Pervasive Developmental Disorders: Understanding the Spectrum and Long Term Prognosis

Pervasive Developmental Disorders: Understanding the Spectrum and Long Term Prognosis ACLI Medical Section Annual Meeting 2010 Nhung T. Tran, MD, FAAP UTHSCSA Developmental-Behavioral Pediatrics

Objectives Use appropriately current medical terminology associated with PDDs Understand the spectrum and co-morbid conditions in PDDs Understand long-term clinical prognosis including mortality considerations of PDDs

Defining autism Core features Limited social relatedness Lack of communication Narrow and repetitive behavior patterns DSM-IV criteria for PDDs: Autistic disorder (AD) Asperger s disorder or syndrome (AS) Pervasive developmental disorder, not otherwise specified (PDD-NOS)

DSM-IV TM criteria for PDD A1: Qualitative impairment of reciprocal social relatedness that is significantly below the child s general level of functioning A2: Qualitative impairment in communication associated with the lack of desire to communicate A3: Restricted repetitive and stereotyped patterns of behavior, interests and activities

DSM-IV TM criteria for PDD A1: Qualitative impairment of reciprocal social relatedness that is significantly below the child s general level of functioning

DSM-IV TM criteria for PDD 1) Marked impairment in the use of multiple nonverbal behaviors to regulate social interaction 2) Failure to develop peer relationships appropriate to developmental level 3) Lack of social or emotional reciprocity 4) A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people Joint attention

Joint attention Core or basis of all screening tests Central to diagnosis in toddlers Specific curriculum to teach joint attention Mastery predicts onset of functional communication within 1 year (Lord, 2001; Mundy et al, 1990)

Theory of mind (ToM) Theory of mind is the ability to understand affective states and sharing emotions with other people Sally and Ann Strange stories

DSM-IV TM criteria for PDD A2: Qualitative impairment in communication associated with the lack of desire to communicate

DSM-IV TM criteria for PDD 1) Delay in, or total lack of, the development or spoken language (not accompanied by an attempt to compensate) 2) In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others 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 TM criteria for PDD A3: Restricted repetitive and stereotyped patterns of behavior, interests and activities

DSM-IV TM criteria for PDD 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 4) Persistent preoccupation with parts of objects

DSM-IV TM criteria for PDD B: Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: Social interaction Language as used in social communication Symbolic or imaginative play

Other features (not diagnostic) Sensory processing disorder Sleep disturbances Feeding disturbances Excessive, unusual fears and no fears Savant skills ( splinter skills )

DSM-IV TM criteria for PDD Autistic disorder (AD): 6 criteria met with 2 in A1, 1 in A2, and 3 in A3 Asperger s disorder (AS): 3 criteria met with 2 in A1 and 1 in A3, and no clinically significant general delay in language attainment PDD, not otherwise specified (PDD-NOS): 3 criteria met with 2 in A1 and either 1 in A2 or 1 in A3 Clinically significant impairment in functioning Cannot be explained by other diagnoses

Note on terminology PDD is the categorical, diagnostic terminology Autistic Disorder Asperger s Disorder PDD-NOS Childhood disintegrative disorder: (Rett Syndrome)

Note on terminology Autism Spectrum Disorders recognizes wide presentation, is synonymous with PDD but not a diagnostic term

Note on terminology Atypical autism is synonymous with PDD-NOS High functioning autism is autistic disorder without cooccurring intellectual disability (IQ > 70), descriptive not diagnostic terminology Subtypes (Wing) Aloof Passive Active but odd

Note on onset Onset < 3 years old Abnormalities in prenatal brain development Subtle abnormalities detected at 1 year old (Osterling et al, 1992) Caution if evaluations initiated beyond 3 years old: recall bias, wide DDX in the older child

Differential diagnosis Language disorders, especially pragmatic Nonverbal learning disability Intellectual disability with autistic features Childhood (early onset) schizophrenia Schizoaffective personality disorder Anxiety disorders Attention deficit disorders language disorder intellectual disability HFA AD PDD AS

Prevalence Estimated 2 to 6 per 1000 live births Males > females (3-4:1) Up 10-17% yearly until mid-1990s due to terminology Autism 1970 1 per 10,000 Autism 1990 1 per 1,000 ASD 2003 3-4 per 1,000 ASD 2004 ~6 per 1,000 ASD 2006 5.5-5.7 per 1,000 ASD 2009 1 in 91 (citation)

