Autism Mythbusters: Updates on Screening, DX, and Rx

Transcription

1 Autism Mythbusters: Updates on Screening, DX, and Rx Learning Objectives 1. Discuss the primary factors underlying the increase in ASD prevalence 2. Identify the diagnostic features of ASD and the recommended medical workup for a child newly diagnosed with ASD 3. Recognize the different types of behavioral interventions for children with ASD and the challenges underlying clinical trials in behavioral intervention 4. Identify the indications for medication use in ASD Faculty Shafali Spurling Jeste, MD Associate Professor in Psychiatry and Neurology Semel Institute for Neuroscience and Human Behavior UCLA Center for Autism Research and Treatment David Geffen School of Medicine at UCLA, Los Angeles, California Slides are current as of the time of printing and may differ from the live presentation due to copyright issues. Please reference for the most up-to-date version of slide sets. West Annual Conference Anaheim, California April 27-30, 2016

2 Pediatrics Psychiatry Neurology Education Autism Spectrum Disorders: Myth Busters Center for Autism Research and Treatment Research Child and Adult Neurodevelopmental (CAN) Clinic CART Collaborations with Other Allied UCLA Programs Shafali Spurling Jeste, MD Assistant Professor in Psychiatry and Neurology Director, Neurophysiology Core Director, Developmental Neurogenetics Clinic UCLA Center for Autism Research and Treatment Early Markers Genetics/Eti ology Biomarkers Treatment Multidisciplinary Evaluations Treatments Long-term medical and psychiatric care Referrals for genetic testing Early Childhood Partial Hospitalization Program PEERS ABC Partial Program Parenting and Children s Friendship Program Secret Agent Society (SAS) History of Autism 1910: Term autism first coined by Bleuler from Greek word "autos," meaning self, referring to an extreme withdrawal of oneself from the fabric of social life in Schizophrenia (1) Epidemiology (2) Diagnosis and Comorbidities 1943: Described as a unique clinical syndrome by Leo Kanner in "Autistic Disturbance of Affective Contact (Nervous Child) and by Hans Asperger's in Autistic Psychopathy in Childhood (1) Neurobiology (2) Treatment 1980: First recognized as clinical syndrome in DSM III Why the increase? CDC revises estimates March sites across US Diagnosis based on clinical records of children birth to age 8, DSM IV TR 1 in 68 children nationwide: 23% increase from 2010 estimate 4:1 Male: Female ratio (1:42 boys) Diagnostic practices More often Earlier Environmental factors Parental age Exposures: lead, pesticides? Maternal infection CDC MMWR Surveillance Summaries, March 2014 Polyak, 2015

3 Is it the vaccines? Interest in role of vaccines (MMR) resulted from British study in 1998 Lancet (Wakefield et al) Wakefield described 12 children with regression after receiving vaccines, including MMR May 2004, WHO, IOM,CDC published consensus statements favoring rejection of a causal relationship between thimerosal containing vaccines and autism Feb 2010: Lancet retracted Wakefield study because of data falsification December 2010 Wakefield loses medical license January 2011 BMJ states that Wakefield is an elaborate fraud. Honda et al, JCPP 2005 ASD is a neurodevelopmental disorder (DSM 5) (1) Epidemiology Autism spectrum disorder (ASD) Intellectual disability (ID) Global developmental delay (GDD) Attention Deficit Hyperactivity Disorder (ADHD) Social Communication Disorder (2) Diagnosis and Comorbidities (1) Neurobiology (2) Treatment 1. Deficits in social emotional reciprocity 2. Deficits in nonverbal communicative behaviors used for social interaction 3. Deficits in developing, maintaining and understanding relationships 1. Stereotyped or repetitive motor movements, use of objects or speech 2. Insistence on sameness, inflexible adherence to routines 3. Highly restricted, fixated interests that are abnormal in intensity or focus 4. Hyper or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment CHANGES from DSM IV Social and communication domains combined Social communication impairment Repetitive behaviors and restricted interests One spectrum rather than categories (PDD NOS, Asperger's, Autistic Disorder) Expressive Language Level Level of Support Needed Diagnostic and Statistical Manual-5 th Edition Sensory impairment part of the diagnostic criteria Comorbid ADHD can be diagnosed No minimum age of onset of symptoms

