DIAGNOSIS AND MEDICAL EVALUATION OF CHILDREN WITH AUTISM SPECTRUM DISORDERS

DIAGNOSIS AND MEDICAL EVALUATION OF CHILDREN WITH AUTISM SPECTRUM DISORDERS Frank Aiello, M.D. Assistant Professor of Pediatrics EVMS, CHKD Children’s Specialty Group

Autism Spectrum Disorders: Pretest • The 3 fundamental characteristics of all autism spectrum disorders are: • Qualitative impairments in reciprocal social interaction • Abnormal verbal and nonverbal communication, and • Choose the best answer from these: • Obsessive compulsive disorder • Echolalia • Restricted, repetitive, stereotyped pattern of interests and behavior • Self stimulatory behaviors • Which of the following statements about Asperger Syndrome is NOT TRUE: • Is often associated with a narrow range of interests or preoccupation • Is associated with the presence of mental retardation • Is characterized by normal early language development • Is sometimes associated with the presence of an anxiety disorder • In order to best guide treatment, it is important to identify the specific autism subtype for each affected child. • True • False

DIAGNOSIS OF AUTISM SPECTRUM DISORDERS • Background, neurobiology and epidemiology • Diagnosis • Diagnostic criteria • ASD subtypes • Clinical symptoms in young children • Medical work-up • Outcome • Summary

“Since 1938, there have come to our attention a number of children whose condition differs so markedly and uniquely from anything reported so far, that each case merits-and, I hope, will eventually receive-a detailed consideration of its fascinating peculiarities.” Kanner L, “Autistic Disturbances of Affective Contact,” Nervous Child 2 (1943): 217-250.

AUTISM SPECTRUM DISORDERS • Autistic Spectrum Disorder = Pervasive Developmental Disorders • A heterogeneous group of behavioral syndromes…not a disease • Indistinct end points, especially at the mild end of the spectrum • A static (in most) encephalopathy Rapin, 1991 • Etiology unknown in vast majority, identifiable in only a small minority • Milder forms more common than classic Autism

ASD NEUROBIOLOGY • Abnormal intrahemispheric connectivity • Postulated interhemispheric connectivity abnormality • Minicolumns, radially oriented neuronal arrays believed to be the smallest unit of cortical information processing, are increased in number, narrower in width and with smaller neuronal cell bodies • Mirror neuron dysfunction: active during observation, imitation and understanding the intention of others. When acting in conjunction with the limbic system mediates understanding of the emotional state of others (empathy), “might be the core of the social and emotional deficit of autism” • Common theme regardless of severity: impaired cortical connectivity and information processing capacity Minshew NJ, Williams DL. The New Neurobiology of Autism. Arch Neurol, 2007; 64(7):945-950.

ASD CANDIDATE GENES • MET: 7q31, encodes a protein involved in neuronal growth and organization • SLC6A4: encodes a protein involved in serotonin re-uptake • RELN: 7q22, encodes a protein that controls intercellular interactions involved in neuronal migration and positioning in brain development • Tumor Suppressor Genes: PTEN, TSC1, TSC2: prevent uncontrolled cell growth and division • Neuroligins, Neurexins: encode proteins which effect synaptic maturation and function

ASD: EPIDEMIOLOGY • Overall prevalence of ASD’s estimated presently at 1/150 • Studies report rates varying from 5/10,000 to 73/10,000 (1/150) • Prevalence of Asperger Syndrome • Estimated at 10/10,000 • Reported rates vary from 0.3/10,000 to 48/10,000 (1/200) • Prevalence of PDD-NOS, 33/10,000 • Male:Female 4:1 *Fombonne, et al. Child and Adolescent Psychiatric Clinics of North America. 12:1, January 2003

ASD: EPIDEMIOLOGY • Over 1.5 million Americans are affected by an ASD • U.S. rate of growth over the last decade:Population: 13%Non-autism-related disabilities: 16%Autism Spectrum Disorder: 173% • Why this increase? • Broadening of the diagnostic criteria, diagnostic substitution • Rates have risen regardless of immunization status or exposure to thimerosal • Although no environmental factors identified, this is an area of concern • Inheritability for ASDs > ADHD, Bipolar, Height • Genetic and epigenetic mechanisms

Genetics of Idiopathic ASDs • Twin studies: Concordance rates • Monozygotic twins 70%-90% • Dizygotic twins 0-10% • Family studies: recurrence risk • For a couple with 1 affected child, recurrence risk for subsequent children is 5%-10%

