ADVANCES IN AUTISM INTERVENTIONS FOR CHILDREN WITH AUTISM SPECTRUM DISORDER
FOLINIC ACID IMPROVES VERBAL COMMUNICATION IN CHILDREN WITH AUTISM
CLUSTER RANDOMIZED TRIAL OF THE CLASSROOM SCRTS INTERVENTION FOR ELEMENTARY STUDENS WITH AUTISM SPECTRUM DISORDER
TEACHING PARENTS BEHAVIORAL STRATEGIES FOR AUTISM SPECTRUM DISORDER (ASD): EFFECTS ON STRESS, STRAIN AND COMPETENCE
EXTRA AXIAL CEREBROSPINAL FLUID IN HIGH RISK AND NORMAL RISK CHILDREN WITH AUTISM AGED 2 – 4 YEARS: A CASE CONTROL STUDY
BEYOND INFECTION: MATERNAL INMUNE ACTIVATION BY ENVIRONMENTAL FACTORS, MICROGLIAL DEVELOPMENT AND RELEVANCE FOR AUTISM SPECTRUM DISORDERS
THREE 2018 REPORTS: Prevalence of Autism Spectrum Disorder in United States:
Importance of monitoring early symptoms and severity in autism spectrum disorder
Advances in the genetics of autism
SOME PAGES WEB
Autism Society.com
There are many webs concerning the autism desorder, some examples:
Autism Speaks
NHS website
Autism spectrum Australia
Wu Medical Center
MOLECULAR AUTISM Part of Sprinter Nature
Prediction of Autism at 3 Years from Behavioural and Developmental Measures in High-Risk Infants: A Longitudinal Cross-Domain Classifier Analysis
G. Bussu1 · E. J. H. Jones2 · T. Charman3 · M. H. Johnson2 · J. K. Buitelaar1 · the BASIS Team
© The Author(s) 2018. This article is an open access publication
Abstract We integrated multiple behavioural and developmental measures from multiple time-points using machine learning to improve early prediction of individual Autism Spectrum Disorder (ASD) outcome. We examined Mullen Scales of Early Learning, Vineland Adaptive Behavior Scales, and early ASD symptoms between 8 and 36 months in high-risk siblings (HR; n = 161) and low-risk controls (LR; n = 71). Longitudinally, LR and HR-Typical showed higher developmental level and functioning, and fewer ASD symptoms than HR-Atypical and HR-ASD. At 8 months, machine learning classified HRASD at chance level, and broader atypical development with 69.2% Area Under the Curve (AUC). At 14 months, ASD and broader atypical development were classified with approximately 71% AUC. Thus, prediction of ASD was only possible with moderate accuracy at 14 months. Keywords Autism · Early prediction · Machine learning · Data integration · Individual prediction · High-risk · Longitudinal study
Introduction
Although symptoms of Autism Spectrum Disorders (ASD) typically emerge early in life, a reliable diagnosis is usually not achieved before age 3 or later (Steiner et al. 2012). Evidence suggests that the best prognosis for ASD currently lies in early targeted intervention aimed to improve later outcome by modifying emergent atypical developmental trajectories (Fernell et al. 2013; MacDonald et al. 2014). A recent
follow-up study on the effects of parent-mediated social communication intervention in infants at high familial risk of ASD between 9 and 14 months shows a treatment effect on symptom severity extended 24 months after intervention end (Green et al. 2017). However, the sustained delivery of behavioural intervention to all infants at risk for ASD based only on traits would be too expensive, and the risk/benefit ratio may be less favourable for infants who would have developed typically anyway. Thus, individual prediction of later development of ASD as soon as early signs emerge could help to better target early intervention strategies. Limits to detection of ASD before 24 months come from the high heterogeneity of the disorder and the relatively late emergence of the core characteristics of ASD. Heterogeneity in onset, aetiology, phenotype, neurobiology, and developmental trajectory points to multiple underlying processes acting together and leading to the disorder rather than a unitary biological process (Jones et al. 2014; Lai et al. 2013; Vorstman et al. 2017). Therefore, the investigation of different types of data is essential to capture the different aspects of the disorder. Machine learning holds the potential to provide a robust algorithm for prediction of later clinical outcome combining complementary information from different sources in an efficient way, and allowing the identification of
Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1080 3-018-3509-x) contains supplementary material, which is available to authorized users.
- G. Bussu g.bussu@donders.ru.nl 1 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands 2 Centre for Brain and Cognitive Development, Birkbeck, University of London, 32 Torrington Square, London WC1E 7JL, UK 3 Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
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the most predictive combination of measures. The application of these methods has already shown promise for classification of children with ASD (Ingalhalikar et al. 2014; Uddin et al. 2013; Wee et al. 2014). In the present study we apply machine learning algorithms to predict clinical outcome at 36 months from different combinations of behavioural and developmental measures at 8 and 14 months. Despite a general consensus on the added value of data integration for prediction of ASD, the method has not previously been applied to behavioural measures and standard developmental assessments. Research in the early recognition and diagnosis of ASD has been focused on prospective longitudinal studies of infants at high-risk for autism because they have an older sibling with ASD. High-risk infants (HR) have about a 20% risk of developing ASD, significantly higher than the population prevalence of 1.5% (Christensen 2016; Ozonoff et al. 2011; Sandin et al. 2014; Szatmari et al. 2016), and thus the high-risk design allows us to study the early manifestations of the condition and understand the behavioural, cognitive and neural mechanisms that precede the clinical onset of ASD (Jones et al. 2014). Yet, these studies have mainly focused on average differences between infants who later develop ASD and their typically developing peers, measuring group differences by means of p-values. Convergent evidence supports the emergence of overt behavioural markers for ASD by the end of the second year of life, such as atypical eye contact, visual tracking, disengagement of visual attention and orienting to name (Elsabbagh and Johnson 2010; Gliga et al. 2014; Jones et al. 2014; Ozonoff et al. 2010; Rogers 2009; Yirmiya and Charman 2010; Zwaigenbaum et al. 2015). Objectively measured behavioural signs for ASD emerging before 12 months include a fall in fixation to the eye region between 2 and 6 months (Jones and Klin 2013), reduced gaze fixation to people at 6 months (Chawarska et al. 2013), and vocal atypicalities (Paul et al. 2011). But early markers for ASD are not limited to social domains. By 14 months, high-risk siblings developing ASD performed significantly worse than unaffected siblings on all scales of the Mullen Scales of Early Learning (MSEL) except for Visual Reception (Landa and Garrett-Mayer 2006), and impairments in verbal skills (particularly receptive language) (Barbaro and Dissanayake 2012), and motor skills were associated with later diagnosis of ASD (Chawarska et al. 2007; Landa and Garrett-Mayer 2006; Landa et al. 2013; MacDonald et al. 2013), even already by the age of 7 months (Leonard et al., 2014; Libertus et al. 2014). Few studies so far have conducted analyses that combined measures from different domains. Estes and colleagues (2015) investigated trajectories of developmental abilities, as measured by the MSEL; adaptive functioning, as measured by the Vineland Adaptive Behavior
