Autism: A Developmental Pediatric Perspective

From Pediatrics Update 2009, presented by Phoenix Children’s Hospital

Raun D. Melmed, MD, Medical Director, Southwest Autism Research and Resource Center, Phoenix, AZ, and Director, Melmed Center, Scottsdale, AZ

Epidemiology

Educational objectives

The goal of this program is to improve diagnosis and treatment of children with autism. After hearing and assimilat­ing this program, the clinician will be better able to:

1.   Identify the social, behavioral, and communicative impairments that are exhibited in autism.

2.   Describe the various autism spectrum disorders (ASDs) and the signs and symptoms that characterize each.

3.   Explain current evidence for the genetic etiology of autism.

4.   Effectively screen and diagnose children with ASD.

5.   List treatment options for children with autism, including behavioral and psychopharmacologic approaches.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Melmed has received research support from or has been on the Speakers’ Bureau of Shire Pharmaceuticals, Eli Lilly, McNeil Phar­maceuticals, Bristol-Myers Squibb, Novartis, and Neuropharm. The planning committee reported nothing to disclose. In his lecture, Dr. Melmed presents information that is related to the off-label or investigational use of a therapy, product, or de­vice.

Acknowledgments

Dr. Melmed spoke in Phoenix, AZ, at 32nd Annual Pediatric Update, presented March 2-5, 2009, by the Phoenix Children’s Hospital. The Audio-Digest Foundation thanks Dr. Melmed and the Phoenix Children’s Hospital for their cooperation in the production of this program.

Background: In 1964, Rimland introduced concept that autism had neurobiologic basis (not caused by “refrigerator mother”); Brazelton and others concluded children different from adults and from one another; Brazelton devel­oped Newborn Behavioral Assessment Scale; autism not single disease; children with autism different from each other

Pervasive developmental disorder (PDD): older umbrella term; now referred to as autism spectrum disorders (ASD), including autistic disorder, Asperger disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), Rett syndrome, and childhood integrative disorder

PDD not otherwise specified: atypical presentation with subthreshold symptoms; diagnosis does not give patient el­igibility for public funding; Diagnostic and Statistical Manual of Mental Disorders, (Fourth Edition) [DSM-IV] re­cently revised to stipulate that patient must have impairment in reciprocal social interaction; impairment in communication and presence of stereotypic behavior not essential

Asperger disorder: criteria for autism include impairments in social functioning, behavior, and communication; As­perger criteria same, but without language component; independent evaluators have difficulty agreeing on diagno­sis of PDD-NOS vs autism or Asperger disorder; good agreement differentiating patients with PDD from those without PDD

Rett syndrome: typically affects girls (»99%); MECP2 gene implicated in »80% of patients; babies develop nor­mally for 1 to 2 yr, then show rapid regression; abnormal electroencephalography (EEG) and unusual respiratory symptoms (eg, hyperventilation, aerophagia); stationary period during teen years followed by motor regression or deterioration; prevalence in general population varies from 1 to 3 per 1000; recent study of mice treated with pep­tide fragment of insulin-like growth factor-1 caused reversal of some symptoms; clinical trials to begin this year

Incidence: according to the Centers for Disease Control and Prevention (CDC), 1 in 150 currently diagnosed with au­tism; half diagnosed with PDD-NOS, one-third with autistic disorder, remainder with Asperger disorder; in last 20 years, 400% increase in number of cases diagnosed; ratio of boys to girls, 4 to 1; in children with severe mental re­tardation, boy to girl ratio 2 to 1; girls appear to be protected in utero, but exhibit more severe autistic symptomatol­ogy after protective barrier breaks down; girls more likely to have seizure disorder

Reasons for increased incidence: DSM-I  —  listed no pediatric psychiatric disorders; therefore, incidences in chil­dren of every psychiatric condition show dramatic increases; perceptions of parents  —  two-thirds of parents with autistic child report noticing “something different” in child by 1 to 2 mo of age; remaining one-third of children di­agnosed later developed appropriately for 15 mo to 2 yr; these children have regressive or late-onset autism; parents look at other occurrences around time of regression (eg, vaccination, otitis media, changes in diet) and suspect link to onset of autism; in blinded studies, children who later regressed could be accurately predicted based on video from birthday party at age 1; children who do regress often verbally advanced and considered gifted by parents be­fore regression; changes in diagnostic criteria  —  in California, number of children diagnosed with mental retarda­tion steadily decreasing while number diagnosed with ASD steadily increasing; public awareness and education  —greatly increased in recent years; availability of services  —limited services for children with diagnosis of intellec­tual disability, while those with diagnosis of autistic disorder eligible for considerable services; true increase in occurrence  —  possibly exists due to, eg, exposure to neurotoxins in environment; Mind Institute study  —  rising prevalence in California, despite controlling for various factors (reason unclear)

