it again: GI issues (both functional and pathological) are over-represented when  it comes to autism (see here). You can call it IBS or similar other bowel related label but the fact of the matter is that such issues are not uncommon and lots more resources need to be poured into looking at and importantly, treating such issues save any further health inequalities appearing alongside the label of autism. It makes good sense that if something like IBS is diagnosed, and the various meta-analyses suggest that probiotics might be one part of an intervention strategy for IBS, their use where IBS clusters with autism should be the same as when autism is not part of the equation. Simple as.

The Grossi case report also highlights how gut and brain, with a healthy portion of gut microbiome, might show some important links for some on the autism spectrum [2]. This is by no means 'a new thing' (see here) and to some extent, justifies the various studies where gut bacteria for example, have been looked at in the context of autism (see here for example). That such a connection might also include issues with gut permeability (see here) is another important detail and is evidenced by the possibility that probiotics may also work on the gut membrane [3] as well as those trillions of wee beasties that call us home.

In short, more research on the use of probiotics with autism is very much implied (and indeed is already in progress). Watch this space.

To close, first we had Mr Pharmacist from The Fall. Now we have Oxymoronic from NOFX. Spot the difference...

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[1] Grossi E. et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Medical Case Reports. 2016; 4: 2050313X16666231.

[2] Inoue R. et al. A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders. Biosci Biotechnol Biochem. 2016 Sep 1:1-9.

[3] Mennigen R. et al. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol. 2009 May;296(5):G1140-9.

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Grossi, E., Melli, S., Dunca, D., & Terruzzi, V. (2016). Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics SAGE Open Medical Case Reports, 4 DOI: 10.1177/2050313X16666231

A 'characteristic chemical signature' to chronic fatigue syndrome?

Today I'm (belatedly) talking about the paper by Robert Naviaux and colleagues [1] (open-access) and some further peer-reviewed discussion concerning the metabolomics of chronic fatigue syndrome (CFS). Suggesting that "targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology" when it comes to CFS, it is not surprising that this work has attracted some media interest (indeed, quite a lot of media interest).

I don't want to regurgitate all the findings given that (a) they are numerous, and (b) the paper is open-access, but there are a few details worth noting.

So:

• Some readers might recognise the names Robert and Jane Naviaux listed as authors on this current paper as one and the same team involved in all that suramin for [mouse] autism work (see here). Their previous focus on the application of metabolomics (specifically the use of mass spectrometry) following the use of suramin hints at the skills and expertise this group have in that field.
• Their research attention was turned to CFS with the aim to put further flesh on the idea that there may be some important biochemistry happening in cases of the condition.
• Eighty-four adults were included for study; 45 diagnosed with CFS by various criteria (yes, there are quite a few of them). They provided blood samples that were subject to analysis: "Targeted, broad-spectrum, chemometric analysis of 612 metabolites from 63 biochemical pathways was performed."
• Results: well, first various 'trigger' factors were linked to onset of CFS participants' symptoms. Biological triggers - "viral, bacterial, fungal/mold, and parasitic infections" - were most common but "no single infectious agent or other stressor was statistically more prevalent." There appear to be many [organic] roads to the development of CFS.
• 'A characteristic chemical signature' is something that many media outlets have jumped on to based on these results. Indeed, with some very pretty Venn diagrams included, there did appear to be some chemical 'signatures' that defined CFS vs. not-CFS.  The sorts of compounds seemingly involved related to the: "Sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid and branch chain amino acid metabolites." I'm particularly interested in the amino acid chemistry detected and how it may overlap with other findings [2].
• The relevance of those chemical signatures in terms of biological processes were quite diverse but led authors to conclude that "the metabolic features of CFS are consistent with a hypometabolic state." Some media outlets have referred to this as a 'semi-hibernation like state' where metabolism is somehow slowed down. I'm not so sure this is the most accurate definition given that hibernation normally implies a time-limit to such a state. Unfortunately, for many, CFS does not magically stop come the biological Spring. There is also mention of how the findings might relate to other research in CFS including a role for mitochondrial function (see here) and NAD (see here).

With some cautions attached to this line of work (see here), not least the quite small participant groups included for study and, I believe, the use of a single blood sample at one specific time point, this is interesting work. Added to a growing tide of research suggesting that if one looks, one might indeed find some biological issues associated with a diagnosis of CFS (see here for example), this is yet another stop in the journey towards understanding CFS is terms of biology not psychology. The next stop is of course independent replication.

