The State of Autism in 2011 from a Neurologist Perspective Bhagwan Moorjani, MD, FAAP, FAAN

Disclosures Hope Neurologic Center –Adult and Pediatric Neurology –Neurophysiology Dent Neurologic Center –Neuroimaging QTC Provider Maximus and MES –Independent Medical Review

Autism diagnosis is a clinical one in 2/3 symptoms first appear in infancy in 1/3 development is normal/near normal until months of age clinical picture is variable, with the presence/absence of mental retardation having a significant impact

Autism Kanner (1943) published his first account of the syndrome he called “early infantile autism” a disorder of behavioral development which may be seen in the first year of life, but almost always identified by 2-3 years of age

Autism 1950’s & 1960’s - abnormalities in social interaction were felt due to cold & distant parents (treatments of intensive psychotherapy & separation from parents largely unsuccessful) 1970’s & 1980’s - abnormalities in communication felt to be the core feature instead

Incidence Prior to 1990: 4-5/10,000 (1/2000 – 1/2500) 1990’s: 21-31/10,000 (1/476 – 1/323) A review of 23 epidemiologic studies between 1966 and 1988: 18.7/10,000 Incidence changes to 91/10,000 when Asperger’s syndrome is included 2009: 1/91 to 1/110; M:F ratio of 4 to 1 556% increase in incidence

Genetics of Autism Complex, behaviorally defined, static disorder of the immature brain Heterogeneous neurodevelopmental syndrome Recurrence rate in siblings: 2-8% Twin studies (MZ) 60% vs. (DZ) 0% –When adding broader phenotype increase from 60% to 92% and 0% to 10%. Many genes, common pathways

Frequencies of recurrent deletions Deleted regionSyndrome/ Phenotype No of cases Frequency in 15,749 cases 16p11.2Autism671 in q13.2-q13.3ID and Epilepsy461 in q11.2-q13PWS & AS411 in p13.11Autism, ID, & Schizophrenia 221 in q12Renal cysts, DM, Autism & Schizophrenia 181 in875 5q35Sotos Syndrome81 in 1969

Frequencies of recurrent duplications Duplicated region Syndrome/ Phenotype No of cases Frequency in 15,749 cases 16p11.2Autism391 in q11.2-q13Autism (BP1/2-3)351 in 450 1q21.1ID and Autism281 in 562 7q11.23Autism161 in 984 5q35Short stature, microcephaly and speech delay 21 in 7,875

Hot of the Press Ozonoff et. al. PEDIATRICS Volume 128, Number 3, September 2011 Prospective longitudinal study of infants at risk for ASD Infants (n664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician. 18.7% of the infants developed ASD. Infant gender and the presence of 1 older affected sibling were significant predictors of ASD outcome, –almost threefold increase in risk for male subjects –and an additional twofold increase in risk if there was 1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant’s older sibling, and other demographic factors did not predict ASD outcome.

Hot of the Press Hallmayer August 2011 California Autism Twin Study 404 children (202 set of twins) –54 monozygotic twins –138 dizygotic twins –Born between 1987 to 2004 Conclusion: Environmental factors (55%) play a larger role than genetic factors (37%) –Parental age –Low birth weight –Multiple births –Maternal infection during pregnancy

Case Born Full term (BW 5 pounds), 1 st child Dad in mid 40 th, mom late 30 th at time of conception 1 st month – colicky, changed formula to soy based improved, no more constant crying Walked at 14 months Speech delayed – single words about 16 months, did say mama at about 10 months but inconsistent Happy Child but clingy to parents, very picky eater Poor weight gain; Normal examination; FH – autism in maternal side Pediatrician agreed to have child evaluated by infant and toddler program at 15 months visit Evaluated by ITP/RC Diagnosis: ?????

ICD-10 Criteria for Autism A.Abnormal or impaired development is evident before the age of 3 in at least one of the following areas: 1.Receptive or expressive language as used in social communication 2.Development of selective social attachments or of reciprocal social interaction 3.Functional or symbolic play

ICD-10 Criteria for Autism B. A total of at least 6 items from 1,2, and 3 must be present with at least two from 1, and one each from 2 & 3: 1. qualitative abnormalities in reciprocal social interaction, are manifested in at least 2 of the following:

ICD-10 Criteria for Autism a. failure adequately to use eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction b. failure to develop peer relationships that involve mutual interests, activities, and emotions c. lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g. by a lack of showing, bringing, or pointing out to others objects of interest to the individual)

ICD-10 Criteria for Autism d. lack of social or emotional reciprocity as shown by an impaired or deviant response to other people’s emotions; or lack of modulation of behavior according to social context; or a weak integration of social, emotional, and communicative behaviors 2. qualitative abnormalities in communication are manifested in at least one of the following: a. delay in, or total lack of, the development of spoken language that is not accompanied by an attempt to compensate through the use of gesture or mine as an alternate mode of communication