4 Clinical heterogeneity of ASD IQ: Intellectual disability from mild to severe in up to 70% Language: 30% remain minimally verbal Epilepsy: 15% with epilepsy, up to 60% with EEG abnormalities at baseline Mood and behavior: Depression, anxiety, irritability, ADHD Epilepsy in ASD Prevalence over a lifetime 12.5% Increases with age (26% in children >13) Epilepsy associated with lower IQ, poorer adaptive and language function and more severe ASD sx More common in girls Sleep: Insomnia in up to 80% Motor and Sensory: Hypotonia, abnormal gait, incoordination, toe walking, delayed milestones, sensory hypo and hyper reactivity Can be associated with profound developmental regression Viscidi et al, 2013 Insomnia occurs in up to 80% of children with ASD Difficulty getting to sleep Frequent night awakenings ( Fragmented sleep ) Early morning awakenings Decreased need for sleep Daytime sleepiness and irritability Insomnia associated with behavioral and cognitive disturbances Neurodevelopmental/Psychiatric comorbidities ADHD (30 50% meet full DSM 5 criteria) Mood disorders (Anxiety rates range from 11 80%) Intellectual disability (up to 75%) Motor impairment (hypotonia, incoordination, toe walking, delayed motor milestones) Accardo, 2015; Malow, 2012 Jeste, 2015; Young, 2015; Roma, 2014 Sleep committee of ATN: Practice parameters (1) Developmental assessment of young children should include questions about ASD (2) If screening positive, thorough diagnostic evaluation should be performed by a trained provider (DSM 5) (3) Coordinate a multidisciplinary assessment, including general medical, GENETICS, neuropsych, +/ neurology (1) All children with ASD should be screened for insomnia (2) Screening should be done for potential contributing factors, including other medical problems (3) The need for therapeutic intervention should be determined Screening questions: 1. Falls asleep within 20 min 2. Falls asleep in parents bed 3. Sleeps too little 4. Awakens once during night Medical Screening: Reflux, constipation, seizures disordered breathing, pain/discomfort, nutrition Exam: tonsils, tone, nasal congestion, dentition wheezing, eczema JCAAP, 2014 Malow et al, J Pediatrics, 2012

5 ASD is a heritable disorder One of the most heritable neuropsychiatric disorders Monozygotic twins 60 70% concordance Dizygotic twins 10 15% concordance (Bailey, 1995; Ronald, 2011) (1) Epidemiology (2) Diagnosis and Comorbidities Recurrence risk in siblings: approximately 10% (higher if proband is female) Some infant sibling studies report recurrence rates as high as 19% (Ozonoff, 2011) Recurrence rate >33% if more than 1 affected child (Werling, 2015) (1) Neurobiology (2) Treatment Sandin, JAMA 2014 Advances in genetic methods used to study children with ASD Advances in methods of genetic testing CMA: chromosomal microarray Copy number variants (CNVs) Structural chromosomal variation that causes deviation from control Duplication or deletion larger than 1 kb Single gene or groups of related genes Karyotyping and FISH (Florescent in situ Hybridization) 3 5 million BPs Chromosomal Microarray 100 Kb Abrahams and Geschwind 2009 Whole exome or genome sequencing Analysis at the level of single base pair (1) acgh: array based comparative genomic hybridization (1) SNP: single nucleotide polymorphism arrays genotyping plus gene dosage, so able to pick up specific inheritance patterns (uniparental disomy) Advances in methods of genetic testing Whole exome or genome sequencing Analysis at the level of single base pair Can identify partial loss of gene function Insight into genes with common functions Large databases of simplex families (Simons Simplex Collection) >30% of individuals with ASD have an identifiable genetic cause Single Gene Disorders: Tuberous Sclerosis Complex (1 2%) Fragile X Syndrome (1 3%) MECP2 related (Rett syndrome) (1%) PTEN related (up to 17% with macrocephaly) De Novo Copy Number Variations and gene mutations (20%): Within these copy number variants, identification of hundreds of genes associated with ASD Neale, 2012 Rauch 2012, De Ligt 2012, O Roak 2012, Sanders 2012, Neale 2012, Iossifov 2012, Jiang 2013, Allen 2013, Guisuner 2013, Xu 2012, Fromer 2014

6 UCLA Developmental Neurogenetics Clinic (Jeste, Martinez, Mehta, Bearden) Themes in neuroimaging Child with neurodevelopmental disorder + genetic syndrome/variant Genetics Comprehensive evaluation by: Genetics: genetic testing, interpretation of testing and diagnosis, anticipatory guidance, family counseling Neurology and/or Psychiatry: clinical assessment, medication consultation, characterization of comorbidities *Study brain development as early as possible (before diagnosis is made) *Link imaging to genetics to help understand mechanisms that cause impairment (genes brain behavior) Autism clinic (CAN) Developmental neurogenetics clinic Outside clinics Psychology/Phenotyping core: cognitive, adaptive, social-communication assessments All patients provided with: -Detailed multi-disciplinary clinical assessment and report -Recommendations for intervention, medical, behavioral and educational -Referrals to appropriate specialists -Enrollment into appropriate research studies *Focus on brain function and brain connectivity in circuits that are important for core deficits in autism Face processing, Reward processing, Language learning, Pattern based learning Can we identify differences even earlier? UCLA Infant Sibling Study Evidence for behavioral signs of ASD between ages 1 3 Reduced social attention and social communication Repetitive behavior with objects Delayed motor development Reliable behavioral markers for ASD in children aged <12 months have not yet been consistently identified Focus on ULTRA high risk Focus on brain connections that should be active by early infancy MRI at 6 weeks and 9 months EEG at 3, 6, 9, 12 months Zwaigenbaum et al, 2015 (1) Epidemiology (2) Diagnosis and Comorbidities (1) Neurobiology (2) Treatment (1) Evidence based, structured educational and behavioral interventions for children with ASD (2) Pharmacotherapy for specific target symptom or comorbid condition (3) Physicians should inquire about the use of alternative / complementary treatments and be prepared to discuss their risks and benefits JCAAP, 2014

