Pervasive developmental disorders (PDD), which include autism, Rett syndrome, childhood disintegrative disorder and Asperger’s syndrome, are chronic life-long conditions with no known cure. Autism has been estimated to affect approximately 1 in 1,000 children in the United States, and other pervasive developmental disorders have been estimated to affect approximately 2 in 1,000 children in the United States. Based on recent prevalence estimates of 10 to 20 cases per 10,000 individuals, between 60,000 and 115,000 children under the age of 15 years meet diagnostic criteria for autism.
According to the American Academy of Neurology (AAN)'s practice parameter, Screening and Diagnosis of Autism (Filipek et al, 2000), autism is characterized by severe deficiencies in reciprocal social interaction, verbal and non-verbal communication, and restricted interests. It usually commences before the age of 3 years and lasts over the whole lifetime. Early signs that distinguish autism from other atypical patterns of development include poor use of eye gaze, lack of gestures to direct other people's attention (especially to show things of interest), decreased social responsiveness, and lack of age-appropriate play with toys (especially imaginative use of toys). A typical symptom of autism is absence of speech development, observed from infancy, taking the form of complete mutism at later stages. It has been emphasized that most pathological symptoms of autism result from altered perception of external stimuli, which arouse fear and anxiety. Currently, there are no biological markers for autism and there is no proven cure for this disorder.
Because there are no biological markers for autism, screening must focus on behavior. Studies comparing autistic and typically developing children demonstrated that problems with eye contact, orienting to one’s name, joint attention, pretend play, imitation, non-verbal communication, and language development are measurable by 18 months of age. These symptoms are stable in children from toddler age through preschool age. Retrospective analysis of home videotapes also has identified behaviors that distinguish infants with autism from other developmental disabilities as early as 8 months of age.
Current screening methods may not identify children with milder variants of autism, those without mental retardation or language delay, such as verbal individuals with high-functioning autism and Asperger’s disorder, or older children, adolescents, and young adults.
There are relatively few appropriately sensitive and specific autism screening tools for infants and toddlers, and this continues to be the current focus of many research centers. The Checklist for Autism in Toddlers (CHAT) for 18-month-old infants, and the Autism Screening Questionnaire for children 4 years of age and older, have been validated on large populations of children. However, it should be noted that the CHAT is less sensitive to milder symptoms of autism, as children later diagnosed with PDD-NOS, Asperger’s, or atypical autism did not yield positive results on the CHAT at 18 months.
The AAN’s practice parameter noted that specific neuropsychological impairments can be identified, even in young children with autism, that correlate with the severity of autistic symptoms. Performance on tasks that rely on rote, mechanical, or perceptual processes are typically spared; deficient performance exists on tasks requiring higher-order conceptual processes, reasoning, interpretation, integration, or abstraction. Dissociations between simple and complex processing are reported in the areas of language, memory, executive function, motor function, reading, mathematics, and perspective-taking. However, there is no reported evidence that confirms or excludes a diagnosis of autism based on these cognitive patterns alone.
The AAN’s practice parameter recommended that diagnosis of autism should include the use of standardized parent interviews regarding current concerns and behavioral history related to autism, and direct, structured observation of social and communicative behavior and play. Recommended instruments for parental interviews include the Gilliam Autism Rating Scale, Parent Interview for Autism, Pervasive Developmental Disorders Screening Test–Stage 3, and Autism Diagnostic Interview–Revised. Recommended instruments for observation include the Childhood Autism Rating Scale, Screening Tool for Autism in Two-Year-Olds, and Autism Diagnostic Observation Schedule-Generic. The AAN practice parameter did not recommend that neuropsychological testing be used for the diagnosis of autism, but insteadshould be performed as needed, in addition to a cognitive assessment, to assess social skills and relationships, educational functioning, problematic behaviors, learning style, motivation and reinforcement, sensory functioning, and self-regulation.
Similarly, the American Academy of Child And Adolescent Psychiatry (AACAP)’s practice parameter for the assessment and treatment of autism recommended neuropsychological testing only when the clinical context indicates that it may be helpful. Psychological testing is recommended in the AACAP practice parameter to assess for cognitive and intellectual functioning, in order to determine eligibility and plan for educational and other services.
Mental retardation (IQ less than 70) is associated with 70 % of cases of autism and seizures with 33 % of cases. Furthermore, the recurrence risk for siblings is about 3 to 5 %, corresponding to an incidence 75 times greater than that in the general population. These features, in conjunction with the increased number of male patients (3:1 male:female ratio), suggest a genetic predisposition. On the other hand, parallel evidence of immune abnormalities in autistic patients argues for an implication of the immune system in pathogenesis. Additionally, some neurological disorders such as tuberous sclerosis, neurofibromatosis, fragile X syndrome, Rett syndrome and phenylketonuria may also be associated with autistic features. In these cases, autism is defined as "secondary".
The AAN's practice parameter Screening and Diagnosis of Autism (Filipek et al, 2000) recommended genetic testing in children with autism, specifically high resolution chromosome analysis (karyotype) and DNA analysis for fragile X syndrome in the presence of mental retardation (or if mental retardation can not be excluded), if there is a family history of fragile X or undiagnosed mental retardation, or if dysmorphic features are present. However, there is little likelihood of positive karyotype or fragile X testing in high-functioning autism.
The AAN (Filipek et al, 2000) recommended selective metabolic testing if the child exhibits clinical and physical findings suggestive of a metabolic disorder such as (i) lethargy, cyclic vomiting, or early seizure, or (ii) dysmorphic or coarse features, or (iii) evidence of mental retardation, or (iv) mental retardation can not be ruled out, or (v) occurrence or adequacy of newborn screening for a birth defect is questionable. The AAN also recommended lead screening if the child exhibits developmental delay and pica.
