Cochrane does chelation for autism

Cochrane, in the title of this post, refers to the Cochrane Collaboration and the sterling work done throughout health care synthesising peer-reviewed evidence pertinent to the goal of evidence-based medicine.

The collaboration has recently turned its eye towards the topic of chelation with autism in mind, a topic that has been discussed previously on this blog (see here). Their conclusions based on the findings reported by Stephen James and colleagues [1] (open-access here), looking at the available evidence up to November 2014 are not entirely unexpected: "no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD [autism spectrum disorder]." Further: "Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits." A further summary of the findings can be found here.

Based on a search of the peer-reviewed literature on chelation and autism, only one study fulfilled the appropriate criteria (i.e. being randomised), that of Jim Adams and colleagues [2] (open-access here). Actually the Adams study brought about two papers (the second is here [3]) covering both medical and behavioural results following oral DMSA (dimercaptosuccinic acid) therapy in cases of autism. The Adams study reported: "Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC [Red Blood Cell] glutathione, and effective in normalizing platelet counts." Further: "Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children."

The Cochrane review however did not share the optimism. "One trial, which had methodological issues and a relatively small sample size, is insufficient to provide robust evidence on chelation for ASD." James et al also suggested that the Adams study was judged to have "have high or uncertain risk of bias and methodological problems that limited the interpretation of outcomes presented." Even worse: "Given the deleterious effects of chelation, misinterpretation and misuse of the study of Adams et al to justify the use of chelation for ASD is unethical and potentially places children unnecessarily in harm’s way." Ouch.

"At the present time, the theory that heavy metals may cause autism or might worsen symptoms has not been established." I'd agree with this sentiment from James et al but with the proviso that there is ample peer-reviewed evidence to suggest that for at least some on the autism spectrum, the burden of heavy metals does seem to be increased (see here for example). The idea that something like lead (Pb) - a known toxicant adversely affecting child development - might be elevated in [some] cases of autism is of particular importance.

The associated comment by Adams et al on what happened to glutathione levels following DMSA use is something that I'd like to see more science resources put into. Not for one moment do I endorse the use of DMSA without appropriate medical oversight, but knowing what we know about glutathione and autism (see here) and the 'elephant in the room' sentiments, I'd be minded to suggest that there may be quite a bit more to see here particularly in light of the findings from Monin and colleagues [4] talking about glutathione deficits and "myelin maturation".

Music: The Beach Boys - Wouldn't It Be Nice. Well, yes rather.

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[1] James S. et al. Chelation for autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2015;5:CD010766.

[2] Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. BMC Clin Pharmacol. 2009 Oct 23;9:16.

[3] Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results. BMC Clin Pharmacol. 2009 Oct 23;9:17.

[4] Monin A. et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry. 2015 Jul;20(7):827-38.

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James S, Stevenson SW, Silove N, & Williams K (2015). Chelation for autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 5 PMID: 26106752

Probiotics to counter heavy metal toxicity?

"In summary, this work has demonstrated the potential value of long-term probiotic-based interventions to counter mercury and arsenic exposure in vulnerable populations, particularly in pregnant women".

Sounds like an '80s man to me...

That was one of the primary conclusions reported by Jordan Bisanz and colleagues [1] (open-access) examining "at-risk populations of pregnant women and in children in Mwanza, Tanzania". The idea being that alongside the use of metal chelating medicines such as dimercaptosuccinic acid (DMSA) and ethylenediaminetetraacetic acid (EDTA) indicated for 'acute' exposure to heavy metals, there may be other ways and means of treating heavy metal exposure over longer periods and where resources may not be as plentiful. Some media about this study can be seen here.