ICD-10 Criteria for Autism b. relative failure to initiate or sustain conversational interchange in which there is reciprocal responsiveness to the communication of the other person c. stereotyped and repetitive use of language or idiosyncratic use of words or phrases d. lack of varied, spontaneous make-believe or social initiative play

ICD-10 Criteria for Autism 3. restricted, repetitive and stereotyped patterns of behavior, interests, and activities, as manifested in at least one of the following: a. an encompassing preoccupation with one or more stereotyped and restricted patterns of interest that are abnormal in their intensity and circumscribed in nature though not in content or focus b. apparently compulsive adherence to specific, nonfunctional routines or rituals

ICD-10 Criteria for Autism c. stereotyped and repetitive motor mannerisms that involve either hand or finger flapping or twisting or complex whole-body movements d. preoccupations with parts-objects or non- functional elements of play materials (such as the feel of their surface, noise or vibration they generate)

ICD-10 Criteria for Autism B. delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: 1) social interaction, 2) language as used in social communication, or 3) symbolic or imaginative play

ICD-10 Criteria for Autism C. The disturbance is not better accounted for by Rett’s Disorder or Childhood Disintegrative Disorder

Bottom Line Deficits in 3 main domains Reciprocal Social interaction Verbal and nonverbal communication Restricted and repetitive behaviors or interests Must be present by 3 years of age

Autism PDD-NOS is used for children who have qualitative impairments in socialization & communication, but do not meet the full criteria for autistic disorder

Case Full Evaluation performed including cognitive evaluation No evidence of Cognitive delays (MR) Speech delay range of about 50% Motor Delay about 18-25% Case worker from RC visit the family to discuss evaluation and to begin therapy Case worker asked parents what do they know about Autism

Autism A Clinical Diagnosis Beware: Autism is over-represented in individuals with an IQ in the severe to profound range –50-60% has the triad of autistic impairments in language, social interaction and imagination Many medical disorders have autistic features and must be excluded

Autism Gillberg (1996) reported 20-25% occurrence of an associated medical disorder in autistic patients which he felt had a “possible or probable link” to the autistic symptomatology trend for higher rates of medical disorders among autistic patients with severe mental retardation

Autism Many other disorders have “autistic features” and must be excluded: Sensory deficits Mental retardation Child abuse/neglect Childhood psychoses Neurodegenerative diseases Primary communication disorders

CONDITIONS ASSOCIATED WITH AUTISM ConditionFeatures EpilepsyPrevalence ranges from 11 to 39 percent Increased risk in girls and persons with intellectual disability Gastrointestinal Primarily diarrhea and constipation. Associated with daytime behavioral problems Sleep DisordersInsomnia very common, associated with daytime behavioral problems. Includes circadian rhythm disturbance and periodic limb movements of sleep Intellectual disability Prevalence of 41 percent; 30% normal/near normal IQ (formerly mental retardation) Motor impairmentsIncludes hypotonia, apraxia (motor planning), clumsiness, toe walking, gross motor delay Psychiatric conditionsHigh prevalence of anxiety, attention-deficit/hyperactivity disorder, depression Sensory processing Differences in the perceptions of sights, sounds, textures, disorder smells, and pain

Role of Pediatric Neurologist Identify secondary causes of Autism

15q11-q13 Causes: 1.Angelman Syndrome 2.Prader-Willie Syndrome detected in 1%-3% of children with autism.

Prader Willie Syndrome

Angelman Syndrome

Trisomy 21 Down’s Syndrome Autism more commonly than expected. The incidence was at least 7% in one study (Kent et al 1999).

Trisomy 21

Tuberous Sclerosis 25%-50% of intellectually disabled individuals with TSC fulfill autism diagnostic criteria, Only 1.1%-1.3% of individuals initially diagnosed with ASD have TSC (Fombonne et al 1997b, Baker et al 1998, Asano et al 2001, de Vries et al 2007). Early-onset infantile spasms and temporal lobe tubers on MRI examination increase the chance that children with TSC2 mutations will also develop autism (Bolton 2004). Prospective study of children with TSC evaluated using the ADOS: –66% of infants met criteria for autism or ASD at age 18 months, –54% at age 24 months, –46% at age 36 months, –50% at age 60 months. –The children with both TSC and autism were more cognitively impaired than those with TSC only (Jeste et al 2008).

Tuberous Sclerosis

Neurofibromatosis, type I NF1 has been diagnosed in children with autism. It is unclear whether this is a true association or the chance simultaneous occurrence of two relatively common childhood disorders (Fombonne et al 1997b, Battaglia & Carey 2006, Schaefer & Lutz 2006). No genetic overlap between mutations in the NF1 gene and autism has been demonstrated (Zafeiriou et al 2007).