Epileptiform abnormalities on electroencephalography (EEG) are common in children with autism spectrum disorders (ASDs), with reported frequencies ranging from 10 % to 72 % (AAP, 2007). Some studies have suggested that epileptiform abnormalities on EEG and/or epilepsy are more common in the subgroup of children with ASDs who have a history of regression, whereas other studies have not demonstrated this association. Autistic regression with epileptiform abnormalities on EEG has been compared by analogy with Landau-Kleffner syndrome and electrical status epilepticus in sleep, but there are important differences between these conditions, and the treatment implications are unclear (AAP, 2007). Whether subclinical seizures have adverse effects on language, cognition, and behavior is debated, and there is no evidence-based recommendation for the treatment of children with ASDs and epileptiform abnormalities on EEG, with or without regression. A report from the American Academy of Pediatrics (AAP, 2007) states that universal screening of patients with ASDs by EEG in the absence of a clinical indication is not currently supported. The report states, however, that because of the increased prevalence of seizures in this population, a high index of clinical suspicion should be maintained, and EEG should be considered when there are clinical spells that might represent seizures.
Localized structural and functional brain correlates of PDD have yet to be established. Structural neuroimaging studies performed in autistic patients have reported abnormalities such as increased total brain volume and cerebellar abnormalities. However, none of these abnormalities fully account for the full range of autistic symptoms. Functional neuroimaging has demonstrated temporal lobe abnormalities and abnormal interaction between frontal and parietal brain areas. However, the value of functional neuroimaging such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional MRI (fMRI) in diagnosing autism has not been established. Functional neuroimaging techniques are at the early stage of identifying abnormalities at the neurotransmitter and systems levels. Further studies with well-defined patient populations and appropriate activation paradigms will better elucidate the pathophysiology of this disorder.
The AAN (Filipek et al, 2000) stated that there is no clinical evidence to support the role of routine clinical neuroimaging (CT, MRI, PET SPECT, and fMRI) in the diagnostic evaluation of autism, even in the presence of megalocephaly. Additionally, the AAN stated that there is insufficient evidence to recommend EEG studies in all individuals with autism. Sleep-deprived EEG study may be performed if (i) the patient has clinical seizures or suspicion of subclinical seizures; or (ii) a history of regression (clinically significant loss of social and communicative function) at any age, but especially in toddlers and pre-schoolers. Moreover, the AAN considered event-related potentials and magnetoencephalography to be research tools, which have no evidence of routine clinical utility (Filipek et al, 2000).
Philip and colleagues (2012) stated that recent years have seen a rapid increase in the investigation of ASD through the use of fMRI. These investigators performed a systematic review and ALE meta-analysis of fMRI studies of ASD. A disturbance to the function of social brain regions is among the most well replicated finding. Differences in social brain activation may relate to a lack of preference for social stimuli as opposed to a primary dysfunction of these regions. Increasing evidence points towards a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to changing task demands in ASD. The authors stated that limitations of the literature to date include the use of small sample sizes and the restriction of investigation to primarily high-functioning males with autism.
The AAN (Filipek et al, 2000) also found inadequate supporting evidence of the following procedures in the management of autism: (i) allergy testing (especially food allergy for gluten, casein, candida, and other molds), (ii) erythrocyte glutathione peroxidase studies, (iii) hair analysis, (iv) intestinal permeability studies, (v) stool analysis, and (vi) tests for celiac antibodies, immunologic or neurochemical abnormalities, micronutrients such as vitamin levels, mitochondrial disorders including lactate and pyruvate, thyroid function, and urinary peptides.
Autistic patients may suffer from gastrointestinal disturbances such as abdominal pains, diarrhea, and the so-called leaky-gut syndrome. Secretin, a hormone produced by the pancreas to stimulate the production of gastric juices, has been used to aid digestion before intestinal biopsy or endoscopy. Early case studies suggested that secretin improved gastrointestinal symptoms as well as behavior, eye contact, alertness, and expressive language in autistic children. However, such claims are not borne out by recent well-designed studies.
A randomized, double blind, placebo-controlled, cross-over study (Corbett et al, 2001) investigated the effect of a single intravenous dose of porcine secretin on autistic children. The authors found that significant differences were not observed on the majority of the dependent variables. Statistically significant differences were observed on measures of positive affect and activity level following secretin infusion. In general, autistic children did not demonstrate the improvements described in the initial retrospective report. This is in agreement with the findings of Owley and colleagues (2001) who reported that there was no evidence for efficacy of secretin in a multi-center, randomized, placebo-controlled, double-blind trial. In a single-blinded, prospective, open-label study, Lightdale and associates (2001) reported that intravenous secretin had no effects in a 5-week period on the language and behavior of 20 children with autism and gastrointestinal symptoms.
The National Academy of Sciences (NAS) (2001) has stated that there is no known cure for autism, and that “[e]ducation, both directly of children, and of parents and teachers, is currently the primary form of treatment for autistic spectrum disorders.” The National Academy of Sciences recommends that educational services begin as soon as a child is suspected of having autistic spectrum disorder, and that those services should include a minimum of 25 hours a week, 12 months a year, in which the child is engaged in systematically planned and developmentally appropriate educational activity toward identified objectives. Brasic (2003) has stated that, while parents may choose to utilize a variety of experimental treatments including medication, they should concurrently utilize intensive individual special education by an educator familiar with instructing children with autistic disorder and related conditions.
The NAS report concluded that “there is little evidence concerning the effectiveness of discipline-specific therapies, and there are no adequate comparisons of different comprehensive treatments. However, there is substantial research supporting the effectiveness of many specific therapeutic techniques and of comprehensive programs in contrast to less intense, nonspecific interventions.” “The consensus across programs is generally strong concerning the need for: early entry into an intervention program; active engagement in intensive instructional programming for the equivalent of a full school day, including services that may be offered in different sites, for a minimum of 5 days a week with full-year programming; use of planned teaching opportunities, organized around relatively brief periods of time for the youngest children (e.g., 15- to 20-minute intervals); and sufficient amounts of adult attention in one-to-one or very small group instruction to meet individualized goals.”
The NAS report concluded that functional communication training has been shown to be effective in treatment of autism: “There is strong empirical support for the efficacy of functional communication training to replace challenging behaviors. This approach includes a functional assessment of the particular behavior to determine its function for a child (e.g., desire for tangible or sensory item, attention, or to escape a situation or demand) and teaching communication skills that serve efficiently and effectively as functional equivalents to challenging behaviors, a method that has been documented to be the most effective for reductions in challenging behavior (Horner et al, 1990; see Horner et al, 2000).”
