Abstract
Introduction
Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child’s Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.
Key Points
Autism is one of a group of pervasive developmental disorders, and is characterised by qualitative impairments in communication and social interaction, and by repetitive and stereotyped behaviours and interests.
Abnormal development is present before the age of 3 years. A quarter of affected children show developmental regression, with loss of previously acquired skills.
One third of children with autism have epilepsy, and three quarters have mental retardation. Only 15% of adults with autism will lead independent lives.
Twin and family studies suggest that most cases of autism occur because of a combination of genetic factors. Autism is not caused by perinatal factors or by the MMR vaccine.
It may be difficult to apply the results of research in practice, as improvements in outcomes assessed in RCTs using standardised assessment tools may not correlate with improvements in function in a particular child with autism.
Some interventions are administered by (or in conjunction with) parents, and may be carried out in the home. Consideration of the direct financial costs, indirect costs (through possible lost earnings), and the impact on relationships within the family (to siblings or spouse) must be balanced against likely and possible improvements in outcome for the child with autism.
There is a lack of good-quality evidence on the effectiveness of early multidisciplinary intervention programmes, or for other treatments for children with autism.
There is consensus, supported by a systematic review, that early intensive behavioural interventions are likely to be beneficial in children with autism.
Attendance at a "More Than Words" training course for parents may improve communication between parents and children, as may participation in Child's Talk.
There is consensus that the Autism Preschool Programme and TEACCH may be effective, although no RCTs or cohort studies evaluating these interventions have been found.
We don't know whether early intervention using the EarlyBird programme, the Portage scheme, Relationship-Development Intervention, Social stories, music therapy, CBT, facilitated communication or Son-Rise are beneficial in children with autism.
Methylphenidate may reduce hyperactivity in children with autism.
Methylphenidate may increase social withdrawal and irritability. Growth and blood pressure monitoring are required.
Risperidone may improve behaviour in children with autism compared with placebo, but its use is limited by adverse effects such as weight gain, drowsiness, prolactinaemia, and tremors.
There is consensus that selective serotonin reuptake inhibitors (SSRIs) improve symptoms in children with autism, although no RCTs have been found. The adverse effects of SSRIs, including possible increases in agitation, hostility, and suicidal ideation, are well documented.
We don't know whether auditory integration training, sensory integration training, chelation, a gluten- and casein-free diet, digestive enzymes, omega-3 fish oil, secretin, vitamin A, vitamin B6 plus magnesium, melatonin, olanzapine, or vitamin C are beneficial for treating children with autism, as few studies have been found.
About this condition
Definition
Autism is one of the pervasive developmental disorders (PDD), a group of conditions that also includes Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), Rett syndrome, and childhood disintegrative disorder. Collectively, autism, Asperger syndrome, and PDD-NOS are often referred to as "autistic spectrum disorders" (ASDs). However, Rett syndrome and childhood disintegrative disorder fall outside the autistic spectrum. Autism is characterised by qualitative impairments in communication and social interaction, and by restricted, repetitive, and stereotyped patterns of behaviours and interests. Abnormal development is present before the age of 3 years. The clinical features required for a diagnosis of autism to be made are set out in International classification of diseases (ICD-10) and Diagnostic and statistical manual of mental disorders 4th ed (DSM-IV). For ICD-10 criteria see table 1 . Individuals with autism have a history of language delay (single word or phrase speech delay), and a quarter lose previously acquired skills (regression), most commonly in the second year of life. A third of individuals develop epilepsy, and three quarters have mental retardation. Males are affected more commonly than females (3.5–4.0:1). The findings of this review apply to children and adolescents with autism, and results may not be generalisable to children with other ASDs. Diagnosis: The generally accepted "gold standard" assessment tools for autism are the Autism Diagnostic Interview-Revised (ADI-R), a semistructured, interviewer-based schedule administered to the primary caregiver, and the Autism Diagnostic Observational Schedule, a semistructured assessment carried out with the individuals themselves. Although these schedules are informative for the clinician, autism remains a clinical diagnosis.
Table 1.
