Diagnosis and Management of Medical Comorbidities in Autism Spectrum Disorder

Shafali Spurling Jeste, MD Associate Professor in Psychiatry, Neurology and Pediatrics

Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles

Outline

(1) Genetics (2) Epilepsy and regression (3) Insomnia

• Diagnosis and definitions • Cause • Clinical considerations • Treatment

Karyotyping and FISH (Florescent in situ Hybridization) 3-5 million BPs

Abrahams and Geschwind 2009

Chromosomal Microarray 100 Kb

Whole exome or genome sequencing Analysis at the level of single base pair

Advances in genetic methods to study neurodevelopmental disorders

Chromosomal abnormalities > 15% of cases of ID Down syndrome (Trisomy 21)

De novo CNV’s in 20% of ASD >700 causative genes identified

Modified from Schaefer et al, 2013

Genetic testing is the only routinely recommended medical workup for individuals with ASD --Chromosomal microarray --Boys: Fragile X --Girls: MECP2 testing

Recommended testing

Vessers, Nature Rev Genetics, 2016

• >30% of ID/ASD have an identified genetic cause

• ID/ASD affect reproductive fitness -Inherited mutations likely underlie milder forms of ASD/ID -Rare de novo mutations likely underlie more severe forms

Rosti et al, DMCN 2014

Etiology Aberrant

brain function

Targeted Symptoms

Targeted Treatments

Targeted Outcomes

Genetics

Psychiatry

Neurology Psychology

Interventionist

Patient Research

Patient with neurodevelopmental disorder and a genetic diagnosis

UCLA Developmental Neurogenetics Clinic

Outline

(1) Genetics (2) Epilepsy and regression (3) Insomnia

• Diagnosis and definitions • Cause • Clinical considerations • Treatment

Epilepsy: What is it and how is it diagnosed? • More than one unprovoked seizure in a lifetime

• Diagnosed by clinical events and also by EEG (electroencephalogram)

• EEG picks up brain activity (firing of neurons) at the surface of the scalp

Epidemiology of epilepsy in ASD

• Known since the first reported case of autism

• Abnormal EEG’s reported in up to 50%

• Prevalence of epilepsy in ASD approximately 20%

• Prevalence increases with age

• No primary seizure type defined

Jeste SS and Tuchman R, 2015 Viscidi et al, 2013

Epidemiology of ASD in epilepsy

• Largest cohort study of epilepsy (64,188), odds ratio of having ASD was 22.2

• Rate of ASD in epilepsy is 5%, but when prospective screening for development performed in patients with epilepsy, rates of neurodevelopmental disorders >60%

Berg, 2011; Geerts, 2011; Selassie 2014

Jeste SS and Geschwind DH, 2013

Jeste and Tuchman, 2015

Amiet et al, 2008, Bolton et al, 2011

• Clear link to intellectual disability • Double the rate of epilepsy

in children with ASD/ID

• More common in girls

• Related to greater autism

severity, poorer adaptive function

Mortality data in ASD from California Department of Developmental Disabilities Services Mortality 5-6x higher in those with ASD plus epilepsy than ASD alone (but still much less than epilepsy alone which was 15x higher) Led to an initiative between Autism Speaks and International League Against Epilepsy

Isolated EEG “abnormalities”

• RATES VARIABLE: 21-60% depending on type of EEG and sample studied

• Spikes do not cause autism…

Buckley, 2016

Authors Rates Notes

Tuchman & Rapin, 1997 21% (68% in epilepsy, 13% without)

Most well cited study: 392 kids

Tuchman et al, 1997 46% 24 hour EEG: No seizures but language regression

Kim et al, 2006 60% 24 hour EEG: Suspicion of seizures but found not to have them

Chez et al, 2006 60% 24 hour EEG: No history or suspicion of seizures

Genes can be grouped into: --activity dependent protein synthesis --neuronal activity --neuronal cell adhesion

Neurobiological convergence of ASD informed by genetics:

--Abnormal brain growth --Disordered cortical organization --Disturbed brain connectivity --E/I Imbalance

Developmental disconnection

Geschwind DH and Levitt P, 2007.

