General Information (including ICD-9/-10 Codes)

Description :

  • childhood disorder, pervasive developmental disorder, developmental behavioral disorder

Also called :

  • infantile autism

ICD-9 Codes :

  • 299.00 infantile autism, current or active state
  • 299.01 infantile autism, residual state

ICD-10 Codes :

  • F84.0 childhood autism
  • F84.1 atypical autism
  • F84.3 other childhood disintegrative disorder
  • F84.4 overactive disorder associated with mental retardation and stereotyped movements
  • F84.5 Asperger's syndrome
  • F84.8 other pervasive developmental disorders
  • F84.9 pervasive developmental disorder, unspecified

Who is most affected :

  • children < 12-15 years old, usually before age 36 months, males more common, females more severe

Incidence/Prevalence :

  • pervasive developmental disorders may be more common than previously reported
    • based on survey of 15,500 children aged 2.5-6.5 years in England
    • children with symptoms suggestive of pervasive developmental disorder were assessed by multidisciplinary team
    • 97 children (79% male) confirmed to have a pervasive developmental disorder
    • prevalence per 10,000 children was 62.6 (95% CI 50.8-76.3)
    • prevalence rates per 10,000 children were 16.8 for autistic disorder and 45.8 for other pervasive developmental disorders
    • Reference - (JAMA 2001 Jun 27;285(24):3093), editorial can be found in JAMA 2001 Jun 27;285(24):3141
  • higher prevalence of autism spectrum disorders reported in children aged 9-10 years in South Thames, UK
    • within total population of 56,946 children aged 9-10 years, 255 with current diagnosis of autistic spectrum disorder and 1,515 at risk children had comprehensive diagnostic assessment
    • prevalence of childhood autism 38.9 per 10,000
    • prevalence of other autistic spectrum disorders 77.2 per 10,000
    • total prevalence of autistic spectrum disorders 116.1 per 10,000
    • Reference - Lancet 2006 Jul 15;368(9531):210, editorial can be found in Lancet 2006 Jul 15;368(9531):179
  • United States prevalence data
    • prevalence of autistic spectrum disorders in US states in 2000-2001 ranged from 0.6 to 4.6 per 1,000 children, and was associated with number of school-based health centers in the state (Arch Pediatr Adolesc Med 2005 Mar;159(3):266 in JAMA 2005 May 18;293(19):2323)
      • prevalence of autistic spectrum disorders 6.7 cases per 1,000 children aged 3-10 and prevalence for autistic disorder was 4 cases per 1,000 children in one US township (Pediatrics 2001 Nov;108(5):1155); studies of prevalence difficult to interpret for conditions with no specific diagnostic test and somewhat arbitrary diagnostic criteria (commentary in Pediatric Notes 2001 Nov 22;25(47):187)
      • prevalence of autism 3.4 per 1,000 children ages 3-10 years in Atlanta, Georgia; autism in this study included autistic disorder, pervasive developmental disorder not otherwise specified, and Asperger's disorder (JAMA 2003 Jan 1;289(1):49), editorial can be found in JAMA 2003 Jan 1;289(1):87
    • prevalence of parent-reported diagnosis of autism was 5.5-5.7 per 1,000 children ages 4-17 years in United States 2003-2004 (MMWR 2006 May 5;55(17):481), summary can be found in Am Fam Physician 2006 Dec 15;74(12):2124
    • prevalence of autism increased in Minnesota after 1990
      • cohort study of children 6-11 years old enrolled in special education in 1981-2002 in Minnesota; autism prevalence rates (per 10,000 children) remained steady at < 2 from 1981-1990, then increased steadily from 3 in 1991 to 52 in 2002; prevalence of all other special education disability disorders increased also, so this may reflect overall improvement in recognition of neurodevelopmental disorders (Arch Pediatr Adolesc Med 2003 Jul;157(7):622 in J Watch Online 2003 Jul 25)
      • age-adjusted incidence of research-identified autism in Olmsted County, Minnesota increased from 5.5 per 100,000 children in 1980-1983 to 44.9 per 100,000 children in 1995-1997; increased confined to children < 10 years old born after 1987; increase likely related to increased recognition and changes in diagnostic criteria (Arch Pediatr Adolesc Med 2005 Jan;159(1):37 in JAMA 2005 Mar 23/30;293(12):1427)
    • increasing prevalence of autism based on US Department of Education data considered unreliable due to numerous data anomalies (Pediatrics 2005 Jul;116(1):e120 full-text)
    • increasing prevalence of autism in US special education population 1994 to 2003 associated with corresponding decreasing prevalence of other dignostic categories, suggesting classification shift instead of epidemiological changes (Pediatrics 2006 Apr;117(4):1028), editorial can be found in Pediatrics 2006 Apr;117(4):1436, 1438, correction can be found in Pediatrics 2006 Aug;118(2):852
  • prevalence of autism 0.87 per 1,000 children in Denmark
    • based on Danish national registry of 943,664 children < 10 years old followed from 1994 to 2001
    • 818 developed autism
    • risk factors for autism included
      • sibling with autism (relative risk 22)
      • sibling with Asperger's syndrome or other pervasive developmental disorder (relative risk 13)
      • male gender (relative risk 2.86)
      • mother with psychiatric disorder (relative risk about 2)
      • and mother born outside Europe (relative risk 1.4)
    • Reference - J Child Psychol Psychiatry 2005 Sep;46(9):963 in Pediatric Notes 2005 Nov 10;29(45):179
  • prevalence of pervasive developmental disorder 6.49 per 1,000 children in Montreal
    • survey of 27,749 children born 1987-1998 and attending 55 schools in Montreal, Quebec, Canada
    • prevalence per 1,000 children was 6.49 for pervasive developmental disorder, 2.16 for autistic disorder, 1.01 for Asperger syndrome and 3.28 for pervasive developmental disorder not otherwise specified
    • thimerosal exposure unrelated to increasing prevalence
    • Reference - Pediatrics 2006 Jul;118(1):e139
  • cumulative incidence up to 0.41% in Taiwan
    • based on national data with 1,70,966 children born 1996-2001 and evaluated in 2004 based on database records, follow-up 3-8 years based on birth cohort
    • cumulative incidence of autism 0.3% at 3 years, 0.39% at 4 years and at 5 years, 0.41% at 6 years, 0.4% at 7 years and 0.34% at 8 years
    • Reference - Pediatrics 2007 Feb;119(2):e435
  • cumulative incidence up to 0.5% at age 9 years in Denmark
    • based on national registries with all 669,995 children born in Denmark 1990-1999
    • cumulative incidence of autism spectrum disorder per 10,000 children at selected ages
      • 2.7 to 4.7 at age 3 years, increasing from 1994 to 1999 birth cohorts
      • 16.1 to 23 at age 5 years, increasing from 1994 to 1999 birth cohorts
      • 35.9 to 40 at age 7 years, increasing from 1994 to 1997 birth cohorts
      • 50.8 at age 9 years, based on 1994-1995 birth cohort
    • cumulative incidence of childhood autism per 10,000 children at selected ages
      • 1.7 to 2.8 at age 3 years, increasing from 1994 to 1999 birth cohorts
      • 8.9 to 14.4 at age 5 years, increasing from 1994 to 1999 birth cohorts
      • 14.8 to 16.1 at age 7 years, increasing from 1994 to 1997 birth cohorts
      • 17.1 at age 9 years, based on 1994-1995 birth cohort
    • Reference - Arch Pediatr Adolesc Med 2007 Feb;161(2):193
  • estimated prevalence of genetic types of autism 45 per 100,000 persons in Europe in 2005 (Lancet 2008 Jun 14;371(9629):2039)