Scales (VABS); and early ASD symptoms, as measured by the Autism Observational Scale for Infants (AOSI), in infants at high and low risk for autism in relation to ASD at 24 months, showing a pattern of symptoms starting in the sensorimotor domain at 6 months and moving to the social-communication domain after 12 months. Thus, prediction of autism may require a multi-measure approach. Although previous findings on group differences between infants who later develop ASD and their typically developing peers are valuable in terms of finding relevant biomarkers for the disorder, there is often substantial overlap between groups in individual variation, making prediction for individual infants difficult. The aim of individual prediction of outcome is to automatically classify each individual into one group (e.g. ASD vs. nonASD outcome), and performance is usually measured by accuracy or Area Under the Curve (AUC). The AUC is a measure of predictive accuracy computed as the area under the Receiver Operating Characteristic (ROC) curve, which is a plot of true positive rate vs. false positive rate for the model under evaluation (Metz 1978). Prediction at chance level results in 50% AUC, while prediction has moderate accuracy for AUC above 70%. Few studies have used behavioural measures to predict individual outcome of ASD, individual prediction being more focused on neuroimaging data (Arbabshirani et al. 2017; Emerson et al. 2017; Libero et al. 2015; Zhou et al. 2014). Macari and colleagues (2012) employed a decision-tree nonparametric learning algorithm to classify typical versus ‘atypical’ high-risk infants using as features measures from the Autism Diagnostic Observation Schedule (ADOS) at 12 months. ‘Atypicality’ included but was not limited to ASD, and was based on clinical evaluation at 24 months. Despite promising results, the study was considered preliminary due to a small sample size (n = 84) and the lack of a confirmatory diagnosis at 36 months. Chawarska and colleagues (2014) used the same methods to predict ASD outcome at 36 months in a cohort of high-risk siblings at 18 months. The aim was to identify the individual items of the ADOS-G at 18 months that best differentiated high-risk siblings who were going to develop ASD from typically developing siblings or siblings with other developmental disorders. The combination of six behavioural features (i.e. repetitive behaviours, eye contact, intonation, gestures, giving objects and spontaneous pretend play) allowed the identification of ASD with high accuracy (83%), while poor eye contact or limited gestures alone did not provide good prognostic value for ASD. This suggests that the interaction between (or combination of) individual behaviours must be considered to enhance predictive value for an early identification of later ASD outcome. Prior to our study, classification of ASD from behavioural measures before 12 months has not been reported, while it would be
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crucial to enable early intervention. Furthermore, previous studies only looked at items from the ADOS, but did not investigate whether different measures of developmental skills and functioning can increase predictive power for ASD at an early age. The aim of the present study was to investigate predictive longitudinal differences from 8 to 36 months between infants at low and high familial risk for autism with different developmental outcomes (typical, ASD, atypical). Further, we investigated whether we could predict ASD or atypical development at 36 months at an individual level within the HR group from data collected at 8 and 14 months. Extending the approach adopted in previous studies, we integrated measures from ASD symptoms, developmental and adaptive functioning, and we compared classifiers based on different combinations of measures to identify which combination is most predictive. We tested the hypothesis that integration of information about symptoms, developmental ability and everyday functioning can improve prediction of ASD compared to prediction from ASD-specific symptoms alone, capturing pervasiveness and addressing the high heterogeneity of ASD. Prediction was also made taking into consideration the dynamics of development by adding the change of scores between 8 and 14 months to cross-sectional measures at 8 months. This allowed us to test our second hypothesis that integration of measures from multiple time-points adds value to prediction of ASD from measures at early age compared to prediction from measures at single time-points.
Methods
Participants
Data presented in the current paper were collected as part of a large longitudinal study, to which 247 infants participated in one of two phases of longitudinal assessments (104 in Phase 1 and 143 in Phase 2). Data from 232 infants (161 [69.4%] high-risk siblings [HR] and 71 [30.6%] low-risk controls [LR]) were included in this study; ten infants were excluded because they did not receive an ADOS evaluation and/or a clinical outcome evaluation at 36 months; five infants were excluded because they did not attend at least one of the visits. HR infants were at increased familial risk because they had an older biological sibling with ASD, while LR controls had an older full sibling with typical development. The sample was balanced in gender (116 males and 116 females), and 85/161 HR siblings (53%) and 31/71 LR controls (44%) were males. We used imputation through expectation maximization to handle missing data (see Supplemental Material for details). Analyses were
performed on SPSS (http://www.ibm.com/analy tics/us/en/ techn ology /spss).
Developmental Assessments
All infants, irrespective of diagnosis and risk group, were followed longitudinally on four visits from an intake evaluation at 8 months [mean = 8.1; standard deviation, SD = 1.2] with further assessments at 14 months [mean = 14.5; SD = 1.3], 24 months [mean = 25.4; SD = 3.1] and 36 months [mean = 38.4; SD = 2.3]. At each assessment, infants were evaluated on the MSEL and VABS. Autism symptoms were assessed through the AOSI at 8 and 14 months, while the ADOS was used at 24 and 36 months. The Autism Diagnostic Interview—Revised (ADI-R; (Kim et al. 2013)), a structured parent interview, was also used to assess autism symptoms at 36 months. Experimenters were aware of infants’ risk status, but assessments were blind to clinical outcome. At the time of enrolment, none of the infants had been diagnosed with any developmental condition.