Epileptic Encephalopathies • Landau Kleffner Syndrome (LKS) • Continuous Spike and Wave in Slow Wave Sleep (CSWS) • Electrical Status Epilepticus of Sleep (ESES)

Regressions related to autism • Regression: Loss of skills after having “normal” development in

the first 1-2 years of life (Lainhart, 2002)

• Based on type of study, rates range from 12-50% • Most studies are based on parent report of skill loss, but some

studies of home videos (Baird, 2008; Lord, 2004; Bernabei, 2007; Werner, 2005)

• Question of whether development is truly typical in the first year of life (Werner, 2005)

• Variable reports on whether ASD-R is related to greater clinical impairment due to differences in sample size and population being studied (Rogers 2004 ; Stefanatos 2008.Matson and Kozlowski 2010)

85 articles, 29,035 individuals Lack of standardized operational definition of regression, most used the ADI-R Overall rate of regression 32.1% Parent reported studies (40.8%) show higher rates than population studies (21.8%) Mean age of onset: 1.8 years Parents of older children reported older age of regression Greater risk in autism vs. ASD or Asperger’s

Barger, JADD 2013

Landau Kleffner Syndrome Autistic Regression

• Age of Onset: After age 3

• Loss of language is dramatic. Loss of fully developed language

• Behavioral Profile: regression primarily affects language. Behavioral abnormalities much less pervasive.

• EEG: Frequent temporal parietal spikes strikingly activated in SWS with pattern of ESES

• Age of Onset: 18-24 months

• Loss of language: clinically subtle: loss of single words, decreased gestures.

• Behavioral Profile: regression affects social communication, repetitive behaviors, and language

• EEG: Centrotemporal spikes and are infrequent and intermittent

Comparisons for Diagnosis

Jeste, Tuchman, 2015

ASD/epilepsy: Recommended Workup

• AAN and AAP guidelines do not recommend routine EEG for children with ASD (2000)

• Obtain prolonged sleep deprived EEG if: • Evidence of clinical seizures • History of developmental regression especially in toddlers and

preschoolers • Situations with high index of suspicion that epilepsy could be present

(Known genetic syndrome that confers a high risk for epilepsy)

Epilepsy: Treatment

• Because of the tremendous heterogeneity in seizure type, there is not one gold standard treatment for epilepsy in ASD

• Early recognition and treatment important

• Anti-epileptics (anti-seizure medications) • Leviteracitam: can cause behavioral side effects

• Valproic acid: have to monitor liver function

• Benzodiazepenes: can cause drowsiness

• Lamotrigine: can cause a serious rash (Steven Johnson syndrome)

Epilepsia, 2015

Outline

(1) Genetics (2) Epilepsy and regression (3) Insomnia

• Diagnosis and definitions • Cause • Clinical considerations • Treatment

Swick TJ. Neurology Clinics. 2005

Biology of sleep-wake cycle (circadian rhythm)

Regulated by: ●Excitatory neurotransmitters (Ach, histamine, dopamine, glutamate, norepinephrine, serotonin ●Inhibitory neurotransmitters (GABA) ●Changes in light and dark (melatonin) ●Dopamine-Opiate system (requires iron as a cofactor for proper functioning)

Blackmer, 2016

Diagnosis of sleep impairment

• Gold standard for identifying sleep problems is overnight sleep study

• Polysomnogram (PSG): records EEG, eye movements, heart rate, blood pressure, blood oxygenation, respirations

• Actigraphy monitors movements and circadian rhythms

• Can be challenging in children with ASD!

Questionnaire Ages Format

Children’s Sleep Habits Questionnaire (CSHQ), toddlers and preschoolers

Ages 4-10 and 2-5.5

45 items in 8 subscales (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night awakenings, daytime sleepiness)

Sleep Disturbance Scale for Children

Behavior over past 6 months in ages 5-15

26 items in 6 subscales: sleep initiation and maintenance, daytime sleepiness, sleep disordered breathing

Family Inventory of Sleep Habits

Ages 3-10 12 items including daytime and pre-bedtime habits, bedtime routine, sleep environment

Behavioral Evaluation of Disorders of Sleep Scale

Ages 5-12 5 types of sleep problems: expressive sleep disturbances, sensitivity to the environment, disoriented awakening, sleep facilitators, apnea/bruxism

