UCLA CART Symposium: Advances in Autism 2016

1. Diagnosis and Managementof 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

2. Outline
(1) Genetics
(2) Epilepsy and regression
(3) Insomnia
• Diagnosis and definitions
• Cause
• Clinical considerations
• Treatment

3. 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

4. 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

5. 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

6. Rosti et al, DMCN 2014

7. Etiology
Aberrant
brain
function
Targeted
Symptoms
Targeted
Treatments
Targeted
Outcomes

8. Genetics
Psychiatry
NeurologyPsychology
Interventionist
Patient Research
Patient with neurodevelopmental disorder and a genetic diagnosis
UCLA Developmental Neurogenetics Clinic

9. Outline
(1) Genetics
(2) Epilepsy and regression
(3) Insomnia
• Diagnosis and definitions
• Cause
• Clinical considerations
• Treatment

10. 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

11. 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

12. 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

13. Jeste SS and Geschwind DH, 2013

14. Jeste and Tuchman, 2015

15. 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

16. 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

17. Isolated EEG “abnormalities”
• RATES VARIABLE: 21-60%
depending on type of EEG and
sample studied
• Spikes do not cause autism…
Buckley, 2016

18. 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

19. 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

20. Developmental disconnection
Geschwind DH and Levitt P, 2007.

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

23. 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)

24. 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

25. 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

26. 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)

27. 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)

28. Epilepsia, 2015

29. Outline
(1) Genetics
(2) Epilepsy and regression
(3) Insomnia
• Diagnosis and definitions
• Cause
• Clinical considerations
• Treatment

30. Swick TJ. Neurology Clinics. 2005

31. 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

32. 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!

33. 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

34. 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

35. 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)

36. 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

37. 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

38. 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)

39. 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.

40. 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

41. (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

42. Insomnia: Behavioral/Educational intervention
www.autismspeaks.org

43. Example of a visual schedule for sleep
www.autismspeaks.org

44. 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

45. 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

46. 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

47. 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

48. 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