ASD: Virginia Public School Systems Children Enrolled and LABELED with Autism Spectrum Disorder Ages 3 to 22. December 1, 1998 - 1521 December 1, 1999 - 1953 December 1, 2000 - 2226 December 1, 2001 - 2710 December 1, 2002 - 3350 December 1, 2003 - 4420 December 1, 2004 - 5179 December 1, 2005 - 5968 December 1, 2006 - 6753 December 1, 2007 - 7854 Compiled By The Autism Program of Virginia using VA Dept. of Education official figures. www.autismva.org

Peter Hotez: “The hardest part about taking care of an autistic child is that you really are alone.” From: Offit, Paul A, Autism’s False Prophets: bad science, risky medicine, and the search for a cure. Columbia University Press, 2008, pg227.

There are 5 separate DSM-IV TR diagnostic entities under the umbrella of PDD • Autistic Disorder • Asperger Syndrome • Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) 4. Rett Syndrome 5. Childhood Disintegrative Disorder

THREE FUNDAMENTAL CHARACTERISTICS OF ALL AUTISM SPECTRUM DISORDERS • Qualitative impairments in reciprocal social interactions • Abnormality of verbal and nonverbal communication and imaginative activity • Restricted, repetitive and stereotyped pattern of interests and behaviors “There is no single behavior or symptom which can either rule-in or rule-out an autism spectrum disorder” National Research Council (2001) Educating Children with Autism.

DSM-IV TR DIAGNOSTIC CRITERIA FORAUTISM & ASPERGER SYNDROME-1 A. Qualitative impairment in social interaction, as manifested by at least two of the following: (1) marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction (2) failure to develop peer relationships appropriate to developmental level (3) a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest to other people) (Joint Attention) (4) lack of social or emotional reciprocity (Mirror Neurons)

DSM-IV TR DIAGNOSTIC CRITERIA FOR AUTISM & ASPERGER SYNDROME-2 B. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: (1) encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus (2) apparently inflexible adherence to specific, nonfunctional routines or rituals (3) stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) (4) persistent preoccupation with parts of objects

DSM-IV TR DIAGNOSTIC CRITERIA FOR AUTISM-3 C. Abnormality of verbal and nonverbal communication & imaginative activity, at least one of the following: (1) Delay in, or total lack of, the development of spoken language (not accompanied by attempts to communicate through gesture) (2) Marked impairment in the ability to initiate or sustain a conversation (3) Stereotyped and repetitive use of language or idiosyncratic language (4) Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level

DSM-IV TR DIAGNOSTIC CRITERIA FOR ASPERGER SYNDROME-3 C. The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning. D. There is no clinically significant general delay in language (e.g., single words used by age 2 years, communicative phrases used by age 3 years). E. There is no clinically significant delay in cognitive development or in the development of age-appropriate self-help skills, adaptive behavior (other than in social interaction), and curiosity about the environment in childhood. F. Criteria are not met for another specific Pervasive Developmental Disorder or Schizophrenia.

ICD-10 RESEARCH DIAGNOSTIC GUIDELINES FOR ASPERGER SYNDROME • There is no clinically significant general delay in spoken or receptive language or cognitive development. Diagnosis requires that single words should have developed by 2 years of age or earlier and that communicative phrases be used by 3 years of age or earlier. Self-help skills, adaptive behavior, and curiosity about the environment during the first 3 years should be at a level consistent with normal intellectual development. However, motor milestones may be somewhat delayed and motor clumsiness is usual (although not a necessary diagnostic feature). Isolated special skills, often related to abnormal preoccupations, are common, but are not required for the diagnosis.

ICD-10 RESEARCH DIAGNOSTIC GUIDELINES FOR ASPERGER SYNDROME • There are qualitative abnormalities in reciprocal social interaction (criteria for autism) • The individual exhibits an unusually intense circumscribed interest or restricted, repetitive, and stereotyped patterns of behavior interests and activities (criteria for autism; however, it would be less usual for these to include either motor mannerisms or preoccupations with part-objects or nonfunctional elements of play materials.)

ICD-10 RESEARCH DIAGNOSTIC GUIDELINES FOR ASPERGER SYNDROME • The disorder is not attributable to other varieties of pervasive developmental disorder; simple schizophrenia, schizotypal disorder, obsessive-compulsive disorder, anakastic personality disorder, reactive and disinhibited attachment disorders of childhood.

PERVASIVE DEVELOPMENTAL DISORDER NOT OTHERWISE SPECIFIED “Use when there is severe and pervasive impairment in the development of reciprocal social interaction, of verbal and nonverbal communication skills, or when stereotyped behavior, interests and activities are present, but the criteria are not met for a specific Pervasive Developmental Disorder, Schizophrenia, Schizotypal Personality disorder, or Avoidant Personality Disorder.”