BAERS Ages 5-18 28 items into 5 subscales: going to bed, falling asleep, awakening, reinitiating sleep, wakefulness

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

• Medications prescribed >40% of cases Accardo, 2015; Malow, 2012; Malow 2016

Sleep impairment = insomnia (inability to sleep)

Behavioral assessments

• Repeated episodes of difficulty initiating or maintaining sleep

• Night awakenings • Early morning awakenings • Decreased need for sleep • Challenges with limit setting

around bedtimes

Actigraphy

• Prolonged sleep onset time (go to bed later)

• Longer sleep latency (take longer to fall asleep)

• Early awakening • Frequent arousals and sleep

fragmentation • Increased duration of stage 1

sleep • Decreased and abnormal non-

REM sleep (stages 2-4)

Restless Leg Syndrome/Periodic Limb Movements

• No systematic studies looking at prevalence of RLS/PLMD

• Iron deficiency is established cause of RLS/PLMD

• Low ferritin levels in 12/23 children with ASD (Latif, 2002)

• Oral iron supplementation (6 mg/kg elemental iron for 8 week open treatment trial) in children with ASD

Insomnia: Clinical characteristics

• Children with ASD and sleep impairment have more comorbid behavioral and cognitive disturbances

• Other associated features: younger age, hypersensitivity, co-sleeping, epilepsy, ADHD, asthma, family history of sleep problems

• “Good sleepers” show less: affective problems, inattention/hyperactivity, restricted/repetitive behaviors and better social interaction than “bad sleepers”.

Accardo, 2015; Malow, 2012; Malow 2016

Etiology of sleep impairment

GABA

• Activation of GABAA receptors promotes sleep

• Interneurons using GABA may be disrupted in ASD

• GABA related genes on 15q (such as Dup15q syndrome) have shown autism like phenotype

Saper, 2005; Levitt et al, 2004, Eagleson et al, 2010)

Etiology of sleep impairment

Melatonin • Melatonin is a neurohormone that is a robust biochemical signal of

night and regulates the circadian rhythm

Tordjman S et al, 2005.

Etiology of sleep impairment

Ignore environmental cues that help entrain the sleep/wake circadian system Perseverate on activities or thoughts that interfere with sleep onset Communication limitations in understanding parents’ expectations for bedtime Hypersensitivities may make settling down harder

(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

ATN Sleep committee, Pediatrics, 2012

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

Insomnia: Recommended workup

Insomnia: Behavioral/Educational intervention

www.autismspeaks.org

Example of a visual schedule for sleep

www.autismspeaks.org

Insomnia: Pharmacological treatment (OFF LABEL)

Melatonin: (RCT) 5-15 mg, given 30 minutes before bedtime, improves total sleep time by 30 minutes and significantly decreases sleep latency Ramelteon: Melatonin receptor agonist, case reports only, improved total sleep time

Insomnia: Pharmacological treatment (OFF LABEL)

Clonidine: 0.05-0.1 mg, improved sleep latency, decreased number of nighttime awakenings Gabapentin: 5 mg/kg, one study showed improved sleep, but higher doses can cause agitation Benzodiazepines: shorten sleep latency and increase total sleep time, but cause daytime sleepiness and risk of withdrawal Iron supplementation: 6 mg/kg x 8 weeks, Improves restless sleep

Data from Autism Speaks Autism Treatment Network Registry 46% of children ages 4-10 were treated with medications Most commonly used: Melatonin and Alpha Agonists Medication use highly correlated with worse daytime behavior and quality of life compared to those without medications

Pediatrics, 2016

Take home points • All children with ASD should undergo genetic testing, as results

can help guide prognosis, screening, and possibly treatments

• Seizures are more common in children with ASD, especially in adolescence, but testing for seizures (EEG) is only indicated if there is a clinical concern

• All children with ASD should be screened for insomnia, and if concerns they should be referred to a specialist for management

When should you see a neurologist?

• Developmental regression • Seizures, or episodes concerning for seizures (VIDEOS help) • Autism plus global developmental delay • Motor problems • Sleep problems (at least for consultation) • Clinician concern about abnormal neurological exam • Known genetic syndrome or variant associated with ASD