7 Autism: Treatment National Research Council: Educating Children with Autism (2000) (1) Treatment intensity >25 hrs/wk (2) High staff:student ratio (1:2) (3) Teachers with special expertise in autism (4) Individualized programs for each child Behavioral intervention is the mainstay of treatment ABA (applied behavior analysis): Umbrella term for most types of treatments used in ASD Shape and reinforce new behaviors and reduce undesirable ones Focused on improving all domains of functioning, including activities of daily living, reading, academic skills, social communication skills DTT (Discrete trial training): Target specific behaviors or domains with constant reinforcement PRT (pivotal response training): Identifies pivotal skills that affect broad range of behavioral responses DIR/Floortime (Developmental, individual difference, relationship based): Builds relationships and abilities by following natural emotions and interests of the child JASPER (Joint attention symbolic play engagement regulation): Play based, child directed learning focusing on joint engagement Behavioral Therapy Continuum Irritability Two medications approved by FDA for children ages 5 16 with ASD for irritability Adult-Led DTT ESDM PRT JASPER Child-Led Floortime Risperidone: Partial D2 and 5HT2 receptor antagonist Aripiprazole: Partial D2 and 5HT1A receptor agonist Irritability comprised of 15 items from the Aberrant Behavior Checklist not a cohesive construct Self injury (3) Aggression (1) Mood (3) Tantrums (4) Loud, dysregulated behavior (4) Courtesy of J McCracken ADHD Methylphenidate Guanfacine ER Insomnia: Pharmacological treatment Melatonin: 2 10 mg, improves sleep latency and total sleep time, + nighttime awakenings (Wright, 2011; Garstand, 2006; Wirojanan, 2009; Paavonen, 2003, Biannotti, 2006; Malow, 2011; Andersen, 2008) Guanfacine Clonidine: 0.1 mg, improved sleep latency and wakings (Ming, 2008) Placebo Baseline 8 Weeks Courtesy of J McCracken Risperidone: improves sleep latency but not sleep duration, high rates of adverse outcomes (Aman, 2005 RUPP study) Iron supplementation: 6 mg/kg x 8 weeks, improves restless sleep (Dosman, 2007)

8 Complementary and Alternative (CAM) Treatments All patients should be asked about CAM, as they are used by >70% of families 5 categories of treatments: (1) Alternative Medical Systems (hyperbaric oxygen, chelation) (2) Mind Body Techniques (meditation) (3) Biologically Based Therapies (supplements, vitamins) (4) Body based therapies (Massage) (5) Energy therapies (Reiki) Primary reason for use: Side effects from and concerns about safety of medications Providers should be aware of them and ask families about their use, because they can interact with traditional treatments and medications, and some can be harmful Dietary modifications Tremendous interest in the Gluten Free Casein Free (GFCF) diet Most studies are small and observational, only two RCT s No statistically significant effect on autism symptoms or behavior Concerns about the nutritional impact of diet restrictions in young children Caution should be taken in a child with any nutritional deficiencies, growth problems, or restricted diet due to food intolerances Hanson, JADD, 2007 Efforts now focused on the identification of etiology based subgroups (informed by genetics) within the autism spectrum, in order to ultimately inform more targeted interventions Treatment: Molecular Targets in neurogenetic syndromes Tuberous Sclerosis Complex: MTOR inhibitors Rett syndrome: IGF 1 Fragile X Syndrome: MGluR inhibitors Fleming, Nature Chemical Biology, 2011 MTOR inhibitors improve cognitive and social deficits in TSC mouse models Cognition Learning and memory impairments found in TSC1 +/ and TSC2 +/ mouse models Brief treatment with rapamycin in ADULT mice rescues not only synaptic plasticity but also spatial learning and contextual discrimination (hippocampal tasks) Can be reversed with brief treatment (Ehninger, 2008) Social deficits MTOR inhibitor improves social interaction in both TSC1 +/ and TSC2 +/ mice Mouse model of TSC1 loss in cerebellum results in autistic like behavior Treatment with MTOR inhibitor leads to improvement in social approach and cognition (Tsai, 2012) Take home points Autism is a behavioral diagnosis based on signs and symptoms Diagnosis is not based on etiology Therefore there is considerable heterogeneity in the clinical presentation, from core symptoms to comorbidities Thus far, behavioral intervention for core deficits and medications for comorbidities have been the mainstay of treatment However, tremendous advances in genetics have led to a focus on etiologybased diagnoses that can then guide targeted treatments PRECISION MEDICINE

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