Causes and Risk Factors

Causes :

  • unidentified brain dysfunction
  • cause of autism spectrum disorders likely genetic but involving multiple genes, based on extensive literature review (Pediatrics 2004 May;113(5):e472 full-text)
  • microdeletion or microduplication of region on chromosome 16p11.2 may account for about 1% of cases
    • based on case-control studies
    • Autism Genetic Resource Exchange (AGRE) study included 751 multiplex families with 1,441cases; controls were 1,420 AGRE parents and 2,814 persons with bipolar or NIMH controls
      • 5 cases vs. 3 controls had microdeletion
      • 7 cases vs. 2 controls had reciprocal microduplication
    • comparing 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder vs. 434 controls
      • 5 (1%) vs. 0 had microdeletion
      • 4 (0.8%) vs. 0 had reciprocal microduplication
    • comparing 299 Icelandic persons with autism spectrum disorder vs. 18,834 Icelandic controls
      • 3 (1%) vs. 2 (0.01%) had microdeletion
      • 0 vs. 5 (0.03%) had reciprocal microduplication
    • Reference - N Engl J Med 2008 Feb 14;358(7):667, editorial can be found in N Engl J Med 2008 Feb 14;358(7):737
  • some children with autism spectrum disorders have clinically relevant epileptiform activity during slow-wave sleep (Pediatrics 1999 Sep;104(3):405), editorial can be found in Pediatrics 1999 Sep;104(3):558, commentary can be found in Pediatrics 2001 May;107(5):1232
  • editorial review of causes of autism spectrum disorders can be found in BMJ 2003 Jan 25;326(7382):173, commentary can be found in BMJ 2003 May 3;326(7396):986