Reasons for the epidemic rise Closing of institutions (ADA 1990) Broader definition captures milder spectrum diagnoses Increased recognition by improved screening Increased recognition via increased media coverage New diagnosis in known conditions (e.g., Downs, former ELBW premature infants) Epidemiology, research design Ex. Phone survey concluding 1 in 91 affected (citation)

Reasons for the epidemic rise Diagnostic substitution : IDEA eligibility category created in 1991 allowed for autism supplemental services (Shattuck, 2006) Intellectual disability ( MR ) All disabilities Autism

Etiologies of PDD PDD is a behavioral phenotype Genetic: 90-95% of identified etiologies Idiopathic (90-95%) 70% normal examination 30% with dysmorphisms and/or brain anomalies Syndromic: spontaneous > familial (5-10%) Chromosomal (many): X, 2, 3, 7q, 15q11-13, 17q, 22q Single gene and others (many): Fragile X Syndrome, Smith-Magenis Syndrome, Angelmans Syndrome, Rett Syndrome

Etiologies of PDD Environmental: 5-10% of identified etiologies Infectious: congenital rubella Toxins: Untreated phenylketonuria Fetal alcohol spectrum disorder Fetal valproate syndrome Second hit phenomenon: environmental interaction with genetic predisposition

Co-occurring conditions Intellectual disability (~50%) Sleep disorders Nutritional deficiencies Attention deficit disorders (~50%) Seizures (20-30%) Onset usually before 30 years old Highest frequency in autism with severe ID

Fragile X Syndrome Most common inherited cause of ID, PDD Mutation of the FMR1 gene on Xq27.3 caused by increased trinucleotide repeats, aberrant methylation Normal 5 to 50 repeats Premutation ~50 to ~200 repeats: 1 in 259 females, variably affected (more so than you might think) Full mutation >200 repeats: 1 in 1,200 males, 1 in 2,500 females

Fragile X Syndrome Affects males>females Cognitive: Carriers, affected females: LD to mild ID Affected males: ID Behavioral: Social anxiety >> PDD Autistic features >> PDD diagnosis ADHD and other psychiatric disorders Carriers: FXTAS, FXPOI

Fetal Alcohol Spectrum Disorders Most common preventable cause of ID, PDD Prevalence estimate 1-2 per 1000 live births Diagnostic findings/criteria: Facial features least specific Growth deficiency (prenatal +/- postnatal) CNS abnormalities: structural and functional, especially executive function impairments Autistic features >> PDD diagnosis May have relative sparing of cognition Confirmation of alcohol exposure

Morbidities & Long-Term Outcomes Pervasive Developmental Disorders

Prognostic factors Underlying etiology Is the etiologic search been completed? Updated? Age of diagnosis and interventions Better if <3 yrs old, interventions in inclusive, natural settings Co-occurring seizures, other neurological or psychiatric disorders

Prognostic factors Communication Poorer prognosis if no functional communication at 5-6 yrs old Non-verbal joint attention predicts language development Cognitive functioning (IQ) More restrictive prognosis (fair to very poor) if IQ < 50 at 5-6 yrs old Neuropsychological deficits Executive function ToM

Prognostic factors Deinstitutionalization, especially later in life Shavelle et al (2005) 1,878 children moved between 1993 and 1996 81 deaths, 47% increase in mortality above expected based on institutional population in 1997-1999 Group 1993 movers 1994 movers 1995/6 movers All movers EMR 10.3 10.1 11.2 10.6 SMR 1.02 1.55 1.63 1.47

Prognosis Wide range of outcomes Autistic symptoms: mild Intellectual disability: severe none severe Adaptive functioning: high low Long-term prognosis ~75% have lifelong challenges ~25% (maybe up to 40%) blend into population, remain odd <5% fully recover (e.g., independent living)

Adolescent outcomes Symptom aggravation with periodicity in 50% Cognitive/behavioral deterioration in 12-32% Symptom improvements in 43% Increased depressive symptomatology Increased frequency of psychotropic medication Under-activity to marked psychomotor retardation without depression Socially inappropriate sexual behaviors Gilberg, et al, 1987; Komoto et al, 1984; Gillberg, 1991; Kobayashi et al, 1992

