In relation to chelation and autism

OK, just to make sure we're straight on this matter:

I am not endorsing chelation therapy for autism in this post.

Carry on Private...

I might have said it before but a few areas of the autism landscape have been, and still, are a bit of a sticking point when it comes to their discussion. Mention for example bowel issues and autism and, in at least some quarters, you can see the eyebrows raising and the eyes beginning their short rolling journey around the eye socket. This despite the fact that bowel issues are to some extent entering the mainstream autism research consciousness as witnessed for example by that recent paper from Susie Chandler and colleagues (discussed here). Dare I even mention gut bacteria and autism as per the recent write-up of Paul Patterson's [pending] work in the New Scientist? Too much?

My hand @ Miss Whiteley  

So it is with some degree of eye-rolling anticipated that I set about discussing the paper by Eleonor Blaucok-Busch and colleagues* (open-access) describing the results of their small trial based on the use of the oral chelator meso-2,3-dimercaptosuccinic acid (DMSA) in cases of autism.

I'm not altogether sure, but I wondered whether we might have already seen some part of this trial published in another paper**.

In truth I wouldn't normally be minded to talk about something like DMSA and autism given that (a) chelation - with general health in mind - is still a bit of a hot potato in many science/medical circles even despite some evidence that the 'metal-snaring' intervention might have some effects, and (b) with autism in mind, chelation is even more of a hot potato given some safety concerns and its link to heavy metals - in particular one heavy metal - onward to a suggested role in the rising numbers of cases of autism by some.

But science is science, and the manuscript by Blaucok-Busch is peer-reviewed science (the journal also indexed in PubMed). Added to the fact that some people have reported positive changes to some features associated with autism following such intervention*** alongside some recent publicity for related work by people like Jim Adams (see this previous post), this post may be timely.

The Blaucok-Busch paper is open-access but a few details might be of some use:

• I don't mean to be a stickler but the opening line of the abstract read slightly unusual to me: "the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD". A research paper designed to provide evidence that something works? Mmm, I perhaps would have worded this differently with regards to things like hypothesis-testing over evidence-producing, but maybe that's just me.
• Anyhow, 44 children diagnosed with an ASD - most boys and most diagnosed with autism - aged between 3-9 years old were included for study. The children were all attending a child development centre in Saudi Arabia. Quite a bit of background data were available for participants and in among the various entry/exclusion criteria were the none use of regular medication including neuroleptics and antiepileptics. 
• The Childhood Autism Rating Scale (CARS) (translated into Arabic) was used to score the presence of autism-related behaviours; both before DMSA use and "six months after treatment". This actually translates as a single dose of DMSA per month (10mg/kg body weight) for a total of 6 months.
• Prior to any use of DMSA, participants were provided with a nutritional supplement including "a multi-mineral-vitamin-amino acid complex" which included zinc gluconate given once-a-day for 3 months prior to chelation.
• Baseline urine samples pre-chelation were collected and alongside (I assume first supplementation) post-DMSA administration urine samples (over 4 hours), analysis was conducted on them using everyone's favourite metal analysis technique, ICP-MS.
• Results: based on analysis for a number of metals, urine samples showed a number of differences between pre- and post-DMSA administration, most notably for increases in cadmium (p=0.006) and lead (p=0.008) excretion. Mercury also showed some difference, but only just from a statistical point of view (p=0.049). Another quote: "For this autistic group, the baseline urine concentration of all metals tested exceeded the given reference range".
• For the CARS, pre- and post-DMSA scores - bearing in mind we are talking 6-months after treatment - showed a few interesting trends in terms of items like sensory-perceptual issues and verbal and non-verbal communication, potentially indicative of positive changes to symptoms.
• The authors conclude: "Our evaluation confirmed specific metals as neuro-developmental toxins, and we observed that a reduction in toxic metals is helpful in reducing some symptoms typically associated with autism".

OK first things first. This was a simple before-and-after study based on the use of DMSA. There was no control group, no randomisation, no placebo, and everything was unblinded. This is not a great example of providing evidence for a cause-and-effect relationship.

Aside from reporting that 2-3 days prior to the DMSA challenge "no fish was eaten" and "all nutritional supplements were stopped" we know very little about what else might have happened in that intervening 6 month period between CARS assessments. Without any sample control group to compare against, we might just as well say that the changes to the CARS might be down to maturation or some other intervention put in place. Indeed I don't know whether this cohort were more or less likely to be using other interventions which might have affected results as a result of their participation in the trial; not least whether anyone went back on to the nutritional supplement after the first chelation event. There are methodological holes in this trial; of this there is no doubt.

