Description of the condition
According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), autism spectrum disorders (ASD) are a set of pervasive neurodevelopmental conditions that are characterised by difficulties in social interaction and communication, and the presence of restricted, repetitive behaviours (i.e. stereotypies) (APA 2012). Historically, Asperger’s disorder, autistic disorder, atypical autism, and pervasive developmental disorder not otherwise specified (PDD NOS) were considered examples of conditions falling within the autism spectrum. However, the latest edition of the DSM (DSM-5) now uses the term ASD for diagnostic classification (APA 2012).
The severity of ASD varies considerably, and there is great variability in symptoms and manifestations. Individuals with ASD have difficulty in social-emotional reciprocity (e.g. such as participating in reciprocal conversations or maintaining eye gaze), communicating verbally and non-verbally, forming and maintaining relationships, and understanding the social behaviour of others (Shattuck 2007; APA 2012). Individuals with ASD also exhibit preoccupations and restricted, repetitive patterns of interest and behaviours, which may include strong adherence to routines and stereotyped speech and motor movements (Lecavalier 2006; APA 2012). Some may present with behavioural symptoms (e.g. such as irritability, aggression, anxiety, self-injury, and hyperactivity), but these features are not part of diagnosis, rather they are co-occurring symptoms. The specific causes of ASD are currently unknown. However, genetic factors and prenatal and perhaps postnatal environmental factors are believed to contribute to the onset of ASD, although the role of environmental triggers remains uncertain (Hallmayer 2011).
There are many interventions for ASD, and while some such as early intensive intervention are effective in improving communication, social interaction, and behaviours, none are capable of producing complete remission of all symptoms. Pharmacologic interventions are often prescribed to individuals with ASD, primarily to target specific associated symptoms or co-occurring features. Currently, however, no pharmacologic interventions target core symptoms of ASD. Individuals with ASD also frequently use complementary and alternative medicine (CAMs); approximately 75% of children with ASD use CAMs (Hanson 2007). Examples of CAMs that are used for ASD include exclusion diets, essential fatty acids, multi-vitamins, acupuncture, auditory integration training, and chelation therapy. To date, there is no consistent evidence that CAMs are effective interventions for core features and associated behaviours of ASD (Nye 2005; Gold 2006; Millward 2008; Cheuk 2011; Sinha 2011; James 2011).
Description of the intervention
Chelation therapy involves the administration of a chelating substance that binds to heavy metals, such as lead and mercury, and is then excreted in urine. Chelating substances are approved for treating cases of heavy metal poisoning. However, they have also been used for unapproved reasons and conditions such as Alzheimer’s disease, coronary heart disease, and ASD (Ernst 2000; Dans 2002; Sinha 2006; Hedge 2009). Types of chelating substances used to reduce heavy metal poisoning are outlined in Table 1 . The administration of chelation therapy for approved uses occurs in a very controlled environment, which is different to the process followed by practitioners administering chelation for unapproved uses, such as for ASD.
|Name||Target heavy metals||Route of administration||FDA-approved indications||Pharmacokinetics||Pharmacodynamics||Common adverse effects|
|Meso-2, 3-dimercaptosuccinic acid (DMSA)||Lead Arsenic and Mercury poisoning||Oral||Lead poisoning in adults and children >12 months|
Tmax: 1 to 2 hours
2 hours to 2 days
Primarily excreted renally
|Forms water soluble chelates with heavy metals which are excreted renally||Rash Gastrointestinal upset|
|Edetate disodium (EDTA)||Calcium||Intravenous (IV)|
Hypercalcaemia (emergency treatment)
Digitalis poisoning Ventricular arrhythmia in adults
1.4 to 3 hours
|Forms soluble chelate with calcium resulting in a rapid decrease in plasma calcium concentrations||Fatigue Hypocalcaemia Thrombophlebitis|
|Sodium 2,3 dimercaptopropanesulphonate (DMPS)|
Mercury Wilson’s disease (copper)
|Intravenous (IV) and oral||Not approved for use in the US||Elimination t1/2 1.8 hours|
Forms water soluble chelates with many heavy metals which are excreted renally
High affinity for mercury
|Edetate calcium disodium||Lead||Intravenous (IV) and intramuscular (IM)|
Acute and chronic lead poisoning
Toxic encephalopathy due to lead in adults and children
20 to 60 minutes (IV)
1.4 to 3 hours (IM)
|An effective chelator of extracellular lead resulting in increased urine excretion||Fatigue Nephrotoxicity|
Cases of heavy metal poisoning, such as acute lead poisoning, require urgent hospitalisation and administration of chelating substances either intravenously or by deep intramuscular injection for four hours. During the treatment of acute lead poisoning, blood and urine are monitored constantly, as significant shifts of the heavy metal can occur between the blood and central nervous system with dire consequences. Moreover, because minerals and metal ions are essential elements that serve important functions in multiple biological processes, excessive removal can result in deleterious consequences; for example, recently a child with ASD experienced fatal myocardial necrosis resulting from hypocalcaemia after receiving chelation therapy (Brown 2006). Additionally, the local health department is notified, as the source of the lead needs to be identified and dealt with appropriately.