The NAS report also concluded that there is evidence to support the use of augmentative and alternative communication strategies (AAC) in children with autism. “For children with autism who do not acquire functional speech or have difficulty processing and comprehending spoken language, augmentative and alternative communication (AAC) and assistive technology (AT) can be useful components of an educational program.” “AAC is defined as ’an area of clinical practice that attempts to compensate (either temporarily or permanently) for the impairment and disability patterns of individuals with severe expressive communication disorders’ (American Speech-Language-Hearing Association, 1989). AAC may involve supporting existing speech or developing independent use of a non-speech symbol system, such as sign language, visual symbols (pictures and words) displayed on communication boards, and voice output devices with synthesized and digitized speech. AT is any commercial, hand-made, or customized device or service used to support or enhance the functional capabilities of individuals with disabilities. AT includes computer-assisted instruction, mobility devices, high and low technology adaptations and AAC.”
A structured evidence assessment of interventions in alternative and augmentive communication (ACC) (training to compensate for the impairment and disability patterns) in persons with severe expressive communication disorders (including autism, mental retardation, and other disabilities) concluded that ACC interventions are effective in terms of behavior change, generalization, and, to a lesser degree, maintenance (Schlosser and Lee, 2000).
A number of discipline-specific intensive intervention programs have been advocated for the treatment of autism, including Lovaas therapy, the Rutgers Program, the LEAP Program, the Denver Program, the Autism Pre-school Program, and TEACCH Program. The objectives of treatment are to improve the child's early social communication and social interaction skills, leading to the potential development of play and flexibility of behavior. The NAS (2001) concluded that, although there is substantial research supporting the effectiveness of comprehensive programs in contrast to less intense, non-specific interventions, “there is little evidence concerning the effectiveness of discipline-specific therapies, and there are no adequate comparisons of different comprehensive treatments.”
Lovaas therapy is a method of early behavioral intervention for the treatment of PDD. It entails the employment of intensive teaching techniques designed to reinforce appropriate social behaviors in children with autism and related disorders. Every task (trial) consists of a directive to the patient, a response from the patient, and a reaction from the therapist. The patient learns to respond in a manner that generates reinforcement reaction from the therapist. Lovaas therapy is usually practiced 30 to 40 hours a week.
Lovaas therapy was based on a study by Lovaas published in 1987; however, the study had several problems which include (i) choice of outcome measure, (ii) criteria for subject selection and the intellectual level of the subjects, and (iii) method for assigning subjects to control groups. These methodological problems made it difficult to ascertain the effects of early behavioral intervention on autistic children. Recent reviews suggested that there is no available treatment that meets criteria for well-established or probably efficacious treatment; and that more research is needed to refine current behavioral treatment approaches.
Delprato (2001) compared discrete trial training (Lovaas Therapy) and normalized behavioral language intervention for young children with autism. The author reported that in studies with language criterion responses, normalized language training was more effective than discrete trial training. Furthermore, in studies that assessed parental affect, normalized treatment yielded more positive affect than discrete trial training.
Boyd and Corley (2001) reported the outcome survey of early intensive behavioral intervention (EIBI) programs for young children with autism in a community setting. Based on both individual case reviews and parent questionnaires, they found that these programs failed to support any instances of "recovery", but yielded a high degree of parental satisfaction. Moreover, a follow-up inquiry into the type of services each child was receiving in his or her post-EIBI setting documented continued dependence on extensive educational and related developmental services, suggesting that the promise of future treatment sparing did not materialize. The authors concluded that there is a need for further research designed to document the effectiveness of services provided to young children with autism.
The Alberta Heritage Foundation for Medical Research (AHFMR) evaluated the effectiveness of intensive intervention programs for children with autism (Ludwig and Harstall, 2001). These programs range from strict operant discrimination learning such as Lovaas therapy to broader applied behavior analysis such as the Rutgers Program to more developmentally oriented programs such as the Denver Program and the Treatment and Education of Autistic and Communication Handicapped Children (TEACCH) Program. Furthermore, these treatment programs vary in their intensity from 40 hours per week for Lovaas Therapy and the Rutgers Program to a range of 15 hours per week for the LEAP Program.
The evaluation by AHFMR was primarily based on the results of 3 systematic evidence reviews, including those by ECRI (2000) and the British Columbia Office of Health Technology Assessment (BCOHTA) (Bassett, 2000). Two of the critical findings of this assessment are as follows: (i) studies on Lovaas therapy were methodologically flawed. ECRI concluded that Lovaas Therapy appears to increase scores on IQ tests and behavioral adaptation, at least in some children with autism. However, given the designs and methodological flaws of the studies, it could not be determined if the changes in IQ and functional parameters could be attributed to the Lovaas therapy. BCOHTA concluded that the original Lovaas study as well as other follow-up studies were still inadequate to establish the degree to which this form of therapy resulted in "normal" children, and (ii) there is insufficient evidence to establish a relationship between amount (intensity and duration) of any intensive intervention treatment program and outcomes measures (intelligence tests, language development, adaptive behavior tests).
Smith (1999) evaluated the evidence supporting intensive intervention programs for autism. Smith noted that most reports of major gains made by children with autism have “withered under scrutiny”. Smith emphasized the need to validate the long-term benefits of these intervention programs. Smith noted that most studies of specific intensive intervention programs do not provide data on the children’s progress following termination of treatment. Smith noted that this is a critical omission because even if treatment is successful while ongoing, the benefits may not be durable. Smith concluded that methodological weaknesses in the research hinder us from drawing conclusions from existing early intervention studies.
An assessment of intensive intervention programs for autism by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) (McGahan, 2001) concluded that “there are few published controlled primary studies regarding the efficacy of behavioral interventions; most have methodological flaws that make interpretation of results difficult. Study design in this area could benefit from the inclusion of an adequate control group and the application of consistent outcome measures used for all children enrolled in a study, administered by the same, blinded assessor at the beginning and end of the study.”
