1. Sleep disturbances in Autism Spectrum Disorder Ujjwal P. Ramtekkar, MD, MPE, MBA Compass Health Network June, 22 nd 2016

2. Disclosures No pharmaceutical consultant fees, speaker, honorariums, relationships No stocks, bonds, or fiduciary relationships with pharmaceuticals Resource funds: - Tele psychiatry committee at AACAP - Publishers: Springer, Elsevier - Missouri Pediatric Behavioral Health Task Force

3. Late Dr. Richard Todd Dr. David DeMaso The good teacher explains. The superior teacher demonstrates. The great teacher inspires.

5. “If sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process ever made.” -Allan Rechtschaffen We all Zzzzzz…….

6. But why ??? Hypothesized role of sleep: - Brain growth and plasticity - Restoration of body functions - Cognitive functions -> consolidation of memory and learning - Regulation of somatic growth - Regulation of neuroendocrine function -Regulation of immune system

7. Sleep 101 A. Non-rapid eye movement (NREM) sleep Stage 1: 30sec – 5 min, Sleep wake transition, hypnogogic hallucinations, hypnic jerks, lowest arousal threshold – ‘light sleep’ Stage 2: 5 – 25 min, Sleep spindles, K-complexes, role in learning/ memory? Stage 3: 30 – 45 min, Slow wave sleep (SWS), most restorative /“deep” sleep (* No stage 4 per new classification) B. Rapid eye movement (REM) sleep or ‘dream’ sleep - first occurs after 70-100 min after sleep onset (REM latency), up to 5 min - ‘Active sleep’, dreaming, episodic bursts of phasic eye movements - Highest brain metabolic rate, possible role in brain development - Lack of thermoregulation, absent muscle tone - Alteration of autonomic parameters  risk of irregular HR and respiration

8. Sleep stages on EEG

9. Sleep Cycles

10. Wake up every hour…???

11. Sleep regulation – Two process model Homeostatic process (Process S): due to accumulation of ‘somnogens’ like adenosine during wakefulness, need for naps, caffeine helps! Circadian rhythm (Process C): regulated by internal circadian clock – suprachiasmatic nucleus (SCN) and other physiologic systems

15. Sleep disturbance in ASD Prevalence: 44-83% More in children than adolescents/adult Independent of severity and cognitive status (IQ) Worse with coexisting medical and psychiatric issues Results in worsening of daytime behaviors, communication impairments, limited response to interventions

16. Most common sleep problems Irregular sleep-wake cycle (circadian disturbance) Short sleep duration (early morning awakenings) Frequent and prolonged night time awakenings ?Obstructive sleep apnea (low tone) ?Periodic limb movements (iron deficiency)

17. Common causes for sleep issues in ASD Altered melatonin secretion Anxiety (41% co-occurance) Cognitive rigidity and transitional difficulties Sensory issues ADHD (31% co-occurance) Genetic (short sleepers) Seizures Environmental issues (medications, changes in surroundings – lighting, temperature, place, routines etc.)

18. Periodic limb movement disorder and RLS Considered distinct disorder but often a precursor of restless leg syndrome (RLS) Clinical features: >5 involuntary movements/hour, sleep disturbance (insomnia, awakenings) in absence of other primary sleep disorder or sensory sxs of RLS. Strongest association: ADHD – 44% Low ferritin (<75 ng/ml) – 75% Treatment: Iron supplementation to achieve 80-100 ng/ml Dopaminergic agents (resistant, adults) RLS – PLMD + sensory sxs (urge to move legs, unpleasant sensations worsening with inactivity and relieved on movements)

19. Assessment: Screening - BEARS

20. Data collection

21. Excess daytime sleepiness

22. Subjective assessment for verbal and high functioning children

23. Treatment approaches Define the problem and goals of treatment Sensory interventions – limited data - weighted blankets, white noise, indirect light, bed surface Behavioral interventions - sleep hygiene and bedtime routine - scheduled visits and graduated extinction CBT-insomnia for adolescents - for anxiety and transitional issues

24. Non-pharmacological approaches for older and high functioning children

25. Medications Primary: Melatonin Secondary: Clonidine Trazodone Adjunct for co-occurring issues: SSRIs Atypical antipsychotics

26. Medications for sleep - review Medication classHalf -lifeSleep effectsInteractionsSide effects Antihistamines - Benadryl - Hydroxyzine - Chlorpheniramine 4-6 hrs↓ SOL, impairs sleep quality EtOH, CNS depressants (opiates, barbiturates) Daytime lethargy, GI problems, anticholinergic S/E Melatonin 0.5-1 hr↓ SOL, circadian rhythm effect NSAIDs, Caffeine, BZD interfere Unknown, ? HPA ↓, immune reactivity Hormone agonist - Remelteon 1-2.5 hr↓ SOL, no other effects P1A2 inhibitors (Fluvoxamine) NONE Trazodone (Desyrel) Biphasic I: 3- 6 hr II: 5-9 hr ↓ SOL, ↓ REM, ↑ SWS, improves sleep continuity Digoxin, phenytoin, antiHTN meds, CNS depressants Dizziness, hypotension, arrhythmias, CNS hyperstimulation Alpha agonists Clonidine Guanfacine 6 -24 hr 17 hr ↓ SOL, ↓ REM, ↓ SWS ---- Bradycardia, hypotension, rebound hypertension

27. Medications for sleep - review Medication classHalf -lifeSleep effectsInteractionsSide effects Non – BZDs Zolpidem (Ambien) Zalepon (Sonata) Eszopiclone (Lunesta) 2.5 – 3 hr 1 hr 5 - 6 hr ↓ SOL, no effect of night awakening EtOH, CNS depressants (opiates, barbiturates) Headache, possible next-day sedation, ? Retrograde amnesia BZDs Temazepam(Restoril) Triazolam (Halcion) Estazolam (ProSom) Flurazpam (Dalmane) 3.5 – 18 hr 2.5 – 6 hr 8 -28 hr 2 – 100 hr Suppress SWS, ↓ frequency night arousals CYP4503Ainhibitor (fluoxetine, grape fruit juice) Barbiturates Daytime sedation, rebound insomnia, anterograde amnesia, cognitive impairment

28. Still awake?

29. Thank you