The unapproved use of chelation therapy, for example when used as an intervention for ASD, may involve practitioners using various chelating substances and unlicensed routes of administration (e.g. such as through the rectum or skin) to remove reported excess levels of mercury or other heavy metals or both (Semple 2011). Prior to treatment, individuals with ASD may undergo preliminary tests with the chelating substance to evoke a response, followed by timed urine collection to determine the levels of heavy metals in the body (Bradstreet 2003; Adams 2009). One of the more commonly used chelating substances, oral dimercaptosuccinic acid (DMSA; also called succimer), is being given on a cyclical basis at doses of 10 mg/kg/day every eight hours for three days, followed by 11 days with no DMSA (Bradstreet 2003; Adams 2009). These two-week cycles are then repeated up to six times, totaling approximately three months of treatment (Adams 2009).
Between 6% and 11% of families of children with ASD in various English speaking countries, including the United States, Canada, and Australia, have sought out and tried chelation therapy, and most of these families perceived chelation therapy to result in improvement of symptoms (Green 2006; Goin-Kochel 2009; Christon 2010).
How the intervention might work
The theoretical basis for mercury or other heavy metals causing ASD draws on a wide variety of hypotheses, none yet confirmed. One hypothesis is that mercury or other heavy metals are present in greater levels in children with ASD, compared to their peers, as a result of intrauterine exposure to maternal stores or intake, increased intake from immunisations (thimerosal), oral ingestion (fish or medication), inhalation (airborne pollution), increased absorption, altered metabolism, or decreased excretion (Bernard 2001; Goldman 2001; Holmes 2003; Levy 2003; Counter 2004; Kern 2007).
The excess of stored or circulating total body mercury or other heavy metals is thought to interfere with developmental processes implicated in ASD, and it has been suggested that symptoms of mercury poisoning and ASD share some characteristics (Bernard 2001). Mercury, in being able to cross the blood-brain barrier and the placental barrier, can affect the nervous system and disrupt normal development of the foetus (Aschner 1990; Liu 2008). Prenatal mercury poisoning may result in neurological impairments and global developmental delay and intellectual disability, while postnatal exposure can result in memory loss, irritability, fatigue, intention tremor, skin discolouration, and other organ involvement, including kidney dysfunction (e.g. nephrotic syndrome or tubular dysfunction or both) (Bakir 1973; Amin-Zaki 1974; Grandjean 1997; Goldman 2001; Counter 2004).
Research has produced contradictory findings with regard to levels of heavy metals in individuals with ASD. Although some studies found higher levels of heavy metals in individuals with ASD compared to individuals without ASD (Cohen 1976; Cohen 1982; Adams 2013), more emerging research found no association between ASD and higher levels of heavy metals (Hertz-Picciotto 2010; Albizzati 2012; Rahbar 2013).
An alternative hypothesis is that mercury or other heavy metals could cause ASD through altered cellular functioning that does not require increased body stores or circulating mercury or other heavy metals. In this context, it is thought that individuals with ASD have an impaired capacity to excrete heavy metals and that the severity of autism symptomatology is inversely correlated with excretion ability (Holmes 2003; Kern 2007). This hypothesis is currently being explored (Deth 2008; Zecavati 2009; Garrecht 2011), but it is unlikely that chelation therapy would be beneficial in this context.
Why it is important to do this review
Novel therapies are used frequently by individuals with ASD (Hanson 2007). Despite their increasing use, most CAMs for ASD lack a robust evidence base (Nye 2005; Gold 2006; Millward 2008; Cheuk 2011; Sinha 2011; James 2011). Chelation therapy is one CAM that continues to be used and promoted as efficacious, despite being discouraged by physicians (Golnik 2009) and reports of harm, including death (Brown 2006). A systematic review that examines potential beneficial and harmful effects of chelation for symptoms of ASD is urgently needed to provide best evidence to inform future decision-making about the use of this intervention. Results from this systematic review will help families with ASD make well-informed decisions about the use of chelation therapy and will assist relevant services and other organisations make decisions about best practice.