Diagnostic criteria for childhood autism − International Classification of Diseases (ICD-10) issued by the WHO
| Qualitative impairments in reciprocal social interaction, as manifested by at least 3 of the following 5: |
| • Failure to adequately use eye-to-eye gaze, facial expression, body posture, and gesture to regulate social interaction |
| • Failure to develop peer relationships |
| • Rarely seeking and using other people for comfort and affection at times of stress or distress, offering comfort and affection to others when they are showing distress or unhappiness, or both |
| • Lack of shared enjoyment in terms of vicarious pleasure in other people's happiness, spontaneous seeking to share their own enjoyment through joint involvement with others, or both |
| • Lack of socioemotional reciprocity |
| Qualitative impairments in communication: |
| • Lack of social usage of whatever language skills are present |
| • Impairment in make believe and social imitation play |
| • Poor synchrony and lack of reciprocity in conversational language |
| • Poor flexibility in language expression and a relative lack of creativity and fantasy in thought processes |
| • Lack of emotional response to other people's verbal and non-verbal overtures |
| • Impaired use of variations in cadence or emphasis to reflect communicative modulation |
| • Lack of accompanying gesture to provide emphasis or aid meaning in spoken communication |
| Restricted, repetitive, and stereotyped patterns of behaviour, interests, and activities, as manifested by at least 2 of the following 6: |
| • Encompassing preoccupation with stereotyped and restricted patterns of interest |
| • Specific attachments to unusual objects |
| • Apparently compulsive adherence to specific, non-functional routines or rituals |
| • Stereotyped and repetitive motor mannerisms |
| • Preoccupations with part-objects or non-functional details of the environment |
| • Distress over changes in small, non-functional details of the environment |
| Developmental abnormalities must have been present in the first 3 years for the diagnosis to be made |
Incidence/ Prevalence
The detected prevalence of autism has increased in recent years, and a recent high-quality UK study found 40/10,000 children to have childhood autism. The prevalence of autism for studies published between 1977 and 1991 was 4.4/10,000, whereas that for the studies published during the period 1992 to 2001 was 12.7/10,000. When considering all autism spectrum disorders, findings suggest the prevalence rises to 120/10,000; many of these people have PDD-NOS.
Aetiology/ Risk factors
Evidence from twin and family studies suggests that most cases of autism arise because of a combination of genetic factors. Family studies indicate that the rate of autism in siblings of autistic individuals is about 2.2%, and the sibling recurrence rate for all PDDs is 5% to 6% — significantly greater than that of the general population. Monozygotic twin studies show 60% to 91% concordance for autism, and therefore it is likely that most cases arise on the basis of multiple susceptibility genes, with influence from environmental or other factors. A minority of cases of autism can be attributed to genetic disorders, including chromosomal abnormalities, fragile X syndrome, tuberose sclerosis, neurofibromatosis type 1, and a variety of other medical conditions. Although perinatal factors have been implicated, it is unlikely that they have a causal role. Research evidence suggests that autism is not caused by the MMR vaccine, or by thimerosal (mercury) in vaccines (see review on measles, mumps, and rubella: prevention). There is strong evidence supporting a neurobiological basis of autism. Ongoing research into the relationship between neurophysiology, neuroanatomy, neurochemistry, and genetic factors is likely to increase our understanding, and represents the best chance of unravelling the complex aetiology of ASD. The presence of phenotypic and genetic heterogeneity may have significant implications for studies of interventions/treatments for autism, as efficacy may vary with phenotype.
Prognosis
Autism is a lifelong condition with a highly variable clinical course throughout childhood and adolescence. Many adults with autism require lifelong full-time care. About 15% of adults with autism will live independent lives, whereas 15% to 20% will live alone with community support. Verbal and overall cognitive capacity seem the most important predictors of ability to live independently as an adult.
Aims of intervention
To improve social function, communication, cognitive ability, and reduce the repetitive, obsessional, and comorbid behaviours seen in autism, with minimal adverse effects of treatment.
Outcomes
Social function; behavioural function; cognitive function; communication; repetitive behaviour; global function; self care; family function; and adverse effects of treatment.