Asperger Syndrome Vs. High Functioning Autism • Do Asperger Syndrome and High Functioning Autism represent points along a continuum of severity in the spectrum of autism? Or, is Asperger Syndrome a distinct entity, within the family of autism spectrum disorders, not simply “a milder form of autism”? • Are there neurobiological differences? • Are there distinct neuropsychological profiles? • Is there a difference in outcomes? • Is there a difference in comorbid conditions?

AS: A Few Final Points • Asperger syndrome is not just mild autism symptoms or “autistic tendencies” • Asperger syndrome is not mood disorder symptoms associated with social skills problems • Asperger syndrome patients cannot have mental retardation • Asperger syndrome patients cannot have clinically apparent speech delay • Asperger syndrome patients do have pragmatic communication impairments and may have prosodic speech abnormality

At our current level of knowledge and understanding, the early recognition of the presence of an autism spectrum disorder and subsequent characterization of that person’s individual profile of strengths and weaknesses has clearly established benefits. Determining which subtype of ASD the person has is of utility primarily to researchers and scientists. National Research Council (2001) Educating Children with Autism. Committee on Educational Interventions for Children with Autism. Catherine Lord and James P. McGee, eds. Division of Behavioral and Social Sciences and Education. Washington, DC: National Academy Press. www.nap.edu

Early Communication Deficits • Abnormal to and fro mother/infant vocalizations at 5-6 months • Babbling that does not increase in complexity • Failure to respond to name (to environ>>social) • Greater proportion of syllables with atypical phonation (e.g. squeals, growls, and yells) • Delayed receptive and expressive language milestones • Delayed and decreased use of gestures • Conventional gestures (e.g., showing, waving, pointing) • Symbolic gestures (e.g., nodding head, depicting actions) • Mostly primitive motoric gestures to communicate (e.g., contact gesture of leading or pulling another’s hand, instrumental communication) Myers SM. “Autism Spectrum Disorders: Important Issues and New Resources.” Lecture delivered at DB:PREP An Intensive Review of Developmental-Behavioral Pediatrics sponsored by the American Academy of Pediatrics. December 5, 2008 Atlanta, GA.

Early Communication Deficits • Increased idiosyncratic or inappropriate means of communication • Self-injurious behavior, aggression, tantrums • Echolalia • Immediate (e.g., response to questions) • Delayed (scripted verses, reciting memorized dialogue) • Implies impaired comprehension • Pronominal reversal (often, “you” for “I” or “me”) • Inconsistent use of words- “pop-up” words • Labeling skills>>functional language • Appearance of expressive>receptive skills, but not functional • Hyperlexia- early, self-taught decoding of written language Myers SM. “Autism Spectrum Disorders: Important Issues and New Resources.” Lecture delivered at DB:PREP An Intensive Review of Developmental-Behavioral Pediatrics sponsored by the American Academy of Pediatrics. December 5, 2008 Atlanta, GA.

Symbolic Communication: 18-24 Months • 9 factors that differentiate ASD groups from DD groups and TD groups • Lack of appropriate gaze • Lack of warm, joyful expressions with gaze • Lack of sharing interest or enjoyment • Lack of response to name • Lack of coordination of gaze, facial expression, gesture and vocalization • Lack of showing • Unusual prosody • Repetitive movements or posturing of body • Repetitive movements with objects (Wetherby A et al. JAAD 2004:34:473-493) • 5 Social communication measures separate those with ASD from DD group matched for age and developmental level: • Gaze shifts • Gaze-point follow • Rate of communicating • Acts for joint attention • Inventory of conventional gestures (Wetherby et al. JADD 2007;37:960-975) Myers SM. “Autism Spectrum Disorders: Important Issues and New Resources.” Lecture delivered at DB:PREP An Intensive Review of Developmental-Behavioral Pediatrics sponsored by the American Academy of Pediatrics. December 5, 2008 Atlanta, GA.

Joint Attention • Joint attention: visually coordinating attention with a partner to an external focus, showing social engagement and awareness of the partner’s mutual interest • Responding • Initiating • Milestone: • 8-10 mo: turning to name, spontaneous gaze monitoring • 10-12 mo: follow a point • 14-16 mo: point to comment/show (protoimperative) • 18mo: joint attention is fully consolidated; coordinated attention for the purpose of ‘commenting’ rather than ‘requesting’ • Greater ability to initiate and respond to JA bids predicts language skills 1, 5, and 8 years later Myers SM. “Autism Spectrum Disorders: Important Issues and New Resources.” Lecture delivered at DB:PREP An Intensive Review of Developmental-Behavioral Pediatrics sponsored by the American Academy of Pediatrics. December 5, 2008 Atlanta, GA.