Measures
Developmental Skills
Verbal and non-verbal cognitive development was measured at each visit by the MSEL (Mullen 1995), a standardized developmental measure used to assess cognitive functioning between birth and 68 months. Scores are obtained in 5 scales and 2 main functional domains: the gross motor scale (GM), and the cognitive scales. The cognitive scales are visual reception (VR), fine motor abilities (FM), receptive (RL) and expressive language (EL). The Mullen Scale provides normative scores for each specific scale (average T-score = 50, standard deviation SD = 10) and a single composite score representing general intelligence (Early Learning Composite, ELC; average standard score = 100, SD = 15). The T-scores from the five MSEL scales were included in this study.
Background and Significance
Many treatments (Txs) have been proposed for Autism Spectrum Disorders (ASD) with the most effective being combined Tx involving specialized and supportive educational programming, communication training (e.g., speech/language therapy), social skills support, and behavioral intervention [1, 2]. Occupational and physical therapy also may promote progress by addressing comorbid difficulties of motor coordination and sensory deficits [3]. Behavior modification (e.g., applied behavior analysis [ABA]) has the most empirical support for a single Tx, with documented improvements in language, social, play, and academic skills, and reduction in severe behavioral problems [4]. However, behavioral Txs are time and staff intensive, requiring up to 30–40 hours of Tx per week for several years by trained staff working directly with the child and typically focusing on one or a few behaviors at a time.
Risperidone (Risperdal) and aripiprazole (Abilify) are the only FDA-approved medications for ASD, and they are approved only for the Tx of irritability in 5–16 year olds with ASD. No medications are currently established to treat ASD core symptoms. “Off-label” medications are often prescribed for cooccurring behaviors such as inattention, impulsivity/hyperactivity, sleep problems, repetitive/perseverative behaviors, anxiety, mood, agitation, aggression, and disruptive and self-injurious behaviors but may have significant side effects [5]. Survey research has estimated the utilization of psychotropic medication for youth with ASD as high as 47% [6], but there is ongoing debate about the role of such agents [7]. Response rates to medication for comorbid diagnoses in children with ASD may be lower than for children without ASD; for example, the response rate of methylphenidate for typically developing children with Attention-Deficit/Hyperactivity Disorder (ADHD) is 70% [8] but for children with ASD and ADHD symptoms it is only 50% [9]. Complementary and alternative medicines are also commonly reported, but their effectiveness remains unproven [10]. Therefore, given the limitations of available Txs for ASD (expense, effort, risk, less than perfect response) and the severe and chronic nature of ASD, there is a large public health need for additional interventions.
The National Center for Complementary and Alternative Medicine (NCCAM) defines complementary and alternative medicine (CAM) as “a group of diverse medical and health care systems, practices, and products that are not generally considered to be part of conventional medicine” [11]. Because these interventions can include both ingestible (i.e., orally administered) and noningestible (i.e., externally administered) Txs we refer to them collectively as complementary and alternative Txs (CATs). They are complementary when these practices are “used together with conventional medicine,” and alternative when “used in place of conventional medicine.” However, to be a truly designated complimentary Tx, incremental effects when added to conventional Tx should be empirically demonstrated. Likewise, to be truly designated an alternative Tx, similar effects when compared to conventional Tx should be demonstrated. Few CATs for any psychiatric condition (and none for ASD) fulfill these requirements, so the majority are not valid CATs but merely “wanna-be” CATs!
Global studies report rates of CAT use for ASD range from 32 to 87% in the US [12–15], 52% in Canada [16] and 41% in China [17]. Even before receiving a diagnosis of ASD for their children approximately one-third of parents were already using dietary CATs [14].
In the US, most parents report concerns regarding medication safety (84%) and side effects (83%) as the main reasons for choosing CATs [12]. CATs are perceived as a risk-free approach that may improve a child’s outcome [18]. Initial referral sources in the US tend to be a physician or nurse, 44%, with “other parents” next at 16% [13]. In Canada, these include friends/family 35%, occupational therapists 27%, physicians 23%, Internet 23%, or books 15% [16]; in Turkey, other parents 30%, Internet/books 24%, scientific journals 22%, or physicians 20% [19].
Regarding the number of CATs used in 2008, the Interactive Autism Network’s (IAN) ongoing online survey of 1000’s of U.S. parents reported a total of 381 different Txs, most of which are CATs, being used at any one time, with an average of five Txs per child (min. = 0, max. = 56 concurrent Txs!), >50% receiving ≤4 Txs, and 5% receiving no Tx at all [20].
In terms of which specific CATs are used, applying NCCAM’s five categories, Hanson et al. [12] reported the following percentages for a US sample: Biologically-Based Therapies (e.g., herbs, foods, and vitamins) 54%, Mind-Body Interventions (e.g., meditation) 30%, Manipulative or Body-Based Methods (e.g., massage) 25%, Energy Therapies (e.g., Reiki or electromagnetic fields) 8%, and Alternative Medical Systems (e.g., homeopathy) 1%. However, usage in other countries/cultures may be different as shown by Şenel et al. [19] in Turkey (vitamins and minerals 84%, special diet 79%, sensory integration 77%, other dietary supplements 50%, and chelation 50%) and by Wong [17] in China (acupuncture 47.5%, sensory integration 42.5%, and Chinese Medicine 30%).
There is limited scientific evidence of efficacy for some CATs, but research on CATs for ASD is imperative because key safety and efficacy questions remain for the majority [11]. Berman and Straus [21] observed that many CAT studies assume that Txs are well defined, including optimal dose/duration/intensity, that the sample has been correctly diagnosed and selected, and that the Tx is consistent from one practitioner to another. They note that CATs should meet the same fundamental requirements as for conventional Txs, using the same tools and techniques as those for conventional research to isolate the specific effects from the nonspecific effects of Tx as much as possible. Such controls include rigorous protocols, randomized controlled trials (RCTs) with, where possible, placebo/sham control conditions with double-blind designs, and careful diagnosis. Such research is vital because, even though people often assume CATs, particularly natural ones, are safe, their use without supportive evidence is risky because they may have dangerous, sometimes life-threatening and irreversible side-effects; fail to reduce symptoms or improve functioning in patients with severely impairing disorders; delay use of other more established Txs; and/or waste families time, energy, and money.
As of December 2011, there have been 14 comprehensive reviews of ASD CATs in Medline and PsychInfo [3, 18, 22–32], and 5 Cochrane reviews of specific ASD CATs (acupuncture [33]; music therapy [34]; omega-3 [35]; gluten/casein-free diets [36]; and B6-magnesium [37]).