But... [cue any eye-rolling] I am particularly interested in the pre- and post-challenge DMSA urine results detailed. Interested that even in the pre-DMSA samples, children with autism were presenting with levels of heavy metals that exceeded reference ranges. Granted, one could ask: from where the reference range is derived and whether it is truly reflective of this particular participant group in terms of age, sex, ethnicity, etc. and the myriad of other potentially influential demographic and geographic factors. I have to take the authors' word for it that it is accurate although I would like to have seen the unit of measurement when it comes to reporting metal excretion levels displayed somewhere in the paper.

Of course this is not the first time that metals like lead have for example cropped up with autism and quite a few other conditions/states in mind. Even superman had problems with lead, so went a past post on this blog. Indeed my discussion on the paper by Yasuda and colleagues quite recently (see here) and their metallomic analysis of children with autism suggested that lead, cadmium and aluminium in relation to some cases of autism were of potential importance, particularly where zinc deficiency was present. This follows similar findings previously reported (yep that Jim Adams study again) and some case studies (see here for example).

I was also interested in the variation in metal excretion following DMSA challenge. Increasing mean levels of urinary lead in the cohort follow what DMSA is supposed to do and add to the evidence already presented with autism in mind**** (open-access). But, as the authors point out, several metals were actually lower in the post challenged samples. Even the mercury results whilst showing a mean higher level showed a vastly increased standard deviation pre- and post-challenge (3.35±3.81 vs. 16.12±36.57) which probably accounts for the relatively modest p-value reported. I assume this denotes that some children were better excretors of things like mercury than others following DMSA challenge? My next question would be: why?

Evidence for the use of chelation in cases of autism is still wanting in terms of research results as per the review by Davis and colleagues*****. This trial by Blaucok-Busch is, unfortunately, unlikely to add anything significant to the existing research literature. The tragic case of Abubakar Tariq Nadama who died following intervention with a chelating agent****** (albeit a different chelating agent) still also hangs over the whole area of metal removal and autism and serves as an important but very unfortunate reminder about what can happen; also re-emphasizing the first law of any intervention: do no harm. No doubt why the NIH trial fell as it did (see here).

That's not however to say that the research door should be slammed shut, bolted, padlocked and alarmed, as several questions still remain unanswered: why for example some kids with autism present with elevations in certain heavy metals in the first place (see the paper by Levallois et al******* for one possibility) and what their relationship might or might not be to presented symptoms. One could argue that getting to the bottom of these questions is the first step, and thereafter to the question of what can or can't be done about it in a more scientifically-rigorous fashion bearing in mind safety first and the fact that not all chelating methods are the same********.

To finish, a final mention: I am not endorsing chelation therapy for autism in this post. Just in case I hadn't got my message across.

Now away from metal, how about listening to The Specials and 'Gangsters' including one of the best lines in music... "Don't call me Scarface". So, don't.... (and as it happens, thanks to a childhood prank gone wrong, I do actually have a scar on my face).

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* Blaucok-Busch E. et al. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar). 2012; 7: 214-221.

** Amin OR. P-252 - Efficacy of oral dimercaptosuccinic acid (DMSA) therapy in a sample of arab children with autistic spectrum disorder. European Psychiatry. 2012; 27 (suppl 1).

*** Senel HG. Parents' views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder. J Autism Dev Disord. 2010; 40: 494-503.

**** 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; 9:16.

***** Davis TN. et al. Chelation treatment for autism spectrum disorders: a systematic review. Research in Autism Spectrum Disorders. 2013; 7: 49-55.

****** Baxter AJ. & Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clinical Toxicology. 2008; 46: 1083-1084.

******* Levallois P. et al. The impact of drinking water, indoor dust and paint on blood lead levels of children aged 1–5 years in Montréal (Québec, Canada). Journal of Exposure Science and Environmental Epidemiology. January 2013.

******** Cohen JP. et al. Plasma and Urine Dimercaptopropanesulfonate Concentrations after Dermal Application of Transdermal DMPS (TD-DMPS). J Med Toxicol. 2013; 9: 9-15.

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Blaucok-Busch E, Amin OR, Dessoki HH, & Rabah T. (2012). Efficacy of DMSA Therapy in a Sample of Arab Children with Autistic Spectrum Disorder. Maedica (Buchar), 7 (3), 214-221