Likely risk factors :

  • fragile X syndrome
  • prenatal complications, maternal rubella, PKU, meningitis, encephalitis
  • newborn encephalopathy associated with increased risk of autism
    • cohort of 276 term infants with encephalopathy and 564 term controls in Western Australia followed for 5 years
    • 13.4% infants with encephalopathy vs. 0.2% controls had died by age 5 years
    • comparing 239 survivors of newborn encephalopathy vs. 563 surviving controls
      • 12 (5%) vs. 5 (0.8%) had autistic spectrum disorder
      • 10 (4.2%) vs. 4 (0.7%) had autism
    • Reference - Dev Med Child Neurol 2006 Feb;48(2):85

Possible risk factors :

  • advanced parental age
    • advanced paternal age associated with autism
      • based on 132,271 Jewish persons born in Israel with data on paternal and maternal age
      • 110 had autism (incidence 8.3 cases per 10,000)
      • paternal age > 40 years associated with increased risk compared to age < 30 years (relative risk 5.75, 95% CI 2.65-12.46)
      • Reference - Arch Gen Psychiatry 2006 Sep;63(9):1026
    • each 10-year increase in maternal or paternal age appears associated with increased risk for autism spectrum disorders in birth cohort study comparing 593 children with autism spectrum disorders with 132,251 controls (Arch Pediatr Adolesc Med 2007 Apr;161(4):334)
  • idiopathic infantile macrocephaly associated with autistic spectrum disorders in case-control study (Lancet 2001 Sep 1;358(9283):726); criticisms of this study include use of autism spectrum disorders and not specifically autism, and lack of evaluation of head circumferences of parents and siblings (Pediatric Notes 2001 Oct 4;25(40):157)
  • association of family history of autoimmune disease and autistic spectrum disorders has limited and inconsistent evidence
    • no association between maternal autoimmune disease overall and autistic spectrum disorder; case-control study comparing 407 children age 3-7 years with autistic spectrum disorder and 2,095 matched controls, no significant differences in proportions of any autoimmune disease in case mothers and control mothers; among 44 specific autoimmune disorders evaluated, only condition with independent significant association was maternal psoriasis with adjusted odds ratio 2.7 (95% CI 1.3-5.8); maternal asthma and allergy diagnoses during second trimester of pregnancy associated with > 2x risk (Arch Pediatr Adolesc Med 2005 Feb;159(2):151 in Pediatric Notes 2005 Mar 31;29(13):49)
    • family history of autoimmune disease may be associated with autistic spectrum disorders; questionnaire survey of 101 families with child with pervasive developmental disorder, 101 families with child with autoimmune disease (70% juvenile rheumatoid arthritis), and 101 families with healthy children; 52% to 75% response rates; mean number of family members with autoimmune disease was 1.87 for pervasive developmental disorder families, 1.44 for autoimmune disease families, and 0.93 for control families (Pediatrics 2003 Nov;112(5):e420 full-text)
  • no single obstetric factor clearly associated with risk for autism; case-control study compared 465 cases, 481 sibling controls, and 1,313 population controls; sibling controls were more similar to cases than controls for most factors; some obstetric complications and interventions were more common among cases, but few odds ratios exceeded 2; only threatened abortion before 20 weeks gestation had odds ratio > 2 (2.09) in logistic regression analysis (Arch Gen Psychiatry 2004 Jun;61(6):618)
  • perinatal environmental factors and parental psychopathology may be associated with risk of autism
    • 698 cases of children with infantile or atypical autism were evaluated (25 matched-controls evaluated for each case) in Denmark
    • risk of autism associated with
      • breech presentation (risk ratio 1.63)
      • low Apgar score at 5 minutes (risk ratio 1.89)
      • gestational age at birth < 35 weeks (risk ratio 2.45)
      • parental psychiatric history (schizophrenia-like psychosis [risk ratio 3.44] and affective disorder [risk ratio 2.91])
    • risk of autism not associated with
      • weight for gestational age
      • parity
      • number of antenatal visits
      • parental age
      • socioeconomic status
    • Reference - Am J Epidemiol 2005 May 15;161(10):916, commentary can be found in Evidence-Based Medicine 2005 Nov-Dec;10(6):184

Factors not associated with increased risk :