Signs and Symptoms

Criteria: neurobiologic disorder diagnosed using behavioral criteria; diagnostic tests based on metabolic and/or pre­dictive markers not yet available; diagnosis still relies on observed impairment in social interaction and verbal and nonverbal communication and restricted patterns of behavior

Socialization: even at 2 mo of age, babies later diagnosed showed lack of engagement with mother; “look through” other children; have trouble sharing; do not discern thoughts and feelings of others; lack joint attention

Communication: early evidence of abnormal communication; »50% of children with autistic disorder remain non­verbal; extreme difficulty with questions beginning with when, why, or where; nonverbal communication also impaired (distinguishes children with ASD from those with hearing impairment); context-specific language; echolalia  —repeating or mimicking words and movements; worse under pressure; children may speak with for­eign accents not shared by parents

Joint attention: capacity to visually coordinate attention with partner to external focus; linked to specific develop­mental pathway; 10- to 12-mo-old baby with autism has difficulty following trajectory of pointed finger (will look at fingertip instead of object being indicated); at 12 to 14 mo, instead of pointing to request something, au­tistic children will take mother’s hand and lead her to object; autistic children cannot perceive perspective of someone outside of themselves (lack theory of mind)

Autism Genetics

Genetic etiology: based on twin studies; monozygotic twins have 30% concordance rate, dizygotic twins <10% con­cordance; individuals in monozygotic pairs who had broader autism phenotype (showing symptoms of autism but not quite meeting autism criteria) had 90% concordance, while dizygotic twins still <10%; multiple malforma­tion syndrome, including chromosomal abnormalities and disorders associated with single genes and teratogens seen in 5% to 10% of autism population; 90% to 95% of autism seen in structurally normal children; spontaneous copy number variations seen in 10% to 20%

Reelin (RELN) gene: strongest candidate gene for autism; seen in structurally normal children; 20% of probands carry long allele of this gene

Phosphatase and tensin homolog (PTEN) gene: helps prevent uncontrolled cell growth; mutations associated with Bannayan-Riley-Ruvalcaba syndrome; macrocephaly most common dysmorphic feature in children with autism (seen in 20%); population with macrocephaly has high rate of mutation of PTEN gene; functions as suppressor gene, so mutation places children at increased risk for malignant gastrointestinal tumors

Screening and Diagnosis

Screening: Southwest Autism Research and Resource Center (SAARC) offers kit featuring developmental surveil­lance and autism-specific screening tools; barriers to screening  —  physicians think “I will know it when I see it”; only 30% of children with autism identified by primary care physicians; SAARC kit offered free of charge

Absolute indicators: no babbling by 12 mo; no pointing or gesturing by 12 mo; no single words by 16 mo; no 2-word spontaneous (nonecholalic) phrases by 24 mo; any regression of language or social skills

Tools for diagnostic evaluation: Child Autism Rating Scale (CARS) acceptable, although it relies heavily on paren­tal reporting and physician observation; qualification via Autism Diagnostic Observation Scale (ADOS) or Autism Diagnostic Inventory (ADI) required for research purposes; Leiter Individual Performance Scales  —  test of nonver­bal intelligence; as many children with autism score high, helpful for parents in preventing teachers from placing “glass ceiling” over their children

Physical examination (PE): many areas to evaluate; use Woods lamp for diagnosis of tuberous sclerosis; macroceph­aly seen in 20% of children with autism; slightly microcephalic at birth, followed by period of accelerating growth between 2 and 3 yr of age, which results in gross macrocephaly; deceleration of growth then occurs (no longer macrocephalic as adults)

Laboratory analyses: microarray comparative genomic hybridization  —  replacing high-resolution chromosomal analysis (HRCA); identifies more disorders, including subtle issues; will ultimately be less expensive than HRCA; does not identify Fragile X or MECP2 gene (require DNA probes); lead and thyroid hormone levels still controver­sial; standard work-up plus others as suggested by history and PE; mitochondrial issues  —  no current accurate means of early identification

Red flags for metabolic work-up: seizures; failure to thrive; dysmorphism factors; poor endurance; significantly de­layed milestones; “staccato” regression (repeating pattern of regression followed by improvement); qualitative dif­ferences; multiple organ system involvement; presence of acidosis, hyperuricemia, or elevated ammonia levels

Symptoms as signs of other diseases: in child with autism, other diagnoses often missed because behavior related to medical condition attributed to autism (eg, head-banging found to be related to tooth pain, improvement in toe-walking after treatment of constipation); speaker cautions physicians to regard patients as “kids first, who happen to have autism”

Comorbidities: many associated with autism; attention-deficit/hyperactivity disorder (ADHD); learning deficits; anxiety disorders; seizure disorders