Neurofibromatosis type I

Fragile X Fragile X syndrome is caused by expansion of the CGG trinucleotide repeat in the FMR1 gene to the full mutation size of 200 or more CGG repeats. 1% to 3% of children ascertained on the basis of an autism diagnosis have fragile X syndrome, at least half the children with fragile X syndrome have some autistic behaviors, including avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities. one study of 63 males with fragile X syndrome, 30% met criteria for autistic disorder and 30% criteria for PDD-NOS (Harris et al 2008) considerable number of children being evaluated for autism are found to have FMR1 premutations ( CGG repeats) (Goodlin-Jones et al 2004, Cornish et al 2005, Reddy 2005, Farzin et al 2006, Loesch et al 2007). 14 boys with premutations ascertained through an autism clinic and found 71% met ASD diagnostic criteria. (Farzin et al 2006)

Fragile X

Rett Syndrome Rett syndrome is one of the original DSM-IV-designated pervasive developmental disorders and the only one for which a specific genetic etiology has been identified (Amir et al 1999). Ninety-six percent of individuals with classic Rett syndrome have mutations in the X-linked MECP2 gene (Moretti & Zoghbi 2006). Vast majority of individuals with MECP2 mutations are girls, MECP2 mutations are identified in 1%-2% of males with developmental disorders, including infantile encephalopathy, intellectual disability with motor deficits and early-onset bipolar disorder and schizophrenia. Most males are identified in families with an X-linked pattern of intellectual disability. MECP2 mutations have been reported in approximately 1% of children diagnosed with autism

Rett Syndrome

Sotos Syndrome cardinal features of typical facial appearance, overgrowth (height and head circumference ≥2 SD above the mean), and learning disability probably not a significant cause of classic autism children with Sotos syndrome and behavioral problems such as difficulty with peer group relationships and lack of awareness of social cues may be referred to autism clinics. (Buxbaum et al 2007b) Eighty to 90% of individuals with Sotos have a demonstrable mutation or deletion of NSD1; inheritance is autosomal dominant.

Sotos Syndrome

Joubert Syndrome three of 11 children with Joubert syndrome met diagnostic criteria for autism and one of 11 for PDD-NOS (Ozonoff et al 1999). Takahashi et al in 2005 delineated behavioral and genetic differences between autism and Joubert syndrome, implying that they are etiologically distinct disorders. In monozygotic twins with Joubert syndrome, the twin with the more severe cerebellar abnormality had autism, suggesting that some disorders may have the potential to cause the autism phenotype if as-yet unidentified autism regions or circuits of the brain are affected (Muhle et al 2004) subset of Joubert syndrome appears related to the AHI1 gene, encoding the ‘jouberin’ protein

Joubert Syndrome

Timothy Syndrome a disorder of calcium channels caused by a mutation in the CACNA1C gene characterized by severe QT prolongation, syndactyly, cardiac defects, dysmorphic faces, developmental delays, and autistic symptoms (Splawski et al 2004). Inheritance is autosomal dominant.

Timothy Syndrome

Mitochondrial and Metabolic Disorders Respiratory Chain disorders –Elevated lactate 14/69 autism children (Oliviera et al 2005) Phenylketonuria (PKU) –2/35 patients (Baieli et al 2003) Adenylosuccinate lyase deficiency –1 out of 420 children with PDD (Stathis et. al 2000) Creatine deficiency syndrome –Have autistic behaviors

Smith Lemli Opitz Syndrome autosomal recessive multiple congenital anomaly and intellectual disability syndrome caused by a deficiency of 7-dehydrocholesterol reductase, an essential enzyme in the biosynthesis of cholesterol. SLOS can be associated with autism and other behavioral characteristics such as repeated self-injury, sensory hyper-reactivity, temperature dysregulation, and sleep disturbance (Tierney et al 2001, Tierney et al 2006). Rates of autistic behavior reported in individuals with SLOS range from 50% to 86% (Manzi et al 2008). One study found that three-fourths of the children with SLOS had ASD, about 50% diagnosed with autistic disorder and the rest with PDD-NOS (Sikora et al 2006) no correlation was found between the abnormal metabolites and the presence or severity of autistic symptoms.

Smith Lemli Opitz Syndrome

Moebius syndrome or sequence unilateral or bilateral palsy of the sixth and seventh cranial nerves Moebius syndrome is characterized by facial paralysis with inability to smile and fully abduct the eyes. It is often associated with abnormal tearing, seizures, hearing loss, and limb anomalies. About 30% of children with Moebius syndrome develop ASD (Johansson et al 2001, Stromland et al 2002, Bandim et al 2003). A recent study confirmed that ASD occurs more frequently in individuals with Moebius syndrome with concurrent intellectual disability (Briegel et al 2009).