  • no correlation between increased prevalence of autism and use of MMR vaccine
  • no association with thimerosal-containing vaccines
    • no association between autistic spectrum disorders and thimerosal-containing vaccines in systematic review of 10 epidemiologic studies, studies suggesting association were poor quality and uninterpretable; 2 pharmacokinetic studies find ethylmercury has short half-life making association unlikely (Pediatrics 2004 Sep;114(3):793), commentary can be found in Pediatrics 2005 Jan;115(1):200
    • no association between autistic spectrum disorders and thimerosal-containing vaccines in cohort of 467,450 children (JAMA 2003 Oct 1;290(13):1763), commentary can be found in JAMA 2004 Jan 14;291(2):180, commentary can be found in POEMs in J Fam Pract 2004 Feb;53(2):94, commentary can be found in Am Fam Physician 2004 Apr 15;69(8):2009
    • no consistent association between thimerosal-containing vaccines and any adverse neurodevelopmental outcome in retrospective study of 140,887 children in 3 HMOs (Pediatrics 2003 Nov;112(5):1039), correction can be found in Pediatrics 2004 Jan;113(1):184, commentary on grading IVH can be found in Pediatrics 2004 Apr;113(4):932
    • no association between thimerosal-containing vaccines in infants and developmental disorders in prospective UK cohort of > 14,000 children (Pediatrics 2004 Sep;114(3):577) or retrospective UK cohort of 109,863 children (Pediatrics 2004 Sep;114(3):584)
    • early thimerosal exposure NOT associated with neuropsychological deficits at age 7-10 years
  • infection in first 2 years of life not associated with autistic spectrum disorders
    • based on case-control study with 403 children with autism and 2,100 matched controls
    • 95% cases vs. 97.5% controls had infection diagnosis in first 2 years of life (not significant)
    • 22.6% cases vs. 18.7% controls had infection in first 30 days of life (not significant)
    • Reference - Pediatrics 2007 Jan;119(1):e61
  • no association between autism and defined gastrointestinal disorders in case-control study; 96 children compared to 449 controls; no children had Crohn's disease or ulcerative colitis; no significant differences in celiac disease (0 cases vs. 1 control), necrotizing enterocolitis (1 case vs. 0 controls), chronic diarrhea (1 vs. 0), malabsorption (0 vs. 1), food intolerance (3 [3%] vs. 11 [2%]), or recurrent gastrointestinal symptoms (4 [4%] vs. 28 [6%]) (BMJ 2002 Aug 24;325(7361):419)
  • no association between autism spectrum disorders and neonatal hyperbilirubinemia in case-control study with 338 children with autism spectrum disorder and 1,817 controls (Pediatrics 2005 Feb;115(2):e135 full-text)

Complications and Associated Conditions

Associated conditions :

  • mental retardation
    • often moderate to severe mental retardation
    • children with mental retardation more prone to develop seizures in adolescence
  • association reported between autism and lymphocytic colitis (J Pediatr 2001 Mar;138(3):366 in Pediatric Notes 2001 Mar 29;25(13):52)
  • infantile spasms may be associated with autistic spectrum disorders
    • based on 17 children aged 5-19 years with history of infantile spasms
    • 14 had neurodevelopmental disorders
    • 6 (35%) had autistic spectrum disorder, of whom 4 were profoundly mentally retarded (intelligence quotient/development quotient < 20)
    • Reference - J Child Neurol 2007 Sep;22(9):1102

History

Chief Concern (CC) :

  • stereotypies (repetitive behaviors)

History of Present Illness (HPI) :

  • language abnormalities, absent or rudimentary imaginative play

Social History (SH) :

  • impaired social interaction (lack of awareness of others, not seeking others for comfort), impaired communication (limited language, echolalia, limited eye contact), restricted repertoire of activities and interests (stereotypies, need for sameness)

Review of Systems (ROS) :

  • insomnia (parent-reported difficulties initiating sleep and daytime sleepiness) reported in 10 of 32 (31%) children with Asperger syndrome or high-functioning autism and none of 33 matched controls (BMC Psychiatry 2006 Apr 28;6:18 full-text)
  • gastrointestinal symptoms common in children with autistic spectrum disorders; questionnaires mailed to families of 258 patients and returned by 176 (68%); compared patients with autistic spectrum disorders to their siblings, 19.2% vs. 2.5% had reflux, 39% vs. 8.9% had diarrhea, 27.5% vs. 10% had malabsorption stools, 26% vs. 6.5% had failure to thrive, 64.5% vs. 31.4% had narrowed food interests and dietary restrictions (Kagan-Kushnir T et al, Annual Meeting of Canadian Pediatric Society 2002 Jun 12-16 in Pediatric Notes 2002 Jul 4;26(27):107)

Physical

General Physical :