In assessing the evidence supporting specific intensive intervention programs for children with autism, the NAS (2001) concluded that “[a]s a group, these studies show that intensive early interventions with children with autistic spectrum disorders makes a clinically significant difference for many children …. However, each of the studies has methodological weaknesses, and most of the reports were descriptive rather than evaluations with controlled experimental research designs. There are virtually no data on the relative merit of one model over another, either overall or as related to individual differences in children …. In sum, it appears that a majority of children participating in comprehensive behavioral interventions made significant progress in at least some developmental domains, although methodological limitations preclude definitive attributions of that progress to specific intervention procedures”.
A New Zealand Health Technology Assessment (Doughty, 2004) reviewed the conclusions of 5 recently published systematic evidence reviews of intensive behavioral interventions for autism-spectrum disorders. The assessment found that all of these systematic evidence reviews draw attention to the lack of well-conducted research on early intervention for autism in young children. The assessment found that all of the systematic evidence reviews reached the same conclusion, that “to date there is insufficient evidence to allow conclusions to be drawn about best practice. Furthermore, researchers have yet to establish a relationship between the amount (per day and total duration) of any form of early comprehensive treatment programme and overall outcome.” The New Zealand Health Technology Assessment also reviewed recently published primary research on intensive behavioral interventions for autism. The assessment found that, despite the relatively large volume of studies published and extent of interest of a variety of stakeholders in the effectiveness of interventions for young children with autism, only 5 primary studies published since 2000 met selection criteria for relevance and methodological quality. The assessment concluded that these studies provide preliminary evidence suggesting that early intervention (note this includes different types of behavioral intervention, across different settings) may lead to selected gains in a number of specific domains. The report concluded, however, that “further research is required to address the methodological limitations of existing studies and replicate their findings. In particular studies with larger sample sizes (from multisite collaborations using identical methods and outcome measures) are required to provide greater statistical power and more precise estimates of effectiveness.”
A position statement on early intervention for autism from the Canadian Paediatric Society (2004) reviewed the published literature on intervention programs, and concluded that the evidence for these programs is "weak" and "suboptimal".
More recently, an assessment by the Scottish Intercollegiate Guidelines Network (SIGN, 2007) stated that "[a]ll studies included in this review [of applied behavioral analysis] were marked by considerable methodological flaws and there was also a concern that many had enrolled high functioning children with autism, making it difficult to generalise from the conclusions". The review concluded that a causal relationship can not be established between a particular program of intensive behavioral intervention and the achievement of "normal functioning". SIGN concluded that "[t]he Lovaas programme should not be presented as an intervention that will lead to normal functioning". SIGN also noted that a comprehensive literature search did not find any good quality evidence for other intensive behavioral interventions.
A systematic evidence review and metanalysis found inadequate evidence that applied behavior intervention programs have better outcomes than standard care for children with autism (Spreckley and Boyd, 2008). The authors reviewed systematic reviews and randomized or quasirandomized controlled trials of applied behavioral interventions delivered to preschool children with autism spectrum disorder. Quantitative data on cognitive, language, and behavior outcomes were extracted and pooled for meta-analysis. The authors reported that thirteen studies met the inclusion criteria. Six of these were randomized comparison trials with adequate methodologic quality. Meta-analysis of 4 studies concluded that, compared with standard care, applied behavioral intervention programs did not significantly improve the cognitive outcomes of children in the experimental group. There was no additional benefit over standard care for expressive language, for receptive language, or adaptive behavior. The authors concluded that there is inadequate evidence that applied behavioral interventions have better outcomes than standard care for children with autism. The authors stated that appropriately powered clinical trials with broader outcomes are required.
An special report on applied behavioral analysis for autism spectrum disorders by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2009) found that the strongest evidence of effectiveness came from 2 randomized controlled clinical trials (Smith et al, 2000; Sallows and Graupner, 2005); however, weaknesses in research design, differences in the treatments and outcomes compared, and inconsistent results mean that the impact of applied behavioral analysis versus other treatments on outcomes for children with autism can not be determined. The report stated that, given the lack of a definitive evidence on the relative effectiveness of applied behavioral analysis, one can not answer the question of whether there are characteristics of children that predict a greater likelihood of success. The assessment also stated that the findings on whether more intense treatment leads to better outcomes were inconsistent, and no conclusions can be drawn.
The BlueCross BlueShield Association's special report on "Early Intensive Behavioral Intervention Based on Applied Behavior Analysis among Children with Autism Spectrum Disorders" (2010) stated that overall, the quality and consistency of results of this body of evidence are weak. Consequently, no conclusions can be drawn from this literature on how well early intensive behavioral intervention (based on applied behavior analysis or ABA; hereafter referred to as “EIBI”) works. Weaknesses in research design and analysis, as well as inconsistent results across studies, undermine confidence in the reported results. It is important to distinguish between certainty about ineffectiveness and uncertainty about effectiveness. Based on the weakness of the available evidence, we are uncertain about the effectiveness of EIBI for autism spectrum disorders (ASDs). Furthermore, the authors stated that the variability of presentation and progression among children with ASDs, as well as potential differences in delivery of behavioral interventions, make this topic challenging to study. Nevertheless, given the importance of caring for children with ASDs, additional research is needed to identify those characteristics of treatment -- content, technique, intensity, starting and ending age, etc. -- that maximize its effectiveness. Because of the challenges in launching a very large randomized controlled trial (RCT) and the ethical necessity to provide some treatment to the control group, this body of research needs to be built piece by piece, with a series of studies that investigate different components of the larger research question. For this to be effective, however, the overall quality of studies needs to be improved, including a greater emphasis on RCTs, where at all possible; substantially larger sample sizes; uniformity of outcomes evaluated and instruments used to measure them; and consistent treatments that do not vary widely within treatment groups (i.e., experimental or control group).
The cost of continuing the current course of assuming that EIBI works may not be obvious. EIBI is costly financially for society and requires a large time commitment from children, their families, and their teachers or therapists. However, these programs may not appear to pose any harm for the children themselves. Nevertheless, the opportunity costs could be high, indeed, of providing sub-optimal care to these children, simply because we as a society do not know what works best. The children may be treated with an intervention that is not as effective as the alternatives. And if we accept an intervention because it seems to work, without solid evidence, research on the alternatives or on how it can be improved is likely to be stifled.