"The study of larger cohorts from diverse geographical areas, and comparison with related medical disorders like depression and posttraumatic stress disorder, will be needed to validate the universality and specificity of these findings. The finding of an objective chemical signature in CFS helps to remove diagnostic uncertainty, will help clinicians monitor individualized responses to treatment, and will facilitate multicenter clinical trials." Big words that indeed require that independent replication, but the research future for CFS is already looking a little brighter as a result of the Naviaux findings.

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[1] Naviaux RK. et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Aug 29. pii: 201607571.

[2] Georgiades E. et al. Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clin Sci (Lond). 2003 Aug;105(2):213-8.

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Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, & Gordon E (2016). Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America PMID: 27573827

The force is strong with autism?

"Tablet and phone games could help diagnose autism, study suggests" went the BBC headline covering the paper by Anna Anzulewicz and colleagues [1] (open-access). The idea being that the way that touch screens are used on tablet and smart phones could potentially 'separate out' those with autism from those with not-autism.

Based on a small participant number of "37 children 3–6 years old with autism and 45 age- and gender-matched children developing typically" researchers set about examining "autism-specific motor patterns in the gameplay of children as they engaged with a smart tablet computer (iPad mini) under natural conditions and with minimal instructions." Motor issues accompanying autism are something gaining some renewed (and welcomed) research attention in recent times (see here). Specifically, researchers were utilising the astounding technology that goes into all those swipes and taps that we're also used to these days, and whether under 'serious' game conditions, aspects like force impact and gesture pressure could differentiate the two groups.

As per the headline and the rather cheesy title to this post, there were some differences picked up between the autism and control groups based on touch and swiping responses being put through their machine-learning paces (something else that has a growing following in autism research circles). So: "The inertial data indicate children with autism engaged in gameplay with greater force of impact than those developing typically." This and other potential differences led researchers to conclude that: "children with autism applied a significantly different distribution of forces into the device during gameplay than the typically developing children did."

Whilst interesting research there is quite a bit more to do before anyone starts using taps and swipes as a means to diagnose autism (or anything else). I don't really need to say that this was a study including a relatively small participant group nor that whilst "All participants had normal or corrected-to-normal vision and no other sensory or motor deficits" this does not preclude the possibility that subtle issues might also be at work (see here). That also recent discussions have suggested moving away from the singular diagnosis of autism as a research starting point is also worth reiterating (see here).

Still, I can see some opportunities arising from this area of research and how perhaps combined with other innovative areas of screening and diagnosis there may be much more to see including how subtle differences in movement might also influence variables such as interaction [2]. Yes indeed, "smart tablet technology offers an attractive, new paradigm for clinical autism assessment and bio-behavioural research of pre-school children, enabling engaging, ecological testing of children’s motor behaviour in a fun, accessible format fit for precise computational analysis of neuropsychological function."

To close: Danny Boy (from the Proms 2013 although this years version was pretty good too).

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[1] Anzulewicz A. et al. Toward the Autism Motor Signature: Gesture patterns during smart tablet gameplay identify children with autism. Scientific Reports. 2016; 6: 31107.

[2] Edey R. et al. Interaction Takes Two: Typical Adults Exhibit Mind-Blindness Towards Those With Autism Spectrum Disorder. J Abnorm Psychol. 2016 Sep 1.

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Anzulewicz A, Sobota K, & Delafield-Butt JT (2016). Toward the Autism Motor Signature: Gesture patterns during smart tablet gameplay identify children with autism. Scientific reports, 6 PMID: 27553971

Prevalence of self-injurious behaviors among children with autism

Just over a quarter of children diagnosed with an autism spectrum disorder (ASD) present with self-injurious behaviour (SIB).

That was the headline finding reported by Gnakub Soke and colleagues [1] who surveyed the 8000+ children "in the Autism and Developmental Disabilities Monitoring (ADDM) Network during the 2000, 2006, and 2008 surveillance years." THE ADDM network, as some people might know, is one and the same network that comes up with the [estimated] prevalence of autism in the United States (see here) and so carries quite a lot of statistical and clinical clout when it comes to data production. The actual figure for SIB was 27% when taking all the various ADDM sites into consideration but, much like the estimated prevalence stats, "with some variation between sites."