Methods
Clinical Evidence search and appraisal May 2009. For this review various sources were used for the identification of studies: Medline 1986 to May 2009, Embase 1986 to April 2009, and The Cochrane Library, Issue 2, 2009. Additional searches were carried out on the NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE) websites. Abstracts of studies retrieved in the search were assessed independently by two information specialists. Predetermined criteria were used to identify relevant studies. Study design criteria included: systematic reviews; RCTs; quasi-randomised trials; controlled clinical trials; and prospective and retrospective cohort studies. Prospective and retrospective cohort studies were included only for interventions for which we could find no RCTs. We included studies with at least 20 participants. There was no minimum level or length of follow-up. We included open-label studies for interventions that could not be blinded. We only included studies of children or adolescents with autism; if studies included individuals with other ASDs, those which provided a subgroup analysis of at least 20 individuals with autism were included. Limitations of the research: The guidance included in this review is applicable to children with autism rather than other ASDs. Many excluded studies have included small numbers of participants, with a range of ASD diagnoses and therefore a range of abilities; combining data on the outcome of individuals with autism and those individuals with other PDDs is unlikely to be either scientifically valid or clinically useful. In addition, participants in studies have frequently been diagnosed using clinical criteria, without standardised assessment tools, and outcomes have been assessed using a variety of measures, often after a short follow-up period. Much of the research is observational and few RCTs were found. Only by conducting well-designed RCTs in large samples of people characterised as having autism using standardised assessment tools, and by measuring outcomes using standardised measures after an acceptable time period, will the effect of interventions be robustly proved. Applying the evidence in practice: For clinicians and parents, various factors require consideration when deciding whether an intervention or treatment may be of benefit to a child with autism. As described, the limitations of the research have led to weaknesses in the evidence base for many established interventions. Some studies have appropriately measured outcome using standardised assessment tools; however, improvements in scale scores on such assessments do not necessarily translate into obvious functional improvements in the everyday life of a child with autism. Longitudinal studies and data on long-term outcome after interventions are lacking; for some children, improvements in outcome may be moderate, and there is at present no way of ascertaining whether a particular group of children may benefit from a specific intervention. In addition to considering the possible adverse effects of treatment, the wider cost of interventions should be considered. Many interventions are expensive, and costs may not necessarily be covered by state funding. Some interventions are administered by (or in conjunction with) parents and may be carried out in the home. Consideration of the direct financial costs, indirect costs (through possible lost earnings), and the impact on relationships within the family (to siblings or spouse) must be balanced against likely and possible improvements in outcome for the individual with autism. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table 1.
GRADE evaluation of interventions for autism.
| Important outcomes | Global improvement, social function, behavioural function, cognitive function, and adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of early intensive multidisciplinary intervention programmes in children with autism? | |||||||||
| 11 (397) | Cognitive function (communication and IQ scores) | Early intensive behavioural interventions v other therapy | 2 | −2 | −1 | 0 | 0 | Very low | Quality points deducted for uncertain follow-up and for comparison of means. Consistency point deducted for different comparisons |
| 11 (397) | Behavioural function | Early intensive behavioural interventions v other therapy | 2 | −2 | −1 | 0 | 0 | Very low | Quality points deducted for uncertain follow-up and for comparison of means. Consistency point deducted for different comparisons |
| 1 (28) | Social function | Child's Talk v existing care | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (29) | Social function | More Than Words v delayed access to programme | 2 | –1 | 0 | 0 | 0 | Very low | Quasi-randomised RCT. Quality point deducted for sparse data |
| 2 (118) | Social function | PECS v other treatment or no treatment | 4 | −3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting, and no subgroup for autism. |
| 1 (22) | Cognitive function | TEACCH v usual care | 2 | –2 | 0 | 0 | 0 | Very low | Quasi-randomised study. Quality points deducted for sparse data and baseline differences |
| What are the effects of dietary interventions in children with autism? | |||||||||
| 1 (20) | Global improvement | Advice to follow gluten and casein free diet v no dietary advice | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and baseline differences |
| What are the effects of drug treatments in children with autism? | |||||||||
| 1 (66) | Behavioural function | Methylphenidate v placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and uncertainty about clinical relevance of improvement |
| 3 (208) | Behavioural function | Risperidone v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting |
| 6 (242) | Global improvement | Secretin v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for heterogeneous population |
| What are the effects of non-drug treatments in children with autism? | |||||||||
| No studies found | |||||||||
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.