Other interventions that have little or insufficient evidence of effectiveness in the treatment of children with autism are auditory integration training (also referred to auditory integration therapy, [AIT]), cognitive rehabilitation, facilitated communication, gluten and milk elimination diets, holding therapy, immune globulin therapy, music therapy, nutritional supplements (e.g., megavitamins, high-dose pyridoxine and magnesium, dimethylglycine), sensory integration therapy, and vision therapy.
An assessment of interventions for autism conducted by the NAS (2001) concluded that there is insufficient evidence of the effectiveness of facilitated communication (FC) for autism. The NAS report stated: “There are over 50 research studies of FC with 143 communicators. Based on these research studies, the American Speech-Language-Hearing Association (1994) has stated that there is a lack of scientific evidence validating FC skills and a preponderance of evidence of facilitator influence on messages attributed to communicators (ASHA Technical Report, 1994). Thus, there is now a large body of research indicating that FC does not have scientific validity.”
The AAP (2001) stated that available information does not support the claims of proponents that FC is effective in the treatment of autism, and considered it experimental. In a review on autism, Levy and colleagues (2009) stated that popular biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, hyperbaric oxygen therapy, off-label drugs (e.g., secretin), and intravenous immunoglobulins. Non-biologically based treatments include AIT, chiropractic therapy, cranio-sacral manipulation, FC, interactive metronome, and transcranial stimulation. However, few studies have addressed the safety and effectiveness of most of these treatments.
The NAS report (2001) concluded that there is insufficient evidence of the effectiveness of sensory integration therapy for autism. By focusing a child on play, sensory integration therapy emphasizes the neurological processing of sensory information as a foundation for learning of higher-level skills. The goal is to improve subcortical (sensory integrative) somatosensory and vestibular functions by providing controlled sensory experiences to produce adaptive motor responses. The hypothesis is that, with these experiences, the nervous system better modulates, organizes, and integrates information from the environment, which in turn provides a foundation for further adaptive responses and higher-order learning. The NAS report states, however, that “[t]here is a paucity of research concerning sensory integration treatments in autism …. These interventions have also not yet been supported by empirical studies.” In addition, the AAP (2001) stated that research data supporting the effectiveness of sensory integration therapy in managing autistic children is scant.
The NAS report (2001) concluded that there is insufficient evidence of the effectiveness of AIT in autism. Proponents of auditory integration therapy suggest that music can “massage” the middle ear (hair cells in the cochlea), reduce hyper-sensitivities and improve overall auditory processing ability. The NAS concluded that “auditory integration therapy has received more balanced investigation than has any other sensory approach to intervention, but in general studies have not supported either its theoretical basis or the specificity of its effectiveness.” Based on a lack of clearly demonstrated effectiveness, the AAP (2001) also recommended against the use of AIT for autism.
A Cochrane review (Sinha et al, 2011) reviewed the evidence for AIT and other sound therapies for autism, and concluded that there is “no evidence that auditory integration therapy or other sound therapies are effective as treatments for autism spectrum disorders.” The evidence review identified 6 relatively small studies of AIT and one of Tomatis therapy met the inclusion criteria for AIT. These largely measured different outcomes and reported mixed results. The report found that, of the seven studies including 182 participants that have been reported to date, only two (with an author in common), involving a total of 35 participants, report statistically significant improvements in the auditory intergration therapy group and for only two outcome measures.
The NAS concluded that there is insufficient evidence of the effectiveness of vision therapy for autism. “A variety of visual therapies (including oculomotor exercises, colored filters, i.e., Irlen lenses, and ambient prism lenses) have been used with children with autism in attempts to improve visual processing or visual spatial perception. There are no empirical studies regarding the efficacy of the use of Irlen lenses or oculomotor therapies specifically in children with autism …. As with auditory integration therapy, studies have not provided clear support for either its theoretical or its empirical basis.”
Bell (2004) assessed the evidence for the effectiveness of music therapy for autism for the Wessex Institute for Health Research and Development, and concluded that there is insufficient evidence to support its use. The assessment concluded that children with autism may demonstrate slight improvements in speech and imitation during music therapy sessions, but the clinical importance of these changes may be negligible. The assessment found that the impact of music therapy on behavior and social functioning is unclear, and the long-term effects are uncertain. The assessment also stated that it is unclear whether music therapy is better than other forms of behavioral therapy for children with autism. The assessment stated that these conclusions are limited by the poor quality of the evidence, in particular the biased selection of the children, the small numbers involved, the contamination effect of the crossover design of many of the studies, the uncertain relevance of many of the outcome measures and the short follow-up. The assessment concluded “[w]ithout further research, no recommendation about the clinical effectiveness of music therapy for autism can be made.”
The AAP stated that speech therapy and physical therapy play important roles in the comprehensive, interdisciplinary management of children with autistic spectrum disorder (2001). An assessment by the National Initiative for Autism: Screening and Assessment (NIASA) (National Autistic Society, 2003) stated that children with co-morbid specific developmental disorders will require additional therapeutic services. “These services include speech and language therapy for augmented communication programmes, physiotherapy and occupational therapy for visual perceptual problems, fine and gross motor co-ordination difficulties including with writing, unusual sensory responses, self-care skills and provision of equipment and environmental adaptations.” However, there is a lack of high-quality evidence for speech/language therapy for autism. The evidence for the effectiveness of speech/language therapy for autism is derived from case reports, single-case research designs, small-scale studies, and anecdotal reports.
Physical therapy for children with autistic spectrum disorders focuses on developing strength, coordination and movement (CARD, 2001). Therapists work on improving gross motor skills, such as running, reaching, and lifting. This therapy is concerned with improving function of the body's larger muscles through physical activities including exercise and massage. Occupational therapists commonly focus on improving fine motor skills, such as brushing teeth, feeding, and writing, or sensory motor skills that include balance (vestibular system), awareness of body position (proprioceptive system), and touch (tactile system).
The AAP (2001) has concluded that there is no scientific evidence to justify the use of infusions of immune globulin in treating autism.
The bulk of the evidence supporting cognitive rehabilitation for autism comes from case studies, anecdotal evidence and expert opinion. The effectiveness of cognitive rehabilitation in treating autism has not been critically evaluated in well-designed studies.