The CATs summarized in this paper (and in Tables 1–3) do not exhaust all those that have been tried or advocated for ASD, but are those for which some positive research evidence exists (Table 4 lists CATs either without positive effects in RCTs or without sufficient evidence to include in this paper). We have not included off-label drugs, which could be technically classified as an alternative Tx, because they are usually considered as “conventional” Txs rather than CATs. The included CATs were identified via Medline and PsychInfo title searches of key terms up to December 2011. For practical purposes we have organized CATs under two main sections: A. Ingestible () and B. Noningestible (). For each CAT we briefly describe its definition; rationale for use; current research support, limitations, and future directions; safety issues; and expected clinical treatment outcomes, with the caveat that such expectations are more likely to occur if the CAT is administered in the same manner as in the research study and if the patient has similar characteristics to the research sample. To help clinicians to decide whether to use a CAT or not, we also apply a clinical guideline: Txs that are Safe, Easy, Cheap, and Sensible (SECS) do not require as much evidence to justify an individual patient trial as do Txs that are Risky, Unrealistic, Difficult, or Expensive (RUDE) [38]. Currently, none of these CATs have enough empirical support to be considered a stand-alone Tx for ASD. See Table 1 for a summary of commonly used ingestible and noningestible CATS, Table 2 for a summary of RCTs on ingestible CATS and Table 3 for a summary of RCTs on noningestible CATS.
2. Ingestible CATs for ASD
2.1. Melatonin
Melatonin is an endogenous neurohormone released by the pineal gland in response to decreasing levels of light, it causes drowsiness, and sets the body’s sleep clock. ASD has a high frequency of sleep problems and melatonin is increasingly used to help children with ASD fall asleep [39, 40]. Rossignol and Frye [41] published a review and meta-analysis of 35 studies and reported that 9 studies of melatonin levels reported at least one sleep abnormality (7 low, 2 high, 4 circadian); 4 studies reported significant correlations between melatonin levels and ASD symptoms; and 5 studies reported gene abnormalities associated with decreased melatonin production. Of 18 Tx studies, 13 were uncontrolled, 5 were randomized, double-blind, placebo-controlled crossover trials, and 6 studies of night-time administration led to improvements in daytime behavior. Within these 5 RCTs (, 2–18 yrs old, 2–10 mg/day), melatonin was associated with increases in sleep duration (44 min, ES = 0.93) and decreases in sleep onset latency (39 min, ES = 1.28), but nighttime awakenings were unchanged. Side effects were minimal to none.
Unfortunately, small sample sizes, variability in sleep assessments, and lack of follow-up limit the conclusiveness of these studies but, overall, melatonin is one of the best studied CATs for ASD. Future research directions include using placebo controlled or comparative effectiveness trials to determine which sleep intervention works best for which child, larger samples identifying inexpensive Tx targets to better match melatonin and other Txs to the individual with ASD, combining melatonin with other Txs for insomnia and ASD, and, based on one of the author’s clinical experiences, identifying those with mid and late insomnia who might respond to higher doses of melatonin. Melatonin is sensible, easy, cheap, and safe; therefore, we recommend a trial of melatonin for sleep delay problems in ASD.
2.2. B6 and Magnesium
One of the oldest and best studied dietary supplementation strategies for ASD is high-dose pyridoxine (vitamin B6) and magnesium (Mg), presumably correcting a metabolic aberration that requires higher than usual intake of those essential nutrients. Improvements maybe noted in social interactions, communication, and stereotyped, repetitive behaviors although the measurements for these symptoms are impressionistic. Pfeiffer et al. [42] identified a dozen studies demonstrating improvements, most controlled in some way, but with many methodological flaws. Reports date back at least to Rimland’s 1973 anecdotal summary [43] suggesting clinically significant benefit. By 1978 a double-blind placebo-controlled withdrawal study of apparent responders [44] reported greater disturbance in autism symptoms upon placebo-masked withdrawal of B6 than upon continuing it, but this could have resulted from an induced B6 dependency [45].
In a prospective open trial [45], 15 of 44 children aged 3–16 with severe ASD (34 on psychotropic medication) responded to B6 30 mg/kg/day (600–1,125 mg/day) +Mg lactate 400–500 mg/day with increased alertness and reduction of outbursts, negativism, self-mutilation, and stereotyped behavior. All but one deteriorated on withdrawal. The prototypical responder was a young small-for-age male. Thirteen responders and 8 nonresponders entered a double-blind crossover with placebo (2 weeks each, random order), and 10 responders versus 2 nonresponders showed more improvement on B6/Mg than on placebo ().
However, a double-blind placebo-controlled study reported no benefit in 10 children with autism treated for 10 weeks [46]. A study of 60-day hospital patients with ASD aged 3–14 involved 4 crossover trials with each trial lasting 8 weeks: 2 wk baseline, 2 wk first Tx, 2 week 2d baseline, 2 wk 2d Tx) [47]. Doses were B6 30 mg/kg/day up to 1 g/day, and Mg 10–15 mg/kg/day. The first crossover () showed improvement for both the combination and Mg alone. In the second (), comparison of the combination versus placebo, they reported significant improvement for the combination, but the placebo comparison was not shown. In the 3rd (B6 versus placebo, ) and 4th (Mg versus placebo, ), there was negligible difference between the active and placebo conditions. In an open study (), significant improvements in ASD symptoms were reported from B6 0.6 mg/kg/day and Mg 6 mg/kg/day for 6 months, with return of symptoms within a few weeks of discontinuation [48]. Improvement was associated with increase towards normal erythrocyte Mg.
In sum, the evidence for B6 + Mg from over 25 studies remains rather equivocal, a bit more positive than negative. Despite encouraging results from open studies, those from RCTs are less promising. Limitations of extant research to be addressed by future research include small samples, inconsistent diagnostic methods and assessments, lack of evidence for mechanism, and lack of blinding. Future studies should involve larger, double-blind placebo-controlled trials using a biomarker of Tx response such as B6 and Mg levels. It is probably safe if the daily doses of B6 are kept well below a gram and daily doses of Mg are not over 200–300 g. Higher doses risk neuropathy from B6 or diarrhea from Mg. It is not expensive or especially difficult. It is credible that the genetic aberration resulting in autistic symptoms might involve a metabolic need for more than usual intake of these two nutrients. Therefore, a carefully monitored trial with moderate doses passes the SECS criterion and is acceptable.
