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Lancet Seminar on Autism

A review focused on progress in our understanding of autism spectrum disorder

Epidemiology
The prevalence of autism spectrum disorder (ASD) has increased since the 1960s and is currently estimated at 60 to 116 cases per 10,000 children. In part, the increase reflects an expanded definition that includes the full spectrum (autism, pervasive developmental disorder not otherwise specified, and Asperger syndrome), new administrative classification systems in special education programs, and greater awareness among professional and parents. (A recent Centers for Disease Control retrospective surveillance study, released after the publication of this seminar, suggests that the rate of ASD in the U.S. is 1%).

Clinical Characteristics and Screening
Core symptoms of ASD affect socialization, communication, and behavior, including impaired use of nonverbal behaviors to regulate social interactions, delay in language development with impaired pragmatic (social use of) language restricted interests, rigidity, repetitive mannerisms, and fascination with parts of objects.

Prospective studies of younger siblings of affected children show that core symptoms might be detected as early as 6–12 months. Early detection enables prompt referral to intervention services. Two methods of early detection are selective screening (symptoms detected by parents and clinicians) and routine developmental surveillance (autism-specific screening at 18 and 24 months or 30 months). Selective screening might miss as many as one third of children with ASD, and routine screening has less than optimal sensitivity and specificity.

Assessment
Children who are identified as at risk during screening should be referred for comprehensive developmental and diagnostic assessment. A multidisciplinary assessment addresses core symptoms, cognition, language, and adaptive sensory and motor skills. Diagnostic assessment should include gold-standard assessments method based on Diagnostic and Statistical Manual of Mental Disorders IV criteria: the Autism Diagnostic Observation Schedule (ADOS) and the revised Autism Diagnostic Interview (ADI-R). Children should also be evaluated for coexisting symptoms or disorders, including cognitive disability, language deficits, attention-deficit/hyperactivity disorder (ADHD), motor delay, anxiety, depression, disruptive behaviors, tactile and auditory sensitivities, food sensitivities, gastroesophageal reflux, and sleep disturbances.

Assessment should also include a detailed history and physical examination with careful attention to dysmorphic features. Genetic tests include karyotype and molecular DNA test for fragile X syndrome, comparative genomic hybridization, or both. Significant developmental regression should lead to a metabolic investigation. Brain imaging and electroencephalogram are not recommended unless specific clinical features indicate an active neurological process.

Neurobiology

• Constructing a unified theory to explain core deficits has been unsuccessful because of the heterogeneity of clinical expression. Biological evidence suggests that autism is a disorder of neuronal–cortical organization causing deficits in information processing in the brain.
  
• Neurocognitive theories include pragmatic language impairment, impairment in interpersonal relationships (theory of mind), executive function deficits, and deficits in connectivity and processing demands.
  
• Brain overgrowth (causing macrocephaly) by age 2–3 years occurs in 20% of children with ASD. Neuroimaging studies show overgrowth in cortical white matter and abnormal patterns of growth in frontal lobes, temporal lobes, and limbic structures. Postmortem brain studies reveal reduced number and size of Purkinje cells and abnormal cortical microcolumns.
  
• Functional magnetic resonance imaging shows hypoactivation of the fusiform face area (located on the ventral surface of the temporal lobe) associated with deficits in perception of people compared with objects. Diffusion tensor imaging has shown disruption of white matter in brain regions associated with social functioning.
  
• Serotonin and genetic differences in serotonin transport might play a role in ASD.
  

Causes
Autism is a genetic disorder. The risk of a second child having ASD is 20 to 50 times higher than in the general population. Twin studies suggest that 90% of variance is due to genetic factors. First-degree relatives who do not have an ASD diagnosis often have delayed language and social development and difficulties with social speech (pragmatic language). Environmental or epigenetic factors can alter gene function and neural architecture (e.g., toxic exposures or psychological stress can alter brain chemistry or affect gene regulation). Genetic causes of ASD are known in 10% to 15% of cases: fragile X syndrome (3%), tuberous sclerosis (2%), maternal duplication of 15q1-q13 (2%), and deletions and duplications of 16p11 (1%). Functions of genes associated with fragile X syndrome (FMR1) and Rett syndrome (MECP2) suggest the involvement of synaptic dysfunction in the pathogenesis of ASD.

Treatment
Interventions target core deficits associated with ASD. The family and educational system are the main sources of treatment. Because parental stress can impede the effectiveness of early intervention, support for parents must be a part of any treatment plan. The best designed treatment programs are based on the principles of applied behavioral analysis. Highly structured, intensive, one-on-one behavioral treatment programs (discrete trial training) have proved effective in about one half of children enrolled in 10 randomized clinical trials. Similar outcomes have been reported with less-structured, naturalistic behavioral programs (pivotal response training). Maintenance of behavior changes are improved when parents are trained to continue therapy. Promising results have also been seen with developmental models of therapy (e.g., relationship-based floor time model and the transactional support model).

Pharmacological treatments are not effective for core symptoms but rather target coexisting behaviors. Methylphenidate for ADHD in children with ASD has positive effects on joint attention as well as core ADHD symptoms. Risperidone is effective for severe irritability and aggression in children with ASD. Studies of selective serotonin reuptake inhibitors to treat anxiety and repetitive behaviors have been mixed. Seizures and tics in children with ASD are treated with medications similar to those used in nonautistic children. Few studies have addressed the safety and effectiveness of complementary and alternative therapies.

Future Directions
Research in the past 10 years has identified deficits in neuronal patterning, cortical connectivity, synaptic organization, and electrophysiology in children with ASD. Recognition of specific clinical phenotypes and possible biological markers will promote development of more-individualized and -effective treatments.

— Martin T. Stein, MD

Published in Journal Watch Pediatrics and Adolescent Medicine February 3, 2010

Citation(s):

Levy SE et al. Autism. Lancet 2009 Nov 7; 374:1627. (http://dx.doi.org/10.1016/S0140-6736(09)61376-3)

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