  • profound deficits in interpersonal and communication skills
  • splinter skills, e.g. repeat TV show but no conversation
  • shorter stature
  • ambidextrous
  • associated deafness
  • cognitive evaluation
    • failure to show relatedness
    • disturbance of communication and language
    • low IQ (60% < 50)
    • resilience (inability to change)

Diagnosis

Making the diagnosis :

  • DSM-IV-TR criteria
    • at least 6 of 12 lis including 2 from A, 1 from B, and 1 from C considered only if abnormal for developmental level:
      • A qualitative impairment in social interaction
      • B qualitative impairment in verbal and nonverbal communication and in imaginative play
      • C markedly restricted repertoire of behaviors, activities and interests
    • delay or abnormal functioning in group A or B by age 3 years
    • symptoms not better accounted for by Rett syndrome or childhood disintegrative disorder

Rule out :

  • schizophrenia with childhood onset, mental retardation with behavioral symptoms, developmental receptive language disorder, congenital deafness (rubella), psychosocial deprivation, disintegrative (regressive) psychoses, genetic disease, profound lack of interaction (stimulation)
  • Asperger's syndrome may represent "high-functioning" autism with good verbal abilities; series of 100 males with Asperger's syndrome can be found in Dev Med Child Neurol 2004 Oct;46(10):652 (Pediatric Notes 2005 Jan 6;29(1):2)
    • Asperger's syndrome may be associated with aberrant processing of sensory information; comparing 58 persons with Asperger's syndrome vs. 56 persons without Asperger's syndrome from within 10 larger families, 47% vs. 11% had face recognition difficulties, 91% vs. 47% had aberrant sensibilities, 48% vs. 23% had sleeping disturbances, and 60% vs. 14% had aberrant eating habits (BMC Psychiatry 2005 Apr 12;5:20)

Imaging studies :

  • generalized enlargement of cerebral cortex (gray and white matter) found in 51 children ages 18-35 months with autism compared to 25 controls; significantly increased rate of head circumference growth found in children with autism in retrospective data from 113 children with autism and 189 controls followed from birth to 3 years (Arch Gen Psychiatry 2005 Dec;62(12):1366)

Other diagnostic testing :

  • auditory evoked potentials is definitive test
  • insufficient evidence to recommend for or against screening EEGs in autistic spectrum disorders; 25 studies reviewed, EEG epileptiform abnormalities are common, seizures reported in 20-30%, efficacy of anticonvulsants and steroids based mainly on case series and case reports (Kagan-Kushnir T and Roberts SW, Annual Meeting of Canadian Pediatric Society 2002 Jun 12-16 in Pediatric Notes 2002 Jul 4;26(27):107)
  • chromosome analysis and fragile X syndrome molecular testing each associated with 2-3% detection of abnormalities in series of 433 patients with autistic traits (BMC Medical Genetics 2005 Jan 18;6:3)

Prognosis

Prognosis :

Treatment

Treatment overview :

  • special education, behavior therapy

Diet :

  • insufficient evidence regarding gluten- and casein-free diets
    • based on Cochrane review
    • systematic review of 2 randomized trials evaluating gluten- and/or casein-free diets in 35 patients with autistic spectrum disorder
    • no meta-analysis was feasible
    • diet intervention associated with
      • improvements in 3 outcomes - overall autistic traits, social isolation, and overall ability to communicate and interact
      • no significant differences in 3 outcomes
      • unable to evaluate 10 outcomes due to skewed data
    • Reference - Cochrane Database Syst Rev 2008 Apr 16;(2):CD003498

Counseling :

Medications :