2.3. Methyl B12
Deficiency of methyl B12 (methylcobalamine) may occur in some people with ASD due to poor dietary intake, poor absorption, or metabolic dysregulation. Methyl B12 is a vital cofactor for the regeneration of methionine from homocysteine by providing methyl groups for the transmethylation and transsulfuration metabolic pathways. Reduced synthesis of the products of the transsulfuration pathway, including cysteine and GSH, may consequently lead to decreased antioxidant capacity. Glutathione dysregulation may be of particular significance, as GSH is a key antioxidant responsible for minimizing macromolecular damage produced by oxidative stress. Improvements may be noted in social relatedness, language, and behavior problems. Methyl B12 is often administered at high dose subcutaneous injections every 2 to 3 days. There are no studies of oral or nasal methyl B12, which are thought to be less effective because they do not keep consistently high levels.
James et al. [49] showed that many children with ASD exhibit low levels of GSH and a decreased GSH/GSSG redox ratio. Further, in a small, open-label trial, one-month administration of methyl B12 resulted in a significant increase in plasma GSH concentrations, although behavioral assessments were not done in this study [50]. Thirty subjects completed a 12-week, double-blind study of subcutaneously injected methyl B12 at a dose of 64.5 mcg/kg given every 3 days and 22 subjects completed the 6-month extension study [51]. No statistically significant mean differences in behavior tests or in glutathione status were identified between active and placebo groups. However, nine (30%) subjects demonstrated clinically significant improvement on the Clinical Global Impression-Severity Scale and at least two additional behavioral measures. More notably, these responders exhibited significantly increased concentrations of GSH and GSH/GSSG. The supplement was well tolerated.
The study mentioned above showing the response to methyl B12 of a subgroup of children with autism is the only published RCT but a new RCT from the same group is being presented at national meetings and will be completed in early 2013. Additional research is needed to delineate a subgroup of responders and ascertain a biomarker of response to methyl B12. Subcutaneous injectable methyl B12 does not meet SECS criteria because it is invasive (not easy) and based on only one published, controlled trial. But it does appear safe from this and other reports. While initial studies are promising for a subgroup of children with ASD and supplementation is well tolerated, additional study is needed to determine whether this is a recommended Tx for ASD.
2.4. Multivitamin/Mineral Supplements
Although multivitamin and mineral levels generally are not found to be abnormal in children with autism, biomarkers of nutritional status have been reported and are found to be associated with autism severity [52]. There are only two clinical trials of vitamin/mineral supplements for children with autism, both from the same group. The first randomized 20 children aged 3–8 yr with ASD to a 31-ingredient vitamin/mineral formula () versus placebo () for 3 months [53]. The doses ranged from below the RDI/RDA (Recommended Daily Intake/Recommended Dietary Allowance) to 10 times as much. B6 was 30 mg as pyridoxal-5-phosphate, magnesium was 200 mg, and zinc 15 mg. The micronutrient supplement yielded significantly better sleep and gastrointestinal symptoms than placebo.
A RCT of oral vitamin/mineral supplement for 3 months with 141 children and adults with ASD showed improved nutritional and metabolic status of children with autism, including improvements in methylation, glutathione, oxidative stress, sulfation, ATP, NADH, and NADPH [54]. The supplement group had significantly greater improvements than did the placebo group on the Parental Global Impression-R Average Change (), Hyperactivity (), and Tantruming ().
A clinic study reported on 44 patients with ASD treated with the vitamin-mineral mix at parent preference (6 were actually treated with prenatal vitamins, available on Medicaid prescription, to save the family money) [55]. The author had a large practice with ASD in which he tracked progress with periodic ratings. He treated most patients conventionally, but some parents did not want to use conventional medication. Upon accumulating 44 cases with 3–6 month Tx, he matched them with 44 conventionally treated patients (taking antipsychotics, SSRIs, and stimulants) on sex, age, initial severity, and duration of Tx. The micronutrient mix yielded significantly better results on the Aberrant Behavior Checklist (ABC, including Irritability Subscale), Clinical Global Impression (CGI), and self-injury; but medication was better on no measure. There were significantly less side effects with micronutrients. This study is not conclusive because it was not randomized, and parent preference might be associated with other prognostic factors. However, initial severity was matched.
In summary, there is limited evidence for the efficacy of vitamin and mineral supplements for ASD although there is widespread usage. The promising results from the open label and 2RCT warrant larger, placebo-controlled RCTs with pre- and postmeasures of vitamin, mineral, and metabolic status. Meanwhile, multiple-vitamin and micronutrient supplementation passes the SECS criterion as long as no ingredient is above the upper tolerable limit. It is recommended for those with a restricted or idiosyncratic diet and those with poor appetite, and is acceptable for all others.
2.5. Folic Acid
Folic acid has been considered because a polymorphism in the gene for methylenetetrahydrofolate reductase (MTHFR C677T) doubles the risk of autism [56]. Expected improvements are on core autism symptoms such as communication. An open trial of folinic acid and B12 in children with ASD and antibodies to the cerebral folate receptor showed significant improvement in receptive and expressive language [49]. It is not clear whether folate or folinate would be the preferred supplement or whether adjunctive B12 is needed. Limitations to be addressed by future research include small sample and lack of randomization and blinding. Given the relative safety, this appears to pass the SECS criterion despite the uncertainly and lack of placebo-controlled evidence, but if tried it should be monitored closely for possible unexpected side effects.
2.6. Omega-3 Fatty Acids
Omega-3 long-chain fatty acid supplementation is reasonable to consider because omega-3 fatty acids are essential to brain development [57], being part of optimal neuronal membranes and being substrate for production of eicosanoids (e.g., prostaglandins) necessary for cell communication and immune regulation, and low levels have been reported in children with ASD[58–60]. The two omega-3 acids of interest are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Based on data from other disorders, they would be expected to improve mood, attention, and activity level as well as possibly autism symptoms.