Play in ASDs • Early abnormalities related to failure to comprehend the symbolic meaning of toys • early lack of interest in toys • Preoccupation with elementary sensory features • Lining, spinning, arranging, hoarding, carrying • Solitary play • Later appreciation of symbolic meaning, appropriate functional use • Sequences of appropriate actions • Impoverished, never achieves typical creativity or variability • Repetitious, mechanical • Often precisely imitated from videos • Pretend play delayed and impaired • Parallel play, interactive physical play • Limited role playing, especially involving other children Myers SM. “Autism Spectrum Disorders: Important Issues and New Resources.” Lecture delivered at DB:PREP An Intensive Review of Developmental-Behavioral Pediatrics sponsored by the American Academy of Pediatrics. December 5, 2008 Atlanta, GA.

AUTISM SPECTRUM DISORDERS: Diagnostic Evaluation-1 • Ideally, should be multidisciplinary • All must be knowledgeable and experienced in ASD • Evaluation by a physician specializing in ASD: Developmental Pediatrician, Psychiatrist, Neurologist • HISTORY: Medical, Behavioral, Psychosocial, Developmental, and Family History • Physical and Neurological Examination • Additional medical, genetic or neurologic tests as clinically indicated American Academy of Pediatrics, Committee on Children With Disabilities. The Pediatrician’s Role in the Diagnosis and Management of Autistic Spectrum Disorder in Children. Pediatrics. 2001;107,5:1221-1226 Filipek PA, Accardo PJ, Ashwal S. et al. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommitteee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000;55:468-479

ASD as One Feature of a Multiple Malformation Syndrome (5-10%) CHROMOSOMAL DISORDERS • 47XYY • 45X/46XY mosaicism • Del 7q • Del 22q11.2 • Del 22q13 • Del 2q37 • Del 18q • Del Xp

ASD as One Feature of a Multiple Malformation SyndromeGENETIC DISORDERS • Angelman syndrome • Bannayan-Riley-Ruvalcaba syndrome (PTEN, phosphatase-tensin homolog) • CHARGE association • Cornelia de Lange syndrome • Down syndrome • Fragile X • Hypomelanosis of Ito • Phenylketonuria • Prader-Willi syndrome • Rett syndrome • Smith-Lemli-Oitz syndrome • Smith-Megenis syndrome • Soto syndrome • Tuberous Sclerosis

INITIAL GENETIC TESTING FOR CHILDREN WITH ASD • When the child has dysmorphic features (multiple malformation syndrome) suggestive of a specific genetic or chromosomal disorder, order appropriate genetic test for that condition • Example: Fragile X vs. Angelman syndrome • Consultation with a clinical geneticist • For the 90-95% without multiple malformation syndrome: • Genetic testing yield is low absent mental retardation • Consider High resolution chromosome analysis, aCHG, PTEN • If mental retardation is present or strongly considered • Molecular Fragile X (do this in all with an X linked pattern of impairment in the family history) • High resolution chromosome analysis • Array Comparative Genomic Hybridization assay (aCGH) • PTEN gene test if OFC>2.5 SD over the mean • Consider consultation with a clinical geneticist

TERATOGENIC/INFECTIOUS DISORDERS ASSOCIATED WITH ASD • Rubella • Toxoplasmosis • HSV, CMV • Valproic acid • Thalidomide

Neurologic disorders associated with ASD • Acquired epileptic aphasia (Landau-Kleffner syndrome) • Myotonic dystrophy Type 1 (Ekstrom, et. al.: Am J Med Genet 147B:918, 2008 • Mitochondrial encephalopathy When is EEG indicated? When is CNS imaging indicated? When are other neurodiagnostic or metabolic tests indicated?