  • haloperidol if seizures in conjunction with high doses pyridoxine
  • risperidone (Risperdal)
    • risperidone may reduce some symptoms of autism spectrum disorder
      • based on Cochrane review with limited evidence
      • systematic review of 3 randomized placebo-controlled trials of risperidone in 211 patients with autism spectrum disorder
      • 1 trial with 31 adults, 2 trials with 180 children
      • comparing risperidone vs. placebo
        • 65% vs. 12% clinical global impression very much improved or improved (p = 0.00008, NNT 2) in 3 trials with 208 patients
        • irritability and hyperactivity scales were reduced (statistically significant) with risperidone
      • Reference - systematic review last updated 2006 Oct 18 (Cochrane Library 2007 Issue 1:CD005040)
    • risperidone (Risperdal) orally disintegrating tablets FDA approved for irritability in autistic children and adolescents (FDA Press Release 2006 Oct 6)
    • in United Kingdom, application for risperidone approval for treatment of irritability in autism was withdrawn by manufacturer after considering conditions of approval (BMJ 2007 May 26;334(7603):1069)
    • risperidone more effective than placebo in 3 randomized trials of patients with pervasive developmental disorder (Ann Gen Hosp Psychiatry 2004 Feb 18;3:4 full-text)
    • risperidone improved irritability and other behavioral symptoms in randomized placebo-controlled trial of 79 children aged 5-12 years with pervasive developmental disorder (Pediatrics 2004 Nov;114(5):e634 full-text), commentary can be found in Pediatrics 2005 May;115(5):1447
    • risperidone reduces serious behavioral problems in short-term trial; 101 children ages 5-17 years with autistic disorder and severe tantrums, aggression or self-injurious behavior were randomized to risperidone 0.5-3.5 mg/day vs. placebo for 8 weeks; primary outcome was Irritability subscale of Aberrant Behavior Checklist, Irritability score was reduced by 57% with risperidone vs. by 14% with placebo; positive response (at least 25% decrease PLUS much improved or very much improved rating on Clinical Global Impressions-Improvement scale) reported in 69% vs. 12% (p < 0.001, NNT 2); much improved or very much improved rating clearly more likely with risperidone, reported in < 15% placebo patients throughout 8-week trial while this outcome reached in risperidone group by 30-40% at 2 weeks, 50-60% at 3 weeks and 75.5% at 8 weeks; mean weight gain 2.7 kg vs. 0.8 kg (p < 0.001); significant adverse effects were increased appetite, fatigue, drowsiness, dizziness, drooling (N Engl J Med 2002 Aug 1;347(5):314), editorial can be found in N Engl J Med 2002 Aug 1;347(5):302 (correction can be found in N Engl J Med 2003 Sep 4;349(10):1010), commentary can be found in POEMs in J Fam Pract 2002 Nov;51(11):915, commentary can be found in N Engl J Med 2002 Dec 5;347(23):1890, summary can be found in Am Fam Physician 2003 Feb 1;67(3):610, commentary can be found in Evidence-Based Medicine 2003 Jan-Feb;8(1):22
    • discontinuation of risperidone associated with relapse (level 2 [mid-level] evidence)
    • AHRQ evidence review of benefits and harms of atypical antipsychotics in autism
      • potential benefits
      • potential harms
        • atypical antipsychotics associated with small but significant increased mortality in placebo-controlled trials in dementia patients
        • risperidone and olanzapine associated with small but significant increased risk for stroke in placebo-controlled trials in dementia patients
        • risperidone, olanzapine and aripiprazole associated with increased risk for neurological side effects (fatigue, headaches, dizziness) in placebo-controlled trials
        • insufficient evidence comparing atypical antipsychotics with each other or other active controls for the above outcomes, insufficient evidence regarding other cardiovascular side effects
        • extrapyramidal symptoms
        • sedation more common with atypical antipsychotics than placebo, and more common with olanzapine than mood stabilizers
        • weight gain more common with olanzapine than placebo, conventional antipsychotics and other atypical antipsychotics; weight gain more common with risperidone than placebo
      • Reference - AHRQ Effective Health Care report 2007 Jan 17:6 PDF
  • medications which may be beneficial but evidence extremely limited
    • galantamine may be modestly effective; 20 boys (mean age 7.4 years, mean IQ 68) with autistic disorder unsuccessfully treated by multiple drugs were randomized to galantamine vs. placebo in double-blind crossover trial; no significant differences in clinicians' scores of videotaped sessions; mean combined parent and teacher scores were slightly but significantly lower for galantamine than placebo on ratings of aberrant behavior checklist, hyperactivity, inadequate eye contact, and inappropriate speech (BMJ 2002 Dec 14;325(7377):1422)
    • fluvoxamine may be useful in adults, based on trial in 30 patients (Arch Gen Psychiatry 1996 Nov;53(11):1001 in Am Fam Physician 1997 Mar;55(4):1375