In a Cochrane review on the use of music therapy for the treatment of autistic spectrum disorders, Gold et al (2006) stated that published studies were of limited applicability to clinical practice. However, the findings indicate that music therapy may help children with autistic spectrum disorder to improve their communicative skills. The authors noted that more research is needed to examine whether the effects of music therapy are enduring, and to investigate the effects of music therapy in typical clinical practice.
In a Cochrane review, Millward et al (2008) noted that it has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of people with autism. These investigators examined the effectiveness of gluten and/or casein free diets as an intervention to improve behavior, cognitive and social functioning in individuals with autism. The authors concluded that research has shown of high rates of use of complementary and alternative therapies for children with autism including gluten and/or casein exclusion diets. However, current evidence for the effectiveness of these diets is poor. They stated that large scale, good quality randomized controlled trials are needed. This is in agreement with the observations of Curtis and Patel (2008) who stated that larger studies are needed to determine optimum multi-factorial treatment plans for autism and attention deficit hyperactivity disorder involving nutrition, environmental control, medication, as well as behavioral/education/speech/physical therapies.
The Tomatis sound therapy has been used to improve language skills in children with autism. It entails the use classical music that includes complex rhythms, melodies and harmonic relationships known to create improved brain function. The music is filtered with a device that Dr. Alfred Tomatis invented and called the Electronic Ear. The filtering or "gating", which the Electronic Ear provides, creates a gymnastic program that activates and rehabilitates the middle ear muscles and the whole auditory system. Programs are progressively filtered to gradually awaken the ear and auditory system to the full range of high frequencies.
Corbett et al (2008) examined the effects of the Tomatis sound therapy on language skills in children with autism utilizing a randomized, double-blind, placebo-controlled, cross-over design. The results indicated that although the majority of the children demonstrated general improvement in language over the course of the study, it did not appear to be related to the treatment condition. The percent change for Group 1 (placebo/treatment) for treatment was 17.41 %, and placebo was 24.84 %. Group 2 (treatment/placebo) showed -3.98 % change for treatment and 14.15 % change for placebo. The results reflect a lack of improvement in language using the Tomatis sound therapy for children with autism.
Rossignol and associates (2009) performed a multi-center, randomized, double-blind, controlled trial to evaluate the effectiveness of hyperbaric treatment in children with autism. A total of 62 children with autism were recruited from 6 centers, aged 2 to 7 years (mean of 4.92 +/- 1.21 years). Subjects were randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmosphere (atm) and 24 % oxygen (treatment group, n = 33) or slightly pressurized room air at 1.03 atm and 21 % oxygen (control group, n = 29). Outcome measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC), and Autism Treatment Evaluation Checklist (ATEC). After 40 sessions, mean physician CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30 children (30 %) in the treatment group were rated as "very much improved" or "much improved" compared to 2/26 (8 %) of controls (p = 0.0471); 24/30 (80 %) in the treatment group improved compared to 10/26 (38 %) of controls (p = 0.0024). Mean parental CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant improvements were observed in the treatment group in total score, irritability, stereotypy, hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group compared to the control group, mean changes on the ABC total score and sub-scales were similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC, sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group compared to the control group. Post-hoc analysis indicated that children over the age of 5 years and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated. The authors concluded that children with autism who received hyperbaric treatment at 1.3 atm and 24 % oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air.
Moreover, the authors stated that because this study was not designed to measure the long-term outcomes of hyperbaric treatment in children with autism, additional studies are needed to determine if the significant improvements observed in this study last beyond the study period. It is possible that ongoing treatments would be necessary to maintain the improvements observed, but this study was not designed to examine that possibility. These findings suggest that additional hyperbaric treatments beyond 40 total sessions may lead to additional improvements; however, further studies are needed to formally validate these observations. Finally, this study was not designed to determine if higher hyperbaric treatment parameters (higher atmospheric pressure and oxygen levels, which can only be provided in a clinic setting) would lead to better or more long-lasting results. Additional studies are needed to investigate that possibility.
It is interesting to note that Yildiz and colleagues (2008) stated that neither the Undersea Hyperbaric Medical Society nor the European Committee for Hyperbaric Medicine "approves" autism as an indication for hyperbaric oxygen therapy. The authors concluded that there is insufficient evidence to support the use of hyperbaric oxygen therapy in the treatment of children with autism.
It has been claimed that weighted blankets are beneficial for patients with autism since they "calm" the nervous system so afflicted individuals can relax and sleep. It is believed that weighted blanket leads to releases of melatonin, which plays a role in the body and brain’s sensory processing. Melantonin has been used for autistic children with sleep disorders despite insufficient evidence of its effectiveness in this population. Moreover, there is a lack of evidence regarding the clinical benefits of weighted blankets for individuals with autism or other pervasive developmental disorders.
Stephenson and Carter (2009) noted that therapists who use sensory integration therapy may recommend that children wear weighted vests as an intervention strategy that they claim may assist in remediating problems such as inattentiveness, hyperactivity, stereotypic behaviors and clumsiness. These investigators reviewed 7 studies on weighted vests. The authors concluded that while there is only a limited body of research and a number of methodological weaknesses, on balance, indications are that weighted vests are ineffective. There may be an arguable case for continued research on this intervention but weighted vests can not be recommended for clinical application at this point.
Floor time therapy is a series of 20- to 30-min periods during which parents interact and play with their autistic child on the floor. The aim of the interaction is to promote social and communicative abilities. A British Medical Journal Clinical Evidence systematic assessment on autism (Parr, 2006) concluded that the effectiveness of floor time therapy for autism is unknown.
Ichim and colleagues (2007) stated that ASDs are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypo-perfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypo-perfusion with symptomatology was reported. Mesenchymal stem cells (MSC) are in late phases of clinical development for treatment of graft versus host disease and Crohn's Disease, 2 conditions of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators, having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children receiving cord blood CD34+ cells. These researchers proposed the combined use of MSC and cord blood CD34+cells may be useful in the treatment of autism.