There have been 4 open trials [59, 61, 62] and 2 double-blind, placebo-controlled randomized pilot trials [63, 64]. Meiri et al. [61] openly gave 10 children aged 4–7 years 1 g daily of omega-3 for 12 weeks and reported that 8 of the 10 improved by 1/3 on the Autism Tx Evaluation Checklist, with no side effects. Politi et al. [62] openly gave 19 adults with ASD 0.93 g/day of EPA+DHA and 5 mg/day of vitamin E and observed 6 more weeks. They reported no effect at the end of Tx but a nonsignificant delayed benefit. Meguid et al. [59] openly gave 30 children aged 3–11 Efalex (240 mg DHA, 52 mg EPA, 48 mg gamma-linolenic acid, and 20 mg arachidonic acid daily) for 30 months. The Child Autism Rating Scale (CARS) score was reduced by 17% (, ). In 10 nonresponders, the CARS score correlated with alpha-linolenic acid, negatively with DHA, suggesting a desaturase enzyme deficiency. Johnson et al. [63] randomized 25 children (mean age 3.5 yr) with ASD to open DHA 400 mg/day or healthy low-sugar diet for 3 months. There was little to no effect in either group. Amminger et al. [64] randomized 13 children aged 5–17 yr to 840 mg eicosapentaenoic acid (EPS) and 700 mg DHA per day () or placebo () for 6 weeks. There were no significant differences between groups on the ABC, possibly due to small sample and insufficient power, but omega-3 appeared nominally superior to placebo for stereotypy (), hyperactivity (), and inappropriate speech (). Bent et al. [65] randomized 27 three–eight year-olds with ASD to 700 mg EPA and 460 mg DHA per day () versus placebo () for 12 weeks. There was no significant difference between groups on the ABC, but with the small sample, power may have been insufficient. Hyperactivity decreased by 2.7 points with omega-3 versus 0.3 points with placebo (). There was no difference in side effects.
With only 2 small placebo-controlled RCTs totaling 38 children, all 3 without statistically significant effects (possibly a power issue), the evidence is rather thin for omega-3 supplementation in ASD. Limitations to be addressed by future studies include sample size, necessary duration of Tx, dose, and ratio of EPA to DHA (one of the failed pilot studies used only DHA). Nevertheless, it is safe, easy, cheap, and sensible in light of the known nutritional need for omega-3 fatty acids and their benefit for cardiovascular health, ADHD, and mood disorders. Thus, it passes the SECS criterion and is acceptable for ASD while awaiting definitive research.
2.7. Probiotics and GI Medication
There is increasing evidence for a gut-brain connection associated with at least some cases of ASD [66]. This suggests benefit from a comprehensive digestive enzyme and probiotics with meals to aid digestion of all exorphin peptides and disaccharides, especially for those with gastrointestinal (GI) disturbance. Probiotics are microorganisms thought to improve digestive health. Some would suggest that these agents may also help to remove toxins and help with immune function.
A double-blind placebo-controlled trial using crossover design over 6 months for 43 children with ASD, aged 3–8 years, did not show any clinically significant improvement of ASD symptoms with enzyme use [67]. However, possible effects on improvement in food variety suggest further detailed investigation. Curemark (http://www.curemark.com/) notes that it has reached its targeted enrollment for their CM-AT Phase III of a total 170 children with autism at 18 sites. CM-AT targets enzyme deficiencies that affect the availability of amino acids in children with autism. Curemark’s autism therapy has received Fast Track review status from the FDA. There are no trials of probiotics for ASD reported. Testimonial evidence is that coordinated use of probiotics significantly increases clinical success in normalizing gut flora in people with ASD. Enzyme treatment and probiotics are proposed to improve self-stimulation and stereotypies, aggression, GI symptoms, socialization, and hyperactivity. Research limitations and future directions include the lack of large double-blind placebo-controlled trials with long-term follow-up. The published results from the Curemark study will likely give much more information.
While there is no published evidence that probiotics or digestive enzymes are effective in treating ASD, their use for treating GI symptoms and their safety profile suggest that they might be considered in treating individuals with ASD and GI symptoms.
2.8. Iron Supplementation
Low serum ferritin and low iron intake are reported in some children with ASD [68]. Low levels are associated with psychomotor retardation, poor sleep, and neurological and behavior problems, which might be logical targets of iron supplementation. Recent investigations suggest that antipsychotic Tx, commonly used for irritability of autism (with FDA-approved indication), is associated with reduced body iron stores (Chadi Calarge, personal communication). An 8 week open trial of 6 mg oral iron per day with 43 children with ASD aged 2–10 with 33 completers found that 69% of the preschool and 35% of the school-aged children had low serum ferritin and dietary iron intake and 79% had restless sleep [69]. With supplementation, mean ferritin increased significantly (16 microg/L to 29 microg/L), as did mean corpuscular volume and hemoglobin, suggesting that low ferritin in this patient group resulted from insufficient iron intake. There were significant improvements in Restless Sleep score but not Sleep Delay or CGI scores. With only an open trial with 33 completers, a larger, double-blind, placebo-controlled RCT with follow-up, multiple assessment domains, and multiple measures of iron deficiency is needed to know the full extent of iron deficiency and supplementation effects in children with ASD. Iron supplementation is safe and sensible for those ASD children with low serum ferritin, easy and cheap, and is therefore recommended for this subgroup. It also would be reasonable to screen children with ASD for iron insufficiency. At the current state of knowledge, it should not be used above the RDA amount without evidence of low iron.
2.9. Chelation
Chelation is a process for removing heavy metals from the blood and is used in treating ASD based on the unproven theory that ASD is caused by heavy metal toxicity. The accumulation of heavy metals, particularly mercury, is theoretically due to either the body’s inability to clear the heavy metals or to increased exposure or both. Detoxification involves courses of oral DMSA (2, 3 dimercaptosuccinic acid) with periodic elemental analysis of urine from subjects and controls. To be successful, detoxification Tx requires two prerequisite Txs that must be successful—clearing the gut of harmful dysbiotic flora, and bolstering metabolism with essential nutrients so that the individual can tolerate detoxification.
Two related studies have been published [70, 71] involving 65 children with ASD who received one round of DMSA (3 days) and based on those who had high urinary excretion of toxic metals, 49 were randomly assigned to a double-blind design to receive either 6 additional rounds of DMSA or placebo. DMSA was reportedly well tolerated and resulted in high excretion of heavy metals, normalization of red blood cell glutathione, and possibly improved ASD symptoms. However, excretion of heavy metals and improvement only occurred after one round of DMSA with the additional six rounds being no better than placebo. Subjects demonstrated improvements in language, cognition, and sociability. Clearly, further studies, including randomized, placebo-controlled trials, are indicated to confirm these results.