Landau Keflner Syndrome A small subset of children with ASD and late regression have LKS. Develop sudden or gradual isolated language regression associated with seizures (epileptic aphasia) and/or severe EEG abnormality in deep sleep (Cortesi et al 2007). In general, both the seizures and language impairment improve with normalization of EEG abnormalities (Spence & Schneider 2009).

Landau Kleffner Syndrome

In Utero Exposure (Bromley et al 2008). The Liverpool and Manchester Neurodevelopment Group long-term study of 632 children exposed to antiepileptic drugs (AEDs) during gestation children exposed to valproate in utero were seven times more likely to develop autism than those not exposed to AEDs. None of the families had a known family history of autism. They recommend that women taking valproate be informed of the risk for autism in children exposed during gestation

Antidepressants Prenatal use of SSRI – twofold increase in risk of Autism SSRI used during the first trimester – three fold increase in risk of Autism

Teratogens Lead and mercury –No evidence linking to mercury in vaccines Thalidomide Misoprotol (Cytotec)

Childhood Immunization Childhood immunizations given around the time that regressive- onset autism is recognized have been a focus of concern. Organic mercury, which constitutes roughly 50% of the preservative thimerosal used in certain injectable vaccines, and the measles-mumps-rubella (MMR) vaccine, which never contained mercury, have been studied. Though parental concern is still significant, multiple studies and lines of scientific evidence have identified no support for a relationship between immunizations and autism (DeStefano & Thompson 2004, Institute of Medicine 2004, Taylor 2006, Schechter & Grether 2008). The original studies by Wakefield et al (1998) and Wakefield (1999) suggesting an associated between immunizations and autism have been disproved and the work was retracted by the journal The Lancet (Murch et al 2004). One of the tragedies resulting from fear of an autism epidemic was the decreased use of childhood immunizations leading to out outbreaks of measles and childhood deaths (Jansen et al 2003, Offit 2008).

Recovery from Autism 25% will blend into varying degree of regular school –Social impairment will continue 75% some improvement with age but need parent, school and societal support Less than 5% completely recover (Nordin and Gilllberg 1998) 20 year follow up of adults with autism and average to near average cognitive abilities (Farley et al 2009) –½ functioned quite well –½ were employed in full time or part time paying jobs –Only 12% lived independently –56% lived with their parents

Recovery from Autism Retrospective evaluation of children whose parents had reported recovery from autism following EIBI treatment: –4 of 8 had IQ in the normal range –7 of 8 still had delays in language Reichow and Wolrey meta-analysis –EIBI is effective –35% were placed in typical classroom –18% met criteria for diagnostic reclassification

Proposed Criteria for Recovery Helt et al Definition: Diagnosis in early childhood (< 5 years) Diagnosis by a specialist who practices at least 50% is in autism Early language delay Review by one member of our team blind to report

Proposed Criteria for Recovery Helt et al Current Functioning: 1.Does not meet the criteria for PDD 2.Does not meet ASD cutoff on social or communication domain of the ADOS 3.Any special education services the participant receives are to remediate difficulties with attention, organization, or specific academic difficulties and not to address features of autism 4.Functioning without an individual assistant in a regular education classroom 5.Verbal IQ, Performance IQ and full scale IQ are all at 78 or above 6.Vineland Communication and Socialization scales are all at 78 or above

Summary Complex Poorer prognosis 30% can be diagnosed with an underlying condition Low sibling recurrence Lower male to female ratio Essential No dysmorphism No microcephaly Accounts for 70-80% Higher sibling recurrence Outcome is better

Summary meticulous physical examination including looking for dysmorphologic features detailed neurologic examination skin examination (wood lamp examination) neuroimaging (e.g. TS) chromosomal studies (e.g. fragile X) EEG (subclinical epilepsy) blood & urine (metabolic disorders) CSF (e.g. encephalitis) visual and auditory evaluations

Summary Treatment –no medication to treat core symptoms, but can be helpful as adjunctive treatment –goal of treatment is to maximize independent functioning in all areas of life +/- special education behavioral interventions supportive psychotherapy where indicated +/- pharmacologic treatment (as above)

Summary Language skills (ability to communicate) and overall intellectual level are the strongest factors related to ultimate prognosis Only about 1/2 develop socially useful language Approximately 70% require some type of supervised living as adults

Case Family told Child had Autism Mom had a puzzling look to her face Dad had a grin and very calm At the end of the visit –Case worker ask why parents were so calm with diagnosis of Autism compared to all other families –Dad responds by telling the case worker the child does not have Autism

Case

No work up was performed Dad did not want any work up unless therapy did not show improvement –Improved significantly with therapy Discharged from PT, and OT Still getting speech therapy and behavioral therapy but significantly decreased in hours. Diagnosis: Developmental delay

Mother – 1st grade teacher Father -