In a systematic review on novel and emerging treatments for ASD, Rossignol (2009) stated that currently, only 1 medication (risperidone) is FDA-approved for the treatment of ASD. The use of novel, unconventional, and off-label treatments for ASD is common, with up to 74 % of children with ASD using these treatments; however, treating physicians are often unaware of this usage. The author performed a systematic review of electronic scientific databases to identify studies of novel and emerging treatments for ASD, including nutritional supplements, diets, medications, and non-biological treatments. A grade of recommendation ("Grade") was then assigned to each treatment using a validated evidence-based guideline as outlined in this review: Grade A: Supported by at least 2 prospective randomized controlled trials (RCTs) or 1 systematic review; Grade B: Supported by at least 1 prospective RCT or 2 non-RCTs; Grade C: Supported by at least 1 non-RCT or 2 case series; and Grade D: Troublingly inconsistent or inconclusive studies or studies reporting no improvements. Potential adverse effects for each treatment were also reviewed. Grade A treatments for ASD include melatonin, acetylcholinesterase inhibitors, naltrexone, and music therapy. Grade B treatments include carnitine, tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists, hyperbaric oxygen treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and vision therapy. Grade C treatments for ASD include carnosine, multi-vitamin/mineral complex, piracetam, polyunsaturated fatty acids, vitamin B6/magnesium, elimination diets, chelation, cyproheptadine, famotidine, glutamate antagonists, acupuncture, AIT, massage, and neurofeedback. The author concluded that the reviewed treatments for ASD are commonly used, and some are supported by prospective RCTs. Promising treatments include melatonin, antioxidants, acetylcholinesterase inhibitors, naltrexone, and music therapy. All of the reviewed treatments are currently considered off-label for ASD and some have adverse effects. The author stated that further studies exploring these treatments are needed.
Thompson and colleagues (2010) summarized data from a review of neurofeedback (NFB) training with 150 patients with Asperger's syndrome (AS) and 9 patients with ASD seen over a 15-year period in a clinical setting. The main objective was to examine if NFB (also known as EEG biofeedback) made a significant difference in patients diagnosed with AS. A further aim of the current report was to provide practitioners with a detailed description of the method used to address some of the key symptoms of AS in order to encourage further research and clinical work to refine the use of NFB plus biofeedback in the treatment of AS. All charts were included for review where there was a diagnosis of AS or ASD and pre- and post-training testing results were available for one or more of the standardized tests used. Patients received 40 to 60 sessions of NFB, which was combined with training in meta-cognitive strategies and, for most older adolescent and adult patients, with biofeedback of respiration, electrodermal response, and, more recently, heart rate variability. For the majority of patients, feedback was contingent on decreasing slow wave activity (usually 3 to 7 Hz), decreasing beta spindling if it was present (usually between 23 and 35 Hz), and increasing fast wave activity termed sensorimotor rhythm (SMR) (12 to 15 or 13 to 15 Hz depending on assessment findings). The most common initial montage was referential placement at the vertex (CZ) for children and at FCz (midway between FZ and CZ) for adults, referenced to the right ear. Meta-cognitive strategies relevant to social understanding, spatial reasoning, reading comprehension, and math were taught when the feedback indicated that the patient was relaxed, calm, and focused. Significant improvements were found on measures of attention (T.O.V.A. and IVA), core symptoms (Australian Scale for Asperger's Syndrome, Conners' Global Index, SNAP version of the DSM-IV criteria for ADHD, and the ADD-Q), achievement (Wide Range Achievement Test), and intelligence (Wechsler Intelligence Scales). The average gain for the Full Scale IQ score was 9 points. A decrease in relevant EEG ratios was also observed. The ratios measured were (4 to 8 Hz)(2)/(13 to 21 Hz)(2), (4 to 8 Hz)/(16 to 20 Hz), and (3 to 7 Hz)/(12 to 15 Hz). The positive outcomes of decreased symptoms of Asperger's and attention deficit hyperactivity disorder (including a decrease in difficulties with attention, anxiety, aprosodias, and social functioning) plus improved academic and intellectual functioning, provided preliminary support for the use of NFB as a helpful component of effective intervention in people with AS.
Lee et al (2011) examined the effectiveness of massage as a treatment option for autism. These investigators searched the following electronic databases using the time of their inception through March 2010: MEDLINE, AMED, CINAHL, EMBASE, PsycINFO, Health Technology Assessment, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Psychology and Behavioral Sciences Collection, 6 Korean medical databases (KSI, DBpia, KISTEP, RISS, KoreaMed, and National Digital Library), China Academic Journal (through China National Knowledge Infrastructure), and 3 Japanese medical databases (Journal@rchive, Science Links Japan, and Japan Science & Technology link). The search phrase used was "(massage OR touch OR acupressure) AND (autistic OR autism OR Asperger's syndrome OR pervasive developmental disorder)". The references in all located articles were also searched. No language restrictions were imposed. Prospective controlled clinical studies of any type of massage therapy for autistic patients were included. Trials in which massage was part of a complex intervention were also included. Case studies, case series, qualitative studies, uncontrolled trials, studies that failed to provide detailed results, and trials that compared one type of massage with another were excluded. All articles were read by 2 independent reviewers, who extracted data from the articles according to predefined criteria. Risk of bias was assessed using the Cochrane classification. Of 132 articles, only 6 studies met inclusion criteria. One RCT found that massage plus conventional language therapy was superior to conventional language therapy alone for symptom severity (p < 0.05) and communication attitude (p < 0.01). Two RCTs reported a significant benefit of massage for sensory profile (p < 0.01), adaptive behavior (p < 0.05), and language and social abilities (p < 0.01) as compared with a special education program. The fourth RCT showed beneficial effects of massage for social communication (p < 0.05). Two non-RCTs suggested that massage therapy is effective. However, all of the included trials have high risk of bias. The main limitations of the included studies were small sample sizes, predefined primary outcome measures, inadequate control for non-specific effects, and a lack of power calculations or adequate follow-up. The authors concluded that limited evidence exists for the effectiveness of massage therapy as a symptomatic treatment of autism. Because the risk of bias was high, firm conclusions can not be drawn. They stated that future, more rigorous RCTs are warranted.