    • famotidine (Pepcid) use being researched in doses of 2 mg/kg/day up to 100 mg/day, researchers noted that famotidine seems to improve withdrawal + other negative symptoms of schizophrenia (Prescriber's Letter 1999 Nov;6(11):65)
    • amantadine reported to be associated with some improvement; 39 patients 5-19 with autism and IQ > 35 given placebo for 1-week, then amantadine 2.5 mg/kg vs. placebo once daily for 1 week, then amantadine 2.5 mg/kg vs. placebo twice daily for 3 weeks; no significant difference in Aberrant Behavior Checklist-Community Version but significant improvement in clinician-rated subscales for hyperactivity and inappropriate speech, parents did not report significant differences (J Am Acad Child Adolesc Psychiatry 2001 Jun;40(6):658 in Pediatric Notes 2001 Jul 5;25(27):107); no convincing benefit, this may be an underpowered negative trial with a few statistically significant measurements being reported as a benefit (DynaMed commentary)
    • antioxidants reported to be associated with improvements in some behavior scores in single double-blind trials of high-dose vitamin C (Prog Neuro-Psychopharmacol Biol Psychiatr 1993;17:765), L-carnosine (J Child Neurol 2002 Nov;17(11):833), vitamin B6 (Am J Psychiatry 1978 Apr;135(4):472), vitamin B6 plus magnesium (Biol Psychiatry 1985 May;20(5):467, J Autism Dev Disord 1981 Jun;11(2):219) (Altern Ther Health Med 2004 Nov-Dec;10(6):22)
  • methylphenidate may be effective for treating hyperactivity associated with pervasive developmental disorders, but magnitude of response less than that seen in developmentally normal children with ADHD
    • randomized placebo-controlled crossover trial with 72 drug-free children aged 5-14 years with pervasive developmental disorders and moderate to severe hyperactivity
    • adverse effects led to discontinuation of study medication in 13 of 72 (18%) children
    • Reference - Arch Gen Psychiatry 2005 Nov;62(11):1266
  • medications demonstrated to be ineffective
    • vitamin B6 and magnesium -- no reliable evidence to suggest benefit
      • systematic review found 3 randomized trials with 33 patients
      • 1 crossover trial provided insufficient data for analysis
      • high-dose pyridoxine and magnesium not significantly better than placebo in 10-week randomized trial of 12 patients with autism (J Autism Dev Disord 1997 Aug;27(4):467)
      • 1 trial with only 8 children with features similar to pyrodoxine-dependent epilepsy reported statistically significant benefit for IQ change scores
      • Reference - systematic review last updated 2005 Aug 9 (Cochrane Library 2005 Issue 4:CD003497)
    • secretin not effective
      • IV secretin (single or multiple dose) not effective for autism (level 1 [likely reliable] evidence); systematic review of 14 randomized placebo-controlled trials of IV secretin in children or adults with autistic spectrum disorders; no significant differences in 25 outcome measures covering core features of autism, communication, behavior, visio-spatial skills, affect and adverse events; systematic review last updated 2005 May 24 (Cochrane Library 2005 Issue 3:CD003495)
      • neither porcine nor synthetic secretin improved autism symptoms compared to placebo in randomized trial of 85 children (J Am Acad Child Adolesc Psychiatry 2002 Nov;41(11):1315 in JAMA 2003 Feb 26;289(8):966)
      • synthetic human secretin 0.4 mcg/kg IV once NOT effective in saline placebo-controlled randomized trial of 56 children 3-14 with autism or pervasive developmental disorder; trial conducted due to publicity of 1 child with autism who improved after single dose of secretin, 69% parents remained interested in secretin even after informed of trial results (N Engl J Med 1999 Dec 9;341(24):1801), editorial can be found in N Engl J Med 1999 Dec 9;341(24):1842, commentary can be found in N Engl J Med 2000 Apr 20;342(16):1216
      • synthetic human secretin 2 CU/kg IV once NOT effective in randomized placebo-controlled crossover trial with 62 children ages 3-8 years with autism spectrum disorder, no differences in behavior or communication (Arch Dis Child 2003 Aug;88(8):731 in BMJ 2003 Sep 13;327(7415):583)
      • porcine secretin in 2 doses 6 weeks apart NOT effective in placebo-controlled trial of 64 children 2-7 with autism (Pediatrics 2001 May;107(5):e71)
      • secretin IV NOT effective in 5-week prospective uncontrolled open-label trial of 20 children with autism and gastrointestinal symptoms (Pediatrics 2001 Nov;108(5):e90)
      • secretin granted FDA "fast track" status for treating pediatric autism (Monthly Prescribing Reference 2001 Nov:A-18)
    • dimethylglycine not effective
      • N,N-dimethylglycine NOT significantly more effective than placebo in 4-week randomized trial of 37 children ages 3-11 years with autism or pervasive development disorder (J Child Neurol 2001 Mar;16(3):169)
      • dimethylglycine for 1 month NOT significantly more effective than placebo in randomized crossover trial of 8 autistic males ages 5-31 years (J Autism Dev Disord 1999 Jun;29(3):191)