Regarding anecdotal evidence, of all the drug, diet, and nutritional therapies listed on the ARI Survey, detoxification is reported to help the highest percentage of individuals with ASD (71%) and it “worsened” only 3%, the second lowest percentage. Those who favor chelation are clinicians who are knowledgeable and experienced with it.
However, chelation is controversial and the Institute of Medicine (IOM) recently warned of unspecified “risks.” Renal and hepatic toxicity is possible with oral agents. Most common side effects are diarrhea and fatigue. Less common side effects include abnormal complete blood count (CBC), Liver Function Tests (TFTs), mineral abnormalities, seizures, sulphur smell, regression, GI symptoms and rash. Therefore, we only recommend chelation for ASD if heavy metal toxicity is confirmed.
2.10. L-Carnosine
L-Carnosine has been considered because it can be neuroprotective or improve function of frontal lobes. In an 8-week double-blind RCT with 31 children aged 3–12 with ASD, l-carnosine (800 mg/day) but not placebo showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all ) [72]. Hyperactivity and excitability were the main side effects. This is the only study of l-carnosine for the Tx of autism. Additional studies replicating these findings with large double-blind placebo-controlled studies are necessary to recommend this Tx. Considering the side effects and equivocal evidence of efficacy, l-carnosine is borderline on the SECS criterion. It would be towards the bottom of a preference list and if tried, it should be monitored closely.
2.11. Ascorbic Acid
The rationale for ascorbic acid (vitamin C) supplementation in large doses is that it blocks binding to DA receptors and possibly corrects redox balance, leading to correction of metabolic stress that may contribute to autism symptoms. In a 20 wk double-blind crossover following a 10-week single-blind ascorbate run-in, 18 residential patients aged 6–19 years were randomized to ascorbate-placebo or placebo-ascorbate order [73]. The dose was 90 mg/kg (8 g/day for 70 kg person). Both double-blind placebo conditions were actually ascorbate withdrawal states. There was a significant difference between ascorbic acid and placebo on the Ritvo-Freeman Real-Life Rating Scale, mainly consisting of improvement in stereotypy. The authors distinguished 3 subgroups: strong responders, modest responders, and nonresponders.
Because ascorbic acid doses this large could interfere with B12 absorption, there is some risk, which could be ameliorated by additional B12, but the amount needed is not established. Due to this safety issue (as well as efficacy) ascorbic acid in these megadoses requires further study, does not currently pass the SECS criterion, and is not recommended.
2.12. Cyproheptadine
High levels of 5-HT have been reported in ASD so Tx with cyproheptadine, a 5-HT2 antagonist, has been proposed. A double-blind, placebo-controlled study with 40 children using haloperidol in each Tx arm found that cyproheptadine was well tolerated and showed greater benefit on two scales (ABC and CARS) than did haloperidol plus placebo [74]. However, cyproheptadine has some risk and recommended use awaits replication and a larger number of subjects assessing core symptoms of autism, disruptive behaviors, and physiological symptoms.
2.13. Immune Therapies
Evidence is accumulating that ASD subgroups have immune deficiencies and autoimmunity [75]. Various approaches have been tried to boost immune function or block autoimmunity. One of the most obvious has been immune globulin (IVIG) but the results have been weak. In one open-label study IVIG Tx improved eye contact, speech, behavior, echolalia, and other autistic features [76]. Others have claimed that IVIG Tx led to improvements in GI signs and symptoms, as well as behavior.
Currently there are six published open-label trials of IVIG Tx with ASD. Other than Gupta’s study [76] finding promising results for IVIG Tx, subsequent studies have reported questionable benefits and mixed results for language and behavior. It is unclear if an underlying immunological dysfunction is present in all individuals with ASD or if Tx should target the inflammatory changes and this CAT has some risk. Therefore, IVIG therapy is not recommended for the Tx of ASD. Other immune boosting therapies may be of benefit but have not been adequately studied.
3. Noningestible CATs for ASD
3.1. Massage Therapy
This CAT involves the manipulation of superficial layers of muscle and connective tissue to enhance bodily functioning, relaxation, and well-being. It has been suggested for ASD to increase connectivity to others and reduce overarousal. Five RCTs (all single blind) have examined massage therapy [77–81] and there is one systematic review [82]. Collectively these studies involved 204 one-to-fifteen year olds, receiving massage therapy 10–60 minutes, 1-7X/week over 3–32 weeks. Reported results include significantly improved total ASD symptoms, social relatedness, sleep, language, social communication, and receptive language and significantly reduced ADHD symptoms, repetitive behaviors, sensory issues, disruptive behavior, and anxiety. Therefore, based on this research, similar clinical outcomes are predicted for massage therapy for youth with ASD. Research limitations and future directions include the lack of large double-blind, sham RCTs with long-term follow-up. As massage therapy appears safe, easy, cheap and sensible, if parents are trained to administer it is likely to improve the parent-child relationship, and is therefore recommended.
3.2. Acupuncture
Based in Traditional Chinese Medicine, acupuncture involves the systematic insertion and manipulation of thin needles into the body, via 400 acupoints, to improve health of body/mind by unblocking the flow of qi (“energy”). For ASD, there are three RCTs (1 DB sham controlled) published in English using scalp [83], tongue [84], and electro acupuncture [85]. These RCTs examined 125 three-to-thirteen year olds, via evidence-based assessment of ASD, using acupuncture for 15 seconds–30 minutes, 2–5X/week, over 4–36 weeks, while monitoring possible adverse effects. All these types of acupuncture were reported to be tolerated by >80%, with few or mild adverse-effects. Reported significant results and, therefore, expected clinical outcomes for this Tx include improvement in attention, receptive language, self-care, language, overall functioning, and communication. Although published after completion of our literature search, it is important to note a recent review of acupuncture for ASD because it includes a further 9 RCTs (mean [range 30–70], 1 single blind) published in Chinese only [86]. Although we could not probably examine this review as it was in Chinese, its English abstract review reported significant “behavioral and/or developmental improvements” (p.1). Therefore, based on all 12 RCTs, acupuncture has overall tolerability but highly variable Tx presentations.