Adult outcomes: autistic symptoms Hofvander et al (2009) 122 consecutively referred adults with normal IQ ASD Results: Persistent problems in core autistic symptoms DSM-IV criteria n AD (n=5) % n AS (n=67) % PDD NOS (n=50) n % A1 5 100 67 100 47 94 A2 5 100 34 51 18 36 A3 5 100 65 97 29 58

Adult outcomes: Axis I diagnoses ADHD Chronic tic disorder Mood disorder Psychotic disorder Substance related disorder Anxiety disorder Obsessive compulsive disorder Impulse control disorder Somatoform disorder Eating disorder 1 DSM-IV disorder AD (n=5) n % 2 40 0 0 3 60 0 0 1 20 0 0 0 0 0 0 0 0 0 0 4 80 AS (n=67) n % 24 36 14 21 35 52 10 15 4 6 34 51 14 21 4 6 2 3 2 3 67 100 PDD NOS (n=50) n % 26 52 11 22 27 54 5 10 14 28 25 50 15 50 7 14 4 8 4 8 50 100 Hofvander et al (2009)

Adult outcomes: psychosocial Education: 65% high school graduate 24% college or university Employment: 43% employed or student Living arrangements: 50% independent Social: 16% long-term relationships Hofvander et al (2009)

Mortality & Causes of Death Pervasive Developmental Disorders

California data Unique state, care for developmental disabilities is an entitlement California Department of Developmental Services Annual Client Development Evaluation Reports (CDER) California Dept. of Health Services (CDHS), Bureau of Vital Statistics Mortality data (by ICD-9 codes)

Shavelle & Strauss (1998) 1980-1996 Subjects: 11,347 with clinical diagnosis of a PDD Mortality information Expected mortality rates using 1992 U.S. Abridged Life Table Observed deaths through CDHS Primary finding: mortality by gender

Mortality ratio by gender Females had strikingly higher mortality rates Number of deaths Observed Expected Mortality ratio Mean Annual Mortality Rate per 1,000 Observed Expected Excess Male 166 99.41 167% 2.5 1.5 1.0 Female 82 16.75 490% 3.7 0.7 2.9 Reduced life expectancy: Age 5 years: by 6.1 years in males, 12.3 years in females Age 60 years: by 3.5 years in males, 4.2 years in females Shavelle & Strauss, 1998

Shavelle et al (2001) 1983 to 1997 Subjects: 13,111 with clinical diagnosis of a PDD Without concomitant Down or Rett Syndrome, CP or TS Without substantial motor impairments Mortality information Subject (202 deaths during study period) & general population Grouped ICD-9 codes into 11 categories Primary findings: mortality rates in PDD without concomitant risks; by gender, cause, severity of ID

Shavelle et al (2001) Males Females All Percent died Age at 1 st evaluation: 9 years old Level of intellectual disability: None Mild Moderate Severe Profound Seizures Medications n = 10,412 1.4% 76% 53.8% 18.6% 13.5% 9.1% 5.0% 3.9% 7.8% n = 2,699 2.2% 74.3% 44.4% 16.9% 14.9% 14.3% 13.3% 5.2% 6.0% n = 13,111 1.5% 75.7% 51.9% 18.2% 13.8% 10.1% 14.7% 4.2% 7.4% Shavelle et al (2001)

Mortality in PDD with no or mild ID Cause of death Cancer Seizures Nervous and sense Circulatory Respiratory Digestive Congenital anomalies All other causes (ICD-9 <800) Drowning Suffocation All other causes (ICD-9 800) All causes Standardized mortality ratio 2-5 yrs 5-10 yrs 10-20 yrs 20+ yrs All ages (1) 3.8 (2) 1.6 (3) 1.9 (6) 33.1 (4) 22.6 (4) (1) 15.9 (3) 4.8 (4) (1) 2.2 (4) 2.3 (5) (1) 1.3 (1) (1) 1.2 (1) (1) (1) (1) 2.0 (3) 8.7 (3) (1) 0.4 (2) 1.0 (6) 5.0 (1) 14.1 (2) 3.9 (3) (1) 5.7 (1) 3.1 (2) 2.6 (3) 0.6 (3) 0.6 (7) 0.8 (15) 1.6 (3) 4.0 (12) 1.5 (11) 1.0 (23) 1.4 (49) Shavelle et al (2001)