The Bisanz paper is open-access but a few pointers might be in order:

• The study was based on the idea that certain strains of bacteria are known to have "an affinity for many toxic metals, including lead and cadmium" as documented in papers such as the one by Monachese and colleagues [2]. Further, that so-called "probiotic yogurt kitchens that service economically disadvantaged people" as a source of potentially beneficial bacteria are already working at the particular location selected by the study authors.
• So, two studies were implemented: (a) looking at school-aged children (SAC) (initial N=44) randomised to receive either a probiotic yoghurt containing "1 × 1010 CFU Lactobacillus rhamnosus GR-1 per 250 g" or "an equivalent portion of ultra-heat-treated milk as a control devoid of lactic acid bacteria" daily for 24 days; and (b) "60 pregnant women [PW] were recruited, of which 26 received a probiotic yogurt containing 1 × 1010 CFU L. rhamnosus GR-1 per 250 g and supplemented with 4.3 g of Moringa, a micronutrient-rich plant, to enhance maternal nutrition". The study entries in the US National Institutes of Health (NIH) database can be found here and here respectively. 
• Analysis of blood metal levels ("blood lead, total mercury, total arsenic, and cadmium") were undertaken at enrolment and follow-up for all participants across the two studies. Analysis of fecal samples for children in study (a) was also undertaken pre- and post-intervention to test for any differences across the yoghurt vs. milk groups. Local fish were also analysed for heavy metal content to ascertain dietary exposure alongside dietary patterns of participants.
• Results: there were quite a few... levels of heavy metals in SAC and PW studied were elevated compared to "levels present in a developed country (Canada)" somewhere in the order of over 6 times greater for lead and mercury. Children (SAC) were particularly vulnerable to an increased heavy metal burden. The authors noted: "Metal exposure from dietary fish intake likely explains why we saw elevated blood levels of mercury in both the SAC and PW groups".
• "The studies provided the first positive evidence for the use of probiotics to combat toxic heavy metal exposure in vulnerable human populations". Well, sort of, is probably the best way that I can comment on this assertion, as the authors noted: "no statistically significant differences were detected in blood metal levels in SAC receiving the probiotic or milk control, although we noted that there was a weak trend of reduced blood levels of lead and arsenic". They did find that in the control group in receipt of milk, "blood levels of mercury and arsenic increased" between the testing occasions "but remained stable in the probiotic group". So concluding that levels of certain heavy metals didn't get any worse following the use of a probiotic is probably a more accurate way of looking at things.
• Insofar as the gut bacteria analysis side of things: "Administration of the probiotic was not observed to have an effect on the gut bacterial community composition". But the authors did report that: "Elevated blood lead was associated with increases in Succinivibrionaceae and Gammaproteobacteria relative abundance levels in stool".

There are some important results to be derived from the Bisanz paper but not necessarily in the way that I think the authors hoped, bearing in mind this was a very short study limited to one specific probiotic strain. That being said, the idea that probiotics might have some kind of protective effect - "probiotic administration may be especially advocated at peak exposure times" - is an interesting one, worthy of quite a bit more investigation. 

I know discussions in certain quarters about the use of chelation therapy for certain conditions have the ability to furrow brows (see here). This despite the fact that when clinically indicated, chelation can provide some powerful results as demonstrated in the recent paper by Thurtle and colleagues [2] (open-access) on the use of oral DMSA for severe lead poisoning in Northern Nigeria. If we are to assume that certain types of bacteria might potentially be able to prevent or reduce uptake of something like heavy metals in the gastrointestinal (GI) tract from oral sources (i.e. food), I'd be minded to say that such inexpensive and potentially safer methods protecting against heavy metal poisoning, might be something to explore. And hopefully I'm talking out of turn when I mention some of the literature on lead and mercury exposure when it comes to autism (see here) as another possible avenue for more formal investigation.

Next up: probiotics and influenza anyone? (With the need for a lot more research and certainly nothing like medical or clinical advice given or intended by me on this topic).

Music then. Domino by Jessie J.

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[1] Bisanz JE. et al. Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children. mBio. 2014. 7 October.

[2] Thurtle N. et al. Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data. PLoS Medicine. 2014; 11: e1001739.

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Jordan E. Bisanz, Megan K. Enos, Joseph R. Mwanga, John Changalucha, Jeremy P. Burton, Gregory B. Gloor, & Gregor Reid (2014). Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children mBio : 10.1128/mBio.01580-14