Glossary
- Auditory integration training
This is based on the hypothesis that individuals have insensitivity or abnormal sensitivity to various frequencies of sound waves, and that behavioural and learning difficulties are a result of this. It is hypothesised that auditory integration training addresses sound sensitivity and "re-educates" hearing, thus improving associated symptoms. Treatment with auditory integration training involves listening to electronically modified music, heard through headphones, for two daily 30-minute sessions over 10 days.
- Autism Preschool Programme
This programme offers parents and carers support in behavioural and language development methods that are then carried out at home or during day care.
- Chelation therapy
This involves the use of a compound that binds to heavy metals such as lead and mercury. Chelation agents are introduced to the body by iv infusion, bind to heavy metals, and are then excreted in the urine. Chelation therapy has been used in children with autism as some individuals believe that autism results from high levels of toxic heavy metals that cause damage to the brain.
- Child's Talk
This programme uses video feedback in order to promote facilitative strategies that lead to closer interpersonal interaction between the child and their parents. Parents are then able to identify which strategies are successful and lead to their child becoming more engaged, thus aiding communication.
- EarlyBird programme
This is a 3-month programme combining group training sessions for parents of children with autism with individual home visits. Video feedback is used to help parents use what they learn to engage and communicate with their child.
- Floortime
This is a series of 20–30 minute periods during which parents interact and play with their child on the floor. The aim of the interaction is to promote social and communicative abilities.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- More Than Words (Hanen programme)
This is designed to help parents of children under the age of 6 years who are experiencing difficulties in social interaction and communication. Parents learn several strategies that may help to improve their child's communication and social interaction.
- Picture exchange communication system (PECS)
This was developed to help young children with autism learn to initiate requests and communicate their needs. PECS uses a behaviourally based programme to teach the child to exchange a picture card for something the child likes and wants. Objects, pictures, or symbols may be used, according to the developmental level of the child. The six phases of PECS are structured to enable a child to: learn the picture exchange; actively find a person to give a symbol to as a request; discriminate between several symbols; use a portable communication book; and construct simple sentences, requests, and comments.
- Portage
This is a home-based teaching support service for pre-school children with special educational needs and their families. Portage offers weekly visits to families by specialist teachers to help plan and support "play-based" programmes, which parents/carers carry out with their children.
- Probiotics
These have recently been suggested as a treatment for autism as some individuals believe that autism is related to the effects of GI tract bacteria.
- Relationship-development intervention
This is a parent-based programme for individuals with autism spectrum and other relationship-based disorders. The goal of the programme is to help people to systematically build up the motivation and strategies in order to successfully interact in social relationships. Relationship-development intervention focuses on improving behaviours such as referencing and enabling individuals to share emotions.
- Sensory integration training
This aims to treat the sensory behaviours of children with autism by exposing them to various sensory stimuli.
- Social skills training
In moderate- and high-functioning individuals with autism, social skills training teaches children and adolescents how to make appropriate social overtures and responses that can be used in common social situations.
- Social stories
This method presents appropriate social behaviours in the form of a story, and aims to enable individuals with autism to interact appropriately with others.
- Son-Rise
This is an intensive home-based, parent-run intervention aimed at children with autism. Son-Rise involves intensive one-to-one contact with the child in a specially designed play room.
- TEACCH (Treatment and Education of Autistic and related Communication handicapped Children)
This structured developmental teaching programme provides continuity in the classroom setting, thus aiming to improve developmental skills in order to enable children to learn. Parents are trained in TEACCH methods and schooling at home, and this is supplemented by day therapy or special schooling, given by professionals.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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