AUTISM SPECTRUM DISORDERS: Diagnostic Evaluation-2 • Psychological (and/or Neuropsychological) Evaluation • Clinical behavioral assessment • Cognitive assessment • Validated and standardized autism specific measures • ADI, ADOS • Validated behavioral assessment instruments • Autism rating scales (GARS, GADS, PDDBI) may be used to identify need for further evaluation; however, they should never be the primary diagnostic test • Speech and language Evaluation • Including Pragmatics and Prosody • Educational Evaluation • Psychosocial Evaluation • Sensory and Motor Evaluations

ASD : COMORBIDITY • Children with ASD may have other comorbid behavior or psychiatric disorders • Some of the comorbid conditions include: • Mental Retardation (Cognitive-Adaptive Disability) (<50%) • ADHD (30%) • Oppositional-Defiant Disorder (30%) • Obsessive-Compulsive Disorder (8%) • Anxiety disorder(s) (up to 50% of AS) • Depression (up to 30% of AS) • Bipolar disorder (5%) • No increased risk for schizophrenia • These require additional assessment on a case-by-case basis depending on clinical suspicion Simonoff E, et. al. Psychiatric Disorders in Children With Autism Spectrum Disorders: Prevalence, Comorbidity, and Associated Factors in a Population-Derived Sample. J. Am. Acad. Child Adolesc. Psychiatry, 2008;47(8):921Y929.

Autism Spectrum Disorder: Outcome • Rates of mental retardation decreasing over time as the diagnostic criteria broaden • Autism symptomatic improvement through adolescence and early adulthood is common • 20% to 30% may show behavioral deterioration in adolescence • 20-33% prevalence of epilepsy (bimodal onset) • Up to 40% experience a comorbid psychiatric disorder • Higher mortality rate than the general population • However, many will outlive their parents • Adaptive behavior is usually markedly lower than intelligence • Possibly related to impaired connectivity in frontal cortex • Independent living compromised even with normal IQ • Those who do spend time in the community are at increased risk for victimization or exploitation • AS individuals are at greater risk for negative outcomes compared to non-affected peers in areas of independent living, employment success, social relationships, psychiatric illness including suicide

Autism Spectrum Disorders: Post test • The 3 fundamental characteristics of all autism spectrum disorders are: • Qualitative impairments in reciprocal social interaction • Abnormal verbal and nonverbal communication, and • Choose the best answer from these: • Obsessive compulsive disorder • Echolalia • Restricted, repetitive, stereotyped pattern of interests and behavior • Self stimulatory behaviors • Which of the following statements about Asperger Syndrome is NOT TRUE: • Is often associated with a narrow range of interests or preoccupation • Is associated with the presence of mental retardation • Is characterized by normal early language development • Is sometimes associated with the presence of an anxiety disorder • In order to best guide treatment, it is important to identify the specific autism subtype for each affected child. • True • False

DIAGNOSIS OF AUTISM SPECTRUM DISORDERS • Background, neurobiology and epidemiology • Diagnosis • Diagnostic criteria • ASD subtypes • Medical work-up • Outcome • Summary

AUTISM SPECTRUM DISORDERS QUESTIONS?

REFERENCES-1 • Johnson CP, Myers SM, et. al. Identification and Evaluation of Children With Autism Spectrum Disorders. Pedaitrics 2007; 120; 1183-1215. • Myers SM, Johnson CP, et. al. Management of Children With Autism Spectrum Disorders. Pediatrics 2007; 120; 1162-1182. • American Academy of Pediatrics, Committee on Children With Disabilities. The Pediatrician’s Role in the Diagnosis and Management of Autistic Spectrum Disorder in Children. Pediatrics. 2001;107,5:1221-1226 • Filipek PA, Accardo PJ, Ashwal S. et al. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommitteee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000;55:468-479 • Offit, Paul A, Autism’s False Prophets: bad science, risky medicine, and the search for a cure. Columbia University Press, 2008. • Kanner L, “Autistic Disturbances of Affective Contact,” Nervous Child 2 (1943): 217-250.

REFERENCES-2 • National Research Council (2001) Educating Children with Autism. Committee on Educational Interventions for Children with Autism. Catherine Lord and James P. McGee, eds. Division of Behavioral and Social Sciences and Education. Washington, DC: National Academy Press. www.nap.edu • American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. • Handbook of Autism and Pervasive Developmental Disorders, 3rd Edition. Fred R. Volkmar, Rhea Paul, Ami Klin, Donald Cohen, eds. John Wiley & Sons, Inc., Hoboken, New Jersey, 2005. • Asperger Syndrome. Ami Klin, Fred R. Volkmar, Sara S. Sparrow, eds. The Guilford Press, New York, NY, 2000. • Asperger Syndrome. Ami Klin, Fred R. Volkmar, eds. Child and Adolescent Psychiatric Clinics of North America, 12:1, 2003. • Developmental-Behavioral Pediatrics, Third edition. Melvin D. Levine, William B. Carey, Allen C. Crocker, eds. W.B. Saunders Co., 1999.

DIAGNOSIS AND MEDICAL EVALUATION OF CHILDREN WITH AUTISM SPECTRUM DISORDERS