The Agency for Healthcare Research and Quality's report on comparative effectiveness of therapies for children with ASDs (AHRQ, 2011) has the following conclusions:
- Early intensive behavioral and developmental interventions such as the UCLA/Lovaas Model improve cognitive, language, and adaptive outcomes in certain subgroups of children (Low confidence scale).
- The evidence is insufficient to understand the effectiveness, benefits, or adverse events from any other behavioral interventions.
- Secretin does not improve language, cognition, behavior, communication, autism symptom severity, or socialization (High confidence scale).
- The evidence is insufficient to understand the effectiveness, benefits, or adverse events from any educational intervention.
- The evidence is insufficient to understand the effectiveness, benefits, or adverse events from any allied health or complementary and alternative medicine intervention.
In a Cochrane review, Sinha et al (2011) examined the effectiveness of AIT or other methods of sound therapy in individuals with ASDs. For this update, these investigators searched the following databases in September 2010: CENTRAL (2010, Issue 2), MEDLINE (1950 to September week 2, 2010), EMBASE (1980 to Week 38, 2010), CINAHL (1937 to current), PsycINFO (1887 to current), ERIC (1966 to current), LILACS (September 2010) and the reference lists of published papers. One new study was found for inclusion. Randomized controlled trials involving adults or children with ASDs were reviewed. Treatment was AIT or other sound therapies involving listening to music modified by filtering and modulation. Control groups could involve no treatment, a waiting list, usual therapy or a placebo equivalent. The outcomes were changes in core and associated features of ASDs, auditory processing, quality of life and adverse events. Two independent review authors performed data extraction. All outcome data in the included papers were continuous. They calculated point estimates and standard errors from t-test scores and post-intervention means. Meta-analysis was inappropriate for the available data. These researchers identified 6 RCTs of AIT and 1 of Tomatis therapy, involving a total of 182 individuals aged 3 to 39 years. Two were cross-over trials; 5 trials had fewer than 20 participants. Allocation concealment was inadequate for all studies. Twenty different outcome measures were used and only 2 outcomes were used by 3 or more studies. Meta-analysis was not possible due to very high heterogeneity or the presentation of data in unusable forms. Three studies (Bettison 1996; Zollweg 1997; Mudford 2000) did not demonstrate any benefit of AIT over control conditions. Three studies (Veale 1993; Rimland 1995; Edelson 1999) reported improvements at 3 months for the AIT group based on the Aberrant Behaviour Checklist, but they used a total score rather than subgroup scores, which is of questionable validity, and Veale's results did not reach statistical significance. Rimland (1995) also reported improvements at 3 months in the AIT group for the Aberrant Behaviour Checklist subgroup scores. The study addressing Tomatis therapy (Corbett 2008) described an improvement in language with no difference between treatment and control conditions and did not report on the behavioral outcomes that were used in the AIT trials. The authors concluded that there is no evidence that AIT or other sound therapies are effective as treatments for ASDs. As synthesis of existing data has been limited by the disparate outcome measures used between studies, there is insufficient evidence to prove that this treatment is ineffective. However, of the 7 studies including 182 participants that have been reported to date, only 2 (with an author in common), involving a total of 35 participants, reported statistically significant improvements in the AIT group and for only 2 outcome measures (Aberrant Behaviour Checklist and Fisher's Auditory Problems Checklist). As such, there is no evidence to support the use of AIT at this time.
Alcantara and associates (2011), using 8 databases, performed a systematic review of the literature on the effectiveness of chiropractic care in patients with ASD. Eligibility criteria for inclusion included: (i) the study was a primary investigation/report published in an English peer-reviewed journal; (ii) the study involved patients less than or equal to 18 years; and (iii) patients are diagnosed with autism, Asperger's Syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), or ASD. Review of the literature revealed a total of 5 articles consisting of 3 case reports, 1 cohort study and 1 randomized comparison trial. The literature is lacking on documenting chiropractic care of children with ASD. These researchers stated that at the heart of the core symptoms of ASD (i.e., impaired social interactions, deficits in communication and repetitive or restricted behavioral patterns) is abnormal sensory processing. Preliminary studies indicated that chiropractic adjustment may attenuate sensorimotor integration based on somatosensory evoked potentials studies. The authors concluded that they encourage further research for definitive studies on chiropractic's effectiveness for ASD.
In a Cochrane review, James et al (2011) examined the efficacy of omega-3 fatty acids for improving core features of ASD (e.g., social interaction, communication, and stereotypies) and associated symptoms. These investigators searched the following databases on June 2, 2010: CENTRAL (2010, Issue 2), MEDLINE (1950 to May Week 3 2010), EMBASE (1980 to 2010 Week 21), PsycINFO (1806 to current), BIOSIS (1985 to current), CINAHL (1982 to current), Science Citation Index (1970 to current), Social Science Citation Index (1970 to current), metaRegister of Controlled Trials (November 20, 2008) and ClinicalTrials.gov (December 10, 2010). Dissertation Abstracts International was searched on December 10, 2008, but was no longer available to the authors or editorial base in 2010. All RCTs of omega-3 fatty acids supplementation compared to placebo in individuals with ASD were reviewed. Three authors independently selected studies, assessed them for risk of bias and extracted relevant data. They conducted meta-analysis of the included studies for 3 primary outcomes (social interaction, communication, and stereotypy) and 1 secondary outcome (hyper-activity). These researchers included 2 trials with a total of 37 children diagnosed with ASD who were randomized into groups that received either omega-3 fatty acids supplementation or a placebo. They excluded 6 trials because they were either non-RCTs, did not contain a control group, or the control group did not receive a placebo. Overall, there was no evidence that omega-3 supplements had an effect on social interaction (mean difference (MD) 0.82, 95 % CI: -2.84 to 4.48, I(2) = 0 %), communication (MD 0.62, 95 % CI: -0.89 to 2.14, I(2) = 0 %), stereotypy (MD 0.77, 95 % CI: -0.69 to 2.22, I(2) = 8 %), or hyper-activity (MD 3.46, 95 % CI: -0.79 to 7.70, I(2) = 0 %). The authors concluded that to date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD. Given the paucity of rigorous studies in this area, there is a need for large well-conducted RCTs that examine both high- and low-functioning individuals with ASD, and that have longer follow-up periods.