Mortality in PDD with moderate-severe ID Cause of death Cancer Seizures Nervous and sense Circulatory Respiratory Digestive Congenital anomalies All other causes (ICD-9 <800) Drowning Suffocation All other causes (ICD-9 800) All causes Standardized mortality ratio 2-5 yrs 5-10 yrs 10-20 yrs 20+ yrs All ages (1) 6.2 (3) 2.4 (11) 2.9 (15) (1) 38.0 (10) 36.9 (11) (1) 12.0 (2) 4.1 (3) 6.2 (6) (1) 3.7 (16) 3.8 (17) 24.5 (3) 9.4 (9) 10.8 (12) (1) 40.8 (2) 5.9 (9) 7.5 (12) (1) 11.1 (4) 8.7 (8) 9.4 (13) (1) 15.0 (6) 3.3 (30) 3.8 (37) 90.6 (3) 11.3 (2) 8.5 (3) 13.7 (8) (1) 110.2 (4) 23.4 (2) 51.4 (7) (1) 0.8 (4) 0.6 (10) 0.6 (15) 10.2 (2) 11.3 (8) 4.4 (32) 2.7 (111) 3.1 (153) Shavelle et al (2001)

Mortality rates by gender and age (Note: No differences by age or cause of death alone) Age 1983-97 Males 1998-02 1993-97 Females 1998-02 1993-07 Overall 1998-02 2-5 yrs 2.3 (4) 1.8 (2) 3.0 (1) 0.0 (0) 2.4 (5) 1.6 (2) 5-10 yrs 3.5 (11) 2.1 (4) 16.8 (9) 3.1 (1) 5.4 (20) 2.2 (5) 10-20 yrs 2.3 (30) 3.3 (13) 9.2 (13) 6.2 (2) 3.0 (43) 3.6 (15) 20+ yrs 1.7 (98) 2.2 (43) 5.3 (36) 5.7 (13) 2.1 (134) 2.5 (56) All 1.7 (143) 2.3 (62) 5.5 (59) 5.2 (16) 2.4 (202) 2.6 (78) Picket et al (2006)

Denmark data Mouridsen et al (2008) 1960-1984, University Clinics of Child Psychiatry, Copenhagen and Aarhus Subjects: 341 children, ages 2-17 years at inpatient admission with PDD, followed to 2006 Danish Central Persons Registry (CPR) Aims: mortality rate by ASD, causes

Mortality by PDD category Autistic disorder Atypical autism Other CDD Asperger syndrome Percent died (#) 5.9% (7) 7.9% (7) 15.4% (2) 8.3% (10) Male, female Admission age (mean) 4, 3 5.4 yrs 4, 3 9.0 yrs 2, 0 5.9 yrs 8, 2 9.7 yrs Follow-up age (mean) Gender (#): Male, female 41.5 yrs 85, 33 44.9 yrs 58, 31 40.6 yrs 9, 4 44.3 yrs 104, 17 IQ: <50 53 20 7 0 50-69 30 15 2 16 >69 34 53 4 105 Death Natural 5 5 2 8 Unnatural 2 2 0 2 Mouridsen et al (2008)

Mortality by years after diagnosis Mouridsen et al (2008) Years after DX Men SMR Women All 0-15 1.98 5.22 2.40 15-30 1.42 3.17 1.65 30-45 1.47 4.08 1.92 0-45 1.57 4.01 1.93

What s next? Further etiologies identified Further understanding of pathophysiology of autism Emphasis on preventative care Long term follow-up studies of children with more recent diagnoses, very different early treatment Hopefully, less press on pseudoscience

References Gillberg C. J Am Acad Child Adolesc Psychiatry, 1991, 20(3): 375-382. Gillberg C, et al. J Autism Dev Disorders, 1987, 17: 273-288. Komoto J, et al. J Autism Dev Disorders, 1984, 14: 81-84. Mouridsen SE, et al. Autism, 2008, 12(4): 403-414. Osterling J, et al. J Autism Dev Disorders, 1992, 24: 247-259. Picket JA, et al. J Autism Dev Disorders, 2006, 36(2): 287-8. Shattuck PT. Pediatrics, 2006, 117(4): 1028-1037. Shavelle RM & Strauss D. J Ins Med, 1998, 30: 220-225. Shavelle RM, et al. J Data Sci, 2005, 3: 371-380. Shavelle RM, et al. J Autism Dev Disorders, 2001, 31(6): 569-576.