Other management :

  • auditory integration training and facilitative communication therapies not recommended (grade C recommendation [lacking direct evidence])
    • AAP Committee on Children With Disabilities review found current data does not support claims of efficacy, recommended use only within research protocols (Pediatrics 1998 Aug;102(2):431)
    • insufficient evidence regarding auditory integration training or other sound therapies for autistic spectrum disorder; existing evidence is limited by very small studies, poor methodology and inconsistent outcomes; systematic review last updated 2003 Sep 9 (Cochrane Library 2004 Issue 1:CD003681)
  • insufficient evidence regarding parent-mediated interventions for children 1-7 years old with autistic spectrum disorders; 1 small trial favored parent training for child language and maternal knowledge of autism, 1 small trial suggested better child outcomes on direct measurement with intensive professional-delivered intervention over parent-mediated early intervention but no differences in perceptions of parents and teachers; systematic review last updated 2002 Jan 29 (Cochrane Library 2003 Issue 1:CD003496)
    • social communication treatment associated with improved communication in pilot trial (level 2 [mid-level] evidence); 28 children with autism randomized to intervention vs. routine care; intervention group had series of parental psychoeducational workshops then monthly treatment sessions for 6 months then less frequent treatment sessions for another 6 months, treatment sessions included therapist review of videotaped parent-child play and planned changes to parent interaction and communication responses, parents asked to spend 30 minutes daily alone with child at home to practice these strategies; no dropouts after treatment started; intervention group had significant improvement in Autism Diagnostic Observation Schedule (especially reciprocal social interaction), expressive language, communicative initiation and parent-child interaction (J Child Psychol Psychiatr 2004 Nov;45(8):1420 in Pediatric Notes 2005 Jan 13;29(2):7)
  • music therapy may help children with autistic spectrum disorder to improve their communicative skills (level 2 [mid-level] evidence)
    • systematic review of 3 controlled trials with 24 autistic children
    • brief music therapy interventions (daily sessions over one week) associated with improved verbal communicative skills (2 trials with 20 patients) and improved gestural communicative skills (2 trials with 20 patients)
    • no significant effects on behavioral problems
    • Reference - systematic review last updated 2006 Jan 29 (Cochrane Library 2006 Issue 2:CD004381)
  • no randomized trials of chelation therapy for autism found in MEDLINE search, case report of fatality upon using chelation with inappropriate agent (BMJ 2006 Oct 7;333(7571):756)
  • review of occupational therapy interventions for autism can be found in Am J Occup Ther 2008 Jul-Aug;62(4):416

Prevention and Screening

Screening :

  • screening instrument for autism has been tested at age 18 months
    • 16,235 children aged 18 months screened using Checklist for Autism in Toddlers (CHAT) and followed up at age 7 years
    • CHAT consisted of brief checklist assessing joint attention and pretend play behaviors, initial CHAT screening done by primary care provider, repeated screening by research team done 1 month later if initial screening was positive
    • 50 cases of childhood autism occurred, 19 were identified by CHAT at 18 months so test characteristics were 38% sensitivity, 98% specificity, 6% positive predictive value and 99.8% negative predictive value
    • repeated screening 1 month later increased positive predictive value to 75% but reduced sensitivity to 20%
    • Reference - J Am Acad Child Adolesc Psychiatry 2000 Jun;39(6):694 in E Resident Psychiatry Journal Watch 2000 Jun;1(2)
    • screening can not be supported by this study alone, not clear that benefit will be achieved by early diagnosis, potential for considerable harm among 94% false positives with 1 screen and 25% false positives with 2 screens, screening not likely to be cost-effective (DynaMed commentary)
  • discussion of improved performance of CHAT with repeat testing at 18 months, better performance with modified CHAT (M-CHAT), and study of additional modifications (CHAT-23) with translation and use in Chinese population can be found in Pediatrics 2004 Aug;114(2):e166 full-text
  • unusual slowing in performance at age 14-24 months associated with autism spectrum disorder in prospective study of 87 infants (J Child Psychol Psychiatry 2006 Jun;47(6):629)
  • failure to response to name by age 12 months suggests developmental abnormality
    • prospective study of 156 infants at risk for autism (55 age 6 months, 101 age 12 months) and 89 controls (43 age 6 months, 46 age 12 months)
    • 46 at-risk infants and 25 control infants followed to age 24 months
    • trend for control infants to require fewer calls to respond to name at age 6 months
    • at age 12 months
      • 100% control infants responded to name on first or second name call
      • 86% at-risk infants responded to name on first or second name call
      • 2/3 infants who did not respond had developmental problems at age 24 months
      • failing to respond to name had 50% sensitivity and 89% specificity for autistic spectrum disorder
      • failing to response to name had 39% sensitivity and 94% specificity for developmental delay
    • Reference - Arch Pediatr Adolesc Med 2007 Apr;161(4):378

References including Reviews and Guidelines

Reviews :

Guidelines :

Patient Information

Patient information :