SIB is a topic that has been discussed on this blog a few times before (see here and see here for example). It's not something that generally makes for polite dinner table conversation and not something that many people would say makes for 'good PR' when it comes to the public perception of autism. Nevertheless, these and other estimates of SIB in autism (including its persistence) are one of the more pressing issues for those that present with such behaviours given not only the damage and distress that SIB can do to a person but also the effect(s) on family and loved ones too.

"Clinicians should inquire about SIB during assessments of children with ASD." I think that sentence is taken as read in light of the coincidence of autism and SIB. More than that however I think many people would like to see a lot more research into the potential hows and whys of SIB [2] and what can be done to minimise such 'challenging behaviour'. Yes, such acts may in some way be communicative for some people on the autism spectrum (i.e. pain, discomfort, etc), and if so, the use of a 'chemical cosh' is likely to have repercussions for such possible communication attempts. But where such SIB acts place someone at risk of permanent physical injury and/or increase the likelihood of extremes such as the need for corrective surgery, I don't think many people would hold back with the idea of appropriate management for such extreme behaviours.

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[1] Soke GN. et al. Brief Report: Prevalence of Self-injurious Behaviors among Children with Autism Spectrum Disorder-A Population-Based Study. J Autism Dev Disord. 2016 Aug 26.

[2] Yuan X. & Devine DP. The role of anxiety in vulnerability for self-injurious behaviour: studies in a rodent model. Behavioural Brain Research. 2016; 311: 201-209.

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Soke GN, Rosenberg SA, Hamman RF, Fingerlin T, Robinson C, Carpenter L, Giarelli E, Lee LC, Wiggins LD, Durkin MS, & DiGuiseppi C (2016). Brief Report: Prevalence of Self-injurious Behaviors among Children with Autism Spectrum Disorder-A Population-Based Study. Journal of autism and developmental disorders PMID: 27565654

Post-exertional malaise (PEM) in CFS might mean more than one thing

"The results suggest that post-exertional malaise [PEM] is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue."

So said the findings reported by Stephanie McManimen and colleagues [1] looking at one of the most common and debilitating aspects of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and how rough-and-ready generalised descriptions often do little to reveal the complexities of this particular symptom.

The research group at the centre of this new paper based at DePaul University under the stewardship of Leonard Jason have some previous interest in this facet of ME/CFS as per other recent publications [2] talking about the trials and tribulations of defining PEM. Once again, the very multiple and very complicated ways that CFS/ME is currently diagnosed (see here for example) comes into play as the wording used to define PEM seems to count in terms of who is more or less likely to display this symptom. I might also add that even the words 'post-exertional malaise' have been subject to question and redefinition as per the use of the term PENE (Postexertional neuroimmune exhaustion) [3].

In their latest paper, McManimen et al set out to "discern whether post-exertional malaise is a unified construct or whether it is composed of two smaller constructs, muscle fatigue and generalized fatigue." As per the opening sentence of this post, researchers came down on the side of PEM meaning more than one thing, and with it the possibility of further revisions being required to the criteria to define this concept. Indeed, going back to yet another paper from this group [4] researchers suggested that several composite items might better define PEM over just one question: "Dead, heavy feeling that occurs quickly after starting to exercise; Next day soreness or fatigue after non-strenuous, everyday activities; Mentally tired after the slightest effort; Physically drained or sick after mild activity; and Minimum exercise makes you physically tired." Words, in a diagnostic sense, need to be used accurately.

And finally, whilst on the topic of CFS/ME, there have been some further developments around the science of CBT and graded exercise...

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[1] McManimen SL. et al. Deconstructing post-exertional malaise: An exploratory factor analysis. J Health Psychol. 2016 Aug 24. pii: 1359105316664139.

[2] Jason LA.  et al. Problems in Defining Post-Exertional Malaise. Journal of prevention & intervention in the community. 2015;43(1):20-31.

[3] Carruthers BM. et al. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. 2011;270(4):327-338.

[4] Jason LA. et al. Fatigue Scales and Chronic Fatigue Syndrome: Issues of Sensitivity and Specificity. Disabil Stud Q. 2011 Winter;31(1). pii: 1375.

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McManimen SL, Sunnquist ML, & Jason LA (2016). Deconstructing post-exertional malaise: An exploratory factor analysis. Journal of health psychology PMID: 27557649

Metformin to tackle medication induced weight gain in autism?

"Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD [autism spectrum disorder]."

So said the paper by Evdokia Anagnostou and colleagues [1] (open-access) tackling an increasingly important health issue related to the pharmacological 'management' of some aspects of some autism.

Metformin is the treatment of choice when it comes to the management of type 2 diabetes (the one where "the pancreas doesn't produce enough insulin or the body's cells don't react to insulin"). It is thought to work by helping the liver to stop producing new glucose and also helping insulin carry more glucose into muscle cells more effectively. Alongside, an increasing body of research has also suggested that metformin might be a useful intervention measure to offset one of the quite well-known side-effects associated with various antipsychotic agents: weight gain.

So Anagnostou et al set about looking to "assess the safety, tolerability, and efficacy of metformin to decrease weight gain associated with the use of atypical antipsychotic medication in children with ASD." They did this using the gold-standard in clinical trial designs: the "double-blind, placebo-controlled, randomized clinical trial" where some 60 children and young adults diagnosed with an ASD and receiving a stable dose of an atypical antipsychotic received either metformin (Riomet) or a placebo over the course of 16 weeks. "The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables." The study protocol was also registered with ClinicalTrials.gov.

As per the opening sentence, there were some important differences in body mass index (BMI) z-scores suggestive that compared with a placebo, those prescribed metformin saw decreases in weight gain. The range of decrease in BMI were in some cases between about 8-9% over the course of the 16 week study period (most of the benefits seemed to be apparent after about 8 weeks of metformin use). Insofar as those secondary variables also examined during the course of the study (glucose levels, insulin, triglycerides, etc.) no significant differences were noted across the study. When it came to the important issue of side-effects, the authors noted that gastrointestinal (GI) effects seemed to be more apparent in the group taking metformin during treatment days. Aside from that, short-term side-effects seemed to be few and far between.

The authors note that their trial "did not address the question of whether coadministration of metformin at the onset of atypical antipsychotic use prevents initial weight gain" but rather whether metformin use after weight gain associated with antipsychotic use could be effective. In that light, these are important results that very much require further independent investigation.

Quite a few times on this blog I've talked about how the physical health of those on the autism spectrum is sometimes neglected as a function on the focus on mental health or behaviour. There is a growing recognition that autism, or at least some of the important comorbidities associated with autism, might somehow predispose to a more sedentary lifestyle and the accompanying health issues that this can bring. Throw into the mix the possibility that some of the pharmacotherapy used in autism might also contribute to something like weight issues [2], and you have a recipe for some pretty severe health issues potentially building up in later life. These latest findings are therefore welcomed as a way to potentially lower the burden of an elevated BMI in cases where such medication is prescribed.

I do have questions however about this approach and how one perhaps needs to be slightly cautious about slipping into the old 'medication to tackle medication side-effects' routine with autism in mind (something noted in an accompanying editorial to the Anagnostou study). Metformin, whilst a very useful drug, is not without side-effects as was noted in the Anagnostou study and given the quite high rates of GI issues noted in cases of autism (see here), one really does not want to make this any worse. I would also like to see more data on the use of metformin in antipsychotic-induced weight gain in autism with a focus on other parameters thought to be altered by such antipsychotic use such as the issue of prolactin levels for example (see here). Yes, there is data to suggest that metformin might more generally work on prolactin levels too [3] but does this similarly apply to children on the autism spectrum? And then also there is the issue of sleep [4]...

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[1] Anagnostou E. et al. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder. JAMA Psychiatry. 2016. Aug 24.

[2] Shedlock K. et al. Autism Spectrum Disorders and Metabolic Complications of Obesity. Journal of Pediatrics. 2016. Sept 2.

[3] Krysiak R. et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med. 2016 May;30:94-8.

[4] Kajbaf F. et al. The relationship between metformin therapy and sleep quantity and quality in patients with Type 2 diabetes referred for potential sleep disorders. Diabet Med. 2014 May;31(5):577-80.

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Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA, Brian J, Arnold LE, Capano L, Hellings JA, Butter E, Mankad D, Tumuluru R, Kettel J, Newsom CR, Hadjiyannakis S, Peleg N, Odrobina D, McAuliffe-Bellin S, Zakroysky P, Marler S, Wagner A, Wong T, Macklin EA, & Veenstra-VanderWeele J (2016). Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA psychiatry PMID: 27556593