Seizure disorders: present in £30% of children with autism; generally manifest at 2 to 3 yr of age, but another sub­set develops seizures during adolescence; 40% to 50% of children with autism have abnormal electroencephalog­raphy (EEG) patterns without spike and wave phenomena (controversial whether these children should receive treatment for seizures); subclinical signs  —  diminished responsiveness; unexplained regression; worsening be­havior; diagnosis requires 24-hr EEG

Gastrointestinal (GI) issues: active area of research; anecdotal evidence that gluten-free casein-free (GFCF) diet has effect on behavior; physicians should monitor children on GFCF diet for nutritional deficiencies; delineate treatment outcome goals to help determine whether diet beneficial; double-blind placebo-controlled studies of secretin showed no effect; oral g-globulin showed no effect on autism or GI symptoms

Sleep challenges: common in children with ASD; has huge impact on family and child’s functioning; some have low levels of melatonin; speaker considers trial of melatonin safe; sleep is learned behavior; children with autism may not perceive signs that time for sleep approaching; essential to establish sleep hygiene routine early

Educational Programs

Behavioral techniques: applied behavioral analysis (ABA)  —popularized by Lovaas; specific behaviors identified and reinforced; viewed negatively by some due to early use of aversive techniques (not recommended today); floortime  —technique developed by Greenspan; more user-friendly, but not as well-supported by research studies; pivotal response treatment  —  ABA technique done in naturalistic environment; utilizes principles from floortime

Social stories: technique for teaching social rules and cues; provides children with management for social situations

Picture exchange communication: encourages nonverbal and verbal exchange; parents often fear technique will hinder oral language development; however, opposite has been demonstrated (encourages language by allowing children to appreciate advantages of increased communication)

Parental and sibling support: calm comfortable mother most important determinant of outcome; depressed mother has most significant negative effect on outcome, considering almost all other risk factors; identifying stress, anxi­ety, and depression in mothers essential; fathers have varying responses (may have fewer outlets for feelings about difficulties with child); impact on siblings also significant

Psychopharmacology

Stimulants: used to treat comorbid ADHD; myth that children with ASD do not respond; use lower dosages; atom­oxetine also possibly helpful

Selective serotonin reuptake inhibitors: speaker has not seen great benefit; recent study by speaker showed fluox­etine failed to reduce repetitive behaviors

Risperidone (eg, Risperdal): Food and Drug Administration-approved; several studies show reduction of aggressive behaviors and irritability in children with autism; speaker has ongoing trial using dosages significantly lower than those in package insert (cites fewer adverse effects, better tolerability, and better outcomes in general with lower dosages)

a-agonists: studies show benefit of treatment with clonidine and guanfacine

Nutraceuticals: potentially harmful or invasive products of concern; important to build bridges between alternative and mainstream medicine; majority of parents rely on physicians unaffiliated with American Academy of Pediat­rics for care of children with autism; need to regain confidence and work in complement with alternative practitio­ners; National Academy of Pediatrics has put together several task forces to facilitate cooperation; electing to have children with autism treated by alternative practitioners results in failure to immunize, lack of nutritional oversight, and lack of support for families

Resources

Southwest Autism Research & Resource Center: www.autismcenter.org.

Suggested Reading

Aman MG et al: Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. J Am Acad Child Adolesc Psychiatry 48:1143, 2009; Buxbaum JD et al: Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet B Neu­ropsychiatr Genet 144:484, 2007; Correia CT et al: Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J 8 Dec 2009; Greenspan, SI and Weider S: Engaging Autism: Using the Floortime Approach to Help Children Relate, Communicate, and Think. Perseus Books, 2003; Grice et al: The genetics of autism spectrum disorders. Neuromolecular Med 8:451, 2006; Hertz-Picciotto I et al: The rise in autism and the role of age at diagnosis. Epidemiology 20:84 2009; Johnson CP et al: Identification and evaluation of children with autism spectrum disorders. Pediatrics 120:1183, 2007; Lovaas, OI: Behavioral treatment and normal educational and intellectual functioning in young children with autism. Journal of Consulting and Clinical Psychology 55:3, 1987; Koegel, LK et al: Pivotal response intervention I: Overview of approach. Journal of the Association for Persons with Severe Handi­caps, 24:174, 1999; Krakowiak P et al: Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study. J Sleep Res 17:197 2008; Levy et al: Autism. Lancet 374:1627 2009; Lin­tas C et al: Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 46:1 2008; Ozonoff S et al: The onset of autism: patterns of symptom emergence in the first years of life. Autism Res 1:320 2008; Windham GC et al: Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay Area. Environ Health Perspect 114:1438 2006; Wirojanan J et al: The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J Clin Sleep Med 5:145 2009.