Research limitations and future directions include the lack of double-blind, sham-controlled RCTs, long-term follow-up, standard Tx protocols, use of standard Tx outcome measures, and monitoring of possibly confounding concomitant Txs. As acupuncture appears safe and seems sensible (from a Traditional Chinese Medicine perspective) and easy, it is acceptable for ASD if not too expensive.
3.3. Exercise
Exercise programs have been found to be beneficial for a variety of psychiatric and developmental disorders [87]. In children with ASD, exercise may reduce hyperactive and repetitive behavior through the release of certain neurotransmitters, such acetylcholine, or beta-endorphins [88]. Antecedent aerobic exercise (the individual participates in a short period of vigorous aerobic exercise prior to a learning task or observational period) has been the most widely studied exercise intervention for children and adults with ASD. Eight within-subject studies () compared the benefit of antecedent aerobic exercise (e.g., jogging, ranging from 6 to 20 minutes) to nonaerobic exercises antecedents (e.g., academic tasks, walking) [89–96]. and one review has been published [97]. Seven out of eight studies found that antecedent aerobic exercise decreased self-stimulatory behavior, and two out of three studies found increased academic performance following aerobic exercise. Research limitations and future directions include the lack of double-blind, sham-controlled RCTs, long-term follow-up, standard Tx protocols, use of standard Tx outcome measures, and monitoring of adverse and concomitant Txs. Antecedent exercise seems sensible, cheap, safe, and easy and is therefore acceptable, before academics or play, if feasible for the child and setting, particularly those with significant repetitive behavior. Several other studies have investigated exercise programs for children with ASD (e.g., swimming lessons, treadmill walking); while many reported increases in sports skills and/or physical fitness, the impact of these types of programs on ASD symptoms is not well evaluated.
3.4. Music Therapy
Music therapy involves structured and unstructured individual and group sessions with and without a leader involving playing and/or listening to music. It has been used to Tx ASD because of its potential for assisting communication, joint attention, expression, engagement, and relationships with the environment [98]. Most research on music therapy involves case studies with only two randomized single-blind, repeated measures, within-subject comparison designs [99–101]. These studies had a total of 20, 3-to-9 year-olds with ASD, with varied Tx presentations, given 1–20X/week for 1–12 weeks for 30 minutes. Significant results and potential clinical outcomes include improvement in imitating signs and words, longer and more eye contact and turn-taking, joint attention, nonverbal communication, longer and more “joy,” emotional synchronicity, initiating engagement and compliant behavior. Research on music therapy for ASD lacks evidence-based assessment of ASD, large samples, RCTs, standardized protocols, double-blind, sham, use of standard Tx outcome measures, follow-up, monitoring of adverse-effects, or concomitant Txs. However, it appears safe, seems sensible, easy and cheap and is therefore acceptable.
3.5. Animal-Assisted Therapy (AAT)
AAT involves structured and supervised therapeutic interaction with animals, which are seen as transitional objects for initial bonding for individuals with ASD before generalizing this attachment to people. Although there are many case studies of AAT, only four studies have recruited multiple subjects, with the most recent being the only RCT [102–105]. Collectively, these studies included 69, four to thirteen year olds, given AAT 15–60 minutes, 1-3X/week over 12–16 weeks. Reported results included significant improvement in playful mood, focus, awareness of social environment, use of language, social interaction, and motivation to interact with the environment, all of which are hoped to occur with clinical application of AAT for youth with ASD. AAT research lacks large RCT, double-blind, evidenced-based assessments of ASD standard Tx outcomes, follow-up, and monitoring of adverse effects and concomitant Txs. AAT appears safe (if done under trained supervision) sensible and possibly easy but it may be expensive, so it is therefore potentially acceptable as a CAT for ASD.
3.6. Neurofeedback (NF)
NF “trains” the brain to improve self-regulation of itself by providing it with real-time video/audio information about its EEG activity. It has been suggested for the Tx of ASD because QEEG studies indicate over- and underconnectivity [106] and a wide variety of significant EEG differences associated with ASD have been reported [107]. One review [108] and three RCTs have been published on NF for ASD. These RCTs involved 47 seven to seventeen year-olds with ASD ([109, 110]), all used Evidence-Based Assessments and provided NF for 21–30 minutes session, 2-3/week for 10–20 weeks. Both Pineda studies [109] used a sham-NF control, with the first study () a single blind and the second study a double-blind design. NF was focused on increasing mu suppression, an EEG correlate of mirror-neuron activity associated with imitation abilities, thought to be limited in ASD. In the first study, compared to controls, mu suppression (EEG correlate of self-imitation) was significantly increased, and Tx increased sustained attention and improved scores on the sensory/cognitive awareness subscale of the parent-rated Autism Treatment Evaluation Checklist (ATEC). Similarly, the second larger study also reported significant improvements in sustained attention and parent-rated ATEC speech/language communication, sociability, health/physical behavior subscales and overall score (but not, curiously enough, for sensory-cognitive subscale), and increased mu suppression. Neither study showed the expected significant behavioral improvements in imitation by the Tx group.
Kouijer et al. [110] used a waitlist control ( in each condition) and reported significant (compared to control) reductions in excessive theta power (reflecting change of activity in the anterior cingulate cortex that thought to be involved in ASD social and executive problems); significant improvements in parent-rated reciprocal social interaction and communication skills, and significant improvement in neuropsychological set shifting skills. Six-month maintenance of Tx gains and some improvements was demonstrated for the Tx but not control group.
Based on these 3 studies, the following clinical improvements are expected with sustained attention and set-shifting skills; parent-rated speech/language communication, sociability, health/physical behavior, reciprocal social interaction, communication skills, and, possibly, sensory/cognitive awareness. Research limitations and future directions include the lack of a large double-blind RCT sham study with follow-up, use of standard Tx outcome measures, monitoring of adverse effects, and concomitant Txs. Even though NF appears safe (although not empirically examined) and seems sensible, it is not easy or cheap and is therefore not recommended at this time.
Finally, the following CATs (with cited reviews) are not recommended because they failed to show positive effects across several RCTs: Auditory Integration Therapy [111], Facilitated Communication [112], Gluten/Casein-Free Diet [36], Hyperbaric Oxygen Therapy [113, 114], and Secretin [115]. Furthermore, we do not recommend packing therapy or faradic skin shock due to ethical/safety issues.
